Osteoporosis is increasing due to the aging of the population. Women with cognitive impairment from childhood are at disproportionally high risk for osteoporosis and fractures. Suggested explanations for this increased risk include high use of anticonvulsant medications, lower peak bone densities, and higher rates of nonambulation. Down syndrome…
Osteoporosis is increasing due to the aging of the population. Women with cognitive impairment from childhood are at disproportionally high risk for osteoporosis and fractures. Suggested explanations for this increased risk include high use of anticonvulsant medications, lower peak bone densities, and higher rates of nonambulation. Down syndrome…
... Emergency Room? What Happens in the Operating Room? Osteoporosis KidsHealth > For Kids > Osteoporosis A A A What's ... you're in your mid-20s. What Is Osteoporosis? If someone has osteoporosis (say: oss-tee-oh- ...
... Too Tall or Too Short All About Puberty Osteoporosis KidsHealth > For Kids > Osteoporosis Print A A A ... you're in your mid-20s. What Is Osteoporosis? If someone has osteoporosis (say: oss-tee-oh- ...
Perreault, Leigh; Færch, Kristine; Kerege, Anna A; Bacon, Samantha D; Bergman, Bryan C
Abnormal endogenous glucose production (EGP) is a characteristic feature in people with impaired fasting glucose (IFG). We sought to determine whether impaired hepatic glucose sensing contributes to abnormal EGP in IFG and whether it could be experimentally restored. Glucose production (rate of appearance; Ra) and flux (glucose cycling) were assessed during a hyperglycemic-euinsulinemic somatostatin clamp with an infusion of [6,6-(2)H2-]glucose and [2-(2)H]glucose before and after enhanced hepatic glucokinase activity via an infusion of low-dose fructose in people with IFG and normal glucose tolerance (NGT). During euglycemia, neither endogenous glucose production [(6,6-(2)H2)-glucose Ra; P = 0.53] or total glucose output (TGO; [2-(2)H]-glucose Ra; P = .12) was different between groups, but glucose cycling ([2-(2)H]glucose Ra to [6,6-(2)H2-]glucose Ra; a surrogate measure of hepatic glucokinase activity in the postabsorptive state) was lower in IFG than NGT (P = .04). Hyperglycemia suppressed EGP more in NGT than IFG (P < .01 for absolute or relative suppression, NGT vs IFG), whereas TGO decreased similarly in both groups (P = .77). The addition of fructose completely suppressed EGP in IFG (P < .01) and tended to do the same to TGO (P = .01; no such changes in NGT, P = .39-.55). Glucose cycling (which reflects glucose-6-phosphatase activity during glucose infusion) was similar in IFG and NGT (P = .51) during hyperglycemia and was unchanged and comparable between groups with the addition of fructose (P = .24). In summary, glucose sensing is impaired in IFG but can be experimentally restored with low-dose fructose. Glucokinase activation may prove to be a novel strategy for the prevention of diabetes in this high-risk group.
Osteoporosis is a condition that leads to loss of bone mass. From the outside, osteoporotic bone is ... disease. Prevention is the best measure for treating osteoporosis by eating a recommended balanced diet including foods ...
Osteoporosis is a disease that thins and weakens the bones. Your bones become fragile and break easily, ... United States, millions of people either already have osteoporosis or are at high risk due to low ...
Riggs, B.L. Melton III, L.J. )
This book contains 20 chapters. Some of the titles are: Radiology of asteoporosis; Quantitative computed tomography in assessment of osteoporosis; Nuclear medicine and densitometry; Assessment of bone turnover by histormorphometry in osteoporosis; and The biochemistry of bone.
Fragachan, F; Perez-Acuña, F; Monsalve, P; Sanabria, A
the free glucose pool at zero time. A significantly higher level was found in hypertensives with pathological Kg values, again indicating an impairment in glucose metabolism in this group: 90.6 +/- 26.5 vs. 65.0 +/- 5.4 g (p less than 0.0001). Another study showed an estimate of the mean cellular glucose uptake (MCUg) per minute and per kilogram body weight. The MCUg following glucose loading decreased considerably in hypertensives with pathological Kg values. The percentage reduction ranged between 50 and 55% hypertensives with pathological Kg values 4.1 +/- 0.8, and normotensives with normal Kg values, 8.0 +/- 0.6 (p less than 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)
Ziemer, David C; Kolm, Paul; Foster, Jovonne K; Weintraub, William S; Vaccarino, Viola; Rhee, Mary K; Varughese, Rincy M; Tsui, Circe W; Koch, David D; Twombly, Jennifer G; Narayan, K M Venkat; Phillips, Lawrence S
With positive results from diabetes prevention studies, there is interest in convenient ways to incorporate screening for glucose intolerance into routine care and to limit the need for fasting diagnostic tests. The aim of this study is to determine whether random plasma glucose (RPG) could be used to screen for glucose intolerance. This is a cross-sectional study. The participants of this study include a voluntary sample of 990 adults not known to have diabetes. RPG was measured, and each subject had a 75-g oral glucose tolerance test several weeks later. Glucose intolerance targets included diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose(110) (IFG(110); fasting glucose, 110-125 mg/dl, and 2 h glucose < 140 mg/dl). Screening performance was measured by area under receiver operating characteristic curves (AROC). Mean age was 48 years, and body mass index (BMI) was 30.4 kg/m(2); 66% were women, and 52% were black; 5.1% had previously unrecognized diabetes, and 24.0% had any "high-risk" glucose intolerance (diabetes or IGT or IFG(110)). The AROC was 0.80 (95% CI 0.74-0.86) for RPG to identify diabetes and 0.72 (0.68-0.75) to identify any glucose intolerance, both highly significant (p < 0.001). Screening performance was generally consistent at different times of the day, regardless of meal status, and across a range of risk factors such as age, BMI, high density lipoprotein cholesterol, triglycerides, and blood pressure. RPG values should be considered by health care providers to be an opportunistic initial screening test and used to prompt further evaluation of patients at risk of glucose intolerance. Such "serendipitous screening" could help to identify unrecognized diabetes and prediabetes.
Nieves, Jeri W; Mosner, Michelle; Silverstein, Shari
Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes a person to increased risk of fracture. Fractures have severe consequences, so fracture prevention is imperative. Risk factor assessment and bone density testing are important tools in the diagnosis of osteoporosis. Actions to promote strong bones include adequate intakes of calcium and vitamin D; being physically active; not smoking; and avoiding excessive alcohol use. There are several FDA-approved medications for the treatment of osteoporosis. The recent attention to osteonecrosis of the jaw (ONJ) and the association between dental and skeletal health speak to the importance of osteoporosis awareness for dental professionals.
Ziemer, David C.; Kolm, Paul; Foster, Jovonne K.; Weintraub, William S.; Vaccarino, Viola; Rhee, Mary K.; Varughese, Rincy M.; Tsui, Circe W.; Koch, David D.; Twombly, Jennifer G.; Venkat Narayan, K. M.
Background With positive results from diabetes prevention studies, there is interest in convenient ways to incorporate screening for glucose intolerance into routine care and to limit the need for fasting diagnostic tests. Objective The aim of this study is to determine whether random plasma glucose (RPG) could be used to screen for glucose intolerance. Design This is a cross-sectional study. Participants The participants of this study include a voluntary sample of 990 adults not known to have diabetes. Measurements RPG was measured, and each subject had a 75-g oral glucose tolerance test several weeks later. Glucose intolerance targets included diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose110 (IFG110; fasting glucose, 110–125 mg/dl, and 2 h glucose < 140 mg/dl). Screening performance was measured by area under receiver operating characteristic curves (AROC). Results Mean age was 48 years, and body mass index (BMI) was 30.4 kg/m2; 66% were women, and 52% were black; 5.1% had previously unrecognized diabetes, and 24.0% had any “high-risk” glucose intolerance (diabetes or IGT or IFG110). The AROC was 0.80 (95% CI 0.74–0.86) for RPG to identify diabetes and 0.72 (0.68–0.75) to identify any glucose intolerance, both highly significant (p < 0.001). Screening performance was generally consistent at different times of the day, regardless of meal status, and across a range of risk factors such as age, BMI, high density lipoprotein cholesterol, triglycerides, and blood pressure. Conclusions RPG values should be considered by health care providers to be an opportunistic initial screening test and used to prompt further evaluation of patients at risk of glucose intolerance. Such “serendipitous screening” could help to identify unrecognized diabetes and prediabetes. PMID:18335280
... is at its highest level. After bone mass peaks, all adults start to lose some bone mass.Osteoporosis occurs if you lose too much bone or don't make enough bone to begin with.What are the risk factors for osteoporosis?The following things put you at ...
Nanes, Mark S; Kallen, Caleb B
Osteoporotic fractures are common and result in extensive morbidity and mortality. It is possible to decrease the risk of fracture in postmenopausal, male, and glucocorticoid-induced osteoporosis with appropriate screening and treatment. The assessment of fracture risk, for which bone densitometry is only 1 component, should be the main focus of patient evaluation. Epidemiologically derived risk-assessment tools such as World Health Organization Fracture Risk Assessment Tool (FRAX) provide physicians with a way to determine the 10-year risk of osteoporotic fracture and effectively choose candidates for therapy. A number of potent skeletal antiresorptive and anabolic drugs have become available to treat osteoporosis and prevent up to 70% of fractures. Here, we provide a detailed update on clinical osteoporosis, the contribution of bone densitometry, and the approach to patients using risk assessment in the consideration of treatments. Progress in osteoporosis is an example of successful bench-to-bedside research benefitting populations worldwide.
... Prevention and Treatment The good news is that osteoporosis can often be prevented and treated. Healthy lifestyle choices such as proper diet, exercise, and treatment medications can help prevent further bone ...
Grant, Suzanne J; Bensoussan, Alan; Chang, Dennis; Kiat, Hosen; Klupp, Nerida L; Liu, Jian Ping; Li, Xun
Around 308 million people worldwide are estimated to have impaired glucose tolerance (IGT); 25% to 75% of these will develop diabetes within a decade of initial diagnosis. At diagnosis, half will have tissue-related damage and all have an increased risk for coronary heart disease. The objective of this review was to assess the effects and safety of Chinese herbal medicines for the treatment of people with impaired glucose tolerance or impaired fasting glucose (IFG). We searched the following databases: The Cochrane Library, PubMed, EMBASE, AMED, a range of Chinese language databases, SIGLE and databases of ongoing trials. Randomised clinical trials comparing Chinese herbal medicines with placebo, no treatment, pharmacological or non-pharmacological interventions in people with IGT or IFG were considered. Two authors independently extracted data. Trials were assessed for risk of bias against key criteria: random sequence generation, allocation concealment, blinding of participants, outcome assessors and intervention providers, incomplete outcome data, selective outcome reporting and other sources of bias. This review examined 16 trials lasting four weeks to two years involving 1391 participants receiving 15 different Chinese herbal medicines in eight different comparisons. No trial reported on mortality, morbidity or costs. No serious adverse events like severe hypoglycaemia were observed. Meta-analysis of eight trials showed that those receiving Chinese herbal medicines combined with lifestyle modification were more than twice as likely to have their fasting plasma glucose levels return to normal levels (i.e. fasting plasma glucose <7.8 mmol/L and 2hr blood glucose <11.1 mmol/L) compared to lifestyle modification alone (RR 2.07; 95% confidence intervall (CI) 1.52 to 2.82). Those receiving Chinese herbs were less likely to progress to diabetes over the duration of the trial (RR 0.33; 95% CI 0.19 to 0.58). However, all trials had a considerable risk of bias and none
Grant, Suzanne J; Bensoussan, Alan; Chang, Dennis; Kiat, Hosen; Klupp, Nerida L; Liu, Jian Ping; Li, Xun
Background Around 308 million people worldwide are estimated to have impaired glucose tolerance (IGT); 25% to 75% of these will develop diabetes within a decade of initial diagnosis. At diagnosis, half will have tissue-related damage and all have an increased risk for coronary heart disease. Objectives The objective of this review was to assess the effects and safety of Chinese herbal medicines for the treatment of people with impaired glucose tolerance or impaired fasting glucose (IFG). Search strategy We searched the following databases: The Cochrane Library, PubMed, EMBASE, AMED, a range of Chinese language databases, SIGLE and databases of ongoing trials. Selection criteria Randomised clinical trials comparing Chinese herbal medicines with placebo, no treatment, pharmacological or non-pharmacological interventions in people with IGT or IFG were considered. Data collection and analysis Two authors independently extracted data. Trials were assessed for risk of bias against key criteria: random sequence generation, allocation concealment, blinding of participants, outcome assessors and intervention providers, incomplete outcome data, selective outcome reporting and other sources of bias. Main results This review examined 16 trials lasting four weeks to two years involving 1391 participants receiving 15 different Chinese herbal medicines in eight different comparisons. No trial reported on mortality, morbidity or costs. No serious adverse events like severe hypoglycaemia were observed. Meta-analysis of eight trials showed that those receiving Chinese herbal medicines combined with lifestyle modification were more than twice as likely to have their fasting plasma glucose levels return to normal levels (i.e. fasting plasma glucose <7.8 mmol/L and 2hr blood glucose <11.1 mmol/L) compared to lifestyle modification alone (RR 2.07; 95% confidence intervall (CI) 1.52 to 2.82). Those receiving Chinese herbs were less likely to progress to diabetes over the duration of the
Ensrud, Kristine E; Crandall, Carolyn J
Osteoporosis is a common systemic skeletal disorder resulting in bone fragility and increased fracture risk. However, management of osteoporosis and fracture prevention strategies are often not addressed by primary care clinicians, even in older patients with recent fractures. Evidence-based screening strategies will improve identification of patients who are most likely to benefit from drug treatment to prevent fracture. In addition, careful consideration of when pharmacotherapy should be started and choice of medication and duration of treatment will maximize the benefits of fracture prevention while minimizing potential harms of long-term drug exposure.
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue, leading to enhanced bone fracture risk. Due to its increasing prevalence (affects more than 10 percent of population) and consequences (bone fractures), osteoporosis is a growing medical, social and economic problem. Of particular importance is hip fracture, with increasing incidence and lethal outcome in 20 percent, and less than 33 percent of patients with complete recovery. For better prevention of such undesired consequences, accurate diagnosis in the early phase of bone loss is necessary. Bone loss is a silent process, without signs and symptoms of the disease, and so active screening of persons at risk is needed, particulary among the postmenopausal women with some of the recognized risk factors for the development of osteoporotic bone fracture. In such persons, for early detection of bone mass loss, diagnostic measurement of bone density should be done, preferably dual-energy x-ray absorptiometry (DEXA). Prevention of osteoporosis is the best approach to the problem, and it should be started in early childhood with general measures (diet with sufficient calcium intake, life style with physical exercise) in a involved national program. Treatment of osteoporosis lasts for many years and includes general measures and medication with osteodensitometric assessment over a two-year period.
Aoyama-Sasabe, Sae; Fukushima, Mitsuo; Xin, Xin; Taniguchi, Ataru; Nakai, Yoshikatsu; Mitsui, Rie; Takahashi, Yoshitaka; Tsuji, Hideaki; Yabe, Daisuke; Yasuda, Koichiro; Kurose, Takeshi; Inagaki, Nobuya; Seino, Yutaka
Objective. To investigate the characteristics of isolated impaired glucose tolerance (IGT) and isolated impaired fasting glucose (IFG), we analyzed the factors responsible for elevation of 2-hour postchallenge plasma glucose (2 h PG) and fasting plasma glucose (FPG) levels. Methods. We investigated the relationship between 2 h PG and FPG levels who underwent 75 g OGTT in 5620 Japanese subjects at initial examination for medical check-up. We compared clinical characteristics between isolated IGT and isolated IFG and analyzed the relationships of 2 h PG and FPG with clinical characteristics, the indices of insulin secretory capacity, and insulin sensitivity. Results. In a comparison between isolated IGT and isolated IFG, insulinogenic index was lower in isolated IGT than that of isolated IFG (0.43 ± 0.34 versus 0.50 ± 0.47, resp.; p < 0.01). ISI composite was lower in isolated IFG than that of isolated IGT (6.87 ± 3.38 versus 7.98 ± 4.03, resp.; p < 0.0001). In isolated IGT group, insulinogenic index showed a significant correlation with 2 h PG (r = −0.245, p < 0.0001) and had the strongest correlation with 2 h PG (β = −0.290). In isolated IFG group, ISI composite showed a significant correlation with FPG (r = −0.162, p < 0.0001) and had the strongest correlation with FPG (β = −0.214). Conclusions. We have elucidated that decreased early-phase insulin secretion is the most important factor responsible for elevation of 2 h PG levels in isolated IGT subjects, and decreased insulin sensitivity is the most important factor responsible for elevation of FPG levels in isolated IFG subjects. PMID:26788515
Di Bonito, P; Pacifico, L; Chiesa, C; Valerio, G; Miraglia Del Giudice, E; Maffeis, C; Morandi, A; Invitti, C; Licenziati, M R; Loche, S; Tornese, G; Franco, F; Manco, M; Baroni, M G
To investigate in a large sample of overweight/obese (OW/OB) children and adolescents the prevalence of prediabetic phenotypes such as impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and to assess their association with cardiometabolic risk (CMR) factors including hepatic steatosis (HS). Population data were obtained from the CARdiometabolic risk factors in children and adolescents in ITALY study. Between 2003 and 2013, 3088 youths (972 children and 2116 adolescents) received oral glucose tolerance test (OGTT) and were included in the study. In 798 individuals, abdominal ultrasound for identification of HS was available. The prevalence of IFG (3.2 vs. 3.3%) and IGT (4.6 vs. 5.0%) was similar between children and adolescents. Children with isolated IGT had a 2-11 fold increased risk of high LDL-C, non-HDL-C, Tg/HDL-C ratio, and low insulin sensitivity, when compared to those with normal glucose tolerance (NGT). No significant association of IFG with any CMR factor was found in children. Among adolescents, IGT subjects, and to a lesser extent those with IFG, showed a worse CMR profile compared to NGT subgroup. In the overall sample, IGT phenotype showed a twofold increased risk of HS compared to NGT subgroup. Our study shows an unexpected similar prevalence of IFG and IGT between children and adolescents with overweight/obesity. The IGT phenotype was associated with a worse CMR profile in both children and adolescents. Phenotyping prediabetes conditions by OGTT should be done as part of prediction and prevention of cardiometabolic diseases in OW/OB youth since early childhood.
Lane, J M; Russell, L; Khan, S N
Osteoporosis is a disorder of decreased bone mass, microarchitectural deterioration, and fragility fractures. Osteoporosis is widespread and can affect people of all ethnic backgrounds and many older women and men. An essential element in preventing osteoporosis is the achievement of normal peak bone mass. Adequate nutrition, appropriate calcium and vitamin D intake, regular menstrual cycles and a well balanced exercise program of exercise are essential elements in achieving peak bone mass. At menopause women undergo accelerated bone loss. Thereafter, women and men gradually lose bone mass. A loss of one standard deviation give rise to an enhanced twofold risk of spine fractures or a 2.5 risk of hip fracture. Bone mass is determined by dual energy x-ray absorptiometry, quantitative computed tomography scan, and a peripheral ultrasound. Dual energy x-ray absorptiometry has outstanding precision (within 1% to 2%), and has the ability to show the efficacy of drug intervention. Peripheral measurements may identify osteoporosis but only have a 70% correlation with hip and spine bone mass. Dual energy x-ray absorptiometry determines bone mass in a patient but the bone collagen breakdown products (N-telopeptide crosslinks) establish the current rate of bone loss. Major risk factors leading to fragility fracture include low body weight, history of fracture, family history of osteoporosis, and smoking. All individuals should ingest adequate calcium and vitamin D, exercise, and prevent falls. Women with low bone mass, high urinary bone collagen breakdown products, and/or major risk factors should consider hormone replacement therapy or a selective estrogen receptor modulator (Evista), calcitonin and bisphosphonates (alendronate). These agents successfully increase bone mass and limit fracture risk. Men at risk for fragility fractures respond similarly as women to alendronate and calcitonin. Although vertebral compression fractures can occur spontaneously, hip fractures are
Liver cirrhosis may be accompanied by osteoporosis and, rarely, osteomalacia. Normal liver function is required for normal digestion and absorption of calcium-containing nutrients. The liver plays an important role for the metabolisation of vitamin D: the 25-hydroxylation takes place in the liver. However, the respective enzymatic capacity is not limited by liver diseases except for almost complete liver insufficiency. Therefore, true hypovitaminosis D only rarely plays a role in hepatic osteopenia, but direct toxic effects on bone forming cells (osteoblasts) are discussed: e.g. by bile salts. Coexisting hypogonadism leads to further bone loss. Patients with primary biliary cirrhosis in part present with osteoporosis and fractures. Bone histology reveals normal resorption, but decreased formation. Calcitropic hormones are generally normal. Chronic alcoholism induces the same histologic picture in bone, i.e. normal resorption and diminished formation. These changes are reversible after abstinence and as long as of cirrhosis has not yet developed. Patients undergoing liver transplantation due to end stage liver insufficiency including cirrhosis present with diminished bone mass before receiving a new liver, and they show further bone loss after the transplantation due to immunosuppressive treatment including glucocorticoids. There is no specific treatment of bone loss or osteoporosis due to liver cirrhosis. Preventive efforts should be devoted to the avoidance of suboptimal calcium and vitamin D supply, immobilization, and hypogonadism. Fluorides may increase bone mass after liver transplantation--perhaps they are also useful in liver cirrhosis. Antiresorption agents like calcitonins or bisphosphonates may be cautiously tried.
