Metabolomics Study of Type 2 Diabetes Mellitus and the AntiDiabetic Effect of Berberine in Zucker Diabetic Fatty Rats Using Uplc-ESI-Hdms.

PubMed

Dong, Yu; Chen, Yi-Tao; Yang, Yuan-Xiao; Zhou, Xiao-Jie; Dai, Shi-Jie; Tong, Jun-Feng; Shou, Dan; Li, Changyu

2016-05-01

The present study aimed to evaluate the pathogenesis of type 2 diabetes mellitus (T2DM) and the anti-diabetic effect of berberine in Zucker diabetic fatty (ZDF) rats. A urinary metabolomics analysis was performed with ultra-performance liquid chromatography/electrospray ionization synapt high-definition mass spectrometry. Pattern recognition approaches were integrated to discover differentiating metabolites. We identified 29 ions (13 in negative mode and 16 in positive mode) as 'differentiating metabolites' with this metabolomic approach. A functional pathway analysis revealed that the alterations were mainly associated with glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions and sphingolipid metabolism. These results indicated that the dysfunctions of glycometabolism and lipometabolism are involved in the pathological process of T2DM. Berberine could decrease the serum levels of glycosylated hemoglobin, total cholesterol and triglyceride and increase the secretion of insulin. The urinary metabolomics analysis showed that berberine could reduce the concentrations of citric acid, tetrahydrocortisol, ribothymidine and sphinganine to a near-normal state. These results suggested that the anti-diabetic effect of berberine occurred mainly via its regulation of glycometabolism and lipometabolism and activation of adenosine 5'-monophosphate-activated protein kinase. Our work not only provides a better understanding of the anti-diabetic effect of berberine in ZDF rats but also supplies a useful database for further study in humans and for investigating the pharmacological actions of drugs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Deposition of dietary fatty acids in young Zucker rats fed a cafeteria diet.

PubMed

Rafecas, I; Esteve, M; Fernández-López, J A; Remesar, X; Alemany, M

1992-10-01

The content and accretion of fatty acids in 30, 45 and 60-day-old Zucker lean Fa/? and obese fa/fa rats fed either reference chow or a cafeteria diet has been studied, together with their actual fatty acid intake during each period. Diet had little overall effect on the pattern of deposition of fatty acids, but quantitatively the deposition of fat was much higher in cafeteria-fed rats. The fat-rich cafeteria diet allowed the direct incorporation of most fatty acids into the rat lipids, whilst chow feeding activated lipogenesis and the deposition of a shorter chain and more saturated pattern of fatty acids. Genetic, obesity induced a significant expansion of net lipogenesis when compared with lean controls. Cafeteria-fed obese rats accrued a high proportion of fatty acids, which was close to that ingested, but nevertheless showed a net de novo synthesis of fatty acids. It is postulated that the combined effects of genetic obesity and a fat-rich diet result in high rates of fat accretion with limited net lipogenesis. Lean Zucker rats show a progressive impairment of their delta 5-desaturase system, a situation also observed in obese rats fed a reference diet. In Zucker obese rats, cafeteria feeding resulted in an alteration of the conversion of C18:2 into C20:3. The cafeteria diet fully compensated for these drawbacks by supplying very high amounts of polyunsaturated fatty acids.

Oral Administration of Interferon Tau Enhances Oxidation of Energy Substrates and Reduces Adiposity in Zucker Diabetic Fatty Rats

PubMed Central

Tekwe, Carmen D.; Lei, Jian; Yao, Kang; Rezaei, Reza; Li, Xilong; Dahanayaka, Sudath; Carroll, Raymond J.; Meininger, Cynthia J.; Bazer, Fuller W.; Wu, Guoyao

2013-01-01

Male Zucker diabetic fatty (ZDF) rats were used to study effects of oral administration of interferon tau (IFNT) in reducing obesity. Eighteen ZDF rats (28 days of age) were assigned randomly to receive 0, 4 or 8 μg IFNT/kg body weight (BW) per day (n=6/group) for 8 weeks. Water consumption was measured every two days. Food intake and BW were recorded weekly. Energy expenditure in 4-, 6-, 8-, and 10-week-old rats was determined using indirect calorimetry. Starting at 7 weeks of age, urinary glucose and ketone bodies were tested daily. Rates of glucose and oleate oxidation in liver, brown adipose tissue, and abdominal adipose tissue, leucine catabolism in skeletal muscle, and lipolysis in white and brown adipose tissues were greater for rats treated with 8 μg IFNT/kg BW/day in comparison with control rats. Treatment with 8 μg IFNT/kg BW/day increased heat production, reduced BW gain and adiposity, ameliorated fatty liver syndrome, delayed the onset of diabetes, and decreased concentrations of glucose, free fatty acids, triacylglycerol, cholesterol, and branched-chain amino acids in plasma, compared to control rats. Oral administration of 8 μg IFNT/kg BW/day ameliorated oxidative stress in skeletal muscle, liver and adipose tissue, as indicated by decreased ratios of oxidized glutathione to reduced glutathione and increased concentrations of the antioxidant tetrahydrobiopterin. These results indicate that IFNT stimulates oxidation of energy substrates and reduces obesity in ZDF rats and may have broad important implications for preventing and treating obesity-related diseases in mammals. PMID:23804503

Resistant Starch but Not Enzymatically Modified Waxy Maize Delays Development of Diabetes in Zucker Diabetic Fatty Rats.

PubMed

Hedemann, Mette Skou; Hermansen, Kjeld; Pedersen, Sven; Bach Knudsen, Knud Erik

2017-05-01

Background: The incidence of type 2 diabetes (T2D) is increasing worldwide, and nutritional management of circulating glucose may be a strategic tool in the prevention of T2D. Objective: We studied whether enzymatically modified waxy maize with an increased degree of branching delayed the onset of diabetes in male Zucker diabetic fatty (ZDF) rats. Methods: Forty-eight male ZDF rats, aged 5 wk, were divided into 4 groups and fed experimental diets for 9 wk that contained 52.95% starch: gelatinized corn starch (S), glucidex (GLU), resistant starch (RS), or enzymatically modified starch (EMS). Blood glucose after feed deprivation was assessed every second week; blood samples taken at run-in and at the end of the experiment were analyzed for glycated hemoglobin (HbA1c) and plasma glucose, insulin, and lipids. During weeks 2 and 8, urine was collected for metabolomic analysis. Results: Based on blood glucose concentrations in feed-deprived rats, none of the groups developed diabetes. However, in week 9, plasma glucose after feed deprivation was significantly lower in rats fed the S and RS diets (13.5 mmol/L) than in rats fed the GLU and EMS diets (17.0-18.9 mmol/L), and rats fed RS had lower HbA1c (4.9%) than rats fed the S, GLU, and EMS (5.6-6.1%) diets. The homeostasis model assessment of insulin resistance was significantly lower in rats fed RS than in rats fed the other diets (185 compared with 311-360), indicating that rats fed the S, GLU, and EMS diets were diabetic, and a 100% higher urine excretion during week 8 in rats fed the GLU and EMS diets than that of rats fed S and RS showed that they were diabetic. Urinary nontargeted metabolomics revealed that the diabetic state of rats fed S, GLU, and EMS diets influenced microbial metabolism, as well as amino acid, lipid, and vitamin metabolism. Conclusions: EMS did not delay the onset of diabetes in ZDF rats, whereas rats fed RS showed no signs of diabetes. © 2017 American Society for Nutrition.

Treadmill exercise prevents diabetes-induced increases in lipid peroxidation and decreases in Cu,Zn-superoxide dismutase levels in the hippocampus of Zucker diabetic fatty rats.

PubMed

Kim, Jong Whi; Chae, Junghyun; Nam, Sung Min; Kim, Yo Na; Yoo, Dae Young; Choi, Jung Hoon; Jung, Hyo Young; Song, Wook; Hwang, In Koo; Seong, Je Kyung; Yoon, Yeo Sung

2015-01-01

In the present study, we investigated the effects of treadmill exercise on lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) levels in the hippocampus of Zucker diabetic fatty (ZDF) rats and lean control rats (ZLC) during the onset of diabetes. At 7 weeks of age, ZLC and ZDF rats were either placed on a stationary treadmill or made to run for 1 h/day for 5 consecutive days at 16~22 m/min for 5 weeks. At 12 weeks of age, the ZDF rats had significantly higher blood glucose levels and body weight than the ZLC rats. In addition, malondialdehyde (MDA) levels in the hippocampus of the ZDF rats were significantly higher than those of the ZLC rats whereas SOD1 levels in the hippocampus of the ZDF rats were moderately decreased. Notably, treadmill exercise prevented the increase of blood glucose levels in ZDF rats. In addition, treadmill exercise significantly ameliorated changes in MDA and SOD1 levels in the hippocampus although SOD activity was not altered. These findings suggest that diabetes increases lipid peroxidation and decreases SOD1 levels, and treadmill exercise can mitigate diabetes-induced oxidative damage in the hippocampus.

Evaluation of Visceral Adipose Tissue Oxygenation by Blood Oxygen Level-Dependent MRI in Zucker Diabetic Fatty Rats.

PubMed

Shi, Hong-Jian; Li, Yan-Feng; Ji, Wen-Jie; Lin, Zhi-Chun; Cai, Wei; Chen, Tao; Yuan, Bin; Niu, Xiu-Long; Li, Han-Ying; Shu, Wen; Li, Yu-Ming; Yuan, Fei; Zhou, Xin; Zhang, Zhuoli

2018-06-01

This study aimed to investigate the feasibility of blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate visceral adipose tissue (VAT) oxygenation in Zucker diabetic fatty (ZDF) rats and its associations with systemic metaflammation. Five-week-old ZDF rats and Zucker lean (ZL) rats were fed a high-fat diet (HFD) for 18 weeks. A baseline BOLD-MRI scan of perirenal adipose tissue was performed after 8 weeks of HFD feeding, and then the rats were randomized to receive pioglitazone or a vehicle for the following 10 weeks. At sacrifice, BOLD-MRI scan, Hypoxyprobe-1 injection, and circulating T helper 17 (Th17), regulatory T (Treg) cells, and monocyte subtype flow cytometry analysis were performed. HFD feeding led to a significant increase in VAT BOLD-MRI R2* signals (20.14 ± 0.23 per second vs. 21.53 ± 0.20 per second; P = 0.012), an indicator for decreased oxygenation. R2* signal was significantly correlated with VAT pimonidazole adduct-positive area, insulin resistance, Th17 and Treg cells, CD43 + and CD43+ + monocyte subtypes, and VAT macrophage infiltration. Pioglitazone treatment improved the insulin resistance and was associated with a delayed progression of VAT oxygenation. This work demonstrated the feasibility of BOLD-MRI for detecting the VAT oxygenation status in ZDF rats, and the BOLD-MRI signals were associated with insulin resistance and systemic metaflammation in ZDF rats during the development of obesity. © 2018 The Obesity Society.

Long Term Osmotic Mini Pump Treatment with Alpha-MSH Improves Myocardial Function in Zucker Diabetic Fatty Rats.

PubMed

Szokol, Miklos; Priksz, Daniel; Bombicz, Mariann; Varga, Balazs; Kovacs, Arpad; Fulop, Gabor Aron; Csipo, Tamas; Posa, Aniko; Toth, Attila; Papp, Zoltan; Szilvassy, Zoltan; Juhasz, Bela

2017-10-12

The present investigation evaluates the cardiovascular effects of the anorexigenic mediator alpha-melanocyte stimulating hormone (MSH), in a rat model of type 2 diabetes. Osmotic mini pumps delivering MSH or vehicle, for 6 weeks, were surgically implanted in Zucker Diabetic Fatty (ZDF) rats. Serum parameters, blood pressure, and weight gain were monitored along with oral glucose tolerance (OGTT). Echocardiography was conducted and, following sacrifice, the effects of treatment on ischemia/reperfusion cardiac injury were assessed using the isolated working heart method. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was measured to evaluate levels of oxidative stress, and force measurements were performed on isolated cardiomyocytes to determine calcium sensitivity, active tension and myofilament co-operation. Vascular status was also evaluated on isolated arterioles using a contractile force measurement setup. The echocardiographic parameters ejection fraction (EF), fractional shortening (FS), isovolumetric relaxation time (IVRT), mitral annular plane systolic excursion (MAPSE), and Tei-index were significantly better in the MSH-treated group compared to ZDF controls. Isolated working heart aortic and coronary flow was increased in treated rats, and higher Hill coefficient indicated better myofilament co-operation in the MSH-treated group. We conclude that MSH improves global heart functions in ZDF rats, but these effects are not related to the vascular status.

Nebivolol ameliorated kidney damage in Zucker diabetic fatty rats by regulation of oxidative stress/NO pathway: comparison with captopril.

PubMed

Wang, Yan; An, Wenjing; Zhang, Fei; Niu, Mengzhen; Liu, Yu; Shi, Ruizan

2018-06-23

The aim was to evaluate the effects and mechanisms of nebivolol on renal damage in Zucker diabetic fatty (ZDF) rats, in comparison with those of atenolol and captopril. Animals were divided into: control lean Zucker rats, ZDF rats, ZDF rats orally treated with nebivolol (10 mg/kg), atenolol (100 mg/kg) or captopril (40 mg/kg) for 6 months. Systolic blood pressure (SBP), blood glucose, kidney structure and function, plasma and kidney levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA), and oxidant status were evaluated. Kidney expressions of AMP-activated protein kinase (AMPK), NADPH oxidase (NOX) isoforms 2 and 4 and subunit p22 phox , nitric oxide synthase (NOS) isoforms, eNOS uncoupling, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 were tested. All drugs induced a similar control of SBP. Nebivolol did not affect the increased plasma glucose. Unlike atenolol, nebivolol prevented the decrease in plasma insulin, and, like captopril, it reduced plasma lipid contents. Nebivolol ameliorated, to a greater extent than captopril, damages to renal structure and function, which were associated with an improvement in interlobular artery dysfunction. Nebivolol elevated kidney phosphorylation of AMPK, attenuated NOX4 and p22 phox expression and oxidative stress marker levels. Nebivolol increased plasma and renal NO, enhanced expressions of eNOS, p-eNOS and nNOS, and suppressed eNOS uncoupling and iNOS expression. High ADMA in plasma and kidney were decreased by nebivolol through increasing DDAH2 and decreasing PRMT1. Long-term treatment of nebivolol ameliorated diabetic nephropathy, at least in part, via regulation of renal oxidative stress/NO pathway. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

α-Motoneurons maintain biophysical heterogeneity in obesity and diabetes in Zucker rats.

PubMed

MacDonell, Christopher W; Chopek, Jeremy W; Gardiner, Kalan R; Gardiner, Phillip F

2017-10-01

Small-diameter sensory dysfunction resulting from diabetes has received much attention in the literature, whereas the impact of diabetes on α-motoneurons (MN) has not. In addition, the chance of developing insulin resistance and diabetes is increased in obesity. No study has examined the impact of obesity or diabetes on the biophysical properties of MN. Lean Zucker rats and Zucker diabetic fatty (ZDF) rats were separated into lean, obese (ZDF fed standard chow), and diabetic (ZDF fed high-fat diet that led to diabetes) groups. Glass micropipettes recorded hindlimb MN properties from identified flexor and extensor MN. MN were separated within their groups on the basis of input conductance, which created high- and low-input conductance subpopulations for each. A significant shorter (20%) afterhyperpolarization half-decay (AHP 1/2 ) was found in low-conductance MN for the diabetic group only, whereas AHP½ tended to be shorter in the obese group (19%). Significant positive correlations were found among rheobase and input conductance for both lean and obese animals. No differences were found between the groups for afterhyperpolarization amplitude (AHP amp ), input conductance, rheobase, or any of the rhythmic firing properties (frequency-current slope and spike-frequency adaptation index). MN properties continue to be heterogeneous in obese and diabetic animals. Obesity does not seem to influence lumbar MN. Despite the resistance of MN to the impact of diabetes, the reduced AHP 1/2 decay and the tendency for a reduction in AHP amp may be the first sign of change to MN function. NEW & NOTEWORTHY Knowledge about the impact of obesity and diabetes on the biophysical properties of motoneurons is lacking. We found that diabetes reduces the duration of the afterhyperpolarization and that motoneuron function is unchanged by obesity. A reduced afterhyperpolarization may impact discharge characteristics and may be the first sign of change to motoneuron function. Copyright �

Resistance training inhibits the elevation of skeletal muscle derived-BDNF level concomitant with improvement of muscle strength in zucker diabetic rat

PubMed Central

Kim, Hee-Jae; So, Byunghun; Son, Jun Seok; Song, Han Sol; Oh, Seung Lyul; Seong, Je Kyung; Lee, Hoyoung; Song, Wook

2015-01-01

[Purpose] In the present study, we investigated the effects of 8 weeks of progressive resistance training on the level of skeletal muscle derived BDNF as well as glucose intolerance in Zucker diabetic rats. [Methods] Six week-old male Zucker diabetic fatty (ZDF) and Zucker lean control (ZLC) rats were randomly divided into 3 groups: sedentary ZLC (ZLC-Con), sedentary ZDF (ZDF-Con), and exercised ZDF (ZDF-Ex). Progressive resistance training using a ladder and tail weights was performed for 8 weeks (3 days/week). [Results] After 8 weeks of resistance training, substantial reduction in body weight was observed in ZDF-Ex compared to ZDF-Con. Though the skeletal muscle volume did not change, grip strength grip strength was significantly higher in ZDF-Ex compared to ZDF-Con. In the soleus, the level of BDNF was increased in ZDF-Con, but was significantly decreased (p<0.05) in ZDF-Ex, showing a training effect. Moreover, we found that there was a negative correlation (r=-0.657; p=0.004) between grip strength and BDNF level whereas there was a positive correlation (r=0.612; p=0.008) between plasma glucose level and BDNF level in skeletal muscle. [Conclusion] Based upon our results, we demonstrated that resistance training inhibited the elevation of skeletal muscle derived-BDNF expression concomitant with the improvement of muscle strength in zucker diabetic rats. In addition, muscle-derived BDNF might be a potential mediator for the preventive effect of resistance training on the progress of type 2 diabetes. PMID:27274460

Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats.

PubMed

Berthiaume, Nathalie; Carlson, Christian J; Rondinone, Cristina M; Zinker, Bradley A

2005-11-01

In the present study, we investigated the effects of long-term treatment with the endothelin (ET) antagonist atrasentan, an ET(A)-selective antagonist, on whole body glucose metabolism and insulin signaling in a commonly used model of insulin resistance, the Zucker fatty rat. Zucker lean and fatty rats were maintained for 6 weeks on either control or atrasentan-treated water. Euglycemic-hyperinsulinemic clamps (4 mU/kg per minute) were performed at the end of the 6-week treatment on a subset of rats (n=10/treatment). In another subset (n=5/treatment), an insulin tolerance test was performed; liver and muscle tissues were harvested 10 minutes following the challenge for further analysis. Results of the clamps demonstrated that long-term atrasentan treatment significantly increased whole body glucose metabolism in fatty rats compared with vehicle control subjects. Insulin-induced insulin receptor substrate 1 tyrosine and protein kinase B serine phosphorylation were significantly reduced in the liver and muscle of fatty animals compared with their lean littermates. This reduction was overcome with atrasentan treatment in the liver but not in the muscle. There was no difference between lean and fatty animals, however, in insulin receptor substrate 1 and protein kinase B protein expression in the liver and muscle and no effect by atrasentan. In contrast, expression of the regulatory subunit of PI-3 kinase (p85alpha) was significantly increased in the liver but not in the muscle of fatty animals compared with their lean littermates and this was normalized to levels of lean animals with atrasentan treatment. These findings indicate that long-standing ET antagonism improves whole body glucose metabolism in Zucker fatty rats through improvements in insulin signaling in the liver. These results indicate that therapeutic ET antagonism may assist in correcting the insulin-resistant state.

Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat.

PubMed

Dana, S L; Hoener, P A; Bilakovics, J M; Crombie, D L; Ogilvie, K M; Kauffman, R F; Mukherjee, R; Paterniti, J R

2001-08-01

Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. Copyright 2001 by W.B. Saunders Company

Genetic profiling of two phenotypically distinct outbred rats derived from a colony of the Zucker fatty rats maintained at Tokyo Medical University

PubMed Central

Nakanishi, Satoshi; Kuramoto, Takashi; Kashiwazaki, Naomi; Yokoi, Norihide

2016-01-01

The Zucker fatty (ZF) rat is an outbred rat and a well-known model of obesity without diabetes, harboring a missense mutation (fatty, abbreviated as fa) in the leptin receptor gene (Lepr). Slc:Zucker (Slc:ZF) outbred rats exhibit obesity while Hos:ZFDM-Leprfa (Hos:ZFDM) outbred rats exhibit obesity and type 2 diabetes. Both outbred rats have been derived from an outbred ZF rat colony maintained at Tokyo Medical University. So far, genetic profiles of these outbred rats remain unknown. Here, we applied a simple genotyping method using Ampdirect reagents and FTA cards (Amp-FTA) in combination with simple sequence length polymorphisms (SSLP) markers to determine genetic profiles of Slc:ZF and Hos:ZFDM rats. Among 27 SSLP marker loci, 24 loci (89%) were fixed for specific allele at each locus in Slc:ZF rats and 26 loci (96%) were fixed in Hos:ZFDM rats, respectively. This indicates the low genetic heterogeneity in both colonies of outbred rats. Nine loci (33%) showed different alleles between the two outbred rats, suggesting considerably different genetic profiles between the two outbred rats in spite of the same origin. Additional analysis using 72 SSLP markers further supported these results and clarified the profiles in detail. This study revealed that genetic profiles of the Slc:ZF and Hos:ZFDM outbred rats are different for about 30% of the SSLP marker loci, which is the underlying basis for the phenotypic difference between the two outbred rats. PMID:27795491

In Vivo Cannabidiol Treatment Improves Endothelium-Dependent Vasorelaxation in Mesenteric Arteries of Zucker Diabetic Fatty Rats

PubMed Central

Wheal, Amanda J.; Jadoon, Khalid; Randall, Michael D.; O’Sullivan, Saoirse E.

2017-01-01

Background and purpose: We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD in vivo would also enhance endothelial function. Experimental approach: Male ZDF rats, or ZDF Lean rats, were treated for 7 days (daily i.p. injection) with either 10mg/kg CBD or vehicle (n = 6 per group). Sections of mesenteric resistance arteries, femoral arteries and thoracic aortae were mounted on a wire myograph, and cumulative concentration-response curves to endothelium-dependent (acetylcholine, ACh, 1 nM–100 μM) or endothelium-independent (sodium nitroprusside, SNP, 1 nM–100 μM) agents were constructed. Multiplex analysis was used to measure serum metabolic and cardiovascular biomarkers. Key results: Vasorelaxation to ACh was significantly enhanced in mesenteric arteries from CBD-treated ZDF rats, but not ZDF Lean rats. The enhanced vasorelaxation in ZDF mesenteric arteries was no longer observed after COX inhibition using indomethacin or nitric oxide (NO) inhibition using L-NAME. Increased levels of serum c-peptide, insulin and intracellular adhesion molecule-1 observed in the ZDF compared to ZDF Lean rats were no longer significant after 7 days CBD treatment. Conclusion and implications: Short-term in vivo treatment with CBD improves ex vivo endothelium-dependent vasorelaxation in mesenteric arteries from ZDF rats due to COX- or NO-mediated mechanisms, and leads to improvements in serum biomarkers. PMID:28572770

Chronic hyperinsulinemia contributes to insulin resistance under dietary restriction in association with altered lipid metabolism in Zucker diabetic fatty rats.

PubMed

Morita, Ippei; Tanimoto, Keiichi; Akiyama, Nobuteru; Naya, Noriyuki; Fujieda, Kumiko; Iwasaki, Takanori; Yukioka, Hideo

2017-04-01

Hyperinsulinemia is widely thought to be a compensatory response to insulin resistance, whereas its potentially causal role in the progression of insulin resistance remains to be established. Here, we aimed to examine whether hyperinsulinemia could affect the progression of insulin resistance in Zucker fatty diabetic (ZDF) rats. Male ZDF rats at 8 wk of age were fed a diet ad libitum (AL) or dietary restriction (DR) of either 15 or 30% from AL feeding over 6 wk. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. ZDF rats in the AL group progressively developed hyperglycemia and hyperinsulinemia by 10 wk of age, and then plasma insulin rapidly declined to nearly normal levels by 12 wk of age. Compared with AL group, DR groups showed delayed onset of hyperglycemia and persistent hyperinsulinemia, leading to weight gain and raised plasma triglycerides and free fatty acids by 14 wk of age. Notably, insulin sensitivity was significantly reduced in the DR group rather than the AL group and inversely correlated with plasma levels of insulin and triglyceride but not glucose. Moreover, enhanced lipid deposition and upregulation of genes involved in lipogenesis were detected in liver, skeletal muscle, and adipose tissues of the DR group rather than the AL group. Alternatively, continuous hyperinsulinemia induced by insulin pellet implantation produced a decrease in insulin sensitivity in ZDF rats. These results suggest that chronic hyperinsulinemia may lead to the progression of insulin resistance under DR conditions in association with altered lipid metabolism in peripheral tissues in ZDF rats. Copyright © 2017 the American Physiological Society.

Development of insulin resistance and endothelin-1 levels in the Zucker fatty rat.

PubMed

Berthiaume, Nathalie; Mika, Amanda K; Zinker, Bradley A

2003-07-01

In order to determine the effects of increasing insulin resistance on endothelin-1 (ET-1) levels, Zucker lean and fatty rats were studied at basal and during a complete nutrient meal tolerance test (MTT) at 7, 12, and 15 weeks of age. The fatty rats were mildly hyperglycemic, severely hyperinsulinemic and glucose-intolerant at all ages versus lean animals and this progressed with age within groups, as previously published. Basal ET-1 levels, at 7 weeks, were significantly increased in fatty versus lean rats (3.2+/-0.5 v 2.0+/-0.3 pg/mL, respectively; P<.05); however, we did not observe any significant basal difference at 12 or 15 weeks. At 7 weeks, ET-1 levels between fatty and lean rats were not different during the MTT (15 minutes: 2.9+/-0.4 v 2.7+/-0.7; 120 minutes: 6.5+/-0.8 v 6.6+/-0.5 pg/mL, fatty v lean, respectively). At 12 weeks, though there was no difference in basal levels, fatty rats had higher ET-1 levels during the MTT compared to lean animals (15 minutes: 6.9+/-1.4 v 1.8+/-0.4; 120 minutes: 9.4+/-1.7 v 3.2+/-0.5 pg/mL, respectively; P<.01). At 15 weeks, ET-1 levels during the MTT receded to levels similar to those observed at 7 weeks, which were significantly higher in fatty versus lean rats 15 minutes following the challenge (3.4+/-0.4 v 2.4+/-0.2 pg/mL, respectively; P<.05). In conclusion, ET-1 levels in the Zucker fatty rat: (1) were increased in the early stages of the progression of insulin resistance at 7 weeks, but were unchanged under basal conditions with age thereafter, and (2) were increased under nutrient challenge conditions with advanced insulin resistance up to 12 weeks, and were still significantly but to a lesser degree increased at 15 weeks of age. The explanation for these results and their relationship to the observed insulin resistance is unclear and will require further investigation.

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

PubMed Central

Brader, Lea; Overgaard, Ann; Christensen, Lars P.; Jeppesen, Per B.; Hermansen, Kjeld

2013-01-01

BACKGROUND: Bilberries and blackcurrants are nutrient sources rich in bioactive components, including dietary fibers, polyphenols, and anthocyanins, which possess potent cardiovascular protective properties. Few studies investigating the cardio-protective effects of natural components have focused on whole bilberries or blackcurrants. OBJECTIVE: The aim of this trial was to investigate whether a diet enriched with bilberries or blackcurrants has beneficial effects on glucose metabolism, lipid profile, blood pressure, and expression of genes related to glucose and lipid metabolism. METHODS: Male Zucker Diabetic Fatty (ZDF) rats (n = 48) were randomly assigned to either a control, bilberry-enriched, blackcurrant-enriched, or fiber-enriched diet for 8 weeks ad libitum. Real-time quantitative PCR analysis was performed on liver, adipose, and muscle tissue. Berry polyphenol content was determined by HPLC and LC-MS analysis. RESULTS: Bilberry enrichment reduced total (-21%, p = 0.0132) and LDL-cholesterol (-60%, p = 0.0229) levels, but increased HDL-cholesterol to a lesser extent than in controls. This may partly be due to the altered hepatic liver X receptor-α expression (-24%, p < 0.001). Neither bilberries nor blackcurrants influenced glucose metabolism or blood pressure. Nevertheless, transcriptional analysis implied a better conservation of hepatic and adipocyte insulin sensitivity by bilberry enrichment. Anthocyanins constituted 91% and 87% of total polyphenol content in bilberries and blackcurrants, respectively. However, total anthocyanin content (3441 mg/100 g) was 4-fold higher in bilberries than in blackcurrants (871 mg/100 g). CONCLUSIONS: Bilberry consumption ameliorated total and LDL-cholesterol levels, but not HDL-cholesterol levels in ZDF rats. Neither bilberry nor blackcurrant enrichment delayed the development of diabetes or hypertension. Thus, in rats, bilberries may be valuable as a dietary preventive agent against hypercholesterolemia, probably by

Repeated electroacupuncture in obese Zucker diabetic fatty rats: adiponectin and leptin in serum and adipose tissue.

PubMed

Peplow, Philip V

2015-04-01

Fasted, male, obese, Zucker, diabetic fatty rats aged 10-16 weeks were anesthetized with 1% halothane in nitrous oxide-oxygen (3:1) on alternate weekdays over 2 weeks. Group 1 (n = 4) did not receive electroacupuncture (controls); Group 2 (n = 4) received electroacupuncture using the Zhongwan and the Guanyuan acupoints; Group 3 (n = 4) received electroacupuncture using the bilateral Zusanli acupoints; Group 4 (n = 6) received neither halothane in nitrous oxide:oxygen nor electroacupuncture. At the end of study, animals were injected with sodium pentobarbitone (60 mg/mL, i.p.), and blood and white adipose tissue were collected. Analysis of variance and Duncan's tests showed that the mean leptin in serum was significantly lower and the adiponectin:leptin ratio was significantly higher in Group 2 than in Group 1 (p < 0.05); for Group 4, the serum leptin was significantly higher than it was for Groups 1-3 (p < 0.05), and the adiponectin:leptin ratio was significantly lower than it was for Group 2 (p < 0.05). Similar changes occurred for the leptin levels in the pelvic adipose tissue. In addition, for Group 2, the mean serum insulin: glucose ratio was significantly higher than it was for Group 1 (p < 0.05); for Group 4 the mean serum insulin and insulin: glucose ratio were significantly higher than they were for Groups 1 and 3 (p < 0.05), but not Group 2 (p > 0.05). No significant differences in the serum or the adipose-tissue measurements between Groups 1 and 3 were observed (p > 0.05). Copyright © 2015. Published by Elsevier B.V.

Renal protection by a soy diet in obese Zucker rats is associated with restoration of nitric oxide generation.

PubMed

Trujillo, Joyce; Ramírez, Victoria; Pérez, Jazmín; Torre-Villalvazo, Ivan; Torres, Nimbe; Tovar, Armando R; Muñoz, Rosa M; Uribe, Norma; Gamba, Gerardo; Bobadilla, Norma A

2005-01-01

The obese Zucker rat is a valuable model for studying kidney disease associated with obesity and diabetes. Previous studies have shown that substitution of animal protein with soy ameliorates the progression of renal disease. To explore the participation of nitric oxide (NO) and caveolin-1 in this protective effect, we evaluated proteinuria, creatinine clearance, renal structural lesions, nitrites and nitrates urinary excretion (UNO(2)(-)/NO(3)V), and mRNA and protein levels of neuronal NO synthase (nNOS), endothelial NOS (eNOS), and caveolin-1 in lean and fatty Zucker rats fed with 20% casein or soy protein diet. After 160 days of feeding with casein, fatty Zucker rats developed renal insufficiency, progressive proteinuria, and renal structural lesions; these alterations were associated with an important fall of UNO(2)(-)/NO(3)V, changes in nNOS and eNOS mRNA levels, together with increased amount of eNOS and caveolin-1 present in plasma membrane proteins of the kidney. In fatty Zucker rats fed with soy, we observed that soy diet improved renal function, UNO(2)(-)/NO(3)V, and proteinuria and reduced glomerulosclerosis, tubular dilation, intersticial fibrosis, and extracapilar proliferation. Renal protection was associated with reduction of caveolin-1 and eNOS in renal plasma membrane proteins. In conclusion, our results suggest that renal protective effect of soy protein appears to be mediated by improvement of NO generation and pointed out to caveolin-1 overexpression as a potential pathophysiological mechanism in renal disease.

Defective glycogenesis contributes toward the inability to suppress hepatic glucose production in response to hyperglycemia and hyperinsulinemia in zucker diabetic fatty rats.

PubMed

Torres, Tracy P; Fujimoto, Yuka; Donahue, E P; Printz, Richard L; Houseknecht, Karen L; Treadway, Judith L; Shiota, Masakazu

2011-09-01

Examine whether normalizing net hepatic glycogenesis restores endogenous glucose production and hepatic glucose phosphorylation in response to diabetic levels of plasma glucose and insulin in Zucker diabetic fatty rats (ZDF). Hepatic glucose and intermediate fluxes (µmol · kg(-1) · min(-1)) were measured with and without a glycogen phosphorylase inhibitor (GPI) using [2-(3)H]glucose, [3-(3)H]glucose, and [U-(14)C]alanine in 20 h-fasted conscious ZDF and their lean littermates (ZCL) under clamp conditions designed to maintain diabetic levels of plasma glucose and insulin. With infusion of GPI into ZDF (ZDF-GPI+G), compared with vehicle infused ZDF (ZDF-V), high glycogen phosphorylase a activity was decreased and low synthase I activity was increased to that of ZCL. Low net glycogenesis from plasma glucose rose to 75% of ZCL levels (4 ± 1 in ZDF-V, 18 ± 1 in ZDF-GPI+G, and 24 ± 2 in ZCL) and phosphoenolpyruvate 260% (4 ± 2 in ZDF-V, 16 ± 1 in ZDF+GPI-G, and 6 ± 2 in ZCL). High endogenous glucose production was suppressed with GPI infusion but not to that of ZCL (46 ± 4 in ZDF-V, 18 ± 4 in ZDF-GPI+G, and -8 ± 3 in ZCL). This was accompanied by reduction of the higher glucose-6-phosphatase flux (75 ± 4 in ZDF-V, 41 ± 4 in ZDF-GPI+G, and 86 ± 12 in ZCL) and no change in low glucose phosphorylation or total gluconeogenesis. In the presence of hyperglycemic-hyperinsulinemia in ZDF, reduced glycogenic flux partially contributes to a lack of suppression of hepatic glucose production by failing to redirect glucose-6-phosphate flux from production of glucose to glycogen but is not responsible for a lower rate of glucose phosphorylation.

Impaired Expression of Neuronal Nitric Oxide Synthase in the Gracile Nucleus Is Involved in Neuropathic Changes in Zucker Diabetic Fatty Rats with and without 2,5-Hexanedione Intoxication

PubMed Central

Ma, Sheng-Xing; Peterson, Richard G.; Magee, Edward M.; Lee, Paul; Lee, Wai-Nang Paul; Li, Xi-Yan

2015-01-01

These studies examined the influence of 2,5-hexanedione (2,5-HD) intoxication on expression of neuronal nitric oxide synthase (nNOS) in the brainstem nuclei in Zucker Diabetic Fatty (ZDF) vs. lean control (LC) rats. Functional neuropathic changes were also investigated following axonal damage and impaired axonal transport induced by the treatment. Animals were intoxicated by i.p. injection of 2,5-HD plus unilateral administration of 2,5-HD over the sciatic nerve. The mechanical thresholds and withdrawal latencies to heat and cold stimuli on the foot were measured at baseline and after intoxication. The medulla sections were examined by nNOS immunohistochemistry and NADPH-diaphorase histochemistry at the end of the treatments. The mechanical thresholds and withdrawal latencies were significantly decreased while nNOS immunostained neurons and NADPH-diaphorase positive cells were selectively reduced in the gracile nucleus at baseline in ZDF vs. LC rats. NADPH-diaphorase reactivity and nNOS positive neurons were increased in the ipsilateral gracile nucleus in LC rats following 2,5-HD intoxication, but its up-regulation was attenuated in ZDF rats. These results suggest that diabetic and chemical intoxication-induced nNOS expression is selectively reduced in the gracile nucleus in ZDF rats. Impaired axonal damage-induced nNOS expression in the gracile nucleus is involved in neuropathic pathophysiology in type II diabetic rats. PMID:26519861

IVGTT-based simple assessment of glucose tolerance in the Zucker fatty rat: Validation against minimal models.

PubMed

Morettini, Micaela; Faelli, Emanuela; Perasso, Luisa; Fioretti, Sandro; Burattini, Laura; Ruggeri, Piero; Di Nardo, Francesco

2017-01-01

For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman's correlation coefficient, r = 0.88; P<0.001). Both FPIR3 and FPIR5 showed a significant (P<0.001) strong correlation with Φ1 (r = 0.76 and r = 0.75, respectively). Both SPIR3 and SPIR5 showed a significant (P<0.001) strong correlation with Φ2 (r = 0.85 and r = 0.83, respectively). ISI is able to detect (P<0.001) the well-recognized reduction in insulin sensitivity in ZFRs, compared to ZLRs. The insulin-based indexes of insulin secretion are able to detect in ZFRs (P<0.001) the compensatory increase of first- and second-phase secretion, associated to the insulin-resistant state. The ability of the surrogate indexes in describing glucose tolerance in the ZFRs was confirmed by the Disposition Index analysis. The model-based validation performed in the present study supports the utilization of low-cost, insulin-based indexes for the assessment of glucose tolerance in Zucker rat, reliable animal model of human metabolic syndrome.

Evaluation of treadmill exercise effect on muscular lipid profiles of diabetic fatty rats by nanoflow liquid chromatography-tandem mass spectrometry

NASA Astrophysics Data System (ADS)

Lee, Jong Cheol; Kim, Il Yong; Son, Yeri; Byeon, Seul Kee; Yoon, Dong Hyun; Son, Jun Seok; Song, Han Sol; Song, Wook; Seong, Je Kyung; Moon, Myeong Hee

2016-07-01

We compare comprehensive quantitative profiling of lipids at the molecular level from skeletal muscle tissues (gastrocnemius and soleus) of Zucker diabetic fatty rats and Zucker lean control rats during treadmill exercise by nanoflow liquid chromatography-tandem mass spectrometry. Because type II diabetes is caused by decreased insulin sensitivity due to excess lipids accumulated in skeletal muscle tissue, lipidomic analysis of muscle tissues under treadmill exercise can help unveil the mechanism of lipid-associated insulin resistance. In total, 314 lipid species, including phospholipids, sphingolipids, ceramides, diacylglycerols (DAGs), and triacylglycerols (TAGs), were analyzed to examine diabetes-related lipid species and responses to treadmill exercise. Most lysophospholipid levels increased with diabetes. While DAG levels (10 from the gastrocnemius and 13 from the soleus) were >3-fold higher in diabetic rats, levels of most of these decreased after exercise in soleus but not in gastrocnemius. Levels of 5 highly abundant TAGs (52:1 and 54:3 in the gastrocnemius and 48:2, 50:2, and 52:4 in the soleus) displaying 2-fold increases in diabetic rats decreased after exercise in the soleus but not in the gastrocnemius in most cases. Thus, aerobic exercise has a stronger influence on lipid levels in the soleus than in the gastrocnemius in type 2 diabetic rats.

Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight.

PubMed

Rohrbach, K; Thomas, M A; Glick, S; Fung, E N; Wang, V; Watson, L; Gregory, P; Antel, J; Pelleymounter, M A

2012-06-01

To test the antidiabetic efficacy of ibipinabant, this new cannabinoid receptor 1 (CB1) antagonist was compared with food-restriction-induced weight loss, rosiglitazone (4 mg/kg) and rimonabant (3 and 10 mg/kg), using parameters of glycaemic control in male Zucker diabetic fatty (ZDF) rats. Body weight, food and water intake, fasted and non-fasted glucose and insulin, glucose tolerance and glycosylated haemoglobin (HbA1c) were all assessed over the course of the 9-week study. Pancreatic insulin content and islet area were also evaluated. At the end of the study, vehicle-treated ZDF rats were severely hyperglycaemic and showed signs of β-cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (-61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, -44%) and HbA1c (-50%). Furthermore, non-fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction. Ibipinabant may have weight loss-independent antidiabetic effects and may have the potential to attenuate β-cell loss in a model of progressive β-cell dysfunction. © 2012 Blackwell Publishing Ltd.

Age-related decrease in sensitivity to glucagon and dibutyryl cyclic AMP inhibition of fatty acid synthesis in hepatocytes isolated from obese female Zucker rats.

PubMed

McCune, S A; Durant, P J; Harris, R A

1984-02-01

Hepatocytes were isolated from 3 and 5 month old female genetically obese Zucker rats and their lean littermate controls. An age-dependent loss in sensitivity of fatty acid synthesis to inhibition by both glucagon and dibutyryl cyclic AMP was observed with hepatocytes from the obese rats. Hepatocytes from lean animals were much more sensitive to these agents, regardless of age. Low concentrations of glucagon and dibutyryl cyclic AMP actually produced some stimulation of fatty acid synthesis with hepatocytes prepared from the older obese rats. 5-Tetradecyloxy-2-furoic acid, a compound which inhibits fatty acid synthesis, was a very effective inhibitor of fatty acid synthesis by hepatocytes isolated from all rats used in the study. An inhibition of lactate plus pyruvate accumulation and a strong stimulation of glycogenolysis occurred in response to both glucagon and dibutyryl cyclic AMP with hepatocytes from both age groups of lean and obese rats. The results suggest that with aging of the obese female Zucker rat some step of hepatic fatty acid synthesis becomes progressively less sensitive to inhibition by glucagon and dibutyryl cyclic AMP. This may play an important role in maintenance of obesity in these animals.

Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats.

PubMed

Weigt, Carmen; Hertrampf, Torsten; Flenker, Ulrich; Hülsemann, Frank; Kurnaz, Pinar; Fritzemeier, Karl Heinrich; Diel, Patrick

2015-11-01

The leptin resistant Zucker diabetic fatty (ZDF) rats are hyperphagic and become obese, but whereas the males develop type 2 diabetes mellitus (T2DM), the females remain euglycaemic. As estrogen deficiency is known to increase the risk of developing T2DM, we evaluated the role of ER subtypes alpha and beta in the development of glucose tolerance in leptin resistant ovariectomized (OVX) ZDF rats. At least six rats per group were treated with either vehicle (OVX), 17β-estradiol (E2), ER subtype-selective agonists (Alpha and Beta), or genistein (Gen) for 17 weeks. At the end of the treatment period a glucose tolerance assay was performed and the metabolic flux of (13)C-glucose for the E2 group was investigated. OVX ZDF rats treated with E2, Alpha, Beta, and Gen tolerated the glucose significantly better than untreated controls. E2 treatment increased absorbance/flux of (13)C-glucose to metabolic relevant tissues such liver, adipose tissue, gastrocnemius, and soleus muscle. Moreover, whereas Alpha treatment markedly increased mRNA expression of GLUT4 in gastrocnemius muscle, Beta treatment resulted in the largest fiber sizes of the soleus muscle. Treatment with Gen increased both the mRNA expression of GLUT 4 and the fiber sizes in the skeletal muscle. In addition, E2 and Alpha treatment decreased food intake and body weight gain. In summary, estrogen-improved glucose absorption is mediated via different molecular mechanisms: while activation of ER alpha seems to stimulate muscular GLUT4 functionality, activation of ER beta results in a hypertrophy of muscle fibers. In addition, selective activation of ER alpha decreased food intake and body weight gain. Our data further indicate that ER subtype-selective agonists and genistein improve systemic glucose tolerance also in the absence of a functional leptin signaling pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative studies on fatty acid synthesis, glycogen metabolism, and gluconeogenesis by hepatocytes isolated from lean and obese Zucker rats.

PubMed

McCune, S A; Durant, P J; Jenkins, P A; Harris, R A

1981-12-01

Hepatocytes isolated from genetically obese female Zucker rats and lean female Zucker rats were compared. Hepatocytes from fed obese rats exhibited greater rates of fatty acid synthesis, more extensive accumulation of lactate and pyruvate from their glycogen stores, increased rates of net glucose utilization but produced less ketone bodies from exogenous fatty acids and had lower citrate levels than hepatocytes from lean rats. Lipogenesis was not as sensitive to dibutyryl cyclic AMP (DBcAMP) inhibition in hepatocytes from obese rats but glycogenolysis was stimulated to the same extent by this nucleotide in both preparations. Ketogenesis was less sensitive to stimulation by DBcAMP in hepatocytes from obese rats. A difference in sensitivity of lipogenesis to DBcAMP was not found when lactate plus pyruvate was added to the incubation medium, suggesting that a greater rate of glycolysis by hepatocytes from obese rats accounts for their relative insensitivity to DBcAMP. Citrate levels were elevated by DBcAMP to a greater extent in hepatocytes from obese rats. Hepatocytes prepared from lean rats starved for 48 hr were glycogen depleted and lacked significant capacity for lipogenesis and glycogen synthesis. In contrast, hepatocytes isolated from starved obese rats retained considerable amounts of liver glycogen and exhibited detectable rates of lipogenesis and glycogen synthesis. Hepatocytes prepared from starved lean rats gave faster apparent rates of lactate gluconeogenesis than hepatocytes prepared from starved obese rats. Thus, hepatocytes prepared from obese Zucker rats are more glycogenic, glycolytic, and lipogenic but less ketogenic and glucogenic than hepatocytes prepared from lean rats.

Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export.

PubMed

White, Phillip J; Lapworth, Amanda L; An, Jie; Wang, Liping; McGarrah, Robert W; Stevens, Robert D; Ilkayeva, Olga; George, Tabitha; Muehlbauer, Michael J; Bain, James R; Trimmer, Jeff K; Brosnan, M Julia; Rolph, Timothy P; Newgard, Christopher B

2016-07-01

A branched-chain amino acid (BCAA)-related metabolic signature is strongly associated with insulin resistance and predictive of incident diabetes and intervention outcomes. To better understand the role that this metabolite cluster plays in obesity-related metabolic dysfunction, we studied the impact of BCAA restriction in a rodent model of obesity in which BCAA metabolism is perturbed in ways that mirror the human condition. Zucker-lean rats (ZLR) and Zucker-fatty rats (ZFR) were fed either a custom control, low fat (LF) diet, or an isonitrogenous, isocaloric LF diet in which all three BCAA (Leu, Ile, Val) were reduced by 45% (LF-RES). We performed comprehensive metabolic and physiologic profiling to characterize the effects of BCAA restriction on energy balance, insulin sensitivity, and glucose, lipid and amino acid metabolism. LF-fed ZFR had higher levels of circulating BCAA and lower levels of glycine compared to LF-fed ZLR. Feeding ZFR with the LF-RES diet lowered circulating BCAA to levels found in LF-fed ZLR. Activity of the rate limiting enzyme in the BCAA catabolic pathway, branched chain keto acid dehydrogenase (BCKDH), was lower in liver but higher in skeletal muscle of ZFR compared to ZLR and was not responsive to diet in either tissue. BCAA restriction had very little impact on metabolites studied in liver of ZFR where BCAA content was low, and BCKDH activity was suppressed. However, in skeletal muscle of LF-fed ZFR compared to LF-fed ZLR, where BCAA content and BCKDH activity were increased, accumulation of fatty acyl CoAs was completely normalized by dietary BCAA restriction. BCAA restriction also normalized skeletal muscle glycine content and increased urinary acetyl glycine excretion in ZFR. These effects were accompanied by lower RER and improved skeletal muscle insulin sensitivity in LF-RES fed ZFR as measured by hyperinsulinemic-isoglycemic clamp. Our data are consistent with a model wherein elevated circulating BCAA contribute to development of

Matrix Metalloproteinase-9 Expression Is Enhanced in Renal Parietal Epithelial Cells of Zucker Diabetic Fatty Rats and Is Induced by Albumin in In Vitro Primary Parietal Cell Culture

PubMed Central

Zhang, Yuanyuan; George, Jasmine; Li, Yun; Olufade, Rebecca; Zhao, Xueying

2015-01-01

As a subfamily of matrix metalloproteinases (MMPs), gelatinases including MMP-2 and MMP-9 play an important role in remodeling and homeostasis of the extracellular matrix. However, conflicting results have been reported regarding their expression level and activity in the diabetic kidney. This study investigated whether and how MMP-9 expression and activity were changed in glomerular epithelial cells upon albumin overload. In situ zymography, immunostaining and Western blot for renal MMP gelatinolytic activity and MMP-9 protein expression were performed in Zucker lean and Zucker diabetic rats. Confocal microscopy revealed a focal increase in gelatinase activity and MMP-9 protein in the glomeruli of diabetic rats. Increased glomerular MMP-9 staining was mainly observed in hyperplastic parietal epithelial cells (PECs) expressing claudin-1 in the diabetic kidneys. Interestingly, increased parietal MMP-9 was often accompanied by decreased staining for podocyte markers (nephrin and podocalyxin) in the sclerotic area of affected glomeruli in diabetic rats. Additionally, urinary excretion of podocyte marker proteins was significantly increased in association with the levels of MMP-9 and albumin in the urine of diabetic animals. To evaluate the direct effect of albumin on expression and activity of MMP-9, primary cultured rat glomerular PECs were incubated with rat serum albumin (0.25 - 1 mg/ml) for 24 - 48 hrs. MMP-9 mRNA levels were significantly increased following albumin treatment. Meanwhile, albumin administration resulted in a dose-dependent increase in MMP-9 protein and activity in culture supernatants of PECs. Moreover, albumin activated p44/42 mitogen-activated protein kinase (MAPK) in PECs. Inhibition of p44/42 MAPK suppressed albumin-induced MMP-9 secretion from glomerular PECs. Taken together, we have demonstrated that an up-regulation of MMP-9 in activated parietal epithelium is associated with a loss of adjacent podocytes in progressive diabetic nephropathy

Green tea polyphenols ameliorate non-alcoholic fatty liver disease through upregulating AMPK activation in high fat fed Zucker fatty rats.

PubMed

Tan, Yi; Kim, Jane; Cheng, Jing; Ong, Madeleine; Lao, Wei-Guo; Jin, Xing-Liang; Lin, Yi-Guang; Xiao, Linda; Zhu, Xue-Qiong; Qu, Xian-Qin

2017-06-07

To investigate protective effects and molecular mechanisms of green tea polyphenols (GTP) on non-alcoholic fatty liver disease (NAFLD) in Zucker fatty (ZF) rats. Male ZF rats were fed a high-fat diet (HFD) for 2 wk then treated with GTP (200 mg/kg) or saline (5 mL/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP-activated protein kinase (AMPK) acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein 1c (SREBP1c). Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain (10.1%, P = 0.052) and significantly lowered visceral fat (31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels (both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFα and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172 ( P < 0.05) and phosphorylated ACC and SREBP1c (both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats. The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway.

Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid.

PubMed

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-08-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Serum adipokine profile and fatty acid composition of adipose tissues are affected by conjugated linoleic acid and saturated fat diets in obese Zucker rats.

PubMed

Martins, Susana V; Lopes, Paula A; Alfaia, Cristina M; Rodrigues, Pedro O; Alves, Susana P; Pinto, Rui M A; Castro, Matilde F; Bessa, Rui J B; Prates, José A M

2010-03-01

Conjugated linoleic acid (CLA) has been reported as having body fat lowering properties and the ability to modulate the inflammatory system in several models. In the present study, the effects of CLA added to saturated fat diets, from vegetable and animal origins, on the serum adipokine profile of obese Zucker rats were assessed. In addition, the fatty acid composition of epididymal and retroperitoneal adipose tissues was determined and a principal component analysis (PCA) was used to assess possible relationships between fatty acids and serum metabolites. Atherogenic diets (2 % cholesterol) were formulated with palm oil and ovine fat and supplemented or not with 1 % of a mixture (1:1) of cis-9, trans-11 and trans-10, cis-12-CLA isomers. CLA-fed animals exhibited lower daily feed intake, final body and liver weights, and hepatic lipids content. Total and LDL-cholesterol levels were increased in CLA-supplemented groups. CLA also promoted higher adiponectin and lower plasminogen activator inhibitor-1 (PAI-1) serum concentrations. In contrast to palm oil diets, ovine fat increased insulin resistance and serum levels of leptin, TNF-alpha and IL-1beta. Epididymal and retroperitoneal adipose tissues had similar deposition of individual fatty acids. The PCA analysis showed that the trans-10, cis-12-CLA isomer was highly associated with adiponectin and PAI-1 levels. Summing up, CLA added to vegetable saturated enriched diets, relative to those from animal origin, seems to improve the serum profile of adipokines and inflammatory markers in obese Zucker rats due to a more favourable fatty acid composition.

Regular exercise prevents the development of hyperglucocorticoidemia via adaptations in the brain and adrenal glands in male Zucker diabetic fatty rats.

PubMed

Campbell, Jonathan E; Király, Michael A; Atkinson, Daniel J; D'souza, Anna M; Vranic, Mladen; Riddell, Michael C

2010-07-01

We determined the effects of voluntary wheel running on the hypothalamic-pituitary-adrenal (HPA) axis, and the peripheral determinants of glucocorticoids action, in male Zucker diabetic fatty (ZDF) rats. Six-week-old euglycemic ZDF rats were divided into Basal, Sedentary, and Exercise groups (n = 8-9 per group). Basal animals were immediately killed, whereas Sedentary and Exercising rats were monitored for 10 wk. Basal (i.e., approximately 0900 AM in the resting state) glucocorticoid levels increased 2.3-fold by week 3 in Sedentary rats where they remained elevated for the duration of the study. After an initial elevation in basal glucocorticoid levels at week 1, Exercise rats maintained low glucocorticoid levels from week 3 through week 10. Hyperglycemia was evident in Sedentary animals by week 7, whereas Exercising animals maintained euglycemia throughout. At the time of death, the Sedentary group had approximately 40% lower glucocorticoid receptor (GR) content in the hippocampus, compared with the Basal and Exercise groups (P < 0.05), suggesting that the former group had impaired negative feedback regulation of the HPA axis. Both Sedentary and Exercise groups had elevated ACTH compared with Basal rats, indicating that central drive of the axis was similar between groups. However, Sedentary, but not Exercise, animals had elevated adrenal ACTH receptor and steroidogenic acute regulatory protein content compared with the Basal animals, suggesting that regular exercise protects against elevations in glucocorticoids by a downregulation of adrenal sensitivity to ACTH. GR and 11beta-hydroxysteroid dehydrogenase type 1 content in skeletal muscle and liver were similar between groups, however, GR content in adipose tissue was elevated in the Sedentary groups compared with the Basal and Exercise (P < 0.05) groups. Thus, the gradual elevations in glucocorticoid levels associated with the development of insulin resistance in male ZDF rats can be prevented with regular

Joint Feedback Analysis Modeling of Nonesterified Fatty Acids in Obese Zucker Rats and Normal Sprague–Dawley Rats after Different Routes of Administration of Nicotinic Acid

PubMed Central

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-01-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague–Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague–Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration–response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the “degree of disease” can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2571–2584, 2014 PMID:24986056

Supplemental fructose attenuates postprandial glycemia in Zucker fatty fa/fa rats.

PubMed

Wolf, Bryan W; Humphrey, Phillip M; Hadley, Craig W; Maharry, Kati S; Garleb, Keith A; Firkins, Jeffrey L

2002-06-01

Experiments were conducted to evaluate the effects of supplemental fructose on postprandial glycemia. After overnight food deprivation, Zucker fatty fa/fa rats were given a meal glucose tolerance test. Plasma glucose response was determined for 180 min postprandially. At a dose of 0.16 g/kg body, fructose reduced (P < 0.05) the incremental area under the curve (AUC) by 34% when supplemented to a glucose challenge and by 32% when supplemented to a maltodextrin (a rapidly digested starch) challenge. Similarly, sucrose reduced (P = 0.0575) the incremental AUC for plasma glucose when rats were challenged with maltodextrin. Second-meal glycemic response was not affected by fructose supplementation to the first meal, and fructose supplementation to the second meal reduced (P < 0.05) postprandial glycemia when fructose had been supplemented to the first meal. In a dose-response study (0.1, 0.2, and 0.5 g/kg body), supplemental fructose reduced (P < 0.01) the peak rise in plasma glucose (linear and quadratic effects). In the final experiment, a low dose of fructose (0.075 g/kg body) reduced (P < 0.05) the incremental AUC by 18%. These data support the hypothesis that small amounts of oral fructose or sucrose may be useful in lowering the postprandial blood glucose response.

L-cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats.

PubMed

Jain, Sushil K; Kanikarla-Marie, Preeti; Warden, Cassandra; Micinski, David

2016-05-01

Vitamin D binding protein (VDBP) status has an effect on and can potentially improve the status of 25(OH) vitamin D and increase the metabolic actions of 25(OH) vitamin D under physiological and pathological conditions. Diabetes is associated with lower levels of glutathione (GSH) and 25(OH) vitamin D. This study examined the hypothesis that upregulation of GSH will also upregulate blood levels of VDBP and 25(OH) vitamin D in type 2 diabetic rats. L-cysteine (LC) supplementation was used to upregulate GSH status in a FL83B hepatocyte cell culture model and in vivo using Zucker diabetic fatty (ZDF) rats. Results show that LC supplementation upregulates both protein and mRNA expression of VDBP and vitamin D receptor (VDR) and GSH status in hepatocytes exposed to high glucose, and that GSH deficiency, induced by glutamate cysteine ligase knockdown, resulted in the downregulation of GSH, VDBP, and VDR and an increase in oxidative stress levels in hepatocytes. In vivo, LC supplementation increased GSH and protein and mRNA expression of VDBP and vitamin D 25-hydroxylase (CYP2R1) in the liver, and simultaneously resulted in elevated blood levels of LC and GSH, as well as increases in VDBP and 25(OH) vitamin D levels, and decreased inflammatory biomarkers in ZDF rats compared with those in placebo-supplemented ZDF rats consuming a similar diet. LC supplementation may provide a novel approach by which to raise blood levels of VDBP and 25(OH) vitamin D in type 2 diabetes. © 2016 The Authors. Molecular Nutrition & Food Research Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Carnitine supplementation to obese Zucker rats prevents obesity-induced type II to type I muscle fiber transition and favors an oxidative phenotype of skeletal muscle

PubMed Central

2013-01-01

Background In the present study, we tested the hypothesis that carnitine supplementation counteracts obesity-induced muscle fiber transition from type I to type II. Methods 24 obese Zucker rats were randomly divided into two groups of 12 rats each (obese control, obese carnitine) and 12 lean Zucker rats were selected for lean control group. A control diet was given to both control groups and a carnitine supplemented diet (3 g/kg diet) was given to obese carnitine group for 4 wk. Components of the muscle fiber transformation in skeletal muscle were examined. Results The plasma level of carnitine were lower in the obese control group compared to the lean control group and higher in the obese carnitine group than in the other groups (P < 0.05). Plasma concentrations of triglycerides and non-esterified fatty acids were increased in obese animals compared to lean animals and the obese carnitine group had lower level compared to the obese control group (P < 0.05). The obese carnitine group had an increased number of type I muscle fibers and higher mRNA levels of type I fiber-specific myosin heavy chain, regulators of muscle fiber transition and of genes involved in carnitine uptake, fatty acid transport, β-oxidation, angiogenesis, tricarboxylic acid cycle and thermo genesis in M. rectus femoris compared to the other groups (P < 0.05). Conclusion The results demonstrate that carnitine supplementation to obese Zucker a rat counteracts the obesity-induced muscle fiber transition and restores the muscle oxidative metabolic phenotype. Carnitine supplementation is supposed to be beneficial for the treatment of elevated levels of plasma lipids during obesity or diabetes. PMID:23842456

Dietary fish protein hydrolysates containing bioactive motifs affect serum and adipose tissue fatty acid compositions, serum lipids, postprandial glucose regulation and growth in obese Zucker fa/fa rats.

PubMed

Drotningsvik, Aslaug; Mjøs, Svein A; Pampanin, Daniela M; Slizyte, Rasa; Carvajal, Ana; Remman, Tore; Høgøy, Ingmar; Gudbrandsen, Oddrun A

2016-10-01

The world's fisheries and aquaculture industries produce vast amounts of protein-containing by-products that can be enzymatically hydrolysed to smaller peptides and possibly be used as additives to functional foods and nutraceuticals targeted for patients with obesity-related metabolic disorders. To investigate the effects of fish protein hydrolysates on markers of metabolic disorders, obese Zucker fa/fa rats consumed diets with 75 % of protein from casein/whey (CAS) and 25 % from herring (HER) or salmon (SAL) protein hydrolysate from rest raw material, or 100 % protein from CAS for 4 weeks. The fatty acid compositions were similar in the experimental diets, and none of them contained any long-chain n-3 PUFA. Ratios of lysine:arginine and methionine:glycine were lower in HER and SAL diets when compared with CAS, and taurine was detected only in fish protein hydrolysate diets. Motifs with reported hypocholesterolemic or antidiabetic activities were identified in both fish protein hydrolysates. Rats fed HER diet had lower serum HDL-cholesterol and LDL-cholesterol, and higher serum TAG, MUFA and n-3:n-6 PUFA ratio compared with CAS-fed rats. SAL rats gained more weight and had better postprandial glucose regulation compared with CAS rats. Serum lipids and fatty acids were only marginally affected by SAL, but adipose tissue contained less total SFA and more total n-3 PUFA when compared with CAS. To conclude, diets containing hydrolysed rest raw material from herring or salmon proteins may affect growth, lipid metabolism, postprandial glucose regulation and fatty acid composition in serum and adipose tissue in obese Zucker rats.

Characterization of the Prediabetic State in a Novel Rat Model of Type 2 Diabetes, the ZFDM Rat.

PubMed

Gheni, Ghupurjan; Yokoi, Norihide; Beppu, Masayuki; Yamaguchi, Takuro; Hidaka, Shihomi; Kawabata, Ayako; Hoshino, Yoshikazu; Hoshino, Masayuki; Seino, Susumu

2015-01-01

We recently established a novel animal model of obese type 2 diabetes (T2D), the Zucker fatty diabetes mellitus (ZFDM) rat strain harboring the fatty mutation (fa) in the leptin receptor gene. Here we performed a phenotypic characterization of the strain, focusing mainly on the prediabetic state. At 6-8 weeks of age, fa/fa male rats exhibited mild glucose intolerance and severe insulin resistance. Although basal insulin secretion was remarkably high in the isolated pancreatic islets, the responses to both glucose stimulation and the incretin GLP-1 were retained. At 10-12 weeks of age, fa/fa male rats exhibited marked glucose intolerance as well as severe insulin resistance similar to that at the earlier age. In the pancreatic islets, the insulin secretory response to glucose stimulation was maintained but the response to the incretin was diminished. In nondiabetic Zucker fatty (ZF) rats, the insulin secretory responses to both glucose stimulation and the incretin in the pancreatic islets were similar to those of ZFDM rats. As islet architecture was destroyed with age in ZFDM rats, a combination of severe insulin resistance, diminished insulin secretory response to incretin, and intrinsic fragility of the islets may cause the development of T2D in this strain.

Aerobic interval exercise improves parameters of nonalcoholic fatty liver disease (NAFLD) and other alterations of metabolic syndrome in obese Zucker rats.

PubMed

Kapravelou, Garyfallia; Martínez, Rosario; Andrade, Ana M; Nebot, Elena; Camiletti-Moirón, Daniel; Aparicio, Virginia A; Lopez-Jurado, Maria; Aranda, Pilar; Arrebola, Francisco; Fernandez-Segura, Eduardo; Bermano, Giovanna; Goua, Marie; Galisteo, Milagros; Porres, Jesus M

2015-12-01

Metabolic syndrome (MS) is a group of metabolic alterations that increase the susceptibility to cardiovascular disease and type 2 diabetes. Nonalcoholic fatty liver disease has been described as the liver manifestation of MS. We aimed to test the beneficial effects of an aerobic interval training (AIT) protocol on different biochemical, microscopic, and functional liver alterations related to the MS in the experimental model of obese Zucker rat. Two groups of lean and obese animals (6 weeks old) followed a protocol of AIT (4 min at 65%-80% of maximal oxygen uptake, followed by 3 min at 50%-65% of maximal oxygen uptake for 45-60 min, 5 days/week, 8 weeks of experimental period), whereas 2 control groups remained sedentary. Obese rats had higher food intake and body weight (P < 0.0001) and suffered significant alterations in plasma lipid profile, area under the curve after oral glucose overload (P < 0.0001), liver histology and functionality, and antioxidant status. The AIT protocol reduced the severity of alterations related to glucose and lipid metabolism and increased the liver protein expression of PPARγ, as well as the gene expression of glutathione peroxidase 4 (P < 0.001). The training protocol also showed significant effects on the activity of hepatic antioxidant enzymes, although this action was greatly influenced by rat phenotype. The present data suggest that AIT protocol is a feasible strategy to improve some of the plasma and liver alterations featured by the MS.

Potential utility of combination therapy with nateglinide and telmisartan for metabolic derangements in Zucker Fatty rats.

PubMed

Kajioka, T; Miura, K; Kitahara, Y; Yamagishi, S

2007-12-01

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular disease. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial hyperglycemia. In this study, we investigated the potential utility of combination therapy with telmisartan, an angiotensin II receptor blocker and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial hyperglycemia and metabolic derangements in Zucker Fatty (ZF) rats. ZF rats fed twice daily were given vehicle, 50 mg/kg of nateglinide, 5 mg/kg of telmisartan, or both for 6 weeks. Combination therapy with nateglinide and telmisartan for 2 weeks ameliorated postprandial hyperglycemia in ZF rats fed twice daily. Furthermore, 6-week treatment with nateglinide and telmisartan not only decreased fasting plasma insulin, triglycerides, and free fatty acid levels, but also improved the responses of blood glucose to insulin and subsequently reduced the decremental glucose areas under the curve in the ZF rats. Combination therapy also restored the decrease of plasma adiponectin levels in the ZF rats. Monotherapy with nateglinide or telmisartan alone didnot significantly improve these metabolic parameters. These observations demonstrate that combination therapy with nateglinide and telmisartan may improve the metabolic derangements by ameliorating early phase of insulin secretion as well as insulin resistance in ZF rats fed twice daily. Our present findings suggest that the combination therapy with nateglinide and telmisartan could be a promising therapeutic strategy for the treatment of the metabolic syndrome.

Influence of benzodiazepines on body weight and food intake in obese and lean Zucker rats.