Capiotti, Katiucia Marques; Antonioli, Régis; Kist, Luiza Wilges; Bogo, Maurício Reis; Bonan, Carla Denise; Da Silva, Rosane Souza
Diabetes mellitus (DM) affects over 10% of the world's population. Hyperglycemia is the main feature for the diagnosis of this disease. The zebrafish (Danio rerio) is an established model organism for the study of various metabolic diseases. In this paper, hyperglycemic zebrafish, when immersed in a 111 mM glucose solution for 14 days, developed increased glycation of proteins from the eyes, decreased mRNA levels of insulin receptors in the muscle, and a reversion of high blood glucose level after treatment with anti-diabetic drugs (glimepiride and metformin) even after 7 days of glucose withdrawal. Additionally, hyperglycemic zebrafish developed an impaired response to exogenous insulin, which was recovered after 7 days of glucose withdrawal. These data suggest that the exposure of adult zebrafish to high glucose concentration is able to induce persistent metabolic changes probably underlined by a hyperinsulinemic state and impaired peripheral glucose metabolism.
Sambrook, Philip; Cooper, Cyrus
Osteoporosis is a serious public health issue. The past 10 years have seen great advances in our understanding of its epidemiology, pathophysiology, and treatment, and further advances are rapidly being made. Clinical assessment will probably evolve from decisions mainly being made on the basis of bone densitometry, to use of algorithms of absolute fracture risk. Biochemical markers of bone turnover are also likely to become more widely used. Bisphosphonates will probably remain the mainstay of therapy, but improved understanding of the optimum amount of remodelling suppression and duration of therapy will be important. At the same time, other diagnostic and therapeutic approaches, including biological agents, are likely to become more widespread.
Malenda, Agata; Skrobanska, Anna; Issat, Tadeusz; Winiarska, Magdalena; Bil, Jacek; Oleszczak, Bozenna; Sinski, Maciej; Firczuk, Małgorzata; Bujnicki, Janusz M; Chlebowska, Justyna; Staruch, Adam D; Glodkowska-Mrowka, Eliza; Kunikowska, Jolanta; Krolicki, Leszek; Szablewski, Leszek; Gaciong, Zbigniew; Koziak, Katarzyna; Jakobisiak, Marek; Golab, Jakub; Nowis, Dominika A
Statins, HMG-CoA reductase inhibitors, are used in the prevention and treatment of cardiovascular diseases owing to their lipid-lowering effects. Previous studies revealed that, by modulating membrane cholesterol content, statins could induce conformational changes in cluster of differentiation 20 (CD20) tetraspanin. The aim of the presented study was to investigate the influence of statins on glucose transporter 1 (GLUT1)-mediated glucose uptake in tumor cells. We observed a significant concentration- and time-dependent decrease in glucose analogs' uptake in several tumor cell lines incubated with statins. This effect was reversible with restitution of cholesterol synthesis pathway with mevalonic acid as well as with supplementation of plasma membrane with exogenous cholesterol. Statins did not change overall GLUT1 expression at neither transcriptional nor protein levels. An exploratory clinical trial revealed that statin treatment decreased glucose uptake in peripheral blood leukocytes and lowered (18)F-fluorodeoxyglucose ((18)F-FDG) uptake by tumor masses in a mantle cell lymphoma patient. A bioinformatics analysis was used to predict the structure of human GLUT1 and to identify putative cholesterol-binding motifs in its juxtamembrane fragment. Altogether, the influence of statins on glucose uptake seems to be of clinical significance. By inhibiting (18)F-FDG uptake, statins can negatively affect the sensitivity of positron emission tomography, a diagnostic procedure frequently used in oncology.
Reno, Candace M; Puente, Erwin C; Sheng, Zhenyu; Daphna-Iken, Dorit; Bree, Adam J; Routh, Vanessa H; Kahn, Barbara B; Fisher, Simon J
GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
Bon, Jessica; Kahloon, Rehan; Zhang, Yingze; Xue, Jianmin; Fuhrman, Carl R; Tan, Jiangning; Burger, Mathew; Kass, Daniel J; Csizmadia, Eva; Otterbein, Leo; Chandra, Divay; Bhargava, Arpit; Pilewski, Joseph M; Roodman, G David; Sciurba, Frank C; Duncan, Steven R
Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders. To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers. Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays. Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7-5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7-13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively). Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of
Pradat, Pierre-Francois; Bruneteau, Gaelle; Gordon, Paul H; Dupuis, Luc; Bonnefont-Rousselot, Dominique; Simon, Dominique; Salachas, Francois; Corcia, Philippe; Frochot, Vincent; Lacorte, Jean-Marc; Jardel, Claude; Coussieu, Christiane; Le Forestier, Nadine; Lacomblez, Lucette; Loeffler, Jean-Philippe; Meininger, Vincent
Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.
Giugliano, D; Quatraro, A; Consoli, G; Stante, A; Simeone, V; Ceriello, A; Paolisso, G; Torella, R
Plasma glucose, insulin, C-peptide, glucagon and growth hormone responses to intravenous glucose were evaluated in 10 heroin addicts in the basal state and during an infusion of sodium salicylate, an inhibitor of endogenous prostaglandin synthesis. Ten normal subjects, matched for age, sex and weight served as controls. In the basal state, the heroin addicts had markedly reduced insulin responses to intravenous glucose and low glucose disappearance rates (p less than 0.01 vs controls). The infusion of sodium salicylate caused a striking increase of the acute insulin response to intravenous glucose (from 14.5 +/- 4 microU/ml to 88 +/- 11 microU/ml, p less than 0.001) and restored to normal the reduced glucose tolerance (KG from 1.10 +/- 0.1% min-1 to 2.04 +/- 0.19% min-1). Hypoglycemic values were found in all addicts at the end of the test during salicylate infusion. Indomethacin pretreatment in five additional addicts also caused normalization of the impaired insulin responses to the intravenous glucose challenge and restored to normal the reduced glucose disappearance rate. Plasma glucagon and growth hormone levels were normally suppressed by glucose in addicts in basal conditions; sodium salicylate infusion completely overturned these hormonal responses which became positive in the first 15 min following the glucose challenge. These results demonstrate that the two prostaglandin synthesis inhibitors can restore the impaired B-cell response to glucose in heroin addicts to normal, indicating that this response is not lost but is inhibited by heroin itself or by other substances, perhaps by the endogenous prostaglandins.
Ettinger, Adrienne S.; Zota, Ami R.; Amarasiriwardena, Chitra J.; Hopkins, Marianne R.; Schwartz, Joel; Hu, Howard; Wright, Robert O.
Background Accumulating evidence has shown an increased risk of type 2 diabetes in general populations exposed to arsenic, but little is known about exposures during pregnancy and the association with gestational diabetes (GD). Objectives We studied 532 women living proximate to the Tar Creek Superfund Site to investigate whether arsenic exposure is associated with impaired glucose tolerance during pregnancy. Methods Blood glucose was measured between 24 and 28 weeks gestation after a 1-hr oral glucose tolerance test (GTT) as part of routine prenatal care. Blood and hair were collected at delivery and analyzed for arsenic using inductively coupled plasma mass spectrometry with dynamic reaction cell. Results Arsenic concentrations ranged from 0.2 to 24.1 μg/L (ppb) (mean ± SD, 1.7 ±1.5) and 1.1 to 724.4 ng/g (ppb) (mean ± SD, 27.4 ± 61.6) in blood and hair, respectively. One-hour glucose levels ranged from 40 to 284 mg/dL (mean ± SD, 108.7 ± 29.5); impaired glucose tolerance was observed in 11.9% of women when using standard screening criterion (> 140 mg/dL). Adjusting for age, Native-American race, prepregnancy body mass index, Medicaid use, and marital status, women in the highest quartile of blood arsenic exposure had 2.8 higher odds of impaired GTT than women in the lowest quartile of exposure (95% confidence interval, 1.1–6.9) (p-trend = 0.008). Conclusions Among this population of pregnant women, arsenic exposure was associated with increased risk of impaired GTT at 24–28 weeks gestation and therefore may be associated with increased risk of GD. PMID:19654913
Different levels of thyroid hormones between impaired fasting glucose and impaired glucose tolerance: free T3 affects the prevalence of impaired fasting glucose and impaired glucose tolerance in opposite ways.
Jing, Su; Xiaoying, Ding; Ying, Xu; Rui, Liu; Mingyu, Gu; Yuting, Chen; Yanhua, Yin; Yufan, Wang; Haiyan, Sun; Yongde, Peng
There is an association between thyroid disorders and diabetes mellitus. To investigate thyroid hormone levels in different glucose metabolic statuses, analyse relationships between thyroid hormone levels and different categories of prediabetes and metabolic parameters within a large euthyroid nondiabetic population. A total of 3328 subjects without diabetes or thyroid dysfunction were included in this cross-sectional study. Subjects were divided in to four groups [normal glucose tolerance (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined glucose intolerance (CGI)] according to the results of oral glucose tolerance test. Participants were then divided into four groups according to the quartile of free T3 (FT3) in their blood. Subjects with IFG had higher levels of FT3 and ratio of FT3 to FT4 (FT3/FT4), but lower level of free T4 (FT4) than subjects with IGT. FT3/FT4 was negatively associated with postprandial plasma glucose (PPG) [standardized β (β) = -0·087; P < 0·001]. The prevalence of IFG and CGI was increased with the level of FT3, while the prevalence of IGT was decreased with the level of FT3 (P for trend: <0·001, 0·003 and <0·001, respectively). FT3 was negatively associated with the risk of IGT (OR = 0·409, 95% CI 0·179-0·935), whereas FT4 was positively associated with the risk of IGT (OR = 1·296, 95% CI 1·004-1·673). Free thyroid hormone levels were different between subjects with IFG and IGT. FT3 affects the prevalence of IFG and IGT in opposite ways. The difference in thyroid hormone levels may play an important role in the different pathological mechanisms of IFG and IGT. © 2013 John Wiley & Sons Ltd.
Wickenberg, Jennie; Lindstedt, Sandra; Berntorp, Kerstin; Nilsson, Jan; Hlebowicz, Joanna
Previous studies on healthy subjects have shown that the intake of 6 g Cinnamomum cassia reduces postprandial glucose and that the intake of 3 g C. cassia reduces insulin response, without affecting postprandial glucose concentrations. Coumarin, which may damage the liver, is present in C. cassia, but not in Cinnamomum zeylanicum. The aim of the present study was to study the effect of C. zeylanicum on postprandial concentrations of plasma glucose, insulin, glycaemic index (GI) and insulinaemic index (GII) in subjects with impaired glucose tolerance (IGT). A total of ten subjects with IGT were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with placebo or C. zeylanicum capsules. Finger-prick capillary blood samples were taken for glucose measurements and venous blood for insulin measurements, before and at 15, 30, 45, 60, 90, 120, 150 and 180 min after the start of the OGTT. The ingestion of 6 g C. zeylanicum had no significant effect on glucose level, insulin response, GI or GII. Ingestion of C. zeylanicum does not affect postprandial plasma glucose or insulin levels in human subjects. The Federal Institute for Risk Assessment in Europe has suggested the replacement of C. cassia by C. zeylanicum or the use of aqueous extracts of C. cassia to lower coumarin exposure. However, the positive effects seen with C. cassia in subjects with poor glycaemic control would then be lost.
Sargin, Mehmet; Ikiişik, Murat; Sargin, Haluk; Orçun, Asuman; Kaya, Müjgan; Gözü, Hülya; Dabak, Reşat; Bayramiçli, Oya Uygur; Yayla, Ali
Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk groups for type 2 diabetes. Type 2 diabetes is characterized by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycemia may differ due to heterogeneity of the disease. Combined glucose intolerance (CGI), on the other hand, seems to represent a more advanced stage of prediabetes that bears a distinctly higher risk of progression to diabetes and its comorbidities. This study has the aim to compare isolated IFG and CGI categories with respect to the degree of early phase insulin secretion abnormalities and insulin resistance. Subjects who had IFG (fasting glucose: 110-126 mg/dl) were included in the study. A 75-g oral glucose tolerance test (OGTT) with insulin response was done and subjects were classified according to the WHO criteria. Six subjects were excluded because they had diabetic glucose tolerance. A total of 66 patients (53.4 +/- 11.1 years, female/male: 48/18) were divided into two groups according to their glucose tolerance in OGGT (Group 1: isolated IFG and group 2: CGI). Early phase insulin secretion was measured by intravenous glucose tolerance test (IVGTT) and OGTT. Insulin resistance was assessed by the R value of the homeostasis model assessment (HOMA). We did not find any statistically significant difference between groups according to age, gender, body mass index (BMI), fasting glucose, fasting insulin, insulin-AUC (0-180 min) and HOMA-R values. In OGGT there was no statistically significant difference between 0', 30', 60' and 90' insulin levels of the groups; only 120' and 180' insulin levels were higher in CGI than in IFG group (p<0.05). In IVGTT, there was no statistically significant difference between glucose levels of the groups. Furthermore, insulin response to intravenous glucose was higher in IFG than in CGI (p<0.05). Our data demonstrate that isolated IFG and CGI are similar with respect to
Leiherer, Andreas; Muendlein, Axel; Saely, Christoph H.; Kinz, Elena; Brandtner, Eva M.; Fraunberger, Peter; Drexel, Heinz
Abstract Uromodulin is the most abundant urine protein under physiological conditions. It has recently been described as a serum and plasma marker for kidney disease. Whether uromodulin is associated with impaired glucose metabolism is unknown. We therefore measured serum uromodulin and glucose traits in a cohort of 529 consecutively recruited patients. Serum uromodulin was significantly and inversely correlated with fasting plasma glucose (r = −0.161; P < 0.001), with plasma glucose 2 hours after an oral 75 g glucose challenge (r = −0.158; P = 0.001), and with HbA1c (r = −0.103; P = 0.018). A total of 146 (27.6%) of our patients had type 2 diabetes mellitus (T2DM). Analysis of covariance confirmed that T2DM was an independent determinant of serum uromodulin (F = 5.5, P = 0.020) after multivariate adjustment including hypertension and glomerular filtration rate. Prospectively, uromodulin was lowest in patients with T2DM at baseline, higher in initially nondiabetic subjects who developed diabetes during follow-up (FU) and highest among nondiabetic patients (147.7 ± 69.9 vs 164 ± 67 vs 179.9 ± 82.2 ng/mL, Ptrend < 0.001). Similar results were seen with respect to prediabetes (168.0 ± 81.2 vs 172.8 ± 66.3 vs 188.2 ± 74.0 ng/mL, P = 0.011). We conclude that serum uromodulin is significantly associated with impaired glucose metabolism and the development of prediabetes and diabetes. PMID:28151855
Leppänen, Olli V.; Sievänen, Harri; Jokihaara, Jarkko; Pajamäki, Ilari; Kannus, Pekka; Järvinen, Teppo L. N.
Background According to prevailing understanding, skeletal mechano-responsiveness declines with age and this apparent failure of the mechano-sensory feedback system has been attributed to the gradual bone loss with aging (age-related osteoporosis). The objective of this study was to evaluate whether the capacity of senescent skeleton to respond to increased loading is indeed reduced as compared to young mature skeleton. Methods and Findings 108 male and 101 female rats were randomly assigned into Exercise and Control groups. Exercise groups were subjected to treadmill training either at peak bone mass between 47–61 weeks of age (Mature) or at senescence between 75–102 weeks of age (Senescent). After the training intervention, femoral necks and diaphysis were evaluated with peripheral quantitative computed tomography (pQCT) and mechanical testing; the proximal tibia was assessed with microcomputed tomography (μCT). The μCT analysis revealed that the senescent bone tissue was structurally deteriorated compared to the mature bone tissue, confirming the existence of age-related osteoporosis. As regards the mechano-responsiveness, the used loading resulted in only marginal increases in the bones of the mature animals, while significant exercise-induced increases were observed virtually in all bone traits among the senescent rats. Conclusion The bones of senescent rats displayed a clear ability to respond to an exercise regimen that failed to initiate an adaptive response in mature animals. Thus, our observations suggest that the pathogenesis of age-related osteoporosis is not attributable to impaired mechano-responsiveness of aging skeleton. It also seems that strengthening of even senescent bones is possible – naturally provided that safe and efficient training methods can be developed for the oldest old. PMID:18648530
de Abreu, L; Holloway, Kara L; Kotowicz, Mark A; Pasco, Julie A
Diabetes mellitus is a growing health problem worldwide. This study aimed to describe dysglycaemia and determine the impact of body composition and clinical and lifestyle factors on the risk of progression or regression from impaired fasting glucose (IFG) to diabetes or normoglycaemia in Australian women. This study included 1167 women, aged 20-94 years, enrolled in the Geelong Osteoporosis Study. Multivariable logistic regression was used to identify predictors for progression to diabetes or regression to normoglycaemia (from IFG), over 10 years of follow-up. At baseline the proportion of women with IFG was 33.8% and 6.5% had diabetes. Those with fasting dysglycaemia had higher obesity-related factors, lower serum HDL cholesterol, and lower physical activity. Over a decade, the incidence of progression from IFG to diabetes was 18.1 per 1,000 person-years (95% CI, 10.7-28.2). Fasting plasma glucose and serum triglycerides were important factors in both progression to diabetes and regression to normoglycaemia. Our results show a transitional process; those with IFG had risk factors intermediate to normoglycaemics and those with diabetes. This investigation may help target interventions to those with IFG at high risk of progression to diabetes and thereby prevent cases of diabetes.
Stuart, Charles A.; Ross, Ian R.; Howell, Mary E. A.; McCurry, Melanie P.; Wood, Thomas G.; Ceci, Jeffrey D.; Kennel, Stephen J.; Wall, Jonathan
Mouse brain expresses three principle glucose transporters. Glut1 is an endothelial marker and is the principal glucose transporter of the blood-brain barrier. Glut3 and Glut6 are expressed in glial cells and neural cells. A mouse line with a null allele for Glut3 has been developed. The Glut3−/− genotype is intrauterine lethal by seven days post-coitis, but the heterozygous (Glut3+/−) littermate survives, exhibiting rapid post-natal weight gain, but no seizures or other behavioral aberrations. At twelve weeks of age, brain uptake of tail vein-injected 3H-2-deoxy glucose in Glut3+/− mice was not different from Glut3+/+ littermates, despite 50% less Glut3 protein expression in the brain. The brain uptake of injected 18F-2-fluoro-2-deoxy glucose was similarly not different from Glut3+/− littermates in the total amount, time course, or brain imaging in the Glut3+/− mice. Glut1 and Glut6 protein expressions evaluated by immunoblots were not affected by the diminished Glut3 expression in the Glut3+/− mice. We conclude that a 50% decrease in Glut3 is not limiting for the uptake of glucose into the mouse brain, since Glut3 haploinsufficiency does not impair brain glucose uptake or utilization. PMID:21316350
Eun, Young-Mi; Kang, Sung-Goo; Song, Sang-Wook
Prediabetes is associated with an increased risk of cardiovascular disease (CVD). While the association of impaired glucose tolerance with CVD has been shown in many studies, the relationship between impaired fasting glucose (IFG) and CVD remains unclear. The purpose of this study was to compare the coronary artery calcium (CAC) scores of participants with normal fasting glucose versus those with IFG, according to fasting plasma glucose (FPG) levels, and to assess whether differences in CAC scores were independent of important confounders. Retrospective study. Health Promotion Center of the University Hospital (Gyeonggi-do, South Korea), during the period 2010-2014. Participants were enrolled from the general population who visited for a medical check-up. CAC was assessed in asymptomatic individuals by multidetector computed tomography. Anthropometric parameters and metabolic profiles were also recorded. Subjects were divided into four fasting glucose groups. Participants with a history of CVD or diabetes mellitus were excluded. Correlation between FPG and CAC scores, CAC score categories, and association between CAC score and FPG categories. Of 1112 participants, 346 (34.2%) had a CAC score > 0. FPG values in the IFG patients were positively but weakly correlated with CAC scores (r=0.099, P=.001). The incidence of CAC differed according to FPG level (P < .001) and in Kruskal-Wallis test the mean CAC score differed by FPG group (P < .001). After adjustment for other factors in a multiple logistic regression analysis, those subjects with FPG >=110 mg/dL had a significantly higher risk of CAC than did subjects with normal fasting glucose (110.
Wu, Jin-Shang; Yang, Yi-Ching; Lin, Thy-Sheng; Huang, Ying-Hsiang; Chen, Jia-Jin; Lu, Feng-Hwa; Wu, Chih-Hsing; Chang, Chih-Jen
Autonomic dysfunction is present in diabetes mellitus (DM), but no study is available on alteration in cardiac autonomic function (CAF) across different glycemic statuses including normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM. Our objective was to examine whether CAF is altered in subjects with IGT and isolated IFG. The study was a stratified systematic cluster sampling design within the general community. A total of 1440 subjects were classified as NGT (n = 983), isolated IFG (n = 163), IGT (n = 188), and DM (n = 106). CAF was determined by 1) standard deviation of normal-to-normal (SDNN) or RR interval, power spectrum in low and high frequency (LF, 0.04-0.15 Hz; HF, 0.15-0.40 Hz), and LF/HF ratio in supine position for 5 min; 2) ratio between 30th and 15th RR interval after standing from supine position (30/15 ratio); and 3) average heart rate change during breathing of six deep breaths for 1 min (HR(DB)). Univariate analysis showed significant differences in SDNN, 30/15 ratio, HR(DB), HF power, and LF/HF ratio among subjects with NGT, isolated IFG, IGT, and DM. In multivariate analysis, none of the indices of CAF was related to isolated IFG in the reference group of NGT. IGT and DM were negatively associated with 30/15 ratio and HF power but positively associated with LF/HF ratio. In addition, DM was also related to a lower SDNN. DM and IGT subjects had an impaired CAF independent of other cardiovascular risk factors. The risk of altered CAF is not apparent in subjects with isolated IFG.