PubMed

Blasi, C

2000-05-01

1. The gamma-aminobutyric acid (GABA)-ergic system, which is functionally altered in obese (fa/fa) Zucker rats, plays an important role in controlling energy balance within the central nervous system. 2. GABA receptors seem to be involved in the dysfunction of the hypothalamic energy homeostasis-controlling mechanisms in these animals due to a genetically-induced defect of the leptin-neuropeptide Y system. 3. To shed further light on the possible role played by the GABA system in the pathogenesis of this rat model, two benzodiazepine (BDZ) receptor agonists (diazepam and clonazepam) and one BDZ antagonist (flumazenil) were administered intraperitoneally in obese and lean Zucker rats. 4. Body weight gain was reduced by the BDZ agonists in both phenotypes, and one receptor-agonist (diazepam) lowered insulin concentration in obese rats. In GABA-antagonist-treated obese rats, the daily amount of body weight gain and food intake acquired an oscillatory rhythm similar to that of normal rodents. 5. By demonstrating the role of BDZ receptors, these findings may help clarify the pathophysiology of obesity and insulin resistance in fatty Zucker rats.

Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects.

PubMed

Zoja, Carla; Corna, Daniela; Nava, Valeria; Locatelli, Monica; Abbate, Mauro; Gaspari, Flavio; Carrara, Fabiola; Sangalli, Fabio; Remuzzi, Giuseppe; Benigni, Ariela

2013-03-15

Bardoxolone methyl is an antioxidant inflammation modulator acting through induction of Keap1-Nrf2 pathway. Results from a recent phase IIb clinical trial reported that bardoxolone methyl was associated with improvement in the estimated glomerular filtration rate in patients with advanced chronic kidney disease and Type 2 diabetes. However, increases in albuminuria, serum transaminase, and frequency of adverse events were noted. We studied the effect of 3-mo treatment with RTA 405, a synthetic triterpenoid analog of bardoxolone methyl in Zucker diabetic fatty rats with overt Type 2 diabetes. Rats were treated from 3 mo of age with vehicle, RTA 405, ramipril, or RTA 405 plus ramipril. RTA 405 caused severe changes in food intake and diuresis with decline in body weight, worsening of dyslipidemia, and increase in blood pressure. Early elevation in serum transaminase was followed by liver injury. RTA 405 worsened proteinuria, glomerulosclerosis, and tubular damage. Ramipril was renoprotective, but when given with RTA 405 it was not able to limit its worsening effects. These data could be due to degradation products in the drug substance used, as disclosed by the company once the study was concluded. To overcome such a drawback, the company offered to test dh404, a variant of RTA 405, in Zucker diabetic fatty rats. The dh404 did not display beneficial effects on proteinuria, glomerulosclerosis, and interstitial inflammation. Rather, kidneys from three rats receiving dh404 showed the presence of a granulomatous and inflammatory process reminiscent of a pseudotumor. Altogether these data raise serious concerns on the use of bardoxolone analogs in Type 2 diabetic nephropathy.

Engineering brown fat into skeletal muscle using ultrasound-targeted microbubble destruction gene delivery in obese Zucker rats: Proof of concept design.

PubMed

Bastarrachea, Raul A; Chen, Jiaxi; Kent, Jack W; Nava-Gonzalez, Edna J; Rodriguez-Ayala, Ernesto; Daadi, Marcel M; Jorge, Barbara; Laviada-Molina, Hugo; Comuzzie, Anthony G; Chen, Shuyuan; Grayburn, Paul A

2017-09-01

Ultrasound-targeted microbubble destruction (UTMD) is a novel means of tissue-specific gene delivery. This approach systemically infuses transgenes precoupled to gas-filled lipid microbubbles that are burst within the microvasculature of target tissues via an ultrasound signal resulting in release of DNA and transfection of neighboring cells within the tissue. Previous work has shown that adenovirus containing cDNA of UCP-1, injected into the epididymal fat pads in mice, induced localized fat depletion, improving glucose tolerance, and decreasing food intake in obese diabetic mice. Our group recently demonstrated that gene therapy by UTMD achieved beta cell regeneration in streptozotocin (STZ)-treated mice and baboons. We hypothesized that gene therapy with BMP7/PRDM16/PPARGC1A in skeletal muscle (SKM) of obese Zucker diabetic fatty (fa/fa) rats using UTMD technology would produce a brown adipose tissue (BAT) phenotype with UCP-1 overexpression. This study was designed as a proof of concept (POC) project. Obese Zucker rats were administered plasmid cDNA contructs encoding a gene cocktail with BMP7/PRDM16/PPARGC1A incorporated within microbubbles and intravenously delivered into their left thigh. Controls received UTMD with plasmids driving a DsRed reporter gene. An ultrasound transducer was directed to the thigh to disrupt the microbubbles within the microcirculation. Blood samples were drawn at baseline, and after treatment to measure glucose, insulin, and free fatty acids levels. SKM was harvested for immunohistochemistry (IHC). Our IHC results showed a reliable pattern of effective UTMD-based gene delivery in enhancing SKM overexpression of the UCP-1 gene. This clearly indicates that our plasmid DNA construct encoding the gene combination of PRDM16, PPARGC1A, and BMP7 reprogrammed adult SKM tissue into brown adipose cells in vivo. Our pilot established POC showing that the administration of the gene cocktail to SKM in this rat model of genetic obesity using UTMD

Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats.

PubMed

Jain, Sushil K; Croad, Jennifer L; Velusamy, Thirunavukkarasu; Rains, Justin L; Bull, Rebeca

2010-09-01

Chromium and cysteine supplementation can improve glucose metabolism in animal studies. This study examined the hypothesis that a cysteinate complex of chromium is significantly beneficial than either of them in lowering blood glucose and vascular inflammation markers in Zucker diabetic fatty (ZDF) rats. Starting at the age of 6 wk, ZDF rats were supplemented orally (daily gavages for 8 more weeks) with saline-placebo (D) or chromium (400 microg Cr/Kg body weight) as chromium dinicocysteinate (CDNC), chromium dinicotinate (CDN) or chromium picolinate (CP) or equimolar L-cysteine (LC, img/Kg body weight), and fed Purina 5008 diet for 8 wk. ZDF rats of 6 wk age before any supplementations and onset of diabetes were considered as baseline. D rats showed elevated levels of fasting blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and oxidative stress (lipid peroxidation) and lower adiponectin and vitamin C, when compared with baseline rats. In comparison to D group, CDNC group had significantly lower blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and lipid peroxidation and increased vitamin C and adiponectin levels. CDN, CP or LC showed significantly less or no effect on these biomarkers. Only CDNC lowered blood creatinine levels in comparison to D. While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats. CDNC effect on glycemia, NFkappaB, Akt and IRS-1 in liver was significantly greater compared with LC. Blood chromium levels did not differ between Cr-groups. Exogenous vitamin C supplementation significantly inhibited MCP-1 secretion in U937 monocytes cultured in high-glucose-medium. CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats.

Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to obese-prone rats impairs glucose and insulin tolerance.

PubMed

Hamilton, Melissa; Hopkins, Loren E; AlZahal, Ousama; MacDonald, Tara L; Cervone, Daniel T; Wright, David C; McBride, Brian W; Dyck, David J

2015-09-28

We recently demonstrated that feeding a natural CLAt10,c12-enriched butter to lean female rats resulted in small, but significant increases in fasting glucose and insulin concentrations, and impaired insulin tolerance. Our goal was to extend these findings by utilizing the diabetes-prone female fatty Zucker rat. Rats were fed custom diets containing 45 % kcal of fat derived from control and CLAt10,c12-enriched butter for 8 weeks. CLA t10,c12-enriched butter was prepared from milk collected from cows fed a high fermentable carbohydrate diet to create subacute rumen acidosis (SARA); control (non-SARA) butter was collected from cows fed a low grain diet. Female fatty Zucker rats (10 weeks old) were randomly assigned to one of four diet treatments: i) low fat (10 % kcal), ii) 45 % kcal lard, iii) 45 % kcal SARA butter, or iv) 45 % kcal non-SARA butter. A low fat fed lean Zucker group was used as a control group. After 8 weeks, i) glucose and insulin tolerance tests, ii) insulin signaling in muscle, adipose and liver, and iii) metabolic caging measurements were performed. Glucose and insulin tolerance were significantly impaired in all fatty Zucker groups, but to the greatest extent in the LARD and SARA conditions. Insulin signaling (AKT phosphorylation) was impaired in muscle, visceral (perigonadal) adipose tissue and liver in fatty Zucker rats, but was generally similar across dietary groups. Physical activity, oxygen consumption, food intake and weight gain were also similar amongst the various fatty Zucker groups. Increasing the consumption of a food naturally enriched with CLAt10,c12 significantly worsens glucose and insulin tolerance in a diabetes-prone rodent model. This outcome is not explained by changes in tissue insulin signaling, physical activity, energy expenditure, food intake or body mass.

Rodent models of diabetic nephropathy: their utility and limitations

PubMed Central

Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

2016-01-01

Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic

Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus.

PubMed

Kuzuya, Teiji; Katano, Yoshiaki; Nakano, Isao; Hirooka, Yoshiki; Itoh, Akihiro; Ishigami, Masatoshi; Hayashi, Kazuhiko; Honda, Takashi; Goto, Hidemi; Fujita, Yuko; Shikano, Rie; Muramatsu, Yuji; Bajotto, Gustavo; Tamura, Tomohiro; Tamura, Noriko; Shimomura, Yoshiharu

2008-08-15

The branched-chain alpha-keto acid dehydrogenase (BCKDH) complex is the most important regulatory enzyme in branched-chain amino acid (BCAA) catabolism. We examined the regulation of hepatic BCKDH complex activity in spontaneous type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Zucker diabetic fatty rats. Hepatic BCKDH complex activity in these rats was significantly lower than in corresponding control rats. The amount of BCKDH complex in OLETF rats corresponded to the total activity of the complex. Activity and abundance of the bound form of BCKDH kinase, which is responsible for inactivation of the complex, showed an inverse correlation to BCKDH complex activity in OLETF rats. Dietary supplementation of 5% BCAAs for 10 weeks markedly increased BCKDH complex activity, and decreased the activity and bound form of BCKDH kinase in the rats. These results suggest that BCAA catabolism in type 2 diabetes is downregulated and enhanced by BCAA supplementation.

A casein diet added isoflavone-enriched soy protein favorably affects biomarkers of steatohepatitis in obese Zucker rats.

PubMed

Gudbrandsen, Oddrun Anita; Wergedahl, Hege; Berge, Rolf Kristian

2009-05-01

Dietary supplementation of a soy protein enriched with isoflavones (HDI) has been shown to improve fatty liver in obese rats. The main objective of this study was to investigate whether HDI would influence the inflammatory status in livers of obese rats with fatty liver. Male obese Zucker fa/fa rats were fed casein (controls) or casein supplemented with HDI (containing 4.00 g of genistein and 4.50 g of daidzein per kilogram of diet) for 6 wk. The HDI-fed rats had a markedly lower hepatic concentration of triacylglycerol when compared with controls. The decreased aspartate transaminase/alanine transaminase ratio in plasma, together with lower circulating levels of alkaline phosphatase and bile acids after HDI feeding, implied an improved hepatitis. This was supported by decreased plasma and hepatic mRNA levels of tumor necrosis factor-alpha, lower plasma levels of interleukin-1beta and monocyte chemoattractant protein-1, and an increased anti-inflammatory fatty acid index in plasma. HDI also seemed to protect the rats from oxidative damage, because the level of lipid peroxides in triacylglycerol-rich lipoproteins after in vitro copper oxidation was lower for HDI-fed rats when compared with controls. These results show that isoflavone-enriched soy protein favorably affects biomarkers of hepatic inflammation in obese Zucker fa/fa rats with fatty liver. Thus, dietary soy proteins enriched in isoflavones may be a promising agent to improve steatohepatitis in patients.

Reduction of adult hippocampal neurogenesis is amplified by aluminum exposure in a model of type 2 diabetes

PubMed Central

Nam, Sung Min; Kim, Jong Whi; Yoo, Dae Young; Jung, Hyo Young; Choi, Jung Hoon; Hwang, In Koo; Seong, Je Kyung

2016-01-01

In this study, we investigated the effects of chronic aluminum (Al) exposure for 10 weeks on cell proliferation and neuroblast differentiation in the hippocampus of type 2 diabetic rats. Six-week-old Zucker diabetic fatty (ZDF) and Zucker lean control (ZLC) rats were selected and randomly divided into Al- and non-Al-groups. Al was administered via drinking water for 10 weeks, after which the animals were sacrificed at 16 weeks of age. ZDF rats in both Al- and non-Al-groups showed increases in body weight and blood glucose levels compared to ZLC rats. Al exposure did not significantly affect body weight, blood glucose levels or pancreatic β-cells and morphology of the pancreas in either ZLC or ZDF rats. However, exposure to Al reduced cell proliferation and neuroblast differentiation in both ZLC and ZDF rats. Exposure to Al resulted in poor development of the dendritic processes of neuroblasts in both ZLC and ZDF rats. Furthermore, onset and continuation of diabetes reduced cell proliferation and neuroblast differentiation, and Al exposure amplified reduction of these parameters. These results suggest that Al exposure via drinking water aggravates the impairment in hippocampal neurogenesis that is typically observed in type 2 diabetic animals. PMID:27051335

Thyroid hormone modulates food intake and glycemia via ghrelin secretion in Zucker fatty rats.

PubMed

Patel, K; Joharapurkar, A; Dhanesha, N; Patel, V; Kshirsagar, S; Raval, P; Raval, S; Jain, M R

2014-10-01

Hyperthyroidism is known to increase food intake and central administration of thyroid hormone shows acute orexigenic effects in rodents. We investigated whether T3 influences appetite and glucose homeostasis by modulating circulating ghrelin, an important orexigenic hormone, in Zucker fatty rats. The acute anorectic effects of T3 and ghrelin mimetic MK-0677 were studied in rats trained for fasting induced food intake. The serum concentration of T3, ghrelin, glucose, triglycerides, and liver glycogen were estimated. The involvement of sympathetic nervous system was evaluated by conducting similar experiments in vagotomized rats. T3 increased food intake and glucose in rats over 4 h, with increase in serum T3 and decrease in liver glycogen. T3 treatment was associated with increase in serum ghrelin. An additive effect on appetite and glucose was observed when T3 (oral) was administered with central (intracerebroventricular) administration of a ghrelin mimetic, MK-0677. Ghrelin antagonist, compound 8a, antagonized the hyperglycemic and hyperphagic effects of T3. In vagotomized rats, T3 did not show increase in appetite as well as glucose. Serum ghrelin levels were unchanged in these animals after T3 treatment. However, T3 showed increase in serum triglyceride levels indicating its peripheral lipolytic effect, in vagotomized as well as sham treated animals. To conclude, acute orexigenic and hyperglycemic effects of T3 are associated with ghrelin secretion and activity. This effect seems to be mediated via vagus nerves, and is independent of glucoregulatory hormones. © Georg Thieme Verlag KG Stuttgart · New York.

Effects of a diabetes-specific enteral nutrition on nutritional and immune status of diabetic, obese, and endotoxemic rats: interest of a graded arginine supply.

PubMed

Breuillard, Charlotte; Darquy, Sylviane; Curis, Emmanuel; Neveux, Nathalie; Garnier, Jean-Pierre; Cynober, Luc; De Bandt, Jean-Pascal

2012-08-01

Obese and type 2 diabetic patients present metabolic disturbance-related alterations in nonspecific immunity, to which the decrease in their plasma arginine contributes. Although diabetes-specific formulas have been developed, they have never been tested in the context of an acute infectious situation as can be seen in intensive care unit patients. Our aim was to investigate the effects of a diabetes-specific diet enriched or not with arginine in a model of infectious stress in a diabetes and obesity situation. As a large intake of arginine may be deleterious, this amino acid was given in graded fashion. Randomized, controlled experimental study. University research laboratory. Zucker diabetic fatty rats. Gastrostomized Zucker diabetic fatty rats were submitted to intraperitoneal lipopolysaccharide administration and fed for 7 days with either a diabetes-specific enteral nutrition without (G group, n=7) or with graded arginine supply (1-5 g/kg/day) (GA group, n=7) or a standard enteral nutrition (HP group, n=10). Survival rate was better in G and GA groups than in the HP group. On day 7, plasma insulin to glucose ratio tended to be lower in the same G and GA groups. Macrophage tumor necrosis factor-α (G: 5.0±1.1 ng/2×10⁶ cells·hr⁻¹; GA: 3.7±0.8 ng/2×10⁶ cells·hr⁻¹; and HP: 1.7±0.6 ng/2×10⁶ cells·hr⁻¹; p<.05 G vs. HP) and nitric oxide (G: 4.5±1.1 ng/2×10⁶ cells·hr⁻¹; GA: 5.1±1.0 ng/2×10⁶ cells·hr⁻¹; and HP: 1.0±0.5 nmol/2×10⁶ cells·hr⁻¹; p<.05 G and GA vs. HP) productions were higher in the G and GA groups compared to the HP group. Macrophages from the G and GA groups exhibited increased arginine consumption. In diabetic obese and endotoxemic rats, a diabetes-specific formula leads to a lower mortality, a decreased insulin resistance, and an improvement in peritoneal macrophage function. Arginine supplementation has no additional effect. These data support the use of such disease-specific diets in critically ill

Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats.

PubMed

Schuelert, N; Gorodetskaya, N; Just, S; Doods, H; Corradini, L

2015-04-16

Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Differential impact of diabetes mellitus type II and arterial hypertension on collateral artery growth and concomitant macrophage accumulation.

PubMed

Ito, Wulf D; Lund, Natalie; Sager, Hendrik; Becker, Wiebke; Wenzel, Ulrich

2015-01-01

Diabetes mellitus type II and arterial hypertension are major risk factors for peripheral arterial disease and have been considered to reduce collateral growth (arteriogenesis). Collateral growth proceeds through different stages. Vascular proliferation and macrophage accumulation are hallmarks of early collateral growth. We here compare the impact of arterial hypertension and diabetes mellitus type II on collateral proliferation (Brdu incorporation) and macrophage accumulation (ED 2 staining) as well as collateral vessel function (collateral conductance) in a rat model of peripheral vascular disease (femoral artery occlusion), diabetes mellitus type II (Zucker fatty diabetic rats and Zucker lean rat controls) and arterial hypertension (induced via clip placement around the right renal arteriy). We furthermore tested the impact of monocyte chemoattractant protein-1 (MCP‑1) on collateral proliferation and macrophage accumulation in these models Diabetic animals showed reduced vascular proliferation and macrophage accumulation, which however did not translate into a change of collateral conductance. Hypertensive animals on the contrary had reduced collateral conductances without altered macrophage accumulation and only a marginal reduction in collateral proliferation. Infusion of MCP‑1 only enhanced vascular proliferation in diabetic animals. These findings illustrate that impaired monocyte/macrophage recruitment is responsible for reduced collateral growth under diabetic conditions but not in arterial hypertension suggesting that diabetes mellitus in particular affects early stages of collateral growth whereas hypertension has its impact on later remodeling stages. Successful pro-arteriogenic treatment strategies in a patient population that presents with diabetes mellitus and arterial hypertension need to address different stages of collateral growth and thus different molecular and cellular targets simultaneously.

Glucomannan- and glucomannan plus spirulina-enriched pork affect liver fatty acid profile, LDL receptor expression and antioxidant status in Zucker fa/fa rats fed atherogenic diets

PubMed Central

González-Torres, Laura; Matos, Cátia; Vázquez-Velasco, Miguel; Santos-López, Jorge A.; Sánchez-Martínez, Iria; García–Fernández, Camino; Bastida, Sara; Benedí, Juana; Sánchez-Muniz, Francisco J.

2017-01-01

ABSTRACT We evaluated the effects of glucomannan or glucomannan plus spirulina-restructured pork (RP) on liver fatty acid profile, desaturase/elongase enzyme activities and oxidative status of Zucker fa/fa rats for seven weeks. Control (C), glucomannan (G) and glucomannan/spirulina (GS)-RP; HC (cholesterol-enriched control), HG and HGS (cholesterol-enriched glucomannan and glucomannan/spirulina-RP) experimental diets were tested. Increased metabolic syndrome markers were found in C, G and GS rats. Cholesterol feeding increased liver size, fat, and cholesterol and reduced antioxidant enzyme levels and expressions. Cholesterolemia was lower in HG and HGS than in HC. GS vs. G showed higher stearic but lower oleic levels. SFA and PUFA decreased while MUFA increased by cholesterol feeding. The arachidonic/linoleic and docosahexaenoic/alpha-linolenic ratios were lower in HC, HG, and HGS vs. C, G, and GS, respectively, suggesting a delta-6-elongase-desaturase system inhibition. Moreover, cholesterol feeding, mainly in HGS, decreased low-density-lipoprotein receptor expression and the delta-5-desaturase activity and increased the delta-9-desaturase activity. In conclusion, the liver production of highly unsaturated fatty acids was limited to decrease their oxidation in presence of hypercholesterolaemia. Glucomannan or glucomannan/spirulina-RP has added new attributes to their functional properties in meat, partially arresting the negative effects induced by high-fat-high-cholesterol feeding on the liver fatty acid and antioxidant statuses. PMID:28325998

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

PubMed Central

Wang, Bingxuan; P., Charukeshi Chandrasekera; Pippin, John J.

2014-01-01

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management. PMID:24809394

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

PubMed

Wang, Bingxuan; Chandrasekera, P Charukeshi; Pippin, John J

2014-03-01

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Experimental Diabetes Mellitus in Different Animal Models

PubMed Central

Al-awar, Amin; Veszelka, Médea; Szűcs, Gergő; Attieh, Zouhair; Murlasits, Zsolt; Török, Szilvia; Pósa, Anikó; Varga, Csaba

2016-01-01

Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. PMID:27595114

Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats.

PubMed

Oakes, Nicholas D; Thalén, Pia; Hultstrand, Therese; Jacinto, Severina; Camejo, Germán; Wallin, Boel; Ljung, Bengt

2005-10-01

Insulin resistance, impaired glucose tolerance, high circulating levels of free fatty acids (FFA), and postprandial hyperlipidemia are associated with the metabolic syndrome, which has been linked to increased risk of cardiovascular disease. We studied the metabolic responses to an oral glucose/triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three groups of conscious 7-h fasted Zucker rats: lean healthy controls, obese insulin-resistant/dyslipidemic controls, and obese rats treated with the dual peroxisome proliferator-activated receptor alpha/gamma agonist, tesaglitazar, 3 mumol.kg(-1).day(-1) for 4 wk. Untreated obese Zucker rats displayed marked insulin resistance, as well as glucose and lipid intolerance in response to the glucose/TG load. The 2-h postload area under the curve values were greater for glucose (+19%), insulin (+849%), FFA (+53%), and TG (+413%) compared with untreated lean controls. Treatment with tesaglitazar lowered fasting plasma glucose, improved glucose tolerance, substantially reduced fasting and postload insulin levels, and markedly lowered fasting TG and improved lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. Mechanisms of tesaglitazar-induced lowering of plasma TG were studied separately using the Triton WR1339 method. In anesthetized, 5-h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced very low-density lipoprotein (VLDL) apolipoprotein CIII content by 86%, compared with obese controls. In conclusion, the glucose/lipid tolerance test in obese Zucker rats appears to be a useful model of the metabolic syndrome that can be used to evaluate therapeutic effects on impaired postprandial glucose and lipid metabolism. The present work demonstrates that tesaglitazar ameliorates these abnormalities and enhances insulin sensitivity in this animal model.

Ancient Wheat Diet Delays Diabetes Development in a Type 2 Diabetes Animal Model

PubMed Central

Thorup, Anne C.; Gregersen, Søren; Jeppesen, Per B.

2014-01-01

AIM: The main objective was to investigate the physiological effects of ancient wheat whole grain flour diets on the development and progression of type 2 diabetes in Zucker diabetic fatty (ZDF) rats, and specifically to look at the acute glycemic responses. METHODS: An intervention study was conducted, involving 40 ZDF rats consuming one of 5 different diets (emmer, einkorn, spelt, rye and refined wheat) for 9 weeks. Refined wheat flour and whole grain rye flour were included as negative and positive controls, respectively. RESULTS: After 9 weeks of intervention, a downregulation of the hepatic genes PPAR-α, GLUT2, and SREBP-1c was observed in the emmer group compared to the control wheat group. Likewise, expression of hepatic SREBP-2 was lower for emmer, einkorn, and rye compared with the control group. Furthermore, spelt and rye induced a low acute glycemic response. The wheat group had higher HDL- and total cholesterol levels. CONCLUSIONS: Ancient wheat diets caused a downregulation of key regulatory genes involved in glucose and fat metabolism, equivalent to a prevention or delay of diabetes development. Spelt and rye induced a low acute glycemic response compared to wheat. PMID:26177485

Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan.

PubMed

Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

2017-06-01

Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females.

Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan

PubMed Central

Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

2017-01-01

Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females. PMID:28553763

Circadian rhythms of temperature and activity in obese and lean Zucker rats

NASA Technical Reports Server (NTRS)

Murakami, D. M.; Horwitz, B. A.; Fuller, C. A.

1995-01-01

The circadian timing system is important in the regulation of feeding and metabolism, both of which are aberrant in the obese Zucker rat. This study tested the hypothesis that these abnormalities involve a deficit in circadian regulation by examining the circadian rhythms of body temperature and activity in lean and obese Zucker rats exposed to normal light-dark cycles, constant light, and constant dark. Significant deficits in both daily mean and circadian amplitude of temperature and activity were found in obese Zucker female rats relative to lean controls in all lighting conditions. However, the circadian period of obese Zucker rats did not exhibit differences relative to lean controls in either of the constant lighting conditions. These results indicate that although the circadian regulation of temperature and activity in obese Zucker female rats is in fact depressed, obese rats do exhibit normal entrainment and pacemaker functions in the circadian timing system. The results suggest a deficit in the process that generates the amplitude of the circadian rhythm.

Renal redox stress and remodeling in metabolic syndrome, type 2 diabetes mellitus, and diabetic nephropathy: paying homage to the podocyte.

PubMed

Hayden, Melvin R; Whaley-Connell, Adam; Sowers, James R

2005-01-01

Type 2 diabetes mellitus has reached epidemic proportions and diabetic nephropathy is the leading cause of end-stage renal disease. The metabolic syndrome constitutes a milieu conducive to tissue redox stress. This loss of redox homeostasis contributes to renal remodeling and parallels the concurrent increased vascular redox stress associated with the cardiometabolic syndrome. The multiple metabolic toxicities, redox stress and endothelial dysfunction combine to weave the complicated mosaic fabric of diabetic glomerulosclerosis and diabetic nephropathy. A better understanding may provide both the clinician and researcher tools to unravel this complicated disease process. Cellular remodeling of podocyte foot processes in the Ren-2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27) and the Zucker diabetic fatty model of type 2 diabetes mellitus have been observed in preliminary studies. Importantly, angiotensin II receptor blockers have been shown to abrogate these ultrastructural changes in the foot processes of the podocyte in preliminary studies. An integrated, global risk reduction, approach in therapy addressing the multiple metabolic abnormalities combined with attempts to reach therapeutic goals at an earlier stage could have a profound effect on the development and progressive nature to end-stage renal disease and ultimately renal replacement therapy.

Analysis of the "endocannabinoidome" in peripheral tissues of obese Zucker rats.

PubMed

Iannotti, F A; Piscitelli, F; Martella, A; Mazzarella, E; Allarà, M; Palmieri, V; Parrella, C; Capasso, R; Di Marzo, V

2013-08-01

The endocannabinoid system (ECS) represents one of the major determinants of metabolic disorders. We investigated potential changes in the endogenous levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) in some peripheral organs and tissues of obese Zucker(fa/fa) and lean Zucker(fa/+) rats by qPCR, liquid chromatography mass spectrometry, western blot and enzymatic activity assays. At 10-12 weeks of age AEA levels were significantly lower in BAT, small intestine and heart and higher in soleus of Zucker(fa/fa) rats. In this tissue, also the expression of CB1 receptors was higher. By contrast in Zucker(fa/fa) rats, 2-AG levels were changed (and lower) solely in the small and large intestine. Finally, in Zucker(fa/fa), PEA levels were unchanged, whereas OEA was slightly lower in BAT, and higher in the large intestine. Interestingly, these differences were accompanied by differential alterations of the genes regulating ECS tone. In conclusion, the levels of endocannabinoids are altered during obesity in a way partly correlating with changes of the genes related to their metabolism and activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain☆

PubMed Central

Cohen-Kutner, Moshe; Khomsky, Lena; Trus, Michael; Ben-Yehuda, Hila; Lenhard, James M.; Liang, Yin; Martin, Tonya; Atlas, Daphne

2014-01-01

Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38MAPK), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells. Daily i.p. injection of CB3 to ZDF rats inhibited the phosphorylation of JNK and p38MAPK, and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70S6K kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38MAPK activity in the absence of a change in plasma glucose implies a decrease in oxidative or neuroinflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK–AMPK–mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that by attenuating neuro-inflammatory processes in the brain Trx1 mimetic peptides could become beneficial for preventing neurological

Vitamin A status affects obesity development and hepatic expression of key genes for fuel metabolism in Zucker fatty rats.

PubMed

Zhang, Yan; Li, Rui; Li, Yang; Chen, Wei; Zhao, Shi; Chen, Guoxun

2012-08-01

We hypothesized that vitamin A (VA) status may affect obesity development. Male Zucker lean (ZL) and fatty (ZF) rats after weaning were fed a synthetic VA deficient (VAD) or VA sufficient (VAS) diet for 8 weeks before their plasma parameters and hepatic genes' expression were analyzed. The body mass (BM) of ZL or ZF rats fed the VAD diet was lower than that of their corresponding controls fed the VAS diet at 5 or 2 weeks, respectively. The VAD ZL and ZF rats had less food intake than the VAS rats after 5 weeks. The VAD ZL and ZF rats had lower plasma glucose, triglyceride, insulin, and leptin levels, as well as lower liver glycogen content, net mass of epididymal fat, and liver/BM and epididymal fat/BM ratios (ZL only) than their respective VAS controls. VAD rats had lower hepatic Cyp26a1, Srebp-1c, Fas, Scd1, Me1, Gck, and Pklr (ZL and ZF); and higher Igfbp1 (ZL and ZF), Pck1(ZF only), and G6pc (ZF only) mRNA levels than their respective VAS controls. We conclude that ZL and ZF rats responded differently to dietary VA deficiency. VA status affected obesity development and altered the expression of hepatic genes for fuel metabolism in ZF rats. The mechanisms will help us to combat metabolic diseases.

trans-trans Conjugated linoleic acid enriched soybean oil reduces fatty liver and lowers serum cholesterol in obese zucker rats.

PubMed

Gilbert, William; Gadang, Vidya; Proctor, Andrew; Jain, Vishal; Devareddy, Latha

2011-10-01

Conjugated linoleic acid (CLA) is a collection of octadecadienoic fatty acids that have been shown to possess numerous health benefits. The CLA used in our study was produced by the photoisomerization of soybean oil and consists of about 20% CLA; this CLA consists of 75% trans-trans (a mixture of t8,t10; t9,t11; t10,t12) isomers. This method could be readily used to increase the CLA content of all soybean oil used as a food ingredient. The objective of this study was to determine the effects of trans-trans CLA-rich soy oil, fed as a dietary supplement, on body composition, dyslipidemia, hepatic steatosis, and markers of glucose control and liver function of obese fa/fa Zucker rats. The trans-trans CLA-rich soy oil lowered the serum cholesterol and low density lipoprotein-cholesterol levels by 41 and 50%, respectively, when compared to obese controls. Trans-trans CLA-rich soy oil supplementation also lowered the liver lipid content significantly (P < 0.05) with a concomitant decrease in the liver weight in the obese rats. In addition, glycated hemoglobin values were improved in the group receiving CLA-enriched soybean oil in comparison to the obese control. PPAR-γ expression in white adipose tissue was unchanged. In conclusion, trans-trans CLA-rich soy oil was effective in lowering total liver lipids and serum cholesterol.

Manganese supplementation increases adiponectin and lowers ICAM-1 and creatinine blood levels in Zucker type 2 diabetic rats, and downregulates ICAM-1 by upregulating adiponectin multimerization protein (DsbA-L) in endothelial cells.

PubMed

Burlet, Elodie; Jain, Sushil K

2017-05-01

Blood and tissue levels of manganese (Mn) are lower in type 2 diabetic and atherosclerosis patients compared with healthy subjects. Adiponectin has anti-diabetic and anti-atherogenic properties. Impairment in Disulfide bond A-like protein (DsbA-L) is associated with low adiponectin levels and diabetes. This study investigates the hypothesis that the beneficial effects of Mn supplementation are mediated by adiponectin and DsbA-L. At 6 weeks of age, Male Zucker diabetic fatty rats (ZDF) were randomly divided into two groups: diabetic controls and Mn-supplemented diabetic rats. Each rat was supplemented with Mn (D+Mn, 16 mg/kg BW) or water (placebo, D+P) daily for 7 weeks by oral gavage. For cell culture studies, Human Umbilical Vein Endothelial Cells (HUVEC) or 3T3L1 adipocytes were pretreated with Mn (0-10 µM MnCl 2 ) for 24 h, followed by high glucose (HG, 25 mM) or normal glucose (5 mM) exposure for another 24 h. Mn supplementation resulted in higher adiponectin (p = 0.01), and lower ICAM-1 (p = 0.04) and lower creatinine (p = 0.04) blood levels compared to those in control ZDF rats. Mn-supplemented rats also caused reduced oxidative stress (ROS) and NADPH oxidase, and higher DsbA-L expression in the liver (p = 0.03) of ZDF rats compared to those in livers of control rats; however, Fe levels in liver were lower but not significant (p = 0.08). Similarly, treatment with high glucose (25 mM) caused a decrease in DsbA-L, which was prevented by Mn supplementation in HUVEC and adipocytes. Mechanistic studies with DsbA-L siRNA showed that the beneficial effects of Mn supplementation on ROS, NOX4, and ICAM-1 expression were abolished in DsbA-L knock-down HUVEC. These studies demonstrate that DsbA-L-linked adiponectin mediates the beneficial effects observed with Mn supplementation and provides evidence for a novel mechanism by which Mn supplementation can increase adiponectin and reduce the biomarkers of endothelial dysfunction in diabetes.

Effects on Glycemic Control in Impaired Wound Healing in Spontaneously Diabetic Torii (SDT) Fatty Rats.

PubMed

Katsuhiro, Miyajima; Hui Teoh, Soon; Yamashiro, Hideaki; Shinohara, Masami; Fatchiyah, Fatchiyah; Ohta, Takeshi; Yamada, Takahisa

2018-02-01

Impaired diabetic wound healing is an important issue in diabetic complications. The present study aims to evaluate the protective effect on glycemic control against impaired diabetic wound healing using a diabetic rat model. We investigated the wound healing process and effect on the impaired wound repair by glycemic control in the Spontaneously Diabetic Torii (SDT) fatty rat, which is a new animal model of obese type 2 diabetes and may be a good model for study impaired wound healing. Male SDT fatty rats at 15 weeks of age were administered orally with sodium glucose co-transporter (SGLT) 2 inhibitor for 3 weeks. Wounds were induced at 2 weeks after SGLT 2 inhibitor treatment, and the wound areas were periodically examined in morphological and histological analyses. The SDT fatty rats showed a delayed wound healing as compared with the normal rats, but a glycemic control improved the impaired wound healing. In histological analysis in the skin of SDT fatty rats showed severe infiltration of inflammatory cell, hemorrhage and many bacterial masses in the remaining and slight fibrosis of crust on skin tissue . Thought that this results skin performance to be a delay of crust formation and regeneration of epithelium; however, these findings were ameliorated in the SGLT 2 inhibitor treated group. Glycemic control is effective for treatment in diabetic wounds and the SDT fatty rat may be useful to investigate pathophysiological changes in impaired diabetic wound healing.

Esculetin prevents non-alcoholic fatty liver in diabetic mice fed high-fat diet.

PubMed

Choi, Ra-Yeong; Ham, Ju Ri; Lee, Mi-Kyung

2016-12-25

This study investigated the effects and mechanism of esculetin (6,7-dihydroxycoumarin) on non-alcoholic fatty liver in diabetic mice fed high-fat diet (HFD). The diabetic mice model was induced by injection of streptozotocin, after which they were fed HFD diet with or without esculetin for 11 weeks. Non-diabetic mice were provided a normal diet. Diabetes induced hepatic hypertrophy, lipid accumulation and droplets; however, esculetin reversed these changes. Esculetin treatment in diabetic mice fed HFD significantly down-regulated expression of lipid synthesis genes (Fasn, Dgat2 and Plpp2) and inflammation genes (Tlr4, Myd88, Nfkb, Tnfα and Il6). Moreover, the activities of hepatic lipid synthesis enzymes (fatty acid synthase and phosphatidate phosphohydrolase) and gluconeogenesis enzyme (glucose-6-phosphatase) in the esculetin group were decreased compared with the diabetic group. In addition, esculetin significantly reduced blood HbA 1c , serum cytokines (TNF-α and IL-6) and chemokine (MCP-1) levels compared with the diabetic group without changing the insulin content in serum and the pancreas. Hepatic SOD activity was lower and lipid peroxidation level was higher in the diabetic group than in the normal group; however, esculetin attenuates these differences. Overall, these results demonstrated that esculetin supplementation could protect against development of non-alcoholic fatty liver in diabetes via regulation of lipids, glucose and inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Opuntia ficus indica (nopal) attenuates hepatic steatosis and oxidative stress in obese Zucker (fa/fa) rats.

PubMed

Morán-Ramos, Sofía; Avila-Nava, Azalia; Tovar, Armando R; Pedraza-Chaverri, José; López-Romero, Patricia; Torres, Nimbe

2012-11-01

Nonalcoholic fatty liver disease (NAFLD) is associated with multiple factors such as obesity, insulin resistance, and oxidative stress. Nopal, a cactus plant widely consumed in the Mexican diet, is considered a functional food because of its antioxidant activity and ability to improve biomarkers of metabolic syndrome. The aim of this study was to assess the effect of nopal consumption on the development of hepatic steatosis and hepatic oxidative stress and on the regulation of genes involved in hepatic lipid metabolism. Obese Zucker (fa/fa) rats were fed a control diet or a diet containing 4% nopal for 7 wk. Rats fed the nopal-containing diet had ∼50% lower hepatic TG than the control group as well as a reduction in hepatomegaly and biomarkers of hepatocyte injury such as alanine and aspartate aminotransferases. Attenuation of hepatic steatosis by nopal consumption was accompanied by a higher serum concentration of adiponectin and a greater abundance of mRNA for genes involved in lipid oxidation and lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in liver. Hepatic reactive oxygen species and lipid peroxidation biomarkers were significantly lower in rats fed nopal compared with the control rats. Furthermore, rats fed the nopal diet had a lower postprandial serum insulin concentration and a greater liver phosphorylated protein kinase B (pAKT):AKT ratio in the postprandial state. This study suggests that nopal consumption attenuates hepatic steatosis by increasing fatty acid oxidation and VLDL synthesis, decreasing oxidative stress, and improving liver insulin signaling in obese Zucker (fa/fa) rats.

Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes

PubMed Central

Esterson, Yonah B.; Carey, Michelle; Boucai, Laura; Goyal, Akankasha; Raghavan, Pooja; Zhang, Kehao; Mehta, Deeksha; Feng, Daorong; Wu, Licheng; Kehlenbrink, Sylvia; Koppaka, Sudha; Kishore, Preeti

2016-01-01

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes. PMID:27207526

Plasma Fatty Acid–Binding Protein 4, Nonesterified Fatty Acids, and Incident Diabetes in Older Adults

PubMed Central

Djoussé, Luc; Khawaja, Owais; Bartz, Traci M.; Biggs, Mary L.; Ix, Joachim H.; Zieman, Susan J.; Kizer, Jorge R.; Tracy, Russell P.; Siscovick, David S.; Mukamal, Kenneth J.

2012-01-01

OBJECTIVE To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults. RESEARCH DESIGN AND METHODS We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992–2007) based on the use of hypoglycemic medications, fasting glucose ≥126 mg/dL, or nonfasting glucose ≥200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993. RESULTS Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10–1.65) for women and 1.45 (1.13–1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m2 (HR per SD: 1.78 [95% CI 1.13–2.81]). There was a modest and nonsignificant association of NEFA with diabetes (Ptrend = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12–2.53), and 1.63 (1.07–2.50) across consecutive tertiles of NEFA (Ptrend = 0.03). CONCLUSIONS Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up. PMID:22584136

Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults.

PubMed

Djoussé, Luc; Khawaja, Owais; Bartz, Traci M; Biggs, Mary L; Ix, Joachim H; Zieman, Susan J; Kizer, Jorge R; Tracy, Russell P; Siscovick, David S; Mukamal, Kenneth J

2012-08-01

To examine the relation of fatty acid-binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults. We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992-2007) based on the use of hypoglycemic medications, fasting glucose ≥ 126 mg/dL, or nonfasting glucose ≥ 200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993. Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10-1.65) for women and 1.45 (1.13-1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m(2) (HR per SD: 1.78 [95% CI 1.13-2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P(trend) = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12-2.53), and 1.63 (1.07-2.50) across consecutive tertiles of NEFA (P(trend) = 0.03). Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.

LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training.

PubMed

Sriwijitkamol, Apiradee; Ivy, John L; Christ-Roberts, Christine; DeFronzo, Ralph A; Mandarino, Lawrence J; Musi, Nicolas

2006-05-01

AMPK is a key regulator of fat and carbohydrate metabolism. It has been postulated that defects in AMPK signaling could be responsible for some of the metabolic abnormalities of type 2 diabetes. In this study, we examined whether insulin-resistant obese Zucker rats have abnormalities in the AMPK pathway. We compared AMPK and ACC phosphorylation and the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcriptional coactivator PPARgamma coactivator-1 (PGC-1) in gastrocnemius of sedentary obese Zucker rats and sedentary lean Zucker rats. We also examined whether 7 wk of exercise training on a treadmill reversed abnormalities in the AMPK pathway in obese Zucker rats. In the obese rats, AMPK phosphorylation was reduced by 45% compared with lean rats. Protein expression of the AMPK kinase LKB1 was also reduced in the muscle from obese rats by 43%. In obese rats, phosphorylation of ACC and protein expression of PGC-1alpha, two AMPK-regulated proteins, tended to be reduced by 50 (P = 0.07) and 35% (P = 0.1), respectively. There were no differences in AMPKalpha1, -alpha2, -beta1, -beta2, and -gamma3 protein content between lean and obese rats. Training caused a 1.5-fold increase in AMPKalpha1 protein content in the obese rats, although there was no effect of training on AMPK phosphorylation and the other AMPK isoforms. Furthermore, training also significantly increased LKB1 and PGC-1alpha protein content 2.8- and 2.5-fold, respectively, in the obese rats. LKB1 protein strongly correlated with hexokinase II activity (r = 0.75, P = 0.001), citrate synthase activity (r = 0.54, P = 0.02), and PGC-1alpha protein content (r = 0.81, P < 0.001). In summary, obese insulin-resistant rodents have abnormalities in the LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training.

Long-term AICAR administration and exercise prevents diabetes in ZDF rats.

PubMed

Pold, Rasmus; Jensen, Lasse S; Jessen, Niels; Buhl, Esben S; Schmitz, Ole; Flyvbjerg, Allan; Fujii, Nobuharu; Goodyear, Laurie J; Gotfredsen, Carsten F; Brand, Christian L; Lund, Sten

2005-04-01

Lifestyle interventions including exercise programs are cornerstones in the prevention of obesity-related diabetes. The AMP-activated protein kinase (AMPK) has been proposed to be responsible for many of the beneficial effects of exercise on glucose and lipid metabolism. The effects of long-term exercise training or 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside (AICAR) treatment, both known AMPK activators, on the development of diabetes in male Zucker diabetic fatty (ZDF) rats were examined. Five-week-old, pre-diabetic ZDF rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group. In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats (P < 0.01). In addition, pancreatic beta-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve beta-cell function. Our results suggest that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in beta-cell function associated with type 2 diabetes.

Assessment of the fatty liver index as an indicator of hepatic steatosis for predicting incident diabetes independently of insulin resistance in a Korean population.

PubMed

Jung, C H; Lee, W J; Hwang, J Y; Yu, J H; Shin, M S; Lee, M J; Jang, J E; Leem, J; Park, J-Y; Kim, H-K

2013-04-01

Fatty liver disease, especially non-alcoholic fatty liver disease, is considered to be the hepatic manifestation of the metabolic syndrome, both closely associated with insulin resistance. Furthermore, fatty liver disease assessed by ultrasonography is known to be a predictor of the development of Type 2 diabetes mellitus. However, it remains unclear whether fatty liver disease plays a role in the pathogenesis of Type 2 diabetes independently of insulin resistance. In this study, we investigated whether fatty liver disease assessed by the fatty liver index can predict the development of Type 2 diabetes independently of systemic insulin resistance. We examined the clinical and laboratory data of 7860 subjects without diabetes who underwent general routine health evaluations at the Asan Medical Center in 2007 and had returned for follow-up examinations in 2011. Fatty liver index was calculated using an equation that considers serum triglyceride levels, γ-glutamyltransferase, waist circumference and BMI. During a 4-year period, 457 incident diabetes cases (5.8%) were identified. The odds ratios for the development of Type 2 diabetes were significantly higher in the group with a fatty liver index ≥ 60 (fatty liver index-positive) than in the group with a fatty liver index < 20 (fatty liver index-negative) after adjusting for various confounding variables including homeostasis model assessment of insulin resistance. Odds ratios were significant regardless of the insulin resistance status at baseline. Our results suggest that fatty liver index as a simple surrogate indicator of hepatic steatosis is valuable in identifying subjects at high risk for Type 2 diabetes. In addition, fatty liver disease itself contributes to the development of Type 2 diabetes independently of systemic insulin resistance. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy

PubMed Central

Fillmore, N; Mori, J; Lopaschuk, G D

2014-01-01

Heart disease is a leading cause of death worldwide. In many forms of heart disease, including heart failure, ischaemic heart disease and diabetic cardiomyopathies, changes in cardiac mitochondrial energy metabolism contribute to contractile dysfunction and to a decrease in cardiac efficiency. Specific metabolic changes include a relative increase in cardiac fatty acid oxidation rates and an uncoupling of glycolysis from glucose oxidation. In heart failure, overall mitochondrial oxidative metabolism can be impaired while, in ischaemic heart disease, energy production is impaired due to a limitation of oxygen supply. In both of these conditions, residual mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation. In diabetes, the ratio of cardiac fatty acid oxidation to glucose oxidation also increases, although primarily due to an increase in fatty acid oxidation and an inhibition of glucose oxidation. Recent evidence suggests that therapeutically regulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation can improve cardiac function of the ischaemic heart, the failing heart and in diabetic cardiomyopathies. In this article, we review the cardiac mitochondrial energy metabolic changes that occur in these forms of heart disease, what role alterations in mitochondrial fatty acid oxidation have in contributing to cardiac dysfunction and the potential for targeting fatty acid oxidation to treat these forms of heart disease. LINKED ARTICLES This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24147975

Impulsive-choice patterns for food in genetically lean and obese Zucker rats

PubMed Central

Boomhower, Steven R.; Rasmussen, Erin B.; Doherty, Tiffany S.

2012-01-01

Behavioral-economic studies have shown that differences between lean and obese Zuckers in food consumption depend on the response requirement for food. Since a response requirement inherently increases the delay to reinforcement, differences in sensitivity to delay may also be a relevant mechanism of food consumption in the obese Zucker rat. Furthermore, the endocannabinoid neurotransmitter system has been implicated in impulsivity, but studies that attempt to characterize the effects of cannabinoid drugs (e.g., rimonabant) on impulsive choice may be limited by floor effects. The present study aimed to characterize impulsive-choice patterns for sucrose using an adjusting-delay procedure in genetically lean and obese Zuckers. Ten lean and ten obese Zucker rats chose between one lever that resulted in one pellet after a standard delay (either 1 s or 5 s) and a second lever that resulted in two or three pellets after an adjusting delay. After behavior stabilized under baseline, rimonabant (0–10 mg/kg) was administered prior to some choice sessions in the two-pellet condition. Under baseline, obese Zuckers made more impulsive choices than leans in three of the four standard-delay/pellet conditions. Additionally, in the 2-pellet condition, rimonabant increased impulsive choice in lean rats in the 1-s standard-delay condition; however, rimonabant decreased impulsive choice in obese rats in the 1-s and 5-s standard-delay conditions. These data suggest that genetic factors that influence impulsive choice are stronger in some choice conditions than others, and that the endocannabinoid system may be a relevant neuromechanism. PMID:23261877

Impulsive-choice patterns for food in genetically lean and obese Zucker rats.

PubMed

Boomhower, Steven R; Rasmussen, Erin B; Doherty, Tiffany S

2013-03-15

Behavioral-economic studies have shown that differences between lean and obese Zuckers in food consumption depend on the response requirement for food. Since a response requirement inherently increases the delay to reinforcement, differences in sensitivity to delay may also be a relevant mechanism of food consumption in the obese Zucker rat. Furthermore, the endocannabinoid neurotransmitter system has been implicated in impulsivity, but studies that attempt to characterize the effects of cannabinoid drugs (e.g., rimonabant) on impulsive choice may be limited by floor effects. The present study aimed to characterize impulsive-choice patterns for sucrose using an adjusting-delay procedure in genetically lean and obese Zuckers. Ten lean and ten obese Zucker rats chose between one lever that resulted in one pellet after a standard delay (either 1 s or 5 s) and a second lever that resulted in two or three pellets after an adjusting delay. After behavior stabilized under baseline, rimonabant (0-10 mg/kg) was administered prior to some choice sessions in the two-pellet condition. Under baseline, obese Zuckers made more impulsive choices than leans in three of the four standard-delay/pellet conditions. Additionally, in the 2-pellet condition, rimonabant increased impulsive choice in lean rats in the 1-s standard-delay condition; however, rimonabant decreased impulsive choice in obese rats in the 1-s and 5-s standard-delay conditions. These data suggest that genetic factors that influence impulsive choice are stronger in some choice conditions than others, and that the endocannabinoid system may be a relevant neuromechanism. Copyright © 2012 Elsevier B.V. All rights reserved.

Alterations of Na,K-ATPase isoenzymes in the rat diabetic neuropathy: protective effect of dietary supplementation with n-3 fatty acids.

PubMed

Gerbi, A; Maixent, J M; Barbey, O; Jamme, I; Pierlovisi, M; Coste, T; Pieroni, G; Nouvelot, A; Vague, P; Raccah, D

1998-08-01

Diabetic neuropathy is a degenerative complication of diabetes accompanied by an alteration of nerve conduction velocity (NCV) and Na,K-ATPase activity. The present study in rats was designed first to measure diabetes-induced abnormalities in Na,K-ATPase activity, isoenzyme expression, fatty acid content in sciatic nerve membranes, and NCV and second to assess the preventive ability of a fish oil-rich diet (rich in n-3 fatty acids) on these abnormalities. Diabetes was induced by intravenous streptozotocin injection. Diabetic animals (D) and nondiabetic control animals (C) were fed the standard rat chow either without supplementation or supplemented with either fish oil (DM, CM) or olive oil (DO, CO) at a daily dose of 0.5 g/kg by gavage during 8 weeks. Analysis of the fatty acid composition of purified sciatic nerve membranes from diabetic animals showed a decreased incorporation of C16:1(n-7) fatty acids and arachidonic acids. Fish oil supplementation changed the fatty acid content of sciatic nerve membranes, decreasing C18:2(n-6) fatty acids and preventing the decreases of arachidonic acids and C18:1(n-9) fatty acids. Protein expression of Na,K-ATPase alpha subunits, Na,K-ATPase activity, and ouabain affinity were assayed in purified sciatic nerve membranes from CO, DO, and DM. Na,K-ATPase activity was significantly lower in sciatic nerve membranes of diabetic rats and significantly restored in diabetic animals that received fish oil supplementation. Diabetes induced a specific decrease of alpha1- and alpha3-isoform activity and protein expression in sciatic nerve membranes. Fish oil supplementation restored partial activity and expression to varying degrees depending on the isoenzyme. These effects were associated with a significant beneficial effect on NCV. This study indicates that fish oil has beneficial effects on diabetes-induced alterations in sciatic nerve Na,K-ATPase activity and function.

Triglyceride, nonesterified fatty acids, and prediabetic neuropathy: role for oxidative-nitrosative stress.

PubMed

Lupachyk, Sergey; Watcho, Pierre; Hasanova, Nailia; Julius, Ulrich; Obrosova, Irina G

2012-04-15

Peripheral neuropathy develops in human subjects with prediabetes and metabolic syndrome before overt hyperglycemia. The contributions of impaired glucose tolerance and insulin signaling, hypertriglyceridemia and/or increased nonesterified fatty acids (NEFA), and hypercholesterolemia to this condition remain unknown. Niacin and its derivatives alleviate dyslipidemia with a minor effect on glucose homeostasis. This study evaluated the roles of impaired glucose tolerance versus dyslipidemia in prediabetic neuropathy using Zucker fatty (fa/fa) rats and the niacin derivative acipimox, as well as the interplay of hypertriglyceridemia, increased NEFA, and oxidative-nitrosative stress. Sixteen-week-old Zucker fatty rats with impaired glucose tolerance, obesity, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and increased NEFA displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. Acipimox (100 mg kg(-1) day(-1), 4 weeks) reduced serum insulin, NEFA, and triglyceride concentrations without affecting glucose tolerance and hypercholesterolemia. It alleviated sensory nerve conduction velocity deficit and changes in behavioral measures of sensory function and corrected oxidative-nitrosative stress, but not impaired insulin signaling, in peripheral nerve. Elevated NEFA increased total and mitochondrial superoxide production and NAD(P)H oxidase activity in cultured human Schwann cells. In conclusion, hypertriglyceridemia and/or increased NEFA concentrations cause prediabetic neuropathy through oxidative-nitrosative stress. Lipid-lowering agents and antioxidants may find a use in the management of this condition. Copyright © 2012 Elsevier Inc. All rights reserved.

Longitudinal associations of serum fatty acid composition with type 2 diabetes risk and markers of insulin secretion and sensitivity in the Finnish Diabetes Prevention Study.

PubMed

Takkunen, Markus J; Schwab, Ursula S; de Mello, Vanessa D F; Eriksson, Johan G; Lindström, Jaana; Tuomilehto, Jaakko; Uusitupa, Matti I J

2016-04-01

To examine the longitudinal associations of serum fatty acid composition with type 2 diabetes, insulin secretion and insulin sensitivity over several years. We conducted a prospective cohort study derived from the randomized Finnish Diabetes Prevention Study. Total serum fatty acid composition was measured using gas chromatography in 407 overweight, middle-aged people with impaired glucose tolerance at baseline (1993-1998) and annually during the intervention period (1994-2000). Longitudinal associations of 20 fatty acids and three desaturase activities (Δ5 (20:4n-6/20:3n-6, D5D), Δ6 (18:3n-6/18:2n-6, D6D), stearoyl-CoA desaturase-1 (16:1n-7/16:0, SCD-1)) with type 2 diabetes incidence, and estimates of insulin sensitivity (Matsuda), secretion (ratio of insulin and glucose concentrations) and β-cell function (disposition index) by an oral glucose tolerance test were analyzed using Cox regression and linear mixed models. We validated estimated D5D and D6D using a known FADS1 gene variant, rs174550. The baseline proportions of 20:5n-3, 22:5n-3 and 22:6n-3, and D5D were associated with lower incidence of type 2 diabetes during a median follow-up of 11 years (HR per 1SD: 0.72, 0.74, 0.73, 0.78, respectively, P ≤ 0.01). These long-chain omega-3 fatty acids and D5D were associated with higher insulin sensitivity in subsequent years but not with disposition index. Saturated, monounsaturated and trans fatty acids and 18:3n-3, 18:2n-6, SCD-1 and D6D were inconsistently associated with type 2 diabetes or related traits. Serum long-chain omega-3 fatty acids and D5D predicted lower type 2 diabetes incidence in people at a high risk of diabetes attending to an intervention study; a putative mechanism behind these associations was higher insulin sensitivity.

Impaired Ca2+ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase.

PubMed

Villalba, Nuria; Contreras, Cristina; Hernández, Medardo; García-Sacristán, Albino; Prieto, Dolores

2011-06-01

Diabetes is associated with an increased vascular tone usually involved in the pathogenesis of diabetic cardiovascular complications such as hypertension, stroke, coronary artery disease, or erectile dysfunction (ED). Enhanced contractility of penile erectile tissue has been associated with augmented activity of the RhoA/Rho kinase (RhoK) pathway in models of diabetes-associated ED. The present study assessed whether abnormal vasoconstriction in penile arteries from prediabetic obese Zucker rats (OZRs) is due to changes in the intracellular Ca(2+) concentration ([Ca(2+)](i)) and/or in myofilament Ca(2+) sensitivity. Penile arteries from OZRs and lean Zucker rats (LZRs) were mounted on microvascular myographs for simultaneous measurements of [Ca(2+)](i) and tension. The relationships between [Ca(2+)](i) and contraction for the α(1)-adrenergic vasoconstrictor phenylephrine (PE) were left shifted and steeper in OZRs compared with LZRs, although the magnitude of the contraction was similar in both groups. In contrast, the vasoconstriction induced by the thromboxane A(2) receptor agonist U-46619 was augmented in arteries from OZRs, and this increase was associated with an increase in both the sensitivity and maximum responses to Ca(2+). The RhoK inhibitor Y-27632 (10 μM) reduced the vasoconstriction induced by PE to a greater extent in OZRs than in LZRs, without altering Ca(2+). Y-27632 inhibited with a greater potency the contraction elicited by high KCl in arteries from OZRs compared with LZRs without changing [Ca(2+)](i). RhoK-II expression was augmented in arteries from OZRs. These results suggest receptor-specific changes in the Ca(2+) handling of penile arteries under conditions of metabolic syndrome. Whereas augmented vasoconstriction upon activation of the thromboxane A(2) receptor is coupled to enhanced Ca(2+) entry, a RhoK-mediated enhancement of myofilament Ca(2+) sensitivity is coupled with the α(1)-adrenergic vasoconstriction in penile arteries from OZRs.

The persistence of fatty liver has a differential impact on the development of diabetes: The Kangbuk Samsung Health Study.

PubMed

Bae, Ji Cheol; Han, Ji Min; Cho, Jung Hwan; Kwon, Hyemi; Park, Se Eun; Park, Cheol-Young; Lee, Won-Young; Oh, Ki-Won; Kwon, Sam; Park, Sung-Woo; Rhee, Eun Jung

2018-01-01

To evaluate whether variable fatty liver status over time influence the risk of type 2 diabetes differently. We analyzed the data from 7849 subjects without type 2 diabetes who underwent comprehensive health check-ups annually for 5 years. All subjects had an abdominal ultrasonography annually. The risk of incident diabetes was assessed in individuals with sustained non-alcoholic fatty liver disease (NAFLD), individuals with changed fatty liver status (intermittent NAFLD group), and individuals who did not have NAFLD (never NAFLD group) during the study period. A subgroup analysis was done in subjects of the intermittent NAFLD group. Incident diabetes was compared according to the number of time diagnosed as NAFLD by annual ultrasonography. During the mean follow-up of 4 years, subjects in the sustained NAFLD group had a HR of 1.50 (95% CI 1.13-1.98) for the development of diabetes compared with those in the never NAFLD group, whereas the risk was not higher in the intermittent NAFLD group (HR 0.99, 95% CI 0.76-1.31). When compared with the intermittent NAFLD group, multivariable adjusted HR for incident diabetes was 1.50 (95% CI 1.20-1.89) in the sustained NAFLD group. As the number of times diagnosed as NAFLD increased, the proportion of subjects who developed diabetes also increased (p = .002). The presence of fatty liver was differentially associated with incident diabetes based on its duration. The persistence of fatty liver status is an important factor for an independent association between NAFLD and incident diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Leucine and Protein Metabolism in Obese Zucker Rats

PubMed Central

She, Pengxiang; Olson, Kristine C.; Kadota, Yoshihiro; Inukai, Ayami; Shimomura, Yoshiharu; Hoppel, Charles L.; Adams, Sean H.; Kawamata, Yasuko; Matsumoto, Hideki; Sakai, Ryosei; Lang, Charles H.; Lynch, Christopher J.

2013-01-01

Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-14C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (∼300%), but lower plantaris and gastrocnemius masses (−21–24%). Plasma BCAAs and BCKAs were elevated 45–69% and ∼100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (−47–66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23–29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193–418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and

The Combined Intervention with Germinated Vigna radiata and Aerobic Interval Training Protocol Is an Effective Strategy for the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) and Other Alterations Related to the Metabolic Syndrome in Zucker Rats.

PubMed

Kapravelou, Garyfallia; Martínez, Rosario; Nebot, Elena; López-Jurado, María; Aranda, Pilar; Arrebola, Francisco; Cantarero, Samuel; Galisteo, Milagros; Porres, Jesus M

2017-07-19

Metabolic syndrome (MetS) is a group of related metabolic alterations that increase the risk of developing non-alcoholic fatty liver disease (NAFLD). Several lifestyle interventions based on dietary treatment with functional ingredients and physical activity are being studied as alternative or reinforcement treatments to the pharmacological ones actually in use. In the present experiment, the combined treatment with mung bean ( Vigna radiata ), a widely used legume with promising nutritional and health benefits that was included in the experimental diet as raw or 4 day-germinated seed flour, and aerobic interval training protocol (65-85% VO₂ max) has been tested in lean and obese Zucker rats following a 2 × 2 × 2 (2 phenotypes, 2 dietary interventions, 2 lifestyles) factorial ANOVA (Analysis of Variance) statistical analysis. Germination of V. radiata over a period of four days originated a significant protein hydrolysis leading to the appearance of low molecular weight peptides. The combination of 4 day-germinated V. radiata and aerobic interval training was more efficient compared to raw V. radiata at improving the aerobic capacity and physical performance, hepatic histology and functionality, and plasma lipid parameters as well as reverting the insulin resistance characteristic of the obese Zucker rat model. In conclusion, the joint intervention with legume sprouts and aerobic interval training protocol is an efficient treatment to improve the alterations of glucose and lipid metabolism as well as hepatic histology and functionality related to the development of NAFLD and the MetS.

Regulation of hepatic branched-chain alpha-keto acid dehydrogenase kinase in a rat model for type 2 diabetes mellitus at different stages of the disease.

PubMed

Doisaki, Masao; Katano, Yoshiaki; Nakano, Isao; Hirooka, Yoshiki; Itoh, Akihiro; Ishigami, Masatoshi; Hayashi, Kazuhiko; Goto, Hidemi; Fujita, Yuko; Kadota, Yoshihiro; Kitaura, Yasuyuki; Bajotto, Gustavo; Kazama, Shunsuke; Tamura, Tomohiro; Tamura, Noriko; Feng, Guo-Gang; Ishikawa, Naohisa; Shimomura, Yoshiharu

2010-03-05

Branched-chain alpha-keto acid dehydrogenase (BCKDH) kinase (BDK) is responsible for the regulation of BCKDH complex, which is the rate-limiting enzyme in the catabolism of branched-chain amino acids (BCAAs). In the present study, we investigated the expression and activity of hepatic BDK in spontaneous type 2 diabetes using hyperinsulinemic Zucker diabetic fatty rats aged 9weeks and hyperglycemic, but not hyperinsulinemic rats aged 18weeks. The abundance of hepatic BDK mRNA and total BDK protein did not correlate with changes in serum insulin concentrations. On the other hand, the amount of BDK bound to the complex and its kinase activity were correlated with alterations in serum insulin levels, suggesting that hyperinsulinemia upregulates hepatic BDK. The activity of BDK inversely corresponded with the BCKDH complex activity, which was suppressed in hyperinsulinemic rats. These results suggest that insulin regulates BCAA catabolism in type 2 diabetic rats by modulating the hepatic BDK activity. 2010 Elsevier Inc. All rights reserved.

Obesity decreases serum selenium levels in DMBA-induced mammary tumor using Obese Zucker Rat Model

USDA-ARS?s Scientific Manuscript database

Recently, we reported that obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. Several studies suggest that lower serum selenium may play an important role in increasing the risk of several types of cancers (e.g, colon, breast and prostate canc...

Dietary fat and the diabetic state alter insulin binding and the fatty acyl composition of the adipocyte plasma membrane.

PubMed Central

Field, C J; Ryan, E A; Thomson, A B; Clandinin, M T

1988-01-01

Control and diabetic rats were fed on semi-purified high-fat diets providing a polyunsaturated/saturated fatty acid ratio (P/S) of 1.0 or 0.25, to examine the effect of diet on the fatty acid composition of major phospholipids of the adipocyte plasma membrane. Feeding the high-P/S diet (P/S = 1.0) compared with the low-P/S diet (P/S = 0.25) increased the content of polyunsaturated fatty acids in membrane phospholipids in both control and diabetic animals. The diabetic state decreased the content of polyunsaturated fatty acids, particularly arachidonic acid, in adipocyte membrane phospholipids. The decrease in arachidonic acid in membrane phospholipids of diabetic animals tended to be normalized to within the control values when high-P/S diets were given. For control animals, altered plasma-membrane composition was associated with change in insulin binding, suggesting that change in plasma-membrane composition may have physiological consequences for insulin-stimulated functions in the adipocyte. PMID:3052424

Obese and Lean Zucker Rats Demonstrate Differential Sensitivity to Rates of Food Reinforcement in a Choice Procedure

PubMed Central

Buckley, Jessica L.; Rasmussen, Erin B.

2012-01-01

The obese Zucker rat carries two recessive fa alleles that result in the expression of an obese phenotype. Obese Zuckers have higher food intake than lean controls in free-feed studies in which rats have ready access to a large amount of one type of food. The present study examined differences in obese and lean Zucker rats using concurrent schedules of reinforcement, which more ecologically models food selection using two food choices that have limited, but generally predictable, availability. Lever-pressing of ten lean (Fa/Fa or Fa/fa) and ten obese (fa/fa) Zucker rats was placed under three concurrent variable interval variable interval (conc VI VI) schedules of sucrose and carrot reinforcement, in which the reinforcer ratios for 45-mg food pellets were 5:1, 1:1, and 1:5. Allocation of responses to the two food alternatives was characterized using the generalized matching equation, which allows sensitivity to reinforcer rates (a) and bias toward one alternative (log k) to be quantified. All rats showed a bias to sucrose, though there were no differences between lean and obese Zucker rats. In addition, obese Zucker rats exhibited higher sensitivity to reinforcement rates than lean rats. This efficient pattern of responding was related to overall higher deliveries of food pellets. Effective matching for food, then, may be another behavioral pattern that contributes to an obese phenotype. PMID:23046726

Regulation of palmitoyl-CoA chain elongation by clofibric acid in the liver of Zucker fa/fa rats.

PubMed

Toyama, Tomoaki; Kudo, Naomi; Mitsumoto, Atsushi; Kawashima, Yoichi

2005-05-01

The regulation of palmitoyl-CoA chain elongation (PCE) by clofibric acid [2-(4-chlorophenoxy)-2-methylpropionic acid] was investigated in comparison with stearoyl-CoA desaturase (SCD) in the liver of obese Zucker fa/fa rats. The proportion of oleic acid in the hepatic lipids of Zucker obese rats is 2.7 times higher than that of lean littermates. The activities of PCE and SCD in the liver of Zucker obese rats were markedly higher than in lean rats, and the hepatic uptake of 2-deoxyglucose (2-DG) was also higher in Zucker obese rats compared with lean rats. The increased activities of SCD and PCE in Zucker obese rats were due to the enhanced expression of mRNA of both SCD1 and rat FA elongase 2 (rELO2), but not SCD2 or rELO1. The proportion of oleic acid in the liver was significantly increased by the administration of clofibric acid to Zucker obese rats, and the hepatic PCE activity and rELO2 mRNA expression, but not the SCD activity or SCD1 mRNA expression, were increased in response to clofibric acid treatment. By contrast, the activities of both PCE and SCD and the mRNA expression of SCD1 and rELO2 in the liver were increased by the treatment of Zucker lean rats with clofibric acid. Multiple regression analysis, which was performed to determine the relationships involving PCE activity, SCD activity, and the proportion of oleic acid, revealed that the three parameters were significantly correlated and that the standardized partial regression coefficient of PCE was higher than that of SCD. These results indicate that oleic acid is synthesized by the concerted action of PCE and SCD and that PCE plays a crucial role in the formation of oleic acid when Zucker fa/fa rats are given clofibric acid.

Development of a sleeve gastrectomy weight loss model in obese Zucker rats.

PubMed

Lopez, Peter P; Nicholson, Susannah E; Burkhardt, Gabriel E; Johnson, Robert A; Johnson, Fruzsina K

2009-12-01

Obesity promotes the development of diabetes and cardiovascular disease. The most effective weight loss treatment is bariatric surgery, but results greatly vary depending on the procedure. Sleeve gastrectomy (SG) has recently emerged as a reduced risk weight loss procedure for super obese patients. However, the mechanism of weight loss from SG and its effects on obesity-induced complications are yet to be determined. Our goal was to develop an experimental model of SG in genetically obese rats. Male obese Zucker rats (400-500 g, leptin-insensitive) were anesthetized with isoflurane. After a midline laparotomy, the stomach was clamped, the greater curvature was excised, and a triple suture line was used to close the gastric remnant. Sham rats underwent laparotomy only. Metabolic parameters were followed for 14 d after surgery. Caloric intake and body weight decreased in SG rats over 14 d by 98 +/- 10 kcal/d and 74 +/- 14 g, respectively. Blood total cholesterol levels were lower in rats that lost weight. Furthermore, blood glucose levels were lower in rats that lost weight. Active ghrelin levels were unchanged in SG rats 14 d after surgery. These results show that SG promotes weight loss in obese Zucker rats. Furthermore, SG-induced weight loss is accompanied by improved plasma cholesterol and glucose profile. However, SG does not promote a prolonged decrease in ghrelin levels. These results suggest that SG is an effective weight loss procedure in leptin insensitivity to improve the lipid profile and decrease insulin resistance and these effects might be independent of changes in ghrelin levels.

Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study.

PubMed

Ma, Wenjie; Wu, Jason H Y; Wang, Qianyi; Lemaitre, Rozenn N; Mukamal, Kenneth J; Djoussé, Luc; King, Irena B; Song, Xiaoling; Biggs, Mary L; Delaney, Joseph A; Kizer, Jorge R; Siscovick, David S; Mozaffarian, Dariush

2015-01-01

Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes. We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs. In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively. At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with

Effect of combination treatment of S–amlodipine with peroxisome proliferator-activated receptor agonists on metabolic and cardiovascular parameters in Zucker fa/fa rats

PubMed Central

2014-01-01

Background Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, impaired glucose tolerance and insulin resistance associated with dyslipidemia and hypertension. The available drugs are not sufficiently efficacious in reducing cardiovascular risk and restoring normal glucose metabolism associated with type 2 diabetes as a mono- or a combination therapy. The present study examined the combined effects of an antihypertensive (S-Amlodipine) and an insulin-sensitizing agent, peroxisome proliferator-activated receptor (PPAR) agonists (Pioglitazone and Ragaglitazar), on cardiovascular risk factors in aged diabetic and insulin-resistant Zucker fa/fa rats. Methods Following combination treatment for 14 days, blood pressure (BP), serum glucose, total cholesterol and triglycerides were measured. Aortic ring study was conducted to determine the effect of combination treatments on phenylephrine-induced vasoconstriction and acetylcholine (Ach)-induced vasorelaxation. Results In combination, S-Amlodipine and Pioglitazone significantly reduced blood glucose (115.1 ± 6.6 vs. 81.7 ± 4.2), BP (184.4 ± 5.0 vs. 155.1 ± 5.0), serum triglycerides (362.5 ± 47.5 vs. 211.1 ± 23.7) and glucose intolerance when compared with vehicle treated Zucker fa/fa rats. Similar results were observed with the combination of S-Amlodipine and Ragaglitazar (Triglycerides, 362.5 ± 47.5 vs. 252.34 ± 27.86; BP, 184.4 ± 5.0 vs. 159.0 ± 8.0) except for serum glucose. ACh-induced vasorelaxation in aortic rings was also superior with both of the combinations compared to individual treatment. Furthermore, there was less body weight gain and food intake with S-Amlodipine and Pioglitazone combination in Zucker fa/fa rats. S-Amlodipine itself caused significant reduction in glucose (115.1 ± 6.6 vs. 89.7 ± 2.7) and BP (184.4 ± 5.0 vs. 156.1 ± 4.0) with improvement in insulin sensitivity observed through oral glucose

Topical fentanyl stimulates healing of ischemic wounds in diabetic rats

PubMed Central

FAROOQUI, Mariya; ERICSON, Marna E; GUPTA, Kalpna

2016-01-01

Background Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. Methods We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-PDGFR-β were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Results Fentanyl significantly promoted wound closure as compared to PBS. Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho PDGFR-β co-localized with CD31 co-staining for vasculature. Conclusions Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing. PMID:25266258

Assessment of the relationship between non-alcoholic fatty liver disease and diabetic complications.

PubMed

Yan, Li-Hui; Mu, Biao; Guan, Yue; Liu, Xinyu; Zhao, Nan; Pan, Da; Wang, Shao-Zhen

2016-11-01

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder of the liver. The relationship between NAFLD and type 2 diabetes remains largely unknown. The aim of the present study was to determine the incidence of complications arising from the interaction between NAFLD and type 2 diabetes. A total of 212 individuals with type 2 diabetes were included in the study. The presence of NAFLD was determined in individuals using abdominal ultrasonography for the diagnosis of fatty liver disease. Patients were divided into three groups based on the duration of diabetes and NAFLD diagnosis. Type 2 diabetes patients were placed in group A; patients with type 2 diabetes longer than NAFLD were placed in group B; and patients with NAFLD longer than type 2 diabetes were placed in group C. All individuals had undergone electrocardiogram, blood pressure measurements, and thorough medical history and physical examinations (Doppler ultrasound, electrophysiology, fundoscopy, cardiac computed tomography). Laboratory measurements included fasting blood glucose, glycated hemoglobin, oral glucose tolerance test, liver and renal function, lipid profile, and urinary albumin excretion. Compared with groups A and B, the patients of group C showed a higher prevalence of significant coronary artery disease and hypertension (P < 0.05). Compared with groups A and B, the patients of group C showed a lower prevalence of diabetic retinopathy and diabetic peripheral neuropathy (P < 0.05). There was no significant difference in the prevalence of diabetic nephropathy among the three groups (P > 0.05). NAFLD combined with type 2 diabetes is associated with the presence of significant coronary artery disease and hypertension. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 on hepatic steatosis in Zucker rats.

PubMed

Plaza-Diaz, Julio; Gomez-Llorente, Carolina; Abadia-Molina, Francisco; Saez-Lara, Maria Jose; Campaña-Martin, Laura; Muñoz-Quezada, Sergio; Romero, Fernando; Gil, Angel; Fontana, Luis

2014-01-01

We have previously described the safety and immunomodulatory effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 in healthy volunteers. The scope of this work was to evaluate the effects of these probiotic strains on the hepatic steatosis of obese rats. We used the Zucker rat as a genetic model of obesity. Zucker-Lepr(fa/fa) rats received one of three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo for 30 days. An additional group of Zucker-lean+/fa rats received a placebo for 30 days. No alterations in intestinal histology, in the epithelial, lamina propria, muscular layers of the ileal or colonic mucosa, or the submucosae, were observed in any of the experimental groups. Triacylglycerol content decreased in the liver of Zucker-Lepr(fa/fa) rats that were fed L. rhamnosus, B. breve, or the mixture of B. breve and L. paracasei. Likewise, the area corresponding to neutral lipids was significantly smaller in the liver of all four groups of Zucker-Lepr(fa/fa) rats that received probiotics than in rats fed the placebo. Zucker-Lepr(fa/fa) rats exhibited significantly greater serum LPS levels than Zucker-lean+/fa rats upon administration of placebo for 30 days. In contrast, all four groups of obese Zucker-Lepr(fa/fa) rats that received LAB strains exhibited serum LPS concentrations similar to those of Zucker-lean+/fa rats. Serum TNF-α levels decreased in the Zucker-Lepr(fa/fa) rats that received B. breve, L. rhamnosus, or the mixture, whereas L. paracasei feeding decreased IL-6 levels in the serum of Zucker-Lepr(fa/fa) rats. In conclusion, the probiotic strains reduced hepatic steatosis in part by lowering serum LPS, and had an anti-inflammatory effect in obese Zucker rats.

Depression-related behavioural and neuroendocrine changes in the Spontaneously Diabetic Torii (SDT) fatty rat, an animal model of Type 2 Diabetes Mellitus.

PubMed

Sakimura, Katsuya; Maekawa, Tatsuya; Sasagawa, Kazuo; Ishii, Yukihito; Kume, Shin-Ichi; Ohta, Takeshi

2018-05-14

Depression is one of the most common psychiatric diseases and is commonly comorbid with type 1 or 2 diabetes mellitus (DM). However, the pathophysiology underlying the depressive state in DM remains poorly understood. Animal models are useful tools to investigate the association between depression and DM. In the present study we investigated whether the Spontaneously Diabetic Torii (SDT) fatty rat, a novel animal model of type 2 DM, shows depression-related features. We assessed depression-like behaviour, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmitter levels in the brain. Behaviour was evaluated using a forced swimming test, and the HPA axis was evaluated with changes in plasma corticosterone levels after a swimming stress exposure or dexamethasone challenge. In addition, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, glutamate and γ-aminobutyric acid (GABA) concentrations in the frontal cortex, hippocampus and brain stem were measured. In the forced swimming test, SDT fatty rats exhibited increased duration of immobility compared with control Sprague-Dawley (SD) rats. Moreover, basal corticosterone levels were significantly elevated in SDT fatty compared with control SD rats. However, there were no stress-induced increases or changes in dexamethasone-induced suppression of corticosterone in SDT fatty compared with control SD rats. Furthermore, there were significant changes in 5-HT concentrations in the prefrontal cortex, and in GABA and glutamate concentrations in the hippocampus in SDT fatty compared with controls. The results of the present study suggest that the SDT fatty rat may be an appropriate model for diabetes with comorbid depression associated with neurotransmitter impairments and aberrant basal HPA hyperactivity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Role of Omega-3 Fatty Acids on Lipid Profile in Diabetic Dyslipidaemia: Single Blind, Randomised Clinical Trial.

PubMed

Chauhan, Shaylika; Kodali, Hanish; Noor, Jawad; Ramteke, Karuna; Gawai, Vidisha

2017-03-01

Diabetic dyslipidaemia is characterised by hypertriglyceridaemia, low High Density Lipoprotein (HDL), postprandial lipimea, small and dense LDL particles is considered to be a major predisposing factor for various macrovascular complications. Omega-3 fatty acids are fish oil derivative introduced in the market for dyslipidaemia associated with increased triglyceride level. To study the effect of omega-3 fatty acids on lipid profile in Type II diabetes patients. This study was prospective, single blind, randomized comparative trial. Hundred patients were randomized into three groups. Group I received metformin 500 mg twice daily and placebo, Group II received metformin 500 mg twice daily and omega-3 fatty acids (1 gram) once daily and the Group III received metformin 500 mg twice daily and omega-3 fatty acids (1 gram) twice daily. ANOVA test was applied for analysis. Group II was effective in reducing the triglyceride level from 144.59±14.18 mg/dl to 101±13.31 mg/dl which was significant as compared to Group I from 147.67±18.57 mg/dl to 145.8±19.86 mg/dl respectively. Group III containing 1 g of omega-3 fatty acids twice daily showed decrease from 144.83±22.17 mg/dl to 86±17.46 mg/dl and was more effective in reducing triglyceride levels than Group II containing 1 gram of omega-3 fatty acids once daily. Omega-3 fatty acids can be given in conjunction with metformin to reduce triglyceride levels in diabetic dyslipidaemia without any adverse drug reactions or any drug interaction. Omega-3 fatty acids were effective in reducing the triglyceride level significantly as compared to placebo. Two grams of omega-3 fatty acids were more effective than 1 gram of omega-3 fatty acids in reducing triglyceride levels.

Cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in obese Zucker rats.

PubMed

Overton, J M; Williams, T D; Chambers, J B; Rashotte, M E

2001-04-01

The primary purpose of the study was to test the hypothesis that reduced leptin signaling is necessary to elicit the cardiovascular and metabolic responses to fasting. Lean (Fa/?; normal leptin receptor; n = 7) and obese (fa/fa; mutated leptin receptor; n = 8) Zucker rats were instrumented with telemetry transmitters and housed in metabolic chambers at 23 degrees C (12:12-h light-dark cycle) for continuous (24 h) measurement of metabolic and cardiovascular variables. Before fasting, mean arterial pressure (MAP) was higher (MAP: obese = 103 +/- 3; lean = 94 +/- 1 mmHg), whereas oxygen consumption (VO(2): obese = 16.5 +/- 0.3; lean = 18.6 +/- 0.2 ml. min(-1). kg(-0.75)) was lower in obese Zucker rats compared with their lean controls. Two days of fasting had no effect on MAP in either lean or obese Zucker rats, whereas VO(2) (obese = -3.1 +/- 0.3; lean = -2.9 +/- 0.1 ml. min(-1). kg(-0.75)) and heart rate (HR: obese = -56 +/- 4; lean = -42 +/- 4 beats/min) were decreased markedly in both groups. Fasting increased HR variability both in lean (+1.8 +/- 0.4 ms) and obese (+2.6 +/- 0.3 ms) Zucker rats. After a 6-day period of ad libitum refeeding, when all parameters had returned to near baseline levels, the cardiovascular and metabolic responses to 2 days of thermoneutrality (ambient temperature 29 degrees C) were determined. Thermoneutrality reduced VO(2) (obese = -2.4 +/- 0.2; lean = -3.3 +/- 0.2 ml. min(-1). kg(-0.75)), HR (obese = -46 +/- 5; lean = -55 +/- 4 beats/min), and MAP (obese = -13 +/- 6; lean = -10 +/- 1 mmHg) similarly in lean and obese Zucker rats. The results indicate that the cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in Zucker rats and suggest that intact leptin signaling may not be requisite for the metabolic and cardiovascular responses to reduced energy intake.

Combined n-benzoyl-d-phenylalanine and metformin treatment reverses changes in the fatty acid composition of streptozotocin diabetic rats.

PubMed

Kumar, Natarajan Ashok; Pari, Leelavinothan

2006-01-01

The present investigation was carried out to evaluate the effect of N-benzoyl-D-phenylalanine (NBDP) and metformin on blood glucose, plasma insulin, and on the fatty acid composition of total lipids in the livers and kidneys of control and experimental diabetic rats. When compared with nondiabetic control rats, neonatal streptozotocin (nSTZ) diabetic rats showed a significant increase in blood glucose and decreased plasma insulin. Analysis of fatty acids revealed a significant increase in the concentration of palmitic, stearic, and oleic acids in liver and kidney, whereas linolenic and arachidonic acids were significantly decreased. In diabetic rats, the oral administration of combined NBDP/metformin for 6 wk decreased the high concentrations of palmitic, stearic, and oleic acids and elevated the low levels of linolenic and arachidonic acids. The results suggest that the NBDP/metformin combination exhibits both antidiabetic and antihyperlipidemic effects in nSTZ diabetic rats and prevents the fatty acid changes produced during diabetes.

Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes

PubMed Central

Tiano, Joseph P.; Delghingaro-Augusto, Viviane; Le May, Cedric; Liu, Suhuan; Kaw, Meenakshi K.; Khuder, Saja S.; Latour, Martin G.; Bhatt, Surabhi A.; Korach, Kenneth S.; Najjar, Sonia M.; Prentki, Marc; Mauvais-Jarvis, Franck

2011-01-01

The failure of pancreatic β cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from β cell failure. We previously found that the hormone 17β-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against β cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERβ in a rat β cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα–/–) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα–/– mice were predisposed to islet lipid accumulation and β cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited β cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent β cell failure in T2D. PMID:21747171

Peripheral Blood Mitochondrial DNA Damage as a Potential Noninvasive Biomarker of Diabetic Retinopathy

PubMed Central

Mishra, Manish; Lillvis, John; Seyoum, Berhane; Kowluru, Renu A.

2016-01-01

Purpose In the development of diabetic retinopathy, retinal mitochondria become dysfunctional, and mitochondrial DNA (mtDNA) is damaged. Because retinopathy is a progressive disease, and circulating glucose levels are high in diabetes, our aim was to investigate if peripheral blood mtDNA damage can serve as a potential biomarker of diabetic retinopathy. Methods Peripheral blood mtDNA damage was investigated by extended-length PCR in rats and mice, diabetic for 10 to 12 months (streptozotocin-induced, type 1 model), and in 12- and 40-week-old Zucker diabetic fatty rats (ZDF, type 2). Mitochondrial copy number (in gDNA) and transcription (in cDNA) were quantified by qPCR. Similar parameters were measured in blood from diabetic patients with/without retinopathy. Results Peripheral blood from diabetic rodents had significantly increased mtDNA damage and decreased copy numbers and transcription. Lipoic acid administration in diabetic rats, or Sod2 overexpression or MMP-9 knockdown in mice, the therapies that prevent diabetic retinopathy, also ameliorated blood mtDNA damage and restored copy numbers and transcription. Although blood from 40-week-old ZDF rats had significant mtDNA damage, 12-week-old rats had normal mtDNA. Diabetic patients with retinopathy had increased blood mtDNA damage, and decreased transcription and copy numbers compared with diabetic patients without retinopathy and nondiabetic individuals. Conclusions Type 1 diabetic rodents with oxidative stress modulated by pharmacologic/genetic means, and type 2 animal model and patients with/without diabetic retinopathy, demonstrate a strong relation between peripheral blood mtDNA damage and diabetic retinopathy, and suggest the possibility of use of peripheral blood mtDNA as a noninvasive biomarker of diabetic retinopathy. PMID:27494345

Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study12345

PubMed Central

Wu, Jason HY; Wang, Qianyi; Lemaitre, Rozenn N; Mukamal, Kenneth J; Djoussé, Luc; King, Irena B; Song, Xiaoling; Biggs, Mary L; Delaney, Joseph A; Kizer, Jorge R; Siscovick, David S; Mozaffarian, Dariush

2015-01-01

Background: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes. Objectives: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n–9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n–7), 7-hexadecenoic acid (16:1n–9), and vaccenic acid (18:1n–7)] and estimated dietary SFAs and MUFAs. Design: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively. Results: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs

Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus.

PubMed

Targher, Giovanni; Lonardo, Amedeo; Byrne, Christopher D

2018-02-01

Nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus are common diseases that often coexist and might act synergistically to increase the risk of hepatic and extra-hepatic clinical outcomes. NAFLD affects up to 70-80% of patients with type 2 diabetes mellitus and up to 30-40% of adults with type 1 diabetes mellitus. The coexistence of NAFLD and diabetes mellitus increases the risk of developing not only the more severe forms of NAFLD but also chronic vascular complications of diabetes mellitus. Indeed, substantial evidence links NAFLD with an increased risk of developing cardiovascular disease and other cardiac and arrhythmic complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus. NAFLD is also associated with an increased risk of developing microvascular diabetic complications, especially chronic kidney disease. This Review focuses on the strong association between NAFLD and the risk of chronic vascular complications in patients with type 1 diabetes mellitus or type 2 diabetes mellitus, thereby promoting an increased awareness of the extra-hepatic implications of this increasingly prevalent and burdensome liver disease. We also discuss the putative underlying mechanisms by which NAFLD contributes to vascular diseases, as well as the emerging role of changes in the gut microbiota (dysbiosis) in the pathogenesis of NAFLD and associated vascular diseases.

Submandibular Gland and Caries Susceptibility in the Obese Zucker Rat

PubMed Central

Mozaffari, Mahmood S.; Abdelsayed, Rafik; Zakhary, Ibrahim; El-Salanty, Mohammed; Liu, Jun Yao; Wimborne, Hereward; El-Marakby, Ahmed

2010-01-01

Background Obesity is a prevalent disorder characterized as marked insulin resistance and low grade inflammation. We tested the hypothesis that obesity upregulates inflammatory markers in the submandibular gland in association with derangements of its architecture and predisposition to caries in obese Zucker rats. We also examined the potential impact of chromium picolinate (Cr(Pic)3), a nutritional supplement suggested to improve glycemic control, on the aforementioned parameters. Design Male obese Zucker rats (OZR) were treated with diets lacking and containing 5 or 10 mg/kg chromium (as Cr(Pic)3) from 6 weeks to about 6 months of age; lean Zucker rats (LZR) served as controls. Thereafter, glycemic status, salivary tissue architecture and levels of several inflammatory markers were determined in association with caries susceptibility. Results OZR showed reduced insulin sensitivity, increased ratio of phospho-nuclear factor kappa B (NF-κB) to total NF-κB and increased intercellular adhesion molecule-1 level but similar histological features compared to LZR. Importantly, compared to LZR, OZR displayed rampant caries and a tendency for reduced dentin mineral density. Treatment of OZR with Cr(Pic)3 attenuated upregulation of these proinflammatory indicators in association with reduced severity of caries without improving insulin sensitivity. Conclusions Obesity promotes proinflammatory changes within the submandibular gland, without affecting glandular architecture, in association with rampant caries; Cr(Pic)3 treatment provided some protective effects. PMID:20973827

Higher cord blood levels of fatty acids in pregnant women with type 1 diabetes mellitus.

PubMed

Djelmis, Josip; Ivaniševic, Marina; Desoye, Gernot; van Poppel, Mireille; Berberovic, Edina; Soldo, Dragan; Oreskovic, Slavko

2018-05-01

Type 1 diabetes mellitus is associated with a disturbance of carbohydrate and lipid metabolism. To determine whether type 1 diabetes mellitus (T1DM) alters maternal and neonatal fatty acid levels. Observational study. Academic hospital. Sixty pregnant women (30 women with T1DM with good glycemic control and 30 healthy women) were included in the study. Maternal blood, umbilical vein and artery blood samples were collected immediately upon delivery. Following lipid extraction, the fatty acid profiles of the total fatty acid pool of maternal serum and umbilical vein and artery serum were determined by gas chromatography. Total fatty acid concentration in maternal serum did not differ between the study groups; it was significantly higher in umbilical vein serum of the T1DM group compared with that in the control group, median (interquartile range), T1DM: 2126.2 (1446.4 - 3181.3), control: 1073.8 (657.5 - 2226.0); (P<0.001) and in umbilical artery vein serum T1DM: 1805.7 (1393.1 - 2125.0), control: 990.0 (643.3 - 1668.0); (P<0.001). Composition of fatty acids in umbilical vein serum fatty acids showed significantly higher concentrations of saturated, monounsaturated and polyunsaturated fatty acids in the T1DM group than in compared with those in the control group (P=0.001). Also cord blood levels of leptin (P<0.001), C-peptide (P<0.001), and insulin resistance (P=0.015) were higher in the T1DM group compared to controls. The neonates born to T1DM mothers had higher concentrations of total fatty acids, saturated and monounsaturated fatty acids, as well as polyunsaturated fatty acids, compared to control group newborns.

Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes.

PubMed

Thaung, H P Aye; Baldi, J Chris; Wang, Heng-Yu; Hughes, Gillian; Cook, Rosalind F; Bussey, Carol T; Sheard, Phil W; Bahn, Andrew; Jones, Peter P; Schwenke, Daryl O; Lamberts, Regis R

2015-08-01

Elevated sympathetic nerve activity (SNA) coupled with dysregulated β-adrenoceptor (β-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the β-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to β-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular β1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial β2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac β-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Obesity measures, metabolic profiles and dietary fatty acids in lean and obese postmenopausal diabetic Asian Indian women.

PubMed

Ghosh, Arnab

2009-03-01

The present investigation was aimed to compare anthropometric, metabolic and dietary fatty acids profiles in lean and obese postmenopausal diabetic Asian Indian women. A total of 125 postmenopausal Asian Indian women (Group I: lean postmenopausal control, n = 50; Group II: lean postmenopausal diabetic, n = 40 and Group III: obese postmenopausal diabetic, n = 35) aged 40 years and above were studied. Anthropometric [height, weight, waist (WC) and hip circumference] metabolic [total cholesterol (TC), triglyceride (TG), high (HDL), low density lipoprotein (LDL) and fasting plasma glucose (FPG)] and dietary profiles were collected from each participant. Body mass index (BMI), waist-hip ratio (WHR) and conicity index (CI) were subsequently computed. Obesity was defined as women having a BMI > or = 25 kg/m2. An open-ended 24 h food recall schedule was used to collect nutrient information from each participant. Daily intake of nutrients including saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) were also estimated on weekly and monthly basis. Group I had significantly lower mean than both Group II and Group III for WC, WHR, CI, TC, TG, LDL, FPG and total carbohydrates. On the other hand, Group I had significantly greater mean than both Group II and Group III for UFA/SFA, MUFA/SFA and PUFA/SFA. Discriminant analysis had revealed that overall 88% of all cases were correctly (positively) classified in three groups using fatty acids and their ratios. It seems reasonable to argue that while dealing with postmenopausal diabetic women, clinicians should consider obesity measures, lipids and dietary fatty acids simultaneously to better comprehend clinical assessments and risk stratification.

Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats.

PubMed

Merroun, Ikram; Sánchez-González, Cristina; Martínez, Rosario; López-Chaves, Carlos; Porres, Jesús M; Aranda, Pilar; Llopis, Juan; Galisteo, Milagros; Zarzuelo, Antonio; Errami, Mohammed; López-Jurado, María

2013-11-01

Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome. Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed. Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers. Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome. © 2013.

Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

PubMed

Jenks, S J; Conway, B R; Hor, T J; Williamson, R M; McLachlan, S; Robertson, C; Morling, J R; Strachan, M W J; Price, J F

2014-09-01

We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Effect of Omega-3 Fatty Acids Dietary Supplementation on Ocular Surface and Tear Film in Diabetic Patients with Dry Eye.

PubMed

Georgakopoulos, Constantine D; Makri, Olga E; Pagoulatos, Dionisios; Vasilakis, Panagiotis; Peristeropoulou, Politimi; Kouli, Vasiliki; Eliopoulou, Maria I; Psachoulia, Caterina

2017-01-01

The objective of this study was to investigate the effect of dietary supplementation with omega-3 fatty acids on ocular surface and tear film in patients with type 2 diabetes suffering from dry eye. Thirty-six patients suffering from type 2 diabetes and moderate to severe dry eye syndrome were included in the study. Patients were assigned to receive omega-3 long-chain polyunsaturated fatty acids for 3 months. Tear film break-up time test, Schirmer-I test, and conjunctival impression cytology analysis were performed on all patients at baseline and after 1 and 3 months. The subjective symptoms of dry eye were evaluated with the Ocular Surface Disease Index (OSDI) questionnaire at the same time points. Patients' average age was 65.57 ± 4.27 years and the mean duration of diabetes was 14.85 ± 5.4 years. There was a statistically significant increase in Schirmer-I test results and tear break-up time score after 3 months of supplementary intake of omega-3 fatty acids compared to baseline (p < 0.05 and p < 0.001, respectively). Impression cytology demonstrated a significantly lower grade of conjunctival squamous cell metaplasia after 1 and 3 months of omega-3 fatty acids intake compared to baseline (p < 0.05 and p < 0.01, respectively). The OSDI score was statistically significant lower both at 1 and 3 months after omega-3 fatty acids supplementation compared to baseline (p < 0.001). Omega-3 fatty acids may effectively improve tear film characteristics, reverse ocular surface features, and alleviate the subjective symptoms associated with dry eye syndrome in patients with type 2 diabetes.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

PubMed Central

Firneisz, Gábor

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients. PMID:25083080

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

PubMed

Firneisz, Gábor

2014-07-21

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

Dietary ω-3 polyunsaturated fatty acids improves learning performance of diabetic rats by regulating the neuron excitability.

PubMed

Yang, R-H; Wang, F; Hou, X-H; Cao, Z-P; Wang, B; Xu, X-N; Hu, S-J

2012-06-14

Previous research has demonstrated that diabetes induced learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids (PUFA), have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. Sprague-Dawley rats were used in the present study to investigate the effect of fish oil supplementation on spatial learning and memory of streptozotocin (STZ)-induced diabetic rats with the Morris Water Maze. The excitability of CA1 pyramidal neurons and the related ionic currents was also examined. Diabetes impaired spatial learning and memory of rats. Diabetes decreased the sodium currents and increased the potassium currents, and further led to the reduction of excitability of CA1 pyramidal neurons, effects which may contribute to the behavioral deficits. Fish oil dietary supplementation decreased the transient currents and Kv4.2 expression in the hippocampus and partially improved learning performance of diabetic rats. The results of the present study suggested that sodium and potassium currents contributed to the inhibitory effect of diabetes on neuron excitability, further influencing learning and memory processing. Dietary fish oil may modulate the membrane excitability and is a possible strategy for preventing the impairments of diabetes on hippocampal function. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Metabolic responses with endothelin antagonism in a model of insulin resistance.

PubMed

Berthiaume, Nathalie; Wessale, Jerry L; Opgenorth, Terry J; Zinker, Bradley A

2005-06-01

Atrasentan, an endothelin antagonist, would have beneficial effects on metabolic responses in a model of insulin resistance. Zucker lean or fatty rats were maintained either on regular (lean and fatty control, n = 12) or atrasentan-treated water (5 mg/kg/d, fatty atrasentan, n = 13) for 6 weeks. There was no significant difference in water intake and body weight with the atrasentan-treated group compared with fatty controls. Although atrasentan had no effect on 3-hour fasting glucose levels, it reduced fasting insulin levels between weeks 2 and 4 of treatment by 53% (fatty control vs fatty atrasentan, P < .01). Atrasentan decreased the incremental area under the plasma glucose response curve ( Delta AUC) after a nutritionally complete meal tolerance test (MTT), by 28% in the atrasentan-treated group compared with fatty controls ( P < .05), and decreased the MTT-induced insulin Delta AUC by 63% in treated animals compared with the fatty control group ( P < .01). In addition, atrasentan significantly decreased the MTT-induced glucose-insulin index Delta AUC by 58% in treated rats compared with fatty controls ( P < .01). In summary, in the Zucker fatty rat, atrasentan significantly reduces (1) 3-hour fasting insulin levels at 4 weeks, (2) glucose and insulin MTT-induced Delta AUCs, and (3) the MTT-induced glucose-insulin index Delta AUC. These results demonstrate an improvement in hyperinsulinemia as well as in glucose tolerance and insulin sensitivity with chronic endothelin antagonism in a model of insulin resistance and suggest that chronic endothelin antagonism may have benefits in the treatment of insulin resistance and/or diabetes.

Elevated fasting plasma C-peptide occurs in non-diabetic individuals with fatty liver, irrespective of insulin resistance.

PubMed

Perseghin, G; Caumo, A; Lattuada, G; De Cobelli, F; Ntali, G; Esposito, A; Belloni, E; Canu, T; Ragogna, F; Scifo, P; Del Maschio, A; Luzi, L

2009-09-01

Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B-cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C-peptide, an index of fasting B-cell function, was related to intra-hepatic fat (IHF) content in non-diabetic humans. We assessed, retrospectively, fasting plasma C-peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy ((1)H-MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C-peptide (P < 0.005) and lower insulin sensitivity (HOMA2-%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C-peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2-%S. These data were analysed by conditional logistic regression which showed that, when HOMA2-%S was matched between groups, fasting C-peptide remained the only significant predictor of fatty liver. Non-diabetic individuals with fatty liver are characterized by increased fasting plasma C-peptide concentration, irrespective of their insulin resistant state.

Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity

PubMed Central

Wang, Yun; Botolin, Daniela; Xu, Jinghua; Christian, Barbara; Mitchell, Ernestine; Jayaprakasam, Bolleddula; Nair, Muraleedharan; Peters, Jeffery M.; Busik, Julia; Olson, L. Karl; Jump, Donald B.

2009-01-01

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor α (PPARα)-deficient mice establish that PPARα was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Δ5 desaturase (Δ5D), Δ6D, and Δ9D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Δ5D, Δ6D, and Δ9D. Only Δ9D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of L-type pyruvate kinase, Δ9D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Δ9D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lepob/ob), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Δ9D expression and the massive accumulation of monoun-saturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARα, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition. PMID:16790840

Mild and Short-Term Caloric Restriction Prevents Obesity-Induced Cardiomyopathy in Young Zucker Rats without Changing in Metabolites and Fatty Acids Cardiac Profile

PubMed Central

Ruiz-Hurtado, Gema; García-Prieto, Concha F.; Pulido-Olmo, Helena; Velasco-Martín, Juan P.; Villa-Valverde, Palmira; Fernández-Valle, María E.; Boscá, Lisardo; Fernández-Velasco, María; Regadera, Javier; Somoza, Beatriz; Fernández-Alfonso, María S.

2017-01-01

Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30–65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile. PMID:28203206

Dietary fructans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats.

PubMed

Daubioul, Catherine; Rousseau, Nicolas; Demeure, Roger; Gallez, Bernard; Taper, Henryk; Declerck, Barbara; Delzenne, Nathalie

2002-05-01

This study was designed to compare the effects of dietary supplementation with nondigestible carbohydrates, differing in fermentability by colonic bacteria, on hepatic steatosis in growing obese Zucker rats. Male Zucker fa/fa rats were divided into three groups: a control group that received the basal diet, a fructan group that received 10 g highly fermented Synergy 1/100 g diet and a cellulose group that received 10 g poorly fermented Vivapur Microcrystalline cellulose/100 g diet. Rats consuming fructan had a lower energy intake, a lower body weight and less triacylglycerol accumulation in the liver as assessed in vivo by nuclear magnetic resonance (NMR) spectroscopy, and ex vivo by biochemical and histochemical analysis compared with the control and/or cellulose groups. The high fermentation of fructans compared with cellulose was reflected by greater cecal contents and by a twofold greater propionate concentration in the portal vein of rats fed fructan compared with those fed cellulose. By measuring the capacity of hepatocytes isolated from liver of Zucker rats to synthesize triglycerides or total lipids from different precursors, we showed that propionate, at the concentrations measured in the portal vein of rats treated with fructan, selectively decreased the incorporation of acetate into total lipids, a phenomenon that could contribute, along with the lower energy intake, to less triglyceride accumulation in the liver of obese Zucker rats fed dietary fructans.

TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity.

PubMed

Yamamoto, K; Uchida, S; Kitano, K; Fukuhara, N; Okumura-Kitajima, L; Gunji, E; Kozakai, A; Tomoike, H; Kojima, N; Asami, J; Toyoda, H; Arai, M; Takahashi, T; Takahashi, K

2011-09-01

The renal sodium-glucose cotransporter 2 (SGLT2) plays an important role in the reuptake of filtered glucose in the proximal tubule and therefore may be an attractive target for the treatment of diabetes mellitus. This study characterizes the pharmacological profile of TS-071 ((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol hydrate), a novel SGLT2 inhibitor in vitro and in vivo. Inhibition of glucose uptake by TS-071 was studied in CHO-K1 cells stably expressing either human SGLT1 or SGLT2. Single oral dosing studies were performed in rats, mice and dogs to assess the abilities of TS-071 to increase urinary glucose excretion and to lower plasma glucose levels. TS-071 inhibited SGLT2 activity in a concentration-dependent manner and was a potent and highly selective inhibitor of SGLT2. Orally administered TS-071 increased urinary glucose excretion in Zucker fatty rats and beagle dogs at doses of 0.3 and 0.03 mg·kg(-1) respectively. TS-071 improved glucose tolerance in Zucker fatty rats without stimulating insulin secretion and reduced hyperglycaemia in streptozotocin (STZ)-induced diabetic rats and db/db mice at a dose of 0.3 mg·kg(-1). These data indicate that TS-071 is a potent and selective SGLT2 inhibitor that improves glucose levels in rodent models of type 1 and 2 diabetes and may be useful for the treatment for diabetes mellitus. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis.

PubMed

Hernández Vera, Rodrigo; Vilahur, Gemma; Ferrer-Lorente, Raquel; Peña, Esther; Badimon, Lina

2012-09-01

Patients with diabetes mellitus have an increased risk of suffering atherothrombotic syndromes and are prone to clustering cardiovascular risk factors. However, despite their dysregulated glucose metabolism, intensive glycemic control has proven insufficient to reduce thrombotic complications. Therefore, we aimed to elucidate the determinants of thrombosis in a model of type 2 diabetes mellitus with cardiovascular risk factors clustering. Intravital microscopy was used to analyze thrombosis in vivo in Zucker diabetic fatty rats (ZD) and lean normoglycemic controls. Bone marrow (BM) transplants were performed to test the contribution of each compartment (blood or vessel wall) to thrombogenicity. ZD showed significantly increased thrombosis compared with lean normoglycemic controls. BM transplants demonstrated the key contribution of the hematopoietic compartment to increased thrombogenicity. Indeed, lean normoglycemic controls transplanted with ZD-BM showed increased thrombosis with normal glucose levels, whereas ZD transplanted with lean normoglycemic controls-BM showed reduced thrombosis despite presenting hyperglycemia. Significant alterations in megakaryopoiesis and platelet-endoplasmic reticulum stress proteins, protein disulfide isomerase and 78-kDa glucose-regulated protein, were detected in ZD, and increased tissue factor procoagulant activity was detected in plasma and whole blood of ZD. Our results indicate that diabetes mellitus with cardiovascular risk factor clustering favors BM production of hyperreactive platelets with altered protein disulfide isomerase and 78-kDa glucose-regulated protein expression that can contribute to increase thrombotic risk independently of blood glucose levels.

Free Fatty Acid-Induced PP2A Hyperactivity Selectively Impairs Hepatic Insulin Action on Glucose Metabolism

PubMed Central

Galbo, Thomas; Olsen, Grith Skytte; Quistorff, Bjørn; Nishimura, Erica

2011-01-01

In type 2 Diabetes (T2D) free fatty acids (FFAs) in plasma are increased and hepatic insulin resistance is “selective”, in the sense that the insulin-mediated decrease of glucose production is blunted while insulin's effect on stimulating lipogenesis is maintained. We investigated the molecular mechanisms underlying this pathogenic paradox. Primary rat hepatocytes were exposed to palmitate for twenty hours. To establish the physiological relevance of the in vitro findings, we also studied insulin-resistant Zucker Diabetic Fatty (ZDF) rats. While insulin-receptor phosphorylation was unaffected, activation of Akt and inactivation of the downstream targets Glycogen synthase kinase 3α (Gsk3α and Forkhead box O1 (FoxO1) was inhibited in palmitate-exposed cells. Accordingly, dose-response curves for insulin-mediated suppression of the FoxO1-induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin-stimulated glucose oxidation and glycogen synthesis were impaired. In contrast, similar to findings in human T2D, the ability of insulin to induce triglyceride (TG) accumulation and transcription of the enzymes that catalyze de novo lipogenesis and TG assembly was unaffected. Insulin-induction of these genes could, however, be blocked by inhibition of the atypical PKCs (aPKCs). The activity of the Akt-inactivating Protein Phosphatase 2A (PP2A) was increased in the insulin-resistant cells. Furthermore, inhibition of PP2A by specific inhibitors increased insulin-stimulated activation of Akt and phosphorylation of FoxO1 and Gsk3α. Finally, PP2A mRNA levels were increased in liver, muscle and adipose tissue, while PP2A activity was increased in liver and muscle tissue in insulin-resistant ZDF rats. In conclusion, our findings indicate that FFAs may cause a selective impairment of insulin action upon hepatic glucose metabolism by increasing PP2A activity. PMID:22087313

Diabetes mellitus and non-alcoholic fatty liver disease: the thread of Ariadne.

PubMed

Kosmidou, Maria; Milionis, Haralampos

2017-06-01

Non alcoholic fatty liver disease (NAFLD, the hepatic fat accumulation) and non alcoholic steatohepatitis (NASH, the aggressive form of liver steatosis plus inflammation and hepatocyte necrosis) are reaching epidemic dimensions in subjects with diabetes mellitus (DM). Taking into account that the incidence of DM increases worldwide, these entities represent major health problems. There is accumulating evidence that diabetic subjects with NASH are at increased risk not only for cardiovascular disease compications but also for cirrhosis and hepatocellular cancer. On the other hand, the presence of NAFLD correlates with an increased risk for the development of DM. The most-widely accepted pathophysiological mechanisms relating DM and NAFLD include central obesity and insulin resistanc, but new insights are under scrutiny. Therapeutic modalities used for the management of diabetes have been studied for their impact on NAFLD/NASH and both neutral and beneficial effects have been reported. In this review, we discuss issues regarding the epidemiology, the pathophysiological pathways relating NAFLD with DM and consider strategies that may be useful in the management of NAFLD in the diabetic population.

Erythrocyte trans-fatty acids, type 2 diabetes and cardiovascular risk factors in middle-aged and older Chinese individuals

PubMed Central

Yu, D.X.; Sun, Q.; Ye, X.W.; Pan, A.; Zong, G.; Zhou, Y.H.; Li, H.X.; Hu, F.B.; Lin, X.

2013-01-01

Aims/hypothesis Few data are available about intakes and food sources of trans-fatty acids (TFAs) or their associations with cardiometabolic outcomes in Asian people who consume a prudent diet but are experiencing rapid nutritional transitions. We aimed to investigate the relationships between TFA biomarkers and type 2 diabetes and cardiovascular risk factors in Chinese individuals. Methods Erythrocyte fatty acids were measured by gas chromatography among 3,107 men and women (50–70 years) recruited from urban and rural areas in Beijing and Shanghai, China. Results Total trans-18:1 and two trans-18:2 isomers were detected and accounted for 0.37% of the total fatty acids in the erythrocytes. Concentrations of TFAs were higher in women than men, and in urban than rural residents. Of the TFAs, trans-18:1, but not trans-18:2, showed a modest association with dairy consumption (β=0.27), but not with other foods. After adjustment for BMI, social-demographic, lifestyle and dietary factors and other TFAs, erythrocyte trans-18:1 was shown to be associated with a lower risk of type 2 diabetes (OR comparing extreme quartiles=0.68, 95% CI=0.48, 0.97, ptrend=0.02), as well as 20–50% lower odds of central obesity, dyslipidaemia, hyperglycemia, insulin resistance and chronic inflammation. In contrast, trans-18:2 fatty acids were positively associated with high triacylglycerol (ptrend<0.001) and LDL-cholesterol (ptrend=0.03) levels, but not with diabetes and other cardiometabolic risk factors. Conclusions/interpretation Among middle-aged and older Chinese individuals with overall low erythrocyte TFAs levels, trans-18:1 might serve as a marker of dairy intake. Higher trans-18:1 levels were associated with a lower risk of type 2 diabetes, whereas higher trans-18:2 levels were associated with dyslipidaemia. PMID:22886370

Influence of non-alcoholic fatty liver disease on the development of diabetes mellitus.

PubMed

Kasturiratne, Anuradhani; Weerasinghe, Sanjaya; Dassanayake, Anuradha S; Rajindrajith, Shaman; de Silva, Arjuna P; Kato, Norihiro; Wickremasinghe, A Rajitha; de Silva, H Janaka

2013-01-01

Non-alcoholic fatty liver disease (NAFLD) is linked to metabolic syndrome, and is known to be associated with impaired fasting glycemia and diabetes mellitus. This prospective community-based study was conducted to determine the association between NAFLD and incidence of diabetes mellitus in an urban adult population in Sri Lanka. Participants of the Ragama Health Study cohort were assessed for NAFLD using established ultrasound criteria in 2007. Those who were free of diabetes at baseline were followed up for 3 years. Incidence rates of diabetes mellitus were compared between subjects with and without NAFLD at baseline. Out of 2984 subjects, 926 had NAFLD and 676 had diabetes in 2007. Of the 2276 subjects who were free of diabetes in 2007, 1914 were re-assessed in 2010. After 3 years, 104 out of 528 subjects with NAFLD and 138 out of 1314 subjects without NAFLD had developed diabetes mellitus de novo. Incidence rates of diabetes were respectively 64.2 and 34 per 1000 person-years of follow up for those with and without NAFLD. NAFLD was an independent predictor of developing diabetes mellitus. Other independent predictors were impaired fasting glycemia and dyslipidemia. Subjects with ultrasonically diagnosed NAFLD have an increased risk of developing diabetes mellitus. Intervention for NAFLD through lifestyle modification may prevent progression of the current diabetes epidemic. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Association of serum gamma-glutamyltransferase and alanine aminotransferase activities with risk of type 2 diabetes mellitus independent of fatty liver.

PubMed

Kim, Chul-Hee; Park, Joong-Yeol; Lee, Ki-Up; Kim, Jin-Ho; Kim, Hong-Kyu

2009-01-01

Although elevated serum concentrations of gamma-glutamyltrans- ferase (GGT) or alanine aminotransferase (ALT) have been associated with type 2 diabetes mellitus, it is unclear whether each is an independent predictor of type 2 diabetes or merely a surrogate marker for fatty liver or hepatic injury. We assessed clinical and laboratory findings in 3556 non-diabetic subjects (2217 men, 1339 women; age, 45.7 +/- 8.1 (range 20-79) years) without fatty liver or clinically significant hepatic dysfunction who underwent voluntary medical check-ups at a 5-year interval. The odds ratio of developing type 2 diabetes increased significantly with increasing GGT and ALT levels at baseline. In multiple logistic regression models adjusted for age, sex, alcohol consumption, smoking, body mass index (BMI), triglycerides, high-density lipoprotein (HDL)-cholesterol, fasting glucose, and ALT, the highest quartile of GGT remained significantly associated with type 2 diabetes. Compared with the first GGT quartile, the odds ratios of the second, third, and fourth GGT quartiles were 0.64 (95% CI, 0.25-1.65), 1.12 (0.45-2.78), and 3.07 (1.21-7.76), respectively. The adjusted odds ratios for the second, third, and fourth ALT quartiles in the same logistic regression model were 2.40 (0.83-6.94), 2.85 (1.03-7.90), and 4.31 (1.56-11.88), respectively. The risk of type 2 diabetes was additive with respect to GGT and ALT quartiles. Increased serum GGT and ALT levels are independent, additive risk factors for the development of type 2 diabetes mellitus in subjects without fatty liver or hepatic dysfunction. Copyright 2009 John Wiley & Sons, Ltd.

Fatty acid intake and its dietary sources in relation with markers of type 2 diabetes risk: The NEO study.

PubMed

Wanders, A J; Alssema, M; de Koning, E J P; le Cessie, S; de Vries, J H; Zock, P L; Rosendaal, F R; Heijer, M den; de Mutsert, R

2017-02-01

The aim of this study was to examine the relations between intakes of total, saturated, mono-unsaturated, poly-unsaturated and trans fatty acids (SFA, MUFA, PUFA and TFA), and their dietary sources (dairy, meat and plant) with markers of type 2 diabetes risk. This was a cross-sectional analysis of baseline data of 5675 non-diabetic, middle-aged participants of the Netherlands Epidemiology of Obesity (NEO) study. Associations between habitual dietary intake and fasting and postprandial blood glucose and insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), HOMA of β-cell function (HOMA-B) and Disposition Index were assessed through multivariable linear regression models with adjustments for demographic, lifestyle and dietary factors. Mean (s.d.) intakes in percent of energy (En%) were 34.4 (5.8) for total fatty acids, 12.4 (2.9) for SFA, 12.2 (2.4) for MUFA, 6.9 (1.9) for PUFA and 0.6 (0.2) for TFA. As compared with carbohydrates, only SFA was weakly inversely associated with fasting insulin, HOMA-IR and HOMA-B. When stratified by dietary source, all fatty acids from meat were positively associated with fasting insulin - total fatty acids meat (per 5 En%: 10.0%; 95% confidence interval: 4.0, 16.3), SFA meat (per 1 En%: 3.7%; 0.4, 7.2), MUFA meat (per 1 En%: 5.0%; 2.0, 8.1), PUFA meat (per 1 En%: 17.3%; 6.0, 29.7) and TFA meat (per 0.1 En%: 10.5%; 3.2, 18.3). Similarly, all fatty acids from meat were positively associated with HOMA-IR and HOMA-B and inversely with Disposition Index. Our study suggests that the relations between fatty acid intakes and markers of type 2 diabetes risk may depend on the dietary sources of the fatty acids. More epidemiological studies on diet and cardiometabolic disease are needed, addressing possible interactions between nutrients and their dietary sources.

Beneficial effects of gamma linolenic acid supplementation on nerve conduction velocity, Na+, K+ ATPase activity, and membrane fatty acid composition in sciatic nerve of diabetic rats.

PubMed

Coste, T; Pierlovisi, M; Leonardi, J; Dufayet, D; Gerbi, A; Lafont, H; Vague, P; Raccah, D

1999-07-01

Metabolic and vascular abnormalities are implicated in the pathogenesis of diabetic neuropathy. Two principal metabolic defects are altered lipid metabolism resulting from the impairment of delta-6-desaturase, which converts linoleic acid (LA) into gamma linolenic acid (GLA), and reduced nerve Na+, K+ ATPase activity. This reduction may be caused by a lack of incorporation of (n-6) fatty acids in membrane phospholipids. Because this ubiquitous enzyme maintains the membrane electrical potential and allows repolarization, disturbances in its activity can alter the process of nerve conduction velocity (NCV). We studied the effects of supplementation with GLA (260 mg per day) on NCV, fatty acid phospholipid composition, and Na+, K+ ATPase activity in streptozotocin-diabetic rats. Six groups of 10 rats were studied. Two groups served as controls supplemented with GLA or sunflower oil (GLA free). Two groups with different durations of diabetes were studied: 6 weeks with no supplementation and 12 weeks supplemented with sunflower oil. To test the ability of GLA to prevent or reverse the effects of diabetes, two groups of diabetic rats were supplemented with GLA, one group for 12 weeks and one group for 6 weeks, starting 6 weeks after diabetes induction. Diabetes resulted in a 25% decrease in NCV (P < 0.0001), a 45% decrease in Na+, K+ ATPase activity (P < 0.0001), and an abnormal phospholipid fatty acid composition. GLA restored NCV both in the prevention and reversal studies and partially restored Na+, K+ ATPase activity in the preventive treatment group (P < 0.0001). These effects were accompanied by a modification of phospholipid fatty acid composition in nerve membranes. Overall, the results suggest that membrane fatty acid composition plays a direct role in NCV and confirm the beneficial effect of GLA supplementation in diabetic neuropathy.

Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity.

PubMed

Chin, Melanie; Lee, Chun-Yue Ivy; Chuang, Jen-Chieh; Bumeister, Ron; Wigley, W Christian; Sonis, Stephen T; Ward, Keith W; Meyer, Colin

2013-06-15

Bardoxolone methyl and related triterpenoids are well tolerated and efficacious in numerous animal models potentially relevant to patients with Type 2 diabetes and chronic kidney disease. These agents enhance glucose control and regulate lipid accumulation in rodent models of diabetes and obesity, and improve renal function, reduce inflammation, and prevent structural injury in models of renal disease. However, a recent study in Zucker diabetic fatty (ZDF) rats noted poor tolerability with the bardoxolone methyl analog RTA 405 within 1 mo after treatment initiation, although this study was confounded in part by the use of an impure RTA 405 batch. To investigate these discordant observations, the present studies were conducted to further characterize triterpenoids in rodent models of diabetes and obesity. A follow-up study was conducted in ZDF rats with two related triterpenoids (RTA 405 and dh404) for 1.5 mo. Consistent with previous rodent experience, and in contrast to the more recent ZDF report, ZDF rats administered RTA 405 or dh404 exhibited no adverse clinical signs, had laboratory values similar to controls, and exhibited no evidence of adverse liver or kidney histopathology. Additionally, RTA 405 was well tolerated in streptozotocin-induced Type 1 diabetic rats and high-fat-diet-induced obese mice. The present results are consistent with the overall published body of data obtained with triterpenoids and provide further evidence that these molecules are well tolerated without adverse effects on hepatobiliary or renal function in rodent models of diabetes and obesity.

Non-alcoholic fatty liver disease (NAFLD) and significant hepatic fibrosis defined by non-invasive assessment in patients with type 2 diabetes.

PubMed

Sobhonslidsuk, Abhasnee; Pulsombat, Akharawit; Kaewdoung, Piyaporn; Petraksa, Supanna

2015-01-01

Non-alcoholic fatty liver disease (NAFLD), the most common liver problem in diabetes, is a risk factor for liver cancer. Diabetes, high body mass index (BMI) and old age can all contribute to NAFLD progression. Transient elastography (TE) is used for non-invasive fibrosis assessment. To identify the prevalence of NAFLD and significant hepatic fibrosis in diabetic patients and to assess associated factors. One hundred and forty-one diabetic and 60 normal subjects were screened. Fatty liver was diagnosed when increased hepatic echogenicity and vascular blunting were detected by ultrasonography. Liver stiffness measurement (LSM) representing hepatic fibrosis was assessed by TE. LSM ≥7 kPa was used to define significant hepatic fibrosis. Four cases were excluded due to positive hepatitis B viral markers and failed TE. Diabetic patients had higher BMI, systolic blood pressure, waist circumference and fasting glucose levels than normal subjects. Fatty liver was diagnosed in 82 (60.7%) diabetic patients but in none of the normal group. BMI (OR: 1.31; 95%CI: 1.02-1.69; p=0.038) and alanine aminotransferase (ALT)(OR: 1.14; 95%CI: 1.05-1.23; p=0.002) were associated with NAFLD. Diabetic patients with NAFLD had higher LSM than those without [5.99 (2.4) vs 4.76 (2.7) kPa, p=0.005)]. Significant hepatic fibrosis was more common in diabetic patients than in normal subjects [22 (16.1%) vs 1 (1.7%), p=0.002]. Aspartate aminotransferase (AST)(OR: 1.24; 95%CI: 1.07-1.42; p=0.003) was associated with significant hepatic fibrosis. Sixty and sixteen percent of diabetic patients were found to have NAFLD and significant hepatic fibrosis. High BMI and ALT levels are the predictors of NAFLD, and elevated AST level is associated with significant hepatic fibrosis.

Effects of the Soluble Fiber Complex PolyGlycopleX® on Glucose Homeostasis and Body Weight in Young Zucker Diabetic Rats

PubMed Central

Grover, Gary James; Koetzner, Lee; Wicks, Joan; Gahler, Roland J.; Lyon, Michael R.; Reimer, Raylene A.; Wood, Simon

2011-01-01

Dietary fiber can reduce insulin resistance, body weight, and hyperlipidemia depending on fiber type, water solubility, and viscosity. PolyGlycopleX® (PGX®) is a natural, novel water soluble, non-starch polysaccharide complex that with water forms a highly viscous gel compared to other naturally occurring dietary fiber. We determined the effect of dietary PGX® vs. cellulose and inulin on the early development of insulin resistance, body weight, hyperlipidemia, and glycemia-induced tissue damage in young Zucker diabetic rats (ZDFs) in fasted and non-fasted states. ZDFs (5 weeks old) were fed a diet containing 5% (wgt/wgt) cellulose, inulin, or PGX® for 8 weeks. Body weight, lipids, insulin, and glucose levels were determined throughout the study and homeostasis model assessment (HOMA) was used to measure insulin sensitivity throughout the study in fasted animals. At study termination, insulin sensitivity (oral glucose tolerance test, OGTT) and kidney, liver, and pancreatic histopathology were determined. Body weight and food intake were significantly reduced by PGX® vs. inulin and cellulose. Serum insulin in fasted and non-fasted states was significantly reduced by PGX® as was non-fasted blood glucose. Insulin resistance, measured as a HOMA score, was significantly reduced by PGX® in weeks 5 through 8 as well as terminal OGTT scores in fed and fasted states. Serum total cholesterol was also significantly reduced by PGX®. PGX® significantly reduced histological kidney and hepatic damage in addition to reduced hepatic steatosis and cholestasis. A greater mass of pancreatic β-cells was found in the PGX® group. PGX® therefore may be a useful dietary additive in the control of the development of the early development of the metabolic syndrome. PMID:21922008

PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease

PubMed Central

Dumont, Vincent; Tolvanen, Tuomas A.; Kuusela, Sara; Wang, Hong; Nyman, Tuula A.; Lindfors, Sonja; Tienari, Jukka; Nisen, Harry; Suetsugu, Shiro; Plomann, Markus; Kawachi, Hiroshi; Lehtonen, Sanna

2017-01-01

Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker diabetic fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.—Dumont, V., Tolvanen, T. A., Kuusela, S., Wang, H., Nyman, T. A., Lindfors, S., Tienari, J., Nisen, H., Suetsugu, S., Plomann, M., Kawachi, H., Lehtonen, S. PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. PMID:28550045

n-3 Fatty Acids Attenuate the Risk of Diabetes Associated With Elevated Serum Nonesterified Fatty Acids: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

Steffen, Brian T.; Steffen, Lyn M.; Zhou, Xia; Ouyang, Pamela; Weir, Natalie L.

2015-01-01

OBJECTIVE Chronically high nonesterified fatty acids (NEFAs) are a marker of metabolic dysfunction and likely increase risk of type 2 diabetes. By comparison, n-3 fatty acids (FAs) have been shown to have various health benefits and may protect against disease development. In 5,697 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we examined whether serum levels of NEFAs relate to risk of incident type 2 diabetes and further tested whether plasma n-3 FA levels may interact with this relation. RESEARCH DESIGN AND METHODS NEFAs were measured in fasting serum using an enzymatic colorimetric assay and phospholipid n-3 FAs eicosapentaenoic and docosahexaenoic acids were determined in plasma through gas chromatography-flame ionization detection in 5,697 MESA participants. Cox proportional hazards regression evaluated the association between NEFA levels and incident type 2 diabetes and whether plasma n-3 FAs modified this association adjusting for age, sex, race, education, field center, smoking, and alcohol use. RESULTS Over a mean 11.4 years of the study period, higher diabetes incidence was found across successive NEFA quartiles (Q) (hazard ratio [95% CI]): Q1, 1.0; Q2, 1.35 (1.07, 1.71); Q3, 1.58 (1.24, 2.00); and Q4, 1.86 (1.45, 2.38) (Ptrend < 0.001). A significant interaction of n-3 FAs on the relation between NEFAs and type 2 diabetes was also observed (Pinteraction = 0.03). For individuals with lower n-3 levels (<75th percentile), a higher risk of type 2 diabetes was observed across quartiles of NEFAs: Q1, 1.0; Q2, 1.41 (1.07, 1.84); Q3, 1.77 (1.35, 2.31); and Q4, 2.18 (1.65, 2.88) (Ptrend < 0.001). No significant associations were observed in those with n-3 FAs ≥75th percentile (Ptrend = 0.54). CONCLUSIONS NEFAs are a marker of type 2 diabetes and may have clinical utility for detecting risk of its development. The modifying influence of n-3 FAs suggests a protective effect against disease and/or metabolic dysfunction related to NEFAs and

Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects.

PubMed

Takase, Takahiro; Nakamura, Akinobu; Miyoshi, Hideaki; Yamamoto, Chiho; Atsumi, Tatsuya

2017-03-31

In this study, we investigated the ameliorating effects of ipragliflozin on fatty liver in patients with type 2 diabetes. The factors that influenced the amelioration of fatty liver were also examined. Analysis included data of 21 Japanese patients with type 2 diabetes obtained from our prospective observational study. After obtaining patients' informed consent, once-daily ipragliflozin (50 mg/day) was given for 16 weeks. In addition to several clinical parameters, body composition was also compared before and after 16 weeks of treatment. The extent of fatty liver was estimated using a fatty liver index (FLI). After 16 weeks, FLI significantly decreased, from 70.1 ± 19.4 to 60.3 ± 25.5 (p = 0.0009) as well as levels of fasting plasma glucose (FPG), HbA1c, body weight, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and fat mass. To reveal the factors influencing the FLI changes observed on ipragliflozin treatment, correlations between changes in FLI and several other measured parameters were examined. Changes in FPG (correlation coefficient = 0.4683, p = 0.0323) and HbA1c (correlation coefficient = 0.4383, p = 0.0469) showed significant positive correlations with changes in FLI. On the other hand, no correlations of changes in FLI were observed with body weight, VAT, SAT nor fat mass. In conclusion, ipragliflozin ameliorated FLI in Japanese patients with type 2 diabetes. Improvement in FLI was associated with that of glucose intolerance.

Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids

USDA-ARS?s Scientific Manuscript database

Type 2 diabetes (T2D) has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well described in T2D, effects on circulating signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of ...

[Therapeutic effect of saxagliptin in rat models of nonalcoholic fatty liver and type 2 diabetes].

PubMed

Liu, Yan; Zhang, Zhen; Chen, Rongping; Sun, Jia; Chen, Hong

2014-06-01

To observe the therapeutic effect of saxagliptin in a rat model of nonalcoholic fatty liver and type 2 diabetes and investigate the possible mechanism. Rats models of nonalcoholic fatty liver and type 2 diabetes established by feeding on a high glucose and fat diet and streptozotocin injection were treated with saxagliptin (daily dose of 10 mg/kg) gavage for 8 weeks, using saline as the control. After the treatment, fasting blood glucose, serum insulin, blood lipids, liver function, liver oxidative indices, and hepatic pathologies were evaluated in all the rats, and the expressions of Bcl-2 and Bax in the liver tissue were detected with immunohistochemistry and Western blotting. Compared with the model group, saxagliptin intervention significantly reduced blood glucose and HOMA-IR, improved the liver function and SOD activity (P<0.01), lowered the liver weight, liver index (P<0.01) and MDA level (P<0.05), and slightly lowered the body weight and blood lipids (P>0.05); AST level was similar between the normal control group and saxagliptin intervention group (P>0.05). HE and oil red staining showed obvious hepatic pathologies in the model group, and saxagliptin intervention significantly reduced lipid droplets in the hepatocytes and improved the structural damage of the liver. Hepatic Bax expression significantly increased and Bcl-2 expression decreased in the model group, and these changes were reversed by saxagliptin. Saxagliptin shows good therapeutic effect in rat models of nonalcoholic fatty liver and type 2 diabetes possibly by controlling blood glucose, lowering insulin resistance, alleviating hepatic oxidative stress and hepatocyte damage, and regulating the expression of apoptosis-related proteins.

Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes.

PubMed

Draganski, Andrew; Tar, Moses T; Villegas, Guillermo; Friedman, Joel M; Davies, Kelvin P

2018-05-01

Curcumin, a naturally occurring anti-inflammatory compound, has shown promise in pre-clinical studies to treat erectile dysfunction (ED) associated with type-1 diabetes. However, poor bioavailability following oral administration limits its efficacy. The present study evaluated the potential of topical application of curcumin-loaded nanoparticles (curc-np) to treat ED in a rat model of type-2 diabetes (T2D). Determine if topical application of curc-np treats ED in a T2D rat model and modulates expression of inflammatory markers. Curc-np (4 mg curcumin) or blank nanoparticles were applied every 2 days for 2 weeks to the shaved abdomen of 20-week-old Zucker diabetic fatty male rats (N = 5 per group). Lean Zucker diabetic fatty male rat controls were treated with blank nanoparticles (N = 5). Penetration of nanoparticles and curcumin release were confirmed by 2-photon fluorescence microscopy and histology. Erectile function was determined by measuring intracorporal pressure (ICP) normalized to systemic blood pressure (ICP/BP) following cavernous nerve stimulation. Corporal tissue was excised and reverse transcription and quantitative polymerase chain reaction used to determine expression of the following markers: nuclear factor (NF)-κβ, NF-κβ-activating protein (Nkap), NF erythroid 2-related factor-2, Kelch-like enoyl-CoA hydratase-associated protein-1, heme oxygenase-1 (HO-1), variable coding sequence-A1, phosphodiesterase-5, endothelial and neuronal nitric oxide synthase, Ras homolog gene family member A, and Rho-associated coiled-coil containing protein kinases-1 and -2. Erectile function by determination of ICP/BP and expression of molecular markers in corporal tissue by RT-qPCR. Nanoparticles penetrated the abdominal epidermis and persisted in hair follicles for 24 hours. Curc-np-treated animals exhibited higher average ICP/BP than animals treated with blank nanoparticles at all levels of stimulation and this was statistically significant (P < .05) at 0.75 m

n-3 Fatty acids attenuate the risk of diabetes associated with elevated serum nonesterified fatty acids: the multi-ethnic study of atherosclerosis.