Coate, Katie C; Kraft, Guillaume; Shiota, Masakazu; Smith, Marta S; Farmer, Ben; Neal, Doss W; Williams, Phil; Cherrington, Alan D; Moore, Mary Courtney
Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of ≈25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n = 6) or excessive (Hkcal; n = 7) amounts for 4 wk (cumulative weight gain 0.0 ± 0.3 and 1.5 ± 0.5 kg, respectively, P < 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4× basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg·kg(-1)·min(-1) plus Pe glucose for the final 90 min (P2). NHGU was blunted (P < 0.05) in Hkcal during both periods (mg·kg(-1)·min(-1); P1: 1.7 ± 0.2 vs. 0.3 ± 0.4; P2: 3.6 ± 0.3 vs. 2.3 ± 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P < 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P < 0.05), with a 91% increase in glycogen phosphorylase activity (P < 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism. Copyright © 2015 the American Physiological Society.
Bouchard, Luigi; Thibault, Stéphanie; Guay, Simon-Pierre; Santure, Marta; Monpetit, Alexandre; St-Pierre, Julie; Perron, Patrice; Brisson, Diane
OBJECTIVE To verify whether the leptin gene epigenetic (DNA methylation) profile is altered in the offspring of mothers with gestational impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS Placental tissues and maternal and cord blood samples were obtained from 48 women at term including 23 subjects with gestational IGT. Leptin DNA methylation, gene expression levels, and circulating concentration were measured using the Sequenom EpiTYPER system, quantitative real-time RT-PCR, and enzyme-linked immunosorbent assay, respectively. IGT was assessed after a 75-g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation. RESULTS We have shown that placental leptin gene DNA methylation levels were correlated with glucose levels (2-h post-OGTT) in women with IGT (fetal side: ρ = −0.44, P ≤ 0.05; maternal side: ρ = 0.53, P ≤ 0.01) and with decreased leptin gene expression (n = 48; ρ ≥ −0.30, P ≤ 0.05) in the whole cohort. Placental leptin mRNA levels accounted for 16% of the variance in maternal circulating leptin concentration (P < 0.05). CONCLUSIONS IGT during pregnancy was associated with leptin gene DNA methylation adaptations with potential functional impacts. These epigenetic changes provide novel mechanisms that could contribute to explaining the detrimental health effects associated with fetal programming, such as long-term increased risk of developing obesity and type 2 diabetes. PMID:20724651
Menini, Stefano; Iacobini, Carla; Blasetti Fantauzzi, Claudia; Pesce, Carlo M.; Pugliese, Giuseppe
Galectin-3 is an important modulator of several biological functions. It has been implicated in numerous disease conditions, particularly in the long-term complications of diabetes because of its ability to bind the advanced glycation/lipoxidation end products that accumulate in target organs and exert their toxic effects by triggering proinflammatory and prooxidant pathways. Recent evidence suggests that galectin-3 may also participate in the development of obesity and type 2 diabetes. It has been shown that galectin-3 levels are higher in obese and diabetic individuals and parallel deterioration of glucose homeostasis. Two studies in galectin-3 knockout mice fed a high-fat diet (HFD) have shown increased adiposity and adipose tissue and systemic inflammation associated with altered glucose homeostasis, suggesting that galectin-3 negatively modulates the responsiveness of innate and adaptive immunity to overnutrition. However, these studies have also shown that impaired glucose homeostasis occurs in galectin-3 knockout animals independently of obesity. Moreover, another study reported decreased weight and fat mass in HFD-fed galectin-3 knockout mice. In vitro, galectin-3 was found to stimulate differentiation of preadipocytes into mature adipocytes. Altogether, these data indicate that galectin-3 deserves further attention in order to clarify its role as a potential player and therapeutic target in obesity and type 2 diabetes. PMID:26770660
Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases. PMID:21261970
Huang, Danshan; Dhawan, Tania; Young, Stephen; Yong, William H; Boros, Laszlo G; Heaney, Anthony P
Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases.
Amadid, Hanan; Johansen, Nanna B; Bjerregaard, Anne-Louise; Vistisen, Dorte; Færch, Kristine; Brage, Søren; Lauritzen, Torsten; Witte, Daniel R; Sandbæk, Annelli; Jørgensen, Marit E
Physical activity (PA) is important in the prevention of type 2 diabetes, yet little is known about the role of specific dimensions of PA, including sedentary time in subgroups at risk of impaired glucose metabolism (IGM). We applied a data driven decision tool to identify dimensions of PA associated with IGM across age, sex and body mass index (BMI) groups. This cross-sectional study included 1,501 individuals (mean (SD) age 65.6 (6.8) years) at high risk of type 2 diabetes from the ADDITION-PRO study. PA was measured by an individually calibrated combined accelerometer and heart rate monitor worn for 7 days. PA energy expenditure, time spent in different activity intensities, bout duration and sedentary time were considered determinants of IGM together with age, sex and BMI. Decision tree analysis was applied to identify subgroup-specific dimensions of PA associated with IGM. IGM was based on oral glucose tolerance test results and defined as fasting plasma glucose ≥ 6.1 mmol/L and/or 2-hour plasma glucose ≥ 7.8 mmol/L. Among overweight (BMI ≥ 25kg/m) men, accumulating less than 30 minutes/day of moderate-to-vigorous PA was associated with IGM, while in overweight women sedentary time was associated with IGM. Among individuals aged > 53 years with normal weight (BMI < 25kg/m), time spent in light PA was associated with IGM. None of the dimensions of PA were associated with IGM among individuals aged ≤ 53 years with normal weight. We identified subgroups in which different activity dimensions were associated with IGM. Methodology and results from this study may suggest a preliminary step towards the goal of tailoring and targeting PA interventions aimed at type 2 diabetes prevention.
Kashiwagi, Aki; Fein, Mikaela J; Shimada, Masako
The ubiquitously expressed Calpains 1 and 2 belong to a family of calcium-dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large subunit and a small regulatory subunit encoded by the gene Capns1. To investigate a role for the calpain small subunit in cells of the osteoblast lineage in vivo, we previously generated osteoblast-specific Capns1 knockout mice and characterized their bone phenotype. In this study, we further examined effects of low calcium and high fat diets on their bone, fat, and glucose homeostasis. Osteoblast-specific Capns1 knockout mice showed significantly reduced serum levels of total and uncarboxylated osteocalcin, and this was presumably due to their impaired bone formation and bone resorption. The reduced bone resorptive function of the mutant mice was also significant under a low calcium diet. Thus, these results suggest that reduced uncarboxylated osteocalcin levels of mutant mice were, at least in part, due to their osteoporotic bone with impaired bone resorptive function. Interestingly, unlike osteocalcin knockout mice, mutant mice on a normal chow diet were leaner than control littermates; this was likely due to their reduced food intake and overall lower energy homeostasis. To test this hypothesis, we next provided mutant mice with a high fat diet and further examined an effect of their reduced uncarboxylated osteocalcin levels on body composition and glucose metabolism. The average mean body weight of mutant mice became indistinguishable with that of controls after 2 weeks on a high fat diet, and continued to show an upward trend, at least, up to 6weeks. Moreover, mutant mice on a high fat diet exhibited a significant increase in serum levels of leptin and resistin, adipocyte-specific adipokines, and developed impaired glucose tolerance. Collectively, mice with osteoporosis and reduced bone resorptive function showed reduced serum uncarboxylated osteocalcin levels and were susceptible to
Goossens, Gijs H; Moors, Chantalle C M; Jocken, Johan W E; van der Zijl, Nynke J; Jans, Anneke; Konings, Ellen; Diamant, Michaela; Blaak, Ellen E
Altered skeletal muscle fatty acid (FA) metabolism contributes to insulin resistance. Here, we compared skeletal muscle FA handling between subjects with impaired fasting glucose (IFG; n = 12 (7 males)) and impaired glucose tolerance (IGT; n = 14 (7 males)) by measuring arterio-venous concentration differences across forearm muscle. [²H₂]-palmitate was infused intravenously, labeling circulating endogenous triacylglycerol (TAG) and free fatty acids (FFA), whereas [U-(13)C]-palmitate was incorporated in a high-fat mixed-meal, labeling chylomicron-TAG. Skeletal muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid content, their fractional synthetic rate (FSR) and degree of saturation, and gene expression. Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. Net skeletal muscle glucose uptake was lower (p = 0.018) and peripheral insulin sensitivity tended to be reduced (p = 0.064) in IGT as compared to IFG subjects. Furthermore, IGT showed higher skeletal muscle extraction of VLDL-TAG (p = 0.043), higher muscle TAG content (p = 0.025), higher saturation of FFA (p = 0.004), lower saturation of TAG (p = 0.017) and a tendency towards a lower TAG FSR (p = 0.073) and a lower saturation of DAG (p = 0.059) versus IFG individuals. Muscle oxidative gene expression was lower in IGT subjects. In conclusion, increased liver-derived TAG extraction and reduced lipid turnover of saturated FA, rather than DAG content, in skeletal muscle accompany the more pronounced insulin resistance in IGT versus IFG subjects.
Goossens, Gijs H.; Moors, Chantalle C. M.; Jocken, Johan W. E.; van der Zijl, Nynke J.; Jans, Anneke; Konings, Ellen; Diamant, Michaela; Blaak, Ellen E.
Altered skeletal muscle fatty acid (FA) metabolism contributes to insulin resistance. Here, we compared skeletal muscle FA handling between subjects with impaired fasting glucose (IFG; n = 12 (7 males)) and impaired glucose tolerance (IGT; n = 14 (7 males)) by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously, labeling circulating endogenous triacylglycerol (TAG) and free fatty acids (FFA), whereas [U-13C]-palmitate was incorporated in a high-fat mixed-meal, labeling chylomicron-TAG. Skeletal muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid content, their fractional synthetic rate (FSR) and degree of saturation, and gene expression. Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. Net skeletal muscle glucose uptake was lower (p = 0.018) and peripheral insulin sensitivity tended to be reduced (p = 0.064) in IGT as compared to IFG subjects. Furthermore, IGT showed higher skeletal muscle extraction of VLDL-TAG (p = 0.043), higher muscle TAG content (p = 0.025), higher saturation of FFA (p = 0.004), lower saturation of TAG (p = 0.017) and a tendency towards a lower TAG FSR (p = 0.073) and a lower saturation of DAG (p = 0.059) versus IFG individuals. Muscle oxidative gene expression was lower in IGT subjects. In conclusion, increased liver-derived TAG extraction and reduced lipid turnover of saturated FA, rather than DAG content, in skeletal muscle accompany the more pronounced insulin resistance in IGT versus IFG subjects. PMID:26985905
Guerrero-Romero, Fernando; Violante, Rafael; Rodríguez-Morán, Martha
Published data on the distribution of fasting plasma glucose (FPG) in children are scarce. We therefore set out to examine the distribution of FPG and determine the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes (T2-DM) in Mexican children aged 6-18 years in a community-based cross-sectional study. A total of 1534 apparently healthy children were randomly enrolled and underwent an oral glucose tolerance test. IFG was defined by an FPG value between >or=100 and <126 mg/dL, IGT by glucose concentration 2-h post-load between >or=140 and <200 mg/dL, and T2-DM by glucose concentration 2-h post-load >or=200 mg/dL. The FPG level at the 75(th) percentile of distribution was 98.0, 100.0 and 99.0 mg/dL for children aged 6-9, 10-14 and 15-18 years, respectively; the 95(th) percentile of FPG was greater than 100 mg/dL for all the age strata. In the population overall, the prevalences of IFG, IGT, and T2-DM were 18.3%, 5.2% and 0.6%, respectively. Among obese children and adolescents, the prevalences of IFG, IGT, IFG + IGT and T2-DM were 19.1%, 5.7%, 2.5% and 1.3%. Our study shows a high prevalence of prediabetes and is the first that reports the distribution of FPG in Mexican children and adolescents.
Simental-Mendía, Luis E; Rodríguez-Morán, Martha; Guerrero-Romero, Fernando
The objective of this study was to determine if hypertriglyceridemia is associated with isolated impaired glucose tolerance in subjects without insulin resistance. A total of 365 apparently healthy individuals aged 20-65 years were enrolled in a population-based cross-sectional study. Subjects were allocated into the groups with and without hypertriglyceridemia. Age, gender, body mass index, and waist circumference were matched criteria. Individuals with impaired fasting glucose, impaired fasting glucose+impaired glucose tolerance, diabetes, homeostasis model assessment of insulin resistance index ≥ 2.5, and/or chronic illnesses such as renal disease or malignancy were excluded. Hypertriglyceridemia was defined by triglycerides levels ≥ 150 mg/dL. Impaired glucose tolerance was defined by plasma glucose concentration 2-h post-load glucose ≥ 140 mg/dL <200 mg/dL. Subjects with impaired glucose tolerance were required to have fasting plasma glucose levels <100 mg/dL. Logistic regression analysis was used to compute the odds ratio between hypertriglyceridemia (independent variable) and impaired glucose tolerance (dependent variable). A total of 132 and 233 subjects were allocated into the groups with and without hypertriglyceridemia, respectively. The frequency of impaired glucose tolerance was 13.6% and 5.6% in the individuals with and without hypertriglyceridemia, p = 0.01. The logistic regression analysis adjusted by gender, blood pressure, and high-density lipoprotein cholesterol showed that hypertriglyceridemia is significantly associated with impaired glucose tolerance (OR 2.34; 95% CI: 1.02-5.32, p = 0.04). Results of this study indicate that hypertriglyceridemia is independently associated with isolated impaired glucose tolerance in subjects without insulin resistance.
Hanley, Anthony J.; Zinman, Bernard; Sheridan, Patrick; Yusuf, Salim; Gerstein, Hertzel C.
OBJECTIVE The objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed β-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals. RESEARCH DESIGN AND METHODS The present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. β-Cell function was assessed using the fasting proinsulin–to–C-peptide ratio (PI/C) and the insulinogenic index (defined as 30–0 min insulin/30–0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]). RESULTS Subjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (−0.010 vs. −0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and −0.007 vs. −0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: −0.003 vs. −0.001, P = 0.07). CONCLUSIONS Treatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of β-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was
Holloway, Kara L; De Abreu, Lelia L F; Hans, Didier; Kotowicz, Mark A; Sajjad, Muhammad A; Hyde, Natalie K; Pasco, Julie A
Diabetes is associated with increased skeletal fragility, despite higher bone mineral density (BMD). Alternative measures are necessary to more accurately determine fracture risk in individuals with diabetes. Therefore, we aimed to describe the relationship between trabecular bone score (TBS) and normoglycaemia, impaired fasting glucose (IFG) and diabetes and determine whether TBS-adjusted FRAX (Aus) score differed between these groups. This study included 555 men (68.7 ± 12.2 years) and 514 women (62.0 ± 12.0 years), enrolled in the observational Geelong Osteoporosis Study. IFG was considered as fasting plasma glucose (FPG) ≥ 5.5 mmol/L and diabetes as FPG ≥ 7.0 mmol/L, with the use of antihyperglycaemic medication and/or self-report. Using multivariable regression, the relationship between groups and TBS was determined. Men and women (all ages) with diabetes had lower mean TBS compared to those with normoglycaemia, in models adjusted for age, height and weight/waist circumference (all p < 0.05). Men with IFG had lower mean TBS in the age-adjusted models only (all p < 0.05). The addition of TBS to the FRAX score improved the discrimination between glycaemia groups, particularly for younger women (< 65 years). There was no difference in TBS detected between normoglycaemia and IFG; however, those with diabetes had lower TBS. Thus, the increased fracture risk in men and women with diabetes may be a result of BMD-independent bone deterioration. TBS adjustment of FRAX scores may be useful for younger women (< 65 years) with diabetes. This suggests that halting or reversing progression from IFG to diabetes could be important to prevent skeletal fragility in diabetes.
Zilliox, Lindsay A.; Ruby, Sandra K.; Singh, Sujal; Zhan, Min; Russell, James W.
AIMS Disagreement exists on effective and sensitive outcome measures in neuropathy associated with impaired glucose tolerance (IGT). Nerve conduction studies and skin biopsies are costly, invasive and may have their problems with reproducibility and clinical applicability. A clinical measure of neuropathy that has sufficient sensitivity and correlates to invasive measures would enable significant future research. METHODS Data was collected prospectively on patients with IGT and symptomatic early neuropathy (neuropathy symptoms < 2 years) and normal controls. The seven scales that were examined were the Neuropathy Impairment Score of the Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), modified Toronto Clinical Neuropathy Scale (mTCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), the Early Neuropathy Score (ENS), and the Neuropathy Disability Score (NDS). RESULTS All seven clinical scales were determined to be excellent in discriminating between patients with neuropathy from controls without neuropathy. The strongest discrimination was seen with the mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc. Most scales show a stronger correlation with measures of large than small fiber neuropathy. CONCULSIONS All seven scales identify patients with neuropathy. For the purpose of screening potential patients for a clinical study, the mTCNS followed by the TNSc would be most helpful to select patients with neuropathy. PMID:25690405
Cali, Anna M G; Pierpont, Bridget M; Taksali, Sara E; Allen, Karin; Shaw, Melissa M; Savoye, Mary; Caprio, Sonia
Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor β-cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and β-cell function. In a small randomized, double-blind, placebo (PLA)-controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z-score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z-score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, magnetic resonance imaging, and (1)H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short-term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and β-cell function, two principal pathophysiological abnormalities of IGT.
Smith, A Gordon
Idiopathic neuropathy is one of the most common clinical problems encountered in general medical and neurological practices, accounting for up to 40% of all neuropathies in referral series. Several groups have reported an elevated prevalence of impaired glucose tolerance (IGT) in idiopathic neuropathy subjects, although the only carefully conducted case-control study suggested hypertriglyceridemia was a more important risk factor. The nature of the relationship between IGT and neuropathy is a subject of active debate. An evolving literature suggests metabolic syndrome, particularly dyslipidemia and obesity, are potent neuropathy risk factors for both idiopathic and diabetic neuropathy patients. Once established, diabetic neuropathy is likely to be very difficult to reverse. IGT-associated neuropathy, however, may be more amenable to therapy and could represent an ideal population in which to examine potential therapies for diabetes and obesity related neuropathies. Further research is needed to better define the epidemiological relation between IGT, metabolic syndrome, and neuropathy, its underlying pathophysiology, and to develop appropriate surrogate measures and clinical trials strategies.
Djelti, Fathia; Dhenain, Marc; Terrien, Jérémy; Picq, Jean-Luc; Hardy, Isabelle; Champeval, Delphine; Perret, Martine; Schenker, Esther; Epelbaum, Jacques; Aujard, Fabienne
Age-associated cognitive impairment is a major health and social issue because of increasing aged population. Cognitive decline is not homogeneous in humans and the determinants leading to differences between subjects are not fully understood. In middle-aged healthy humans, fasting blood glucose levels in the upper normal range are associated with memory impairment and cerebral atrophy. Due to a close evolutional similarity to Man, non-human primates may be useful to investigate the relationships between glucose homeostasis, cognitive deficits and structural brain alterations. In the grey mouse lemur, Microcebus murinus, spatial memory deficits have been associated with age and cerebral atrophy but the origin of these alterations have not been clearly identified. Herein, we showed that, on 28 female grey mouse lemurs (age range 2.4-6.1 years-old), age correlated with impaired fasting blood glucose (rs=0.37) but not with impaired glucose tolerance or insulin resistance. In middle-aged animals (4.1-6.1 years-old), fasting blood glucose was inversely and closely linked with spatial memory performance (rs=0.56) and hippocampus (rs=−0.62) or septum (rs=−0.55) volumes. These findings corroborate observations in humans and further support the grey mouse lemur as a natural model to unravel mechanisms which link impaired glucose homeostasis, brain atrophy and cognitive processes. PMID:28039490
Ling, Zhaoli; Shu, Nan; Xu, Ping; Wang, Fan; Zhong, Zeyu; Sun, Binbin; Li, Feng; Zhang, Mian; Zhao, Kaijing; Tang, Xiange; Wang, Zhongjian; Zhu, Liang; Liu, Li; Liu, Xiaodong
Accumulating evidences demonstrated that statins impaired glucose utilization. This study was aimed to investigate whether PXR was involved in the atorvastatin-impaired glucose utilization. Rifampicin/PCN served as PXR activator control. Glucose utilization, glucose uptake, protein levels of GLUT2, GCK, PDK2, PEPCK1 and G6Pase in HepG2 cells were measured. PXR inhibitors, PXR overexpression and PXR siRNA were applied to verify the role of PXR in atorvastatin-impaired glucose utilization in cells. Hypercholesterolemia rats induced by high fat diet feeding, orally received atorvastatin (5 and 10 mg/kg), pravastatin (10 mg/kg) for 14 days, or intraperitoneally received PCN (35 mg/kg) for 4 days. Results showed that glucose utilization was markedly inhibited by atorvastatin, simvastatin, pitavastatin, lovastatin and rifampicin. Neither rosuvastatin nor pravastatin showed the similar effect. Atorvastatin and pravastatin were selected for the following study. Atorvastatin and rifampicin significantly inhibited glucose uptake and down-regulated GLUT2 and GCK expressions. Similarly, overexpressed PXR significantly down-regulated GLUT2 and GCK expressions and impaired glucose utilization. Ketoconazole and resveratrol attenuated the impaired glucose utilization by atorvastatin and rifampicin in both parental and overexpressed PXR cells. PXR knockdown significantly up-regulated GLUT2 and GCK proteins and abolished the decreased glucose consumption and uptake by atorvastatin and rifampicin. Animal experiments showed that atorvastatin and PCN significantly elicited postprandial hyperglycemia, leading to increase in glucose AUC. Expressions of GLUT2 and GCK in rat livers were markedly down-regulated by atorvastatin and PCN. In conclusion, atorvastatin impaired glucose utilization in hepatocytes via repressing GLUT2 and GCK expressions, which may be partly due to PXR activation.