PubMed

Steffen, Brian T; Steffen, Lyn M; Zhou, Xia; Ouyang, Pamela; Weir, Natalie L; Tsai, Michael Y

2015-04-01

Chronically high nonesterified fatty acids (NEFAs) are a marker of metabolic dysfunction and likely increase risk of type 2 diabetes. By comparison, n-3 fatty acids (FAs) have been shown to have various health benefits and may protect against disease development. In 5,697 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we examined whether serum levels of NEFAs relate to risk of incident type 2 diabetes and further tested whether plasma n-3 FA levels may interact with this relation. NEFAs were measured in fasting serum using an enzymatic colorimetric assay and phospholipid n-3 FAs eicosapentaenoic and docosahexaenoic acids were determined in plasma through gas chromatography-flame ionization detection in 5,697 MESA participants. Cox proportional hazards regression evaluated the association between NEFA levels and incident type 2 diabetes and whether plasma n-3 FAs modified this association adjusting for age, sex, race, education, field center, smoking, and alcohol use. Over a mean 11.4 years of the study period, higher diabetes incidence was found across successive NEFA quartiles (Q) (hazard ratio [95% CI]): Q1, 1.0; Q2, 1.35 (1.07, 1.71); Q3, 1.58 (1.24, 2.00); and Q4, 1.86 (1.45, 2.38) (P(trend) < 0.001). A significant interaction of n-3 FAs on the relation between NEFAs and type 2 diabetes was also observed (P(interaction) = 0.03). For individuals with lower n-3 levels (<75th percentile), a higher risk of type 2 diabetes was observed across quartiles of NEFAs: Q1, 1.0; Q2, 1.41 (1.07, 1.84); Q3, 1.77 (1.35, 2.31); and Q4, 2.18 (1.65, 2.88) (P(trend) < 0.001). No significant associations were observed in those with n-3 FAs ≥ 75th percentile (P(trend) = 0.54). NEFAs are a marker of type 2 diabetes and may have clinical utility for detecting risk of its development. The modifying influence of n-3 FAs suggests a protective effect against disease and/or metabolic dysfunction related to NEFAs and requires further study. © 2015 by the American

Normal Postprandial Nonesterified Fatty Acid Uptake in Muscles Despite Increased Circulating Fatty Acids in Type 2 Diabetes

PubMed Central

Labbé, Sébastien M.; Croteau, Etienne; Grenier-Larouche, Thomas; Frisch, Frédérique; Ouellet, René; Langlois, Réjean; Guérin, Brigitte; Turcotte, Eric E.; Carpentier, André C.

2011-01-01

OBJECTIVE Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes. RESEARCH DESIGN AND METHODS Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [11C]acetate and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups. RESULTS In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol ⋅ g−1 ⋅ min−1, P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol ⋅ g−1 ⋅ min−1, P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005). CONCLUSIONS Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon. PMID:21228312

Normal postprandial nonesterified fatty acid uptake in muscles despite increased circulating fatty acids in type 2 diabetes.

PubMed

Labbé, Sébastien M; Croteau, Etienne; Grenier-Larouche, Thomas; Frisch, Frédérique; Ouellet, René; Langlois, Réjean; Guérin, Brigitte; Turcotte, Eric E; Carpentier, André C

2011-02-01

Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes. Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [(11)C]acetate and 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups. In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol·g(-1)·min(-1), P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol·g(-1)·min(-1), P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005). Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon.

Maternal intake of fatty acids and their food sources during lactation and the risk of preclinical and clinical type 1 diabetes in the offspring.

PubMed

Niinistö, S; Takkinen, H-M; Uusitalo, L; Rautanen, J; Vainio, N; Ahonen, S; Nevalainen, J; Kenward, M G; Lumia, M; Simell, O; Veijola, R; Ilonen, J; Knip, M; Virtanen, S M

2015-08-01

We examined maternal dietary intake of fatty acids and foods which are sources of fatty acids during lactation and whether they are associated with the risk of preclinical and clinical type 1 diabetes in the offspring. The subjects comprised a cohort of 2,939 mother-child pairs from the prospective Type 1 Diabetes Prediction and Prevention Study. Composition of maternal diet during the third month of lactation was assessed by a validated food frequency questionnaire. Among the children with HLA-conferred susceptibility to type 1 diabetes, 172 developed preclinical and 81 clinical diabetes. Average follow-up for preclinical type 1 diabetes was 7.5 years (range 0.2-14.0 years) and for clinical type 1 diabetes 7.7 years (0.2-14.0 years). Maternal intake of fatty acids during lactation was not associated with the risk of type 1 diabetes in the offspring. After adjusting for putative confounders, maternal total consumption of red meat and meat products during lactation was associated both with increased risk for preclinical [hazard ratio (HR) 1.19, 95 % CI 1.02-1.40, p = 0.038] and clinical type 1 diabetes (HR 1.27, 95 % CI 1.06-1.52, p = 0.025). In particular, consumption of processed meat products showed an association with increased risk for type 1 diabetes (HR 1.23, 95 % CI 1.02-1.48, p = 0.045). Maternal use of vegetable oils was associated with increased risk for preclinical type 1 diabetes (HR 1.21, 95 % CI 1.03-1.41, p = 0.023). Maternal consumption of red meat, especially processed meat, during lactation may increase the risk of type 1 diabetes.

Effect of dietary n - 3 polyunsaturated fatty acids on oxidant/antioxidant status in macrosomic offspring of diabetic rats.

PubMed

Guermouche, B; Soulimane-Mokhtari, N A; Bouanane, S; Merzouk, H; Merzouk, S; Narce, M

2014-01-01

The aim of this work was to determine the effect of dietary n - 3 PUFA on oxidant/antioxidant status, in vitro very low and low density lipoprotein (VLDL-LDL), and VLDL-LDL-fatty acid composition in macrosomic pups of diabetic mothers. We hypothesized that n - 3 PUFA would improve oxidative stress in macrosomia. Diabetes was induced in female Wistar rats fed with the ISIO diet (control) or with the EPAX diet (enriched in n - 3 PUFAs), by streptozotocin. The macrosomic pups were killed at birth (day 0) and at adulthood (day 90). Lipid parameters and VLDL-LDL-fatty acid composition were investigated. The oxidant/antioxidant status was determined by measuring plasma oxygen radical absorbance capacity (ORAC), hydroperoxides, carbonyl proteins, and VLDL-LDL oxidation. Macrosomic rats of ISIO fed diabetic mothers showed an increase in plasma and VLDL-LDL-triglycerides and VLDL-LDL-cholesterol levels and altered VLDL-LDL-fatty acid composition. Plasma ORAC was low with high hydroperoxide and carbonyl protein levels. The in vitro oxidizability of VLDL-LDL was enhanced in these macrosomic rats. The EPAX diet corrected lipid parameters and improved oxidant/antioxidant status but increased VLDL-LDL susceptibility to oxidation. Macrosomia is associated with lipid abnormalities and oxidative stress. n - 3 PUFA exerts favorable effects on lipid metabolism and on the oxidant/antioxidant status of macrosomic rats. However, there are no evident effects on VLDL-LDL oxidation.

Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

PubMed Central

Leite, Nathalie C; Villela-Nogueira, Cristiane A; Cardoso, Claudia R L; Salles, Gil F

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus. PMID:25024596

n-3 Fatty Acids, Ventricular Arrhythmia–Related Events, and Fatal Myocardial Infarction in Postmyocardial Infarction Patients With Diabetes

PubMed Central

Kromhout, Daan; Geleijnse, Johanna M.; de Goede, Janette; Oude Griep, Linda M.; Mulder, Barbara J.M.; de Boer, Menko-Jan; Deckers, Jaap W.; Boersma, Eric; Zock, Peter L.; Giltay, Erik J.

2011-01-01

OBJECTIVE We carried out a secondary analysis in high-risk patients with a previous myocardial infarction (MI) and diabetes in the Alpha Omega Trial. We tested the hypothesis that in these patients an increased intake of the n-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid (ALA) will reduce the incidence of ventricular arrhythmias and fatal MI. RESEARCH DESIGN AND METHODS A subgroup of 1,014 post-MI patients with diabetes aged 60–80 years was randomly allocated to receive one of four trial margarines, three with an additional amount of n-3 fatty acids and one placebo for 40 months. The end points were ventricular arrhythmia–related events and fatal MI. The data were analyzed according to the intention-to-treat principle, using multivariable Cox proportional hazards models. RESULTS The patients consumed on average 18.6 g of margarine per day, which resulted in an additional intake of 223 mg EPA plus 149 mg DHA and/or 1.9 g ALA in the active treatment groups. During follow-up, 29 patients developed a ventricular arrhythmia–related events and 27 had a fatal MI. Compared with placebo patients, the EPA-DHA plus ALA group experienced less ventricular arrhythmia–related events (hazard ratio 0.16; 95% CI 0.04–0.69). These n-3 fatty acids also reduced the combined end-point ventricular arrhythmia–related events and fatal MI (0.28; 0.11–0.71). CONCLUSIONS Our results suggest that low-dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia–related events in post-MI patients with diabetes. PMID:22110169

The Effect of Meal Frequency on the Fatty Acid Composition of Serum Phospholipids in Patients with Type 2 Diabetes.

PubMed

Kahleova, Hana; Malinska, Hana; Kazdova, Ludmila; Belinova, Lenka; Tura, Andrea; Hill, Martin; Pelikanova, Terezie

2016-01-01

Fatty acids are important cellular constituents that can affect many metabolic processes relevant for the development of diabetes and its complications. We previously demonstrated a positive effect of eating just 2 meals a day, breakfast and lunch, compared to 6 small meals. The aim of this secondary analysis was to explore the effect of meal frequency on the fatty acid composition of serum phospholipids in subjects with type 2 diabetes (T2D). In a randomized, crossover study, we assigned 54 patients with T2D to follow one of 2 regimens of a hypocaloric diet (-500 kcal/day), each for 12 weeks: 6 meals (A6) or 2 meals a day, breakfast and lunch (B2). The diet in both regimens had the same macronutrient and energy content. The fatty acid composition of serum phospholipids was measured at weeks 0, 12, and 24, using gas liquid chromatography. Insulin sensitivity was derived as an oral glucose insulin sensitivity (OGIS) index. Saturated fatty acids (mainly myristic and palmitic acids) decreased (p < 0.001) and n6 polyunsaturated fatty acids increased (p < 0.001) in response to both regimens but more with B2 (p < 0.001 for both). Monounsaturated fatty acids decreased (p < 0.05) and n3 polyunsaturated fatty acids increased (p < 0.001) in response to both regimens, with no difference between the regimens. An increase in OGIS correlated positively with changes in the proportion of linoleic acid in B2. This correlation remained significant even after adjustment for changes in body mass index (BMI; r = +0.38; p = 0.012). We demonstrated that meal frequency affects the fatty acid composition of serum phospholipids. The B2 regimen had more marked positive effects, with saturated fatty acids and the ratio of saturated to unsaturated fatty acids decreasing more. The increase in linoleic acid could partly explain the insulin-sensitizing effect of B2 in T2D.

Effects of the Soluble Fiber Complex PolyGlycopleX on Glucose Homeostasis and Body Weight in Young Zucker Diabetic Rats.

PubMed

Grover, Gary James; Koetzner, Lee; Wicks, Joan; Gahler, Roland J; Lyon, Michael R; Reimer, Raylene A; Wood, Simon

2011-01-01

Dietary fiber can reduce insulin resistance, body weight, and hyperlipidemia depending on fiber type, water solubility, and viscosity. PolyGlycopleX(®) (PGX(®)) is a natural, novel water soluble, non-starch polysaccharide complex that with water forms a highly viscous gel compared to other naturally occurring dietary fiber. We determined the effect of dietary PGX(®) vs. cellulose and inulin on the early development of insulin resistance, body weight, hyperlipidemia, and glycemia-induced tissue damage in young Zucker diabetic rats (ZDFs) in fasted and non-fasted states. ZDFs (5 weeks old) were fed a diet containing 5% (wgt/wgt) cellulose, inulin, or PGX(®) for 8 weeks. Body weight, lipids, insulin, and glucose levels were determined throughout the study and homeostasis model assessment (HOMA) was used to measure insulin sensitivity throughout the study in fasted animals. At study termination, insulin sensitivity (oral glucose tolerance test, OGTT) and kidney, liver, and pancreatic histopathology were determined. Body weight and food intake were significantly reduced by PGX(®) vs. inulin and cellulose. Serum insulin in fasted and non-fasted states was significantly reduced by PGX(®) as was non-fasted blood glucose. Insulin resistance, measured as a HOMA score, was significantly reduced by PGX(®) in weeks 5 through 8 as well as terminal OGTT scores in fed and fasted states. Serum total cholesterol was also significantly reduced by PGX(®). PGX(®) significantly reduced histological kidney and hepatic damage in addition to reduced hepatic steatosis and cholestasis. A greater mass of pancreatic β-cells was found in the PGX(®) group. PGX(®) therefore may be a useful dietary additive in the control of the development of the early development of the metabolic syndrome.

Effects of habitual exercise on the eHsp72-induced release of inflammatory cytokines by macrophages from obese Zucker rats.

PubMed

Garcia, J J; Martin-Cordero, L; Hinchado, M D; Bote, M E; Ortega, E

2013-06-01

Regular exercise is a good non-pharmacological treatment of metabolic syndrome in that it improves obesity, diabetes, and inflammation. The 72 kDa extracellular heat shock protein (eHsp72) is released during exercise, thus stimulating the inflammatory responses. The aim of the present work was to evaluate the effect of regular exercise on the eHsp72-induced release of IL-1β, IL-6, and TNFα by macrophages from genetically obese Zucker rats (fa/fa) (ObZ), using lean Zucker (LZ) rats (Fa/fa) to provide reference values. ObZ presented a higher plasma concentration of eHsp72 than LZ, and exercise increased that concentration. In response to eHsp72, the macrophages from ObZ released less IL-1β and TNFα, but more IL-6, than macrophages from LZ. While eHsp72 stimulated the release of IL-1β, TNFα, and IL-6 in the macrophages from healthy LZ (with respect to the constitutive release), it inhibited the release of IL-1β and IL-6 in macrophages from ObZ. The habitual exercise improved the release of inflammatory cytokines by macrophages from ObZ in response to eHsp72 (it increased IL-1β and TNFα, and decreased IL-6), tending to values closer to those determined in healthy LZ. A deregulated macrophage inflammatory and stress response induced by eHsp72 underlies MS, and this is improved by habitual exercise. © Georg Thieme Verlag KG Stuttgart · New York.

Long-term physical exercise and atrial natriuretic peptide in obese Zucker rats.

PubMed

Pörsti, Ilkka; Kähönen, Mika; Wu, Xiumin; Arvola, Pertti; Ruskoaho, Heikki

2002-07-01

Endurance training increases natriuretic peptide synthesis in the hypertrophied myocardium of spontaneously hypertensive rats. We examined the effects of 22-week-long treadmill exercise on plasma and tissue atrial natriuretic peptide in Zucker rats, a model of genetic obesity and moderate hypertension without clear cardiac hypertrophy. The blood pressures of the animals were measured by the tail-cuff method, and plasma and tissue samples for the peptide determinations were taken at the end of the study. The training increased heart weight to body weight ratio, while atrial natriuretic peptide contents in the right and left atrium, ventricular tissue, and plasma did not change. The exercise prevented the elevation of blood pressure, which was observed in non-exercised obese Zucker rats, and also reduced blood pressure in the lean rats. In conclusion, these results suggest that in the absence of preceding myocardial hypertrophy, the long-term exercise-induced workload is not deleterious to the heart in experimental obesity, since no changes in plasma and tissue atrial natriuretic peptide were detected.

Proteome-based systems biology analysis of the diabetic mouse aorta reveals major changes in fatty acid biosynthesis as potential hallmark in diabetes mellitus-associated vascular disease.

PubMed

Husi, Holger; Van Agtmael, Tom; Mullen, William; Bahlmann, Ferdinand H; Schanstra, Joost P; Vlahou, Antonia; Delles, Christian; Perco, Paul; Mischak, Harald

2014-04-01

Macrovascular complications of diabetes mellitus are a major risk factor for cardiovascular morbidity and mortality. Currently, studies only partially described the molecular pathophysiology of diabetes mellitus-associated effects on vasculature. However, better understanding of systemic effects is essential in unraveling key molecular events in the vascular tissue responsible for disease onset and progression. Our overall aim was to get an all-encompassing view of diabetes mellitus-induced key molecular changes in the vasculature. An integrative proteomic and bioinformatics analysis of data from aortic vessels in the low-dose streptozotocin-induced diabetic mouse model (10 animals) was performed. We observed pronounced dysregulation of molecules involved in myogenesis, vascularization, hypertension, hypertrophy (associated with thickening of the aortic wall), and a substantial reduction of fatty acid storage. A novel finding is the pronounced downregulation of glycogen synthase kinase-3β (Gsk3β) and upregulation of molecules linked to the tricarboxylic acid cycle (eg, aspartate aminotransferase [Got2] and hydroxyacid-oxoacid transhydrogenase [Adhfe1]). In addition, pathways involving primary alcohols and amino acid breakdown are altered, potentially leading to ketone-body production. A number of these findings were validated immunohistochemically. Collectively, the data support the hypothesis that in this diabetic model, there is an overproduction of ketone-bodies within the vessels using an alternative tricarboxylic acid cycle-associated pathway, ultimately leading to the development of atherosclerosis. Streptozotocin-induced diabetes mellitus in animals leads to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway. This working hypothesis could form the basis for the development of novel therapeutic intervention and disease management approaches.

A comparative study of effects of omega-3 Fatty acids, alpha lipoic Acid and vitamin e in type 2 diabetes mellitus.

PubMed

Udupa, A; Nahar, P; Shah, S; Kshirsagar, M; Ghongane, B

2013-07-01

Diabetes Mellitus is a metabolic disorder characterized by abnormal lipid and glucose metabolism. Various modes of adjuvant therapy have been advocated to ameliorate insulin resistance. This study was intended to assess the effects of antioxidants; alpha lipoic acid (ALA), omega 3 fatty acid and vitamin E on parameters of insulin sensitivity (blood glucose and HbA1c) in patients of type 2 diabetes mellitus with documented insulin resistance. It was a prospective, randomized, double blind, placebo controlled, single centered study. 104 patients with type 2 diabetes mellitus with insulin resistance were recruited. They were given ALA, omega 3 fatty acid, vitamin E or placebo. Fasting blood glucose and HbA1c were measured at first visit (V1) and after 90 days (V2). Statistical analysis was carried out by paired t-test by using SPSS software version 11 (SPSS, Chicago, USA). Analysis of baseline (V1) vs. end of treatment period (V2) parameters, showed significant decrease in HbA1c in the three treatment group. We also observed decrease in fasting blood glucose in the three treatment group but it was not statistically significant (Gr. I = 0.51, Gr. II = 0.05, Gr. III = 0.22, Gr. IV = 0.88). ALA, Omega 3 fatty acid and vitamin E can be used as add on therapy in patients with type 2 diabetes mellitus to improve insulin sensitivity and lipid metabolism.

Combination of ciclopirox olamine and sphingosine-1-phosphate as granulation enhancer in diabetic wounds.

PubMed

Lim, Natalie Sheng Jie; Sham, Adeline; Chee, Stella Min Ling; Chan, Casey; Raghunath, Michael

2016-09-01

Granulation tissue formation requires a robust angiogenic response. As granulation tissue develops, collagen fibers are deposited and compacted. Forces generated in the wake of this process drive wound contraction to reduce the wound area. In diabetics, both angiogenesis and wound contraction are diminished leading to impaired wound healing. To emulate this pathology and to address it pharmacologically, we developed a wound healing model in the diabetic Zucker fatty rat and tested a topical proangiogenic strategy combining antifungal agent ciclopirox olamine (CPX) and lysophospholipid sphingosine-1-phosphate (S1P) to promote diabetic wound closure. In vitro, we demonstrated that CPX + S1P up-regulates a crucial driver of angiogenesis, hypoxia-inducible factor-1, in endothelial cells. Injection of CPX + S1P into subcutaneously implanted sponges in experimental rats showed, in an additive manner, a fivefold increased endothelial infiltration and lectin-perfused vessel length. We developed a splinted diabetic rodent model to achieve low wound contraction rates that are characteristic for the healing mode of diabetic ulcers in humans. We discovered specific dorsal sites that allowed for incremental full-thickness excisional wound depths from 1 mm (superficial) to 3 mm (deep). This enabled us to bring down wound contraction from 51% in superficial wounds to 8% in deep wounds. While the effects of topical gel treatment of CPX + S1P were masked by the rodent-characteristic dominant contraction in superficial wounds, they became clearly evident in deep diabetic wounds. Here, a fivefold increase of functional large vessels resulted in accelerated granulation tissue formulation, accompanied by a 40% increase of compacted thick collagen fibers. This was associated with substantially reduced matrix metalloproteinase-3 and -13 expression. These findings translated into a fivefold increase in granulation-driven contraction, promoting diabetic wound closure. With CPX

Effects of 2-AG on the reinforcing properties of wheel activity in obese and lean Zucker rats.

PubMed

Smith, Shilo L; Rasmussen, Erin B

2010-07-01

The endocannabinoid system plays a role in obesity, primarily by its role in food reward. Activity, also involved in obesity, seems to be at least partially controlled by the endocannabinoid system, but the relevant behavioral and neurochemical mechanisms have not been well established. This study represents an attempt to begin elucidating these mechanisms by examining the effects of an endogenous cannabinoid ligand, 2-arachidonoylglycerol (2-AG), on the reinforcing properties of exercise reinforcement in lean and obese Zucker rats. Ten obese and 10 lean Zucker rats pressed a locked door under a progressive ratio schedule of reinforcement that, when unlocked, provided access to a running wheel for 2-min periods. After baseline breakpoints were established, doses of 2-AG (0.3-3 mg/kg) were administered before experimental sessions. Obese rats exhibited lower breakpoints for wheel activity, lower response rates, and fewer revolutions compared with lean rats. 2-AG decreased breakpoints, response rates, and revolutions for obese rats, and revolutions only for lean rats. These data suggest that 2-AG may reduce the reinforcing properties of activity, and that obese Zuckers may show a greater sensitivity to 2-AG. The data also suggest that endocannabinoids may play a role in the reinforcing properties of exercise.

Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function.

PubMed

Hamann, Christine; Goettsch, Claudia; Mettelsiefen, Jan; Henkenjohann, Veit; Rauner, Martina; Hempel, Ute; Bernhardt, Ricardo; Fratzl-Zelman, Nadja; Roschger, Paul; Rammelt, Stefan; Günther, Klaus-Peter; Hofbauer, Lorenz C

2011-12-01

Patients with diabetes mellitus have an impaired bone metabolism; however, the underlying mechanisms are poorly understood. Here, we analyzed the impact of type 2 diabetes mellitus on bone physiology and regeneration using Zucker diabetic fatty (ZDF) rats, an established rat model of insulin-resistant type 2 diabetes mellitus. ZDF rats develop diabetes with vascular complications when fed a Western diet. In 21-wk-old diabetic rats, bone mineral density (BMD) was 22.5% (total) and 54.6% (trabecular) lower at the distal femur and 17.2% (total) and 20.4% (trabecular) lower at the lumbar spine, respectively, compared with nondiabetic animals. BMD distribution measured by backscattered electron imaging postmortem was not different between diabetic and nondiabetic rats, but evaluation of histomorphometric indexes revealed lower mineralized bone volume/tissue volume, trabecular thickness, and trabecular number. Osteoblast differentiation of diabetic rats was impaired based on lower alkaline phosphatase activity (-20%) and mineralized matrix formation (-55%). In addition, the expression of the osteoblast-specific genes bone morphogenetic protein-2, RUNX2, osteocalcin, and osteopontin was reduced by 40-80%. Osteoclast biology was not affected based on tartrate-resistant acidic phosphatase staining, pit formation assay, and gene profiling. To validate the implications of these molecular and cellular findings in a clinically relevant model, a subcritical bone defect of 3 mm was created at the left femur after stabilization with a four-hole plate, and bone regeneration was monitored by X-ray and microcomputed tomography analyses over 12 wk. While nondiabetic rats filled the defects by 57%, diabetic rats showed delayed bone regeneration with only 21% defect filling. In conclusion, we identified suppressed osteoblastogenesis as a cause and mechanism for low bone mass and impaired bone regeneration in a rat model of type 2 diabetes mellitus.

The effects of n-3 long-chain polyunsaturated fatty acid supplementation on AGEs and sRAGE in type 2 diabetes mellitus.

PubMed

Kurt, Asuman; Andican, Gülnur; Siva, Zeynep Oşar; Andican, Ahat; Burcak, Gülden

2016-12-01

In diabetes mellitus, chronic hyperglycemia leads to formation of advanced glycation end products (AGEs). Binding of AGEs to receptors of AGE (RAGE) causes deleterious effects. In populations with a high consumption of n-3 long-chain polyunsaturated fatty acids, a lower prevalence of diabetes mellitus has been reported. We aimed to investigate the effects of n-3 fatty acid (EPA and DHA) supplementation on the levels of AGEs (carboxymethyl lysine (CML) and pentosidine), sRAGE, and nuclear factor kappa B (NF-kB) in type 2 diabetes mellitus (T2DM). T2DM patients (n = 38) treated with oral hypoglycemic agents, without insulin were supplemented with n-3 fatty acids (1.2 g/day) for 2 months. Plasma CML, pentosidine, sRAGE, and NF-kB levels were measured by ELISA both before and after the supplementation. n-3 fatty acid supplementation significantly reduced fasting glucose (p < 0.01), glycated hemoglobin (HbA 1c ) (p < 0.05), and pentosidine (p < 0.05) levels. The supplementation induced percentage changes in pentosidine and HbA 1c and in pentosidine and creatinine were observed to be correlated (r = 0.349, p < 0.05) and (r = 0.377, p < 0.05), respectively. Waist circumference and systolic and diastolic pressures were significantly decreased due to n-3 supplementation (p < 0.001, p < 0.01, p < 0.01), respectively. Our results show that supplementation with n-3 fatty acid has beneficial effects on waist circumference; systolic and diastolic blood pressures; and the levels of glucose, HbA 1c , and pentosidine in T2DM patients. However, the supplementation failed to decrease these parameters to the reference ranges for healthy subjects. In addition, the supplementation did not appear to induce any significant differences in CML, sRAGE, or NF-kB.

Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

PubMed

Kim, Ji Yeon; Park, Keon Jae; Hwang, Joo-Yeon; Kim, Gyu Hee; Lee, DaeYeon; Lee, Yoo Jeong; Song, Eun Hyun; Yoo, Min-Gyu; Kim, Bong-Jo; Suh, Young Ho; Roh, Gu Seob; Gao, Bin; Kim, Won; Kim, Won-Ho

2017-08-01

Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications.

PubMed

Noh, Hyunjin; Yu, Mi Ra; Kim, Hyun Joo; Lee, Ji Hye; Park, Byoung-Won; Wu, I-Hsien; Matsumoto, Motonobu; King, George L

2017-07-01

Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2-adrenergic receptor (β2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, β2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective β2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced β-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The β2AR agonists enhanced β-arrestin2 and its interaction with IκBα, leading to downregulation of NF-κB. A siRNA specific for β-arrestin2 reversed β2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a β2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, β2AR agonists might have protective effects against diabetic renal and cardiovascular complications. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Free fatty acid receptors: emerging targets for treatment of diabetes and its complications

PubMed Central

Vangaveti, Venkat; Shashidhar, Venkatesh; Jarrod, Ghassan; Baune, Bernhard T.; Kennedy, R. Lee

2010-01-01

Fatty acids (FAs) are important as metabolic substrates and as structural components of biological membranes. However, they also function as signalling molecules. Recently, a series of G protein-coupled receptors (GPRs) for FAs has been described and characterized. These receptors have differing specificities for FAs of differing chain length and degree of saturation, for FA derivatives such as oleoylethanolamide, and for oxidized FAs. They are a critical component of the body's nutrient sensing apparatus, and small molecule agonists and antagonists of these receptors show considerable promise in the management of diabetes and its complications. Agonists of the long-chain free fatty acid receptors FFAR1 and GPR119 act as insulin secretagogues, both directly and by increasing incretins. Although, drugs acting at short-chain FFA receptors (FFAR2 and FFAR3) have not yet been developed, they are attractive targets as they regulate nutrient balance through effects in the intestine and adipose tissue. These include regulation of the secretion of cholecystokinin, peptide YY and leptin. Finally, GPR132 is a receptor for oxidized FAs, which may be a sensor of lipid overload and oxidative stress, and which is involved in atherosclerosis. Regulation of its signalling pathways with drugs may decrease the macrovascular risk experienced by diabetic patients. In summary, FA receptors are emerging drug targets that are involved in the regulation of nutrient status and carbohydrate tolerance, and modulators of these receptors may well figure prominently in the next generation of antidiabetic drugs. PMID:23148161

Unsaturated Fatty Acids Improve Atherosclerosis Markers in Obese and Overweight Non-diabetic Elderly Patients.

PubMed

de Oliveira, Patrícia Amante; Kovacs, Cristiane; Moreira, Priscila; Magnoni, Daniel; Saleh, Mohamed Hassan; Faintuch, Joel

2017-10-01

Several studies have demonstrated the benefits of replacing trans and saturated fats with unsaturated fatty acids on cardiovascular diseases. We aimed to demonstrate the effect of polyunsaturated and monounsaturated fat supplementation on the biochemical and endothelial markers of atherosclerotic disease in obese or overweight non-diabetic elderly patients. Seventy-nine patients were randomly divided into three groups: flaxseed oil, olive oil, and sunflower oil; patients in each group received 30 mL of oil for 90 days. Patients were subjected to anthropometric and bioimpedance assessments; biochemical and endothelial evaluations were performed through ultrasonography of the brachial artery and carotid artery for endothelium-dependent dilation and intima-media thickness assessment, respectively, before and after the intervention. The participants' usual diet remained unchanged. The flaxseed oil group had improved ultra-sensitive C-reactive protein levels (p = 0.074) and reduced carotid intima-media thickness (CIMT) (p = 0.028); the olive oil group exhibited an improved apolipoprotein (Apo)B/ApoA ratio (p = 0.021), reduced CIMT (p = 0.028), and improved flow-mediated vasodilation (FMV) (p = 0.054); and similarly, the sunflower oil group showed an improved ApoB/ApoA ratio (p = 0.024), reduced CIMT (p = 0.048), and improved FMV (p = 0.001). Unsaturated fatty acid supplementation using the three vegetable oils attenuated pro-inflammatory properties and improved prothrombotic conditions. Therefore, introducing or replacing saturated and trans fat with unsaturated fatty acids is beneficial for cardiovascular risk reduction in obese or overweight non-diabetic elderly people. Further studies are needed to determine which unsaturated fat best prevents cardiovascular disease in elderly patients.

ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity

PubMed Central

Bi, Xinyun; Li, Fanghong; Liu, Shanshan; Jin, Yan; Zhang, Xin; Yang, Tao; Dai, Yifan; Li, Xiaoxi; Zhao, Allan Zijian

2017-01-01

Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, mfat-1, normalized blood glucose and insulin levels for at least 182 days, blocked the development of autoimmunity, prevented lymphocyte infiltration into regenerated islets, and sharply elevated the expression of the β cell markers pancreatic and duodenal homeobox 1 (Pdx1) and paired box 4 (Pax4). The findings suggest that ω-3 PUFAs could potentially serve as a therapeutic modality for T1D. PMID:28375156

Creation and Transplantation of an Adipose-derived Stem Cell (ASC) Sheet in a Diabetic Wound-healing Model.

PubMed

Kato, Yuka; Iwata, Takanori; Washio, Kaoru; Yoshida, Toshiyuki; Kuroda, Hozue; Morikawa, Shunichi; Hamada, Mariko; Ikura, Kazuki; Kaibuchi, Nobuyuki; Yamato, Masayuki; Okano, Teruo; Uchigata, Yasuko

2017-08-04

Artificial skin has achieved considerable therapeutic results in clinical practice. However, artificial skin treatments for wounds in diabetic patients with impeded blood flow or with large wounds might be prolonged. Cell-based therapies have appeared as a new technique for the treatment of diabetic ulcers, and cell-sheet engineering has improved the efficacy of cell transplantation. A number of reports have suggested that adipose-derived stem cells (ASCs), a type of mesenchymal stromal cell (MSC), exhibit therapeutic potential due to their relative abundance in adipose tissue and their accessibility for collection when compared to MSCs from other tissues. Therefore, ASCs appear to be a good source of stem cells for therapeutic use. In this study, ASC sheets from the epididymal adipose fat of normal Lewis rats were successfully created using temperature-responsive culture dishes and normal culture medium containing ascorbic acid. The ASC sheets were transplanted into Zucker diabetic fatty (ZDF) rats, a rat model of type 2 diabetes and obesity, that exhibit diminished wound healing. A wound was created on the posterior cranial surface, ASC sheets were transplanted into the wound, and a bilayer artificial skin was used to cover the sheets. ZDF rats that received ASC sheets had better wound healing than ZDF rats without the transplantation of ASC sheets. This approach was limited because ASC sheets are sensitive to dry conditions, requiring the maintenance of a moist wound environment. Therefore, artificial skin was used to cover the ASC sheet to prevent drying. The allogenic transplantation of ASC sheets in combination with artificial skin might also be applicable to other intractable ulcers or burns, such as those observed with peripheral arterial disease and collagen disease, and might be administered to patients who are undernourished or are using steroids. Thus, this treatment might be the first step towards improving the therapeutic options for diabetic wound

Maternal dietary fatty acid intake during pregnancy and the risk of preclinical and clinical type 1 diabetes in the offspring.

PubMed

Niinistö, Sari; Takkinen, Hanna-Mari; Uusitalo, Liisa; Rautanen, Jenna; Nevalainen, Jaakko; Kenward, Michael G; Lumia, Mirka; Simell, Olli; Veijola, Riitta; Ilonen, Jorma; Knip, Mikael; Virtanen, Suvi M

2014-03-14

The aim of the present study was to examine the associations between the maternal intake of fatty acids during pregnancy and the risk of preclinical and clinical type 1 diabetes in the offspring. The study included 4887 children with human leucocyte antigen (HLA)-conferred type 1 diabetes susceptibility born during the years 1997-2004 from the Finnish Type 1 Diabetes Prediction and Prevention Study. Maternal diet was assessed with a validated FFQ. The offspring were observed at 3- to 12-month intervals for the appearance of type 1 diabetes-associated autoantibodies and development of clinical type 1 diabetes (average follow-up period: 4·6 years (range 0·5-11·5 years)). Altogether, 240 children developed preclinical type 1 diabetes and 112 children developed clinical type 1 diabetes. Piecewise linear log-hazard survival model and Cox proportional-hazards regression were used for statistical analyses. The maternal intake of palmitic acid (hazard ratio (HR) 0·82, 95 % CI 0·67, 0·99) and high consumption of cheese during pregnancy (highest quarter v. intermediate half HR 0·52, 95 % CI 0·31, 0·87) were associated with a decreased risk of clinical type 1 diabetes. The consumption of sour milk products (HR 1·14, 95 % CI 1·02, 1·28), intake of protein from sour milk (HR 1·15, 95 % CI 1·02, 1·29) and intake of fat from fresh milk (HR 1·43, 95 % CI 1·04, 1·96) were associated with an increased risk of preclinical type 1 diabetes, and the intake of low-fat margarines (HR 0·67, 95 % CI 0·49, 0·92) was associated with a decreased risk. No conclusive associations between maternal fatty acid intake or food consumption during pregnancy and the development of type 1 diabetes in the offspring were detected.

APOA2 -256T>C polymorphism interacts with saturated fatty acids intake to affect anthropometric and hormonal variables in type 2 diabetic patients.

PubMed

Basiri, Marjan Ghane; Sotoudeh, Gity; Alvandi, Ehsan; Djalali, Mahmood; Eshraghian, Mohammad Reza; Noorshahi, Neda; Koohdani, Fariba

2015-05-01

Recent studies have established the interaction between APOA2 -256T>C polymorphism and dietary saturated fatty acids intake in relation to obesity on healthy individuals. In the current study, we investigate the effects of this interaction on anthropometric variables and serum levels of leptin and ghrelin in patients with type 2 diabetes. In this cross-sectional study, 737 patients with type 2 diabetes mellitus (290 males and 447 females) were recruited from diabetes clinics in Tehran. The usual dietary intake of all participants during the last year was obtained by validated semiquantitative food frequency questionnaire. APOA2 genotyping was performed by real-time PCR on genomic DNA. No significant relation was obtained by univariate analysis between anthropometric variables and APOA2 genotypes. However, after adjusting for age, gender, physical activity and total energy intake, we identified a significant interaction between APOA2-saturated fatty acids intake and body mass index (BMI). After adjusting for potential confounders, serum levels of ghrelin in CC genotype patients were significantly higher than T allele carriers (p = 0.03), whereas the case with leptin did not reveal a significant difference. The result of this study confirmed the interaction between APOA2 -256T>C polymorphism and SFAs intake with BMI in type 2 diabetic patients. In fact, homozygous patients for the C allele with high saturated fatty acids intake had higher BMI. The APOA2 -256T>C polymorphism was associated with elevated levels of serum ghrelin.

Correlation between non-alcoholic fatty liver disease (NAFLD) and dyslipidemia in type 2 diabetes.

PubMed

Krishan, Saini

2016-01-01

Non-alcoholic fatty liver means the presence of hepatosteatosis without significant alcohol consumption; it is strongly associated with obesity and metabolic disorder like type 2 diabetes and dyslipideamia. NASH may progress to advanced stages of hepatic fibrosis and cirrhosis. Increased body mass index and viral genotype contribute to steatosis in chronic hepatitis. The sonographic features of NAFLD include the presence of bright hepatic echotexture deep attenuation, and vascular blurring either singly or in combination. Dyslipidemia in patients with NAFLD is atherogenic in nature and it is characterized by increased levels of serum triglycerides and decreased levels of HDL cholesterol. Statins are potent lipid-lowering agents which decrease LDL cholesterol by 20-60%, decrease triglycerides by 10-33% and increase HDL cholesterol by 5-10% for the patients with NAFLD. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Damage to enteric neurons occurs in mice that develop fatty liver disease but not diabetes in response to a high-fat diet.

PubMed

Rivera, L R; Leung, C; Pustovit, R V; Hunne, B L; Andrikopoulos, S; Herath, C; Testro, A; Angus, P W; Furness, J B

2014-08-01

Disorders of gastrointestinal functions that are controlled by enteric neurons commonly accompany fatty liver disease. Established fatty liver disease is associated with diabetes, which itself induces enteric neuron damage. Here, we investigate the relationship between fatty liver disease and enteric neuropathy, in animals fed a high-fat, high-cholesterol diet in the absence of diabetes. Mice were fed a high-fat, high-cholesterol diet (21% fat, 2% cholesterol) or normal chow for 33 weeks. Liver injury was assessed by hematoxylin and eosin, picrosirius red staining, and measurement of plasma alanine aminotransaminase (ALT). Quantitative immunohistochemistry was performed for different types of enteric neurons. The mice developed steatosis, steatohepatitis, fibrosis, and a 10-fold increase in plasma ALT, indicative of liver disease. Oral glucose tolerance was unchanged. Loss and damage to enteric neurons occurred in the myenteric plexus of ileum, cecum, and colon. Total numbers of neurons were reduced by 15-30% and neurons expressing nitric oxide synthase were reduced by 20-40%. The RNA regulating protein, Hu, became more concentrated in the nuclei of enteric neurons after high-fat feeding, which is an indication of stress on the enteric nervous system. There was also disruption of the neuronal cytoskeletal protein, neurofilament medium. Enteric neuron loss and damage occurs in animals with fatty liver disease in the absence of glucose intolerance. The enteric neuron damage may contribute to the gastrointestinal complications of fatty liver disease. © 2014 John Wiley & Sons Ltd.

Epoxy fatty acids mediate analgesia in murine diabetic neuropathy.

PubMed

Wagner, K; Lee, K S S; Yang, J; Hammock, B D

2017-03-01

Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics. We tested diabetic neuropathic wild-type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu-opioid receptor antagonist. The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids. The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions. EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects. © 2016 European Pain Federation - EFIC®.

Peroxisomal palmitoyl-CoA oxidation in the Zucker rat.

PubMed Central

Brady, P S; Hoppel, C L

1983-01-01

The effects of 3 or 6 days of starvation on hepatic peroxisomal palmitoyl-CoA oxidation were examined in adult lean and obese Zucker rats. When expressed either per mg of DNA or per total liver, obese rats had almost 2-fold higher oxidation rates than the lean rats. Within 6 days of starvation rates fell by 50% among both phenotypes. When data were expressed per 100 g body wt., lean and obese rats had similar rates, falling from a mean of 0.57 to 0.28 mumol/min per 100 g body wt. within 6 days of starvation. Peroxisomal oxidative changes paralleled mitochondrial beta-oxidative changes. PMID:6882399

Image analysis of fatty infiltration in labial salivary gland biopsies: extent and its correlation to age, obesity and diabetes.

PubMed

Katona, Krisztián; Elekes, Eszter; Farkas, Nelli; Kneif, Mária; Sütő, Gábor; Tornóczky, Tamás

2017-08-01

Fatty infiltration of minor salivary gland parenchyma is relatively frequent, but not extensively examined histopathological phenomenon in biopsy samples. Its extent and relation to several suspected background diseases are not well understood. In this study, we examined the presence and extent of fatty infiltration on digitally scanned versions of the periodic acid/Schiff-stained minor salivary gland slides of 275 patients. As a result of the image analysis, fatty infiltration was expressed in per cent of the whole selected area. The presence and extent of this change were compared to age, diabetes mellitus and body mass index in various statistical analyses. Significantly higher age and body mass index values were found in the fatty infiltration positive than in the negative group. We also found that not only the number of fatty infiltration positive cases was increased significantly in the gradually worsened body mass index groups, but the extent of fatty infiltration also increased as the obesity worsened. Age also showed significant correlation with the extent of fatty infiltration. All of these findings support that the age (which seemed the only independent variable) shows strong correlation with the presence of the fatty infiltration but obesity may also play important role in the development and the extent of this change. Because of its frequency in elderly, at least partly, the fatty infiltration might be responsible for the xerostomia. We also think that presence of fatty infiltration should be mentioned in the histopathological report of salivary gland biopsies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Standard analgesics reverse burrowing deficits in a rat CCI model of neuropathic pain, but not in models of type 1 and type 2 diabetes-induced neuropathic pain.

PubMed

Rutten, Kris; Gould, Stacey A; Bryden, Luke; Doods, Henri; Christoph, Thomas; Pekcec, Anton

2018-09-17

Burrowing is a rodent behavior validated as a robust and reproducible outcome measure to infer the global effect of pain in several inflammatory pain models. However, less is known about the effect of analgesics on burrowing in neuropathic pain models and no studies have determined burrowing performance in models of diabetes-associated neuropathic pain. To compare the sensitivity of the burrowing assay in different neuropathic pain models: mononeuropathic pain and diabetic polyneuropathy. Burrowing performance was determined by the amount of substrate left in a hollow tube by rats with chronic constriction injury (CCI). In addition, burrowing performance, locomotion and pain development was assessed in the Zucker diabetic fatty (ZDF) rat model, resembling type-2 diabetes. Efficacy of clinically-active reference drugs (opioids, gabapentin and/or pregabalin) were investigated in these models. Burrowing behavior was additionally assessed in a second model, induced by streptozotocin (STZ) treatment, resembling type-1 diabetes. In the CCI model, moderate but consistent burrowing deficits were observed that persisted over a period of ≥20 days. Systemic administration of morphine, pregabalin and gabapentin reversed this deficit. In contrast, none of the reference drugs improved marked burrowing deficits detected in ZDF rats, and pregabalin did not reverse severe burrowing deficits observed in STZ rats. Burrowing performance cannot necessarily be used as pain-related readout across pain models and largely depends on the model used, at least in models of neuropathy. Specifically, analgesic drug effects might be masked by general diabetes-associated alteration of the animals' well-being, resulting in false negative outcomes. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Non alcoholic fatty liver disease in a Nigerian population with type II diabetes mellitus.

PubMed

Olusanya, Titilola Osawaye; Lesi, Olufunmilayo Adenike; Adeyomoye, Adekunle Ayokunle; Fasanmade, Olufemi Adetola

2016-01-01

Worldwide, Non-alcoholic fatty liver disease (NAFLD) has become an important cause of chronic liver disease and cardiovascular morbidity, even more so in subjects with Type II Diabetes Mellitus (T2DM). The aim of this study was to determine the prevalence and risk factors of NAFLD in an African population with Type II Diabetes Mellitus. We performed a case control study and evaluated anthropometric and biochemical risk factors for NAFLD in 336 subjects (T2DM and non-diabetic controls). Parameters assessed included estimation of BMI (Body Mass Index), measurement of waist circumference (WC), serum cholesterol including HDL-C, LDL-C and triglyceride and serum transaminases (ALT and AST). Hepatitis B and C viral antibody screening was also performed. The diagnosis of NAFLD was confirmed by identification of hepatic steatosis on abdominal ultrasound scan evaluation and exclusion of significant alcohol consumption. NAFLD was identified in 16.7% (28 of 168) patients with T2DM compared with 1.2% (2 of 168) non-diabetic controls (Odds Ratio 16.6; p < 0.001). Central obesity (WC > 102cm) and dyslipidaemia (HDL-c < 40mg/dl) were independently associated with NAFLD in male subjects with T2DM (p = 0.03 and p = 0.04 respectively). NAFLD occurred more frequently in patients with T2DM than controls and was associated with central obesity and dyslipidaemia. The diabetic subjects with NAFLD will require more intensive therapy to decrease the risk of hepatic, cardiovascular and other adverse events.

Effects of vitamin A, C and E, or omega-3 fatty acid supplementation on the level of paraoxonase and arylesterase activity in streptozotocin-induced diabetic rats: an investigation of activities in plasma, and heart and liver homogenates.

PubMed

Zarei, Mahnaz; Fakher, Shima; Tabei, Seyed Mohammad Bagher; Javanbakht, Mohammad Hassan; Derakhshanian, Hoda; Farahbakhsh-Farsi, Payam; Sadeghi, Mohammad Reza; Mostafavi, Ebrahim; Djalali, Mahmoud

2016-03-01

This study was designed and conducted to evaluate the effects of vitamin A, C and E supplementation, and omega-3 fatty acid supplementation on the activity of paraoxonase and arylesterase in an experimental model of diabetes mellitus. A total of 64 male Sprague Dawley® rats, each weighing 250 g, were randomly distributed into four groups: (a) normal control; (b) diabetic control; (c) diabetic with vitamin A, C and E supplementation; and (d) diabetic with omega-3 fatty acid supplementation. The animals were anaesthetised after four weeks of intervention, and paraoxonase and arylesterase activity in blood plasma, and liver and heart homogenates were measured. Arylesterase activity in the heart and liver homogenates was significantly lower in the diabetic control group than in the normal control group (p < 0.01). Vitamin A, C and E supplementation, and omega-3 fatty acid supplementation significantly increased liver arylesterase activity (p < 0.05). No significant change was observed in paraoxonase activity and other investigated factors. Vitamin A, C and E, or omega-3 fatty acid supplementation were found to increase liver arylesterase activity in streptozotocin-induced diabetic rats. These supplements may be potential agents for the treatment of diabetes mellitus complications. Copyright: © Singapore Medical Association.

Effects of triple antioxidant combination (vitamin E, vitamin C and alpha-lipoic acid) with insulin on lipid and cholesterol levels and fatty acid composition of brain tissue in experimental diabetic and non-diabetic rats.

PubMed

Ozkan, Yusuf; Yilmaz, Okkeş; Oztürk, Ali Ihsan; Erşan, Yasemin

2005-09-01

The aim of this research was to examine the effects of a triple antioxidant combination (vitamins E (VE) and C (VC) plus alpha-lipoic acid (LA)) on the total lipid and cholesterol levels and the fatty acid composition of brain tissues in experimental diabetic and non-diabetic rats. VE and LA were injected intraperitoneally (50 mg/kg) four times per week and VC was provided as a supplement dissolved in the drinking water (50 mg/kg). In addition, rats in the diabetes 1 and D+VELAVC groups were given daily by subcutaneous insulin injections (8 IU/kg), but no insulin was given to rats in the diabetes 2 group. The results indicate that the brain lipid levels in the D+VELAVC, diabetes 1 and diabetes 2 groups were higher than in the control group (P<0.01). Total lipid was also higher in the non-diabetic rats treated with LA and VC. Total cholesterol was higher in the diabetes 1 and diabetes 2 groups (P<0.05) than in controls. Cholesterol levels were similar in the D+VELAVC and LA groups but lower in the VC, VE and VELAVC groups of non-diabetic rats (P<0.05 and P<0.01). In respect of fatty acid composition, palmitic acid levels were lower in the diabetes 2 and non-diabetic VE groups than the control group (P<0.05), but higher in the non-diabetic LA group (P<0.05). Oleic acid (18:1 n-9) levels were lower in the diabetic and non-diabetic groups than the control group (P<0.01), but higher in the non-diabetic LA group. Arachidonic acid (20:4 n-6) levels were similar in the diabetes 1, D+VELAVC and control groups (P>0.05) but higher in the non-diabetic VE, VC, LA and VEVCLA groups (P<0.05) and lower in the diabetes 2 group (P<0.05). Docosahexaenoic acid (22:6 n-3) was elevated in the diabetes 2 and VEVCLA groups (P<0.01, P<0.05). In conclusion, the current study confirmed that treatment with a triple combination of VE, VC and LA protects the arachidonic acid level in the brains of diabetic and non-diabetic rats.

Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease.

PubMed

Newton, Kimberly P; Hou, Jiayi; Crimmins, Nancy A; Lavine, Joel E; Barlow, Sarah E; Xanthakos, Stavra A; Africa, Jonathan; Behling, Cynthia; Donithan, Michele; Clark, Jeanne M; Schwimmer, Jeffrey B

2016-10-03

Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown. To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH). This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network. The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values. There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (P < .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5-6.2) compared with those with normal glucose. In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes

Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice.

PubMed

Suzuki, Masayuki; Honda, Kiyofumi; Fukazawa, Masanori; Ozawa, Kazuharu; Hagita, Hitoshi; Kawai, Takahiro; Takeda, Minako; Yata, Tatsuo; Kawai, Mio; Fukuzawa, Taku; Kobayashi, Takamitsu; Sato, Tsutomu; Kawabe, Yoshiki; Ikeda, Sachiya

2012-06-01

Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.

Association between the Fatty Liver Index and Risk of Type 2 Diabetes in the EPIC-Potsdam Study

PubMed Central

Jäger, Susanne; Jacobs, Simone; Kröger, Janine; Stefan, Norbert; Fritsche, Andreas; Weikert, Cornelia; Boeing, Heiner; Schulze, Matthias B.

2015-01-01

The fatty liver index (FLI) predicts fatty liver by using BMI, waist circumference, γ-glutamyltransferase and triglycerides. We investigated the association between the FLI and the risk of type 2 diabetes and evaluated to what extent single FLI components contribute to the diabetes risk. We analysed a case-cohort study (random sub-cohort: 1922; incident cases: 563) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. The proportion of exposure effect (PEE) explained by single FLI components was evaluated and effect decomposition using inverse probability weighting (IPW) was applied. Women and men with a FLI ≥60 compared to those with a FLI <30 had a multivariable-adjusted Hazard Ratio (HR) of 17.6; 95% confidence interval (CI) 11.1-28.0 and HR: 10.9; 95% CI 6.22-19.2, respectively. Adjustment for BMI or waist circumference attenuated this association in men [PEEBMI (95% CI) = 53.8% (43.9%-65.8%); PEEwaist (95% CI) = 54.8% (44.2%-68.8%)]. In women, adjustment for waist circumference attenuated the association to a lesser degree than in men [PEEwaist (95% CI) = 31.1%; (21.9%-43.1%)] while BMI had no appreciable effect [PEEBMI (95% CI) = 11.0% (2.68%-21.0%)]. γ-glutamyltransferase and triglycerides showed only a small attenuation in women [PEEGGT(95% CI) = 3.11% (-0.72%-4.48%); PEETG (95% CI) = 6.36% (3.81%-9.92%)] and in men [PEEGGT = 0%; PEETG (95% CI) = 6.23% (2.03%-11.8%)]. In women, the total effect was decomposed into a direct effect and 4 indirect effects (HRBMI = 1.10; HRwaist = 1.28; HRGGT = 0.97 and HRTG = 1.03). In men, the 4 indirect effects were HRBMI = 1.25; HRwaist = 1.29; HRGGT = 0.97 and HRTG = 0.99. These data suggest that the FLI, as a proxy for fatty liver, is associated with risk of type 2 diabetes. This association is only partly explained by standard estimates of overall and abdominal body fatness, particularly among women. PMID:25902304

Effects of clenbuterol on insulin resistance in conscious obese Zucker rats.

PubMed

Pan, S J; Hancock, J; Ding, Z; Fogt, D; Lee, M; Ivy, J L

2001-04-01

The present study was conducted to determine the effect of chronic administration of the long-acting beta(2)-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats (fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin. kg(-1). min(-1)) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.

Effects of Moderate Alcohol Intake in the Bladder of the Otsuka Long Evans Tokushima Fatty Diabetic Rats.

PubMed

Bae, Woong Jin; Choi, Yong Sun; Kim, Su Jin; Cho, Hyuk Jin; Hong, Sung Hoo; Kim, Sae Woong; Hwang, Tae-Kon; Kim, Dai Jin; Lee, Ji Youl

2015-09-01

Diabetes is related with a number of cystopathic complications. However, there have been no studies about the influence of alcohol consumption in the bladder of type 2 diabetes. Thus, we investigated the effect of moderate alcohol intake in the bladder of the Otsuka Long Evans Tokushima Fatty (OLETF) diabetic rat. The non-diabetic Long-Evans Tokushima Otsuka (LETO, n=14) and the OLETF control group (n=14) were fed an isocaloric diet; the LETO (n=14) and the OLETF ethanol group (n=14) were fed 36% ethanol 7 g/kg/day. After ten weeks, muscarinic receptors, RhoGEFs, myogenic change, and the level of oxidative stress were evaluated. Moderate alcohol intake significantly decreased excessive muscarinic receptor and Rho kinase expressions in the OLETF rats compared with the LETO rats. In addition, iNOS and collagen expression were not changed in the OLETF rats in spite of alcohol consumption. Superoxide dismutase levels, which is involved in antioxidant defense, in the LETO rats were significantly decreased after alcohol consumption, however those in the OLETF rats were similar. Moderate alcohol consumption reduces the oxidative stress, and may prevent molecular and pathologic changes of the bladder of rats with type 2 diabetes.

Fatty liver index and hepatic steatosis index for prediction of non-alcoholic fatty liver disease in type 1 diabetes.

PubMed

Sviklāne, Laura; Olmane, Evija; Dzērve, Zane; Kupčs, Kārlis; Pīrāgs, Valdis; Sokolovska, Jeļizaveta

2018-01-01

Little is known about the diagnostic value of hepatic steatosis index (HSI) and fatty liver index (FLI), as well as their link to metabolic syndrome in type 1 diabetes mellitus. We have screened the effectiveness of FLI and HSI in an observational pilot study of 40 patients with type 1 diabetes. FLI and HSI were calculated for 201 patients with type 1 diabetes. Forty patients with FLI/HSI values corresponding to different risk of liver steatosis were invited for liver magnetic resonance study. In-phase/opposed-phase technique of magnetic resonance was used. Accuracy of indices was assessed from the area under the receiver operating characteristic curve. Twelve (30.0%) patients had liver steatosis. For FLI, sensitivity was 90%; specificity, 74%; positive likelihood ratio, 3.46; negative likelihood ratio, 0.14; positive predictive value, 0.64; and negative predictive value, 0.93. For HSI, sensitivity was 86%; specificity, 66%; positive likelihood ratio, 1.95; negative likelihood ratio, 0.21; positive predictive value, 0.50; and negative predictive value, 0.92. Area under the receiver operating characteristic curve for FLI was 0.86 (95% confidence interval [0.72; 0.99]); for HSI 0.75 [0.58; 0.91]. Liver fat correlated with liver enzymes, waist circumference, triglycerides, and C-reactive protein. FLI correlated with C-reactive protein, liver enzymes, and blood pressure. HSI correlated with waist circumference and C-reactive protein. FLI ≥ 60 and HSI ≥ 36 were significantly associated with metabolic syndrome and nephropathy. The tested indices, especially FLI, can serve as surrogate markers for liver fat content and metabolic syndrome in type 1 diabetes. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Urinary Liver-Type Fatty Acid–Binding Protein and Progression of Diabetic Nephropathy in Type 1 Diabetes

PubMed Central

Panduru, Nicolae M.; Forsblom, Carol; Saraheimo, Markku; Thorn, Lena; Bierhaus, Angelika; Humpert, Per M.; Groop, Per-Henrik

2013-01-01

OBJECTIVE Diabetic nephropathy (DN) has mainly been considered a glomerular disease, although tubular dysfunction may also play a role. This study assessed the predictive value for progression of a tubular marker, urinary liver-type fatty acid–binding protein (L-FABP), at all stages of DN. RESEARCH DESIGN AND METHODS At baseline, 1,549 patients with type 1 diabetes had an albumin excretion rate (AER) within normal reference ranges, 334 had microalbuminuria, and 363 had macroalbuminuria. Patients were monitored for a median of 5.8 years (95% CI 5.7–5.9). In addition, 208 nondiabetic subjects were studied. L-FABP was measured by ELISA and normalized with urinary creatinine. Different Cox proportional hazard models for the progression at every stage of DN were used to evaluate the predictive value of L-FABP. The potential benefit of using L-FABP alone or together with AER was assessed by receiver operating characteristic curve analyses. RESULTS L-FABP was an independent predictor of progression at all stages of DN. As would be expected, receiver operating characteristic curves for the prediction of progression were significantly larger for AER than for L-FABP, except for patients with baseline macroalbuminuria, in whom the areas were similar. Adding L-FABP to AER in the models did not significantly improve risk prediction of progression in favor of the combination of L-FABP plus AER compared with AER alone. CONCLUSIONS L-FABP is an independent predictor of progression of DN irrespective of disease stage. L-FABP used alone or together with AER may not improve the risk prediction of DN progression in patients with type 1 diabetes, but further studies are needed in this regard. PMID:23378622

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

PubMed Central

Hutchins, G. D.; Perry, K.; Territo, W.; Chisholm, R.; Acton, A.; Glick-Wilson, B.; Considine, R. V.; Moberly, S.; DeGrado, T. R.

2015-01-01

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m−2·min−1) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. PMID:26732686

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.

PubMed

Mather, K J; Hutchins, G D; Perry, K; Territo, W; Chisholm, R; Acton, A; Glick-Wilson, B; Considine, R V; Moberly, S; DeGrado, T R

2016-03-15

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. Copyright © 2016 the American Physiological Society.

Nonalcoholic Fatty Liver Is Associated With Further Left Ventricular Abnormalities in Patients With Type 2 Diabetes Mellitus: A 3-Dimensional Speckle-Tracking Study.

PubMed

Wang, Qingqing; Ma, Wenyan; Xia, Jizhu

2018-01-24

The aim of this study was to detect left ventricular (LV) structure and function abnormalities in patients with type 2 diabetes mellitus with or without nonalcoholic fatty liver (NAFL) using 3-dimensional speckle-tracking echocardiography. Eighty patients with type 2 diabetes and a normal LV ejection fraction (≥55%), including 40 with coexistent NAFL, and 40 age- and sex-matched control participants were recruited. Conventional echocardiography and 3-dimensional speckle-tracking echocardiography were performed, and global longitudinal strain, global circumferential strain, global area strain, and global radial strain values were measured. Significant differences in 2-dimensional LV functional patterns were found among the 3 groups (P = .031), and LV hypertrophy was the most prevalent in patients with diabetes and NAFL. The patients with diabetes only had significantly lower global longitudinal strain, global circumferential strain, and global radial strain than the controls (all P < .05). The patients with diabetes and NAFL had severely lower global longitudinal strain, global circumferential strain, global area strain, and global radial strain than the controls (all P < .001), and they also had severely lower global longitudinal strain, global area strain, and global radial strain than the patients with diabetes only (all P < 0.001). The hemoglobin A 1c level and NAFL were independently associated with strain values in all patients with diabetes. The strain values in multiple directions (≥2 of global longitudinal, global circumferential, global area, and global radial strain) decreased significantly in the patients with diabetes and moderate and severe NAFL compared to those with mild NAFL (all P < .05). Nonalcoholic fatty liver could aggravate LV hypertrophy and dysfunction in patients with type 2 diabetes. The combined application of conventional and 3-dimensional speckle-tracking echocardiography could detect these asymptomatic

Trouble and Triumph: German Life-Turkish Tradition in Renan Demirkan's "Schwarzer Tee mit drei Stuck Zucker"

ERIC Educational Resources Information Center

Ebert, Reika

2004-01-01

This paper explores Demirkan's narrative strategies in "Schwarzer Tee mit drei Stuck Zucker" to negotiate issues of a life between two cultures and traditions. Based on Bhabha's insights that mainstream culture needs intellectual and artistic infusion from the margins of a society in order to remain vital; and that cultural production…

Furan fatty acids - Beneficial or harmful to health?

PubMed

Xu, Long; Sinclair, Andrew J; Faiza, Muniba; Li, Daoming; Han, Xianlin; Yin, Huiyong; Wang, Yonghua

2017-10-01

Furan fatty acids are found in plants, algae, and fish, and reported to have some positive health benefits, including anti-oxidant and anti-inflammatory activities, and inhibition of non-enzymatic lipid peroxidation. A major metabolite of furan fatty acids, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), has been reported to be increased in patients who progress from prediabetes to type 2 diabetes, although CMPF is not necessarily associated with impaired glucose metabolism. Other studies report that CMPF levels are lower in subjects with diabetes than control subjects. Plasma CMPF levels increase in subjects who consume fish or fish oil, and in patients with renal failure. It is not known where furan fatty acids are converted to CMPF and it is speculated that this might be a result of microbiome activity. The plasma levels reported for CMPF in healthy, diabetic and patients with renal disease vary by factors of more than 100-fold within each of these three groups, so measurement error appears to be limiting the ability to interpret studies. This review explores these controversies and raises questions about whether CMPF is a marker for healthy diets or indeed associated with diabetes and renal health. The review concludes that, on balance, furan fatty acids are beneficial for health. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

PubMed Central

Kwak, Kyung Min; Kim, Ju-Young; Yu, Seung Hee; Lee, Sihoon; Kim, Yeun Sun; Park, Ie Byung; Kim, Kwang-Won; Lee, Kiyoung

2016-01-01

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model. PMID:27997588

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats.

PubMed

Eom, Young Sil; Gwon, A-Ryeong; Kwak, Kyung Min; Kim, Ju-Young; Yu, Seung Hee; Lee, Sihoon; Kim, Yeun Sun; Park, Ie Byung; Kim, Kwang-Won; Lee, Kiyoung; Kim, Byung-Joon

2016-01-01

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Type 2 diabetes mellitus and non-alcoholic fatty liver disease: a systematic review and meta-analysis.

PubMed

Amiri Dash Atan, Nasrin; Koushki, Mehdi; Motedayen, Morteza; Dousti, Majid; Sayehmiri, Fatemeh; Vafaee, Reza; Norouzinia, Mohsen; Gholami, Reza

2017-01-01

The aim of this study was the evaluation of the prevalence of NAFLD in patients with type 2 diabetes mellitus. Non-alcoholic fatty liver disease (NAFLD) is an emerging disease with high prevalence in patients with type 2 diabetes mellitus (T2DM). Many studies have reported the prevalence of NAFLD in type 2 diabetes mellitus patients. However, these results are inconsistent. A Literature search was conducted in PubMed, Scopus, web of science and Science Direct from 2005 to August 2017. The necessary information was extracted. Heterogeneity was evaluated using I 2 statistic. Meta-regression analyses were performed to the estimation of the relationship between the year of study and sample size with the prevalence of NAFLD. Publication bias was assessed by both Begg rank correlation and Egger tests. Subgroup analysis was performed for identification of sources heterogeneity. Seventeen studies involving 10897 type 2 diabetes mellitus patients with NAFLD were included in this meta-analysis. The overall prevalence of NAFLD in type 2 diabetes mellitus patients by random effects models was 54% (95% CI, 45%- 64%). There is a significant heterogeneity across studies with (I 2 = 99%, p> 0.01). The funnel plot as graphically and Begg and Egger as statistically showed no publication bias among studies. Subgroup analysis indicated that the prevalence of NAFLD in type 2 diabetes mellitus patients differed in predictive factors such as lipid profile, BMI, HbA1c, AST, and ALT. This finding in spite of heterogeneity of documents is corresponding to the positive correlation between NAFLD and type 2 diabetes mellitus. The findings indicated that the overall prevalence of NAFLD among type 2 diabetes mellitus patients is significantly higher. It can be concluded that type 2 diabetes mellitus patients should be managed to prevent NAFLD.

Functionality of cow milk naturally enriched with polyunsaturated fatty acids and polyphenols in diets for diabetic rats.

PubMed

Yoshimura, Emerson H; Santos, Nadine W; Machado, Erica; Agustinho, Bruna C; Pereira, Lucelia M; de Aguiar, Sílvia C; Sá-Nakanishi, Anacharis B; Mareze-da-Costa, Cecília E; Zeoula, Lucia M

2018-01-01

The increasing incidence of diabetes mellitus is becoming a serious threat to human health in various parts of the world. Studies with dairy products have shown a potential beneficial effect against diabetes. This experiment evaluated the supplementation of milk naturally enriched with polyunsaturated fatty acids (PUFA) and polyphenols in rats with streptozotocin-induced diabetes. Forty male 28-day-old Wistar rats were distributed in four experimental treatments of diabetic animals (streptozotocin induction) and a normal group (non-induced). Experimental treatments were: control (water), whole common milk (COM-M), milk enriched with PUFA (PUFA-M), milk enriched with PUFA and polyphenols (PUFA/P-M) through a special diet offered to dairy cows. Milk supplementation at a dose 5 mL/kg body weight was performed for 77 days, 42 days before and 35 days after diabetes induction. The COM-M supplementation increased brown fat deposits, reduced post-induction glucose levels, reduced blood fructosamine levels, and improved glucose tolerance. Milk enriched with PUFA reduced final fasting glucose, LDL levels, and improved blood antioxidant capacity. Milk enriched with PUFA and polyphenols promoted an increase in gastrocnemius muscle mass, and a reduction in mesenteric fat and LDL levels. Milk intake, with an emphasis on milk enriched with PUFA and polyphenols, attenuated the metabolic disorders of streptozotocin-induced diabetes in rats.

Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus.

PubMed

Bonapace, Stefano; Valbusa, Filippo; Bertolini, Lorenzo; Pichiri, Isabella; Mantovani, Alessandro; Rossi, Andrea; Zenari, Luciano; Barbieri, Enrico; Targher, Giovanni

2014-01-01

Recent epidemiological data suggest that non-alcoholic fatty liver disease (NAFLD) is closely associated with aortic valve sclerosis (AVS), an emerging risk factor for adverse cardiovascular outcomes, in nondiabetic and type 2 diabetic individuals. To date, nobody has investigated the association between NAFLD and AVS in people with type 2 diabetes, a group of individuals in which the prevalence of these two diseases is high. We recruited 180 consecutive type 2 diabetic patients without ischemic heart disease, valvular heart disease, hepatic diseases or excessive alcohol consumption. NAFLD was diagnosed by liver ultrasonography whereas AVS was determined by conventional echocardiography in all participants. In the whole sample, 120 (66.7%) patients had NAFLD and 53 (29.4%) had AVS. No patients had aortic stenosis. NAFLD was strongly associated with an increased risk of prevalent AVS (odds ratio [OR] 2.79, 95% CI 1.3-6.1, p<0.01). Adjustments for age, sex, duration of diabetes, diabetes treatment, body mass index, smoking, alcohol consumption, hypertension, dyslipidemia, hemoglobin A1c and estimated glomerular filtration rate did not attenuate the strong association between NAFLD and risk of prevalent AVS (adjusted-OR 3.04, 95% CI 1.3-7.3, p = 0.01). Our results provide the first demonstration of a positive and independent association between NAFLD and AVS in patients with type 2 diabetes mellitus.

Increased adipogenic conversion of muscle satellite cells in obese Zucker rats.

PubMed

Scarda, A; Franzin, C; Milan, G; Sanna, M; Dal Prà, C; Pagano, C; Boldrin, L; Piccoli, M; Trevellin, E; Granzotto, M; Gamba, P; Federspil, G; De Coppi, P; Vettor, R

2010-08-01

Visceral and intermuscular adipose tissue (IMAT) depots account for most obesity-related metabolic and cardiovascular complications. Muscle satellite cells (SCs) are mesenchymal stem cells giving rise to myotubes and also to adipocytes, suggesting their possible contribution to IMAT origin and expansion. We investigated the myogenic differentiation of SCs and the adipogenic potential of both preadipocytes and SCs from genetically obese Zucker rats (fa/fa), focusing on the role of Wnt signaling in these differentiation processes. SCs were isolated by single-fiber technique from flexor digitorum brevis muscle and preadipocytes were extracted from subcutaneous adipose tissue (AT). Morphological features and gene expression profile were evaluated during in vitro myogenesis and adipogenesis. Wingless-type MMTV integration site family member 10b (Wnt10b) expression was quantified by quantitative PCR in skeletal muscle and AT. We did not observe any difference in the proliferation rate and in the myogenic differentiation of SCs from obese and lean rats. However, a decreased insulin-induced glucose uptake was present in myotubes originating from fa/fa rats. Under adipogenic conditions, preadipocytes and SCs of obese animals displayed an enhanced adipogenesis. Wnt10b expression was reduced in obese rats in both muscle and AT. Our data suggest that the increase in different fat depots including IMAT and the reduced muscle insulin sensitivity, the major phenotypical alteration of obese Zucker rats, could be ascribed to an intrinsic defect, either genetically determined or acquired, still present in both muscle and fat precursors. The involvement of Wnt10b as a regulator of both adipogenesis and muscle-to-fat conversion is suggested.

Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo.

PubMed

Huhn, R; Heinen, A; Hollmann, M W; Schlack, W; Preckel, B; Weber, N C

2010-12-01

Hyperglycaemia blocks sevoflurane-induced postconditioning, and cardioprotection in hyperglycaemic myocardium can be restored by inhibition of the mitochondrial permeability transition pore (mPTP). We investigated whether sevoflurane-induced postconditioning is also blocked in the prediabetic heart and if so, whether cardioprotection could be restored by inhibiting mPTP. Zucker lean (ZL) and Zucker obese (ZO) rats were assigned to one of seven groups. Animals underwent 25 min of ischaemia and 120 min of reperfusion. Control (ZL-/ZO Con) animals were not further treated. postconditioning groups (ZL-/ZO Sevo-post) received sevoflurane for 5 min starting 1min prior to the onset of reperfusion. The mPTP inhibitor cyclosporine A (CsA) was administered intravenously in a concentration of 5 (ZO CsA and ZO CsA+Sevo-post) or 10 mg/kg (ZO CsA10+Sevo-post) 5 min before the onset of reperfusion. At the end of reperfusion, infarct sizes were measured by TTC staining. Blood samples were collected to measure plasma levels of insulin, cholesterol and triglycerides. Sevoflurane postconditioning reduced infarct size in ZL rats to 35±12% (p<0.05 vs. ZL Con: 60±6%). In ZO rats sevoflurane postconditioning was abolished (ZO Sevo-post: 59±12%, n.s. vs. ZO Con: 58±6%). 5 mg and 10 mg CsA could not restore cardioprotection (ZO CsA+Sevo-post: 59±7%, ZO CsA10+Sevo-post: 57±14%; n.s. vs. ZO Con). In ZO rats insulin, cholesterol and triglyceride levels were significant higher than in ZL rats (all p<0.05). Inhibition of mPTP with CsA failed to restore cardioprotection in the prediabetic but normoglycaemic heart of Zucker obese rats in vivo. Copyright © 2009 Elsevier B.V. All rights reserved.

CAN ULTRASOUND ABDOMEN HELP IN EARLY DIAGNOSIS OF DIABETES MELLITUS? AN OBSERVATIONAL STUDY.

PubMed

Anwar, Javed; Aamir, Muhammad Omer; Sanaullah; Imdad, Zeeshan ul Hasnain; Parveen, Ishrat; Yousaf, Nasreen

2015-01-01

Diabetes mellitus is a common disease. Similarly, ultrasound findings of fatty change and renal crystals are commonly seen on ultrasound. In the personal observation of the main author over the past so many years it was noticed that Diabetes Mellitus, Fatty liver and renal crystals all sit well together. This study tries to establish a relationship between diabetes mellitus renal echogenic foci and fatty liver. This study is first of its kind, as nobody has ever before investigated an association between the renal echogenic foci and fatty liver in relation to diabetes mellitus. This cross-sectional, observational study was conducted at Radiology Department Combined Military Hospital, Kohat From 2nd June 2013 to 30th May 2014. Three hundred patients were collected on the basis of having fatty liver and renal echogenic foci on ultrasound and three hundred more patients were collected who had no fatty liver or renal echogenic foci on ultrasound. Their labs were done for diabetes mellitus. The patients having renal echogenic foci together with fatty liver had 83% positive rate of being diabetics, while patients with no fatty liver and no echogenic foci on ultrasonography had only 0.6% Positive rate of being diabetics. Our results provided the first demonstration of an association between renal echogenic foci together with fatty liver with the diabetes mellitus. Thus ultrasound examination of abdomen can be helpful in its early diagnosis if we make a protocol of doing fasting and random blood sugars in all those patients who have positive renal echogenic foci and fatty liver on their ultrasound examination.

Docosahexaenoic Acid-Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties.

PubMed

Kuda, Ondrej; Brezinova, Marie; Rombaldova, Martina; Slavikova, Barbora; Posta, Martin; Beier, Petr; Janovska, Petra; Veleba, Jiri; Kopecky, Jan; Kudova, Eva; Pelikanova, Terezie; Kopecky, Jan

2016-09-01

White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans. © 2016 by the American Diabetes Association.

Rimonabant reduces the essential value of food in the genetically obese Zucker rat: an exponential demand analysis.

PubMed

Rasmussen, Erin B; Reilly, William; Buckley, Jessica; Boomhower, Steven R

2012-02-01

Research on free-food intake suggests that cannabinoids are implicated in the regulation of feeding. Few studies, however, have characterized how environmental factors that affect food procurement interact with cannabinoid drugs that reduce food intake. Demand analysis provides a framework to understand how cannabinoid blockers, such as rimonabant, interact with effort in reducing demand for food. The present study examined the effects rimonabant had on demand for sucrose in obese Zucker rats when effort to obtain food varied and characterized the data using the exponential ("essential value") model of demand. Twenty-nine male (15 lean, 14 obese) Zucker rats lever-pressed under eight fixed ratio (FR) schedules of sucrose reinforcement, in which the number of lever-presses to gain access to a single sucrose pellet varied between 1 and 300. After behavior stabilized under each FR schedule, acute doses of rimonabant (1-10mg/kg) were administered prior to some sessions. The number of food reinforcers and responses in each condition was averaged and the exponential and linear demand equations were fit to the data. These demand equations quantify the value of a reinforcer by its sensitivity to price (FR) increases. Under vehicle conditions, obese Zucker rats consumed more sucrose pellets than leans at smaller fixed ratios; however, they were equally sensitive to price increases with both models of demand. Rimonabant dose-dependently reduced reinforcers and responses for lean and obese rats across all FR schedules. Data from the exponential analysis suggest that rimonabant dose-dependently increased elasticity, i.e., reduced the essential value of sucrose, a finding that is consistent with graphical depictions of normalized demand curves. Copyright © 2011 Elsevier Inc. All rights reserved.

TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models

PubMed Central

Tsushima, Yu; Tamura, Azusa; Hasebe, Makiko; Kanou, Masanobu; Kato, Hirotsugu; Kobayashi, Tsunefumi

2017-01-01

Glucokinase (GK) plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. GK activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. However, clinical development of GK activators has failed due to the loss of glucose-lowering effects and increased plasma triglyceride levels after chronic treatment. Here, we generated a novel GK activator, TMG-123, examined its in vitro and in vivo pharmacological characteristics, and evaluated its risks of aforementioned clinical issues. TMG-123 selectively activated GK enzyme activity without increasing Vmax. TMG-123 improved glucose tolerance without increasing plasma insulin levels in both insulin-deficient (Goto-Kakizaki rats) and insulin-resistant (db/db mice) models. The beneficial effect on glucose tolerance was greater than results observed with clinically available antidiabetic drugs such as metformin and glibenclamide in Zucker Diabetic Fatty rats. TMG-123 also improved glucose tolerance in combination with metformin. After 4 weeks of administration, TMG-123 reduced the Hemoglobin A1c levels without affecting liver and plasma triglyceride levels in Goto-Kakizaki rats and Diet-Induced Obesity mice. Moreover, TMG-123 sustained its effect on Hemoglobin A1c levels even after 24 weeks of administration without affecting triglycerides. Taken together, these data indicate that TMG-123 exerts glucose-lowering effects in both insulin-deficient and -resistant diabetes, and sustains reduced Hemoglobin A1c levels without affecting hepatic and plasma triglycerides even after chronic treatment. Therefore, TMG-123 is expected to be an antidiabetic drug that overcomes the concerns previously reported with other GK activators. PMID:28207836

TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models.

PubMed

Tsumura, Yoshinori; Tsushima, Yu; Tamura, Azusa; Hasebe, Makiko; Kanou, Masanobu; Kato, Hirotsugu; Kobayashi, Tsunefumi

2017-01-01

Glucokinase (GK) plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. GK activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. However, clinical development of GK activators has failed due to the loss of glucose-lowering effects and increased plasma triglyceride levels after chronic treatment. Here, we generated a novel GK activator, TMG-123, examined its in vitro and in vivo pharmacological characteristics, and evaluated its risks of aforementioned clinical issues. TMG-123 selectively activated GK enzyme activity without increasing Vmax. TMG-123 improved glucose tolerance without increasing plasma insulin levels in both insulin-deficient (Goto-Kakizaki rats) and insulin-resistant (db/db mice) models. The beneficial effect on glucose tolerance was greater than results observed with clinically available antidiabetic drugs such as metformin and glibenclamide in Zucker Diabetic Fatty rats. TMG-123 also improved glucose tolerance in combination with metformin. After 4 weeks of administration, TMG-123 reduced the Hemoglobin A1c levels without affecting liver and plasma triglyceride levels in Goto-Kakizaki rats and Diet-Induced Obesity mice. Moreover, TMG-123 sustained its effect on Hemoglobin A1c levels even after 24 weeks of administration without affecting triglycerides. Taken together, these data indicate that TMG-123 exerts glucose-lowering effects in both insulin-deficient and -resistant diabetes, and sustains reduced Hemoglobin A1c levels without affecting hepatic and plasma triglycerides even after chronic treatment. Therefore, TMG-123 is expected to be an antidiabetic drug that overcomes the concerns previously reported with other GK activators.

Alpha-Lipoic Acid Reduces LDL-Particle Number and PCSK9 Concentrations in High-Fat Fed Obese Zucker Rats

PubMed Central

Carrier, Bradley; Wen, Shin; Zigouras, Sophia; Browne, Richard W.; Li, Zhuyun; Patel, Mulchand S.; Williamson, David L.; Rideout, Todd C.

2014-01-01

We characterized the hypolipidemic effects of alpha-lipoic acid (LA, R-form) and examined the associated molecular mechanisms in a high fat fed Zucker rat model. Rats (n = 8) were assigned to a high fat (HF) diet or the HF diet with 0.25% LA (HF-LA) for 30 days and pair fed to remove confounding effects associated with the anorectic properties of LA. Compared with the HF controls, the HF-LA group was protected against diet-induced obesity (102.5±3.1 vs. 121.5±3.6,% change BW) and hypercholesterolemia with a reduction in total-C (−21%), non-HDL-C (−25%), LDL-C (−16%), and total LDL particle number (−46%) and an increase in total HDL particles (∼22%). This cholesterol-lowering response was associated with a reduction in plasma PCSK9 concentration (−70%) and an increase in hepatic LDLr receptor protein abundance (2 fold of HF). Compared with the HF-fed animals, livers of LA-supplemented animals were protected against TG accumulation (−46%), likely through multiple mechanisms including: a suppressed lipogenic response (down-regulation of hepatic acetyl-CoA carboxylase and fatty acid synthase expression); enhanced hepatic fat oxidation (increased carnitine palmitoyltransferase Iα expression); and enhanced VLDL export (increased hepatic diacylglycerol acyltransferase and microsomal triglyceride transfer protein expression and elevated plasma VLDL particle number). Study results also support an enhanced fatty acid uptake (2.8 fold increase in total lipase activity) and oxidation (increased CPT1β protein abundance) in muscle tissue in LA-supplemented animals compared with the HF group. In summary, in the absence of a change in caloric intake, LA was effective in protecting against hypercholesterolemia and hepatic fat accumulation under conditions of strong genetic and dietary predisposition toward obesity and dyslipidemia. PMID:24595397

Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats.

PubMed

Frisbee, Jefferson C

2003-07-01

Whereas previous studies have demonstrated that the development of syndrome X in obese Zucker rats (OZR) is associated with impaired arteriolar reactivity to vasoactive stimuli, additional results from these studies indicate that the passive diameter of skeletal muscle arterioles is reduced in OZR versus lean Zucker rats (LZR). On the basis of these prior observations, the present study evaluated structural alterations to the skeletal muscle microcirculation as potential contributors to an elevated vascular resistance. Isolated skeletal muscle resistance arterioles exhibited a reduced passive diameter at all levels of intralumenal pressure and a left-shifted stress-strain curve in OZR versus LZR, indicative of structural remodeling of individual arterioles. Histological analyses using Griffonia simplicifolia I lectin-stained sections of skeletal muscle demonstrated reduced microvessel density (rarefaction) in OZR versus LZR, suggesting remodeling of entire microvascular networks. Finally, under maximally dilated conditions, constant flow-perfused skeletal muscle of OZR exhibited significant elevations in perfusion pressure versus LZR, indicative of an increased resistance to perfusion within the microcirculation. These data suggest that developing structural alterations to the skeletal muscle microcirculation in OZR result in elevated vascular resistance, which may, acting in concert with impaired arteriolar reactivity, contribute to blunted active hyperemic responses and compromised performance of in situ skeletal muscle with elevated metabolic demand.

Genetic variants in desaturase gene, erythrocyte fatty acids, and risk for type 2 diabetes in Chinese Hans.

PubMed

Huang, Tao; Sun, Jianqin; Chen, Yanqiu; Xie, Hua; Xu, Danfeng; Huang, Jinyan; Li, Duo

2014-01-01

The aim of this study was to examine the association of the genetic variants in the fatty acid desaturase (FADS) gene cluster with erythrocyte phospholipid fatty acids (PLFA), and their relation to risk for type 2 diabetes mellitus (T2DM) in Han Chinese. Seven hundred and fifty-eight patients with T2DM and 400 healthy individuals were recruited. The erythrocyte PLFA and single-nucleotide polymorphism were determined by standard method. Minor allele homozygotes and heterozygotes of rs174575 and rs174537 had lower PL 20:4 ω-6 levels in healthy individuals. Minor allele homozygotes and heterozygotes of rs174455 in FADS3 gene had lower levels of 22:5 ω-3, 20:4 ω-6, and Δ5desaturase activity in patients with T2DM. Erythrocyte membrane PL 18:3 ω-3 (P for trend = 0.002), 22:5 ω-3 (P for trend < 0.001), ω-3 polyunsaturated fatty acid (P for trend < 0.001), and ω-3:ω-6 (P for trend < 0.001) were significantly inversely associated with risk for T2DM. Genetic variants in the FADS gene cluster are associated with altered erythrocyte PLFAs. High levels of PL 18:3 ω-3, 22:5 ω-3, and total ω-3 polyunsaturated fatty acid were associated with low risk for T2DM. Copyright © 2014 Elsevier Inc. All rights reserved.

Differences in the serum nonesterified Fatty Acid profile of young women associated with a recent history of gestational diabetes and overweight/obesity.

PubMed

Fugmann, Marina; Uhl, Olaf; Hellmuth, Christian; Hetterich, Holger; Kammer, Nora N; Ferrari, Uta; Parhofer, Klaus G; Koletzko, Berthold; Seissler, Jochen; Lechner, Andreas

2015-01-01

Nonesterified fatty acids (NEFA) play pathophysiological roles in metabolic syndrome and type 2 diabetes (T2D). In this study, we analyzed the fasting NEFA profiles of normoglycemic individuals at risk for T2D (women with a recent history of gestational diabetes (GDM)) in comparison to controls (women after a normoglycemic pregnancy). We also examined the associations of NEFA species with overweight/obesity, body fat distribution and insulin sensitivity. Using LC-MS/MS, we analyzed 41 NEFA species in the fasting sera of 111 women (62 post-GDM, 49 controls). Clinical characterization included a five-point oral glucose tolerance test (OGTT), biomarkers and anthropometrics, magnetic resonance imaging (n = 62) and a food frequency questionnaire. Nonparametric tests with Bonferroni correction, binary logistic regression analyses and rank correlations were used for statistical analysis. Women after GDM had a lower molar percentage of total saturated fatty acids (SFA; 38.55% vs. 40.32%, p = 0.0002) than controls. At an explorative level of significance several NEFA species were associated with post-GDM status (with and without adjustment for body mass index (BMI) and HbA1c): The molar percentages of 14:0, 16:0, 18:0 and 18:4 were reduced, whereas those of 18:1, 18:2, 20:2, 24:4, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and total n-6 NEFA were increased. BMI and the amount of body fat correlated inversely with several SFA and MUFA and positively with various PUFA species over the whole study cohort (abs(ρ)≥0.3 for all). 14:0 was inversely and BMI-independently associated with abdominal visceral adiposity. We saw no correlations of NEFA species with insulin sensitivity and the total NEFA concentration was similar in the post-GDM and the control group. In conclusion, we found alterations in the fasting NEFA profile associated with a recent history of gestational diabetes, a risk marker for T2D. NEFA composition also varied with overweight

A low-protein diet exerts a beneficial effect on diabetic status and prevents diabetic nephropathy in Wistar fatty rats, an animal model of type 2 diabetes and obesity.

PubMed

Kitada, Munehiro; Ogura, Yoshio; Suzuki, Taeko; Monno, Itaru; Kanasaki, Keizo; Watanabe, Ai; Koya, Daisuke

2018-01-01

The objective of this study is to investigate the effects of a low-protein diet (LPD) starting from a young age on diabetic status and renal injury in a rat model of type 2 diabetes and obesity. Diabetic male Wistar fatty ( fa/fa ) rats (WFRs) were fed a standard diet (23.84% protein) or an LPD (5.77% protein) for 24 weeks beginning at 6 weeks of age. We investigated the effects of the LPD on total body weight (BW); fat weight (FW); lower-limb muscle weight (MW); several measures of diabetic status, including fasting/random glucose levels, HOMA-IR and the IPITT; and renal injuries, including renal hypertrophy, albuminuria and histological changes. Additionally, autophagy and activation of mTORC1 were evaluated in the diabetic renal cortex. Furthermore, plasma FGF21 and high-molecular-weight (HMW) adiponectin levels, as well as UCP1 expression levels in brown adipose tissue (BAT), were evaluated. Increases in BW and FW in WFRs were significantly reduced by the LPD, and the LPD resulted in a significant reduction of lower-limb MW in WFRs. The LPD suppressed the elevation of glucose levels in WFRs through improvement of insulin resistance. The LPD also elevated the plasma FGF21 and HMW adiponectin of WFRs, as well as UCP1 expression in the BAT of the animals. Renal hypertrophy, albuminuria, renal histological changes, and increased expression of p62 and phospho-S6 ribosomal protein (p-S6RP) were observed in WFRs compared with the values from WLRs. The LPD clearly prevented the diabetic kidneys from sustaining any damage. The LPD prevented the progression of diabetic status; this effect may have been associated with the reduction of FW and the elevation of plasma FGF21 and HMW adiponectin, as well as UCP1 expression in BAT, resulting in suppression of diabetic nephropathy. However, MW was decreased in rats by the consumption of an LPD from a young age; therefore, further research is needed to resolve the nutritional issue of LPD on decreasing in MW.

New animal models reveal that coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8) are candidate genes for the onset of type 2 diabetes associated with obesity in rats.

PubMed

Sasaki, Daiki; Kotoh, Jun; Watadani, Risa; Matsumoto, Kozo

2015-12-01

Obesity is a major risk factor for the onset of type 2 diabetes; however, little is known about the gene(s) involved. Therefore, we developed new animal models of obesity to search for diabetogenic genes associated with obesity. We generated double congenic rat strains with a hyperglycaemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr-/-) locus derived from the Zucker Fatty rat; phenotypic analysis for plasma glucose and insulin levels and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blotting analyses, respectively. The double congenic strain F344-fa-nidd2 (Lepr-/- and Nidd2/of) exhibited significantly higher glucose levels and significantly lower hypoglycaemic response to insulin than the obese control strain F344-fa (Lepr-/-). These phenotypes were clearly observed in the obese strains but not in the lean strains. These results indicate that the Nidd2/of locus harbours a diabetogenic gene associated with obesity. We measured the expression of 60 genes in the Nidd2/of QTL region between the strains and found that the mRNA expression levels of five genes were significantly different between the strains under the condition of obesity. However, three of the five genes were differentially expressed in both obese and lean rats, indicating that these genes are not specific for the condition of obesity. Conversely, the other two genes, coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8), were differentially expressed only in the obese rats, suggesting that these two genes are candidates for the onset of type 2 diabetes associated with obesity in rats.

Association between omega-3 fatty acids consumption and the risk of type 2 diabetes: A meta-analysis of cohort studies.

PubMed

Chen, Cai; Yang, Yan; Yu, Xuefeng; Hu, Shuhong; Shao, Shiying

2017-07-01

Epidemiological evidence for the effect of omega-3 fatty acids on the risk of type 2 diabetes is controversial. A meta-analysis based on prospective cohorts was carried out to evaluate this issue. Pooled diabetic risk was calculated using a fixed or random effects model. The dose-response relationship was assessed by meta-regression analysis. The study showed that consumption of single omega-3 was associated with an increased risk of type 2 diabetes (relative risk [RR] = 1.45, P < 0.001); whereas the RR for mixed omega-3 was statistically insignificant. The dose-response curve presented an inverted U-shape of diabetes risk corresponding to the dose of omega-3 consumption. Subanalysis showed that omega-3 was inversely associated with type 2 diabetes risk in Asians (RR = 0.82, P < 0.001); whereas the risk was increased in Westerners (RR = 1.30, P < 0.001). Studies with follow-up duration ≥16 years and baseline age ≥54 years showed a positive association between type 2 diabetes risk and omega-3 intake. The present findings suggest that dosage and composition of omega-3, ethnicity, trial duration, and age could influence the effect of omega-3 on type 2 diabetes progression. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Prevalence and clinical characteristics of non-alcoholic fatty liver disease in newly diagnosed patients with ketosis-onset diabetes.

PubMed

Li, T-T; Wang, A-P; Lu, J-X; Chen, M-Y; Zhao, C-C; Tang, Z-H; Li, L-X; Jia, W-P

2018-03-21

As the prevalence and clinical characteristics of non-alcoholic fatty liver disease (NAFLD) are still unknown in ketosis-onset diabetes, the present study compared the characteristics of NAFLD in type 1 diabetes (T1D), ketosis-onset and non-ketotic type 2 diabetes (T2D) patients. This cross-sectional study was performed with newly diagnosed Chinese patients with diabetes, including 39 T1D, 165 ketosis-onset and 173 non-ketotic T2D, with 30 non-diabetics included as controls. NAFLD was determined by hepatic ultrasonography, then its clinical features were analyzed and its associated risk factors evaluated. NAFLD prevalence in patients with ketosis-onset diabetes (61.8%) was significantly higher than in controls (23.3%; P=0.003) and in T1D patients (15.4%; P<0.001). However, there was no difference in prevalence between ketosis-onset and non-ketotic T2D patients (52.6%; P=0.229), although BMI and alanine aminotransferase (ALT) proved to be independent risk factors for the presence of NAFLD in both these groups whereas, in T1D patients, serum uric acid levels were independent risk factors. NAFLD prevalence and risk factors in ketosis-onset diabetes were similar to those in non-ketotic T2D, but different from those in T1D. These data provide further evidence that ketosis-onset diabetes should be classified as a subtype of T2D rather than idiopathic T1D. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Effects of coronary artery disease and percutaneous intervention on the cardiac metabolism of nonesterified fatty acids and insulin: Implications of diabetes mellitus.

PubMed

Jaumdally, R J; Lip, G Y H; Patel, J V; MacFadyen, R J; Varma, C

2009-06-01

Nonesterified fatty acids (NEFA) and insulin have been implicated in the pathogenesis of diabetes mellitus (Type 2 diabetes) and coronary artery disease (CAD). We hypothesized that intracardiac levels of insulin and NEFA within the aortic root, coronary sinus and systemic venous levels would be different in patients with coronary atherosclerosis and/or diabetes. We also studied the metabolic cardiac response following percutaneous coronary intervention (PCI). A total of 67 subjects (42 males; mean age 60 +/- 11 years) were recruited, of which three groups were identified: Group I - those with no CAD or Type 2 diabetes (n = 17); Group II - those with CAD but no Type 2 diabetes (n = 40); and Group III - patients with Type 2 diabetes and CAD (n = 10). Of the whole cohort, 34 patients (51%) proceeded to PCI. NEFA and insulin levels were analysed using enzymatic colorimetric and a monoclonal immuno-autoanalyser techniques, respectively. Subsequently, fractional extraction (FFE) of both variables was calculated. Nonesterified fatty acids and insulin concentrations were lower in the aortic root versus coronary sinus (both P < 0.05). FFE of NEFA was 2x higher in Group I (P < 0.01) with a sevenfold reduction in insulin FFE in Group III. Following PCI, systemic NEFA levels increased significantly (P < 0.05) with no significant change seen within the coronary sinus (P = NS), whilst a reduction in insulin concentrations at all three sites was observed (all P < 0.01). No significant difference in FFE of NEFA was seen after PCI when comparing Groups II and III. There was a drop in insulin extraction in Group II (nondiabetic subjects, from 12% to -4%, P = 0.04), compared with an increase seen in Group III (Type 2 diabetes patients, from -4% to 3%, P = 0.03). There is an intracardiac gradient of NEFA and insulin in Groups I-III. Cardiac NEFA metabolism was higher in those with mild CAD compared with those with obstructive CAD whereas intracardiac insulin extraction was lower in

Protein source in a high-protein diet modulates reductions in insulin resistance and hepatic steatosis in fa/fa Zucker rats.

PubMed

Wojcik, Jennifer L; Devassy, Jessay G; Wu, Yinghong; Zahradka, Peter; Taylor, Carla G; Aukema, Harold M

2016-01-01

High-protein diets are being promoted to reduce insulin resistance and hepatic steatosis in metabolic syndrome. Therefore, the effect of protein source in high-protein diets on reducing insulin resistance and hepatic steatosis was examined. Fa/fa Zucker rats were provided normal-protein (15% of energy) casein, high-protein (35% of energy) casein, high-protein soy, or high-protein mixed diets with animal and plant proteins. The high-protein mixed diet reduced area under the curve for insulin during glucose tolerance testing, fasting serum insulin and free fatty acid concentrations, homeostatic model assessment index, insulin to glucose ratio, and pancreatic islet cell area. The high-protein mixed and the high-protein soy diets reduced hepatic lipid concentrations, liver to body weight ratio, and hepatic steatosis rating. These improvements were observed despite no differences in body weight, feed intake, or adiposity among high-protein diet groups. The high-protein casein diet had minimal benefits. A high-protein mixed diet was the most effective for modulating reductions in insulin resistance and hepatic steatosis independent of weight loss, indicating that the source of protein within a high-protein diet is critical for the management of these metabolic syndrome parameters. © 2015 The Obesity Society.

Changes in UCP expression in tissues of Zucker rats fed diets with different protein content.

PubMed

Masanés, R M; Yubero, P; Rafecas, I; Remesar, X

2002-09-01

The effect of dietary protein content on the uncoupling proteins (UCP) 1, 2 and 3 expression in a number of tissues of Zucker lean and obese rats was studied. Thirty-day-old male Zucker lean (Fa/?) and obese (fa/fa) rats were fed on hyperproteic (HP, 30% protein), standard (RD, 17% protein) or hypoproteic (LP, 9% protein) diets ad libitum for 30 days. Although dietary protein intake affected the weights of individual muscles in lean and obese animals, these weights were similar. In contrast, huge differences were observed in brown adipose tissue (BAT) and liver weights. Lean rats fed on the LP diet generally increased UCP expression, whereas the HP group had lower values. Obese animals, HP and LP groups showed higher UCP expression in muscles, with slight differences in BAT and lower values for UCP3 in subcutaneous adipose tissue. The mean values of UCP expression in BAT of obese rats were lower than in their lean counterpart, whereas the expression in skeletal muscle was increased. Thus, expression of UCPs can be modified by dietary protein content, in lean and obese rats. A possible thermogenic function of UCP3 in muscle and WAT in obese rats must be taken into account.

Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

PubMed

Williamson, Rachel M; Price, Jackie F; Glancy, Stephen; Perry, Elisa; Nee, Lisa D; Hayes, Peter C; Frier, Brian M; Van Look, Liesbeth A F; Johnston, Geoffrey I; Reynolds, Rebecca M; Strachan, Mark W J

2011-05-01

Type 2 diabetes is an established risk factor for development of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). We aimed to determine the prevalence and clinical correlates of these conditions in a large cohort of people with type 2 diabetes. A total of 939 participants, aged 61-76 years, from the Edinburgh Type 2 Diabetes Study (ET2DS)-a large, randomly selected population of people with type 2 diabetes-underwent liver ultrasonography. Ultrasound gradings of steatosis were compared with magnetic resonance spectroscopy in a subgroup. NAFLD was defined as hepatic steatosis in the absence of a secondary cause (screened by questionnaire assessing alcohol and hepatotoxic medication use, plasma hepatitis serology, autoantibodies and ferritin, and record linkage to determine prior diagnoses of liver disease). Binary logistic regression was used to analyze independent associations of characteristics with NAFLD. Hepatic steatosis was present in 56.9% of participants. After excluding those with a secondary cause for steatosis, the prevalence of NAFLD in the study population was 42.6%. Independent predictors of NAFLD were BMI, lesser duration of diabetes, HbA(1c), triglycerides, and metformin use. These remained unchanged after exclusion of participants with evidence of hepatic fibrosis from the group with no hepatic steatosis. Prevalences of hepatic steatosis and NAFLD were high in this unselected population of older people with type 2 diabetes, but lower than in studies in which ultrasound gradings were not compared with a gold standard. Associations with features of the metabolic syndrome could be used to target screening for this condition.

Effects of alpha lipoic acid, ascorbic acid-6-palmitate, and fish oil on the glutathione, malonaldehyde, and fatty acids levels in erythrocytes of streptozotocin induced diabetic male rats.

PubMed

Yilmaz, Okkeş; Ozkan, Yusuf; Yildirim, Mehmet; Oztürk, A Ihsan; Erşan, Yasemin

2002-01-01

In this research, it has been aimed to evaluate the improvement effects of alpha lipoic acid (ALA), ascorbic acid-6-palmitate (AA6P), fish oil (FO), and their combination (COM) on some biochemical properties in erythrocytes of streptozotocin (STZ)-induced diabetic male rats. According to experimental results, glutathione (GSH) level in erythrocytes decreased in diabetes (P < 0.01), D + ALA, and D + AA6P groups (P < 0.001). Malonaldehyde (MA) level increased in diabetes (P < 0.05), D + FO, and D + COM groups (P < 0.001), but its level in D + AA6P and D + ALA groups was lower in diabetes group (P < 0.01). Total lipid level in diabetes and diabetes plus antioxidant administered groups were higher than control. Total cholesterol level was high in diabetes and D + ALA groups (P < 0.05), but its level reduced in D + FO compared to control and diabetes groups, P < 0.05, < 0.001, respectively. Total triglyceride (TTG) level was high in the D + ALA (P < 0.05) and D + COM (P < 0.001) groups. In contrast, TTG level in blood of diabetes group was higher than diabetes plus antioxidant and FO administered groups (P < 0.001). According to gas chromatography analysis results, while the palmitic acid raised in diabetes group (P < 0.05), stearic acid in D + FO, D + ALA, and diabetes groups was lower than control (P < 0.05), oleic acid reduced in D + COM and D + FO groups, but its level raised in D + AA6P and D + ALA groups (P < 0.01). As the linoleic acid (LA) elevated in ALA + D, D + AA6P, and diabetes groups, linolenic acid level in diabetes, D + AA6P, and D + FO groups was lower than control (P < 0.001). Arachidonic acid (AA) decreased in D + ALA, D+ AA6P, and diabetes groups (P < 0.01), but its level in D + COM and D + FO was higher than control (P < 0.05). Docosahexaenoic acid (DHA) increased in D + AA6P and D + COM (P < 0.05). While the total saturated fatty acid level raised in diabetes group, its level reduced in D + ALA and D + FO groups (P < 0.05). In contrast, total

Local Non-Esterified Fatty Acids Correlate With Inflammation in Atheroma Plaques of Patients With Type 2 Diabetes

PubMed Central

Mas, Sebastián; Martínez-Pinna, Roxana; Martín-Ventura, Jose Luis; Pérez, Raul; Gomez-Garre, Dulcenombre; Ortiz, Alberto; Fernandez-Cruz, Arturo; Vivanco, Fernando; Egido, Jesús

2010-01-01

OBJECTIVE Atherosclerosis is prevalent in diabetic patients, but there is little information on the localization of nonesterified fatty acids (NEFAs) within the plaque and their relationship with inflammation. We sought to characterize the NEFA composition and location in human diabetic atheroma plaques by metabolomic analysis and imaging and to address their relationship with inflammation activity. RESEARCH DESIGN AND METHODS Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used for metabolomic analysis imaging of frozen carotid atheroma plaques. Carotid endarterectomy specimens were used for conventional immunohistochemistry, laser-capture microdissection quantitative PCR, and in situ Southwestern hybridization. Biological actions of linoleic acid were studied in cultured vascular smooth muscle cells (VSMCs). RESULTS TOF-SIMS imaging evidenced a significant increase in the quantity of several NEFA in diabetic versus nondiabetic atheroma plaques. Higher levels of NEFA were also found in diabetic sera. The presence of LPL mRNA in NEFA-rich areas of the atheroma plaque, as well as the lack of correlation between serum and plaque NEFA, suggests a local origin for plaque NEFA. The pattern of distribution of plaque NEFA is similar to that of MCP-1, LPL, and activated NF-κB. Diabetic endarterectomy specimens showed higher numbers of infiltrating macrophages and T-lymphocytes—a finding that associated with higher NEFA levels. Finally, linoleic acid activates NF-κB and upregulates NF-κB–mediated LPL and MCP-1 expression in cultured VSMC. DISCUSSION There is an increased presence of NEFA in diabetic plaque neointima. NEFA levels are higher in diabetic atheroma plaques than in nondiabetic subjects. We hypothesize that NEFA may be produced locally and contribute to local inflammation. PMID:20200316

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease.

PubMed

Vanjiappan, Sivabal; Hamide, Abdoul; Ananthakrishnan, Ramesh; Periyasamy, Senthilkumar Gandhipuram; Mehalingam, Vadivelan

2018-01-31

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them. Prospective observational study. The study was conducted on 300 patients with type 2 diabetes mellitus attending the outpatient department of a tertiary care teaching hospital. All patients underwent hepatic ultrasonography to look for hepatic steatosis. Among the 300 patients, 124 were divided into NAFLD and non-NAFLD groups based on the ultrasound findings. These patients were subjected to electrocardiogram, 2D echocardiogram, carotid intima media thickness (CIMT) measurement and ankle brachial pressure index measurement along with measurement of markers of oxidative stress. Hepatic steatosis was present in 61% of diabetic patients in this study. Cardiovascular disease was not found to be significantly associated in diabetic patients with NAFLD. However, cardiovascular risk factors like CIMT, high sensitivity c-reactive protein (hs-CRP) and malondialdehyde (MDA) were elevated in these patients. hs-CRP and MDA levels were found to be significantly associated with the severity of NAFLD. There is a high prevalence of NAFLD in type 2 diabetic patients. No correlation was detected between the presence of NAFLD and cardiovascular disease in them; although there was an association between cardiovascular risk factors and NAFLD. Copyright © 2018. Published by Elsevier Ltd.

Omega-6 fatty acid biomarkers and incident type 2 diabetes: Pooled analysis of individual-level data for 39740 adults from 20 prospective cohort studies

USDA-ARS?s Scientific Manuscript database

The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2...

Metabolism, hypoxia and the diabetic heart.

PubMed

Heather, Lisa C; Clarke, Kieran

2011-04-01

The diabetic heart becomes metabolically remodelled as a consequence of exposure to abnormal circulating substrates and hormones. Fatty acid uptake and metabolism are increased in the type 2 diabetic heart, resulting in accumulation of intracellular lipid intermediates and an increased contribution of fatty acids towards energy generation. Cardiac glucose uptake and oxidation are decreased, predominantly due to increased fatty acid metabolism, which suppresses glucose utilisation via the Randle cycle. These metabolic changes decrease cardiac efficiency and energetics in both humans and animal models of diabetes. Diabetic hearts have decreased recovery following ischemia, indicating a reduced tolerance to oxygen-limited conditions. There is evidence that diabetic hearts have a compromised hypoxia signalling pathway, as hypoxia-inducible factor (HIF) and downstream signalling from HIF are reduced following ischemia. Failure to activate HIF under oxygen-limited conditions results in less angiogenesis, and an inability to upregulate glycolytic ATP generation. Given that glycolysis is already suppressed in the diabetic heart under normoxic conditions, the inability to upregulate glycolysis in response to hypoxia may have deleterious effects on ATP production. Thus, impaired HIF signalling may contribute to metabolic and energetic abnormalities, and impaired collateral vessel development following myocardial infarction in the type 2 diabetic heart. Copyright © 2011 Elsevier Ltd. All rights reserved.

RABL2 Is Required for Hepatic Fatty Acid Homeostasis and Its Dysfunction Leads to Steatosis and a Diabetes-Like State.

PubMed

Yi Lo, Jennifer Chi; O'Connor, Anne E; Andrews, Zane B; Lo, Camden; Tiganis, Tony; Watt, Matthew J; O'Bryan, Moira K

2016-12-01

Fatty liver, or hepatic steatosis, is an alarmingly common pathology in western societies, in large part because if left unheeded, it can lead to life-threatening forms of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. As such, it is essential that we attain a greater understanding of the pathways that control energy partitioning in the liver and ultimately how they are impacted by environmental factors. Here, we define the essential requirement for a member of the Ras-related protein in the brain (RAB)-like (RABL) clade of small GTPases, RABL2, in fatty acid metabolism including in microtubule-associated mitochondrial movement within the liver. RABL2 dysfunction, even in mice fed a low-fat chow diet, leads to retarded hepatic mitochondria movement associated with and a cascading phenotype of interrelated metabolic defects reminiscent of a type 2 diabetic state: hepatic steatosis, insulin resistance, glucose intolerance, and adult onset obesity. RABL2 dysfunction does not, however, alter mitochondrial content, or the inherent respiratory capacity of individual mitochondria per se. Rather, it is associated with a decreased capacity for fatty oxidation in the context of the intact cell, suggesting a complex, and important, role for mitochondrial movement in metabolic health. Our data highlight the importance of RABL2 and mitochondrial dynamics in hepatic fatty acid oxidation and in the achievement of metabolic balance.

Non-alcoholic fatty liver disease predicts type 2 diabetes mellitus, but not prediabetes, in Xi'an, China: a five-year cohort study.

PubMed

Ming, Jie; Xu, Shaoyong; Gao, Bin; Liu, Guocai; Ji, Yufei; Yang, Fan; Jia, Yunan; Fang, Yujie; Ji, Qiuhe

2015-11-01

Emerging studies have focused the association between non-alcoholic fatty liver disease (NAFLD) and the risk of type 2 diabetes mellitus (T2DM) but the results were inconsistent. In addition, few studies have put focus on the association between NAFLD and the risk of prediabetes. We aimed to investigate whether NAFLD diagnosed by ultrasonography could predict the risk of future T2DM and prediabetes in Chinese population. The population-based cohort study held in Xi'an, Northwestern China, was based on China National Diabetes and Metabolic Disorders Survey. During a follow-up of 5 years, 508 healthy subjects were included as study sample. NAFLD was determined by abdominal ultrasonography. T2DM and prediabetes were diagnosed based on oral glucose tolerance test. Of 508 subjects, 97 (19.1%) were diagnosed as NAFLD and 411 (80.9%) were as non-NAFLD; 20 (3.9%) developed diabetes and 85 (16.7%) developed prediabetes during follow-up. The incidence of diabetes and prediabetes in the NAFLD group was 20.6 and 51.6 per 1000 person-years, respectively, whereas that in non-NAFLD group was 4.9 and 29.2 per 1000 person-years respectively. Cox proportional hazard regression showed that the multivariable-adjusted relative risk (RR) of T2DM and prediabetes in the NAFLD group was 4.462 [95% confidence interval (CI): 1.855-10.734, P < 0.001] and 1.642 (95% CI: 0.965-2.793, P = 0.067), respectively, compared with non-NAFLD group. Non-alcoholic fatty liver disease was a significant predictor for future diabetes, but not for prediabetes, in Xi'an, China. More cohort studies are needed to confirm our findings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Differences in the Serum Nonesterified Fatty Acid Profile of Young Women Associated with a Recent History of Gestational Diabetes and Overweight/Obesity

PubMed Central

Fugmann, Marina; Uhl, Olaf; Hellmuth, Christian; Hetterich, Holger; Kammer, Nora N.; Ferrari, Uta; Parhofer, Klaus G.; Koletzko, Berthold; Seissler, Jochen; Lechner, Andreas

2015-01-01

Background Nonesterified fatty acids (NEFA) play pathophysiological roles in metabolic syndrome and type 2 diabetes (T2D). In this study, we analyzed the fasting NEFA profiles of normoglycemic individuals at risk for T2D (women with a recent history of gestational diabetes (GDM)) in comparison to controls (women after a normoglycemic pregnancy). We also examined the associations of NEFA species with overweight/obesity, body fat distribution and insulin sensitivity. Subjects and Methods Using LC-MS/MS, we analyzed 41 NEFA species in the fasting sera of 111 women (62 post-GDM, 49 controls). Clinical characterization included a five-point oral glucose tolerance test (OGTT), biomarkers and anthropometrics, magnetic resonance imaging (n = 62) and a food frequency questionnaire. Nonparametric tests with Bonferroni correction, binary logistic regression analyses and rank correlations were used for statistical analysis. Results Women after GDM had a lower molar percentage of total saturated fatty acids (SFA; 38.55% vs. 40.32%, p = 0.0002) than controls. At an explorative level of significance several NEFA species were associated with post-GDM status (with and without adjustment for body mass index (BMI) and HbA1c): The molar percentages of 14:0, 16:0, 18:0 and 18:4 were reduced, whereas those of 18:1, 18:2, 20:2, 24:4, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and total n-6 NEFA were increased. BMI and the amount of body fat correlated inversely with several SFA and MUFA and positively with various PUFA species over the whole study cohort (abs(ρ)≥0.3 for all). 14:0 was inversely and BMI-independently associated with abdominal visceral adiposity. We saw no correlations of NEFA species with insulin sensitivity and the total NEFA concentration was similar in the post-GDM and the control group. Conclusion In conclusion, we found alterations in the fasting NEFA profile associated with a recent history of gestational diabetes, a risk marker for T2

Roux-en Y gastric bypass is superior to duodeno-jejunal bypass in improving glycaemic control in Zucker diabetic fatty rats.

PubMed

Seyfried, Florian; Bueter, Marco; Spliethoff, Kerstin; Miras, Alexander D; Abegg, Kathrin; Lutz, Thomas A; le Roux, Carel W

2014-11-01

Whilst weight loss results in many beneficial metabolic consequences, the immediate improvement in glycaemia after Roux-en-Y Gastric bypass (RYGB) remains intriguing. Duodenal jejunal bypass (DJB) induces similar glycaemic effects, while not affecting calorie intake or weight loss. We studied diabetic ZDF(fa/fa) rats to compare the effects of DJB and RYGB operations on glycaemia. Male ZDF(fa/fa) rats, aged 12 weeks underwent RYGB, DJB or sham operations. Unoperated ZDF(fa/fa) and ZDF(fa/+w)ere used as controls. Body weight, food intake, fasting glucose, insulin and gut hormones were measured at baseline and on postoperative days 2, 10 and 35. An oral glucose tolerance test (OGTT) was performed on days 12 and 26. DJB had similar food intake and body weight to sham-operated and unoperated control ZDF(fa/fa) rats (p = NS), but had lower fasting glucose (p < 0.05). RYGB had lower food intake, body weight and fasting glucose compared to all groups (p < 0.001). DJB prevented the progressive decline in fasting insulin observed in the sham-operated or unoperated ZDF(fa/fa) rats, while RYGB with normalized glycaemia reduced the physiological requirement for raised fasting insulin. Bypassing the proximal small bowel with the DJB has mild to moderate body weight independent effects on glucose homeostasis and preservation of fasting insulin levels in the medium term. These effects might be further amplified by the additional anatomical and physiological changes after RYGB.

Defects in oxygen supply to skeletal muscle of prediabetic ZDF rats

PubMed Central

Goldman, Daniel; Hanson, Madelyn; Stephenson, Alan H.; Milkovich, Stephanie; Benlamri, Amina; Ellsworth, Mary L.; Sprague, Randy S.

2010-01-01

In humans, prediabetes is characterized by marked increases in plasma insulin and near normal blood glucose levels as well as microvascular dysfunction of unknown origin. Using the extensor digitorum longus muscle of 7-wk inbred male Zucker diabetic fatty rats fed a high-fat diet as a model of prediabetes, we tested the hypothesis that hyperinsulinemia contributes to impaired O2 delivery in skeletal muscle. Using in vivo video microscopy, we determined that the total O2 supply to capillaries in the extensor digitorum longus muscle of prediabetic rats was reduced to 64% of controls with a lower O2 supply rate per capillary and higher O2 extraction resulting in a decreased O2 saturation at the venous end of the capillary network. These findings suggest a lower average tissue Po2 in prediabetic animals. In addition, we determined that insulin, at concentrations measured in humans and Zucker diabetic fatty rats with prediabetes, inhibited the O2-dependent release of ATP from rat red blood cells (RBCs). This inability to release ATP could contribute to the impaired O2 delivery observed in rats with prediabetes, especially in light of the finding that the endothelium-dependent relaxation of resistance arteries from these animals is not different from controls and is not altered by insulin. Computational modeling confirmed a significant 8.3-mmHg decrease in average tissue Po2 as well as an increase in the heterogeneity of tissue Po2, implicating a failure of a regulatory system for O2 supply. The finding that insulin attenuates the O2-dependent release of ATP from RBCs suggests that this defect in RBC physiology could contribute to a failure in the regulation of O2 supply to meet the demand in skeletal muscle in prediabetes. PMID:20207810

A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.

PubMed

Jang, Cholsoon; Oh, Sungwhan F; Wada, Shogo; Rowe, Glenn C; Liu, Laura; Chan, Mun Chun; Rhee, James; Hoshino, Atsushi; Kim, Boa; Ibrahim, Ayon; Baca, Luisa G; Kim, Esl; Ghosh, Chandra C; Parikh, Samir M; Jiang, Aihua; Chu, Qingwei; Forman, Daniel E; Lecker, Stewart H; Krishnaiah, Saikumari; Rabinowitz, Joshua D; Weljie, Aalim M; Baur, Joseph A; Kasper, Dennis L; Arany, Zoltan

2016-04-01

Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

Role of 14-3-3η protein on cardiac fatty acid metabolism and macrophage polarization after high fat diet induced type 2 diabetes mellitus.

PubMed

Sreedhar, Remya; Arumugam, Somasundaram; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Koga, Yusuke; Nakamura, Takashi; Harima, Meilei; Watanabe, Kenichi

2017-07-01

Diabetic cardiomyopathy (DCM), a metabolic disorder, is one of the leading causes of mortality around the world and its pathogenesis involves cardiac inflammation and altered metabolic profile. Altered fatty acid metabolism during DCM can cause macrophage polarization in which inflammatory M1 phenotype dominates over the anti-inflammatory M2 phenotype. Hence, it is essential to identify a specific target, which could revert the metabolic profile and thereby reducing the M1 macrophage polarization. 14-3-3η protein has several cellular protective functions especially in the heart as plenty of reports available in various animal models of heart failure including diabetes mellitus. However, its role in the cardiac fatty acid metabolism and macrophage polarization remains unidentified. The present study has been designed to delineate the effect of cardiospecific dominant negative mutation of 14-3-3η protein (DN14-3-3) on various lipid metabolism related marker proteins expressions and cardiac macrophage phenotype in high fat diet (HFD) fed mice. Feeding HFD for 12 weeks has produced significant increase in body weight in the DN14-3-3 (TG) mice than C57BL6/J (WT) mice. Western blotting and immunohistochemical staining analysis of the heart tissue has revealed an increase in the expression of markers of cardiac fatty acid synthesis related proteins in addition to the reduced expression of fatty acid oxidation related proteins in TG mice fed HFD than WT mice fed HFD. Furthermore, the M1 macrophage marker proteins were increasingly expressed while M2 markers expressions were reduced in the hearts of TG mice fed HFD. In conclusion, our current study has identified that there is a definite role for the 14-3-3η protein against the pathogenesis of heart failure via regulation of cardiac fatty acid metabolism and macrophage polarization. Copyright © 2017. Published by Elsevier Ltd.

Plasma Levels of Fatty Acid-Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes: A 22-Year Prospective Study.

PubMed

Liu, Gang; Ding, Ming; Chiuve, Stephanie E; Rimm, Eric B; Franks, Paul W; Meigs, James B; Hu, Frank B; Sun, Qi

2016-11-01

To examine select adipokines, including fatty acid-binding protein 4, retinol-binding protein 4, and high-molecular-weight (HMW) adiponectin in relation to cardiovascular disease (CVD) mortality among patients with type 2 diabetes mellitus. Plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, and HMW adiponectin were measured in 950 men with type 2 diabetes mellitus in the Health Professionals Follow-up Study. After an average of 22 years of follow-up (1993-2015), 580 deaths occurred, of whom 220 died of CVD. After multivariate adjustment for covariates, higher levels of fatty acid-binding protein 4 were significantly associated with a higher CVD mortality: comparing extreme tertiles, the hazard ratio and 95% confidence interval of CVD mortality was 1.78 (1.22-2.59; P trend=0.001). A positive association was also observed for HMW adiponectin: the hazard ratio (95% confidence interval) was 2.07 (1.42-3.06; P trend=0.0002), comparing extreme tertiles, whereas higher retinol-binding protein 4 levels were nonsignificantly associated with a decreased CVD mortality with an hazard ratio (95% confidence interval) of 0.73 (0.50-1.07; P trend=0.09). A Mendelian randomization analysis suggested that the causal relationships of HMW adiponectin and retinol-binding protein 4 would be directionally opposite to those observed based on the biomarkers, although none of the Mendelian randomization associations achieved statistical significance. These data suggest that higher levels of fatty acid-binding protein 4 and HMW adiponectin are associated with elevated CVD mortality among men with type 2 diabetes mellitus. Biological mechanisms underlying these observations deserve elucidation, but the associations of HMW adiponectin may partially reflect altered adipose tissue functionality among patients with type 2 diabetes mellitus. © 2016 American Heart Association, Inc.

The influence of major dietary fatty acids on insulin secretion and action.

PubMed

López, Sergio; Bermúdez, Beatriz; Abia, Rocío; Muriana, Francisco J G

2010-02-01

To briefly summarize recent advances towards understanding the influence of major dietary fatty acids on beta-cell function and evaluate their implications for insulin resistance. Studies in humans have shown that beta-cell function and insulin sensitivity improve progressively in the postprandial period as the proportion of monounsaturated fatty acids (MUFAs) with respect to saturated fatty acids (SFAs) in dietary fats increases. However, cell-culture experiments have revealed a dichotomy in the ability of fatty acids to moderate hyperactivity of, and induce lipotoxicity in, beta-cells. There are also some novel findings regarding the ability of HDL to protect beta-cells against oxidized LDL-induced apoptosis in vitro and of reconstituted HDL to attenuate insulin resistance in vivo. These findings raise new questions regarding the contribution of dietary fatty acids to insulin secretion and action. These new findings point to a critical role for major dietary fatty acids in the etiology and pathogenesis of diabetes, which appears to be of particular relevance during postprandial periods and mainly depends on the fatty acid type. This underscores the importance of dietary fatty acids in standard diabetes management.

Effects of insulin therapy on porosity, non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitus.

PubMed

Campbell, G M; Tiwari, S; Picke, A-K; Hofbauer, C; Rauner, M; Morlock, M M; Hofbauer, L C; Glüer, C-C

2016-10-01

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+50.1%, p=0.001) and Ct.Po (+22.9%, p=0.004), as well as to reduced mechanical competence (max. stress: -14.2%, p=0.041, toughness: -29.7%, p=0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R(2)=0.41, p<0.001, Ct.Po: R(2)=0.34, p=0.003) and HbA1c (NEG: R(2)=0.42, p<0.001, Ct.Po: R(2)=0.28, p=0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R(2)=0.21, p=0.023, yield stress: R(2)=0.17, p=0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone. Copyright © 2016 Elsevier Inc. All rights reserved.

Serum Fatty Acid Binding Protein 4 (FABP4) Predicts Pre-eclampsia in Women With Type 1 Diabetes.

PubMed

Wotherspoon, Amy C; Young, Ian S; McCance, David R; Patterson, Chris C; Maresh, Michael J A; Pearson, Donald W M; Walker, James D; Holmes, Valerie A

2016-10-01

To examine the association between fatty acid binding protein 4 (FABP4) and pre-eclampsia risk in women with type 1 diabetes. Serum FABP4 was measured in 710 women from the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) in early pregnancy and in the second trimester (median 14 and 26 weeks' gestation, respectively). FABP4 was significantly elevated in early pregnancy (geometric mean 15.8 ng/mL [interquartile range 11.6-21.4] vs. 12.7 ng/mL [interquartile range 9.6-17]; P < 0.001) and the second trimester (18.8 ng/mL [interquartile range 13.6-25.8] vs. 14.6 ng/mL [interquartile range 10.8-19.7]; P < 0.001) in women in whom pre-eclampsia later developed. Elevated second-trimester FABP4 level was independently associated with pre-eclampsia (odds ratio 2.87 [95% CI 1.24-6.68], P = 0.03). The addition of FABP4 to established risk factors significantly improved net reclassification improvement at both time points and integrated discrimination improvement in the second trimester. Increased second-trimester FABP4 independently predicted pre-eclampsia and significantly improved reclassification and discrimination. FABP4 shows potential as a novel biomarker for pre-eclampsia prediction in women with type 1 diabetes. © 2016 by the American Diabetes Association.

Metabolomic Profiling of Fatty Acid and Amino Acid Metabolism in Youth With Obesity and Type 2 Diabetes

PubMed Central

Mihalik, Stephanie J.; Michaliszyn, Sara F.; de las Heras, Javier; Bacha, Fida; Lee, SoJung; Chace, Donald H.; DeJesus, Victor R.; Vockley, Jerry; Arslanian, Silva A.

2012-01-01

OBJECTIVE We compared acylcarnitine (AcylCN) species, common amino acid and fat oxidation (FOX) byproducts, and plasma amino acids in normal weight (NW; n = 39), obese (OB; n = 64), and type 2 diabetic (n = 17) adolescents. RESEARCH DESIGN AND METHODS Fasting plasma was analyzed by tandem mass spectrometry, body composition by dual energy X-ray absorptiometry and computed tomography, and total-body lipolysis and substrate oxidation by [2H5]glycerol and indirect calorimetry, respectively. In vivo insulin sensitivity (IS) was assessed with a 3-h hyperinsulinemic-euglycemic clamp. RESULTS Long-chain AcylCNs (C18:2-CN to C14:0-CN) were similar among the three groups. Medium- to short-chain AcylCNs (except C8 and C10) were significantly lower in type 2 diabetes compared with NW, and when compared with OB, C2-, C6-, and C10-CN were lower. Amino acid concentrations were lower in type 2 diabetes compared with NW. Fasting lipolysis and FOX were higher in OB and type 2 diabetes compared with NW, and the negative association of FOX to C10:1 disappeared after controlling for adiposity, Tanner stage, and sex. IS was lower in OB and type 2 diabetes with positive associations between IS and arginine, histidine, and serine after adjusting for adiposity, Tanner stage, and sex. CONCLUSIONS These metabolomics results, together with the increased rates of in vivo FOX, are not supportive of defective fatty acid or amino acid metabolism in obesity and type 2 diabetes in youth. Such observations are consistent with early adaptive metabolic plasticity in youth, which over time—with continued obesity and aging—may become dysfunctional, as observed in adults. PMID:22266733

The association of substituting carbohydrates with total fat and different types of fatty acids with mortality and weight change among diabetes patients.

PubMed

Campmans-Kuijpers, Marjo J; Sluijs, Ivonne; Nöthlings, Ute; Freisling, Heinz; Overvad, Kim; Boeing, Heiner; Masala, Giovanna; Panico, Salvatore; Tumino, Rosario; Sieri, Sabina; Johansson, Ingegerd; Winkvist, Anna; Katzke, Verena A; Kuehn, Tilman; Nilsson, Peter M; Halkjær, Jytte; Tjønneland, Anne; Spijkerman, Annemieke M; Arriola, Larraitz; Sacerdote, Carlotta; Barricarte, Aurelio; May, Anne M; Beulens, Joline W

2016-10-01

Substitution of carbohydrates with fat in a diet for type 2 diabetes patients is still debated. This study aimed to investigate the association between dietary carbohydrate intake and isocaloric substitution with (i) total fat, (ii) saturated fatty acids (SFA), (iii) mono-unsaturated fatty acids (MUFA) and (iv) poly-unsaturated fatty acids (PUFA) with all-cause and cardiovascular (CVD) mortality risk and 5-year weight change in patients with type 2 diabetes. The study included 6192 patients with type 2 diabetes from 15 cohorts of the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake was assessed at recruitment with country-specific food-frequency questionnaires. Cox and linear regression were used to estimate the associations with (CVD) mortality and weight change, adjusting for confounders and using different methods to adjust for energy intake. After a mean follow-up of 9.2 y ± SD 2.3 y, 791 (13%) participants had died, of which 268 (4%) due to CVD. Substituting 10 g or 5 energy% of carbohydrates by total fat was associated with a higher all-cause mortality risk (HR 1.07 [1.02-1.13]), or SFAs (HR 1.25 [1.11-1.40]) and a lower risk when replaced by MUFAs (HR 0.89 [0.77-1.02]). When carbohydrates were substituted with SFAs (HR 1.22 [1.00-1.49]) or PUFAs (HR 1.29 [1.02-1.63]) CVD mortality risk increased. The 5-year weight was lower when carbohydrates were substituted with total fat or MUFAs. These results were consistent over different energy adjustment methods. In diabetes patients, substitution of carbohydrates with SFAs was associated with a higher (CVD) mortality risk and substitution by total fat was associated with a higher all-cause mortality risk. Substitution of carbohydrates with MUFAs may be associated with lower mortality risk and weight reduction. Instead of promoting replacement of carbohydrates by total fat, dietary guideline should continue focusing on replacement by fat-subtypes; especially SFAs by MUFAs

Heart-type fatty acid binding protein levels in elderly diabetics without known cardiovascular disease.

PubMed

Beysel, Selvihan; Kizilgul, Muhammed; Ozbek, Mustafa; Caliskan, Mustafa; Kan, Seyfullah; Apaydin, Mahmut; Ozcelik, Ozgur; Cakal, Erman

2017-01-01

Cardiovascular disease (CVD) is reported to be higher in elderly diabetics. Serum heart-type fatty acid binding protein (H-FABP) is a serum marker of myocardial ischemia. We aimed to investigate the association between serum H-FABP level and conventional cardiovascular risk factors, inflammatory markers and subclinical atherosclerosis in elderly diabetics without overt CVD. A total of 50 elderly diabetic patients without overt CVD and 30 age-, sex- and body mass index (BMI)-matched healthy controls were enrolled. Anthropometric and biochemical parameters, serum H-FABP, high-sensitivity C-reactive protein (hs-CRP), fibrinogen and carotid intima-media thickness (CIMT) were measured. Logistic regression analyses (adjustments for age, sex, hypertension, smoking, diabetes, BMI, blood pressure, lipid, blood glucose, hemoglobin A1c, hs-CRP and fibrinogen) were performed to evaluate the association between H-FABP and cardiovascular risk factors and atherosclerosis indices. Serum fibrinogen (421.50±85.52 mg/dL vs 319.17±30.77 mg/dL, p =0.023), CIMT (0.70±0.12 mm vs 0.59±0.06 mm, p <0.001) and hs-CRP (5.72±4.50 mg/dL vs 1.60±0.72 mg/dL, p <0.001) were significantly higher in diabetic patients than controls. The mean serum H-FABP level did not differ between groups (1571.79±604.60 ng/mL vs 1500.25±463.35 ng/mL, p =0.905). H-FABP was positively correlated with fibrinogen ( r 2 =0.473, p <0.001), hs-CRP ( r 2 =0.323, p =0.003) and CIMT ( r 2 =0.467, p <0.001). After full adjustments, the serum H-FABP level was independently associated with an increase in the fibrinogen level (odds ratio [OR] =4.21, 95% confidence level [CI] =1.49-11.90). Serum H-FABP was similar in the elderly diabetic patients without known CVD when compared with the nondiabetic control group. H-FABP does not possess a high diagnostic value as a cardiovascular marker when used alone; however, it may add supplementary information in patients with a high fibrinogen level.

Cereal based diets modulate some markers of oxidative stress and inflammation in lean and obese Zucker rats

PubMed Central

2011-01-01

Background The potential of cereals with high antioxidant capacity for reducing oxidative stress and inflammation in obesity is unknown. This study investigated the impact of wheat bran, barley or a control diet (α-cellulose) on the development of oxidative stress and inflammation in lean and obese Zucker rats. Methods Seven wk old, lean and obese male Zucker rats (n = 8/group) were fed diets that contained wheat bran, barley or α-cellulose (control). After 3 months on these diets, systolic blood pressure was measured and plasma was analysed for glucose, insulin, lipids, oxygen radical absorbance capacity (ORAC), malondialdehyde, glutathione peroxidase and adipokine concentration (leptin, adiponectin, interleukin (IL)-1β, IL-6, TNFα, plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1). Adipokine secretion rates from visceral and subcutaneous adipose tissue explants were also determined. Results Obese rats had higher body weight, systolic blood pressure and fasting blood lipids, glucose, insulin, leptin and IL-1β in comparison to lean rats, and these measures were not reduced by consumption of wheat bran or barley based diets. Serum ORAC tended to be higher in obese rats fed wheat bran and barley in comparison to control (p = 0.06). Obese rats had higher plasma malondialdehyde (p < 0.01) and lower plasma glutathione peroxidase concentration (p < 0.01) but these levels were not affected by diet type. PAI-1 was elevated in the plasma of obese rats, and the wheat bran diet in comparison to the control group reduced PAI-1 to levels seen in the lean rats (p < 0.05). These changes in circulating PAI-1 levels could not be explained by PAI-1 secretion rates from visceral or subcutaneous adipose tissue. Conclusions A 3-month dietary intervention was sufficient for Zucker obese rats to develop oxidative stress and systemic inflammation. Cereal-based diets with moderate and high antioxidant capacity elicited modest improvements in indices of

The effects of repetitive vibration on sensorineural function: biomarkers of sensorineural injury in an animal model of metabolic syndrome

PubMed Central

Kiedrowski, Megan; Waugh, Stacey; Miller, Roger; Johnson, Claud; Krajnak, Kristine

2016-01-01

Exposure to hand-transmitted vibration in the work-place can result in the loss of sensation and pain in workers. These effects may be exacerbated by pre-existing conditions such as diabetes or the presence of primary Raynaud's phenomena. The goal of these studies was to use an established model of vibration-induced injury in Zucker rats. Lean Zucker rats have a normal metabolic profile, while obese Zucker rats display symptoms of metabolic disorder or Type II diabetes. This study examined the effects of vibration in obese and lean rats. Zucker rats were exposed to 4 h of vibration for 10 consecutive days at a frequency of 125 Hz and acceleration of 49 m/s2 for 10 consecutive days. Sensory function was checked using transcutaneous electrical stimulation on days 1, 5 and 9 of the exposure. Once the study was complete the ventral tail nerves, dorsal root ganglia and spinal cord were dissected, and levels of various transcripts involved in sensorineural dysfunction were measured. Sensorineural dysfunction was assessed using transcutaneous electrical stimulation. Obese Zucker rats displayed very few changes in sensorineural function. However they did display significant changes in transcript levels for factors involved in synapse formation, peripheral nerve remodeling, and inflammation. The changes in transcript levels suggested that obese Zucker rats had some level of sensory nerve injury prior to exposure, and that exposure to vibration activated pathways involved in injury and re-innervation. PMID:26433044

Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice.

PubMed

Sapieha, P; Chen, J; Stahl, A; Seaward, M R; Favazza, T L; Juan, A M; Hatton, C J; Joyal, J-S; Krah, N M; Dennison, R J; Tang, J; Kern, T S; Akula, J D; Smith, L E H

2012-07-23

Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks-26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs. This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM.

Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice

PubMed Central

Sapieha, P; Chen, J; Stahl, A; Seaward, M R; Favazza, T L; Juan, A M; Hatton, C J; Joyal, J-S; Krah, N M; Dennison, R J; Tang, J; Kern, T S; Akula, J D; Smith, L E H

2012-01-01

Objective: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). Design: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks–26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. Results: The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs. Conclusion: This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM. PMID:23448719

Effects of parathyroid hormone on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitus.