D'Amelio, Patrizia; Sassi, Francesca; Buondonno, Ilaria; Spertino, Elena; Tamone, Cristina; Piano, Simonetta; Zugna, Daniela; Richiardi, Lorenzo; Isaia, Giovanni Carlo
We investigated the effect of bone turnover on glucose homeostasis, fat distribution and adipokine production during anabolic treatment with PTH. This is a parallel, randomized controlled, open label, trial. The randomization was done by computer generated tables to allocate treatments. Forty-six postmenopausal osteoporotic non-diabetic women were assigned to treatment with calcium and colecalcipherol with (24) or without (22) PTH 1-84. Patients were recalled after 3, 6, 12 and 18 months of treatment and markers of bone turnover, glucose metabolism, adipokine secretion and fat distribution were analyzed. Markers of bone turnover and adipokines were measured by ELISA. Glucose metabolism was evaluated by an oral glucose load test and insulin resistance and secretion were calculated. Fat and lean mass were evaluated by anthropometric measures. The effect of treatment on measured variables was analyzed by repeated measure test, and its effect on glucose was also evaluated by mediation analysis after correction for possible confounders. Twenty patients in the calcium and vitamin D groups and 19 in the group treated with PTH 1-84 completed the study. There were no significance adverse events. Treatment with PTH increases osteocalcin, both total (OC) and undercarboxylated (uOC), and decreases blood glucose, without influence on insulin secretion, resistance and pancreatic β cell function. Treatment with PTH does not influence fat distribution and adipokine production. The results of the mediation analyses suggest a total effect of PTH on blood glucose, moderately mediated by OC and to a less extent by uOC. Here we suggest that treatment with PTH influences glucose metabolism partially through its effect on bone turnover, without influence on insulin secretion, resistance, pancreatic β cell function and fat mass. Copyright © 2015 Elsevier Inc. All rights reserved.
Mensink, M; Feskens, E J M; Kruijshoop, M; de Bruin, T W A; Saris, W H M; Blaak, E E
To assess whether adding anthropometric measurements to an oral glucose tolerance test (OGTT) can help to distinguish between transient and persistent impaired glucose tolerance (IGT). From the SLIM project (Study on Lifestyle-Intervention and IGT Maastricht), a study designed to evaluate whether diet and physical activity intervention can improve glucose tolerance in subjects at risk for diabetes, 108 subjects with IGT underwent a repeated OGTT 2-4 months after the initial OGTT. Following the second test, subjects were classified as transient IGT, or persistent IGT. Anthropometric measurements, including body mass index, waist and hip circumference, sagittal and transverse abdominal diameters and skinfold thickness measurements, were done during the second OGTT. Persistent IGT was diagnosed in 47 subjects (44%), transient IGT in 40 (37%), impaired fasting glucose in eight subjects (7%), and diabetes in 13 cases (12%). Two-hour blood glucose levels at the initial OGTT and subscapular skinfold thickness were significantly higher in subjects with persistent IGT (2-h blood glucose 9.8+/-0.1 mmol/l vs. 10.2+/-0.1 mmol/l for transient IGT and persistent IGT, respectively; subscapular skinfold thickness 25.4+/-1.4 mm vs. 29.8+/-1.2 mm for transient IGT and persistent IGT, respectively). After adjustment for age, sex and family history of diabetes mellitus, logistic regression indicated that 2-h blood glucose level during the initial OGTT represented the strongest predictor of persistent IGT (P<0.02), followed by subscapular skinfold thickness (P<0.05). After adjustment for 2-h blood glucose levels during the first OGTT, subscapular skinfold thickness remained significantly associated with persistent IGT (odds ratio 1.84; P<0.05). In addition to the 2-h blood glucose level, subscapular skinfold thickness was the best predictor of persistent IGT, suggesting that adding simple anthropometric measures to oral glucose tolerance testing may improve the distinction between
Petzinger, R. A.
This article describes devices that people with visual impairments and diabetes can use to monitor blood glucose levels and measure insulin. A table lists devices, their manufacturers (including address and telephone number), and comments about the devices. (DB)
Petzinger, R. A.
This article describes devices that people with visual impairments and diabetes can use to monitor blood glucose levels and measure insulin. A table lists devices, their manufacturers (including address and telephone number), and comments about the devices. (DB)
Serum high-molecular weight adiponectin decreases abruptly after an oral glucose load in subjects with normal glucose tolerance or impaired fasting glucose, but not those with impaired glucose tolerance or diabetes mellitus.
Ozeki, Noriyuki; Hara, Kenji; Yatsuka, Chikako; Nakano, Tomoki; Matsumoto, Sachiko; Suetsugu, Mariko; Nakamachi, Takafumi; Takebayashi, Kohzo; Inukai, Toshihiko; Haruki, Kohsuke; Aso, Yoshimasa
Adiponectin exists in the blood as 3 forms, which are a trimer, a hexamer, and a high-molecular weight (HMW) form. We investigated whether circulating HMW adiponectin levels were altered by oral glucose or fat ingestion. Forty male subjects underwent a 75-g oral glucose loading test (OGTT), and 11 healthy subjects (5 women and 6 men) received a fat loading test. Serum levels of HMW and total adiponectin were measured during the OGTT and the fat loading test. The fat loading test was performed for at least 8 hours. Among the 40 male subjects, 11 had normal glucose tolerance (NGT), 9 had impaired fasting glucose (IFG), 11 had impaired glucose tolerance, and 9 had diabetes mellitus (DM). In all 40 subjects, the serum total adiponectin level did not change significantly, whereas serum HMW adiponectin decreased significantly after a glucose load and reached 92.2% of the basal level at 120 minutes after the OGTT (P < .01). The HMW to total adiponectin ratio decreased significantly from 0.47 +/- 0.15 at baseline to 0.43 +/- 0.13 at 120 minutes after a glucose load (P < .05). Serum HMW adiponectin measured at 120 minutes after the OGTT decreased significantly to 86.0% and 85.6% of the basal level in subjects with NGT or IFG, respectively (both P < .01). In subjects with impaired glucose tolerance or DM, however, serum HMW adiponectin did not change. The area under the curve for insulin at 30 minutes after a glucose load during the OGTT was significantly larger in subjects with NGT or IFG than in those with DM (P < .05). In addition, the insulinogenic index (DeltaI(0-30)/DeltaG(0-30)) was significantly higher in subjects with NGT or IFG than in those with DM (P < .001). Percentage changes in serum HMW adiponectin of the baseline at 120 minutes correlated negatively with those in serum insulin (r = -0.468, P = .0023), but not plasma glucose, of the baseline at 30 minutes in 40 subjects. On the other hand, serum triglycerides increased significantly after an oral fat load in
Borel, A L; Nazare, J A; Smith, J; Aschner, P; Barter, P; Van Gaal, L; Eng Tan, C; Wittchen, H U; Matsuzawa, Y; Kadowaki, T; Ross, R; Brulle-Wohlhueter, C; Alméras, N; Haffner, S M; Balkau, B; Després, J P
To examine the specific distribution of liver fat content, visceral and subcutaneous adiposity in normal glucose tolerance (NGT/NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined conditions (IFG+IGT), as well as with newly diagnosed type 2 diabetes (nT2D). Multicenter, international observational study: cross-sectional analysis. Two thousand five hundred and fifteen patients (50.0% women, 54.5% non-Caucasian) without previously known diabetes were recruited from 29 countries. Abdominal fat distribution was measured by computed tomography (CT). Liver fat was estimated using the CT-liver mean attenuation. Compared with NGT/NGT patients, increased visceral adiposity was found in iIFG, iIGT, IFG+IGT and nT2D; estimated liver fat progressively increased across these conditions. A one-s.d. increase in visceral adiposity was associated with an increased risk of having iIFG (men: odds ratio (OR) 1.41 (95% confidence interval (CI) 1.15-1.74), women: OR 1.62 (1.29-2.04)), iIGT (men: OR 1.59 (1.15-2.01), women: OR 1.30 (0.96-1.76)), IFG+IGT (men: OR 1.64 (1.27-2.13), women: OR 1.83 (1.36-2.48)) and nT2D (men: OR 1.80 (1.35-2.42), women: OR 1.73 (1.25-2.41)). A one-s.d. increase in estimated liver fat was associated with iIGT (men: OR 1.46 (1.12-1.90), women: OR 1.81 (1.41-2.35)), IFG+IGT (men: OR 1.42 (1.14-1.77), women: OR 1.74 (1.35-2.26)) and nT2D (men: OR 1.77 (1.40-2.27), women: OR 2.38 (1.81-3.18)). Subcutaneous abdominal adipose tissue showed an inverse relationship with nT2D in women (OR 0.63 (0.45-0.88)). Liver fat was associated with iIGT but not with iIFG, whereas visceral adiposity was associated with both. Liver fat and visceral adiposity were associated with nT2D, whereas subcutaneous adiposity showed an inverse relationship with nT2D in women.
Traub, Michael L; Jain, Akas; Maslow, Bat-Sheva; Pal, Lubna; Stein, Daniel T; Santoro, Nanette; Freeman, Ruth
The aim of this study was to compare the effectiveness of the "muffin test" (MT) with that of the oral glucose tolerance test (OGTT) in diagnosing impaired glucose tolerance (IGT). This is a cross-sectional study in a single academic institution. The participants were 73 women aged 42 to 58 years, less than 36 months after menopause, recruited for the Kronos Early Estrogen Prevention Study Trial. After a 10-hour fasting blood draw, the participants were provided a muffin and a beverage. Two-hour glucose levels were assessed. A subset underwent metabolic testing consisting of an OGTT (n = 12) and a mixed-meal tolerance test (n = 10). The main outcome measures were the prevalence of IGT and 2-hour glucose measurements after each testing method. Two-hour glucose levels were linearly related to fasting values by multivariable linear regression. This association was exaggerated in overweight (body mass index, 25 kg/m2) women (coefficient, 1.43; P < 0.001). Two-hour OGTT and MT glucose levels were comparable (P > 0.05); 2-hour glucose levels after OGTT were slightly lower than after the mixed-meal tolerance test (P < 0.05). The prevalence of IGT was 11% (8 of 73). Fasting plasma glucose alone would have missed 63% of cases (five of eight cases). The MT demonstrated 100% sensitivity and specificity for diagnosing IGT compared with the gold standard OGTT. This small pilot study should be confirmed in a larger prospective group of participants.
Bi, Mingxin; Niu, Yucun; Li, Xue; Li, Ying; Sun, Changhao
To investigate the effects of barley flake (BF) on the glucose-lipid metabolism in patients with impaired fasting glucose (IFG). 100 patients with IFG were divided into the oat meal (OM) control group and barley flake experimental group for three months intervention according to randomized controlled trail (RCT). Biochemical indicators, glucose-lipid metabolism related enzymes, the area under curve (AUC) of blood glucose and insulin after oral glucose tolerance test (OGTT) were assessed before and after intervention. In addition, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by FBG (mmol/L) x INS (microU/L)/ 22.5. At the end of the three month active intervention, the mean fasting blood glucose (FBG) and insulin (INS) in the patients with BF treatment decreased by 9.26% (P < 0.001) and 13.37% (P = 0.001) separately compared with that in patients with OM treatment; meanwhile, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in patients with BF treatment also decreased by 7.20% (P < 0.001) and 9.42% (P = 0. 002), respectively. Glycosylated hemoglobin (HbA1c), HOMA-IR, total glyceride (TG), Apo-B, the AUC of blood glucose and insulin after OGTT were also significantly decreased separately (P < 0.01 or < 0.05 ). However, statistically significant differences failed to be found in HDL-C, Apo-A, ALP and SOD between these two groups. BF had favorable effect on improvement of glucose-lipid metabolism in the patients with impaired fasting glucose.
Grandone, A; Amato, A; Luongo, C; Santoro, N; Perrone, L; del Giudice, E Miraglia
The natural history of impaired glucose tolerance (IGT) and Type 2 diabetes among obese children is not clear. Although the cut-off for impaired fasting glucose (IFG) has recently been changed from 110 (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), it does not seem a reliable way to find all subjects with impaired glucose homeostasis. The aim of our study was to determine whether high-normal fasting glucose level could predict the occurrence of IGT and metabolic syndrome. Three hundred and twenty-three Italian obese children and adolescents were included in the study (176 females, mean age 11+/-2.9 yr; mean body mass index z-score: 3+/-0.6). Waist circumference, serum glucose, insulin, triglyceride, cholesterol HDL, blood pressure were evaluated and an oral glucose tolerance test (OGTT) was performed. The prevalence of IFG and IGT were respectively 1.5% (5 subjects) and 5% (18 patients); no diabetic patients were found. Metabolic syndrome was diagnosed in 20% of patients. Fasting glycemia values <100 mg/dl (5.6 mmol/l) have been divided in quintiles. Metabolic syndrome prevalence increased across quintiles, although not in a statistically significantly manner, but it could depend on the selected diagnostic criteria as no univocal definition exists for metabolic syndrome in youths. Interestingly high-normal fasting plasma glucose levels constitute an independent risk factor for IGT among obese children and adolescents; therefore, this very easy-to-use parameter may help to identify obese patients at increased risk of diabetes or at least could suggest in which subjects to perform an OGTT.
Rysä, J; Buler, M; Savolainen, M J; Ruskoaho, H; Hakkola, J; Hukkanen, J
We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.
Morris, Ken A; Chang, Qing; Mohler, Eric G; Gold, Paul E
Increases in blood glucose levels are an important component of the mechanisms by which epinephrine enhances memory formation. The present experiments addressed the hypothesis that a dysfunction in the blood glucose response to circulating epinephrine contributes to age-related memory impairments. Doses of epinephrine and glucagon that significantly increased blood glucose levels in young adult rats were far less effective at doing so in 2-year-old rats. In young rats, epinephrine and glucose were about equally effective in enhancing memory and in prolonging post-training release of acetylcholine in the hippocampus. However, glucose was more effective than epinephrine in enhancing both memory and acetylcholine release in aged rats. These results suggest that an uncoupling between circulating epinephrine and glucose levels in old rats may lead to an age-related reduction in the provision of glucose to the brain during training. This in turn may contribute to age-related changes in memory and neural plasticity.
Baker, Arthur M; Haeri, Sina
Our objective was to identify potentially modifiable risk factors and outcomes for gestational diabetes and impaired glucose tolerance in a contemporary American teen population. We conducted a retrospective cohort analysis of all teenage deliveries (≤18 years old) at one institution over a 4-year period with documented oral glucose tolerance testing. All cases of gestational diabetes and impaired glucose tolerance were identified using the Carpenter and Coustan diagnostic criteria and compared with teenage mothers with normal glucose tolerance testing. Of the 670 included teen deliveries, 668 were either African American or Hispanic/Latino; 31 (5%) were diagnosed with gestational diabetes (n = 5) or impaired glucose tolerance (n = 26). Higher maternal prepregnancy body mass index (34.3 ± 7.8 vs 30.3 ± 6.4, p = 0.001) and morbid obesity (body mass index ≥ 35 kg/m(2) , RR 2.0, 95% CI 1.1-3.6) were associated with gestational diabetes and impaired glucose tolerance. There was no association with weight gain above the Institute of Medicine recommended levels (RR 1.6, 95% CI 0.77-3.4). On postpregnancy follow up, three of the five (60%) teens with gestational diabetes and none of the 26 (0%) teens with impaired glucose tolerance were diagnosed with diabetes mellitus. Higher prepregnancy body mass index, especially morbid obesity, places the gravid teen at higher risk for development of gestational diabetes and impaired glucose tolerance in pregnancy. The potentially modifiable nature of these risk factors coupled with the emerging teen obesity epidemic underscores the need for increased public health focus on this problem. Copyright © 2012 John Wiley & Sons, Ltd.
Satin, Leslie S.; Butler, Peter C.; Ha, Joon; Sherman, Arthur S.
Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM. PMID:25637831
Baker, Nicki A.; English, Victoria; Sunkara, Manjula; Morris, Andrew J.; Pearson, Kevin J.; Cassis, Lisa A.
Resveratrol (RSV) is a plant polyphenol that exhibits several favorable effects on glucose homeostasis in adipocytes. Recent studies from our laboratory demonstrated that coplanar polychlorinated biphenyls (PCBs) that are ligands of the aryl hydrocarbon receptor (AhR) impair glucose homeostasis in mice. PCB-induced impairment of glucose homeostasis was associated with augmented expression of inflammatory cytokines in adipose tissue, a site for accumulation of lipophilic PCBs. This study determined if RSV protects against PCB-77 induced impairment of glucose disposal in vitro and in vivo, and if these beneficial effects are associated with enhanced nuclear factor erythoid 2-related factor 2 (Nrf2) signaling in adipose tissue. PCB-77 increased oxidative stress and abolished insulin stimulated 2-deoxy-D-glucose (2DG) uptake in 3T3-L1 adipocytes. These effects were restored by RSV, which resulted in a concentration-dependent increase in NAD(P)H:quinone oxidoreductase 1 (NQO1), the downstream target of Nrf2 signaling. We quantified glucose and insulin tolerance and components of Nrf2 and insulin signaling cascades in adipose tissue of male C57BL/6 mice administered vehicle or PCB-77 (50 mg/kg) and fed a diet with or without resVida® (0.1%, or 160 mg/kg/day). PCB-77 impaired glucose and insulin tolerance, and these effects were reversed by RSV. PCB-77 induced reductions in insulin signaling in adipose tissue were also abolished by RSV, which increased NQO1 expression. These results demonstrate that coplanar PCB-induced impairment of glucose homeostasis in mice can be prevented by RSV, potentially through stimulation of Nrf2 signaling and enhanced insulin stimulated glucose disposal in adipose tissue. PMID:24231106
Unger, Roger H.
Glucose uptake into pancreatic β cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal β-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of β cells to hyperglycemia may improve the management and prevention of diabetes.
OGAWA, SOSUKE; MATSUMAE, TOMOYUKI; KATAOKA, TAKESHI; YAZAKI, YOSHIKAZU; YAMAGUCHI, HIDEYO
Numerous in vitro and animal studies, as well as clinical trials have indicated that plant-derived polyphenols exert beneficial effects on glucose intolerance or type 2 diabetes. This clinical study aimed to investigate the effects of acacia polyphenol (AP) on glucose and insulin responses to an oral glucose tolerance test (OGTT) in non-diabetic subjects with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled trial was conducted in a total of 34 enrolled subjects. The subjects were randomly assigned to the AP-containing dietary supplement (AP supplement; in a daily dose of 250 mg as AP; n=17) or placebo (n=17) and the intervention was continued for 8 weeks. Prior to the start of the intervention (baseline) and after 4 and 8 weeks of intervention, plasma glucose and insulin were measured during a two-hour OGTT. Compared with the baseline, plasma glucose and insulin levels at 90 and/or 120 min, as well as the total area under the curve values during the OGTT (AUC0→2h) for glucose and insulin, were significantly reduced in the AP group, but not in the placebo group after intervention for 8 weeks. The decline from baseline in plasma glucose and insulin at 90 or 120 min of the OGTT for the AP group was significantly greater compared with that of the placebo group after 8 weeks of intervention. No AP supplement-related adverse side-effects nor any abnormal changes in routine laboratory tests and anthropometric parameters were observed throughout the study period. The AP supplement may have the potential to improve glucose homeostasis in subjects with IGT. PMID:23837032
Miyake, Teruki; Kumagi, Teru; Furukawa, Shinya; Hirooka, Masashi; Kawasaki, Keitarou; Koizumi, Mitsuhito; Todo, Yasuhiko; Yamamoto, Shin; Abe, Masanori; Kitai, Kohichiro; Matsuura, Bunzo; Hiasa, Yoichi
Background It is not clear whether elevated uric acid is a risk factor for the onset of impaired fasting glucose after stratifying by baseline fasting plasma glucose levels. We conducted a community-based retrospective longitudinal cohort study to clarify the relationship between uric acid levels and the onset of impaired fasting glucose, according to baseline fasting plasma glucose levels. Methods We enrolled 6,403 persons (3,194 men and 3,209 women), each of whom was 18–80 years old and had >2 annual check-ups during 2003–2010. After excluding persons who had fasting plasma glucose levels ≥6.11 mM and/or were currently taking anti-diabetic agents, the remaining 5,924 subjects were classified into quartiles according to baseline fasting plasma glucose levels. The onset of impaired fasting glucose was defined as fasting plasma glucose ≥6.11 mM during the observation period. Results In the quartile groups, 0.9%, 2.1%, 3.4%, and 20.2% of the men developed impaired fasting glucose, respectively, and 0.1%, 0.3%, 0.5%, and 5.6% of the women developed impaired fasting glucose, respectively (P trend <0.001). After adjusting for age, body mass index, systolic blood pressure, triacylglycerols, high density lipoprotein-cholesterol, creatinine, fatty liver, family history of diabetes, alcohol consumption, and current smoking, uric acid levels were positively associated with onset of impaired fasting glucose in men with highest-quartile fasting plasma glucose levels (adjusted hazard ratio, 1.003; 95% confidence interval, 1.0001–1.005, P = 0.041). Conclusions Among men with high fasting plasma glucose, hyperuricemia may be independently associated with an elevated risk of developing impaired fasting glucose. PMID:25237894
Jarrett, Catherine L; Ahmed, Zoha; Faust, James J; Sweazea, Karen L
Normal avian plasma glucose levels are 1.5-2 times greater than mammals of similar size. In mammals, hyperglycemia induces oxidative stress and impaired endothelium-dependent vasodilation. Prior work has shown that mourning doves have high levels of antioxidants and isolated vessels have low endogenous oxidative stress. Therefore, the hypothesis was that endothelium-dependent vasodilation of isolated avian arteries would not be impaired following acute exposure to high glucose. Isolated small resistance cranial tibial arteries (c. tibial) were cannulated and pressurized in a vessel chamber then incubated with either normal or high glucose (20mM vs. 30mM) for 1h at 41°C. Vessels were then pre-constricted to 50% of resting inner diameter with phenylephrine (PE) followed by increasing doses of acetylcholine (ACh; 10(-9) to 10(-5)M, 5min per step). Percent vasodilation was measured by tracking the inner diameter with edge-detection software. Contrary to our hypothesis, ACh-induced vasodilation was impaired with acute exposure to high glucose (p=0.013). The impairment was not related to increased osmolarity since vasodilation of arteries exposed to an equimolar combination of 20mM d-glucose and 10mM l-glucose was not different from controls (p=0.273). Rather, the impaired vasodilation was attributed to oxidative stress since superoxide levels were elevated 168±42% (p=0.02) and pre-exposure of arteries to the superoxide dismutase mimetic tiron (10mM) improved vasodilation (p<0.05). Therefore, isolated arteries from doves do not have endogenous mechanisms to prevent impaired vasodilation resulting from high glucose-mediated increases in oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.
Chen, Xiaoqiang; Fang, Yapeng; Nishinari, Katsuyoshi; We, Heng; Sun, Chaochao; Li, Jianrong; Jiang, Yongwen
Hot-water extracts were prepared from fresh tea leaves and fractionated by DEAE-cellulose DE-52 column chromatography to yield one unexplored polysaccharide-conjugate fraction TPC-L (tea polysaccharide conjugates). Chemical components, molecular weight and its distribution, water vapor sorption properties, zeta potentials and optical characteristics of TPC-L were investigated. As compared with injured cell group, the two dosages of TPC-L (150 and 300 μg/mL) were discovered to possess remarkably protective effect on human umbilical vein endothelial cells against impairments induced by high glucose in a dose-dependent manner (p < 0.05, p < 0.001, respectively). Compared with group NC (normal control), the ingestion of 40 mg/kg of TPC-L could significantly reduce blood glucose levels of normal mice ingesting starch, and significant difference of AUC (area under the curve of blood glucose) and ΔAUC (p < 0.05, p < 0.01) at the postprandial time point of 0.5 and 1.0 h were observed. The three dosages of TPC-L (10, 40 and 160 mg/kg) did not significantly lower postprandial blood glucose levels of normal mice ingesting glucose. TPC-L could improve starch tolerance to prevent impaired glucose tolerance (IGT) from developing into diabetes as well as protective effects on HUVE cells against impairments induced by high glucose It was suggested that TPC-L improved IGT through its capability of inhibition on digestive enzymes.
Marini, Maria Adelaide; Fiorentino, Teresa Vanessa; Andreozzi, Francesco; Mannino, Gaia Chiara; Perticone, Maria; Sciacqua, Angela; Perticone, Francesco; Sesti, Giorgio
It has been suggested that glucose levels ≥155 mg/dl at 1-h during an oral glucose tolerance test (OGTT) may predict development of type 2 diabetes and cardiovascular events among adults with normal glucose tolerance (NGT 1 h-high). Studies showed a link between increased blood viscosity and type 2 diabetes. However, whether blood viscosity is associated with dysglycemic conditions such as NGT 1 h-high, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) is unsettled. 1723 non-diabetic adults underwent biochemical evaluation and OGTT. A validated formula based on hematocrit and total plasma proteins was employed to estimate whole blood viscosity. Subjects were categorized into NGT with 1 h glucose <155 mg/dL (NGT-1 h-low), NGT-1 h-high, IFG and/or IGT. Hematocrit and blood viscosity values appeared significantly higher in individuals with NGT 1 h-high, IFG and/or IGT as compared to NGT 1 h-low subjects. Blood viscosity was significantly correlated with age, waist circumference, blood pressure, HbA1c, fasting, 1- and 2-h post-challenge insulin levels, total cholesterol and low-density lipoprotein, triglycerides, fibrinogen, white blood cell, and inversely correlated with high-density lipoprotein and insulin sensitivity. Of the four glycemic parameters, 1-h post-challenge glucose showed the strongest correlation with blood viscosity (β = 0.158, P < 0.0001) in a multivariate regression analysis model including several atherosclerosis risk factors. Our results demonstrate a positive relationship between blood viscosity and 1-h post-challenge plasma glucose. They also suggest that a subgroup of NGT individuals with 1-h post-challenge plasma >155 mg/dl have increased blood viscosity comparable to that observed in subjects with IFG and/or IGT.
Bielohuby, Maximilian; Sisley, Stephanie; Sandoval, Darleen; Herbach, Nadja; Zengin, Ayse; Fischereder, Michael; Menhofer, Dominik; Stoehr, Barbara J M; Stemmer, Kerstin; Wanke, Rüdiger; Tschöp, Matthias H; Seeley, Randy J; Bidlingmaier, Martin
Moderate low-carbohydrate/high-fat (LC-HF) diets are widely used to induce weight loss in overweight subjects, whereas extreme ketogenic LC-HF diets are used to treat neurological disorders like pediatric epilepsy. Usage of LC-HF diets for improvement of glucose metabolism is highly controversial; some studies suggest that LC-HF diets ameliorate glucose tolerance, whereas other investigations could not identify positive effects of these diets or reported impaired insulin sensitivity. Here, we investigate the effects of LC-HF diets on glucose and insulin metabolism in a well-characterized animal model. Male rats were fed isoenergetic or hypocaloric amounts of standard control diet, a high-protein "Atkins-style" LC-HF diet, or a low-protein, ketogenic, LC-HF diet. Both LC-HF diets induced lower fasting glucose and insulin levels associated with lower pancreatic β-cell volumes. However, dynamic challenge tests (oral and intraperitoneal glucose tolerance tests, insulin-tolerance tests, and hyperinsulinemic euglycemic clamps) revealed that LC-HF pair-fed rats exhibited impaired glucose tolerance and impaired hepatic and peripheral tissue insulin sensitivity, the latter potentially being mediated by elevated intramyocellular lipids. Adjusting visceral fat mass in LC-HF groups to that of controls by reducing the intake of LC-HF diets to 80% of the pair-fed groups did not prevent glucose intolerance. Taken together, these data show that lack of dietary carbohydrates leads to glucose intolerance and insulin resistance in rats despite causing a reduction in fasting glucose and insulin concentrations. Our results argue against a beneficial effect of LC-HF diets on glucose and insulin metabolism, at least under physiological conditions. Therefore, use of LC-HF diets for weight loss or other therapeutic purposes should be balanced against potentially harmful metabolic side effects.
Kanaya, Alka M; Herrington, David; Vittinghoff, Eric; Lin, Feng; Bittner, Vera; Cauley, Jane A; Hulley, Stephen; Barrett-Connor, Elizabeth
Type 2 diabetes increases risk for cardiovascular disease. Persons with impaired fasting glucose levels may also have increased risk. To evaluate the association between glucose status and cardiovascular outcomes and the effect of lowering the fasting glucose level criterion for impaired fasting glucose from a lower limit of 6.1 mmol/L (110 mg/dL) to 5.6 mmol/L (100 mg/dL). Prospective cohort study. 20 U.S. clinical centers. 2763 postmenopausal women with established coronary heart disease (CHD) who were followed for 6.8 years. Any CHD event (nonfatal myocardial infarction or CHD death), stroke or transient ischemic attack (TIA), congestive heart failure (CHF) hospitalization, and any cardiovascular event. During follow-up, 583 women had a CHD event, 329 women had a stroke or TIA, and 348 women were hospitalized for CHF. Women with diabetes were at an approximately 75% increased risk for each outcome compared with normoglycemic women. The 218 women with impaired fasting glucose according to the 1997 definition (fasting glucose level, 6.1 to 6.9 mmol/L [110 to 125 mg/dL]) had increased risk for any CHD event (hazard ratio, 1.37 [95% CI, 1.08 to 1.74]), while the 698 women with impaired fasting glucose according to the 2003 definition (fasting glucose level, 5.6 to 6.9 mmol/L [100 to 125 mg/dL]) were not at increased risk (hazard ratio, 1.09 [CI, 0.90 to 1.34]). Most of the women (n = 480) with fasting glucose levels between 5.6 mmol/L (100 mg/dL) and 6.0 mmol/L (109 mg/dL) had no increased risk for CHD (hazard ratio, 0.90 [CI, 0.73 to 1.12]). Women with impaired fasting glucose according to either definition were not at increased risk for stroke or TIA or CHF. These findings may not be generalizable to men or women without existing heart disease. Among postmenopausal women with coronary artery disease, the 2003 definition for impaired fasting glucose was not associated with increased risk for new CHD, stroke or TIA, or CHF.
Stage, Tore Bjerregaard; Damkier, Per; Christensen, Mette Marie Hougaard; Nielsen, Lene Buch-Krogh; Højlund, Kurt; Brøsen, Kim
The purpose of this study was to examine whether the over-the-counter herbal medicinal plant St. John's wort affects glucose tolerance in healthy men. To do this, we included 10 healthy men who were examined by a 2-hr oral glucose tolerance test on three occasions: A: baseline; B: after 21 days of treatment with St. John's wort; and C: at least 6 weeks after the last capsule of St. John's wort was ingested. Plasma glucose, serum insulin and C-peptide levels were measured during an oral glucose tolerance test and used for estimation of area under the concentration-time curve (AUC) as well as indices of insulin sensitivity and insulin secretion. We found that treatment with St. John's wort increased total and incremental glucose AUC and 2-hr plasma glucose levels. Surprisingly, this effect was sustained and even further increased 6 weeks after the last capsule of St. John's wort was taken. No effect on indices of insulin sensitivity was seen, but indices of insulin secretion were reduced even after adjustment for insulin sensitivity. In conclusion, this study indicates that long-term treatment with St. John's wort may impair glucose tolerance by reducing insulin secretion in young, healthy men. The unregulated use of this over-the-counter drug might be a risk factor for impaired glucose tolerance and type 2 diabetes.
García-Alcalá, Hector; Genestier-Tamborero, Christelle Nathalie; Hirales-Tamez, Omara; Salinas-Palma, Jorge; Soto-Vega, Elena
Background As a first step in the prevention of diabetes, the International Diabetes Federation recommends identification of persons at risk using the Finnish type 2 Diabetes Risk Assessment (FINDRISC) survey. The frequency of diabetes mellitus, impaired fasting glucose, and glucose intolerance in high-risk groups identified by FINDRISC is unknown in our country. The aim of this study was to determine the frequency of diabetes mellitus, impaired fasting glucose, and glucose intolerance in higher-risk groups using a FINDRISC survey in an urban population. Methods We used a television program to invite interested adults to fill out a survey at a television station. An oral glucose tolerance test was performed in all persons with a FINDRISC score ≥ 15 points (high-risk and very high-risk groups). Patients were classified as normal (fasting glucose < 100 mg/dL and 2-hour glucose < 140 mg/dL), or having impaired fasting glucose (fasting glucose 100–125 mg/dL and 2-hour glucose < 140 mg/dL), glucose intolerance (fasting glucose < 126 mg/dL and 2-hour glucose 140–199 mg/dL), and diabetes mellitus (fasting glucose ≥ 126 mg/dL or 2-hour glucose ≥ 200 mg/dL). We describe the frequency of each diagnostic category in this selected population according to gender and age. Results A total of 186 patients had a score ≥ 15. The frequencies of diabetes mellitus, impaired fasting glucose, glucose intolerance, and normal glucose levels were 28.6%, 25.9%, 29.2%, and 16.2%, respectively. We found a higher frequency of diabetes mellitus and impaired fasting glucose in men than in women (33% versus 27% and 40% versus 21%, respectively) and more glucose intolerance in women than in men (34% versus 16%, P < 0.05). Patients with diabetes mellitus (52.55 ± 9.2 years) were older than those with impaired fasting glucose (46.19 ± 8.89 years), glucose intolerance (46.15 ± 10.9 years), and normal levels (41.9 ± 10.45 years, P < 0.05). We found a higher frequency of diabetes
García-Alcalá, Hector; Genestier-Tamborero, Christelle Nathalie; Hirales-Tamez, Omara; Salinas-Palma, Jorge; Soto-Vega, Elena
As a first step in the prevention of diabetes, the International Diabetes Federation recommends identification of persons at risk using the Finnish type 2 Diabetes Risk Assessment (FINDRISC) survey. The frequency of diabetes mellitus, impaired fasting glucose, and glucose intolerance in high-risk groups identified by FINDRISC is unknown in our country. The aim of this study was to determine the frequency of diabetes mellitus, impaired fasting glucose, and glucose intolerance in higher-risk groups using a FINDRISC survey in an urban population. We used a television program to invite interested adults to fill out a survey at a television station. An oral glucose tolerance test was performed in all persons with a FINDRISC score ≥ 15 points (high-risk and very high-risk groups). Patients were classified as normal (fasting glucose < 100 mg/dL and 2-hour glucose < 140 mg/dL), or having impaired fasting glucose (fasting glucose 100-125 mg/dL and 2-hour glucose < 140 mg/dL), glucose intolerance (fasting glucose < 126 mg/dL and 2-hour glucose 140-199 mg/dL), and diabetes mellitus (fasting glucose ≥ 126 mg/dL or 2-hour glucose ≥ 200 mg/dL). We describe the frequency of each diagnostic category in this selected population according to gender and age. A total of 186 patients had a score ≥ 15. The frequencies of diabetes mellitus, impaired fasting glucose, glucose intolerance, and normal glucose levels were 28.6%, 25.9%, 29.2%, and 16.2%, respectively. We found a higher frequency of diabetes mellitus and impaired fasting glucose in men than in women (33% versus 27% and 40% versus 21%, respectively) and more glucose intolerance in women than in men (34% versus 16%, P < 0.05). Patients with diabetes mellitus (52.55 ± 9.2 years) were older than those with impaired fasting glucose (46.19 ± 8.89 years), glucose intolerance (46.15 ± 10.9 years), and normal levels (41.9 ± 10.45 years, P < 0.05). We found a higher frequency of diabetes mellitus in those aged over 50 years
Bone, Henry G; Lindsay, Robert; McClung, Michael R; Perez, Alfonso T; Raanan, Marsha G; Spanheimer, Robert G
Meta-analyses of clinical studies have suggested an increased incidence of peripheral fractures in postmenopausal women with type 2 diabetes mellitus taking pioglitazone. The mechanism behind this apparent increase is unknown. The objective of the study was to examine the effects of pioglitazone on bone mineral density (BMD) and turnover. Twenty-five sites (in the United States) enrolled participants in this randomized, double-blind, placebo-controlled study. Postmenopausal women (n = 156) with impaired fasting glucose or impaired glucose tolerance participated in the study. The intervention consisted of pioglitazone 30 mg/d (n = 78) or placebo (n = 78), increased to 45 mg/d after 1 month, for 12 months of treatment total, followed by 6 months of washout/follow-up. Percentage changes from baseline to month 12 and from month 12 to month18 in BMD in total proximal femur (primary end point), total body, femoral neck, lumbar spine, and radius were measured. Least squares mean changes from baseline to month 12 in total proximal femur BMD were -0.69% for pioglitazone and -0.14% for placebo (P = .170). No statistically significant between-group differences were observed for any BMD or bone remodeling marker end point. We observed improved glycemic control and insulin sensitivity with pioglitazone treatment. In addition, pioglitazone appeared to increase body fat, which may affect bone density measurements, especially in the lumbar spine. One pioglitazone-treated and three placebo-treated women experienced confirmed fractures. Over 18 months, one pioglitazone-treated (1.3%) and eight placebo-treated women (10.3%) developed overt type 2 diabetes mellitus. The pattern and incidence of adverse events with pioglitazone were consistent with clinical experience with thiazolidinediones. Maximal-dose pioglitazone had no effects on BMD or bone turnover, while improving glycemic control as expected, in postmenopausal women with impaired fasting glucose or impaired glucose tolerance.
Gómez-Díaz, Rita; Aguilar-Salinas, Carlos A; Morán-Villota, Segundo; Barradas-González, Rosalinda; Herrera-Márquez, Rocio; Cruz López, Miguel; Kumate, Jesus; Wacher, Niels H
The aim of this study was to describe the agreement between impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) in children with excess body weight using the original and the revised definitions of IFG. Obese and overweight children aged 4-17 years were included (n = 533). Anthropometric parameters and biochemical tests (fasting and 2-h glucose tests after an oral glucose load [1.75 g/kg]) were performed. Case subjects with a fasting plasma glucose >/=126 mg/dl were excluded. The diagnostic parameters of the original and the revised definitions of IFG for detecting IGT were estimated. The analysis of agreement between these categories was made using the kappa test. The prevalence of IFG increased from 6.2 to 13.3% using the new criteria. The prevalence of IFG became closer to the prevalence of IGT (14.8%). The revised criteria increased the sensitivity from 26.6 to 36.7%. However, the new IFG definition was not useful for identifying IGT cases. Of the 71 case subjects with IFG, only 29 (40.8%) had IGT. In addition, 50 case subjects with IGT (9.4%) and 13 with diabetes (2.4%) had a fasting glycemia <100 mg/dl. A poor agreement was found between the 2003 IFG definition and abnormal 2-h postchallenge plasma glucose (kappa = 0.359). The proportion of false-positive cases increased (36.3-59.1%) under the new definition. The new definition modestly increases the sensitivity of IFG for detecting IGT in children with excess body weight. Despite this, more than one-half of these cases are not detected. In addition, the false-positive rate was increased by 61%.
Kobzar, Gennadi; Mardla, Vilja; Samel, Nigulas
Aspirin treatment reduces cardiovascular events and deaths in high-risk non-diabetic patients, but not in patients suffering from diabetes. In these patients, hyperglycemia has been found to cause reduced platelet sensitivity to aspirin. It is supposed that long-term exposure of platelets to glucose leads to non-enzymatic glycosylation and impairs aspirin inhibition of platelet aggregation. On the other hand, short-term exposure of platelets to glucose also attenuates the effect of aspirin on platelets. The aim of the present work was to analyse the effect of short-term exposure of glucose on the inhibition of platelet aggregation by aspirin and other cyclooxygenase (COX) inhibitors. Already a 15 min exposure of platelets to glucose impaired aspirin inhibition of the platelet aggregation induced by collagen, thrombin, adenosine diphosphate (ADP), and arachidonic acid (AA). Aspirin inhibition of platelet aggregation in platelet-rich plasma (PRP) was attenuated by 5.6, 11.2, 16.8, and 22.4 mM of glucose in a concentration-dependent way. The same effect was observed with indomethacin and acetaminophen used as cyclooxygenase inhibitors instead of aspirin. N-methyl-L-arginine, an inhibitor of nitric oxide synthase, prevented the effect of glucose on aspirin, indomethacin and acetaminophen inhibition of platelet aggregation. Other monosaccharides, for example fructose and galactose, impaired aspirin inhibition as did glucose. Lactic acid (0.1, 0.2, 0.4, 0.8 mM), the end product of anaerobic glycolysis in platelets, impaired the inhibition of platelet aggregation with aspirin in a concentration-dependent way but did not affect indomethacin. It is suggested that lactic acid might be a mediator of the effect of glucose on aspirin inhibition in platelets.
Taylor, David; Young, Corina; Mohamed, Radia; Paton, Carol; Walwyn, Rebecca
The associations between psychosis, antipsychotic drugs and diabetes mellitus have not been precisely defined but it has been repeatedly suggested that atypical antipsychotics are more likely to give rise to diabetes than are conventional drugs. This belief is largely based on healthcare database analyses which, in part, rely on the assumption that all cases of diabetes are identified in practice. We examined records of 606 hospitalized patients receiving antipsychotic treatment and found an apparent prevalence of diabetes and impaired fasting glucose of 6.4%. From this sample of patients, we investigated 166 patients (fasting blood samples) who were not known to have any disorder of glucose homeostasis and identified 10 cases of impaired fasting glucose and nine cases of diabetes mellitus (11.4% of those tested). Nine of these cases had documented evidence of previous testing for diabetes. Apparent prevalence of diabetes and impaired fasting glucose was 16.9% in those tested in practice or the study. Diagnosis was significantly associated with age [odds ratio (OR) 1.02] and treatment duration with current drug (OR 1.01). Adjusted ORs of diagnosis were not significantly different for any atypical antipsychotic compared with conventional drugs. It is concluded that there was a clinically significant prevalence of undiagnosed diabetes and impaired fasting glucose in those individuals receiving antipsychotics. Importantly, database analyses may underestimate the true prevalence of diabetes in similar populations and erroneously ascribe increased risk to certain drug treatments.
Liang, So-Jung; Liou, Tsan-Hon; Lin, Hui-Wen; Hsu, Chun-Sen; Tzeng, Chii-Ruey; Hsu, Ming-I
To evaluate the contribution to glucose intolerance and metabolic syndrome of obesity combined with the diagnostic criteria of polycystic ovary syndrome (PCOS). Prospective study. University teaching hospital from 31 August 2010 to 31 August 2011. Two hundred and twenty women with PCOS and seventy normal control women. The clinical and biochemical characteristics of women with PCOS and control women were evaluated. Main outcome measures. The impact of obesity, hyperandrogenism, oligo-anovulation and polycystic ovary morphology on impaired glucose tolerance and metabolic disturbances. Obese women with PCOS had significantly higher insulin resistance than obese normal control women. Logistic regression analysis showed that obesity was the only factor that predicted impaired glucose tolerance and metabolic syndrome. Use of the area under the receiver operating characteristic curve (AUROC) for the body mass index to predict impaired glucose tolerance and metabolic syndrome was more accurate than AUROCs for serum total testosterone level and the average menstrual interval. Body weight status was the major factor determining the risk of impaired glucose tolerance and metabolic syndrome in women with PCOS. Obesity should be treated as the major factor determining long-term health consequences associated with PCOS. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.