PubMed

Campbell, G M; Tiwari, S; Hofbauer, C; Picke, A-K; Rauner, M; Huber, G; Peña, J A; Damm, T; Barkmann, R; Morlock, M M; Hofbauer, L C; Glüer, C-C

2016-01-01

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats. Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75μg/kg PTH (1-84) or vehicle 5days per week over 12weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence. Diabetes increased Ct.Po (vertebra (vert): +40.6%, femur (fem): +15.5% vs. ND group, p<0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (-73% vs untreated group, p<0.05), and increased femoral NEG in the DB vs. ND groups (+63%, p<0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (-22%) and toughness (-42%) were observed in the DB vs. ND group (p<0.05). PTH improved maximum strain in the vertebra of the ND animals (+21%, p<0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+21%) and toughness (+28%) in ND and decreased femoral maximum stress (-13%) and toughness (-27%) in the DB animals (treated vs. untreated, p<0.05). Ct.Po correlated negatively with maximum stress (fem: R=-0.35, p<0.05, vert: R=-0.57, p<0.01), maximum strain (fem: R=-0.35, p<0.05, vert: R=-0.43, p<0.05) and toughness (fem: R=-0.34, p<0.05, vert: R=-0.55, p<0.01), and NEG correlated negatively with toughness at the femur (R=-0.34, p<0.05) and maximum strain at the vertebra (R=-0.49, p<0.05). Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs

Susceptibility to fatty acid-induced β-cell dysfunction is enhanced in prediabetic diabetes-prone biobreeding rats: a potential link between β-cell lipotoxicity and islet inflammation.

PubMed

Tang, Christine; Naassan, Anthony E; Chamson-Reig, Astrid; Koulajian, Khajag; Goh, Tracy T; Yoon, Frederick; Oprescu, Andrei I; Ghanim, Husam; Lewis, Gary F; Dandona, Paresh; Donath, Marc Y; Ehses, Jan A; Arany, Edith; Giacca, Adria

2013-01-01

β-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, β-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on β-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased β-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced β-cell dysfunction in the BB rat, which suggests a link between β-cell lipotoxicity and islet inflammation.

Unlike type 2 diabetes, type 1 does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene.

PubMed

Georgopoulos, Angeliki; Aras, Omer; Noutsou, Marina; Tsai, Michael Y

2002-08-01

In type 2 diabetes, the threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein 2 gene is associated with elevated fasting and postprandial triglycerides and dyslipidemia when compared with the wild type (Ala-54/Ala-54). To assess whether this is the case in patients with type 1 diabetes, who usually do not manifest the metabolic syndrome, we screened 181 patients with similar glycemic control as the type 2 patients. Thirty percent were heterozygous, and 9% were homozygous for the polymorphism. Mean (+/-SEM) fasting plasma triglyceride levels in patients with the wild type (n = 84), those heterozygous for Ala-54/Thr-54 (n = 44), and those homozygous for the Thr-54 (n = 13) were 1.0 +/- 0.07, 1.1 +/- 0.17, and 1.2 +/- 0.23 mmol/liter, respectively. In addition, there were no differences in total, low-density lipoprotein, high-density lipoprotein, and non-high density lipoprotein cholesterol among the three groups. After a fat load, the postprandial area under the curve of triglyceride in plasma, chylomicrons, and very low-density lipoprotein were similar between the wild type (n = 18) and the Thr-54 homozygotes (n = 12). In conclusion, in contrast to type 2, type 1 diabetes does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene to cause hypertriglyceridemia/dyslipidemia. Insulin resistance could account possibly for this difference.

Role of APN and TNF-α in type 2 diabetes mellitus complicated by nonalcoholic fatty liver disease.

PubMed

Lin, X; Zhang, Z; Chen, J M; Xu, Y Y; Ye, H R; Cui, J; Fang, Y; Jin, Y; Zhu, D R; Yuan, L

2015-04-10

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by non-excessive alcohol consumption and is the most common cause of elevated levels of serum liver enzymes. We examined changes in adiponectin (APN) and tumor necrosis factor-α (TNF-α) in type 2 diabetes mellitus (T2DM) complicated by NAFLD and their relationships with insulin resistance (IR). Forty-two T2DM, 39 NAFLD, and 45 T2DM complicated with NAFLD (complicated group) patients were enrolled in this study. Body mass index, fasting blood plasma glucose (FPG), fasting insulin, triglyceride (TG), alanine aminotransferase, gamma-glutamyl transpeptidase, APN, TNF-α, and homeostasis model of assessment (HOMA)-IR were determined. The degree of fatty liver was graded according to liver/spleen computed tomography ratio and intrahepatic vessel manifestations. Compared with the T2DM and NAFLD groups, fasting blood plasma glucose, alanine aminotransferase, gamma-glutamyl transpeptidase, TG, TNF-α, and HOMA-IR in the complicated group were significantly increased, while APN was significantly reduced. Body mass index in the complicated group was significantly higher than in the T2DM group. The complicated group was prone to severe fatty liver compared with the NAFLD group. APN was negatively correlated with body mass index, fasting blood plasma glucose, TG, TNF-α, and HOMA-IR. TNF-α was negatively correlated with APN, but positively correlated with FPG, fasting insulin, TG, and HOMA-IR. The complicated group had clear IR. A more severe degree of fatty liver was associated with higher HOMA-IR and TNF-α and lower APN. APN was an important factor for antagonizing inflammation and mitigating IR.

Polyunsaturated Fatty Acids in Children

PubMed Central

2013-01-01

Polyunsaturated fatty acids (PUFAs) are the major components of brain and retina, and are the essential fatty acids with important physiologically active functions. Thus, PUFAs should be provided to children, and are very important in the brain growth and development for fetuses, newborn infants, and children. Omega-3 fatty acids decrease coronary artery disease and improve blood flow. PUFAs have been known to have anti-inflammatory action and improved the chronic inflammation such as auto-immune diseases or degenerative neurologic diseases. PUFAs are used for metabolic syndrome related with obesity or diabetes. However, there are several considerations related with intake of PUFAs. Obsession with the intake of unsaturated fatty acids could bring about the shortage of essential fatty acids that are crucial for our body, weaken the immune system, and increase the risk of heart disease, arrhythmia, and stroke. In this review, we discuss types, physiologic mechanism of action of PUFAs, intake of PUFAs for children, recommended intake of PUFAs, and considerations for the intake of PUFAs. PMID:24224148

Effect of Daisaikoto on Expressions of SIRT1 and NF-kappaB of Diabetic Fatty Liver Rats Induced by High-Fat Diet and Streptozotocin

PubMed Central

Qian, Weibin; Cai, Xinrui; Zhang, Xinying; Wang, Yingying; Qian, Qiuhai; Hasegawa, Junichi

2016-01-01

Background Daisaikoto (DSKT), a classical traditional Chinese herbal formula, has been used for treating digestive diseases for 1800 years in China. Therefore, in this study, we are going to investigate the effect of DSKT on diabetic fatty liver rats induced by a high-fat diet and streptozotocin (STZ), and the effects of DSKT on silent mating type information regulation 2 homolog 1 (SIRT1) and nuclear factor kappa B (NF-kappaB). Methods Diabetic fatty liver rat model was selected to establish a high-fat diet and STZ. Sixty Wistar rats were divided into six groups (n = 10): control group, high-fat diet + STZ group, simvastatin treatment group, DSKT low dose, medial dose and high dose treatment groups. After 8 weeks of drug intervention, body and liver weights, blood chemistry, blood glucose and insulin were examined. The expressions of sirtuin 1 and NF-kappaB in the liver were observed by RT-PCR and immunohistochemistry, respectively. Results A high-fat diet increased body, liver weights, and serum cholesterol concentrations. Intraperitoneal injection of STZ increased blood glucose and decreased body weights. DSKT improved them. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) indices were increased in the high-fat diet groups. DSKT improved them too. In histological examinations of the liver, we observed a significant improvement after treatment. Immunostaining expression of NF-kappaB in the liver was improved by DSKT and simvastatin. The mRNA expressions of SIRT1 in the liver were increased by DSKT and simvastatin. Conclusion We have demonstrated that DSKT is capable of reversing dyslipidemia and insulin resistance induced by a high-fat diet and STZ. High dose DSKT reveals a stronger effect than simvastatin on the expressions of SIRT1 and NF-kappaB. Furthermore, DSKT has shown a strong dose-depended protective effect on diabetic fatty liver. PMID:27493486

Diabetic patients have increased perioperative cardiac risk in heart-type fatty acid-binding protein-based assessment.

PubMed

Sari, Munevver; Kilic, Harun; Ariturk, Ozlem Karakurt; Yazihan, Nuray; Akdemir, Ramazan

2015-01-01

To test the potential role of heart-type fatty acid-binding protein (H-FABP) in detecting increased perioperative cardiac risk in comparison with cardiac troponin I (cTnI) in the early postoperative period. Sixty-seven patients who had clinical risk factors and underwent elective intermediate - or high-risk noncardiac surgery were included in this study. Serum specimens were analyzed for H-FABP and cTnI levels before and at 8 h after surgery. None of the patients had chest pain; 27 had a history of ischemic heart disease, 3 of heart failure, 5 of cerebrovascular diseases, 40 of diabetes and 46 of hypertension. The mean duration of the operations was 2.33 ± 1.27 h (range 1-6). In the postoperative period, 27 (40.3%) patients had increased H-FABP levels (≥7.5 ng/ml); the median preoperative serum H-FABP level was 0.13 ng/ml (<0.1-5.9) and the median postoperative H-FABP level was 6.86 ng/ml (<0.1-13.7). Only 1 (1.5%) patient had cTnI >0.1 µg/l during the postoperative period. Correlation analysis revealed that the presence of diabetes was associated with an increased H-FABP level (r = 0.30, p = 0.01). Of the 27 patients with H-FABP ≥7.5 ng/ml, 21 (87%) had diabetes. There was no significant correlation with other clinical risk factors, type or duration of surgery. The H-FABP levels significantly increased in the postoperative period. Most patients with increased postoperative H-FABP levels were diabetic. High H-FABP levels could alert clinicians to increased perioperative cardiovascular risk and could prevent underdiagnosis, especially in diabetic patients. © 2014 S. Karger AG, Basel.

Dietary omega-3 fatty acids for women.

PubMed

Bourre, Jean-Marie

2007-01-01

This review details the specific needs of women for omega-3 fatty acids, including alpha linoleic acid (ALA) and the very long chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acid (dietary or in capsules) ensures that a woman's adipose tissue contains a reserve of these fatty acids for the developing fetus and the breast-fed newborn infant. This ensures the optimal cerebral and cognitive development of the infant. The presence of large quantities of EPA and DHA in the diet slightly lengthens pregnancy, and improves its quality. Human milk contains both ALA and DHA, unlike that of other mammals. Conditions such as diabetes can alter the fatty acid profile of mother's milk, while certain diets, like those of vegetarians, vegans, or even macrobiotic diets, can have the same effect, if they do not include seafood. ALA, DHA and EPA, are important for preventing ischemic cardiovascular disease in women of all ages. Omega-3 fatty acids can help to prevent the development of certain cancers, particularly those of the breast and colon, and possibly of the uterus and the skin, and are likely to reduce the risk of postpartum depression, manic-depressive psychosis, dementias (Alzheimer's disease and others), hypertension, toxemia, diabetes and, to a certain extend, age-related macular degeneration. Omega-3 fatty acids could play a positive role in the prevention of menstrual syndrome and postmenopausal hot flushes. The normal western diet contains little ALA (less than 50% of the RDA). The only adequate sources are rapeseed oil (canola), walnuts and so-called "omega-3" eggs (similar to wild-type or Cretan eggs). The amounts of EPA and DHA in the diet vary greatly from person to person. The only good sources are fish and seafood, together with "omega-3" eggs.

The influence of sleep deprivation and obesity on DNA damage in female Zucker rats.

PubMed

Tenorio, Neuli M; Ribeiro, Daniel A; Alvarenga, Tathiana A; Fracalossi, Ana Carolina C; Carlin, Viviane; Hirotsu, Camila; Tufik, Sergio; Andersen, Monica L

2013-01-01

The aim of this study was to evaluate overall genetic damage induced by total sleep deprivation in obese, female Zucker rats of differing ages. Lean and obese Zucker rats at 3, 6, and 15 months old were randomly distributed into two groups for each age group: home-cage control and sleep-deprived (N = 5/group). The sleep-deprived groups were deprived sleep by gentle handling for 6 hours, whereas the home-cage control group was allowed to remain undisturbed in their home-cage. At the end of the sleep deprivation period, or after an equivalent amount of time for the home-cage control groups, the rats were brought to an adjacent room and decapitated. The blood, brain, and liver tissue were collected and stored individually to evaluate DNA damage. Significant genetic damage was observed only in 15-month-old rats. Genetic damage was present in the liver cells from sleep-deprived obese rats compared with lean rats in the same condition. Sleep deprivation was associated with genetic damage in brain cells regardless of obesity status. DNA damage was observed in the peripheral blood cells regardless of sleep condition or obesity status. Taken together, these results suggest that obesity was associated with genetic damage in liver cells, whereas sleep deprivation was associated with DNA damage in brain cells. These results also indicate that there is no synergistic effect of these noxious conditions on the overall level of genetic damage. In addition, the level of DNA damage was significantly higher in 15-month-old rats compared to younger rats.

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats.

PubMed

Brooks, Steven D; DeVallance, Evan; d'Audiffret, Alexandre C; Frisbee, Stephanie J; Tabone, Lawrence E; Shrader, Carl D; Frisbee, Jefferson C; Chantler, Paul D

2015-12-01

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS. Copyright © 2015 the American Physiological Society.

A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study

PubMed Central

Sharp, Stephen J.; Kröger, Janine; Griffin, Julian L.; Sluijs, Ivonne; Agudo, Antonio; Ardanaz, Eva; Balkau, Beverley; Boeing, Heiner; Chajes, Veronique; Dow, Courtney; Fagherazzi, Guy; Feskens, Edith J. M.; Franks, Paul W.; Gavrila, Diana; Gunter, Marc; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay-Tee; Kühn, Tilman; Melander, Olle; Molina-Portillo, Elena; Nilsson, Peter M.; Olsen, Anja; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Rolandsson, Olov; Sieri, Sabina; Slimani, Nadia; Spijkerman, Annemieke M. W.; Tjønneland, Anne; Langenberg, Claudia; Riboli, Elio

2017-01-01

Background Combinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated. Methods and findings We measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991–1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19–0.29) adjusted for potential confounders and 0.37 (95% CI 0.27–0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0

A Polysaccharide from Ganoderma atrum Improves Liver Function in Type 2 Diabetic Rats via Antioxidant Action and Short-Chain Fatty Acids Excretion.

PubMed

Zhu, Ke-Xue; Nie, Shao-Ping; Tan, Le-He; Li, Chuan; Gong, De-Ming; Xie, Ming-Yong

2016-03-09

The present study was to evaluate the beneficial effect of polysaccharide isolated from Ganoderma atrum (PSG-1) on liver function in type 2 diabetic rats. Results showed that PSG-1 decreased the activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), while increasing hepatic glycogen levels. PSG-1 also exerted strong antioxidant activities, together with upregulated mRNA expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), glucose transporter-4 (GLUT4), phosphoinositide 3-kinase (PI3K), and phosphorylated-Akt (p-Akt) in the liver of diabetic rats. Moreover, the concentrations of short-chain fatty acids (SCFA) were significantly higher in the liver, serum, and faeces of diabetic rats after treating with PSG-1 for 4 weeks. These results suggest that the improvement of PSG-1 on liver function in type 2 diabetic rats may be due to its antioxidant effects, SCFA excretion in the colon from PSG-1, and regulation of hepatic glucose uptake by inducing GLUT4 translocation through PI3K/Akt signaling pathways.

Serum phospholipid omega-3 polyunsaturated fatty acids and insulin resistance in type 2 diabetes mellitus and non-alcoholic fatty liver disease.

PubMed

Lou, Da-Jun; Zhu, Qi-Qian; Si, Xu-Wei; Guan, Li-Li; You, Qiao-Ying; Yu, Zhong-Ming; Zhang, Ai-Zhen

2014-01-01

To investigate the relationship between serum phospholipid omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and insulin resistance (IR) in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). 51 patients with T2DM and NAFLD (T2DM+NAFLD group), 50 with T2DM alone (T2DM group), 45 with NAFLD alone (NAFLD group), and 42 healthy control subjects (NC group) were studied. Serum ω-3 PUFA profiles were analyzed by gas chromatography, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and serum lipid concentrations were measured. Insulin resistance was assessed by the homeostasis model assessment method (HOMA-IR). HOMA-IR levels were higher in the T2DM+NAFLD group than in the T2DM, NAFLD and NC groups (p<0.05), as were ALT, AST, GGT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations (p<0.05). Conversely, serum ω-3 PUFA levels were significantly lower in the T2DM+NAFLD group than in the other groups (p<0.05). The ω-3 PUFA level was negatively correlated with HOMA-IR, TC, LDL-C and TG. Serum phospholipid ω-3 PUFA levels were significantly decreased in patients with T2DM and NAFLD, and were negatively related with insulin resistance. Thus, reduced ω-3 PUFAs may play an important role in the development of T2DM and NAFLD. Copyright © 2014 Elsevier Inc. All rights reserved.

In vitro effects of oil's fatty acids on T cell function in gestational diabetic pregnant women and their newborns.

PubMed

Djelti, Farah; Merzouk, Hafida; Merzouk, Sid Ahmed; Narce, Michel

2015-07-01

The aim of this investigation was to determine the in vitro effects of linseed, olive and Nigel oils on T cell proliferation and function in gestational diabetes. Blood samples were collected from 40 control healthy and 32 gestational diabetic mothers and their newborns. Peripheral blood lymphocytes were isolated using a density gradient of Ficoll. T cell proliferation, interleukin-2 and -4 (IL-2, IL-4) secretion, fatty acid composition and intracellular oxidative status were investigated. Mitogen (Concanavalin A) stimulated lymphocyte proliferation, IL-2 secretion, intracellular reduced glutathione levels, superoxide dismutase (SOD) and catalase activities were lower while intracellular malondialdehyde (MDA) and carbonyl proteins were higher in diabetic mothers and in their newborns as compared to their respective controls. Linseed oil induced a reduction in T-lymphocyte proliferation and IL-2 production, and alpha linolenic acid membrane enrichment in both diabetic and control groups. In the presence of Nigel oil, T-lymphocyte proliferation and IL-2 secretion, phospholipid linoleic and oleic acids were enhanced. Olive oil had no effect on lymphocyte proliferation in all groups. Linseed, olive and Nigel oils induced an increase in T cell levels of reduced glutathione levels and in activities of catalase and SOD with a concomitant decrease in MDA and carbonyl protein contents. Linseed, olive and Nigel oils had beneficial effects on T cell functions in gestational diabetes. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Arginine-supplemented enteral nutrition in critically ill diabetic and obese rats: a dose-ranging study evaluating nutritional status and macrophage function.

PubMed

Bonhomme, Sandra; Belabed, Linda; Blanc, Marie-Céline; Neveux, Nathalie; Cynober, Luc; Darquy, Sylviane

2013-01-01

Critically ill diabetic and obese patients are at high risk of complications. Arginine availability is lowered in diabetes and in stress situations, yet arginine is necessary for immune response, mainly by its action through nitric oxide (NO). These facts argue for arginine-supplemented diets in critically ill patients. However, studies have raised concerns about possible adverse effects of such diets in intensive-care patients. We therefore analyzed the metabolic and immunologic effects of an arginine-enriched diet in stressed diabetic-obese rats. Zucker Diabetic Fatty rats (fa/fa) were made endotoxemic by an intraperitoneal injection of lipopolysaccharide and then fed 4-d enteral nutrition enriched with arginine (ARG group) or a non-essential amino acid mix (NEAA group). The two groups each were subdivided into three subgroups: the ARG subgroups received 0.5 g (ARG0.5), 2 g (ARG2), and 5 g (ARG5) of arginine per kilogram daily, and the NEAA groups were made isonitrogenous with the corresponding ARG subgroups (NEAA0.5, NEAA2, and NEAA5). Plasma and urinary biomarkers were measured. Cytokine and NO production levels and inducible NO synthase and arginase protein levels were determined from peritoneal macrophages. The survival rate was lower in the ARG5 and NEAA5 subgroups than in all the other subgroups. The nitrogen balance was higher in the ARG5 group than in the NEAA5 group. Plasma triacylglycerol levels were lower in the ARG2 group than in the NEAA2 group. Interleukin-6, tumor necrosis factor-α, and NO production in the macrophages decreased and arginase-1 was upregulated in the ARG-treated rats. In this model, mortality was increased by the nitrogen burden rather than by arginine per se. Arginine improved nitrogen balance and had an anti-inflammatory action on macrophages by regulating NO production, probably through arginase-1 expression. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of 2 G on adiposity, leptin, lipoprotein lipase, and uncoupling protein-1 in lean and obese Zucker rats

NASA Technical Reports Server (NTRS)

Warren, L. E.; Horwitz, B. A.; Hamilton, J. S.; Fuller, C. A.

2001-01-01

Male Zucker rats were exposed to 2 G for 8 wk to test the hypothesis that the leptin regulatory pathway contributes to recovery from effects of 2 G on feeding, growth, and nutrient partitioning. After initial hypophagia, body mass-independent food intake of the lean rats exposed to 2 G surpassed that of the lean rats maintained at 1 G, but food intake of the obese rats exposed to 2 G remained low. After 8 wk at 2 G, body mass and carcass fat were less in both genotypes. Leptin and percent fat were lower in lean rats exposed to 2 G vs. 1 G but did not differ in obese rats exposed to 2 G vs. 1 G. Although exposure to 2 G did not alter uncoupling protein-1 levels, it did elicit white fat pad-specific changes in lipoprotein lipase activity in obese but not lean rats. We conclude that 2 G affects both genotypes but that the lean Zucker rats recover their food intake and growth rate and retain "normal" lipoprotein lipase activity to a greater degree than do the obese rats, emphasizing the importance of a functional leptin regulatory pathway in this acclimation.

Screening for non-alcoholic fatty liver disease in children and adolescents with type 1 diabetes mellitus: a cross-sectional analysis.

PubMed

Kummer, Sebastian; Klee, Dirk; Kircheis, Gerald; Friedt, Michael; Schaper, Joerg; Häussinger, Dieter; Mayatepek, Ertan; Meissner, Thomas

2017-04-01

The liver is intensely involved in glucose metabolism and is thereby closely related to diabetes pathophysiology. Adult patients with type 1 diabetes mellitus (DM) are at an increased risk for non-alcoholic fatty liver disease (NAFLD). Here, we studied the prevalence of NAFLD in a cohort of children and adolescents with type 1 DM in a tertiary care paediatric diabetes centre in Germany. We screened 93 children and adolescents with type 1 DM using ultrasound, laboratory investigations, and liver stiffness measurements (Fibroscan® [FS] and acoustic radiation force imaging [ARFI]). Of these, 82 (88.1%) had completely normal results in all examined aspects. Only one patient (1.1%) fulfilled the criteria as potential NAFLD with ALT > twice the upper limit of normal. Ten of the 93 patients (10.8%) showed any mild abnormality in at least one examined category including ALT, conventional ultrasounds and liver stiffness measurements. However, none of these ten fulfilled the NAFLD case definition criteria. Therefore, these slightly abnormal results were judged to be unspecific or at least of unknown significance in terms of NAFLD indication. Compared to data from the general population, our results do not indicate a significantly increased prevalence of NAFLD in this cohort, and advocate against the systematic screening for NAFLD in paediatric type 1 DM. What is Known: • Non-alcoholic fatty liver disease (NAFLD) is common in adults with type 1 DM, and paediatric patients with type 1 DM in Egypt and Saudi Arabia. What is New: • Our results do not indicate a significantly increased prevalence of NAFLD in a cohort of children and adolescents with type 1 DM from Germany compared to prevalence data from the general population. • This finding advocates against the systematic screening for NAFLD in paediatric type 1 DM in western countries.

Parallel effects of β-adrenoceptor blockade on cardiac function and fatty acid oxidation in the diabetic heart: Confronting the maze

PubMed Central

Sharma, Vijay; McNeill, John H

2011-01-01

Diabetic cardiomyopathy is a disease process in which diabetes produces a direct and continuous myocardial insult even in the absence of ischemic, hypertensive or valvular disease. The β-blocking agents bisoprolol, carvedilol and metoprolol have been shown in large-scale randomized controlled trials to reduce heart failure mortality. In this review, we summarize the results of our studies investigating the effects of β-blocking agents on cardiac function and metabolism in diabetic heart failure, and the complex inter-related mechanisms involved. Metoprolol inhibits fatty acid oxidation at the mitochondrial level but does not prevent lipotoxicity; its beneficial effects are more likely to be due to pro-survival effects of chronic treatment. These studies have expanded our understanding of the range of effects produced by β-adrenergic blockade and show how interconnected the signaling pathways of function and metabolism are in the heart. Although our initial hypothesis that inhibition of fatty acid oxidation would be a key mechanism of action was disproved, unexpected results led us to some intriguing regulatory mechanisms of cardiac metabolism. The first was upstream stimulatory factor-2-mediated repression of transcriptional master regulator PGC-1α, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to β-blockers, although repression of carnitine palmitoyltransferase (CPT)-1 has not been reported with other drugs which improve function. The second was the identification of a range of covalent modifications which can regulate CPT-1 directly, mediated by a signalome at the level of the mitochondria. We also identified an important interaction between β-adrenergic signaling and caveolins, which may be a key mechanism of action of β-adrenergic blockade. Our experience with this labyrinthine signaling web illustrates that initial hypotheses and anticipated directions do not have to be right in order to

Parallel effects of β-adrenoceptor blockade on cardiac function and fatty acid oxidation in the diabetic heart: Confronting the maze.

PubMed

Sharma, Vijay; McNeill, John H

2011-09-26

Diabetic cardiomyopathy is a disease process in which diabetes produces a direct and continuous myocardial insult even in the absence of ischemic, hypertensive or valvular disease. The β-blocking agents bisoprolol, carvedilol and metoprolol have been shown in large-scale randomized controlled trials to reduce heart failure mortality. In this review, we summarize the results of our studies investigating the effects of β-blocking agents on cardiac function and metabolism in diabetic heart failure, and the complex inter-related mechanisms involved. Metoprolol inhibits fatty acid oxidation at the mitochondrial level but does not prevent lipotoxicity; its beneficial effects are more likely to be due to pro-survival effects of chronic treatment. These studies have expanded our understanding of the range of effects produced by β-adrenergic blockade and show how interconnected the signaling pathways of function and metabolism are in the heart. Although our initial hypothesis that inhibition of fatty acid oxidation would be a key mechanism of action was disproved, unexpected results led us to some intriguing regulatory mechanisms of cardiac metabolism. The first was upstream stimulatory factor-2-mediated repression of transcriptional master regulator PGC-1α, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to β-blockers, although repression of carnitine palmitoyltransferase (CPT)-1 has not been reported with other drugs which improve function. The second was the identification of a range of covalent modifications which can regulate CPT-1 directly, mediated by a signalome at the level of the mitochondria. We also identified an important interaction between β-adrenergic signaling and caveolins, which may be a key mechanism of action of β-adrenergic blockade. Our experience with this labyrinthine signaling web illustrates that initial hypotheses and anticipated directions do not have to be right in order to

Prevalence and severity of non-alcoholic fatty liver disease are underestimated in clinical practice: impact of a dedicated screening approach at a large university teaching hospital.

PubMed

Marjot, T; Sbardella, E; Moolla, A; Hazlehurst, J M; Tan, G D; Ainsworth, M; Cobbold, J F L; Tomlinson, J W

2018-01-01

To define the attitudes and current clinical practice of diabetes specialists with regard to non-alcoholic fatty liver disease and, based on the results, implement an evidenced-based pathway for non-alcoholic fatty liver disease assessment. An online survey was disseminated to diabetes specialists. Based on findings from this survey, we sought a local solution by launching an awareness campaign and implementing a screening algorithm across all diabetes clinics at a secondary/tertiary referral centre. A total of 133 diabetes specialists responded to the survey. Fewer than 5% of responders correctly assessed the prevalence and severity of advanced fibrotic non-alcoholic fatty liver disease in people with diabetes as 50-75%. Whilst most clinicians performed liver function tests, only 5.7% responded stating that they would use, or had used, a non-invasive algorithm to stage the severity of non-alcoholic fatty liver disease. Implementing a local non-alcoholic fatty liver disease awareness campaign and screening strategy using pre-printed blood request forms, we ensured that 100% (n=395) of all people with Type 1 and Type 2 diabetes mellitus attending secondary/tertiary care diabetes clinics over a 6-month period were appropriately screened for advanced fibrotic non-alcoholic fatty liver disease using the Fib-4 index; 17.9% required further investigation or assessment. The prevalence and severity of non-alcoholic fatty liver disease are underestimated among diabetes specialists. The Fib-4 index can easily be incorporated into clinical practice in secondary/tertiary care to identify those individuals at risk of advanced fibrosis who require further assessment and who may benefit from a dedicated multidisciplinary approach to their management. © 2017 Diabetes UK.

Effects of xanthine oxidase inhibition with febuxostat on the development of nephropathy in experimental type 2 diabetes.

PubMed

Komers, Radko; Xu, Bei; Schneider, Jennifer; Oyama, Terry T

2016-09-01

Elevated serum uric acid (UA) is a risk factor for the development of kidney disease. Inhibitors of xanthine oxidase (XOi), an enzyme involved in UA synthesis, have protective effects at early stages of experimental diabetic nephropathy (DN). However, long-term effects of XOi in models of DN remain to be determined. The development of albuminuria, renal structure and molecular markers of DN were studied in type 2 diabetic Zucker obese (ZO) rats treated for 18 weeks with the XOi febuxostat and compared with vehicle-treated ZO rats, ZO rats treated with enalapril or a combination of both agents, and lean Zucker rats without metabolic defects. Febuxostat normalized serum UA and attenuated the development of albuminuria, renal structural changes, with no significant effects on BP, metabolic control or systemic markers of oxidative stress (OS). Most of these actions were comparable with those of enalapril. Combination treatment induced marked decreases in BP and was more effective in ameliorating structural changes, expression of profibrotic genes and systemic OS than either monotherapy. Febuxostat attenuated renal protein expression of TGF-ß, CTGF, collagen 4, mesenchymal markers (FSP1 and vimentin) and a tissue marker of OS nitrotyrosine. Moreover, febuxostat attenuated TGF-ß- and S100B-induced increased expression of fibrogenic molecules in renal tubular cells in vitro in UA-free media in an Akt kinase-dependent manner. Febuxostat is protective and enhances the actions of enalapril in experimental DN. Multiple mechanisms might be involved, such as a reduction of UA, renal OS and inhibition of profibrotic signalling. © 2016 The British Pharmacological Society.

Fatty acid regulation of hepatic lipid metabolism

PubMed Central

Jump, Donald B.

2012-01-01

Purpose of review To discuss transcriptional mechanisms regulating hepatic lipid metabolism. Recent findings Humans who are obese or have diabetes (NIDDM) or metabolic syndrome (MetS) have low blood and tissue levels of C20–22 polyunsaturated fatty acids (PUFAs). Although the impact of low C20–22 PUFAs on disease progression in humans is not fully understood, studies with mice have provided clues suggesting that impaired PUFA metabolism may contribute to the severity of risk factors associated with NIDDM and MetS. High fat diets promote hyperglycemia, insulin resistance and fatty liver in C57BL/6J mice, an effect that correlates with suppressed expression of enzymes involved in PUFA synthesis and decreased hepatic C20–22 PUFA content. A/J mice, in contrast, are resistant to diet-induced obesity and diabetes; these mice have elevated expression of hepatic enzymes involved in PUFA synthesis and C20–22 PUFA content. Moreover, loss-of-function and gain-of-function studies have identified fatty acid elongase (Elovl5), a key enzyme involved in PUFA synthesis, as a regulator of hepatic lipid and carbohydrate metabolism. Elovl5 activity regulates hepatic C20–22 PUFA content, signaling pathways (Akt and PP2A) and transcription factors (SREBP-1, PPARα, FoxO1 and PGC1α) that control fatty acid synthesis and gluconeogenesis. Summary These studies may help define novel strategies to control fatty liver and hyperglycemia associated with NIDDM and MetS. PMID:21178610

Diabetes, plasma glucose and incidence of fatty liver, cirrhosis and liver cancer: A prospective study of 0.5 million people.

PubMed

Pang, Yuanjie; Kartsonaki, Christiana; Turnbull, Iain; Guo, Yu; Clarke, Robert; Chen, Yiping; Bragg, Fiona; Yang, Ling; Bian, Zheng; Millwood, Iona Y; Hao, Juanzhi; Han, Xianyong; Zang, Yajing; Chen, Junshi; Li, Liming; Holmes, Michael V; Chen, Zhengming

2018-05-07

The prevalence of diabetes is increasing rapidly in China. However, evidence is limited about its effects on chronic liver diseases and liver cancer. We aimed to examine the associations of diabetes with chronic liver diseases and liver cancer and of random plasma glucose (RPG) with these liver diseases among participants without diabetes in Chinese adults, and to assess the possible interaction by hepatitis B virus (HBV) infection. The prospective China Kadoorie Biobank recruited 512,891 adults. During 10 years of follow-up, 2,568 liver cancer, 2,082 cirrhosis, 1,298 hospitalised non-alcoholic fatty liver disease (NAFLD), and 244 hospitalised alcoholic liver disease (ALD) were recorded among 503,993 participants without prior history of cancer or chronic liver diseases at baseline. Cox regression was used to estimate hazard ratios (HRs) for each disease by diabetes status (previously diagnosed or screen-detected) and, among those without previously diagnosed diabetes, by levels of RPG. Overall 5.8% of participants had diabetes at baseline. Compared with those without diabetes, individuals with diabetes had adjusted HRs of 1.49 (95% CI 1.30-1.70) for liver cancer, 1.81 (1.57-2.09) for cirrhosis, 1.76 (1.47-2.16) for NAFLD, and 2.24 (1.42-3.54) for ALD. The excess risks decreased but remained elevated in those with longer duration. Among those without previously diagnosed diabetes, RPG was positively associated with liver diseases, with adjusted HRs per 1 mmol/L higher RPG of 1.04 (1.03-1.06) for liver cancer, 1.07 (1.05-1.09) for cirrhosis, 1.07 (1.05-1.10) for NAFLD, and 1.10 (1.05-1.15) for ALD. These associations did not differ by HBV infection. In Chinese adults, diabetes and higher blood glucose levels among those without known diabetes are associated with increased risks of liver cancer and major chronic liver diseases. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Association between non-alcoholic fatty liver disease and peripheral artery disease in patients with type 2 diabetes.

PubMed

Zou, Yaowu; Li, Xinde; Wang, Can; Wang, Jing; Wang, Fei; Ma, Lidan; You, Wenjun; Li, Changgui

2017-10-01

Non-alcoholic fatty liver disease (NAFLD) is associated with the risk of coronary heart diseases; however, the relationship between NAFLD and peripheral artery disease (PAD) in patients with type 2 diabetes has not been investigated. To investigate the association between NAFLD and PAD in patients with type 2 diabetes. We carried out a cross-sectional study on 2646 type 2 diabetes patients ≥ 40 years. All patients provided fasting blood samples and underwent a liver ultrasonography and ankle-brachial index (ABI) test. PAD was defined as an ABI <0.9. Multiple logistic regression analyses were performed to investigate the odds ratio (OR) for PAD associated with NAFLD. Our analyses showed that patients with NAFLD had a significantly higher prevalence of PAD compared with those without NAFLD (12.8% vs 7.8%). NAFLD was associated with a 75% (OR 1.75, 95% confidence interval (CI) 1.35-2.28) increased risk of PAD after adjustment for demographic factors. Addition of various metabolic risk factors as confounders attenuated the association (OR 1.49, 95% CI 1.12-2.00). Further adjustment for C-reactive protein led the association to be marginally significant (OR 1.33, 95% CI 0.99-1.80). Analyses stratified by gender suggested the association was much stronger among women than among men. Type 2 diabetes patients with NAFLD had a higher prevalence of PAD, and this association was partly, but not entirely, explained by metabolic risk factors and inflammation. © 2017 Royal Australasian College of Physicians.

Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion

PubMed Central

Butler, Judy A.; Hagen, Tory M.; Moreau, Régis

2009-01-01

Elevated blood triacylglycerol (TG) is a significant contributing factor to the current epidemic of obesity-related health disorders, including type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The observation that mice lacking the enzyme sn-glycerol-3-phosphate acyltransferase are protected from insulin resistance suggests the possibility that the regulation of TG synthesis be a target for therapy. Five-week old Zucker Diabetic Fatty (ZDF) rats were fed a diet containing (R)-α-lipoic acid (LA, ~200 mg/kg body weight per day) for 5 weeks. LA offset the rise in blood and liver TG by inhibiting liver lipogenic gene expression (e.g. sn-glycerol-3-phosphate acyltransferase-1 and diacylglycerol O-acyltransferase-2), lowering hepatic TG secretion, and stimulating clearance of TG-rich lipoproteins. LA-induced TG lowering was not due to the anorectic properties of LA, as pair-fed rats developed hypertriglyceridemia. Livers from LA-treated rats exhibited elevated glycogen content, suggesting dietary carbohydrates were stored as glycogen rather than becoming lipogenic substrate. Although AMP-activated protein kinase (AMPK) reportedly mediates the metabolic effects of LA in rodents, no change in AMPK activity was observed, suggesting LA acted independently of this kinase. The hepatic expression of peroxisome proliferator activated receptor α (PPARα) target genes involved in fatty acid β-oxidation was either unchanged or decreased with LA, indicating a different mode of action than for fibrate drugs. Given its strong safety record, LA may have potential clinical applications for the treatment or prevention of hypertriglyceridemia and diabetic dyslipidemia. PMID:19232511

Peroxisomal enzymes in the liver of rats with experimental diabetes mellitus type 2.

PubMed

Turecký, L; Kupčová, V; Uhlíková, E; Mojto, V

2014-01-01

Diabetes mellitus is relatively frequently associated with fatty liver disease. Increased oxidative stress probably plays an important role in the development of this hepatopathy. One of possible sources of reactive oxygen species in liver is peroxisomal system. There are several reports about changes of peroxisomal enzymes in experimental diabetes, mainly enzymes of fatty acid oxidation. The aim of our study was to investigate the possible changes of activities of liver peroxisomal enzymes, other than enzymes of beta-oxidation, in experimental diabetes mellitus type 2. Biochemical changes in liver of experimental animals suggest the presence of liver steatosis. The changes of serum parameters in experimental group are similar to changes in serum of patients with non-alcoholic fatty liver disease. We have shown that diabetes mellitus influenced peroxisomal enzymes by the different way. Despite of well-known induction of peroxisomal beta-oxidation, the activities of catalase, aminoacid oxidase and NADH-cytochrome b(5) reductase were not significantly changed and the activities of glycolate oxidase and NADP-isocitrate dehydrogenase were significantly decreased. The effect of diabetes on liver peroxisomes is probably due to the increased supply of fatty acids to liver in diabetic state and also due to increased oxidative stress. The changes of metabolic activity of peroxisomal compartment may participate on the development of diabetic hepatopathy.

Oxidative stress in normal and diabetic rats.

PubMed

Torres, M D; Canal, J R; Pérez, C

1999-01-01

Parameters related to oxidative stress were studied in a group of 10 Wistar diabetic rats and 10 control rats. The levels of total erythrocyte catalase activity in the diabetic animals were significantly (p<0.001) greater than the control levels. The diabetic animals presented an amount of vitamin E far greater (p<0.0001) than the controls, as was also the case for the vitaminE/polyunsaturated fatty acid (PUFA) and vitaminE/linoleic acid (C18:2) ratios. Greater vitaminE/triglyceride (TG) ratio, however, appeared in the control group. The corresponding vitamin A ratios (vitaminA/TG, vitaminA/PUFA, vitaminA/C 18:2) were higher in the control group. Our work corroborates the findings that fatty acid metabolism presents alterations in the diabetes syndrome and that the antioxidant status is affected.

Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

PubMed Central

Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

2016-01-01

After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

Dietary milled flaxseed and flaxseed oil improve N-3 fatty acid status and do not affect glycemic control in individuals with well-controlled type 2 diabetes.

PubMed

Taylor, Carla G; Noto, Amy D; Stringer, Danielle M; Froese, Sylvia; Malcolmson, Linda

2010-02-01

To determine the effects of dietary consumption of milled flaxseed or flaxseed oil on glycemic control, n-3 fatty acid status, anthropometrics, and adipokines in individuals with type 2 diabetes. Thirty-four participants were randomized into a parallel, controlled trial. The participants were adults with type 2 diabetes (age 52.4 +/- 1.5 years, body mass index 32.4 +/- 1.0 kg/m(2), n = 17 men and 17 women). Participants consumed a selection of bakery products containing no flax (control group [CTL], n = 9), milled flaxseed (FXS, n = 13; 32 g/d), or flaxseed oil (FXO, n = 12; 13 g/d) daily for 12 weeks. The FXS and FXO groups received equivalent amounts of alpha-linolenic acid (ALA; 7.4 g/day). The primary outcome measures were fasting plasma hemoglobin A(1c), glucose, insulin, and phospholipid fatty acid composition. The secondary outcome measures were fasting circulating leptin and adiponectin, as well as body weight, body mass index, and waist circumference. Dietary intake assessment and calculations for homeostasis model assessment for insulin resistance and quantified insulin sensitivity check were also completed. The FXS and FXO groups had increases in plasma phospholipid n-3 fatty acids (ALA, eicosapentaenoic acid [EPA], or decosapentaenoic acid [DPA], but not docosahexaenoic acid), and the FXO group had more EPA and DPA in plasma phospholipids compared to the FXS group. All groups had similar caloric intakes; however, the CTL group experienced a 4% weight gain compared to baseline (p < 0.05), while both flax groups had constant body weights during the study period. All other parameters, including glycemic control, were unchanged by dietary treatment. Milled FXS and FXO intake does not affect glycemic control in adults with well-controlled type 2 diabetes. Possible prevention of weight gain by flax consumption warrants further investigation.

[Non-alcoholic fatty liver disease (NAFLD) in patients with metabolic syndrome and type 2 diabetes mellitus. Pathomechanism, new diagnostic markers].

PubMed

Kieć-Wilk, Beata; Klupa, Tomasz; Dembińska-Kieć, Aldona

2010-01-01

Non-alcoholic fatty liver disease (NAFLD) is a complex of a wide spectrum of liver pathology--from steatosis alone, to cirrhosis and liver cancer. The pathogenic concept of NAFLD covers overnutrition with fatty acids, underactivity. Insulin resistance is believed to play the main role in this process. NAFLD is mostly related to visceral adiposity, metabolic syndrome and type 2 diabetes melitus. The presented work is a review of in vitro and in vivo modern studies, as well as clinical observations on molecular mechanisms leading to development and progress of NAFLD. Up till today their is no treatment od NAFLD, and this pathology is not benign--it may lead to patients' death in 10 years. The clinical approach to NAFLD is prevention of it's development. The manuscript is a review of new biochemical markers allowing for early detection of metabolic disorders leading to NAFLD development, thus to sufficient prevention of this pathology in patients.

Effects of supplementation with omega-3 on insulin sensitivity and non-esterified free fatty acid (NEFA) in type 2 diabetic patients.

PubMed

Farsi, Payam Farahbakhsh; Djazayery, Abolghassem; Eshraghian, Mohammad Reza; Koohdani, Fariba; Saboor-Yaraghi, Ali Akbar; Derakhshanian, Hoda; Zarei, Mahnaz; Javanbakht, Mohammad Hassan; Djalali, Mahmoud

2014-06-01

The aim of this study was to determine the role of omega-3 supplementation on NEFA concentration, insulin sensitivity and resistance, and glucose and lipid metabolism in type 2 diabetic patients. Forty-four type 2 diabetic patients were randomly recruited into two groups. Group A received 4 g/day omega-3 soft gels, and group B received a placebo for 10 wks. Blood samples were collected after 12-h fast. Physical activity records, three-day food records, and anthropometric measurements were obtained from all participants at the beginning and end of the study. Omega-3 supplementation caused a significant reduction in NEFA in the intervention group compared with the placebo group (P = 0.009). Additionally, the administration of omega-3 resulted in significantly greater changes (Diff) for the intervention group in various parameters, such as insulin and Quicki indices compared with the placebo group (P < 0.05). Omega-3 fatty acid supplementation in type 2 diabetic patients improved insulin sensitivity, probably due to the decrease in NEFA concentrations.

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation

PubMed Central

Mansor, Latt S.; Sousa Fialho, Maria da Luz; Yea, Georgina; Coumans, Will A.; West, James A.; Kerr, Matthew; Carr, Carolyn A.; Luiken, Joost J.F.P.; Glatz, Jan F.C.; Evans, Rhys D.; Griffin, Julian L.; Tyler, Damian J.; Clarke, Kieran

2017-01-01

Aims The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress. Methods and results Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels. Conclusions Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel

Effect of Roux-en-Y Gastric Bypass Surgery on Bile Acid Metabolism in Normal and Obese Diabetic Rats

PubMed Central

Bhutta, Hina Y; Rajpal, Neetu; White, Wendy; Freudenberg, Johannes M.; Liu, Yaping; Way, James; Rajpal, Deepak; Cooper, David C.; Young, Andrew; Tavakkoli, Ali; Chen, Lihong

2015-01-01

In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans. PMID:25798945

[CONTENT OF TRANS FATTY ACIDS IN FOOD PRODUCTS IN SPAIN].

PubMed

Robledo de Dios, Teresa; Dal Re Saavedra, M Ángeles; Villar Villalba, Carmen; Pérez-Farinós, Napoleón

2015-09-01

trans fatty acids are associated to several health disorders, as ischemic heart disease or diabetes mellitus. to assess the content of trans fatty acids in products in Spain, and the percentage of trans fatty acids respecting total fatty acids. 443 food products were acquired in Spain, and they were classified into groups. The content in fatty acids was analyzed using gas chromatography. Estimates of central tendency and variability of the content of trans fatty acids in each food group were computed (in g of trans fatty acids/100 g of product). The percentage of trans fatty acids respecting total fatty acids was calculated in each group. 443 products were grouped into 42 groups. Median of trans fatty acids was less than 0.55 g / 100 g of product in all groups except one. 83 % of groups had less than 2 % of trans fatty acids, and 71 % of groups had less than 1 %. the content of trans fatty acids in Spain is low, and it currently doesn't play a public health problem. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

A Randomized Controlled Clinical Trial Investigating the Effects of Omega-3 Fatty Acids and Vitamin E Co-Supplementation on Biomarkers of Oxidative Stress, Inflammation and Pregnancy Outcomes in Gestational Diabetes.

PubMed

Jamilian, Mehri; Hashemi Dizaji, Shahrzad; Bahmani, Fereshteh; Taghizadeh, Mohsen; Memarzadeh, Mohammad Reza; Karamali, Maryam; Akbari, Maryam; Asemi, Zatollah

2017-04-01

Limited data are available for assessing the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic profiles and pregnancy outcomes in gestational diabetes (GDM). This study was designed to determine the effects of omega-3 fatty acids and vitamin E co-supplementation on biomarkers of oxidative stress, inflammation and pregnancy outcomes in women with GDM. This randomized, double-blind, placebo-controlled clinical trial was conducted in 60 patients with GDM who were not taking oral hypoglycemic agents. Patients were randomly allocated to intake either 1000 mg omega-3 fatty acids from flaxseed oil plus 400 IU vitamin E supplements (n=30) or placebo (n=30) for 6 weeks. Fasting blood samples were obtained from the women at the beginning of the study and after the 6-week intervention to quantify related markers. After 6 weeks of intervention, omega-3 fatty acids and vitamin E co-supplementation, compared with the placebo, resulted in a significant rise in total antioxidant capacity (TAC) (+187.5±224.9 vs. -32.5±136.1 mmol/L; p<0.001); nitric oxide (NO) (+5.0±7.7 vs. -12.0±28.0 µmol/L; p=0.002) and a significant decrease in plasma malondialdehyde (MDA) concentrations (-0.1±0.9 vs. +0.6±1.4 µmol/L; p=0.03). Co-supplementation with omega-3 fatty acids and vitamin E showed no detectable changes in plasma glutathione and serum high-sensitivity C-reactive protein levels. Joint omega-3 fatty acids and vitamin E supplementation resulted in lower incidences of hyperbilirubinemia in newborns (10.3% vs. 33.3%; p=0.03). Overall, omega-3 fatty acids and vitamin E co-supplementation for 6 weeks in women with GDM had beneficial effects on plasma TAC, MDA and NO and on the incidence of the newborns' hyperbilirubinemia. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Effect of saturated fatty acid-rich dietary vegetable oils on lipid profile, antioxidant enzymes and glucose tolerance in diabetic rats

PubMed Central

Kochikuzhyil, Benson Mathai; Devi, Kshama; Fattepur, Santosh Raghunandan

2010-01-01

Objective: To study the effect of saturated fatty acid (SFA)-rich dietary vegetable oils on the lipid profile, endogenous antioxidant enzymes and glucose tolerance in type 2 diabetic rats. Materials and Methods: Type 2 diabetes was induced by administering streptozotocin (90 mg/kg, i.p.) in neonatal rats. Twenty-eight-day-old normal (N) and diabetic (D) male Wistar rats were fed for 45 days with a fat-enriched special diet (10%) prepared with coconut oil (CO) – lauric acid-rich SFA, palm oil (PO) – palmitic acid-rich SFA and groundnut oil (GNO) – control (N and D). Lipid profile, endogenous antioxidant enzymes and oral glucose tolerance tests were monitored. Results: D rats fed with CO (D + CO) exhibited a significant decrease in the total cholesterol and non-high-density lipoprotein cholesterol. Besides, they also showed a trend toward improving antioxidant enzymes and glucose tolerance as compared to the D + GNO group, whereas D + PO treatment aggravated the dyslipidemic condition while causing a significant decrease in the superoxide dismutase levels when compared to N rats fed with GNO (N + GNO). D + PO treatment also impaired the glucose tolerance when compared to N + GNO and D + GNO. Conclusion: The type of FA in the dietary oil determines its deleterious or beneficial effects. Lauric acid present in CO may protect against diabetes-induced dyslipidemia. PMID:20871763

Endogenous ω-3 Polyunsaturated Fatty Acid Production Confers Resistance to Obesity, Dyslipidemia, and Diabetes in Mice

PubMed Central

Li, Jie; Li, Fanghong R.; Wei, Dong; Jia, Wei; Kang, Jing X.; Stefanovic-Racic, Maja

2014-01-01

Despite the well-documented health benefits of ω-3 polyunsaturated fatty acids (PUFAs), their use in clinical management of hyperglycemia and obesity has shown little success. To better define the mechanisms of ω-3 PUFAs in regulating energy balance and insulin sensitivity, we deployed a transgenic mouse model capable of endogenously producing ω-3 PUFAs while reducing ω-6 PUFAs owing to the expression of a Caenorhabditis elegans fat-1 gene encoding an ω-3 fatty acid desaturase. When challenged with high-fat diets, fat-1 mice strongly resisted obesity, diabetes, hypercholesterolemia, and hepatic steatosis. Endogenous elevation of ω-3 PUFAs and reduction of ω-6 PUFAs did not alter the amount of food intake but led to increased energy expenditure in the fat-1 mice. The requirements for the levels of ω-3 PUFAs as well as the ω-6/ω-3 ratios in controlling blood glucose and obesity are much more stringent than those in lipid metabolism. These metabolic phenotypes were accompanied by attenuation of the inflammatory state because tissue levels of prostaglandin E2, leukotriene B4, monocyte chemoattractant protein-1, and TNF-α were significantly decreased. TNF-α–induced nuclear factor-κB signaling was almost completely abolished. Consistent with the reduction in chronic inflammation and a significant increase in peroxisome proliferator–activated receptor-γ activity in the fat-1 liver tissue, hepatic insulin signaling was sharply elevated. The activities of prolipogenic regulators, such as liver X receptor, stearoyl-CoA desaturase-1, and sterol regulatory element binding protein-1 were sharply decreased, whereas the activity of peroxisome proliferator–activated receptor-α, a nuclear receptor that facilitates lipid β-oxidation, was markedly increased. Thus, endogenous conversion of ω-6 to ω-3 PUFAs via fat-1 strongly protects against obesity, diabetes, inflammation, and dyslipidemia and may represent a novel therapeutic modality to treat these prevalent

Association of fish and n-3 fatty acid intake with the risk of type 2 diabetes: a meta-analysis of prospective studies.

PubMed

Zhou, Yunping; Tian, Changwei; Jia, Chongqi

2012-08-01

Results from observational studies on the association of fish and n-3 fatty acid consumption with type 2 diabetes mellitus (T2DM) risk are conflicting. Hence, a meta-analysis was performed to investigate this association from cohort studies. A comprehensive search was then conducted to identify cohort studies on the association of fish and/or n-3 fatty acid intake with T2DM risk. In the highest v. lowest categorical analyses, the fixed or random-effect model was selected based on the homogeneity test among studies. Linear and non-linear dose-response relationships were also assessed by univariate and bivariate random-effect meta-regression with restricted maximum likelihood estimation. In the highest v. lowest categorical analyses, the pooled relative risk (RR) of T2DM for intake of fish and n-3 fatty acid was 1·146 (95 % CI 0·975, 1·346) and 1·076 (95 % CI 0·955, 1·213), respectively. In the linear dose-response relationship, the pooled RR for an increment of one time (about 105 g)/week of fish intake (four times/month) and of 0·1 g/d of n-3 fatty acid intake was 1·042 (95 % CI 1·026, 1·058) and 1·057 (95 % CI 1·042, 1·073), respectively. The significant non-linear dose-response associations of fish and n-3 fatty acid intake with T2DM risk were not observed. The present evidence from observational studies suggests that the intake of both fish and n-3 fatty acids might be weakly positively associated with the T2DM risk. Further studies are needed to confirm these results.

Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function.

PubMed

Rial, Eduardo; Rodríguez-Sánchez, Leonor; Gallardo-Vara, Eunate; Zaragoza, Pilar; Moyano, Eva; González-Barroso, M Mar

2010-01-01

Diseases like obesity, diabetes or generalized lipodystrophy cause a chronic elevation of circulating fatty acids that can become cytotoxic, a condition known as lipotoxicity. Fatty acids cause oxidative stress and alterations in mitochondrial structure and function. The uncoupling of the oxidative phosphorylation is one of the most recognized deleterious fatty acid effects and several metabolite transporters are known to mediate in their action. The fatty acid interaction with the carriers leads to membrane depolarization and/or the conversion of the carrier into a pore. The result is the opening of the permeability transition pore and the initiation of apoptosis. Unlike the other members of the mitochondrial carrier superfamily, the eutherian uncoupling protein UCP1 has evolved to achieve its heat-generating capacity in the physiological context provided by the brown adipocyte and therefore it is activated by the low fatty acid concentrations generated by the noradrenaline-stimulated lipolysis. Copyright © 2010 Elsevier B.V. All rights reserved.

Effects of xanthine oxidase inhibition with febuxostat on the development of nephropathy in experimental type 2 diabetes

PubMed Central

Xu, Bei; Schneider, Jennifer; Oyama, Terry T

2016-01-01

Background and Purpose Elevated serum uric acid (UA) is a risk factor for the development of kidney disease. Inhibitors of xanthine oxidase (XOi), an enzyme involved in UA synthesis, have protective effects at early stages of experimental diabetic nephropathy (DN). However, long‐term effects of XOi in models of DN remain to be determined. Experimental Approach The development of albuminuria, renal structure and molecular markers of DN were studied in type 2 diabetic Zucker obese (ZO) rats treated for 18 weeks with the XOi febuxostat and compared with vehicle‐treated ZO rats, ZO rats treated with enalapril or a combination of both agents, and lean Zucker rats without metabolic defects. Results Febuxostat normalized serum UA and attenuated the development of albuminuria, renal structural changes, with no significant effects on BP, metabolic control or systemic markers of oxidative stress (OS). Most of these actions were comparable with those of enalapril. Combination treatment induced marked decreases in BP and was more effective in ameliorating structural changes, expression of profibrotic genes and systemic OS than either monotherapy. Febuxostat attenuated renal protein expression of TGF‐ß, CTGF, collagen 4, mesenchymal markers (FSP1 and vimentin) and a tissue marker of OS nitrotyrosine. Moreover, febuxostat attenuated TGF‐ß‐ and S100B‐induced increased expression of fibrogenic molecules in renal tubular cells in vitro in UA‐free media in an Akt kinase‐dependent manner. Conclusions and Implications Febuxostat is protective and enhances the actions of enalapril in experimental DN. Multiple mechanisms might be involved, such as a reduction of UA, renal OS and inhibition of profibrotic signalling. PMID:27238746

Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.

PubMed

Wu, Jason H Y; Marklund, Matti; Imamura, Fumiaki; Tintle, Nathan; Ardisson Korat, Andres V; de Goede, Janette; Zhou, Xia; Yang, Wei-Sin; de Oliveira Otto, Marcia C; Kröger, Janine; Qureshi, Waqas; Virtanen, Jyrki K; Bassett, Julie K; Frazier-Wood, Alexis C; Lankinen, Maria; Murphy, Rachel A; Rajaobelina, Kalina; Del Gobbo, Liana C; Forouhi, Nita G; Luben, Robert; Khaw, Kay-Tee; Wareham, Nick; Kalsbeek, Anya; Veenstra, Jenna; Luo, Juhua; Hu, Frank B; Lin, Hung-Ju; Siscovick, David S; Boeing, Heiner; Chen, Tzu-An; Steffen, Brian; Steffen, Lyn M; Hodge, Allison; Eriksdottir, Gudny; Smith, Albert V; Gudnason, Vilmunder; Harris, Tamara B; Brouwer, Ingeborg A; Berr, Claudine; Helmer, Catherine; Samieri, Cecilia; Laakso, Markku; Tsai, Michael Y; Giles, Graham G; Nurmi, Tarja; Wagenknecht, Lynne; Schulze, Matthias B; Lemaitre, Rozenn N; Chien, Kuo-Liong; Soedamah-Muthu, Sabita S; Geleijnse, Johanna M; Sun, Qi; Harris, William S; Lind, Lars; Ärnlöv, Johan; Riserus, Ulf; Micha, Renata; Mozaffarian, Dariush

2017-12-01

The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m 2 , who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I 2 =53·9%, p heterogeneity =0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid

Exercise improves adipose function and inflammation and ameliorates fatty liver disease in obese diabetic mice.

PubMed

Haczeyni, Fahrettin; Barn, Vanessa; Mridha, Auvro R; Yeh, Matthew M; Estevez, Emma; Febbraio, Mark A; Nolan, Christopher J; Bell-Anderson, Kim S; Teoh, Narci C; Farrell, Geoffrey C

2015-09-01

Adipose inflammation and dysfunction underlie metabolic obesity. Exercise improves glycemic control and metabolic indices, but effects on adipose function and inflammation are less clear. Accordingly, it was hypothesized that exercise improves adipose morphometry to reduce adipose inflammation in hyperphagic obese mice. Alms1 mutant foz/foz mice housed in pairs were fed an atherogenic or chow diet; half the cages were fitted with a computer-monitored wheel for voluntary exercise. Insulin-induced AKT-phosphorylation, adipocyte size distribution, and inflammatory recruitment were studied in visceral versus subcutaneous depots, and severity of fatty liver disease was determined. Exercise prevented obesity and diabetes development in chow-fed foz/foz mice and delayed their onset in atherogenic-fed counterparts. Insulin-stimulated phospho-AKT levels in muscle were improved with exercise, but not in adipose or liver. Exercise suppressed adipose inflammatory recruitment, particularly in visceral adipose, associated with an increased number of small adipocyte subpopulations, and enhanced expression of beige adipocyte factor PRDM16 in subcutaneous fat. In atherogenic-fed foz/foz mice liver, exercise suppressed development of nonalcoholic steatohepatitis and related liver fibrosis. Exercise confers metabo-protective effects in atherogenic-fed hyperphagic mice by preventing early onset of obesity and diabetes in association with enhanced muscle insulin sensitivity, improved adipose morphometry, and suppressed adipose and liver inflammation. © 2015 The Obesity Society.

Prevalence and Profile of Fibrosis in Diabetic Patients with Non-alcoholic Fatty Liver Disease and the Associated Factors.

PubMed

Prasetya, Ignatius Bima; Hasan, Irsan; Wisnu, Wismandari; Rumende, Cleopas Martin

2017-04-01

the risk of Non-Alcoholic Fatty Liver Disease (NAFLD) is increasing in patients with type-2 diabetes. Prevalence and factors related to the increased risk of NAFLD in diabetic patients in Indonesia has never been studied before. Data regarding the profile of fibrosis in the population has also been unknown. This study aimed to identify the difference on the profile of diabetic patients with and without NAFLD as well as the degree of fibrosis. the study was conducted using a cross-sectional method in type-2 diabetic patients who were treated at the outpatient clinic of endocrinology and metabolic division in Cipto Mangunkusumo Hospital. Sampling was done consecutively. Collected data comprised of age, duration of diabetes, body mass index (BMI), waist circumference, HDL, triglyceride, and HbA1C levels. Abdominal ultrasonography was conducted for all patients to determine the presence of NAFLD. Patients with NAFLD were subsequently underwent transient elastography in order to assess their degree of liver fibrosis. Chi-square or Fisher's-Exact tests were used for bivariate analysis and logistic regression was used for multivariate analysis. as many as 186 patients were analyzed in the study and 84 patients (45.2%) were demonstrated to have NAFLD. Transient elastography examinations were carried out in 68 patients and 17 patients (25.0%) were found with severe fibrosis. Univariate analysis showed significant differences on BMI (PR=1.878; 95%CI= 1.296-2.721; p<0.001) and waist circumference (PR=2.368; 95%CI= 1.117-5.017; p=0.018) between patients with and without NAFLD. However, the multivariate test showed that BMI was the only factor that had a significance difference between both groups (OR=2.989; 95%CI=1.625-5.499; p<0.001). prevalence of NAFLD among type-2 diabetic patients in Cipto Mangunkusumo Hospital has reached 45.2% and 25.0% among them had severe fibrosis. BMI is the only factor found to be associated with the occurrence of NAFLD.

Effects of Omega-3 Fatty Acid Supplementation on Glucose Control and Lipid Levels in Type 2 Diabetes: A Meta-Analysis

PubMed Central

Chen, Cai; Yu, Xuefeng; Shao, Shiying

2015-01-01

Background Many studies assessed the impact of marine omega-3 fatty acids on glycemic homeostasis and lipid profiles in patients with type 2 diabetes (T2DM), but reported controversial results. Our goal was to systematically evaluate the effects of omega-3 on glucose control and lipid levels. Methods Medline, Pubmed, Cochrane Library, Embase, the National Research Register, and SIGLE were searched to identify eligible randomized clinical trials (RCTs). Extracted data from RCTs were analyzed using STATA 11.0 statistical software with fixed or random effects model. Effect sizes were presented as weighted mean differences (WMD) with 95% confidence intervals (95% CI). Heterogeneity was assessed using the Chi-square test with significance level set at p < 0.1. Results 20 RCT trials were included into this meta-analysis. Among patients with omega-3 supplementation, triglyceride (TG) levels were significantly decreased by 0.24 mmol/L. No marked change in total cholesterol (TC), HbA1c, fasting plasma glucose, postprandial plasma glucose, BMI or body weight was observed. High ratio of EPA/DHA contributed to a greater decreasing tendency in plasma insulin, HbAc1, TC, TG, and BMI measures, although no statistical significance was identified (except TG). FPG levels were increased by 0.42 mmol/L in Asians. No evidence of publication bias was observed in this meta-analysis. Conclusions The ratio of EPA/DHA and early intervention with omega 3 fatty acids may affect their effects on glucose control and lipid levels, which may serve as a dietary reference for clinicians or nutritionists who manage diabetic patients. PMID:26431431

Type 2 diabetes mellitus in pediatrics: a new challenge.

PubMed

Van Name, Michelle; Santoro, Nicola

2013-11-01

The increased prevalence of childhood obesity in the last few years has been accompanied by the increase in prevalence of type 2 diabetes in pediatrics. In this paper, we will review the risk factors and the pathogenic determinants leading to type 2 diabetes in youth. We searched on PubMed with the key words: obesity, type 2 diabetes, children, adolescents, youth, non-alcoholic fatty liver disease, genes and selected those publications written in English that we judged to be relevant to the topic of the review. Based on the data present in the literature, we reviewed the following three topics: 1) the role of ectopic fat deposition, in particular of fatty liver, in the pathogenesis of pediatric type 2 diabetes; 2) the progression to type 2 diabetes in pediatrics and how it differs from adults, and 3) current theraputic options. Type 2 diabetes in youth is a complex disease, creating new challenges in treatment and prevention.

Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia.

PubMed Central

Considine, R V; Nyce, M R; Allen, L E; Morales, L M; Triester, S; Serrano, J; Colberg, J; Lanza-Jacoby, S; Caro, J F

1995-01-01

We tested the hypothesis that liver protein kinase C (PKC) is increased in non-insulin-dependent diabetes mellitus (NIDDM). To this end we examined the distribution of PKC isozymes in liver biopsies from obese individuals with and without NIDDM and in lean controls. PKC isozymes alpha, beta, epsilon and zeta were detected by immunoblotting in both the cytosol and membrane fractions. Isozymes gamma and delta were not detected. There was a significant increase in immunodetectable PKC-alpha (twofold), -epsilon (threefold), and -zeta (twofold) in the membrane fraction isolated from obese subjects with NIDDM compared with the lean controls. In obese subjects without NIDDM, the amount of membrane PKC isozymes was not different from the other two groups. We next sought an animal model where this observation could be studied further. The Zucker diabetic fatty rat offered such a model system. Immunodetectable membrane PKC-alpha, -beta, -epsilon, and -zeta were significantly increased when compared with both the lean and obese controls. The increase in immunodetectable PKC protein correlated with a 40% elevation in the activity of PKC at the membrane. Normalization of circulating glucose in the rat model by either insulin or phlorizin treatment did not result in a reduction in membrane PKC isozyme protein or kinase activity. Further, phlorizin treatment did not improve insulin receptor autophosphorylation nor did the treatment lower liver diacylglycerol. We conclude that liver PKC is increased in NIDDM, a change that is not secondary to hyperglycemia. It is possible that PKC-mediated phosphorylation of some component in the insulin signaling cascade contributes to the insulin resistance observed in NIDDM. Images PMID:7769136

Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: The Diabetes Autoimmunity Study in the Young

PubMed Central

Norris, Jill M.; Kroehl, Miranda; Fingerlin, Tasha E.; Frederiksen, Brittni N.; Seifert, Jennifer; Wong, Randall; Clare-Salzler, Michael; Rewers, Marian

2013-01-01

Aims/hypotheses We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY). Methods DAISY is following 2547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)65, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children. Results Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09,0.55), while alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (pinteraction=0.017), at FADS2 rs174570 (pinteraction=0.016) and at FADS2 rs174583 (pinteraction=0.045). Conclusions/interpretation The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically-controlled fatty acid desaturation. PMID:24240437

Does 8 weeks of strenuous bicycle exercise improve diabetes-related inflammatory cytokines and free fatty acids in type 2 diabetes patients and individuals at high-risk of metabolic syndrome?

PubMed

Madsen, Søren Møller; Thorup, Anne Cathrine; Bjerre, Mette; Jeppesen, Per Bendix

2015-01-01

In the present study, the effects of 8 weeks of low volume high intensity interval training (HIIT) was investigated on circulating diabetes-related cytokines and free fatty acids (FFA) in adults with type 2 diabetes (T2D) and matched controls (CON). Participants exercised for 8 weeks (3 weekly sessions: 10 × 60 sec HIIT) on a cycle ergometer supervised by medical staff. Prior to the intervention and after the last HIIT session, venous blood samples were collected. Circulating omentin-1 concentrations increased significantly in both the CON-group (p = 0.003) and in the T2D-group (p = 0.002). Pentraxin-3 (p = 0.010) and IL-1ra (p = 0.031) levels increased significantly in the CON-group. Plasma FFA in the T2D-group was significantly reduced after 60 min (p = 0.011). Post HIIT area under curve of circulating FFAs was reduced by -17.73 ± 6.99% (p = 0.041) in the T2D-group. We observed only modest exercise-induced improvements of multiple diabetes-related cytokines. Circulating levels of FFAs were significantly lowered in the T2D-group.

Dietary fats and prevention of type 2 diabetes.

PubMed

Risérus, Ulf; Willett, Walter C; Hu, Frank B

2009-01-01

Although type 2 diabetes is determined primarily by lifestyle and genes, dietary composition may affect both its development and complications. Dietary fat is of particular interest because fatty acids influence glucose metabolism by altering cell membrane function, enzyme activity, insulin signaling, and gene expression. This paper focuses on the prevention of type 2 diabetes and summarizes the epidemiologic literature on associations between types of dietary fat and diabetes risk. It also summarizes controlled feeding studies on the effects of dietary fats on metabolic mediators, such as insulin resistance. Taken together, the evidence suggests that replacing saturated fats and trans fatty acids with unsaturated (polyunsaturated and/or monounsaturated) fats has beneficial effects on insulin sensitivity and is likely to reduce risk of type 2 diabetes. Among polyunsaturated fats, linoleic acid from the n-6 series improves insulin sensitivity. On the other hand, long-chain n-3 fatty acids do not appear to improve insulin sensitivity or glucose metabolism. In dietary practice, foods rich in vegetable oils, including non-hydrogenated margarines, nuts, and seeds, should replace foods rich in saturated fats from meats and fat-rich dairy products. Consumption of partially hydrogenated fats should be minimized. Additional controlled, long-term studies are needed to improve our knowledge on the optimal proportion of different types of fats to prevent diabetes.

Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease.

PubMed

Cone, Catherine J; Bachyrycz, Amy M; Murata, Glen H

2010-10-01

To report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD). A 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin. Since numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial. This is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.

Increased Postprandial Nonesterified Fatty Acid Appearance and Oxidation in Type 2 Diabetes Is Not Fully Established in Offspring of Diabetic Subjects

PubMed Central

Normand-Lauzière, François; Frisch, Frédérique; Labbé, Sébastien M.; Bherer, Patrick; Gagnon, René; Cunnane, Stephen C.; Carpentier, André C.

2010-01-01

Background It has been proposed that abnormal postprandial plasma nonesterified fatty acid (NEFA) metabolism may participate in the development of tissue lipotoxicity and type 2 diabetes (T2D). We previously found that non-diabetic offspring of two parents with T2D display increased plasma NEFA appearance and oxidation rates during intravenous administration of a fat emulsion. However, it is currently unknown whether plasma NEFA appearance and oxidation are abnormal during the postprandial state in these subjects at high-risk of developing T2D. Methodology Palmitate appearance and oxidation rates and glycerol appearance rate were determined in eleven healthy offspring of two parents with T2D (positive family history, FH+), 13 healthy subjects without first-degree relatives with T2D (FH-) and 12 subjects with T2D at fasting, during normoglycemic hyperinsulinemic clamp and during continuous oral intake of a standard liquid meal to achieve steady postprandial NEFA and triacylglycerols (TG) without and with insulin infusion to maintain similar glycemia in all three groups. Principal Findings Plasma palmitate appearance and oxidation were higher at fasting and during the clamp conditions in the T2D group (all P<0.05). In the postprandial state, palmitate appearance, oxidative and non oxidative rates were all elevated in T2D (all P<0.05) but not in FH+. Both T2D and FH+ displayed elevated postprandial TG vs. FH- (P<0.001). Acute correction of hyperglycemia during the postprandial state did not affect these group differences. Increased waist circumference and BMI were positively associated with elevated postprandial plasma palmitate appearance and oxidation. Conclusions/Significance Postprandial plasma NEFA intolerance observed in subjects with T2D is not fully established in non-diabetic offspring of both parents with T2D, despite the presence of increased postprandial plasma TG in the later. Elevated postprandial plasma NEFA appearance and oxidation in T2D is observed

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats.

PubMed

Luck, Christian; DeMarco, Vincent G; Mahmood, Abuzar; Gavini, Madhavi P; Pulakat, Lakshmi

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750  μ g/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters ( E / E ', E '/ A ', E / Vp ) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFN γ , and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes.

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

PubMed Central

Luck, Christian; DeMarco, Vincent G.; Mahmood, Abuzar; Gavini, Madhavi P.

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E′, E′/A′, E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes. PMID:28408970

The interaction between ApoA2 -265T>C polymorphism and dietary fatty acids intake on oxidative stress in patients with type 2 diabetes mellitus.

PubMed

Zamani, Elham; Sadrzadeh-Yeganeh, Haleh; Sotoudeh, Gity; Keramat, Laleh; Eshraghian, Mohammadreza; Rafiee, Masoumeh; Koohdani, Fariba

2017-08-01

Apolipoprotein A2 (APOA2) -265T>C polymorphism has been studied in relation to oxidative stress and various dietary fatty acids. Since the interaction between APOA2 polymorphism and dietary fatty acids on oxidative stress has not yet discussed, we aimed to investigate the interaction on oxidative stress in type 2 diabetes mellitus (T2DM) patients. The subjects were 180 T2DM patients with known APOA2 genotype, either TT, TC or CC. Superoxide dismutase (SOD) activity was determined by colorimetric method. Total antioxidant capacity (TAC) and serum level of 8-isoprostane F2α were measured by spectrophotometry and ELISA, respectively. Dietary intake was collected through a food frequency questionnaire. Based on the median intake, fatty acids intake was dichotomized into high or low groups. The interaction between APOA2 polymorphism and dietary fatty acids intake was analyzed by ANCOVA multivariate interaction model. Higher than median intake of omega-6 polyunsaturated fatty acids (n-6 PUFA) was associated with increased serum level of 8-isoprostane F2α in subjects with TT/TC genotype (p = 0.004), and higher than median intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) was associated with increased serum SOD activity in CC genotype (p < 0.001). There was a statistically significant interaction between APOA2 polymorphism and n-6 PUFA intake on 8-isoprostane F2α concentration as well as n-3 PUFA intake on serum SOD activity (p-interaction = 0.04 and 0.02, respectively). The current study shows the interaction between APOA2 polymorphism and dietary fatty acids intake on oxidative stress. More investigations on different populations are required to confirm the interaction.

Metabolic effects of Crocus sativus and protective action against non-alcoholic fatty liver disease in diabetic rats

PubMed Central

Konstantopoulos, Panagiotis; Doulamis, Ilias P.; Tzani, Aspasia; Korou, Maria-Laskarina; Agapitos, Emmanouil; Vlachos, Ioannis S.; Pergialiotis, Vasilios; Verikokos, Christos; Mastorakos, George; Katsilambros, Nicholas L.; Perrea, Despina N.

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is the result of the accumulation of adipose tissue deposits in the liver and it is associated with type 2 diabetes. Crocus sativus (saffron) is known for its antioxidant and its potential hypoglycemic effects. We investigated the role of saffron on NAFLD in diabetic rats. Thirty adult male rats were allocated into three groups; control (n=10), which received normal diet; streptozotocin (STZ) group (n=10), which received normal chow diet, 10% fructose in their drinking water and STZ (40 mg/kg body weight; STZ-saffron group (n=10), which followed the same dietary and pharmacological pattern as STZ group and were additionally supplemented with saffron (100 mg/kg/day). Metabolic profile was measured and histopathological examination of the liver was evaluated. STZ group exhibited the highest glucose levels at the end of the experiment (P<0.05), while there was no difference between control and STZ-saffron group (584 vs. 213 mg/dl vs. 209 mg/dl, respectively). STZ group revealed higher percentage of steatosis (5–33%) when compared to the other two groups (P<0.005). Saffron exhibits both hypoglycemic and hepatoprotective actions. Yet, further studies enlightening the exact mechanisms of saffron's mode of actions are required. PMID:28529733

Diets containing salmon fillet delay development of high blood pressure and hyperfusion damage in kidneys in obese Zucker fa/fa rats.

PubMed

Vikøren, Linn A; Drotningsvik, Aslaug; Mwakimonga, Angela; Leh, Sabine; Mellgren, Gunnar; Gudbrandsen, Oddrun A

2018-04-01

Hypertension is the leading risk factor for cardiovascular and chronic renal diseases, affecting more than 1 billion people. Fish intake is inversely correlated with the prevalence of hypertension in several, but not all, studies, and intake of fish oil and fish proteins has shown promising potential to delay development of high blood pressure in rats. The effects of baked and raw salmon fillet intake on blood pressure and renal function were investigated in obese Zucker fa/fa rats, which spontaneously develop hypertension with proteinuria and renal failure. Rats were fed diets containing baked or raw salmon fillet in an amount corresponding to 25% of total protein from salmon and 75% of protein from casein, or casein as the sole protein source (control group) for 4 weeks. Results show lower blood pressure and lower urine concentrations of albumin and cystatin C (relative to creatinine) in salmon diet groups when compared to control group. Morphological examinations revealed less prominent hyperfusion damage in podocytes from rats fed diets containing baked or raw salmon when compared to control rats. In conclusion, diets containing baked or raw salmon fillet delayed the development of hypertension and protected against podocyte damage in obese Zucker fa/fa rats. Copyright © 2018 American Heart Association. Published by Elsevier Inc. All rights reserved.

Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.

PubMed

Ping, Fan; Li, Zeng-Yi; Lv, Ke; Zhou, Mei-Cen; Dong, Ya-Xiu; Sun, Qi; Li, Yu-Xiu

2017-03-01

To investigate the effect of telomere shortening and other predictive factors of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus patients in a 6-year prospective cohort study. A total of 70 type 2 diabetes mellitus (mean age 57.8 ± 6.7 years) patients without NAFLD were included in the study, and 64 of them were successfully followed up 6 years later, excluding four cases with significant alcohol consumption. NAFLD was diagnosed by the hepatorenal ratio obtained by a quantitative ultrasound method using NIH image analysis software. The 39 individuals that developed NAFLD were allocated to group A, and the 21 individuals that did not develop NAFLD were allocated to group B. Fluorescent real-time quantitative polymerase chain reaction was used to measure telomere length. There was no significant difference between the two groups in baseline telomere length; however, at the end of the 6th year, telomere length had become shorter in group A compared with group B. There were significant differences between these two groups in baseline body mass index, waistline, systolic blood pressure, glycated hemoglobin and fasting C-peptide level. In addition, the estimated indices of baseline insulin resistance increased in group A. Fasting insulin level, body mass index, systolic blood pressure at baseline and the shortening of telomere length were independent risk factors of NAFLD in type 2 diabetes mellitus patients. Telomere length became shorter in type 2 diabetes mellitus patients who developed NAFLD over the course of 6 years. Type 2 diabetes mellitus patients who developed NAFLD had more serious insulin resistance compared with those who did not develop NAFLD a long time ago. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Increased urine acylcarnitines in diabetic ApoE-/- mice: Hydroxytetradecadienoylcarnitine (C14:2-OH) reflects diabetic nephropathy in a context of hyperlipidemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirzoyan, Koryun; Université Toulouse III Paul-Sabatier Toulouse; Klavins, Kristaps

Hyperlipidemia is a risk factor for initiation and progression of diabetic nephropathy but the metabolic pathways altered in the diabetic kidney in a context of hyperlipidemia remain incompletely described. Assuming that changes in urine composition reflect the alteration of renal metabolism and function, we analyzed the urine metabolite composition of diabetic (streptozotocin-treatment) and control (non diabetic) ApoE−/− mice fed a high cholesterol diet using targeted quantitative metabolomics. Urine metabolome was also compared to the plasma metabolome of the same animals. As previously shown, urine albuminuria/urine creatinine ratio (uACR) and glomerular area and plasma lipids (cholesterol, triglycerides) were more elevated inmore » diabetic mice compared to control. After adjustment to urine creatinine, the abundance of 52 urine metabolites was significantly different in diabetic mice compared to control. Among them was a unique metabolite, C14:2-OH (3-hydroxytetradecadienoylcarnitine) that, in diabetic mice, was positively and significantly correlated with uACR, glomerular hypertrophy, blood glucose and plasma lipids. That metabolite was not detected in plasma. C14:2-OH is a long-chain acylcarnitine reminiscent of altered fatty acid beta oxidation. Other acylcarnitines, particularly the short chains C3-OH, C3-DC, C4:1, C5-DC, C5-M-DC, C5-OH that are reminiscent of altered oxidation of branched and aromatic amino acids were also exclusively detected in urine but were only correlated with plasma lipids. Finally, the renal gene expression of several enzymes involved in fatty acid and/or amino acid oxidation was significantly reduced in diabetic mice compared to control. This included the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA (Ehhadh) that might play a central role in C14:2-OH production. This study indicate that the development of diabetes in a context of hyperlipidemia is associated with a reduced capacity of kidney to oxidize fatty acids and

Increased urine acylcarnitines in diabetic ApoE-/- mice: Hydroxytetradecadienoylcarnitine (C14:2-OH) reflects diabetic nephropathy in a context of hyperlipidemia.

PubMed

Mirzoyan, Koryun; Klavins, Kristaps; Koal, Therese; Gillet, Marion; Marsal, Dimitri; Denis, Colette; Klein, Julie; Bascands, Jean-Loup; Schanstra, Joost P; Saulnier-Blache, Jean-Sébastien

2017-05-20

Hyperlipidemia is a risk factor for initiation and progression of diabetic nephropathy but the metabolic pathways altered in the diabetic kidney in a context of hyperlipidemia remain incompletely described. Assuming that changes in urine composition reflect the alteration of renal metabolism and function, we analyzed the urine metabolite composition of diabetic (streptozotocin-treatment) and control (non diabetic) ApoE-/- mice fed a high cholesterol diet using targeted quantitative metabolomics. Urine metabolome was also compared to the plasma metabolome of the same animals. As previously shown, urine albuminuria/urine creatinine ratio (uACR) and glomerular area and plasma lipids (cholesterol, triglycerides) were more elevated in diabetic mice compared to control. After adjustment to urine creatinine, the abundance of 52 urine metabolites was significantly different in diabetic mice compared to control. Among them was a unique metabolite, C14:2-OH (3-hydroxytetradecadienoylcarnitine) that, in diabetic mice, was positively and significantly correlated with uACR, glomerular hypertrophy, blood glucose and plasma lipids. That metabolite was not detected in plasma. C14:2-OH is a long-chain acylcarnitine reminiscent of altered fatty acid beta oxidation. Other acylcarnitines, particularly the short chains C3-OH, C3-DC, C4:1, C5-DC, C5-M-DC, C5-OH that are reminiscent of altered oxidation of branched and aromatic amino acids were also exclusively detected in urine but were only correlated with plasma lipids. Finally, the renal gene expression of several enzymes involved in fatty acid and/or amino acid oxidation was significantly reduced in diabetic mice compared to control. This included the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA (Ehhadh) that might play a central role in C14:2-OH production. This study indicate that the development of diabetes in a context of hyperlipidemia is associated with a reduced capacity of kidney to oxidize fatty acids and amino acids

Type 2 Diabetes and Metformin Influence on Fracture Healing in an Experimental Rat Model.

PubMed

La Fontaine, Javier; Chen, Chris; Hunt, Nathan; Jude, Edward; Lavery, Lawrence

2016-01-01

Persons with diabetes have a greater incidence of fractures compared with persons without diabetes. However, very little published information is available concerning the deleterious effect of late-stage diabetes on osseous structure and bone healing. The purpose of the present study was to evaluate the role of diabetes on fracture healing in a rat femur repair model. Thirty-six lean and diabetic Zucker rats were subdivided into 3 groups: (1) 12 lean rats as the control group; (2) 12 diabetic rats without blood glucose control (DM group); and (3) 12 diabetic rats treated with 300 mg/kg metformin to reduce the blood glucose levels (DM + Met group). Radiographs were taken every week to determine the incidence of bone repair and delayed union. All the rats were killed at 6 weeks after surgery. In both the sham-operated and the fractured and repaired femurs, significant decreases in the fracture-load/weight and marginal decreases in the fracture-load between the lean and DM groups were found. Metformin treatment significantly reduced the blood glucose and body weight 12 days postoperatively. Furthermore, a decrease in the fracture-load and fracture-load/weight in the repaired femurs was found in the DM + Met group. Diabetes impairs bone fracture healing. Metformin treatment reduces the blood glucose and body weight but had an adverse effect on fracture repair in diabetic rats. Further investigations are needed to reveal the mechanisms responsible for the effects of type 2 diabetes mellitus on bone and bone quality and the effect of medications such as metformin might have in diabetic bone in the presence of neuropathy and vascular disease. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Brown Norway and Zucker Lean Rats Demonstrate Circadian Variation in Ventilation and Sleep Apnea

PubMed Central

Fink, Anne M.; Topchiy, Irina; Ragozzino, Michael; Amodeo, Dionisio A.; Waxman, Jonathan A.; Radulovacki, Miodrag G.; Carley, David W.

2014-01-01

Study Objectives: Circadian rhythms influence many biological systems, but there is limited information about circadian and diurnal variation in sleep related breathing disorder. We examined circadian and diurnal patterns in sleep apnea and ventilatory patterns in two rat strains, one with high sleep apnea propensity (Brown Norway [BN]) and the other with low sleep apnea propensity (Zucker Lean [ZL]). Design/Setting: Chronically instrumented rats were randomized to breathe room air (control) or 100% oxygen (hyperoxia), and we performed 20-h polysomnography beginning at Zeitgeber time 4 (ZT 4; ZT 0 = lights on, ZT12 = lights off). We examined the effect of strain and inspired gas (twoway analysis of variance) and analyzed circadian and diurnal variability. Measurements and Results: Strain and inspired gas-dependent differences in apnea index (AI; apneas/h) were particularly prominent during the light phase. AI in BN rats (control, 16.9 ± 0.9; hyperoxia, 34.0 ± 5.8) was greater than in ZL rats (control, 8.5 ± 1.0; hyperoxia, 15.4 ± 1.1, [strain effect, P < 0.001; gas effect, P = 0.001]). Hyperoxia reduced respiratory frequency in both strains, and all respiratory pattern variables demonstrated circadian variability. BN rats exposed to hyperoxia demonstrated the largest circadian fluctuation in AI (amplitude = 17.9 ± 3.7 apneas/h [strain effect, P = 0.01; gas effect, P < 0.001; interaction, P = 0.02]; acrophase = 13.9 ± 0.7 h; r2 = 0.8 ± 1.4). Conclusions: Inherited, environmental, and circadian factors all are important elements of underlying sleep related breathing disorder. Our method to examine sleep related breathing disorder phenotypes in rats may have implications for understanding vulnerability for sleep related breathing disorder in humans. Citation: Fink AM; Topchiy I; Ragozzino M; Amodeo DA; Waxman JA; Radulovacki MG; Carley DW. Brown Norway and Zucker Lean rats demonstrate circadian variation in ventilation and sleep apnea. SLEEP 2014

Tang-Nai-Kang Alleviates Pre-diabetes and Metabolic Disorders and Induces a Gene Expression Switch toward Fatty Acid Oxidation in SHR.Cg-Leprcp/NDmcr Rats

PubMed Central

Li, Linyi; Yoshitomi, Hisae; Wei, Ying; Qin, Lingling; Zhou, Jingxin; Xu, Tunhai; Wu, Xinli; Zhou, Tian; Sun, Wen; Guo, Xiangyu; Wu, Lili; Wang, Haiyan; Zhang, Yan; Li, Chunna; Liu, Tonghua; Gao, Ming

2015-01-01

Increased energy intake and reduced physical activity can lead to obesity, diabetes and metabolic syndrome. Transcriptional modulation of metabolic networks has become a focus of current drug discovery research into the prevention and treatment of metabolic disorders associated with energy surplus and obesity. Tang-Nai-Kang (TNK), a mixture of five herbal plant extracts, has been shown to improve abnormal glucose metabolism in patients with pre-diabetes. Here, we report the metabolic phenotype of SHR.Cg-Lepr cp/NDmcr (SHR/cp) rats treated with TNK. Pre-diabetic SHR/cp rats were randomly divided into control, TNK low-dose (1.67 g/kg) and TNK high-dose (3.24 g/kg) groups. After high-dose treatment for 2 weeks, the serum triglycerides and free fatty acids in SHR/cp rats were markedly reduced compared to controls. After 3 weeks of administration, the high dose of TNK significantly reduced the body weight and fat mass of SHR/cp rats without affecting food consumption. Serum fasting glucose and insulin levels in the TNK-treated groups decreased after 6 weeks of treatment. Furthermore, TNK-treated rats exhibited obvious improvements in glucose intolerance and insulin resistance. The improved glucose metabolism may be caused by the substantial reduction in serum lipids and body weight observed in SHR/cp rats starting at 3 weeks of TNK treatment. The mRNA expression of NAD+-dependent deacetylase sirtuin 1 (SIRT1) and genes related to fatty acid oxidation was markedly up-regulated in the muscle, liver and adipose tissue after TNK treatment. Furthermore, TNK promoted the deacetylation of two well-established SIRT1 targets, PPARγ coactivator 1α (PGC1α) and forkhead transcription factor 1 (FOXO1), and induced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in different tissues. These observations suggested that TNK may be an alternative treatment for pre-diabetes and metabolic syndrome by inducing a gene expression switch toward

Dipeptidylpeptidase-IV, a key enzyme for the degradation of incretins and neuropeptides: activity and expression in the liver of lean and obese rats

PubMed Central

Tarantola, E.; Bertone, V.; Milanesi, G.; Capelli, E.; Ferrigno, A.; Neri, D.; Vairetti, M.; Barni, S.; Freitas, I.

2012-01-01

Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns

Dipeptidylpeptidase--IV, a key enzyme for the degradation of incretins and neuropeptides: activity and expression in the liver of lean and obese rats.

PubMed

Tarantola, E; Bertone, V; Milanesi, G; Capelli, E; Ferrigno, A; Neri, D; Vairetti, M; Barni, S; Freitas, I

2012-10-08

Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns

Comparison of speckle-tracking echocardiography with invasive hemodynamics for the detection of characteristic cardiac dysfunction in type-1 and type-2 diabetic rat models.

PubMed

Mátyás, Csaba; Kovács, Attila; Németh, Balázs Tamás; Oláh, Attila; Braun, Szilveszter; Tokodi, Márton; Barta, Bálint András; Benke, Kálmán; Ruppert, Mihály; Lakatos, Bálint Károly; Merkely, Béla; Radovits, Tamás

2018-01-16

Measurement of systolic and diastolic function in animal models is challenging by conventional non-invasive methods. Therefore, we aimed at comparing speckle-tracking echocardiography (STE)-derived parameters to the indices of left ventricular (LV) pressure-volume (PV) analysis to detect cardiac dysfunction in rat models of type-1 (T1DM) and type-2 (T2DM) diabetes mellitus. Rat models of T1DM (induced by 60 mg/kg streptozotocin, n = 8) and T2DM (32-week-old Zucker Diabetic Fatty rats, n = 7) and corresponding control animals (n = 5 and n = 8, respectively) were compared. Echocardiography and LV PV analysis were performed. LV short-axis recordings were used for STE analysis. Global circumferential strain, peak strain rate values in systole (SrS), isovolumic relaxation (SrIVR) and early diastole (SrE) were measured. LV contractility, active relaxation and stiffness were measured by PV analysis. In T1DM, contractility and active relaxation were deteriorated to a greater extent compared to T2DM. In contrast, diastolic stiffness was impaired in T2DM. Correspondingly, STE described more severe systolic dysfunction in T1DM. Among diastolic STE parameters, SrIVR was more decreased in T1DM, however, SrE was more reduced in T2DM. In T1DM, SrS correlated with contractility, SrIVR with active relaxation, while in T2DM SrE was related to cardiac stiffness, cardiomyocyte diameter and fibrosis. Strain and strain rate parameters can be valuable and feasible measures to describe the dynamic changes in contractility, active relaxation and LV stiffness in animal models of T1DM and T2DM. STE corresponds to PV analysis and also correlates with markers of histological myocardial remodeling.

Genetic Relatedness of WNIN and WNIN/Ob with Major Rat Strains in Biomedical Research.

PubMed

Battula, Kiran Kumar; Nappanveettil, Giridharan; Nakanishi, Satoshi; Kuramoto, Takashi; Friedman, Jeffry M; Kalashikam, Rajender Rao

2015-06-01

WNIN (Wistar/NIN) is an inbred rat strain maintained at National Institute of Nutrition (NIN) for more than 90 years, and WNIN/Ob is an obese mutant originated from it. To determine their genetic relatedness with major rat strains in biomedical research, they were genotyped at various marker loci. The recently identified markers for albino and hooded mutations which clustered all the known albino rats into a single lineage also included WNIN and WNIN/Ob rats. Genotyping using microsatellite DNA markers and phylogenetic analysis with 49 different rat strains suggested that WNIN shares a common ancestor with many Wistar originated strains. Fst estimates and Fischer's exact test suggest that WNIN rats differed significantly from all other strains tested. WNIN/Ob though shows hyper-leptinemia, like Zucker fatty rat, did not share the Zucker fatty rat mutation. The above analyses suggest WNIN as a highly differentiated rat strain and WNIN/Ob a novel obese mutant evolved from it.

Inhibitors of Fatty Acid Synthesis Induce PPARα-Regulated Fatty Acid β-Oxidative Genes: Synergistic Roles of L-FABP and Glucose

PubMed Central

Huang, Huan; McIntosh, Avery L.; Martin, Gregory G.; Petrescu, Anca D.; Landrock, Kerstin K.; Landrock, Danilo; Kier, Ann B.; Schroeder, Friedhelm

2013-01-01

While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-α (PPARα) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPARα transcription of the fatty acid β-oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPARα in the context of high glucose at levels similar to those in uncontrolled diabetes. PMID:23533380

Dietary fatty acid metabolism in prediabetes.

PubMed

Noll, Christophe; Carpentier, André C

2017-02-01

Experimental evidences are strong for a role of long-chain saturated fatty acids in the development of insulin resistance and type 2 diabetes. Ectopic accretion of triglycerides in lean organs is a characteristic of prediabetes and type 2 diabetes and has been linked to end-organ complications. The contribution of disordered dietary fatty acid (DFA) metabolism to lean organ overexposure and lipotoxicity is still unclear, however. DFA metabolism is very complex and very difficult to study in vivo in humans. We have recently developed a novel imaging method using PET with oral administration of 14-R,S-F-fluoro-6-thia-heptadecanoic acid (FTHA) to quantify organ-specific DFA partitioning. Our studies thus far confirmed impaired storage of DFA per volume of fat mass in abdominal adipose tissues of individuals with prediabetes. They also highlighted the increased channeling of DFA toward the heart, associated with subclinical reduction in cardiac systolic and diastolic function in individuals with prediabetes. In the present review, we summarize previous work on DFA metabolism in healthy and prediabetic states and discuss these in the light of our novel findings using PET imaging of DFA metabolism. We herein provide an integrated view of abnormal organ-specific DFA partitioning in prediabetes in humans.

Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

PubMed

Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

2013-01-01

While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

Peroxisome proliferator-activated receptor ligands regulate lipid content, metabolism, and composition in fetal lungs of diabetic rats.

PubMed

Kurtz, M; Capobianco, E; Careaga, V; Martinez, N; Mazzucco, M B; Maier, M; Jawerbaum, A

2014-03-01

Maternal diabetes impairs fetal lung development. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors relevant in lipid homeostasis and lung development. This study aims to evaluate the effect of in vivo activation of PPARs on lipid homeostasis in fetal lungs of diabetic rats. To this end, we studied lipid concentrations, expression of lipid metabolizing enzymes and fatty acid composition in fetal lungs of control and diabetic rats i) after injections of the fetuses with Leukotriene B4 (LTB4, PPARα ligand) or 15deoxyΔ(12,14)prostaglandin J2 (15dPGJ2, PPARγ ligand) and ii) fed during pregnancy with 6% olive oil- or 6% safflower oil-supplemented diets, enriched with PPAR ligands were studied. Maternal diabetes increased triglyceride concentrations and decreased expression of lipid-oxidizing enzymes in fetal lungs of diabetic rats, an expression further decreased by LTB4 and partially restored by 15dPGJ2 in lungs of male fetuses in the diabetic group. In lungs of female fetuses in the diabetic group, maternal diets enriched with olive oil increased triglyceride concentrations and fatty acid synthase expression, while those enriched with safflower oil increased triglyceride concentrations and fatty acid transporter expression. Both olive oil- and safflower oil-supplemented diets decreased cholesterol and cholesteryl ester concentrations and increased the expression of the reverse cholesterol transporter ATP-binding cassette A1 in fetal lungs of female fetuses of diabetic rats. In fetal lungs of control and diabetic rats, the proportion of polyunsaturated fatty acids increased with the maternal diets enriched with olive and safflower oils. Our results revealed important changes in lipid metabolism in fetal lungs of diabetic rats, and in the ability of PPAR ligands to modulate the composition of lipid species relevant in the lung during the perinatal period.

The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter.

PubMed

Chon, Young Eun; Kim, Kwang Joon; Jung, Kyu Sik; Kim, Seung Up; Park, Jun Yong; Kim, Do Young; Ahn, Sang Hoon; Chon, Chae Yoon; Chung, Jae Bock; Park, Kyeong Hye; Bae, Ji Cheol; Han, Kwang Hyub

2016-07-01

The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ0.407) or fasting C-peptide (ρ0.402) were demonstrated. Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.

Fatty acid metabolism and the basis of brown adipose tissue function

PubMed Central

Calderon-Dominguez, María; Mir, Joan F.; Fucho, Raquel; Weber, Minéia; Serra, Dolors; Herrero, Laura

2016-01-01

ABSTRACT Obesity has reached epidemic proportions, leading to severe associated pathologies such as insulin resistance, cardiovascular disease, cancer and type 2 diabetes. Adipose tissue has become crucial due to its involvement in the pathogenesis of obesity-induced insulin resistance, and traditionally white adipose tissue has captured the most attention. However in the last decade the presence and activity of heat-generating brown adipose tissue (BAT) in adult humans has been rediscovered. BAT decreases with age and in obese and diabetic patients. It has thus attracted strong scientific interest, and any strategy to increase its mass or activity might lead to new therapeutic approaches to obesity and associated metabolic diseases. In this review we highlight the mechanisms of fatty acid uptake, trafficking and oxidation in brown fat thermogenesis. We focus on BAT's morphological and functional characteristics and fatty acid synthesis, storage, oxidation and use as a source of energy. PMID:27386151

Nutritional Management of Insulin Resistance in Nonalcoholic Fatty Liver Disease (NAFLD)

PubMed Central

Conlon, Beth A.; Beasley, Jeannette M.; Aebersold, Karin; Jhangiani, Sunil S.; Wylie-Rosett, Judith

2013-01-01

Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association’s (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD. PMID:24152749

PPAR ligands improve impaired metabolic pathways in fetal hearts of diabetic rats.

PubMed

Kurtz, Melisa; Capobianco, Evangelina; Martinez, Nora; Roberti, Sabrina Lorena; Arany, Edith; Jawerbaum, Alicia

2014-10-01

In maternal diabetes, the fetal heart can be structurally and functionally affected. Maternal diets enriched in certain unsaturated fatty acids can activate the nuclear receptors peroxisome proliferator-activated receptors (PPARs) and regulate metabolic and anti-inflammatory pathways during development. Our aim was to investigate whether PPARα expression, lipid metabolism, lipoperoxidation, and nitric oxide (NO) production are altered in the fetal hearts of diabetic rats, and to analyze the putative effects of in vivo PPAR activation on these parameters. We found decreased PPARα expression in the hearts of male but not female fetuses of diabetic rats when compared with controls. Fetal treatments with the PPARα ligand leukotriene B4 upregulated the expression of PPARα and target genes involved in fatty acid oxidation in the fetal hearts. Increased concentrations of triglycerides, cholesterol, and phospholipids were found in the hearts of fetuses of diabetic rats. Maternal treatments with diets supplemented with 6% olive oil or 6% safflower oil, enriched in unsaturated fatty acids that can activate PPARs, led to few changes in lipid concentrations, but up-regulated PPARα expression in fetal hearts. NO production, which was increased in the hearts of male and female fetuses in the diabetic group, and lipoperoxidation, which was increased in the hearts of male fetuses in the diabetic group, was reduced by the maternal treatments supplemented with safflower oil. In conclusion, impaired PPARα expression, altered lipid metabolism, and increased oxidative and nitridergic pathways were evidenced in hearts of fetuses of diabetic rats and were regulated in a gender-dependent manner by treatments enriched with PPAR ligands. © 2014 Society for Endocrinology.

Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus.

PubMed

Mantovani, Alessandro; Rigolon, Riccardo; Pichiri, Isabella; Bonapace, Stefano; Morani, Giovanni; Zoppini, Giacomo; Bonora, Enzo; Targher, Giovanni

2017-01-01

Recent studies suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiac tachyarrhythmias (mainly atrial fibrillation) in patients with and without type 2 diabetes mellitus. The aim of this study was to examine whether an association also exists between NAFLD and heart block. We have retrospectively evaluated a hospital-based cohort of 751 patients with type 2 diabetes discharged from our Division of Diabetes and Endocrinology during years 2007-2014. Standard electrocardiograms were performed on all patients. Diagnosis of NAFLD was based on ultrasonography, whereas the severity of advanced hepatic fibrosis was based on the fibrosis (FIB)-4 score and other non-invasive fibrosis markers. Overall, 524 (69.8%) patients had NAFLD and 202 (26.9%) had heart block (defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block) on electrocardiograms. Patients with NAFLD had a remarkably higher prevalence of any persistent heart block than those without NAFLD (31.3% vs. 16.7%, p<0.001); this prevalence was particularly increased among those with higher FIB-4 score. NAFLD was associated with a threefold increased risk of prevalent heart block (adjusted-odds ratio 3.04, 95% CI 1.81-5.10), independently of age, sex, hypertension, prior ischemic heart disease, hemoglobin A1c, microvascular complication status, use of medications and other potentially confounding factors. In conclusion, this is the largest cross-sectional study to show that NAFLD and its severity are independently associated with an increased risk of prevalent heart block in hospitalized patients with type 2 diabetes.

Lipid Composition of Cell Membranes and Its Relevance in Type 2 Diabetes Mellitus

PubMed Central

Weijers, Rob N.M.

2012-01-01

Identifying the causative relationship between the fatty acid composition of cell membranes and type 2 diabetes mellitus fundamentally contributes to the understanding of the basic pathophysiological mechanisms of the disease. Important outcomes of the reviewed studies appear to support the hypotheses that the flexibility of a membrane determined by the ratio of (poly)unsaturated to saturated fatty acyl chains of its phospholipids influences the effectiveness of glucose transport by insulin-independent glucose transporters (GLUTs) and the insulin-dependent GLUT4, and from the prediabetic stage on a shift from unsaturated towards saturated fatty acyl chains of membrane phospholipids directly induces a decrease in glucose effectiveness and insulin sensitivity. In addition, it has become evident that a concomitant increase in stiffness of both plasma and erythrocyte membranes may decrease the microcirculatory flow, leading ultimately to tissue hypoxia, insufficient tissue nutrition, and diabetes-specific microvascular pathology. As to the etiology of type 2 diabetes mellitus, a revised hypothesis that attempts to accommodate the reviewed findings is presented. PMID:22698081

Liver mitochondrial membrane fluidity at early development of diabetes and its correlation with the respiration.

PubMed

Pérez-Hernández, Ismael H; Domínguez-Fuentes, Josué Misael; Palomar-Morales, Martín; Zazueta-Mendizabal, Ana Cecilia; Baiza-Gutman, Arturo; Mejía-Zepeda, Ricardo

2017-06-01

The biological membranes are important in cell function but, during development of diseases such as diabetes, they are impaired. Consequently, membrane-associated biological processes are impaired as well. The mitochondria are important organelles where oxidative phosphorylation takes place, a process closely related with the membranes. In general, it is accepted that the development process of diabetes decreases membrane fluidity. However, in some cases, it has been found to increase membrane fluidity of mitochondria but to decrease the Respiratory Control (RC) index. In this study we found an increase of membrane fluidity and an increase of the RC at an early phase of the development of a type 2 diabetes model. We measured the lipoperoxidation, analyzed the fatty acids composition by gas chromatography, and assessed membrane fluidity using three fluorescent monitors located at different depths inside the bilayer, dipyrenilpropane (DPyP), diphenylhexatriene (DPH), and trimethylammonium diphenylhexatriene (TMA-DPH). Our findings indicate that in the initial stage of diabetes development, when lipoperoxidation still is not significant, the membrane fluidity of liver mitochondria increases because of the increment in the unsaturated to saturated fatty acids ratio (U/S), thus producing an increase of the RC. The membrane fluidity is not the same at all depths in the bilayer. Contrary to the results obtained in mitochondria, the diabetes induced a decrease in the U/S fatty acids ratio of liver total lipids, indicating that the mitochondria might have an independent mechanism for regulating its fatty acids composition.

mTORC1 inhibitors rapamycin and metformin affect cardiovascular markers differentially in ZDF rats.

PubMed

Nistala, Ravi; Raja, Ahmad; Pulakat, Lakshmi

2017-03-01

Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.

[The profile of plasma non-esterified fatty acids in children with different terms of type 1 diabetes mellitus].

PubMed

Akmurzina, V A; Petryairina, E E; Saveliev, S V; Selishcheva, A A

2016-01-01

Composition and quantitative content of non-esterified fatty acids (NEFA) were investigated in plasma samples of healthy children (12) and children with type 1 diabetes mellitus (DM1) (31) by gas chromatography (GC) after preliminary NEFA solid-phase extraction from plasma lipids. There was a significant (p<0.001) 1.6-fold increase in the total level of NEFA regardless of the disease duration. In the group of DM1 children with the disease period less than 1 year there was an increase in the arachidonic acid (20:4) content (30%) and the oleic acid trans-isomer (18:1) content (82%), and also a decrease in the docosahexaenoic acid (22:6 n3) content (26% ) and the docosapentaenoic acids (22:5 n-6) content (60%). In the group of DM1 children with prolonged course of this disease the altered NEFA levels returned to the normal level.

Subclassification of fatty liver by its pathogenesis: cIEFing is believing.

PubMed

Byrne, Frances L; Hoehn, Kyle L

2016-05-01

Fatty liver, also termed hepatic steatosis or fatty liver disease, is a condition characterized by excess fat accumulation in the liver. Common causes of fatty liver include obesity, ageing, medications, genetic disorders, viral hepatitis, excess alcohol or toxins. This diversity in pathogenesis is matched by an equally diverse spectrum of consequences, whereby some individuals remain asymptomatic yet others progress through a series of inflammatory, fibrotic and metabolic disorders that can lead to liver failure, cancer or diabetes. Current treatment approaches for fatty liver do not differ by disease aetiology and primarily involve weight loss strategies or management of co-morbidities. In a recent paper published in this journal, Urasaki et al used capillary isoelectric focusing (cIEF) to create profiles of protein post-translational modifications that distinguish four different models of fatty liver in mice. Importantly, this new cIEF approach has the potential to provide rapid individualized diagnosis of fatty liver pathogenesis that may enable more accurate and personalized treatment strategies. Further testing and optimization of cIEF as a diagnostic screening tool in humans is warranted. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Current Metabolic Status Affects Urinary Liver-Type Fatty-Acid Binding Protein in Normoalbuminuric Patients With Type 2 Diabetes

PubMed Central

Ito, Hiroyuki; Yamashita, Hitomi; Nakashima, Mina; Takaki, Akifusa; Yukawa, Chiduko; Matsumoto, Suzuko; Omoto, Takashi; Shinozaki, Masahiro; Nishio, Shinya; Abe, Mariko; Antoku, Shinichi; Mifune, Mizuo; Togane, Michiko

2017-01-01

Background We aimed to study the association between urinary liver-type fatty acid-binding protein (L-FABP), a biomarker of tubulointerstitial injury, and the clinical characteristics of normoalbuminuric and albuminuric patients with type 2 diabetes in order to detect the factors affecting urinary L-FABP. Methods Urinary L-FABP levels were measured in 788 patients with type 2 diabetes and again in 666 patients at 6 months after the initial measurement. The association between the urinary L-FABP level and the clinical parameters was investigated in a retrospective cross-sectional study and a subsequent observation. Results The HbA1c (odds ratio (OR): 1.42; 95% confidence interval (CI): 1.11 - 1.79; P < 0.01), systolic blood pressure (OR: 1.03; 95% CI: 1.01 - 1.05; P < 0.01) levels and estimated glomerular filtration rate (OR: 0.98; 95% CI: 0.96 - 1.00; P = 0.01) were significantly associated with the high levels of urinary L-FABP (> 8.4 μg/gCr) in normoalbuminuric patients. However, a logistic regression analysis revealed that use of renin-angiotensin system (RAS) inhibitors (OR: 2.22; 95% CI: 1.16 - 4.89; P = 0.02), urinary albumin-to-creatinine ratio (ACR) (OR: 1.01; 95% CI: 1.00 - 1.01; P < 0.01) and serum HDL-cholesterol concentration (OR: 0.33; 95% CI: 0.11 - 0.89; P = 0.03) were significantly associated in albuminuric patients. In the follow-up observation, the change in urinary L-FABP was found to be significantly (P < 0.01) influenced by the change in the HbA1c level in both the normoalbuminuric and albuminuric patients. Conclusions High urinary L-FABP is associated with part of the current metabolic abnormalities, including high levels of HbA1c and systolic blood pressure among normoalbuminuric patients with type 2 diabetes. PMID:28270898

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors.

PubMed

Tikhonova, Irina G

2017-01-01

Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge-pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small-molecule modulators at the FFA receptors.

COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

PubMed

Muñoz, Mercedes; Sánchez, Ana; Pilar Martínez, María; Benedito, Sara; López-Oliva, Maria-Elvira; García-Sacristán, Albino; Hernández, Medardo; Prieto, Dolores

2015-07-01

Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. Copyright © 2015 Elsevier Inc. All rights reserved.

(-)-Epicatechin-3-O-β-D-allopyranoside from Davallia formosana prevents diabetes and dyslipidemia in streptozotocin-induced diabetic mice.

PubMed

Lin, Cheng-Hsiu; Wu, Jin-Bin; Jian, Jia-Ying; Shih, Chun-Ching

2017-01-01

The objective of this study was to evaluate the effects and molecular mechanism of (-)-epicatechin-3-O-β-D-allopyranoside from Davallia formosana (BB) (also known as Gu-Sui-Bu) on type 1 diabetes mellitus and dyslipidemia in streptozotocin (STZ)-induced diabetic mice. This plant was demonstrated to display antioxidant activities and possess polyphenol contents. Diabetic mice were randomly divided into six groups and were given daily oral gavage doses of either BB (at three dosage levels), metformin (Metf) (at 0.3 g/kg body weight), fenofibrate (Feno) (at 0.25 g/kg body weight) or vehicle (distilled water) and a group of control (CON) mice were gavaged with vehicle over a period of 4 weeks. Treatment with BB led to reduced levels of blood glucose, HbA1C, triglycerides and leptin and to increased levels of insulin and adiponectin compared with the vehicle-treated STZ group. The diabetic islets showed retraction from their classic round-shaped as compared with the control islets. The BB-treated groups (at middle and high dosages) showed improvement in islets size and number of Langerhans islet cells. The membrane levels of skeletal muscular glucose transporter 4 (GLUT4) were significantly higher in BB-treated mice. This resulted in a net glucose lowering effect among BB-treated mice. Moreover, BB enhanced the expression of skeletal muscle phospho-AMPK in treated mice. BB-treated mice increased expression of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα) and mRNA levels of carnitine palmitoyl transferase Ia (CPT1a). These mice also expressed lower levels of lipogenic genes such as fatty acid synthase (FAS), as well as lower mRNA levels of sterol regulatory element binding protein 1c (SREBP1c) and liver adipocyte fatty acid binding protein 2 (aP2). This resulted in a reduction in plasma triglyceride levels. BB-treated mice also expressed lower levels of PPARγ and FAS protein. This led to reduced adipogenesis, fatty acid

A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference.

PubMed

Gydesen, Sofie; Hjuler, Sara Toftegaard; Freving, Zenia; Andreassen, Kim Vietz; Sonne, Nina; Hellgren, Lars I; Karsdal, Morten Asser; Henriksen, Kim

2017-04-01

Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight-independent effects of KBP-089 using a weight-matched group. Rats fed a high-fat diet were treated, s.c., with KBP-089 0.625, 1.25, 2.5 μg·kg -1 or vehicle. KB-089 induced in a dose-dependent and sustained weight loss (~17% by 2.5 μg·kg -1 ). Moreover, KBP-089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089 improved glucose homeostasis through improved insulin action. To obtain a weight-matched group, significantly less food was offered (9% less than in the KBP-089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP-089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP-089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. The novel DACRA, KBP-089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss. © 2017 The British Pharmacological Society.

[The effectiveness of the spa and health resort-based treatment with the application of Essentuki-type drinking mineral waters for the management of non-alcoholic fatty liver disease in the patients presenting with type 2 diabetes mellitus].

PubMed

Efimenko, N V; Kaĭsinova, A S; Fedorova, T E; Botvineva, L A

2015-01-01

The objective of the present study was to estimate the effectiveness of the spa and health resort-based treatment of non-alcoholic fatty liver disease in 40 patients at the mean age of 48,8 ± 5.7 years suffering from type 2 diabetes mellitus. All of them received combined therapy including the application of potable Essentuki-Novaya mineral water (20 patients) or Essentuki No 4 water (20 patients). This therapeutic modality resulted in positive dynamics of clinical symptoms of the disease, the functional liver tests, and parameters of intra-hepatic hemodynamics, lipid peroxidation homeostasis, and the hormonal status. It is concluded that the spa and health resort-based treatment with the application of local drinking Essentuki-type mineral waters for the management of non-alcoholic fatty liver disease in the patients presenting with type 2 diabetes mellitus leads to the improvement of the main functions of the liver, stabilizes carbohydrate and lipid metabolism, and prevents progression of the pathological process.

Intake of dietary saturated fatty acids and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort: associations by types, sources of fatty acids and substitution by macronutrients.

PubMed

Liu, Shengxin; van der Schouw, Yvonne T; Soedamah-Muthu, Sabita S; Spijkerman, Annemieke M W; Sluijs, Ivonne

2018-03-09

The association between dietary saturated fatty acids (SFA) intake and type 2 diabetes (T2D) remains unclear. This study aimed at investigating the association between SFA intake and T2D risk based on (1) individual SFA (differing in carbon chain length), (2) food sources of SFA and (3) the substituting macronutrients. 37,421 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort were included in this study. Baseline dietary intake was assessed by a validated food frequency questionnaire. T2D risks were estimated by Cox regression models adjusted for non-dietary and dietary covariates. 893 incident T2D cases were documented during 10.1-year follow-up. We observed no association between total SFA and T2D risk. Marginally inverse associations were found for lauric acid (HR per 1 SD of energy%, 95% CI 0.92, 0.85-0.99), myristic acid (0.89, 0.79-0.99), margaric acid (0.84, 0.73-0.97), odd-chain SFA (pentadecylic plus margaric acids; 0.88, 0.79-0.99), and cheese derived SFA (0.90, 0.83-0.98). Soft and liquid fats derived SFA was found related to higher T2D risk (1.08, 1.01-1.17). When substituting SFA by proteins, carbohydrates and polyunsaturated fatty acids, significantly higher risks of T2D were observed (HRs per 1 energy% ranging from 1.05 to 1.15). In this Dutch population, total SFA does not relate to T2D risk. Rather, the association may depend on the types and food sources of SFA. Cheese-derived SFA and individual SFA that are commonly found in cheese, were significantly related to lower T2D risks. We cannot exclude the higher T2D risks found for soft and liquid fats derived SFA and for substituting SFA with other macronutrients are influenced by residual confounding by trans fatty acids or limited intake variation in polyunsaturated fatty acids and vegetable protein.

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection—Liver: The “Musketeer” in the Spotlight

PubMed Central

Ballestri, Stefano; Nascimbeni, Fabio; Romagnoli, Dante; Baldelli, Enrica; Targher, Giovanni; Lonardo, Amedeo

2016-01-01

The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a “vicious circle”, eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved. PMID:27005620

The effects of vitamin D and omega-3 fatty acids co-supplementation on biomarkers of inflammation, oxidative stress and pregnancy outcomes in patients with gestational diabetes.

PubMed

Razavi, Maryamalsadat; Jamilian, Mehri; Samimi, Mansooreh; Afshar Ebrahimi, Faraneh; Taghizadeh, Mohsen; Bekhradi, Reza; Seyed Hosseini, Elahe; Haddad Kashani, Hamed; Karamali, Maryam; Asemi, Zatollah

2017-01-01

This study was carried out to determine the effects of vitamin D and omega-3 fatty acids co- supplementation on biomarkers of inflammation, oxidative stress and pregnancy outcomes in gestational diabetes (GDM) patients. This randomized, double-blind, placebo-controlled trial was conducted among 120 GDM women. Participants were randomly divided into four groups to receive: 1) 1000 mg omega-3 fatty acids containing 180 mg eicosapentaenoic acid (EPA) and 120 mg docosahexaenoic acid (DHA) twice a day + vitamin D placebo ( n  = 30); 2) 50,000 IU vitamin D every 2 weeks + omega-3 fatty acids placebo (n = 30); 3) 50,000 IU vitamin D every 2 weeks + 1000 mg omega-3 fatty acids twice a day (n = 30) and 4) vitamin D placebo + omega-3 fatty acids placebo (n = 30) for 6 weeks. Subjects who received vitamin D plus omega-3 fatty acids supplements compared with vitamin D, omega-3 fatty acids and placebo had significantly decreased high-sensitivity C-reactive protein (-2.0 ± 3.3 vs. -0.8 ± 4.4, -1.3 ± 2.4 and +0.9 ± 2.7 mg/L, respectively, P  = 0.008), malondialdehyde (-0.5 ± 0.5 vs. -0.2 ± 0.5, -0.3 ± 0.9 and +0.5 ± 1.4 μmol/L, respectively, P  < 0.001), and increased total antioxidant capacity (+92.1 ± 70.1 vs. +55.1 ± 123.6, +88.4 ± 95.2 and +1.0 ± 90.8 mmol/L, respectively, P  = 0.001) and glutathione (+95.7 ± 86.7 vs. +23.0 ± 62.3, +30.0 ± 66.5 and -7.8 ± 126.5 μmol/L, respectively, P = 0.001). In addition, vitamin D and omega-3 fatty acids co-supplementation, compared with vitamin D, omega-3 fatty acids and placebo, resulted in lower incidences of newborns' hyperbilirubinemiain ( P  = 0.037) and newborns' hospitalization ( P  = 0.037). Overall, vitamin D and omega-3 fatty acids co-supplementation for 6 weeks among GDM women had beneficial effects on some biomarkers of inflammation, oxidative stress and pregnancy outcomes.

Comparison between omega-3 and omega-6 polyunsaturated fatty acid intakes as assessed by a food frequency questionnaire and erythrocyte membrane fatty acid composition in young children

PubMed Central

Orton, Heather D.; Szabo, Nancy J.; Clare-Salzler, Michael; Norris, Jill M.

2010-01-01

Objective We conducted a dietary validation study in youth aged 1 to 11 years by comparing dietary intake of omega-3 and omega-6 polyunsaturated fatty acids (PUFA) as assessed by a parent-completed semi-quantitative food frequency questionnaire (FFQ) over time to erythrocyte membrane composition of the same fatty acids. Design The study population included youth aged 1 to 11 years who were participants in the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal study in Denver, Colorado that is following a cohort of youth at risk for developing Type I diabetes. Four hundred four children who had erythrocyte membrane fatty acid data matched to an FFQ corresponding to the same time frame for a total of 917 visits (matches) were included. PUFA intake was expressed as both g/day (adjusted for total energy) and as percent of total fat intake. We used mixed models to test the association and calculate the correlation between the erythrocyte membrane estimates and PUFA intake using all records of data for each youth. Results Intakes of total omega-3 fatty acids (β=0.52, p<0.0001, ρ=0.23) and marine PUFAs (β=1.62, p<0.0001, ρ=0.42), as a percent of total fat in the diet, were associated with percent of omega-3 and marine PUFAs in the erythrocyte membrane. Intakes of omega-6 PUFAs (β=0.04, p=0.418, ρ=0.05) and arachidonic acid (β=0.31, p=0.774, ρ=0.01) were not associated. Conclusions In these young children, a FFQ using parental report provided estimates of average long-term intakes of marine PUFAs that correlated well with their erythrocyte cell membrane fatty acid status. PMID:17440518

Plekhs1 and Prdx3 are candidate genes responsible for mild hyperglycemia associated with obesity in a new animal model of F344-fa-nidd6 rat.

PubMed

Kotoh, Jun; Sasaki, Daiki; Matsumoto, Kozo; Maeda, Akihiko

2016-12-01

Type 2 diabetes is a polygenic disease and characterized by hyperglycemia and insulin resistance, and it is strongly associated with obesity. However, the mechanism by which obesity contributes to onset of type 2 diabetes is not well understood. We generated rat strains with a hyperglycemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr -/- ) locus derived from the Zucker Fatty rat. Phenotypes for plasma glucose, and insulin levels were measured, and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blot analyses, respectively. Compared with the obese control strain F344-fa (Lepr -/- ), plasma glucose levels of the obese F344-fa-nidd6 (Lepr -/- and Nidd6/of) significantly increased, and plasma insulin levels significantly decreased. These phenotypes were not observed in the lean strains, suggesting that the Nidd6/of locus harbors a diabetogenic gene associated with obesity. We measured the expression of 41 genes in the Nidd6/of QTL region of each strain and found that the mRNA expression levels of the two genes significantly differed between the obese strains. The two genes, pleckstrin homology domain-containing, family S member 1 (Plechs1) and peroxiredoxin III (Prdx3), were differentially expressed only in the obese rats, suggesting that these two genes are involved in the mild elevation of blood glucose levels and insulin resistance in obesity.

The Relationship Between Fatty Liver Disease and Periodontal Disease

DTIC Science & Technology

2017-03-22

Periodontitis is a highly prevalent and destructive chronic disease. Numerous studies support an association between periodontal disease and other...systemic diseases (diabetes, cardiovascular disease, chronic kidney disease, adverse pregnancy outcome, etc.). Non-alcoholic fatty liver disease is a... chronic inflammatory disease that is characterized by accumulation of triglycerides and fat in the liver which may lead to fibrosis and even cirrhosis

Pathogenesis of A-beta+ ketosis-prone diabetes

USDA-ARS?s Scientific Manuscript database

A-beta+ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible beta-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. Fasting plasma fatty acids, acylcarnit...

n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.

PubMed

Bosch, Jackie; Gerstein, Hertzel C; Dagenais, Gilles R; Díaz, Rafael; Dyal, Leanne; Jung, Hyejung; Maggiono, Aldo P; Probstfield, Jeffrey; Ramachandran, Ambady; Riddle, Matthew C; Rydén, Lars E; Yusuf, Salim

2012-07-26

The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Metabolic Effects of Monounsaturated Fatty Acid-Enriched Diets Compared With Carbohydrate or Polyunsaturated Fatty Acid-Enriched Diets in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PubMed

Qian, Frank; Korat, Andres Ardisson; Malik, Vasanti; Hu, Frank B

2016-08-01

Dietary interventions in patients with type 2 diabetes (T2D) are important for preventing long-term complications. Although a healthy diet is crucial, there is still uncertainty about the optimal macronutrient composition. We performed a meta-analysis comparing diets high in cis-monounsaturated fatty acids (MUFA) to diets high in carbohydrates (CHO) or in polyunsaturated fatty acids (PUFA) on metabolic risk factors in patients with T2D. We systematically reviewed PubMed, MEDLINE, and Cochrane databases and prior systematic reviews and meta-analyses to identify interventions assessing HbA1c, fasting plasma glucose and insulin, LDL and HDL cholesterol, triglycerides, body weight, or systolic/diastolic blood pressure. Meta-analyses were conducted using both fixed- and random-effects models to calculate the weighted mean difference (WMD) and 95% CI. We identified 24 studies totaling 1,460 participants comparing high-MUFA to high-CHO diets and 4 studies totaling 44 participants comparing high-MUFA to high-PUFA diets. When comparing high-MUFA to high-CHO diets, there were significant reductions in fasting plasma glucose (WMD -0.57 mmol/L [95% CI -0.76, -0.39]), triglycerides (-0.31 mmol/L [-0.44, -0.18]), body weight (-1.56 kg [-2.89, -0.23]), and systolic blood pressure (-2.31 mmHg [-4.13, -0.49]) along with significant increases in HDL cholesterol (0.06 mmol/L [0.02, 0.10]). When high-MUFA diets were compared with high-PUFA diets, there was a significant reduction in fasting plasma glucose (-0.87 mmol/L [-1.67, -0.07]). All of the outcomes had low to medium levels of heterogeneity, ranging from 0.0 to 69.5% for diastolic blood pressure (Phet = 0.011). Our meta-analysis provides evidence that consuming diets high in MUFA can improve metabolic risk factors among patients with T2D. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

PubMed

Jacobson, Peer B; von Geldern, Thomas W; Ohman, Lars; Osterland, Marie; Wang, Jiahong; Zinker, Bradley; Wilcox, Denise; Nguyen, Phong T; Mika, Amanda; Fung, Steven; Fey, Thomas; Goos-Nilsson, Annika; Grynfarb, Marlena; Barkhem, Tomas; Marsh, Kennan; Beno, David W A; Nga-Nguyen, Bach; Kym, Philip R; Link, James T; Tu, Noah; Edgerton, Dale S; Cherrington, Alan; Efendic, Suad; Lane, Benjamin C; Opgenorth, Terry J

2005-07-01

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.

Comparison of the enhancement of plasma glucose levels in type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats by oral administration of sucrose or maple syrup.

PubMed

Nagai, Noriaki; Ito, Yoshimasa; Taga, Atsushi

2013-01-01

Maple syrup is used as a premium natural sweeter, and is known for being good for human health. In the present study, we investigate whether maple syrup is suitable as a sweetener in the management of type 2 diabetes using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. OLETF rats develop type 2 diabetes mellitus by 30 weeks of age, and 60-week-old OLETF rats show hyperglycemia and hypoinsulinemia via pancreatic β-cell dysfunction. The administration of sucrose or maple syrup following an OGT test increased plasma glucose (PG) levels in OLETF rats, but the enhancement in PG following the oral administration of maple syrup was lower than in the case of sucrose administration in both 30- and 60-week-old OLETF rats. Although, the insulin levels in 30-week-old OLETF rats also increased following the oral administration of sucrose or maple syrup, no increase in insulin levels was seen in 60-week-old OLETF rats following the oral administration of either sucrose or maple syrup. No significant differences were observed in insulin levels between sucrose- and maple syrup-administered OLETF rats at either 30 or 60 weeks of age. The present study strongly suggests that the maple syrup may have a lower glycemic index than sucrose, which may help in the prevention of type 2 diabetes.

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol.

PubMed

Toyoda, Takeshi; Cho, Young-Man; Akagi, Jun-Ichi; Mizuta, Yasuko; Matsushita, Kohei; Nishikawa, Akiyoshi; Imaida, Katsumi; Ogawa, Kumiko

2017-01-01

3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.

Differences in Arachidonic Acid Levels and Fatty Acid Desaturase (FADS) Gene Variants in African Americans and European Americans with Diabetes/Metabolic Syndrome

PubMed Central

Sergeant, Susan; Hugenschmidt, Christina E.; Rudock, Megan E.; Ziegler, Julie T.; Ivester, Priscilla; Ainsworth, Hannah C.; Vaidya, Dhananjay; Case, L. Douglas; Langefeld, Carl D.; Freedman, Barry I.; Bowden, Donald W.; Mathias, Rasika A.; Chilton, Floyd H.

2012-01-01

Over the past 50 years, increases in dietary n-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid, have been hypothesized to cause or exacerbate chronic inflammatory diseases. This study examines an individual’s innate capacity to synthesize n-6-long chain PUFAs (LC-PUFAs), with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes/metabolic syndrome. Compared to European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7.9±2.1; AfAm 9.8±1.9 % of total fatty acids, mean ± sd; p<2.29×10−9) and the AA to n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5.4±2.2, AfAm 6.9±2.2; p=1.44×10−5). Seven single nucleotide polymorphisms (SNP) mapping to the FADS locus revealed strong association with AA, eicosapentaenoic acid (EPA) and dihomogamma-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT: 6.3±1.0; GG: 8.5±2.1; p=3.0×10−5) and AA/DGLA ratios (TT: 3.4±0.8; GG: 6.5±2.3; p=2.2×10−7) but higher DGLA levels (TT: 1.9±0.4; GG: 1.4±0.4; p=3.3×10−7) compared to those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0.81) compared to EAm (0.46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are likely important differences in the capacity of different populations to synthesize LC-PUFAs. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent. PMID:21733300

Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α).

PubMed

He, Fang; Jin, Jie-Qiong; Qin, Qing-Qing; Zheng, Yong-Qin; Li, Ting-Ting; Zhang, Yun; He, Jun-Dong

2018-01-01

Abnormal fatty acid β oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid β oxidation needs to be elucidated. We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial β-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms. Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial β-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid β oxidation. Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid β oxidation. © 2018 The Author(s). Published by S. Karger AG, Basel.

Effects of baked and raw salmon fillet on lipids and n-3 PUFAs in serum and tissues in Zucker fa/fa rats​​​​​​​​​​​​​​​​​​​​.

PubMed

Vikøren, Linn A; Drotningsvik, Aslaug; Bergseth, Marthe T; Mjøs, Svein A; Mola, Nazanin; Leh, Sabine; Mellgren, Gunnar; Gudbrandsen, Oddrun A

2017-01-01

Knowledge of the health impact of consuming heat-treated versus raw fish fillet is limited. To investigate effects of baked or raw salmon fillet intake on lipids and n-3 PUFAs in serum and tissues, obese Zucker fa/fa rats were fed diets containing 25% of protein from baked or raw salmon fillet and 75% of protein from casein, or casein as the sole protein source (control group) for four weeks. Salmon diets had similar composition of amino and fatty acids. Growth and energy intake were similar in all groups. Amounts of lipids and n-3 PUFAs in serum, liver and skeletal muscle were similar between rats fed baked or raw salmon fillet. When compared to the control group, rats fed baked salmon had lower serum total and LDL cholesterol and higher serum triacylglycerol levels. Both raw and baked salmon groups had lower HDL cholesterol level when compared to control rats. In conclusion, baking as a preparation method does not alter protein and fat qualities of salmon fillets, and intake of baked and raw salmon fillets gave similar effects on lipids and n-3 PUFAs in serum and tissues from rats.

Effects of baked and raw salmon fillet on lipids and n-3 PUFAs in serum and tissues in Zucker fa/fa rats​​​​​​​​​​​​​​​​​​​​

PubMed Central

Vikøren, Linn A.; Drotningsvik, Aslaug; Bergseth, Marthe T.; Mjøs, Svein A.; Mola, Nazanin; Leh, Sabine; Mellgren, Gunnar; Gudbrandsen, Oddrun A.

2017-01-01

ABSTRACT Knowledge of the health impact of consuming heat-treated versus raw fish fillet is limited. To investigate effects of baked or raw salmon fillet intake on lipids and n-3 PUFAs in serum and tissues, obese Zucker fa/fa rats were fed diets containing 25% of protein from baked or raw salmon fillet and 75% of protein from casein, or casein as the sole protein source (control group) for four weeks. Salmon diets had similar composition of amino and fatty acids. Growth and energy intake were similar in all groups. Amounts of lipids and n-3 PUFAs in serum, liver and skeletal muscle were similar between rats fed baked or raw salmon fillet. When compared to the control group, rats fed baked salmon had lower serum total and LDL cholesterol and higher serum triacylglycerol levels. Both raw and baked salmon groups had lower HDL cholesterol level when compared to control rats. In conclusion, baking as a preparation method does not alter protein and fat qualities of salmon fillets, and intake of baked and raw salmon fillets gave similar effects on lipids and n-3 PUFAs in serum and tissues from rats. PMID:28659746

Early administration of trimetazidine may prevent or ameliorate diabetic cardiomyopathy.

PubMed

Wenmeng, Wang; Qizhu, Tang

2011-02-01

Diabetic cardiomyopathy is a type of cardiac dysfunction resulting from diabetes, independent of vascular or valvular pathology. It clinically manifests initially as asymptomatic diastolic dysfunction and then progresses to symptomatic heart failure. Two major contributors to the development of diabetic cardiomyopathy, which are unique to diabetes, are hyperglycemia and diabetes-related alterations in myocardial metabolism. Diabetes mellitus is characterized by reduced glucose and lactate metabolism and enhanced fatty acid metabolism, which are the early consequences of the disease. Studies on the effect of intensive glucose control on heart failure events in patients with diabetes have been conducted with neutral results. However, no study on the effect of metabolic modulators on the prevention of heart failure has been reported. Trimetazidine, a 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor, shifts cardiac energy metabolism from free fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-KAT, and is used clinically as an effective antianginal agent. Studies have shown that trimetazidine improves heart function in patients with idiopathic cardiomyopathy and in diabetic patients with cardiac ischemia or heart failure. In addition to being effective, trimetazidine has only mild side effects. Therefore, instead of routine administration of trimetazidine for the treatment of diabetic cardiomyopathy, we hypothesize that the early application of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. In addition to life style modifications, ACEI, ARB, and beta-blockers, which have been recommended in the past, trimetazidine should be administered to those patients with impaired glucose tolerance or patients in the early course of diabetes. In this way, we may reduce the prevalence of heart failure and improve the long-term survival of patients with diabetes through early normalization of the myocardial substrate metabolism

Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease.