Li, Xia; Zhu, Ju; Liu, Na; Liu, Jie; Zhang, Zhecheng
Impaired glucose regulation (IGR) is the prestate of diabetes; about 1/3 of IGR patients will develop to diabetes finally. In this study, we investigated the serum tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels in peripheral neuropathy impaired patients with impaired glucose regulation (IGR). A total of 70 IGR patients received the conventional nerve conduction test, including 30 patients with peripheral neuropathy (PN) and 40 patients without peripheral neuropathy (NPN). The other 40 healthy individuals were recruited as controls. The serum TNF-α and IL-6 in IGR patients were higher than in control group, and serum TNF-α and IL-6 levels in IGR-PN group were higher than in IGR-NPN group (27.7 ± 17.8 versus 13.1 ± 6.7 pg/mL and 18.1 ± 17.7 versus 6.4 ± 3.7 pg/mL, resp., both p < 0.05). Multifactors logistic regression analysis showed that TNF-α (OR = 0.893; p = 0.009) was an independent factor affecting whether IGR could combine with peripheral neuropathy. TNF-α and IL-6 could aggregate peripheral neuropathy in impaired glucose regulation patients; TNF-α might be independent risk factor for peripheral neuropathy in glucose regulation impaired patients.
Zhu, Ju; Liu, Na; Liu, Jie
Impaired glucose regulation (IGR) is the prestate of diabetes; about 1/3 of IGR patients will develop to diabetes finally. In this study, we investigated the serum tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels in peripheral neuropathy impaired patients with impaired glucose regulation (IGR). A total of 70 IGR patients received the conventional nerve conduction test, including 30 patients with peripheral neuropathy (PN) and 40 patients without peripheral neuropathy (NPN). The other 40 healthy individuals were recruited as controls. The serum TNF-α and IL-6 in IGR patients were higher than in control group, and serum TNF-α and IL-6 levels in IGR-PN group were higher than in IGR-NPN group (27.7 ± 17.8 versus 13.1 ± 6.7 pg/mL and 18.1 ± 17.7 versus 6.4 ± 3.7 pg/mL, resp., both p < 0.05). Multifactors logistic regression analysis showed that TNF-α (OR = 0.893; p = 0.009) was an independent factor affecting whether IGR could combine with peripheral neuropathy. TNF-α and IL-6 could aggregate peripheral neuropathy in impaired glucose regulation patients; TNF-α might be independent risk factor for peripheral neuropathy in glucose regulation impaired patients. PMID:28251164
Maioli, Mario; Pes, Giovanni Mario; Sanna, Manuela; Cherchi, Sara; Dettori, Mariella; Manca, Elena; Farris, Giovanni Antonio
Sourdough bread has been reported to improve glucose metabolism in healthy subjects. In this study postprandial glycaemic and insulinaemic responses were evaluated in subjects with impaired glucose tolerance (IGT) who had a meal containing sourdough bread leavened with lactobacilli, in comparison to a reference meal containing bread leavened with baker yeast. Sixteen IGT subjects (age range 52-75, average BMI 29.9 +/- 4.2 kg/ m2) were randomly given a meal containing sourdough bread (A) and a meal containing the reference bread (B) in two separate occasions at the beginning of the study and after 7 days. Sourdough bread was leavened for 8 h using a starter containing autochthonous Saccharomyces cerevisiae and several bacilli able to produce a significant amount of D-and L-lactic acid, whereas the reference bread was leavened for 2 h with commercial baker yeast containing Saccharomyces cerevisiae. Plasma glucose and insulin levels were measured at time 0, 30, 60, 120, and 180 min. In IGT subjects sourdough bread induced a significantly lower plasma glucose response at 30 minutes (p = 0.048) and a smaller incremental area under curve (AUC) delta 0-30 and delta 0-60 min (p = 0.020 and 0.018 respectively) in comparison to the bread leavened with baker yeast. Plasma insulin response to this type of bread showed lower values at 30 min (p = 0.045) and a smaller AUC delta 0-30 min (p = 0.018). This study shows that in subjects with IGT glycaemic and insulinaemic responses after the consumption of sourdough bread are lower than after the bread leavened with baker yeast. This effect is likely due to the lactic acid produced during dough leavening as well as the reduced availability of simple carbohydrates. Thus, sour-dough bread may potentially be of benefit in subjects with impaired glucose metabolism.
Udumula, Mary Priyanka; Babu, Mangali Suresh; Bhat, Audesh; Dhar, Indu; Sriram, Dharmarajan; Dhar, Arti
Double stranded RNA (dsRNA) activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase is a key inducer of inflammation, insulin resistance and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of high glucose on cultured rat L6 muscle cells and to investigate whether inhibition of PKR could prevent any deleterious effects of high glucose in these cells. PKR expression was determined by immunofluorescence and immunoblotting. The expression of different insulin signaling gene markers were measured by RT-PCR. Oxidative stress and apoptosis were determined by flow cytometry. High glucose treated L6 muscle cells developed a significant increase in PKR expression. Impaired insulin signaling as well as reduced insulin stimulated glucose uptake was observed in high glucose treated L6 muscle cells. A significant increase in reactive oxygen species generation and apoptosis formation was also observed in high glucose treated cultured L6 muscle cells. All these effects of high glucose were attenuated by a selective PKR inhibitor imoxin. Our study demonstrates PKR may have an additive role against the deleterious effects of high glucose in diabetes. Prevention of PKR activation, by safer and specific inhibitors is a therapeutic option in metabolic disorders that needs to be explored further.
Ionut, Viorica; Castro, Ana Valeria B; Woolcott, Orison O; Stefanovski, Darko; Iyer, Malini S; Broussard, Josiane L; Burch, Miguel; Elazary, Ram; Kolka, Cathryn M; Mkrtchyan, Hasmik; Bediako, Isaac Asare; Bergman, Richard N
The hepatoportal area is an important glucohomeostatic metabolic sensor, sensing hypoglycemia, hyperglycemia, and hormones such as glucagon-like peptide-1 (GLP-1). We have reported previously that activation of hepatoportal sensors by intraportal infusion of glucose and GLP-1 or by subcutaneous administration of GLP-1 receptor activator exenatide and of intraportal glucose improved glycemia independent of corresponding changes in pancreatic hormones. It is not clear whether this effect is mediated via the portal vein (PV) or by direct action on the liver itself. To test whether receptors in the PV mediate exenatide's beneficial effect on glucose tolerance, we performed 1) paired oral glucose tolerance tests (OGTT) with and without exenatide and 2) intravenous glucose tolerance tests before and after PV denervation in canines. Denervation of the portal vein affected oral glucose tolerance; post-denervation (POST-DEN) OGTT glucose and insulin AUC were 50% higher than before denervation (P = 0.01). However, portal denervation did not impair exenatide's effect to improve oral glucose tolerance (exenatide effect: 48 ± 12 mmol·l⁻¹·min before vs. 64 ± 26 mmol·l⁻¹·min after, P = 0.67). There were no changes in insulin sensitivity or secretion during IVGTTs. Portal vein sensing might play a role in controlling oral glucose tolerance during physiological conditions but not in pharmacological activation of GLP-1 receptors by exenatide.
Arora, Nidhi; Papapanou, Panos N.; Rosenbaum, Michael; Jacobs, David R.; Desvarieux, Moïse; Demmer, Ryan T.
Aim We investigated the relationship between periodontal disease, a clinical manifestation of periodontal infection, and prediabetes. Methods The National Health and Nutrition Examination Survey, 2009–2010 enrolled 1,165 diabetes-free adults (51% female) aged 30–80 years (mean ± SD=50±14) who received a full-mouth periodontal examination and an oral glucose tolerance test. Participants were classified as having none/mild, moderate or severe periodontitis and also according to mean probing depth≥2.19 mm or attachment loss≥1.78 mm, (respective 75th percentiles). Pre-diabetes was defined according to ADA criteria as either: i) impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). In multivariable logistic regression models, the odds of IFG and IGT were regressed on levels of periodontitis category. Results The odds ratios and 95% confidence intervals for having IGT among participants with moderate or severe periodontitis, relative to participants with none/mild periodontitis were 1.07[0.50,2.25] and 1.93[1.18,3.17], P=0.02. The ORs for having IFG were 1.14[0.74, 1.77] and 1.12[0.58, 2.18], P =0.84. PD≥75th percentile was related to a 105% increase in the odds of IGT: OR[95%CI] =2.05[1.24, 3.39], P=0.005. Conclusions Periodontal infection was positively associated with prevalent impaired glucose tolerance in a cross-sectional study among a nationally representative sample. PMID:24708451
Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).
Barr, Elizabeth L M; Zimmet, Paul Z; Welborn, Timothy A; Jolley, Damien; Magliano, Dianna J; Dunstan, David W; Cameron, Adrian J; Dwyer, Terry; Taylor, Hugh R; Tonkin, Andrew M; Wong, Tien Y; McNeil, John; Shaw, Jonathan E
Diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. The relationship between milder elevations of blood glucose and mortality is less clear. This study investigated whether impaired fasting glucose and impaired glucose tolerance, as well as diabetes mellitus, increase the risk of all-cause and CVD mortality. In 1999 to 2000, glucose tolerance status was determined in 10,428 participants of the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). After a median follow-up of 5.2 years, 298 deaths occurred (88 CVD deaths). Compared with those with normal glucose tolerance, the adjusted all-cause mortality hazard ratios (HRs) and 95% confidence intervals (CIs) for known diabetes mellitus and newly diagnosed diabetes mellitus were 2.3 (1.6 to 3.2) and 1.3 (0.9 to 2.0), respectively. The risk of death was also increased in those with impaired fasting glucose (HR 1.6, 95% CI 1.0 to 2.4) and impaired glucose tolerance (HR 1.5, 95% CI 1.1 to 2.0). Sixty-five percent of all those who died of CVD had known diabetes mellitus, newly diagnosed diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance at baseline. Known diabetes mellitus (HR 2.6, 95% CI 1.4 to 4.7) and impaired fasting glucose (HR 2.5, 95% CI 1.2 to 5.1) were independent predictors for CVD mortality after adjustment for age, sex, and other traditional CVD risk factors, but impaired glucose tolerance was not (HR 1.2, 95% CI 0.7 to 2.2). This study emphasizes the strong association between abnormal glucose metabolism and mortality, and it suggests that this condition contributes to a large number of CVD deaths in the general population. CVD prevention may be warranted in people with all categories of abnormal glucose metabolism.
van Dam, R M; Dekker, J M; Nijpels, G; Stehouwer, C D A; Bouter, L M; Heine, R J
Coffee contains several substances that may affect glucose metabolism. The aim of this study was to evaluate the relationship between habitual coffee consumption and the incidence of IFG, IGT and type 2 diabetes. We used cross-sectional and prospective data from the population-based Hoorn Study, which included Dutch men and women aged 50-74 years. An OGTT was performed at baseline and after a mean follow-up period of 6.4 years. Associations were adjusted for potential confounders including BMI, cigarette smoking, physical activity, alcohol consumption and dietary factors. At baseline, a 5 cup per day higher coffee consumption was significantly associated with lower fasting insulin concentrations (-5.6%, 95% CI -9.3 to -1.6%) and 2-h glucose concentrations (-8.8%, 95% CI -11.8 to -5.6%), but was not associated with lower fasting glucose concentrations (-0.8%, 95% CI -2.1 to 0.6%). In the prospective analyses, the odds ratio (OR) for IGT was 0.59 (95% CI 0.36-0.97) for 3-4 cups per day, 0.46 (95% CI 0.26-0.81) for 5-6 cups per day, and 0.37 (95% CI 0.16-0.84) for 7 or more cups per day, as compared with the corresponding values for the consumption of 2 or fewer cups of coffee per day (p=0.001 for trend). Higher coffee consumption also tended to be associated with a lower incidence of type 2 diabetes (OR 0.69, CI 0.31-1.51 for >/=7 vs =2 cups per day, p=0.09 for trend), but was not associated with the incidence of IFG (OR 1.35, CI 0.80-2.27 for >/=7 vs =2 cups per day, p=0.49 for trend). Our findings indicate that habitual coffee consumption can reduce the risk of IGT, and affects post-load rather than fasting glucose metabolism.
Robinson, Lindsay E; Savani, Sonali; Battram, Danielle S; McLaren, Drew H; Sathasivam, Premila; Graham, Terry E
Caffeine ingestion negatively affects insulin sensitivity during an oral glucose tolerance test (OGTT) in lean and obese men, but this has not been studied in individuals with type 2 diabetes. We examined the effects of caffeine ingestion on insulin and glucose homeostasis in obese men with type 2 diabetes. Men (n = 12) with type 2 diabetes (age = 49 +/- 2 y, BMI = 32 +/- 1 kg/m(2)) underwent 2 trials, 1 wk apart, in a randomized, double-blind design. Each trial was conducted after withdrawal from caffeine, alcohol, exercise, and oral hypoglycemic agents for 48 h and an overnight fast. Subjects randomly ingested caffeine (5 mg/kg body weight) or placebo capsules and 1 h later began a 3 h 75 g OGTT. Caffeine increased (P < 0.05) serum insulin, proinsulin, and C-peptide concentrations during the OGTT relative to placebo. Insulin area under the curve was 25% greater (P < 0.05) after caffeine than after placebo ingestion. Despite this, blood glucose concentration was also increased (P < 0.01) in the caffeine trial. After caffeine ingestion, blood glucose remained elevated (P < 0.01) at 3 h postglucose load (8.9 +/- 0.7 mmol/L) compared with baseline (6.7 +/- 0.4 mmol/L). The insulin sensitivity index was lower (14%, P = 0.02) after caffeine than after placebo ingestion. Overall, despite elevated and prolonged proinsulin, C-peptide, and insulin responses after caffeine ingestion, blood glucose was also increased, suggesting an acute caffeine-induced impairment in blood glucose management in men with type 2 diabetes.
Kaku, K; Kadowaki, T; Terauchi, Y; Okamoto, T; Sato, A; Okuyama, K; Arjona Ferreira, J C; Goldstein, B J
To evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT). In a double-blind, parallel-group study, 242 Japanese subjects with IGT, determined by a 75-g oral glucose tolerance test (OGTT) at week -1, were randomized (1 : 1 : 1) to placebo (n = 83), sitagliptin 25 mg (n = 82) or 50 mg (n = 77) once daily for 8 weeks. Glycaemic variables were assessed using another OGTT at week 7 and meal tolerance tests (MTTs) at weeks 0 and 8. Primary and secondary endpoints were percent change from baseline in glucose total area under the curve 0-2 h (AUC(0 -2 h)) during the MTT and OGTT, respectively. Least squares mean percent change from baseline in glucose AUC(0 -2 h) during the MTT were -2.4, -9.5 and -11.5%, and during the OGTT were -3.7, -21.4 and -20.1% with placebo, sitagliptin 25 mg once daily, and 50 mg once daily, respectively (p < 0.001 for either sitagliptin dose vs placebo in both tests). Sitagliptin treatment enhanced early insulin response during the OGTT and decreased total insulin response, assessed as the total AUC(0 -2 h) during the MTT. Sitagliptin treatment also suppressed glucagon response during the MTT. The incidence of adverse events, including hypoglycaemia, was low and generally similar in all treatment groups. Treatment with sitagliptin significantly reduced glucose excursions during both an MTT and an OGTT; this effect was associated with an increase in early insulin secretion after oral glucose loading as well as a blunted glucagon response during an MTT. Sitagliptin was generally well tolerated in subjects with IGT. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Lamport, D J; Chadwick, H K; Dye, L; Mansfield, M W; Lawton, C L
There has been no systematic investigation of the individual and combined effects of impaired glucose tolerance (IGT) and obesity on cognitive function in the absence of ageing. The aims were to examine the effects of IGT and increased waist circumference on cognitive function in ostensibly healthy adults, and to investigate whether a low glycaemic load (GL) breakfast can attenuate cognitive impairments in these populations. Sixty five females aged 30-50 years were classified into one of four groups following waist circumference (WC) measurements and an oral glucose tolerance test: NGT/low WC (n = 25), NGT/high WC (n = 22), IGT/low WC (n = 9), IGT/high WC (n = 9). Memory, psychomotor and executive functions were examined 30 and 120 min after consuming low GL, high GL and water breakfasts according to a randomised, crossover, counterbalanced design. IGT was associated with impairment of verbal and spatial memory, and psychomotor function relative to females with NGT, independent of waist circumference. Increased waist circumference was associated with impairment of verbal memory and executive function relative to females with low WC, independent of IGT. Consumption of the LGL breakfast attenuated verbal memory impairment in the IGT/high WC group relative to the HGL breakfast and no energy control. Increased central adiposity and abnormalities in glucose tolerance preceding type 2 diabetes can have demonstrable negative effects on cognitive function, even in ostensibly healthy, middle-aged females. The potential for GL manipulations to modulate glycaemic response and cognitive function in type 2 diabetes and obesity merits further investigation. Copyright © 2014 Elsevier B.V. All rights reserved.
Santana, Marli S; Monteiro, Wuelton M; Costa, Mônica R F; Sampaio, Vanderson S; Brito, Marcelo A M; Lacerda, Marcus V G; Alecrim, Maria G C
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, and it has a significant prevalence in the male population (X chromosome linked). The purpose of this study was to estimate the frequency of impaired fasting glucose and diabetes among G6PD-deficient persons in Manaus, Brazil, an area in the Western Brazilian Amazon to which malaria is endemic. Glucose-6-phosphate dehydrogenase-deficient males had more impaired fasting glucose and diabetes. This feature could be used as a screening tool for G6PD-deficient persons who are unable to use primaquine for the radical cure of Plasmodium vivax malaria.
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Nazarian, Shaban; Peter, John V St; Boston, Raymond C; Jones, Sidney A; Mariash, Cary N
Vitamin D has in vitro and in vivo effects on β-cells and insulin sensitivity. Vitamin D deficiency (VDD) has been associated with onset and progression of type 2 diabetes mellitus (DM-2). However, studies involving supplementation of vitamin D in subjects with previously established diabetes have demonstrated inconsistent effects on insulin sensitivity. The aim of this open-label study was to assess the effects of high dose vitamin D3 supplementation on insulin sensitivity in subjects with VDD and impaired fasting glucose. We studied 8 subjects with VDD and pre-diabetes with the modified frequently sampled intravenous glucose tolerance (mFSIGT) test before and after vitamin D supplementation. Vitamin D3 was administered as 10,000 IU daily for 4 weeks. The mFSIGT was analyzed with MinMod Millennnium to obtain estimates of Acute Insulin Response to Glucose (AIRg), Insulin Sensitivity (SI), and Disposition Index (DI). We found that AIRg decreased (p = 0.011) and insulin sensitivity, expressed as SI, increased (p = 0.012) after a intervention with vitamin D. If these findings are repeated in a randomized, double-blind, sudy the results indicate that orally administered high dose vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose and suggests that high dose vitamin D3 supplementation might provide an inexpensive public health measure in preventing, or at least delaying, the progression from impaired fasting glucose to diabetes. PMID:22005267
Byrne, Heidi K; Kim, Yeonsoo; Hertzler, Steven R; Watt, Celia A; Mattern, Craig O
To compare serum glucose and insulin responses to 3 preexercise snacks before, during, and after exercise in individuals with impaired fasting glucose (IFG) and healthy (H) men. In addition, in an IFG population, the authors sought to determine whether a natural fruit snack (i.e., raisins) yields more desirable glucose and insulin concentrations than an energy bar or a glucose solution. The IFG (n = 11, age = 54.5 ± 1.3 yr, fasting blood glucose [BG] = 6.3 ± 0.1 mmol/L) and H groups (n = 9, age = 48.0 ± 3.1 yr, fasting BG = 4.9 ± 0.1 mmol/L) cycled at 50% of VO2peak for 45 min on 4 occasions after consuming water or 50 g of carbohydrate from raisins (R), an energy bar (EB), or a glucose beverage (GLU). Metabolic markers were measured before, during, and after exercise. In all nutritional conditions, glucose concentrations of the IFG group were consistently higher than in the H group. Differences between IFG and H groups in insulin concentrations were sporadic and isolated. In the IFG group, preexercise glucose concentration was lower in the R condition than in GLU. Ten and 20 min into exercise, glucose concentrations in the R and EB conditions were lower than in GLU. Insulin concentrations were lower in the R condition than in EB and GLU immediately before exercise and at Minute 10 but at 20 min R remained lower than only GLU. Glucose concentrations were higher in the IFG group regardless of preexercise snack. Compared with the glucose solution, raisins lowered both the postprandial glycemic and insulinemic responses, whereas the energy bar reduced glycemia but not insulinemia.
Leiva, E; Mujica, V; Orrego, R; Wehinger, S; Soto, A; Icaza, G; Vásquez, M; Díaz, L; Andrews, M; Arredondo, M
To study the evolution of impaired fasting glucose (IFG), considering glucose and HbA1c levels and risk factors associated, in a period of 6 years. We studied 94 subjects with impaired fasting glucose (IFG) that were diagnosed in 2005 and followed up to 2012. Glucose and HbA1c levels were determined. A descriptive analysis of contingence charts was performed in order to study the evolution in the development of type-2 diabetes mellitus (T2DM). Twenty-eight of ninety-four subjects became T2DM; 51/94 remained with IFG; and 20/94 presented normal fasting glucose. From the 28 diabetic subjects, 9 had already developed diabetes and were under treatment with oral hypoglycemic agents; 5 were diagnosed with plasma glucose < 126 mg/dL, but with HbA1c over 6.5%. In those who developed diabetes, 15/28 had a family history of T2DM in first relative degree. Also, diabetic subjects had a BMI significantly higher than nodiabetics (t test: P < 0.01). The individuals that in 2005 had the highest BMI are those who currently have diabetes. The IFG constitutes a condition of high risk of developing T2DM in a few years, especially over 110 mg/dL and in obesity patients.