PubMed

Tarantino, Giovanni; Finelli, Carmine

2013-10-28

Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing's syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing's syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing's syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing's syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.

Effect of Acrocomia aculeata Kernel Oil on Adiposity in Type 2 Diabetic Rats.

PubMed

Nunes, Ângela A; Buccini, Danieli F; Jaques, Jeandre A S; Portugal, Luciane C; Guimarães, Rita C A; Favaro, Simone P; Caldas, Ruy A; Carvalho, Cristiano M E

2018-03-01

The macauba palm (Acrocomia aculeata) is native of tropical America and is found mostly in the Cerrados and Pantanal biomes. The fruits provide an oily pulp, rich in long chain fatty acids, and a kernel that encompass more than 50% of lipids rich in medium chain fatty acids (MCFA). Based on biochemical and nutritional evidences MCFA is readily catabolized and can reduce body fat accumulation. In this study, an animal model was employed to evaluate the effect of Acrocomia aculeata kernel oil (AKO) on the blood glucose level and the fatty acid deposit in the epididymal adipose tissue. The A. aculeata kernel oil obtained by cold pressing presented suitable quality as edible oil. Its fatty acid profile indicates high concentration of MCFA, mainly lauric, capric and caprilic. Type 2 diabetic rats fed with that kernel oil showed reduction of blood glucose level in comparison with the diabetic control group. Acrocomia aculeata kernel oil showed hypoglycemic effect. A small fraction of total dietary medium chain fatty acid was accumulated in the epididymal adipose tissue of rats fed with AKO at both low and high doses and caprilic acid did not deposit at all.

Clinical and metabolic response to flaxseed oil omega-3 fatty acids supplementation in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial.

PubMed

Soleimani, Zahra; Hashemdokht, Fatemeh; Bahmani, Fereshteh; Taghizadeh, Mohsen; Memarzadeh, Mohammad Reza; Asemi, Zatollah

2017-09-01

Data on the effects of flaxseed oil omega-3 fatty acids supplementation on wound healing and metabolic status in subjects with diabetic foot ulcer (DFU) are scarce. This study was conducted to evaluate the effects of flaxseed oil omega-3 fatty acids supplementation on wound healing and metabolic status in subjects with DFU. The current randomized, double-blind, placebo-controlled trial was conducted among 60 subjects (aged 40-85years old) with grade 3 DFU. Subjects were randomly allocated into two groups (30 subjects each group) to receive either 1000mg omega-3 fatty acids from flaxseed oil supplements or placebo twice a day for 12weeks. After the 12-week intervention, compared with the placebo, omega-3 fatty acids supplementation resulted in significant decreases in ulcer length (-2.0±2.3 vs. -1.0±1.1cm, P=0.03), width (-1.8±1.7 vs. -1.0±1.0cm, P=0.02) and depth (-0.8±0.6 vs. -0.5±0.5cm, P=0.01). Additionally, significant reductions in serum insulin concentrations (-4.4±5.5 vs. +1.4±8.3 μIU/mL, P=0.002), homeostasis model of assessment-estimated insulin resistance (-2.1±3.0 vs. +1.0±5.0, P=0.005) and HbA1c (-0.9±1.5 vs. -0.1±0.4%, P=0.01), and a significant rise in the quantitative insulin sensitivity check index (+0.01±0.01 vs. -0.005±0.02, P=0.002) were seen following supplementation with omega-3 fatty acids compared with the placebo. In addition, omega-3 fatty acids supplementation significantly decreased serum high sensitivity C-reactive protein (hs-CRP) (-25.5±31.5 vs. -8.2±18.9μg/mL, P=0.01), and significantly increased plasma total antioxidant capacity (TAC) (+83.5±111.7 vs. -73.4±195.5mmol/L, P<0.001) and glutathione (GSH) concentrations (+60.7±140.2 vs. -15.5±129.7μmol/L, P=0.03) compared with the placebo. Overall, omega-3 fatty acids supplementation for 12weeks among subjects with DFU had beneficial effects on parameters of ulcer size, markers of insulin metabolism, serum hs-CRP, plasma TAC and GSH levels. In addition, flaxseed oil

Effect of docosahexaenoic acid-enriched fish oil supplementation in pregnant women with Type 2 diabetes on membrane fatty acids and fetal body composition--double-blinded randomized placebo-controlled trial.

PubMed

Min, Y; Djahanbakhch, O; Hutchinson, J; Bhullar, A S; Raveendran, M; Hallot, A; Eram, S; Namugere, I; Nateghian, S; Ghebremeskel, K

2014-11-01

To test if docosahexaenoic acid-enriched fish oil supplementation rectifies red cell membrane lipid anomaly in pregnant women with Type 2 diabetes and their neonates, and alters fetal body composition. Women with Type 2 diabetes (n = 88; 41 fish oil, 47 placebo) and healthy women (n = 85; 45 fish oil, 40 placebo) were supplemented from the first trimester until delivery. Blood fatty acid composition, fetal biometric and neonatal anthropometric measurements were assessed. A total of 117 women completed the trial. The women with Type 2 diabetes who took fish oil compared with those who received placebo had higher percentage of docosahexaenoic acid in red cell phosphatidylethanolamine in the third trimester (12.0% vs. 8.9%, P = 0.000) and at delivery (10.7% vs. 7.4%, P = 0.001). Similarly, the neonates of the women with Type 2 diabetes supplemented with the fish oil had increased docosahexaenoic acid in the red cell phosphatidylethanolamine (9.2% vs. 7.7%, P = 0.027) and plasma phosphatidylcholine (6.1% vs. 4.7%, P = 0.020). Docosahexaenoic acid-rich fish oil had no effect on the body composition of the fetus and neonates of the women with Type 2 diabetes. A daily dose of 600 mg of docosahexaenoic acid was effective in ameliorating red cell membrane docosahexaenoic acid anomaly in pregnant women with Type 2 diabetes and neonates, and in preventing the decline of maternal docosahexaenoic acid during pregnancy. We suggest that the provision of docosahexaenoic acid supplement should be integrated in the antenatal care of pregnant women with Type 2 diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Apolipoprotein A2 -265 T>C polymorphism interacts with dietary fatty acids intake to modulate inflammation in type 2 diabetes mellitus patients.

PubMed

Keramat, Laleh; Sadrzadeh-Yeganeh, Haleh; Sotoudeh, Gity; Zamani, Elham; Eshraghian, Mohammadreza; Mansoori, Anahita; Koohdani, Fariba

2017-05-01

Several investigations have been conducted regarding the interaction between Apolipoprotein A2 (APOA2) -265 T>C polymorphism and dietary intake of saturated fatty acids (SFAs) on obesity in healthy individuals or type 2 diabetes mellitus (T2 DM) patients. The aim of the present study is to examine the effect of this interaction on inflammatory markers in T2 DM patients. This is a comparative cross-sectional study on 180 T2 DM patients with known APOA2 genotype. Dietary intake was assessed by food-frequency questionnaire and serum levels of inflammatory markers (interleukin [IL]-18, pentraxin 3, and high-sensitivity C-reactive protein [hs-CRP]) were measured. The subjects were dichotomized into "high" and "low" categories, based on the median dietary intake of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), and SFAs. The data were analyzed by analysis of covariance multivariate interaction model. In CC genotype, higher median intake of ω-3 PUFAs and MUFAs was associated with decreased serum levels of IL-18 and hs-CRP (P = 0.014 and 0.008, respectively). In T-allele carriers, higher median intake of SFAs was associated with increased serum hs-CRP level (P < 0.001). There was a significant relationship between APOA2 polymorphism and ω-3 PUFA intake on serum IL-18 level (P interaction = 0.03). Moreover, the relationship between this polymorphism and SFA and MUFA intake on serum hs-CRP level was statistically significant (P interaction = 0.03 and 0.024, respectively). In T2 DM patients, the dietary intake of antiinflammatory fatty acids, such as ω-3 PUFAs and MUFAs, could reduce the inflammatory effects associated with the CC genotype. In addition, proinflammatory fatty acids, such as SFAs, could overcome the antiinflammatory effect of the T-allele. Further studies are needed to confirm these findings. Copyright © 2016 Elsevier Inc. All rights reserved.

[Metabolic parameters in patients with steatosis non alcoholic liver and controlled diabetes type 2 versus uncontrolled diabetes type 2].

PubMed

Miranda Manrique, Gonzalo

2016-01-01

Non-alcoholic fatty liver (NASH) is widely distributed around the world and is more common in subjects with dyslipidemia, metabolic syndrome obese and DM2 (34-74%). However, the prevalence of cirrhosis by NASH in general population is unknown which is still subject of research. To determine if there are significant differences between metabolic parameters of non-alcoholic fatty liver in controlled versus uncontrolled diabetes type 2 of recent diagnosis. retrospective case-control study, performed in the Hospital Guillermo Almenara Irigoyen, Lima, Peru from November 2014 to February 2015.This study included 231 patients: 147 patients (NASH with DM2 of recent diagnosis and poor control) and 84 patients (NASH with DM2 ofrecent diagnosis and adequate control). Levene test for evaluating homogeneity of variances intra groups and parametric test for independent samples. After applying Levene test of homogeneity and student test, significant metabolic parameters were the triglycerides, HbA1C level, metformin dose and gender. It is important in diabetic patients to diagnose NASH early for a tighter control, not only of glucose but other metabolic parameters mainly triglycerides which strongly supports existing concept of "multiple hits" which considers NASH affects glucose homeostasis, and it could be the starting point of new research to improve interventions for decreasing progression from to cirrhosis in diabetic patients and also to delay progression of diabetes mellitus in patients with non alcoholic steatohepatitis.

Effect of obese and lean Zucker rat sera on human and rat prostate cancer cells: implications in obesity-related prostate tumor biology.

PubMed

Lamarre, Neil S; Ruggieri, Michael R; Braverman, Alan S; Gerstein, Matthew I; Mydlo, Jack H

2007-01-01

Several reports have demonstrated the effects of obesity on prostate cancer. Also several reports have linked expression of vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (FGF-2) to prostate cancer aggressiveness. The objective of this study was to determine whether a difference exists between lean and obese Zucker rat sera on proliferation prostate cancer cell lines, as well as to examine the differences in FGF-2 and VEGF concentrations. Ten-week-old female obese and lean Zucker rat sera were subjected to charcoal stripping and tested for the proliferation of human LNCaP and rat AT3B-1 prostate cancer cells. An acetonitrile extract of the charcoal used to strip the sera was also tested for mitogenicity. VEGF and FGF-2 concentrations were determined by enzyme-linked immunosorbent assay. Both unstripped and charcoal-stripped obese rat sera had a greater mitogenic effect than did the lean sera on the LNCaP cell line. Charcoal stripping of both obese and lean sera reduced the mitogenic effect on the AT3B-1 cell line. The acetonitrile extract of the charcoal used to strip the sera was unable to recover this proliferative effect. The concentration of VEGF was greater in the obese serum than in the lean serum, and charcoal stripping reduced the concentrations of both FGF-2 and VEGF. The finding of greater VEGF in obese rat sera, as well as greater mitogenic responses on human prostate cancer cells in vitro, suggests this as one of the many possible mechanisms involved in obesity-related prostate cancer biology.

Effect of lateral hypothalamic lesion on brown adipose tissue of Zucker lean and obese rats.

PubMed

Holt, S J; York, D A

1988-01-01

Acute (10-day) lateral hypothalamic (LH) lesion induced a reduction of food intake in both lean and obese Zucker rats which averaged about 50% over the course of the first 10 days. The aphagia associated with a fall in body weight in both genotypes which was greater than their respective pair-fed controls, indicating a change in energetic efficiency. The reduced level of BAT protein, mitochondria and GDP binding observed in the obese rat was restored after LH lesion, suggesting the reestablishment of a normal sympathetic drive to the tissue. The markedly lower plasma insulin concentration in the LH lesioned obese rat is consistent with a reduction in parasympathetic activity in these animals. Food restriction in the sham lean rat reduced BAT protein content and mitochondrial GDP binding, whereas no such changes were observed in the food restricted obese rat. This demonstrates the insensitivity of the obese rat to dietary signals and may imply that LH lesion restores diet-induced BAT thermogenesis in the obese rat.

Correlation of blood glucose, serum chemerin and insulin resistance with NAFLD in patients with type 2 diabetes mellitus.

PubMed

Zhang, Zhengjun; Wang, Jijun; Wang, Hongmei

2018-03-01

Non-alcoholic fatty liver disease (NAFLD) is a form of clinical syndrome characterized by the fatty degeneration in liver histology and should be further investigated. The aim of the study was to investigate the effects of blood glucose, serum chemerin and insulin resistance on non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus to provide a basis for the prevention and treatment thereof. In total, 300 patients with type 2 diabetes mellitus treated and admitted into the Endocrinology Department of our hospital from June 2015 to June 2017 were enrolled and divided into the simple type 2 diabetes mellitus (group A) and concurrent NAFLD (group B) groups. The sex, age, body mass index (BMI), blood pressure, blood biochemical indexes and chemerin level were compared between the two groups. The patients in group B were further divided into the mild fatty liver (group B1), moderate fatty liver (group B2) and severe fatty liver (group B3) groups. The sex, age, BMI blood pressure, blood biochemical indexes and chemerin level were also compared among the three groups. Finally, the risk factors of type 2 diabetes mellitus complicated by NAFLD were analyzed via logistic regression. The BMI, fasting plasma glucose (FPG), 2 h post-prandial plasma glucose (2hPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA-β indexes and serum chemerin level in group B were significantly higher than those in group A (P<0.05 or P<0.01). Notably, the aggravation of NAFLD, the aforementioned indexes were obviously increased (P<0.05 or P<0.01). The regression analysis revealed that BMI, FPG, TC, LDL-c, FINS, HOMA-IR and chemerin were risk factors of concurrent NAFLD. Thus, type 2 diabetes mellitus complicated by NAFLD is closely associated with severe glucose-lipid metabolism disorder and insulin

Bioinformatic profiling of the transcriptional response of adult rat cardiomyocytes to distinct fatty acids

USDA-ARS?s Scientific Manuscript database

Diabetes mellitus, obesity, and dyslipidemia increase risk for cardiovascular disease, and expose the heart to high plasma fatty acid (FA) levels. Recent studies suggest that distinct FA species are cardiotoxic (e.g., palmitate), while others are cardioprotective (e.g., oleate), although the molecul...

Fish oil modulates glycogen synthase kinase-3 signaling pathway in diabetes-induced hippocampal neurons apoptosis.

PubMed

Sun, Li-Juan; Hou, Xiang-Hong; Xue, Sen-Hai; Yan, Feng; Dai, Yu-Jie; Zhao, Chang-Hai; Wang, Feng; Yang, Rui-Hua

2014-07-29

Previous research has demonstrated that diabetes induces learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. The present study investigated the effects of fish oil supplementation on the neuron apoptosis in the hippocampus of streptozotocin (STZ)-induced diabetes rats, further explored the effect of fish oil on the phosphorylation of protein kinase B and glycogen synthase kinase-3 beta. The effects of diabetes and fish oil treatment on the spatial learning and memory were also evaluated using the Morris Water Maze. STZ-induced diabetes impaired spatial learning and memory of rats, which was associated with the apoptosis of hippocampal neurons and oxidative stress. Fish oil administration ameliorated cognitive deficit, reduced oxidative stress, increased AKT phosphorylation, decreased GSK-3β phosphorylation, and decreased pro-apoptotic molecules expression, which protected the hippocampal neurons from apoptosis in diabetic rats. These results suggested a potential role for fish oil as an adjuvant therapy for the prevention and treatment of diabetic complications. Copyright © 2014 Elsevier B.V. All rights reserved.

[Composition of macronutrients in the diabetic diet].

PubMed

Rušavý, Zdeněk; Žourek, Michal

2016-01-01

The diabetic diet is one of the pillars of diabetes treatment. The rapid development of knowledge relating to the treatment of diabetes also includes diet. The paper focuses on the importance of a diet in the treatment of type 2 diabetes and prevention of atherosclerosis. Its main goal is to assess the impact of a composition of macronutrients on individuals with type 2 diabetes. The paper is divided into several parts, each of which ends with a conclusion. The first part examines weight reduction. The diet aimed at a weight loss is effective, it can effectively prevent diabetes, it leads to improvements in glucose control and reduction of the risk factors for atherosclerosis, however it will not impact on cardiovascular morbidity and mortality until after more than 20 years. The second part deals with "healthy" foods. The studies exploring this area are not convincing. The only really rational component of food in relation to atherosclerosis is dietary fibres. Important is a balanced diet combined with regular physical activities. The third part focuses on the composition of macronutrients. It turns out that, considering a low-calorie diet, the effects of high- and low-carbohydrate diets on people with diabetes are similar with regard to weight loss and lowering of HbA1c, however the low-carbohydrate diet is associated with lower glycemic variability and a reduced need for anti-diabetic drugs. We do not know how the comparison of the two extreme diets would come out regarding individuals with a high energy diet. Currently it is useful to focus on the quality of individual macronutrients. Choose foods containing carbohydrates with a low glycemic index and high fibre foods, prefer fats that contain a low proportion of saturated fatty acids. The fourth part discusses the recent recommendation of the Czech Diabetes Society regarding the composition of macronutrients in the diabetic diet. As compared with the diet proposed earlier, lower intake of fibre

Association of grade of non-alcoholic fatty liver disease and glycated albumin to glycated hemoglobin ratio in patients with type 2 diabetes mellitus.

PubMed

Jung, Chan-Hee; Lee, Bora; Choi, Dug-Hyun; Jung, Sang-Hee; Kim, Bo-Yeon; Kim, Chul-Hee; Kang, Sung-Koo; Mok, Ji-Oh

2017-03-01

The aim of this study was to investigate the association between the glycated albumin (GA) to glycated hemoglobin (HbA1c) (GA/HbA1c) ratio and grade of non-alcoholic fatty liver disease (NAFLD) on ultrasonography (US) in patients with type 2 diabetes mellitus (T2DM). This retrospective, cross-sectional study was performed with data obtained from 186 T2DM patients. Participants were assessed for serum GA/HbA1c ratio and fatty liver using US. NAFLD was defined as ultrasonographically detected fatty liver and was graded as normal, mild, moderate, and severe fatty liver. A total of 98 subjects (53%) were diagnosed with NAFLD on US, of which 47 (48%) had moderate-to-severe grade of NAFLD. The mean GA level and GA/HbA1c ratio significantly decreased across increasing NAFLD stages (34% vs. 29% vs. 27% vs. 28%, p=0.023 for trend; 3.1vs. 2.9vs. 2.6vs. 2.7, p=0.001 for trend, respectively), whereas there was no significant difference in HbA1c level among groups (p=0.714 for trend). There was a significant decrease in prevalence of NAFLD across GA/HbA1c ratio tertiles (67% vs. 58% vs. 41%, p for trend=0.007). Multivariate logistic regression analysis showed that individuals with the lowest GA/HbA1c ratio had an odds ratio (OR) of 2.75 (95% CI=1.06-7.13) for having any grade of NAFLD and an OR of 4.48 [1.20-16.74] for moderate-to-severe grade NAFLD compared with the highest GA/HbA1c ratio even after adjustment for confounding factors (p=0.038, p=0.026, respectively). The present study showed that GA/HbA1c ratio was significantly inversely associated with the presence and severity of NAFLD on US. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cardiovascular Disease, Cancer, and Mortality Among People With Type 2 Diabetes and Alcoholic or Nonalcoholic Fatty Liver Disease Hospital Admission.

PubMed

Wild, Sarah H; Walker, Jeremy J; Morling, Joanne R; McAllister, David A; Colhoun, Helen M; Farran, Bassam; McGurnaghan, Stuart; McCrimmon, Rory; Read, Stephanie H; Sattar, Naveed; Byrne, Christopher D

2018-02-01

To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with type 2 diabetes mellitus (T2DM). We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40-89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors. A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality. Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM. © 2017 by the American Diabetes Association.

Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes

PubMed Central

McDuffie, Marcia; Maybee, Nelly A.; Keller, Susanna R.; Stevens, Brian K.; Garmey, James C.; Morris, Margaret A.; Kropf, Elizabeth; Rival, Claudia; Ma, Kaiwen; Carter, Jeffrey D.; Tersey, Sarah A.; Nunemaker, Craig S.; Nadler, Jerry L.

2010-01-01

OBJECTIVE 12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic β-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of β-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in β-cell damage in the streptozotocin model of diabetes. Since the gene encoding 12/15-LO (gene designation Alox15) lies within the Idd4 diabetes susceptibility interval in NOD mice, we hypothesized that 12/15-LO is also a key regulator of diabetes susceptibility in the NOD mouse. RESEARCH DESIGN AND METHODS We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15null) using a “speed congenic” protocol, and the mice were monitored for development of insulitis and diabetes. RESULTS NOD mice deficient in 12/15-LO develop diabetes at a markedly reduced rate compared with NOD mice (2.5 vs. >60% in females by 30 weeks). Nondiabetic female NOD-Alox15null mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved β-cell mass, when compared with age-matched nondiabetic NOD females. Disease resistance is associated with decreased numbers of islet-infiltrating activated macrophages at 4 weeks of age in NOD-Alox15null mice, preceding the development of insulitis. Subsequently, islet-associated infiltrates are characterized by decreased numbers of CD4+ T cells and increased Foxp3+ cells. CONCLUSIONS These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation. PMID:17940120

Short article: A randomized-controlled study of sitagliptin for treating diabetes mellitus complicated by nonalcoholic fatty liver disease.

PubMed

Deng, Xiao-Long; Ma, Rui; Zhu, Hong-Xia; Zhu, Jun

2017-03-01

This study aimed to evaluate the efficacy and safety of sitagliptin for treating Chinese patients with type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD). In total, 72 Chinese T2DM patients with NAFLD were divided randomly into two groups of 36 patients each group. All 72 patients were assigned to receive either sitagliptin or diet and exercise for 52 weeks between January 2013 and December 2015. The outcomes' measurements included serum levels of hemoglobin A1c, fasting plasma glucose, aspartate aminotransferase, and alanine aminotransferase. Seventy patients completed the study. Sitagliptin showed greater efficacy than the diet and exercise in decreasing the hemoglobin A1c and fasting plasma glucose levels at weeks 13, 26, 39, and 52. In addition, no significant changes in the average aspartate aminotransferase and alanine aminotransferase levels were found during the 52-week follow-up in both the sitagliptin and the control groups. The results of this study indicate that sitagliptin is an effective and safe treatment for patients with T2DM and NAFLD.

Echocardiography and NAFLD (non-alcoholic fatty liver disease).

PubMed

Trovato, Francesca M; Martines, Giuseppe F; Catalano, Daniela; Musumeci, Giuseppe; Pirri, Clara; Trovato, Guglielmo M

2016-10-15

Non-alcoholic-fatty-liver-disease (NAFLD) is associated with atherosclerosis, increased cardiovascular risks and mortality. We investigated if, independently of insulin resistance, diet, physical activity and obesity, fatty liver involvement has any relationship with echocardiographic measurements in NAFLD. 660 NAFLD and 791 non-NAFLD subjects, referred to the same out-patients medical unit for lifestyle-nutritional prescription, were studied. Congestive heart failure, myocardial infarction, malignancies, diabetes mellitus, extreme obesity, underweight-bad-nourished subjects and renal insufficiency were exclusion criteria. Liver steatosis was assessed by Ultrasound-Bright-Liver-Score (BLS), left ventricular ejection fraction (LVEF), trans-mitral E/A doppler ratio (diastolic relaxation) and left ventricular myocardial mass (LVMM/m(2)) by echocardiography. Doppler Renal artery Resistive Index (RRI), insulin resistance (HOMA) and lifestyle profile were also included in the clinical assessment. LVMM/m(2) is significantly greater in NAFLD, 101.62±34.48 vs. 88.22±25.61, p<0.0001 both in men and in women. Ejection fraction is slightly smaller only in men with NAFLD; no significant difference was observed for the E/A ratio. BMI (30.42±5.49 vs. 24.87±3.81; p<0.0001) and HOMA (2.90±1.70 vs. 1.85±1.25; p: 0.0001) were significantly greater in NAFLD patients. By Multiple-Linear-Regression, NAFLD and unhealthy dietary profile are associated also in lean non-diabetic subjects with lower systolic function, independently of BMI, dietary profile, physical activity, RRI and insulin resistance. NAFLD may be a meaningful early clue suggestive of diminishing heart function, with similar determining factors. NAFLD is amenable to management and improvement by lifestyle change counseling, addressing a dual target: reducing fatty liver, which is easily monitored by ultrasound, and, independently, maintaining a normal heart function. Copyright © 2016 Elsevier Ireland Ltd. All rights

Microvascular disorders in obese Zucker rats are restored by a rice bran diet.

PubMed

Justo, M L; Claro, C; Vila, E; Herrera, M D; Rodriguez-Rodriguez, R

2014-05-01

Nutritional-based approaches aimed to prevent microvascular dysfunction associated to obesity present potential advantages over pharmacological strategies. Our aim was to test whether a rice bran enzymatic extract (RBEE)-supplemented diet could attenuate microvascular alterations in obese rats. Lean and obese Zucker rats were fed standard diet supplemented or not with 1% and 5% RBEE for 20 weeks. Functional studies were performed in small mesenteric arteries in isometric myograph. Immunoblotting and fluorescence studies were made in arterial homogenates and arterial sections, respectively. RBEE-supplementation restored microvascular function in obese rats through a marked increase in NO and endothelial-derived hyperpolarizing factor contribution by up-regulation of eNOS and calcium-activated potassium channels expression, respectively, in association to a substantial reduction of microvascular inflammation and superoxide anion formation. These data agrees with the beneficial actions of RBEE on dyslipidemia, hyperinsulinemia and hypertension in obesity. The multi-factorial properties of RBEE-diet, especially for restoring the function of small resistance arteries shows this dietary-based approach to be a promising candidate for prevention of microvascular alterations in obesity, which are crucial in cardiovascular events in obese subjects. Copyright © 2013 Elsevier B.V. All rights reserved.

Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats.

PubMed

Mahadevan, Jana; Parazzoli, Susan; Oseid, Elizabeth; Hertzel, Ann V; Bernlohr, David A; Vallerie, Sara N; Liu, Chang-qin; Lopez, Melissa; Harmon, Jamie S; Robertson, R Paul

2013-10-01

We reported earlier that β-cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of β-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent β-cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA1c levels with no effects on body weight. Ebselen doubled β-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal β-cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on β-cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of β-cell mass and function in humans undergoing the onset of type 2 diabetes.

Ciprofibrate, clofibric acid and respective glycinate derivatives. Effects of a four-week treatment on male lean and obese Zucker rats.

PubMed

Lupp, Amelie; Karge, Elke; Deufel, Thomas; Oelschlägers, Herbert; Fleck, Christian

2008-01-01

Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the

Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia

PubMed Central

Irwin, David C.; Garat, Chrystelle V.; Crossno, Joseph T.; MacLean, Paul S.; Sullivan, Timothy M.; Erickson, Paul F.; Jackman, Matthew R.; Harral, Julie W.; Reusch, Jane E. B.

2014-01-01

Abstract Obesity is causally linked to a number of comorbidities, including cardiovascular disease, diabetes, renal dysfunction, and cancer. Obesity has also been linked to pulmonary disorders, including pulmonary arterial hypertension (PAH). It was long believed that obesity-related PAH was the result of hypoventilation and hypoxia due to the increased mechanical load of excess body fat. However, in recent years it has been proposed that the metabolic and inflammatory disturbances of obesity may also play a role in the development of PAH. To determine whether PAH develops in obese rats in the absence of hypoxia, we assessed pulmonary hemodynamics and pulmonary artery (PA) structure in the diet-resistant/diet-induced obesity (DR/DIO) and Zucker lean/fatty rat models. We found that high-fat feeding (DR/DIO) or overfeeding (Zucker) elicited PA remodeling, neomuscularization of distal arterioles, and elevated PA pressure, accompanied by right ventricular (RV) hypertrophy. PA thickening and distal neomuscularization were also observed in DIO rats on a low-fat diet. No evidence of hypoventilation or chronic hypoxia was detected in either model, nor was there a correlation between blood glucose or insulin levels and PAH. However, circulating inflammatory cytokine levels were increased with high-fat feeding or calorie overload, and hyperlipidemia and oxidant damage in the PA wall correlated with PAH in the DR/DIO model. We conclude that hyperlipidemia and peripheral inflammation correlate with the development of PAH in obese subjects. Obesity-related inflammation may predispose to PAH even in the absence of hypoxia. PMID:25610600

Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among Men and Women in the United States in Two Large Prospective Cohorts.

PubMed

Yakoob, Mohammad Y; Shi, Peilin; Willett, Walter C; Rexrode, Kathryn M; Campos, Hannia; Orav, E John; Hu, Frank B; Mozaffarian, Dariush

2016-04-26

In prospective studies, the relationship of self-reported consumption of dairy foods with risk of diabetes mellitus is inconsistent. Few studies have assessed dairy fat, using circulating biomarkers, and incident diabetes mellitus. We tested the hypothesis that circulating fatty acid biomarkers of dairy fat, 15:0, 17:0, and t-16:1n-7, are associated with lower incident diabetes mellitus. Among 3333 adults aged 30 to 75 years and free of prevalent diabetes mellitus at baseline, total plasma and erythrocyte fatty acids were measured in blood collected in 1989 to 1990 (Nurses' Health Study) and 1993 to 1994 (Health Professionals Follow-Up Study). Incident diabetes mellitus through 2010 was confirmed by a validated supplementary questionnaire based on symptoms, diagnostic tests, and medications. Risk was assessed by using Cox proportional hazards, with cohort findings combined by meta-analysis. During mean±standard deviation follow-up of 15.2±5.6 years, 277 new cases of diabetes mellitus were diagnosed. In pooled multivariate analyses adjusting for demographics, metabolic risk factors, lifestyle, diet, and other circulating fatty acids, individuals with higher plasma 15:0 had a 44% lower risk of diabetes mellitus (quartiles 4 versus 1, hazard ratio, 0.56; 95% confidence interval, 0.37-0.86; P-trend=0.01); higher plasma 17:0, 43% lower risk (hazard ratio, 0.57; 95% confidence interval, 0.39-0.83; P-trend=0.01); and higher t-16:1n-7, 52% lower risk (hazard ratio, 0.48; 95% confidence interval, 0.33-0.70; P-trend <0.001). Findings were similar for erythrocyte 15:0, 17:0, and t-16:1n-7, although with broader confidence intervals that only achieved statistical significance for 17:0. In 2 prospective cohorts, higher plasma dairy fatty acid concentrations were associated with lower incident diabetes mellitus. Results were similar for erythrocyte 17:0. Our findings highlight the need to better understand the potential health effects of dairy fat, and the dietary and

Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men--the role of gut microbiota composition: study protocol for the AELC randomized controlled trial.

PubMed

Liu, Wu Yi; Lu, Da Jiang; Du, Xia Ming; Sun, Jian Qin; Ge, Jun; Wang, Ren Wei; Wang, Ru; Zou, Jun; Xu, Chang; Ren, Jie; Wen, Xin Fei; Liu, Yang; Cheng, Shu Mei; Tan, Xiao; Pekkala, Satu; Munukka, Eveliina; Wiklund, Petri; Chen, Yan Qiu; Gu, Qing; Xia, Zheng Chang; Liu, Jun Jun; Liu, Wen Bin; Chen, Xue Bo; Zhang, Yi Min; Li, Rui; Borra, Ronald J H; Yao, Jia Xin; Chen, Pei Jie; Cheng, Sulin

2014-01-17

Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects. A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50-65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3-5 times/week and 30-60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview. Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of

The role of technology in diabetes therapy.

PubMed

Ginsberg, B H

1994-06-01

This decade will bring major changes to the therapy of diabetes. New drugs are likely to include monomeric insulins, fatty-acid-oxidation inhibitors, insulin-secretion inducers, and nutrition modifiers. Likely new devices include improved insulin pens, less invasive methods of insulin administration, and noninvasive blood glucose monitoring. The use of computers will integrate this care, and artificial intelligence will provide new approaches to all of health care. An integrated system for using these new technologies, such as staged diabetes management, will ensure an orderly, cost-effective transition in therapy by the entire health-care community.

Investigating the Role of Twist1 in Diabetes Pathogenesis

DTIC Science & Technology

Several genes associated with diabetes have been identified in genome wide association studies, but their genetic validation as causative factors...of insulin. Loss-of-function genetic experiments demonstrated that Twist1 deletion against fatty pancreas formation driven by obesity, thereby

Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

PubMed Central

Kahali, Bratati; Halligan, Brian; Speliotes, Elizabeth K.

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future. PMID:26676813

Non-alcoholic fatty liver disease in diabetics--prevalence and predictive factors in a multiracial hospital clinic population in Malaysia.

PubMed

Chan, Wah-Kheong; Tan, Alexander Tong-Boon; Vethakkan, Shireene Ratna; Tah, Pei-Chien; Vijayananthan, Anushya; Goh, Khean-Lee

2013-08-01

There is currently no published study comparing prevalence of non-alcoholic fatty liver disease (NAFLD) and associated factors among diabetics of different ethnicity in the Asia-Pacific region. Cross-sectional study of consecutive patients in the Diabetic Clinic in University of Malaya Medical Centre. The Global Physical Activity Questionnaire and a semiquantitative food-frequency questionnaire were used to assess physical activity and dietary intake, respectively. Diagnosis of NAFLD was ultrasound-based and following exclusion of significant alcohol intake. Data for 399 patients were analyzed (mean age 62.3 ± 10.5 years, 43.1% men). The racial distribution was Chinese 43.6%, Indian 33.1%, Malay 22.3%, and others 1.0%. The prevalence of NAFLD was 49.6%. On univariate analysis, factors associated with NAFLD were age < 65 years, race, obesity, central obesity, glycated hemoglobin ≥ 7.0%, and elevated serum alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase levels. Patients with low physical activity were more likely to have NAFLD (odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.06-2.63, P = 0.020). The prevalence of NAFLD was highest among Malays (60.7%), followed by Indians (51.5%), and lowest among Chinese (42.0%) consistent with higher prevalence of central obesity and higher percentage calorie intake from fat in the former groups of patients. On multivariate analysis, independent factors associated with NAFLD were central obesity (OR = 2.20, 95% CI = 1.29-3.75, P = 0.004) and elevated serum ALT level (OR = 1.98, 95% CI = 1.21-3.25, P = 0.007). NAFLD was seen in half of a cohort of diabetic patients and was independently associated with central obesity and elevated serum ALT level. Prevalence of NAFLD was different and paralleled the difference in prevalence of central obesity and in percentage calorie intake from fat among the different ethnic groups. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia

Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

PubMed Central

Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

2015-01-01

Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease.

PubMed

Sullivan, E Madison; Pennington, Edward Ross; Green, William D; Beck, Melinda A; Brown, David A; Shaikh, Saame Raza

2018-05-01

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure-function in metabolic diseases such as obesity, cardiac-ischemia reperfusion injury, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and select cancers.

Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. A comprehensive systematic review.

PubMed

Floresta, Giuseppe; Pistarà, Venerando; Amata, Emanuele; Dichiara, Maria; Marrazzo, Agostino; Prezzavento, Orazio; Rescifina, Antonio

2017-09-29

Small molecule inhibitors of adipocyte fatty acid binding protein 4 (FABP4) have attracted interest following the recent publications of beneficial pharmacological effects of these compounds. FABP4 is predominantly expressed in macrophages and adipose tissue where it regulates fatty acids (FAs) storage and lipolysis and is an important mediator of inflammation. In the past years, hundreds FABP4 inhibitors have been synthesized for effective atherosclerosis and diabetes treatments, including derivatives of niacin, quinoxaline, aryl-quinoline, bicyclic pyridine, urea, aromatic compounds and other novel heterocyclic compounds. This review provides an overview of the synthesized and discovered molecules as adipocyte fatty acid binding protein 4 inhibitors (FABP4is) since the synthesis of the putative FABP4i, BMS309403, highlighting the interactions of the different classes of inhibitors with the targets. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial).

PubMed

Bacchi, Elisabetta; Negri, Carlo; Targher, Giovanni; Faccioli, Niccolò; Lanza, Massimo; Zoppini, Giacomo; Zanolin, Elisabetta; Schena, Federico; Bonora, Enzo; Moghetti, Paolo

2013-10-01

Although lifestyle interventions are considered the first-line therapy for nonalcoholic fatty liver disease (NAFLD), which is extremely common in people with type 2 diabetes, no intervention studies have compared the effects of aerobic (AER) or resistance (RES) training on hepatic fat content in type 2 diabetic subjects with NAFLD. In this randomized controlled trial, we compared the 4-month effects of either AER or RES training on insulin sensitivity (by hyperinsulinemic euglycemic clamp), body composition (by dual-energy X-ray absorptiometry), as well as hepatic fat content and visceral (VAT), superficial (SSAT), and deep (DSAT) subcutaneous abdominal adipose tissue (all quantified by an in-opposed-phase magnetic resonance imaging technique) in 31 sedentary adults with type 2 diabetes and NAFLD. After training, hepatic fat content was markedly reduced (P < 0.001), to a similar extent, in both the AER and the RES training groups (mean relative reduction from baseline [95% confidence interval] -32.8% [-58.20 to -7.52] versus -25.9% [-50.92 to -0.94], respectively). Additionally, hepatic steatosis (defined as hepatic fat content >5.56%) disappeared in about one-quarter of the patients in each intervention group (23.1% in the AER group and 23.5% in the RES group). Insulin sensitivity during euglycemic clamp was increased, whereas total body fat mass, VAT, SSAT, and hemoglobin A1c were reduced comparably in both intervention groups. This is the first randomized controlled study to demonstrate that resistance training and aerobic training are equally effective in reducing hepatic fat content among type 2 diabetic patients with NAFLD. Copyright © 2013 by the American Association for the Study of Liver Diseases.

Small molecule inhibitors of human adipocyte fatty acid binding protein (FABP4).

PubMed

Zhang, Mingming; Zhu, Weiliang; Li, Yingxia

2014-06-01

Fatty acid binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and modulates inflammatory and metabolic response. Studies in FABP4-deficient mice have shown that this lipid carrier has a significant role within the field of metabolic syndrome, inflammation and atherosclerosis; thus, its inhibition may open up new opportunities to develop novel therapeutic agents. A number of potent small molecule inhibitors of FABP4 have been identified and found to have the potential to prevent and treat metabolic diseases such as type-2 diabetes and atherosclerosis. Due to the ubiquity of endogenous fatty acids and the high intracellular concentration of FABP4, the inhibitors need to have significantly greater intrinsic potency than endogenous fatty acids. Furthermore, heart-type FABP (FABP3), which is expressed in both heart and skeletal muscle, is involved in active fatty acid metabolism where it transports fatty acids from the cell membrane to mitochondria for oxidation. However, FABP3 shares high overall sequence identity and similar 3D structure with FABP4, but has a potential problem with selectivity. In this review, we would like to analyze the main inhibitors that have appeared in the literature in the last decade, focusing on chemical structures, biological properties, selectivity and structure-activity relationships.

Caloric restriction or telmisartan control dyslipidemia and nephropathy in obese diabetic Zücker rats

PubMed Central

2014-01-01

Background The obese Zücker diabetic fatty male rat (ZDF:Gmi™-fa) is an animal model of type II diabetes associated with obesity and related metabolic disturbances like dyslipidaemia and diabetic nephropathy. In addition, diabetic dyslipidaemia has been linked to vascular and glomerular damage too. Dietary fat restriction is a current strategy to tackle obesity and, telmisartan, as a renoprotective agent, may mediate cholesterol efflux by activating PPARγ. To test the hypothesis that both therapeutical alternatives may influence dyslipidaemia and nephropathy in the ZDF rat, we studied their effect on development of diabetes. Methods Male Zücker Diabetic Fatty (ZDF) rats received a low-calorie diet, vehicle or telmisartan for 9 weeks. Blood samples were obtained for analyses of lipids and lipoproteins, LDL-oxidisability, HDL structural and functional properties. Urinalysis was carried out to estimate albumin loss. At the end of the experimental period, rats were sacrificed, liver extracted and APOA1 mRNA quantified. Results Results indicated that low-calorie diet and telmisartan can slower the onset of overt hyperglycaemia and renal damage assessed as albuminuria. Both interventions decreased the oxidative susceptibility of LDL and hepatic APOA1 mRNA expression but only dietary restriction lowered hyperlipidaemia. Conclusion Either a dietary or pharmacologic interventions with telmisartan have important beneficial effects in terms of LDL oxidative susceptibility and progression of albuminuria in obesity related type II diabetes. PMID:24468233

Design and rationale of the WELCOME trial: A randomised, placebo controlled study to test the efficacy of purified long chainomega-3 fatty acid treatment in non-alcoholic fatty liver disease [corrected].

PubMed

Scorletti, E; Bhatia, L; McCormick, K G; Clough, G F; Nash, K; Calder, P C; Byrne, C D

2014-03-01

Non-alcoholic fatty liver disease (NAFLD) represents a range of liver conditions from simple fatty liver to progressive end stage liver disease requiring liver transplantation. NAFLD is common in the population and in certain sub groups (e.g. type 2 diabetes) up to 70% of patients may be affected. NAFLD is not only a cause of end stage liver disease and hepatocellular carcinoma, but is also an independent risk factor for type 2 diabetes and cardiovascular disease. Consequently, effective treatments for NAFLD are urgently needed. The WELCOME study is testing the hypothesis that treatment with high dose purified long chain omega-3 fatty acids will have a beneficial effect on a) liver fat percentage and b) two histologically validated algorithmically-derived biomarker scores for liver fibrosis. In a randomised double blind placebo controlled trial, 103 participants with NAFLD were randomised to 15-18months treatment with either 4g/day purified long chain omega-3 fatty acids (Omacor) or 4g/day olive oil as placebo. Erythrocyte percentage DHA and EPA enrichment (a validated proxy for hepatic enrichment) was determined by gas chromatography. Liver fat percentage was measured in three discrete liver zones by magnetic resonance spectroscopy (MRS). We also measured body fat distribution, physical activity and a range of cardiometabolic risk factors. Recruitment started in January 2010 and ended in June 2011. We identified 178 potential participants, and randomised 103 participants who met the inclusion criteria. The WELCOME study was approved by the local ethics committee (REC: 08/H0502/165; www.clinicalTrials.gov registration number NCT00760513). Copyright © 2014 Elsevier Inc. All rights reserved.

Metabolic responses in a model of insulin resistance: comparison between oral glucose and meal tolerance tests.

PubMed

Berthiaume, Nathalie; Zinker, Bradley A

2002-05-01

The purpose of this investigation was to compare the benefits of a meal tolerance test (MTT) against those of an oral glucose tolerance test (OGTT) in one of the most commonly used models of insulin resistance, the Zucker fatty rat. Comparison of these two oral challenges will facilitate determination of the most effective means of inducing both glucose and insulin responses in this particular model and allow for possible therapeutic benefits to be examined more effectively. Eight-week-old Zucker fatty rats (n = 7 or 8) were used to perform either an OGTT or a MTT following an overnight fast. The OGTT contained a final amount of carbohydrate (CHO) of 1.2 g/kg body weight (BW). The MTT (commercially available liquid meal), in addition to having fat and protein, included a final amount of available CHO and volume to match the OGTT. A saline-treated group served as control. A greater glucose excursion was observed following the OGTT compared to the MTT. The maximal change in glucose from baseline was 140 +/- 10 mg/dL (a 2.1-fold rise) for the OGTT compared to 86.3 +/- 6.1 mg/dL (a 1.7-fold rise) for the MTT (P <.05). The MTT induced a greater change from baseline in insulin response compared to the OGTT (7.5 +/- 1.1 v 3.9 +/- 0.5 ng/mL, MTT v OGTT, respectively; P <.05). The saline challenge induced only minimal glucose and insulin responses in comparison to the other treatments. These results suggest that, in a model of insulin resistance, the MTT is a more potent insulin stimulator than glucose alone. A mixed meal, such as a MTT, provides a complete nutrient challenge (CHO, fat, and protein) that will induce both glucose and insulin responses, enabling a better capacity to detect differences in one of the most often used models of insulin resistance, the Zucker fatty rat. Copyright 2002, Elsevier Science (USA). All rights reserved.

[Diabetes insipidus and pregnancy].

PubMed

Gutiérrez Cruz, Oswaldo; Careaga Benítez, Ricardo

2007-04-01

Diabetes insipidus is an uncommon pathology; its incidence varies from two to six cases in 100,000 pregnancies. It has multiple etiologies and it is classified in central and neurogenic. Patients with diabetes insipidus generally show intense thirst, polyuria, neurologic symptoms and hypernatremia. It does not seem to alter the patient's fertility. Diabetes insipidus is usually associated with pre-eclampsia, HELLP syndrome, and fatty liver disease of pregnancy. This is a report of a case seen at the Hospital General de Cholula, in Puebla, Mexico. A 19 year-old female, with 37.2 weeks of pregnancy, had a history of Langerhans cell histiocytosis since she was four years. Patient was treated with intranasal desmopressin until 2005. She went to an obstetric evaluation; laboratory and cabinet studies were obtained. A healthy 1900 g female was obtained through vaginal delivery, with a 7/9 Apgar score. We should be familiarized with this uncommon pathology because of its association with several obstetric emergencies.

Nonalcoholic Fatty Liver Disease: Study of Demographic and Predictive Factors.

PubMed

Shil, Bimal Chandra; Saha, Madhusudan; Ahmed, Faruque; Dhar, Swapan Chandra

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease characterized by excess of fat in liver which ranges from simple steatosis to nonalcoholic steato-hepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC) in the absence of excessive alcohol consumption. The study was carried out in 216 with serologically defined fatty liver. They underwent detailed history evaluation, clinical examination and anthropometric measurements, biochemical and serological tests. The cut-off values for central obesity were waist hip ratio (WHR) > 0.85 in women and > 0.9 in men. The prevalence of NAFLD was highest in the age group of 31 to 60 years. It was more common in males than females. Twenty cases (11.7%) had discomfort at right upper abdomen. Hepatomegaly was found in 27 patients (13.2%), impaired glucose tolerance (IGT) in 29 (14.21%) and diabetes mellitus in 38 (18.63%) patients. Overweight or obesity was found in 110 (53.92%) cases and central obesity was seen in 129 (63.23%) patients. Hence, metabolic syndrome (according to International Diabetes Federation Criteria) was present in 62.25% cases of NAFLD. Alanine aminotransferase (ALT) more than upper limit of normal was found in 36.76% cases. Risk factors for NAFLD in Bangladesh are similar to reported from the rest of the world. Age more than 30 years, male sex, WHR > 0.9 in men and more than 0.85 in female, BMI more than 25, glucose intolerance are predictive factors for NAFLD. Shil BC, Saha M, Ahmed F, Dhar SC. Nonalcoholic Fatty Liver Disease: Study of Demographic and Predictive Factors. Euroasian J Hepato-Gastroenterol 2015;5(1):4-6.

Implications of obesity for tendon structure, ultrastructure and biochemistry: a study on Zucker rats.

PubMed

Biancalana, Adriano; Velloso, Lício Augusto; Taboga, Sebastião Roberto; Gomes, Laurecir

2012-02-01

The extracellular matrix consists of collagen, proteoglycans and non-collagen proteins. The incidence of obesity and associated diseases is currently increasing in developed countries. Obesity is considered to be a disease of modern times, and genes predisposing to the disease have been identified in humans and animals. The objective of the present study was to compare the morphological and biochemical aspects of the deep digital flexor tendon of lean (Fa/Fa or Fa/fa) and genetically obese (fa/fa) Zucker rats. Ultrastructural analysis showed the presence of lipid droplets in both groups, whereas disorganized collagen fibril bundles were observed in obese animals. Lean animals presented a larger amount of non-collagen proteins and glycosaminoglycans than obese rats. We propose that the overweight and lesser physical activity in obese animals may have provoked the alterations in the composition and organization of extracellular matrix components but a genetic mechanism cannot be excluded. These alterations might be related to organizational and structural modifications in the collagen bundles that influence the mechanical properties of tendons and the progression to a pathological state. Copyright © 2011 Elsevier Ltd. All rights reserved.

Skeletal muscle mitochondrial energetics in obesity and type 2 diabetes mellitus: endocrine aspects.

PubMed

Aguer, Céline; Harper, Mary-Ellen

2012-12-01

During the development of type 2 diabetes mellitus, skeletal muscle is a major site of insulin resistance. The latter has been linked to mitochondrial dysfunction and impaired fatty acid oxidation. Some hormones like insulin, thyroid hormones and adipokines (e.g., leptin, adiponectin) have positive effects on muscle mitochondrial bioenergetics through their direct or indirect effects on mitochondrial biogenesis, mitochondrial protein expression, mitochondrial enzyme activities and/or AMPK pathway activation--all of which can improve fatty acid oxidation. It is therefore not surprising that treatment with these hormones has been proposed to improve muscle and whole body insulin sensitivity. However, treatment of diabetic patients with leptin and adiponectin has no effect on muscle mitochondrial bioenergetics showing resistance to these hormones during type 2 diabetes. Furthermore, treatment with most thyroid hormones has unexpectedly revealed negative effects on muscle insulin sensitivity. Future research should focus on development of agents that improve metabolic dysfunction downstream of hormone receptors. Copyright © 2012 Elsevier Ltd. All rights reserved.

Managing non-alcoholic fatty liver disease

PubMed Central

Ngu, Jing Hieng; Goh, George Boon Bee; Poh, Zhongxian; Soetikno, Roy

2016-01-01

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly with the obesity and diabetes mellitus epidemics. It is rapidly becoming the most common cause of liver disease worldwide. NAFLD can progress to serious complications such as cirrhosis, hepatocellular carcinoma and death. Therefore, it is important to recognise this condition so that early intervention can be implemented. Lifestyle modifications and strict control of metabolic risk factors are the mainstay of treatment. As disease progression is slow in the majority of NAFLD patients, most can be managed well by primary care physicians. NAFLD patients with advanced liver fibrosis should be referred to specialist care for further assessment. PMID:27439352

Acute effect of the dual angiotensin-converting enzyme and neutral endopeptidase 24-11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat

PubMed Central

Arbin, V; Claperon, N; Fournié-Zaluski, M -C; Roques, B P; Peyroux, J

2001-01-01

The aim of this study was to determine whether acute dual angiotensin-converting enzyme (ACE)/neutral endopeptidase 24-11 (NEP) inhibition could improve whole body insulin-mediated glucose disposal (IMGD) more than ACE inhibition alone and whether this effect was mediated by the kinin-nitric oxide (NO) pathway activation.We therefore compared in anaesthetized obese (fa/fa) Zucker rats (ZOs) the effects of captopril (2 mg kg−1, i.v.+2 mg kg−1 h−1), retrothiorphan (25 mg kg−1, i.v. +25 mg  kg−1 h−1), a selective NEP inhibitor, and mixanpril (25 mg kg−1, i.v.+25 mg kg−1 h−1), a dual ACE/NEP inhibitor, on IMGD using hyperinsulinaemic euglycaemic clamp technique. The role of the kinin-NO pathway in the effects of mixanpril was tested using a bradykinin B2 receptor antagonist (Hoe-140, 300 μg kg−1) and a NO-synthase inhibitor (Nω-nitro-L-arginine methyl ester, L-NAME, 10 mg kg−1 i.v. +10 mg kg−1 h−1) as pretreatments.Insulin sensitivity index (ISI) was lower in ZO controls than in lean littermates. Increases in ISI were observed in captopril- and retrothiorphan-treated ZOs. In mixanpril-treated ZOs, ISI was further increased, compared to captopril- and retrothiorphan-treated ZOs.In ZOs, Hoe-140 and L-NAME alone did not significantly alter and slightly reduced the ISI respectively. Hoe-140 and L-NAME markedly inhibited the ISI improvement induced by mixanpril.These results show that in obese insulin-resistant Zucker rats, under acute conditions, NEP or ACE inhibition can improve IMGD and that dual ACE/NEP inhibition improves IMGD more effectively than does either single inhibition. This effect is linked to an increased activation of the kinin-NO pathway. PMID:11399666

High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels.

PubMed

Portillo-Sanchez, Paola; Bril, Fernando; Maximos, Maryann; Lomonaco, Romina; Biernacki, Diane; Orsak, Beverly; Subbarayan, Sreevidya; Webb, Amy; Hecht, Joan; Cusi, Kenneth

2015-06-01

Nonalcoholic fatty liver disease (NAFLD) and its more severe form with steatohepatitis (NASH) are common in patients with type 2 diabetes mellitus (T2DM). However, they are usually believed to largely affect those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD by the gold standard, liver magnetic resonance spectroscopy ((1)H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile. We recruited 103 patients with T2DM and normal plasma aminotransferases (age, 60 ± 8 y; body mass index [BMI], 33 ± 5 kg/m(2); glycated hemoglobin [A1c], 7.6 ± 1.3%). We measured the following: 1) liver triglyceride content by (1)H-MRS; 2) systemic insulin sensitivity (homeostasis model assessment-insulin resistance); and 3) adipose tissue insulin resistance, both fasting (as the adipose tissue insulin resistance index: fasting plasma free fatty acids [FFA] × insulin) and during an oral glucose tolerance test (as the suppression of FFA). The prevalence of NAFLD and NASH were much higher than expected (50% and 56% of NAFLD patients, respectively). The prevalence of NAFLD was higher in obese compared with nonobese patients as well as with increasing BMI (P = .001 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (P = .01). Compared with nonobese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle) and, particularly, adipose tissue (fasting/postprandial) insulin resistance (all P < .01). The prevalence of NAFLD is much higher than previously believed in overweight/obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of NASH. Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH.

Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study.

PubMed

Leon-Acuña, A; Alcala-Diaz, J F; Delgado-Lista, J; Torres-Peña, J D; Lopez-Moreno, J; Camargo, A; Garcia-Rios, A; Marin, C; Gomez-Delgado, F; Caballero, J; Van-Ommen, B; Malagon, M M; Perez-Martinez, P; Lopez-Miranda, J

2016-04-19

Previous evidences have shown the presence of a prolonged and exaggerated postprandial response in type 2 diabetes mellitus (T2DM) and its relation with an increase of cardiovascular risk. However, the response in prediabetes population has not been established. The objective was to analyze the degree of postprandial lipemia response in the CORDIOPREV clinical trial (NCT00924937) according to the diabetic status. 1002 patients were submitted to an oral fat load test meal (OFTT) with 0.7 g fat/kg body weight [12 % saturated fatty acids (SFA), 10 % polyunsaturated fatty acids (PUFA), 43 % monounsaturated fatty acids (MUFA), 10 % protein and 25 % carbohydrates]. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 h during postprandial state. Postprandial triglycerides (TG) concentration at any point >2.5 mmol/L (220 mg/dL) has been established as undesirable response. We explored the dynamic response in 57 non-diabetic, 364 prediabetic and 581 type 2 diabetic patients. Additionally, the postprandial response was evaluated according to basal insulin resistance subgroups in patients non-diabetic and diabetic without pharmacological treatment (N = 642). Prevalence of undesirable postprandial TG was 35 % in non-diabetic, 48 % in prediabetic and 59 % in diabetic subgroup, respectively (p < 0.001). Interestingly, prediabetic patients displayed higher plasma TG and large triacylglycerol-rich lipoproteins (TRLs-TG) postprandial response compared with those non-diabetic patients (p < 0.001 and p = 0.003 respectively). Moreover, the area under the curve (AUC) of TG and AUC of TRLs-TG was greater in the prediabetic group compared with non-diabetic patients (p < 0.001 and p < 0.005 respectively). Patients with liver insulin resistance (liver-IR) showed higher postprandial response of TG compared with those patients with muscle-IR or without any insulin-resistance respectively (p < 0.001). Our findings demonstrate that prediabetic patients show a lower

Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism

PubMed Central

Kain, Vasundhara; Kapadia, Bandish; Misra, Parimal; Saxena, Uday

2015-01-01

Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia. PMID:26345110

Diagnosis of non-alcoholic fatty liver disease (NAFLD).

PubMed

Yki-Järvinen, Hannele

2016-06-01

Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT ≈30 U/l in men and ≈20 U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30-50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have 'double trouble', i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of 'triple trouble', but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by John Jones, DOI: 10.1007/s00125

Food Pattern, Lifestyle and Diabetes Mellitus

PubMed Central

Rahati, Sara; Shahraki, Mansour; Arjomand, Golnaz; Shahraki, Touran

2014-01-01

Background: Prevalence of Type 2 diabetes is increasing rapidly worldwide. Recent data is reprehensive of increasing diabetes prevalence from 285 millions in 2010 (6.4%) to 439 millions in 2030 in adults aged 20 to 79 in different countries. Lifestyle and particularly dietary habits play an important role in the development of diabetes. Additionally, specific individual food groups and diet components such as monounsaturated fatty acids, fruits, vegetables, whole grain cereals, dietary fiber, fish, magnesium and nuts may protect against the development of diabetes, possibly through the amelioration of insulin sensitivity and its anti-inflammatory actions, while consumption of red and processed meats and saturated fat may increase the risk of type 2 diabetes. Objectives: In this section, we studied dietary and other factors related to the effect of lifestyle in type 2 diabetes. These factors may affect the incidence of type 2 diabetes which could be corrected by lifestyle modifications. Results: Unfortunately, dietary habits in the developed and developing countries are changing towards an unhealthier direction. Consequently, emphasis should be given on encouraging at population and individual levels for adopting a healthier lifestyle, including dietary habits, to prevent the development of type 2 diabetes. Here we reviewed epidemiologic and clinical trial evidence regarding nutrients, foods and dietary patterns to diabetes risk and involved possible mechanisms. Conclusions: Type 2 diabetes is increasingly growing in young population of developing countries, which causes a large burden on individuals and the society. PMID:24971303

Risk Factor for Diabetes Mellitus and High Blood Glucose With HMG-CoA Reductase Inhibitors Using a Postmarketing Surveillance Database in Japan.

PubMed

Hashiguchi, Masayuki; Maruyama, Junya; Shimizu, Mikiko; Takahashi, Daichi; Shiga, Tsuyoshi

2018-02-20

To investigate whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) use is associated with an increased risk of diabetes mellitus and hyperglycemia, we performed a nested case-control study using a postmarketing surveillance database in Japan. The database cohort included 26,849 cases of statin use and 5308 cases of other lipid-lowering drug use in patients with hyperlipidemia. Participants received at least 1 type of statin, had a clear medication history of statin use, and had no complications of diabetes mellitus. Cases were defined as onset of diabetes mellitus or hyperglycemia during statin intake. For each case, 20 controls were randomly selected and matched by time point. The factors associated with an increased risk of diabetes mellitus and hyperglycemia during statin intake examined included sex, age, body mass index, statin use duration, complications, concomitant medication, and clinical laboratory tests. Statin-associated diabetes mellitus or hyperglycemia was identified based on abnormal elevation of blood glucose concentrations beyond the reference range. A total of 19,868 patients met the inclusion criteria, of whom 24 were patients in the case group. Two complicating factors, fatty liver (adjusted odds ratio 16.10) and hyperuricemia (adjusted odds ratio 28.96), were extracted for onset of diabetes mellitus or hyperglycemia. Nonalcoholic fatty liver was associated with diabetes mellitus, obesity, and insulin resistance, and hyperuricemia was associated with lifestyle. This study suggested that the onset of diabetes mellitus or hyperglycemia might be increased with statin use in patients with complications of fatty liver and hyperuricemia. © 2018, The American College of Clinical Pharmacology.

Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia

PubMed Central

Page, Kathleen A.; Williamson, Anne; Yu, Namyi; McNay, Ewan C.; Dzuira, James; McCrimmon, Rory J.; Sherwin, Robert S.

2009-01-01

OBJECTIVE We examined whether ingestion of medium-chain triglycerides could improve cognition during hypoglycemia in subjects with intensively treated type 1 diabetes and assessed potential underlying mechanisms by testing the effect of β-hydroxybutyrate and octanoate on rat hippocampal synaptic transmission during exposure to low glucose. RESEARCH DESIGN AND METHODS A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU · kg−1 · min−1) euglycemic- (glucose ∼5.5 mmol/l) hypoglycemic (glucose ∼2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests. In vitro rat hippocampal slice preparations were used to assess the ability of β-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced. RESULTS Hypoglycemia impaired cognitive performance in tests of verbal memory, digit symbol coding, digit span backwards, and map searching. Ingestion of medium-chain triglycerides reversed these effects. Medium-chain triglycerides also produced higher free fatty acids and β-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices β-hydroxybutyrate supported synaptic transmission under low-glucose conditions, whereas octanoate could not. Nevertheless, octanoate improved the rate of recovery of synaptic function upon restoration of control glucose concentrations. CONCLUSIONS Medium-chain triglyceride ingestion improves cognition without adversely affecting adrenergic or symptomatic responses to hypoglycemia in intensively treated type 1 diabetic subjects. Medium-chain triglycerides offer the therapeutic advantage of preserving brain function under hypoglycemic conditions without causing deleterious hyperglycemia. PMID:19223595

Differential effects of n-3 polyunsaturated fatty acids on metabolic control and vascular reactivity in the type 2 diabetic ob/ob mouse.

PubMed

Mustad, Vikkie A; Demichele, Stephen; Huang, Yung-Sheng; Mika, Amanda; Lubbers, Nathan; Berthiaume, Nathalie; Polakowski, Jim; Zinker, Brad

2006-10-01

Diets rich in monounsaturated fatty acids (MUFA) are recommended for individuals with type 2 diabetes mellitus (T2DM). The American Heart Association recommends increasing intakes of n-3 polyunsaturated fatty acids (PUFA) to reduce the risk of vascular disease in high-risk individuals; however, the long-term effects of these bioactive fatty acids on glucose metabolism in insulin resistance are controversial. The present studies were conducted to evaluate the effects of diets rich in both MUFA and alpha linolenic acid (C18:3n-3, ALA), eicosapentaenoic acid (C20:5n-3, EPA), or docosahexaenoic acid (C22:6n-3, DHA), on glycemic control and other parameters related to vascular health in a mouse model of T2DM and insulin resistance. Male ob/ob mice (n = 15 per treatment) were fed 1 of 4 lipid-modified formula diets (LFDs) for 4 weeks: (1) MUFA control, (2) ALA blend, (3) EPA blend, and (4) DHA blend. A portion of a MUFA-rich lipid blend in the control LFD was replaced with 11% to 14% energy as n-3 PUFA. After 4 weeks, plasma glucose response to a standard meal (1.5 g carbohydrate/kg body weight) and insulin challenge (2 U/kg body weight, IP) was assessed, and samples were collected for analysis of glucose, insulin, and lipids. Vascular reactivity of isolated aortic rings was assessed in an identical follow-up study. The results showed that insulin-resistant mice fed an LFD with EPA and/or DHA blends had significantly (P < .05) lower triglycerides and free fatty acids, but insulin sensitivity and fasting plasma glucose were not improved. However, mice fed with the ALA blend had significantly improved insulin sensitivity when compared to those fed with other LFD (P < .05). Animals fed an LFD with n-3 PUFA from marine or plant sources showed significantly improved vascular responses as compared with the MUFA-rich LFD (E(max), P < .05) and ob/ob reference mice consuming chow (E(max) and pEC(50), P < .05). In summary, long-term consumption of LFD with n-3 PUFAs improved blood

Association between Plasma Nonesterified Fatty Acids Species and Adipose Tissue Fatty Acid Composition

PubMed Central

Hellmuth, Christian; Demmelmair, Hans; Schmitt, Isabel; Peissner, Wolfgang; Blüher, Matthias; Koletzko, Berthold

2013-01-01

Fatty acid composition of adipose tissue (AT) is an established long-term biomarker for fatty acid (FA) intake and status, but AT samples are not easily available. Nonesterified FA composition in plasma (pNEFA) may be a good indicator of AT FA composition, because pNEFA are mainly generated by AT lipolysis. We investigated the correlation of 42 pNEFA and subcutaneous as well as visceral AT FA in 27 non-diabetic women with a median BMI of 36 kg/m2 (Q0.25: 25 kg/m2; Q0.75: 49 kg/m2). Close correlations of pNEFA and AT FA were found for odd-chain FA (15∶0 r = 0.838 and 0.862 for subcutaneous and visceral AT, respectively) and omega-3 FA (22∶6 r = 0.719/0.535), while no significant or low correlations were found for other FA including 18∶1 (r = 0.384/0.325) and 20∶4 (r = 0.386/0.266). Close correlations of pNEFA and AT FA were found for essential fatty acids, like 18∶2 (r = 0.541/0.610) and 20∶5 (r = 0.561/0.543). The lower correlation for some pNEFA species with AT FA indicates that the variation of most pNEFA is significantly affected by other FA sources and flux of FA to tissue, in addition to release from AT. A relevant influence of BMI on the level of correlation was shown for saturated FA. NEFA analysis in fasted plasma can serve as a virtual AT biopsy for some FA, and as a biomarker for intake of dairy products and sea fish. PMID:24098359

Association between plasma nonesterified fatty acids species and adipose tissue fatty acid composition.

PubMed

Hellmuth, Christian; Demmelmair, Hans; Schmitt, Isabel; Peissner, Wolfgang; Blüher, Matthias; Koletzko, Berthold

2013-01-01

Fatty acid composition of adipose tissue (AT) is an established long-term biomarker for fatty acid (FA) intake and status, but AT samples are not easily available. Nonesterified FA composition in plasma (pNEFA) may be a good indicator of AT FA composition, because pNEFA are mainly generated by AT lipolysis. We investigated the correlation of 42 pNEFA and subcutaneous as well as visceral AT FA in 27 non-diabetic women with a median BMI of 36 kg/m(2) (Q0.25: 25 kg/m(2); Q0.75: 49 kg/m(2)). Close correlations of pNEFA and AT FA were found for odd-chain FA (15∶0 r = 0.838 and 0.862 for subcutaneous and visceral AT, respectively) and omega-3 FA (22∶6 r = 0.719/0.535), while no significant or low correlations were found for other FA including 18∶1 (r = 0.384/0.325) and 20∶4 (r = 0.386/0.266). Close correlations of pNEFA and AT FA were found for essential fatty acids, like 18∶2 (r = 0.541/0.610) and 20∶5 (r = 0.561/0.543). The lower correlation for some pNEFA species with AT FA indicates that the variation of most pNEFA is significantly affected by other FA sources and flux of FA to tissue, in addition to release from AT. A relevant influence of BMI on the level of correlation was shown for saturated FA. NEFA analysis in fasted plasma can serve as a virtual AT biopsy for some FA, and as a biomarker for intake of dairy products and sea fish.