Zeidler, A; Tosco, C; Kumar, D; Slavin, B; Parker, J
Basal plasma glucose, glucose tolerance, and insulin secretion were investigated in young and mature athymic nude BALB/c mice and in age-matched controls. Basal plasma glucose levels in male athymic nude mice were similar to those of controls at 1, 3, and 4 wk of age. At 6, 8, and 12 wk of age, male athymic nudes had significantly higher basal plasma glucose levels when compared with controls (P less than 0.01). Plasma immunoreactive insulin concentrations were similar in athymic nudes and controls at 1 wk of age, but at 3 wk of age and subsequently at 6, 8, and 12 wk athymic nude mice had significantly decreased insulin levels when compared with their age-matched controls (P less than 0.05). We found impaired glucose tolerance in male athymic nude mice at all age groups when compared with both female athymic nudes and control BALB/c mice. The discovery of a spontaneous diabetic syndrome (hyperglycemia, impaired glucose tolerance, and decreased insulin secretion) in a colony of athymic nude mice may provide an excellent model for studying the genetics and interactions between the immune and endocrine systems.
Leiva, E.; Mujica, V.; Orrego, R.; Wehinger, S.; Soto, A.; Icaza, G.; Vásquez, M.; Díaz, L.; Andrews, M.; Arredondo, M.
Aim. To study the evolution of impaired fasting glucose (IFG), considering glucose and HbA1c levels and risk factors associated, in a period of 6 years. Methods. We studied 94 subjects with impaired fasting glucose (IFG) that were diagnosed in 2005 and followed up to 2012. Glucose and HbA1c levels were determined. A descriptive analysis of contingence charts was performed in order to study the evolution in the development of type-2 diabetes mellitus (T2DM). Results. Twenty-eight of ninety-four subjects became T2DM; 51/94 remained with IFG; and 20/94 presented normal fasting glucose. From the 28 diabetic subjects, 9 had already developed diabetes and were under treatment with oral hypoglycemic agents; 5 were diagnosed with plasma glucose < 126 mg/dL, but with HbA1c over 6.5%. In those who developed diabetes, 15/28 had a family history of T2DM in first relative degree. Also, diabetic subjects had a BMI significantly higher than nodiabetics (t test: P < 0.01). The individuals that in 2005 had the highest BMI are those who currently have diabetes. Conclusion. The IFG constitutes a condition of high risk of developing T2DM in a few years, especially over 110 mg/dL and in obesity patients. PMID:25215305
Ladeira, Renata Teixeira; Simioni, Ana Cinthia Marques; Bafi, Antonio Tonete; Nascente, Ana Paula Metran; Freitas, Flavio Geraldo Resende; Machado, Flávia Ribeiro
Objective To evaluate the presence of diabetes mellitus and impaired glucose tolerance in intensive care unit inpatients. Methods The study included patients in post-surgical care for elective and emergency surgery and excluded those patients with known diabetes mellitus. To diagnose prior serum glucose level disorders, we considered the value of glycated hemoglobin (HbA1c) at the time of admission, classifying the patients as normal (<5.7%), glucose intolerant (5.7-6.4%) or diabetic (>6.4%). During the first 3 days of the patient's hospital stay, glycemic control and clinical complications were assessed. Mortality was monitored for 28 days. For the statistical analyses, chi-square, ANOVA, student's t, Kruskal-Wallis or Mann Whitney tests were used. Results Thirty patients were included in the present study, 53% of whom were women; the patients had a mean age of 53.4±19.7 years and an APACHE II score of 13.6±6.6. The majority of patients were admitted for severe sepsis or septic shock followed by post-operative care for elective surgery, oncological surgery, multiple traumas and emergency surgery. When classifying these patients according to HbA1c, despite the absence of a prior history of diabetes mellitus, only 13.3% had a normal HbA1c level, 23.3% had levels compatible with the diagnosis of diabetes mellitus and 63.3% had levels compatible with impaired glucose tolerance. We found a significant association between the diagnosis of diabetes mellitus or impaired glucose tolerance and the use of vasoactive drugs (p=0.04). Conclusion A high prevalence of undiagnosed diabetes mellitus and impaired glucose tolerance was observed in inpatients at a general intensive care unit. PMID:23917931
Ladeira, Renata Teixeira; Simioni, Ana Cinthia Marques; Bafi, Antonio Tonete; Nascente, Ana Paula Metran; Freitas, Flavio Geraldo Resende; Machado, Flávia Ribeiro
To evaluate the presence of diabetes mellitus and impaired glucose tolerance in intensive care unit inpatients. The study included patients in post-surgical care for elective and emergency surgery and excluded those patients with known diabetes mellitus. To diagnose prior serum glucose level disorders, we considered the value of glycated hemoglobin (HbA1c) at the time of admission, classifying the patients as normal (<5.7%), glucose intolerant (5.7-6.4%) or diabetic (>6.4%). During the first 3 days of the patient's hospital stay, glycemic control and clinical complications were assessed. Mortality was monitored for 28 days. For the statistical analyses, chi-square, ANOVA, student's t, Kruskal-Wallis or Mann Whitney tests were used. Thirty patients were included in the present study, 53% of whom were women; the patients had a mean age of 53.4±19.7 years and an APACHE II score of 13.6±6.6. The majority of patients were admitted for severe sepsis or septic shock followed by post-operative care for elective surgery, oncological surgery, multiple traumas and emergency surgery. When classifying these patients according to HbA1c, despite the absence of a prior history of diabetes mellitus, only 13.3% had a normal HbA1c level, 23.3% had levels compatible with the diagnosis of diabetes mellitus and 63.3% had levels compatible with impaired glucose tolerance. We found a significant association between the diagnosis of diabetes mellitus or impaired glucose tolerance and the use of vasoactive drugs (p=0.04). A high prevalence of undiagnosed diabetes mellitus and impaired glucose tolerance was observed in inpatients at a general intensive care unit.
Kamel, Maher A; Helmy, Madiha H; Hanafi, Mervat Y; Mahmoud, Shimaa A; Abo Elfetooh, Hanan
Maternal diabetes can induce permanent changes in glucose homeostasis that can occur pre- and post-natal and leads to type 2 diabetes in adulthood. This study aimed to investigate the effect of maternal diabetes on the F1 offspring peripheral glucose sensing and mitochondrial biogenesis in an attempt to clarify the mechanism of diabetogenic programming. Two groups of female Wistar rats were used (diabetic and control); diabetes was neonatally induced by STZ injection to 5-day old rats. After the pregnancy and delivery, the offspring were weaned to control diet or high-caloric (HCD) diet and followed up for 30 weeks. Every 5 weeks, OGTT was constructed, and serum and tissues were obtained for the assessment of mTFA, mtDNA, UCP2, insulin receptor (IR), phospho-insulin receptor (phospho-IR), and GLUT4. The result indicated impaired glucose tolerance (IGT) and insulin resistance in the offspring under control diet at the 15th week of age and thereafter while those offspring under HCD showed IGT at 10th week, and diabetes was evidenced at the 25th week of age. This defect in glucose metabolism was preceded by impairment in the phosphorylation of IR and decreased IR and Glut4 that cause impaired glucose sensing together with inhibited mitochondrial biogenesis in muscle and adipose tissues. This study indicated that maternal diabetes caused impaired glucose sensing and insulin resistance in the peripheral tissues and caused change in the expression of genes involved in mitochondrial biogenesis and function. Post-natal feeding with HCD may accelerate these changes. Male F1 offspring appears to be more sensitive than females for fetal programming of T2D.
Tavecchio, Michele; Lisanti, Sofia; Bennett, Michael J.; Languino, Lucia R.; Altieri, Dario C.
Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid β-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing β-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet-induced liver damage and weight gain. Therefore, CypD is a novel regulator of mitochondrial bioenergetics, and unexpectedly controls glucose homeostasis, in vivo. PMID:26515038
Huang, Huibin; Guo, Qiuxuan; Qiu, Changsheng; Huang, Baoying; Fu, Xianguo; Yao, Jin; Liang, Jixing; Li, Liantao; Chen, Ling; Tang, Kaka; Lin, Lixiang; Lu, Jieli; Bi, Yufang; Ning, Guang; Wen, Junping; Lin, Caijing; Chen, Gang
Objective To explore the associations of green tea and rock tea consumption with risk of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Methods A multistage, stratified, cluster, random-sampling method was used to select a representative sample from Fujian Province in China. In total, 4808 subjects without cardiovascular disease, hypertension, cancer, or pancreatic, liver, kidney, or gastrointestinal diseases were enrolled in the study. A standard questionnaire was used to gather data on tea (green, rock, and black) consumption and other relevant factors. The assessment of impaired glucose regulation (IGR) was using 75-g oral glucose tolerance test (OGTT), the diagnostic criteria of normal glucose tolerance was according to American Diabetes Association. Results Green tea consumption was associated with a lower risk of IFG, while rock tea consumption was associated with a lower risk of IGT. The adjusted odds ratios for IFG for green tea consumption of <1, 1–15, 16–30, and >30 cups per week were 1.0 (reference), 0.42 (95% confidence intervals (CI) 0.27–0.65), 0.23 (95% CI, 0.12–0.46), and 0.41 (95% CI, 0.17–0.93), respectively. The adjusted odds ratios for IGT for rock tea consumption of <1, 1–15, 16–30, and >30 cups per week were 1.0 (reference), 0.69 (95% CI, 0.48–0.98), 0.59 (95% CI, 0.39–0.90), and 0.64 (95% CI, 0.43–0.97), respectively. A U-shaped association was observed, subjects who consumed 16–30 cups of green or rock tea per week having the lowest odds ratios for IFG or IGT. Conclusions Consumption of green or rock tea may protect against the development of type 2 diabetes mellitus in Chinese men and women, particularly in those who drink 16–30 cups per week. PMID:24260170
Cui, Rongtao; Zhou, Lin; Li, Zuohong; Li, Qing; Qi, Zhiming; Zhang, Junyong
Objective The aim of our study was to investigate the relationship among age, sex, body mass index (BMI), serum lipid profiles, blood glucose (BG), and bone mineral density (BMD), making an assessment of the risk of osteoporosis. Materials and methods A total of 1,035 male and 3,953 female healthy volunteers (aged 41–95 years) were recruited by an open invitation. The basic information, including age, sex, height, weight, waistline, hipline, menstrual cycle, and medical history, were collected by a questionnaire survey and physical examination. Serum lipid profiles, BG, postprandial blood glucose, and glycosylated hemoglobin were obtained after 12 hours fasting. BMD in lumbar spine was measured by dual-energy X-ray absorptiometry scanning. Results The age-adjusted BMD in females was significantly lower than in males. With aging, greater differences of BMD distribution exist in elderly females than in males (P<0.001), and the fastigium of bone mass loss was in the age range from 51 to 55 in females and from 61 to 65 years in males. After adjustment for sex, there were significant differences in BMD among BMI-stratified groups in both males and females. The subjects with a BMI of <18.5 had a higher incidence of osteoporosis than BMI ≥18.5 in both sexes. BMD in type 2 diabetes mellitus with a BG of >7.0 mmol/L was lower than in people with BG of ≤7.0 mmol/L (P<0.001). People with serum high-density lipoprotein cholesterol levels of ≥1.56 mmol/L had a greater prevalence of osteoporosis compared with high-density lipoprotein cholesterol ≤1.55 mmol/L. Logistic regression with odds ratios showed that no association was found among total cholesterol, triglyceride, low-density lipoprotein cholesterol, glycosylated hemoglobin, postprandial blood glucose and BMD. Conclusion The present study further confirmed that factors such as age, sex, weight, BMI, high-density lipoprotein cholesterol, and diabetes are significant predictors of osteoporosis in the Chinese people
Hasegawa, Goji; Yamasaki, Masahiro; Kadono, Mayuko; Tanaka, Muhei; Asano, Mai; Senmaru, Takafumi; Kondo, Yoshitaka; Fukui, Michiaki; Obayashi, Hiroshi; Maruyama, Naoki; Nakamura, Naoto; Ishigami, Akihito
Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout (KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wild-type (WT) mice. Insulin levels in SMP30/GNL KO mice were significantly decreased by 37% at 30 min after glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucose-lowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in beta-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mm glucose or KCl was significantly decreased in SMP30/GNL KO mice. On the other hand, islet ATP content at 20 mm in SMP30/GNL KO mice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging.
Polak, Jan; Shimoda, Larissa A.; Drager, Luciano F.; Undem, Clark; McHugh, Holly; Polotsky, Vsevolod Y.; Punjabi, Naresh M.
Objectives: Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. Interventions: C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Results: Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Conclusions: Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism. Citation: Polak J; Shimoda LA; Drager LF; Undem C; McHugh H; Polotsky VY; Punjabi NM
Kubota, Tetsuya; Kubota, Naoto; Kumagai, Hiroki; Yamaguchi, Shinichi; Kozono, Hideki; Takahashi, Takehiro; Inoue, Mariko; Itoh, Shinsuke; Takamoto, Iseki; Sasako, Takayoshi; Kumagai, Katsuyoshi; Kawai, Tomoko; Hashimoto, Shinji; Kobayashi, Tsuneo; Sato, Maki; Tokuyama, Kumpei; Nishimura, Satoshi; Tsunoda, Masaki; Ide, Tomohiro; Murakami, Koji; Yamazaki, Tomomi; Ezaki, Osamu; Kawamura, Koichi; Masuda, Hirotake; Moroi, Masao; Sugi, Kaoru; Oike, Yuichi; Shimokawa, Hiroaki; Yanagihara, Nobuyuki; Tsutsui, Masato; Terauchi, Yasuo; Tobe, Kazuyuki; Nagai, Ryozo; Kamata, Katsuo; Inoue, Kenji; Kodama, Tatsuhiko; Ueki, Kohjiro; Kadowaki, Takashi
In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance. Copyright © 2011 Elsevier Inc. All rights reserved.
Jauch-Chara, Kamila; Binkofski, Ferdinand; Loebig, Michaela; Reetz, Kathrin; Jahn, Gianna; Melchert, Uwe H; Schweiger, Ulrich; Oltmanns, Kerstin M
Brain energy consumption induced by electrical stimulation increases systemic glucose tolerance in normal-weight men. In obesity, fundamental reductions in brain energy levels, gray matter density, and cortical metabolism, as well as chronically impaired glucose tolerance, suggest that disturbed neuroenergetic regulation may be involved in the development of overweight and obesity. Here, we induced neuronal excitation by anodal transcranial direct current stimulation versus sham, examined cerebral energy consumption with (31)P magnetic resonance spectroscopy, and determined systemic glucose uptake by euglycemic-hyperinsulinemic glucose clamp in 15 normal-weight and 15 obese participants. We demonstrate blunted brain energy consumption and impaired systemic glucose uptake in obese compared with normal-weight volunteers, indicating neuroenergetic dysregulation in obese humans. Broadening our understanding of reduced multifocal gray matter volumes in obesity, our findings show that reduced appetite- and taste-processing area morphometry is associated with decreased brain energy levels. Specifically, gray matter volumes of the insula relate to brain energy content in obese participants. Overall, our results imply that a diminished cerebral energy supply may underlie the decline in brain areas assigned to food intake regulation and therefore the development of obesity. © 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.
Gao, Xiang; Liu, Xiaofang; Xu, Jie; Xue, Changhu; Xue, Yong; Wang, Yuming
Trimethylamine N-oxide (TMAO) is an oxidation product of trimethylamine (TMA) and is present in many aquatic foods. Here, we investigated the effects of TMAO on glucose tolerance in high fat diet (HFD)-fed mice. Male C57BL/6 mice were randomly assigned to the control, high fat (HF), and TMAO groups. The HF group was fed a diet containing 25% fat, and the TMAO group was fed the HFD plus 0.2% TMAO for 4 weeks. After 3 weeks of feeding, oral glucose tolerance tests were performed. Dietary TMAO increased fasting insulin levels and homeostasis model assessment-estimated insulin resistance (HOMA-IR) and exacerbated the impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signal pathway, glycogen synthesis, gluconeogenesis and glucose transport in liver. mRNA levels of the pro-inflammatory cytokine MCP-1 increased significantly and of the anti-inflammatory cytokine IL-10 greatly decreased in adipose tissue. Our results suggest that dietary TMAO exacerbates impaired glucose tolerance, obstructs the hepatic insulin signaling pathway, and causes adipose tissue inflammation in mice fed a high fat diet.
Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta
Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months’ supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake. PMID:27194405
Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta
Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake.
Hackett, Ruth A; Kivimäki, Mika; Kumari, Meena; Steptoe, Andrew
The hypothalamic pituitary-adrenal axis is thought to play a role in type 2 diabetes (T2D). However, evidence for an association between cortisol and future glucose disturbance is sparse. The aim was to examine the association of diurnal cortisol secretion with future T2D and impaired glucose metabolism in a community-dwelling population. This is a prospective cohort study of salivary cortisol measured at the 2002-2004 clinical examination of the Whitehall II study, United Kingdom. We measured cortisol (nmol/l) from six saliva samples obtained over the course of a day: at waking, +30 minutes, +2.5 hours, +8 hours, +12 hours, and bedtime. Participants who were normoglycemic in 2002-2004 (phase 7) were reexamined in 2012-2013 (phase 11). The occupational cohort was originally recruited in 1985-1988. A total of 3270 men and women with an average age of 60.85 years at phase 7 (2002-2004). Incident T2D and impaired fasting glucose in 2012-2013 were measured. Raised evening cortisol at phase 7 was predictive of new-onset T2D at phase 11 (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01-1.37) with a trend for a flatter slope in participants with incident T2D (odds ratio, 1.15; 95% CI, 0.99-1.33). When expanding this analysis to a broader category of glucose disturbance we found that a flattened diurnal cortisol slope at phase 7 was predictive of future impaired fasting glucose or T2D at phase 11 (OR, 1.12; 95% CI, 1.02-1.22), as was high bedtime cortisol (OR, 1.10; 95% CI, 1.01-1.20). In this nonclinical population, alterations in diurnal cortisol patterns were predictive of future glucose disturbance.
Wang, Wenli; Redline, Susan; Khoo, Michael C. K.
Background The association between diabetes and abnormalities in autonomic function is well-known, but it is not clear if this association can be extended to subjects with prediabetic impaired glucose metabolism (IGM). Sleep-disordered breathing (SDB), which commonly occurs in this population, is often overlooked. We sought to determine how autonomic function, monitored in an overnight sleep study setting, may be impaired in subjects with IGM and/or SDB. Methods Polysomnograms (PSGs) selected from the Cleveland Family Study database were categorized into four groups: normal, SDB (respiratory disturbance index > 5/h), IGM, and both SDB and IGM. Impaired glucose metabolism was defined as an oral glucose tolerance test (OGTT) level > 140 mg/dl. Time-domain and frequency-domain indices of heart rate variability were used to quantify autonomic impairment. Baroreflex sensitivity determined using pulse transit time (BRSPTT), an indirect measure of baroreflex sensitivity based on spontaneous pulse transit time fluctuations, was used as a surrogate measure of baroreflex sensitivity. Results Based on 31 PSGs from subjects (16 males, 15 females) ages 20.8–61.2 years, both SDNN and BRSPTT were found to be 20-25% lower in SDB and ~40% lower in IGM and SDB + IGM as compared to subjects without either condition. In analyses of continuous measures, mean standard deviation of 5 min R–R intervals (SDNN) and BRSPTT were found to be negatively correlated with OGTT following adjustment for age and body mass index. Oral glucose tolerance test and age were the two most significant factors for predicting SDNN and BRSPTT. Conclusions Our analyses suggest that cardiac autonomic control is impaired in IGM, regardless of whether SDB is present. The abnormal autonomic function involves degradation of baroreflex regulation. PMID:23063043
The major types of osteoporosis in humans are postmenopausal osteoporosis, disuse osteoporosis, and glucocorticoid-induced osteoporosis. Animal models for postmenopausal osteoporosis are generated by ovariectomy. Bone loss occurs in estrogen deficiency due to enhanced bone resorption and impaired osteoblast function. Estrogen receptor α induces osteoclast apoptosis, but the mechanism for impaired osteoblast function remains to be clarified. Animal models for unloading are generated by tail suspension or hind limb immobilization by sciatic neurectomy, tenotomy, or using plaster cast. Unloading inhibits bone formation and enhances bone resorption, and the involvement of the sympathetic nervous system in it needs to be further investigated. The osteocyte network regulates bone mass by responding to mechanical stress. Osteoblast-specific BCL2 transgenic mice, in which the osteocyte network is completely disrupted, can be a mouse model for the evaluation of osteocyte functions. Glucocorticoid treatment inhibits bone formation and enhances bone resorption, and markedly reduces cancellous bone in humans and large animals, but not consistently in rodents.
Zhao, Fei; Jiang, Guobin; Wei, Penghao; Wang, Hongfang; Ru, Shaoguo
Bisphenol S (BPS) is a substitute of the plastic additive bisphenol A (BPA). Its concentrations detected in surface waters and urine samples are on the same order of magnitude as BPA. Human exposure to BPA has been implicated in the development of diabetes mellitus; however, whether BPS can disrupt glucose homeostasis and increase blood glucose concentration remains unclear. We extensively investigated the effects of environmentally relevant concentrations of BPS on glucose metabolism in male zebrafish (Danio rerio) and the underlying mechanisms of these effects. Male zebrafish were exposed to 1, 10, or 100μg/L of BPS for 28 d. Fasting blood glucose (FBG) levels, glycogen levels in the liver and muscle, and mRNA levels of key glucose metabolic enzymes and the activities of the encoded proteins in tissues were evaluated to assess the effect of BPS on glucose metabolism. Plasma insulin levels and expression of preproinsulin and glucagon genes in the visceral tissue were also evaluated. Compared with the control group, exposure to 1 and 10μg/L of BPS significantly increased FBG levels but decreased insulin levels. Gluconeogenesis and glycogenolysis in the liver were promoted, and glycogen synthesis in the liver and muscle and glycolysis in the muscle were inhibited. Exposure to 100μg/L of BPS did not significantly alter plasma insulin and blood glucose levels, but nonetheless pronouncedly interfered with gluconeogenesis, glycogenolysis, glycolysis, and glycogen synthesis. Our data indicates that BPS at environmentally relevant concentrations impairs glucose homeostasis of male zebrafish possibly by hampering the physiological effect of insulin; higher BPS doses also pronouncedly interfered with glucose metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.
Vestri, Helliner S; Maianu, Lidia; Moellering, Douglas R; Garvey, W Timothy
Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 microM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 microM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These
Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial.
Califf, Robert M; Boolell, Mitradev; Haffner, Steven M; Bethel, M Angelyn; McMurray, John; Duggal, Anil; Holman, Rury R
Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.
Lansey, Melissa N.; Walker, Natalie N.; Hargett, Stefan R.; Stevens, Joseph R.
Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160−/−) mice. We observed increased and normal basal glucose uptake in isolated AS160−/− adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160−/− extensor digitorum longus muscles. In plasma membranes isolated from AS160−/− adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160−/− adipocytes and normal in AS160−/− soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160−/− skeletal muscles and liver but not in AS160−/− adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis. PMID:23011063
Lansey, Melissa N; Walker, Natalie N; Hargett, Stefan R; Stevens, Joseph R; Keller, Susanna R
Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160(-/-)) mice. We observed increased and normal basal glucose uptake in isolated AS160(-/-) adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160(-/-) extensor digitorum longus muscles. In plasma membranes isolated from AS160(-/-) adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160(-/-) adipocytes and normal in AS160(-/-) soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160(-/-) skeletal muscles and liver but not in AS160(-/-) adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis.
McGill-Vargas, Lisa L.; Gastaldelli, Amalia; Seidner, Steven R.; McCurnin, Donald C.; Leland, Michelle M.; Anzueto, Diana G.; Johnson, Marney C.; Liang, Hanyu; DeFronzo, Ralph A.; Musi, Nicolas
Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors. PMID:25560831
Bourn, D M; Williams, S M; Mann, J I
Screening for impaired glucose tolerance (IGT) and Type 2 (non-insulin dependent) diabetes was carried out in 777 people and those with high blood glucose levels completed three 2-h oral glucose tolerance tests (OGTT). Blood lipid levels, fasting and 2-h insulin levels, body mass index, and blood pressure were also measured and family history of Type 2 diabetes recorded. Fifty people were identified with IGT and of these 21 were found to have persistent IGT and 29 transient IGT. A model including the variables body mass index, fasting and 2-h insulin levels, fasting triglycerides and family history of Type 2 diabetes was developed using the Speigelhalter-Knill-Jones weighting method to predict subjects with persistent IGT. This model could be useful in identifying people with persistent IGT and therefore eliminate the need for repeat OGTTs which are time consuming and expensive.
Meex, Ruth C; Hoy, Andrew J; Morris, Alexander; Brown, Russell D; Lo, Jennifer C Y; Burke, Melissa; Goode, Robert J A; Kingwell, Bronwyn A; Kraakman, Michael J; Febbraio, Mark A; Greve, Jan Willem; Rensen, Sander S; Molloy, Mark P; Lancaster, Graeme I; Bruce, Clinton R; Watt, Matthew J
Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition. Copyright © 2015 Elsevier Inc. All rights reserved.
Gao, Ying-Ying; Chen, Li; Wang, Tao; Nie, Zheng-Wen; Zhang, Xia; Miao, Yi-Liang
DNA methylation plays important roles in regulating many physiological behaviors; however, few studies were focused on the changes of DNA methylation during oocyte aging. Early studies showed that some imprinted genes’ DNA methylation had been changed in aged mouse oocytes. In this study, we used porcine oocytes to test the hypothesis that oocyte aging would alter DNA methylation pattern of genes and disturb their expression in age oocytes, which affected the developmental potential of oocytes. We compared several different types of genes and found that the expression and DNA methylation of Neuronatin (NNAT) were disturbed in aged oocytes significantly. Additional experiments demonstrated that glucose transport was impaired in aged oocytes and injection of NNAT antibody into fresh oocytes led to the same effects on glucose transport. These results suggest that the expression of NNAT was declined by elevating DNA methylation, which affected oocyte quality by decreasing the ability of glucose transport in aged oocytes. PMID:27782163
Shi, Ya-Lin; Liu, Wen-Juan; Zhang, Xiao-Fang; Su, Wei-Juan; Chen, Ning-Ning; Lu, Shu-Hua; Wang, Li-Ying; Shi, Xiu-Lin; Li, Zhi-Bin; Yang, Shu-Yu
Background: Diabetes mellitus (DM) remains a major health problem worldwide. Several clinical trials have shown the superiority of the Traditional Chinese Medicine in delaying or reversing the development and progression of DM. This study aimed to evaluate the efficacy of Jinlida (JLD) granule, a Chinese herbal recipe, in the treatment of impaired glucose tolerance (IGT) and its effect on the prevention of DM. Methods: Sixty-five IGT patients were randomized to receive one bag of JLD granules three times daily (JLD group, n = 34) or no drug intervention (control group, n = 31) for 12 weeks. Oral glucose tolerance test, glycated hemoglobin A1c (HbA1c), body mass index, blood lipids levels, fasting insulin, and insulin resistance calculated using homeostatic model assessment (HOMA-IR) of all the patients were observed and compared before and after the treatment. Results: Sixty-one participants completed the trial (32 in JLD group and 29 in the control group). There were statistically significant decreases in HbA1c (P < 0.001), 2-h plasma glucose (P < 0.001), and HOMA-IR (P = 0.029) in JLD group compared with the control group after 12 weeks of treatment. After 12 weeks of treatment, two (6.9%) patients returned to normal blood glucose, and five (17.2%) patients turned into DM in control group, while in the JLD group, 14 (43.8%) returned to normal blood glucose and 2 (6.2%) turned into DM. There was a significant difference in the number of subjects who had normal glucose at the end of the study between two groups (P = 0.001). Conclusions: JLD granule effectively improved glucose control, increased the conversion of IGT to normal glucose, and improved the insulin resistance in patients with IGT. This Chinese herbal medicine may have a clinical value for IGT. PMID:27647185
Shi, Ya-Lin; Liu, Wen-Juan; Zhang, Xiao-Fang; Su, Wei-Juan; Chen, Ning-Ning; Lu, Shu-Hua; Wang, Li-Ying; Shi, Xiu-Lin; Li, Zhi-Bin; Yang, Shu-Yu
Diabetes mellitus (DM) remains a major health problem worldwide. Several clinical trials have shown the superiority of the Traditional Chinese Medicine in delaying or reversing the development and progression of DM. This study aimed to evaluate the efficacy of Jinlida (JLD) granule, a Chinese herbal recipe, in the treatment of impaired glucose tolerance (IGT) and its effect on the prevention of DM. Sixty-five IGT patients were randomized to receive one bag of JLD granules three times daily (JLD group, n = 34) or no drug intervention (control group, n = 31) for 12 weeks. Oral glucose tolerance test, glycated hemoglobin A1c (HbA1c), body mass index, blood lipids levels, fasting insulin, and insulin resistance calculated using homeostatic model assessment (HOMA-IR) of all the patients were observed and compared before and after the treatment. Sixty-one participants completed the trial (32 in JLD group and 29 in the control group). There were statistically significant decreases in HbA1c (P < 0.001), 2-h plasma glucose (P < 0.001), and HOMA-IR (P = 0.029) in JLD group compared with the control group after 12 weeks of treatment. After 12 weeks of treatment, two (6.9%) patients returned to normal blood glucose, and five (17.2%) patients turned into DM in control group, while in the JLD group, 14 (43.8%) returned to normal blood glucose and 2 (6.2%) turned into DM. There was a significant difference in the number of subjects who had normal glucose at the end of the study between two groups (P = 0.001). JLD granule effectively improved glucose control, increased the conversion of IGT to normal glucose, and improved the insulin resistance in patients with IGT. This Chinese herbal medicine may have a clinical value for IGT.
Tolson, Kristen P; Garcia, Christian; Yen, Stephanie; Simonds, Stephanie; Stefanidis, Aneta; Lawrence, Alison; Smith, Jeremy T; Kauffman, Alexander S
The neuropeptide kisspeptin regulates reproduction by stimulating gonadotropin-releasing hormone (GnRH) neurons via the kisspeptin receptor KISS1R. In addition to GnRH neurons, KISS1R is expressed in other brain areas and peripheral tissues, which suggests that kisspeptin has additional functions beyond reproduction. Here, we studied the energetic and metabolic phenotype in mice lacking kisspeptin signaling (Kiss1r KO mice). Compared with WT littermates, adult Kiss1r KO females displayed dramatically higher BW, leptin levels, and adiposity, along with strikingly impaired glucose tolerance. Conversely, male Kiss1r KO mice had normal BW and glucose regulation. Surprisingly, despite their obesity, Kiss1r KO females ate less than WT females; however, Kiss1r KO females displayed markedly reduced locomotor activity, respiratory rate, and energy expenditure, which were not due to impaired thyroid hormone secretion. The BW and metabolic phenotype in Kiss1r KO females was not solely reflective of absent gonadal estrogen, as chronically ovariectomized Kiss1r KO females developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance compared with ovariectomized WT females. Our findings demonstrate that in addition to reproduction, kisspeptin signaling influences BW, energy expenditure, and glucose homeostasis in a sexually dimorphic and partially sex steroid-independent manner; therefore, alterations in kisspeptin signaling might contribute, directly or indirectly, to some facets of human obesity, diabetes, or metabolic dysfunction.
Uchida, Kunitoshi; Dezaki, Katsuya; Damdindorj, Boldbaatar; Inada, Hitoshi; Shiuchi, Tetsuya; Mori, Yasuo; Yada, Toshihiko; Minokoshi, Yasuhiko; Tominaga, Makoto
OBJECTIVE TRPM2 is a Ca2+-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by coapplication of heat and intracellular cyclic adenosine 5′-diphosphoribose, which has been suggested to be involved in intracellular Ca2+ increase in immunocytes and pancreatic β-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice. RESEARCH DESIGN AND METHODS Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type mice. We also measured cytosolic free Ca2+ in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets. RESULTS Basal blood glucose levels were higher in TRPM2-KO mice than in wild-type mice without any difference in plasma insulin levels. The OGTT and IPGTT demonstrated that blood glucose levels in TRPM2-KO mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated β-cells, smaller intracellular Ca2+ increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in wild-type cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an ATP-sensitive potassium channel inhibitor, was not different between the two groups. CONCLUSIONS These results indicate that TRPM2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, TRPM2 may be a new target for diabetes therapy. PMID:20921208
Uslan, Mark M; Eghtesadi, Khosrow; Burton, Darren
Blindness and visual impairment are prevalent among people with diabetes. Blood glucose monitoring systems (BGMSs) have revolutionized diabetes care, but none of the 30 or so commercially available monitoring systems was designed to be fully accessible to blind and visually impaired persons. Seventeen BGMSs were evaluated for accessible use by people who are blind or visually impaired. Features and functionalities (e.g., operating procedures, user interface design, device specifications, and computer interface capabilities) were examined and tabulated, as was usability and accessibility. A subset of these systems with the highest degree of accessibility was selected and thoroughly examined and tested. Additionally, 12 people who are blind or visually impaired and who were issued BGMSs by their physician or diabetes educator were interviewed and videotaped using their meters. Of the 17 BGMSs, only four had voice output capability, an essential component of accessibility for blind and visually impaired persons. The six BGMSs without voice output that had the largest display fonts were found to have few accessibility features for visually impaired persons. Users indicated that voice output and portability were desired attributes of an accessible BGMS. None of the BGMSs evaluated had all of the required accessibility attributes, including the four systems that had voice output capability. The four systems with voice output were much bulkier and heavier than those that did not have this capability. Recommendations are made for design and development of BGMSs that would increase effective usage by blind and visually impaired persons, including integrating text to speech and streamlining the blood glucose monitoring process.
Hanley, Anthony J; Zinman, Bernard; Sheridan, Patrick; Yusuf, Salim; Gerstein, Hertzel C
OBJECTIVE The objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed beta-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals. RESEARCH DESIGN AND METHODS The present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. beta-Cell function was assessed using the fasting proinsulin-to-C-peptide ratio (PI/C) and the insulinogenic index (defined as 30-0 min insulin/30-0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]). RESULTS Subjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (-0.010 vs. -0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and -0.007 vs. -0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: -0.003 vs. -0.001, P = 0.07). CONCLUSIONS Treatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of beta-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a
Shi, Xiarong; Burkart, Alison; Nicoloro, Sarah M; Czech, Michael P; Straubhaar, Juerg; Corvera, Silvia
Adipocyte function is crucial for the control of whole body energy homeostasis. Pathway analysis of differentiating 3T3-L1 adipocytes reveals that major metabolic pathways induced during differentiation involve mitochondrial function. However, it is not clear why differentiated white adipocytes require enhanced respiratory chain activity relative to pre-adipocytes. To address this question, we used small interference RNA to interfere with the induction of the transcription factor Tfam, which is highly induced between days 2 and 4 of differentiation and is crucial for replication of mitochondrial DNA. Interference with Tfam resulted in cells with decreased respiratory chain capacity, reflected by decreased basal oxygen consumption, and decreased mitochondrial ATP synthesis, but no difference in many other adipocyte functions or expression levels of adipose-specific genes. However, insulin-stimulated GLUT4 translocation to the cell surface and subsequent glucose transport are impaired in Tfam knockdown cells. Paradoxically, insulin-stimulated Akt phosphorylation is significantly enhanced in these cells. These studies reveal independent links between mitochondrial function, insulin signaling, and glucose transport, in which impaired respiratory chain activity enhances insulin signaling to Akt phosphorylation, but impairs GLUT4 translocation. These results indicate that mitochondrial respiratory chain dysfunction in adipocytes can cause impaired insulin responsiveness of GLUT4 translocation by a mechanism downstream of the Akt protein kinase.
Abolhassani, Nona; Leon, Julio; Sheng, Zijing; Oka, Sugako; Hamasaki, Hideomi; Iwaki, Toru; Nakabeppu, Yusaku
In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8-oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality lasts long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Shoji, T; Sakurai, Y; Sato, H; Chihara, E; Takeuchi, M
To investigate associations between fasting plasma glucose level and the prevalence of acquired colour vision impairment in type 2 diabetes patients without diabetic retinopathy. Participants in this cross-sectional study of male officials aged 20-60 yr in the Japanese Self Defence Force, underwent colour vision testing, ophthalmic examination, a standardized interview and examination of venous blood samples. Ishihara plates, a Lanthony 15-hue desaturated panel and Standard Pseudoisochromatic Plates Part 2 were used to examine colour vision. The Farnsworth-Munsell 100-hue test was performed to define acquired colour vision impairment. Cardiovascular disease risk factors were determined from serum blood samples, physical records and an interview. We performed logistic regression analysis adjusted for age, diagnosed hypertension, dyslipidaemia, cataract, glaucoma, being overweight, smoking status and alcohol intake. Crude and adjusted odds ratios were calculated for three glucose levels, which included normal fasting glucose, impaired fasting glucose and diabetes. Out of a total of 1042 men enrolled, 872 were eligible for the study, and 31 were diagnosed with acquired colour vision impairment. As compared with the subjects with normal fasting glucose (< 5.6 mmol/l), the crude odds ratio for acquired colour vision impairment was 0.93 (95% CI 0.32-2.74) for the subjects with impaired fasting glucose (5.6-6.9 mmol/l) and 8.07 (95% CI 2.48-26.22) for the patients with type 2 diabetes. The multiple-adjusted odds ratios were 0.77 (95% CI 0.25-2.34) for the subjects with impaired fasting glucose and 5.89 (95% CI 1.55-22.40) for the patients with type 2 diabetes. Our findings suggest that there is a dramatically increased prevalence of acquired colour vision impairment in type 2 diabetes patients without diabetic retinopathy which might be attributable to another pathogenesis associated with diabetic retinopathy. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.
Shiga, Tomoko; Moriyoshi, Yuriko; Nagahara, Hikaru; Shiratori, Keiko
The first aim of this study was to elucidate the relationship between impaired glucose tolerance (IGT) and nonalcoholic fatty liver. The second was to make a rule regarding to whom 75-g oral glucose tolerance tests (OGTTs) should be applied to identify subjects with IGT and diabetes mellitus (DM) in the annual check-up at the human dry dock. A total of 716 subjects who visited the Department of General Medicine of the International Medical Center of Japan from May 2001 through January 2008 for an annual check-up at the human dry dock were analyzed. We evaluated risk factors related to nonalcoholic fatty liver using multivariate logistic regression analysis and compared the difference of body mass index (BMI) and glucose level at 75-g OGTT at two different time points in subjects whose fatty change had improved or worsened. Nonalcoholic fatty liver was strongly related to 2-h- and 1-h-post-challenge glucose level (P<0.0001 and P=0.018, respectively), but not fasting plasma glucose (FPG) (P=0.706). The risk factors for IGT were nonalcoholic fatty liver (P<0.05), low levels of high-density lipoprotein cholesterol (HDL-C) (P=0.026) and age (P=0.013). A clearly positive relationship was observed between the difference of BMI and 2-h-post-challenge glucose level among the subjects whose fatty change had improved or worsened (R=0.6, P=0.018). Nonalcoholic fatty liver was clearly related to the 2-h- or 1-h-post-challenge glucose level, but not to FPG, in 75-g OGTT, and this IGT was corrected by body weight reduction in accordance with diminished nonalcoholic fatty liver. Thus, 75-g OGTT should be applied to subjects with nonalcoholic fatty liver to evaluate IGT.
Baker, Nicki A.; Karounos, Michael; English, Victoria; Fang, Jun; Wei, Yinan; Stromberg, Arnold; Sunkara, Manjula; Morris, Andrew J.; Swanson, Hollie I.
Background: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in persons with type 2 diabetes. Objectives: We investigated the in vitro and in vivo effects of coplanar PCBs on adipose expression of tumor necrosis factor α (TNF-α) and on glucose and insulin homeostasis in lean and obese mice. Methods: We quantified glucose and insulin tolerance, as well as TNF-α levels, in liver, muscle, and adipose tissue of male C57BL/6 mice administered vehicle, PCB-77, or PCB-126 and fed a low fat (LF) diet. Another group of mice administered vehicle or PCB-77 were fed a high fat (HF) diet for 12 weeks; the diet was then switched from HF to LF for 4 weeks to induce weight loss. We quantified glucose and insulin tolerance and adipose TNF-α expression in these mice. In addition, we used in vitro and in vivo studies to quantify aryl hydrocarbon receptor (AhR)-dependent effects of PCB-77 on parameters of glucose homeostasis. Results: Treatment with coplanar PCBs resulted in sustained impairment of glucose and insulin tolerance in mice fed the LF diet. In PCB-77–treated mice, TNF-α expression was increased in adipose tissue but not in liver or muscle. PCB-77 levels were strikingly higher in adipose tissue than in liver or serum. Antagonism of AhR abolished both in vitro and in vivo effects of PCB-77. In obese mice, PCB-77 had no effect on glucose homeostasis, but glucose homeostasis was impaired after weight loss. Conclusions: Coplanar PCBs impaired glucose homeostasis in lean mice and in obese mice following weight loss. Adipose-specific elevations in TNF-α expression by PCBs may contribute to impaired glucose homeostasis. PMID:23099484
Yang, Hye Jeong; Hwang, Jin Taek; Kwon, Dae Young; Kim, Min Jung; Kang, Suna; Moon, Na Rang; Park, Sunmin
Our preliminary study revealed that dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis (unpublished). We therefore evaluated whether long-term oral consumption of yuzu (Citrus junos Tanaka) extract improves cognitive dysfunction and glucose homeostasis in β-amyloid-induced rats. Male rats received hippocampal CA1 infusions of β-amyloid (25-35) [plaque forming β-amyloid; Alzheimer disease (AD)] or β-amyloid (35-25) [non-plaque forming β-amyloid; C (non-Alzheimer disease control)] at a rate of 3.6 nmol/d for 14 d. AD rats were divided into 2 dietary groups that received either 3% lyophilized 70% ethanol extracts of yuzu (AD-Y) or 3% dextrin (AD-C) in high-fat diets (43% energy as fat). The AD-C group exhibited greater hippocampal β-amyloid deposition, which was not detected in the C group, and attenuated hippocampal insulin signaling. Yuzu treatment prevented β-amyloid accumulation, increased tau phosphorylation, and attenuated hippocampal insulin signaling observed in AD-C rats. Consistent with β-amyloid accumulation, the AD-C rats experienced cognitive dysfunction, which was prevented by yuzu. AD-C rats gained less weight than did C rats due to decreased feed consumption, and yuzu treatment prevented the decrease in feed consumption. Serum glucose concentrations were higher in AD-C than in C rats at 40-120 min after glucose loading during an oral-glucose-tolerance test, but not at 0-40 min. Serum insulin concentrations were highly elevated in AD-C rats but not enough to lower serum glucose to normal concentrations, indicating that rats in the AD-C group had insulin resistance and a borderline diabetic state. Although AD-C rats were profoundly insulin resistant, AD-Y rats exhibited normal first and second phases of glucose tolerance and insulin sensitivity and secretion. In conclusion, yuzu treatment prevented the cognitive dysfunction and impaired energy and glucose homeostasis induced by β-amyloid infusion.
Murovets, Vladimir O; Bachmanov, Alexander A; Zolotarev, Vasiliy A
The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+) inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-). Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two-bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3-dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain.
The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+) inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-). Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two-bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3-dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain. PMID:26107521
Perreault, Leigh; Man, Chiara Dalla; Hunerdosse, Devon M; Cobelli, Claudio; Bergman, Bryan C
To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG). People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6-(2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration. EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group. Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG.
Iozzo, Patricia; Turpeinen, Anu K; Takala, Teemu; Oikonen, Vesa; Bergman, Jörgen; Grönroos, Tove; Ferrannini, Ele; Nuutila, Pirjo; Knuuti, Juhani
The liver exchanges high fluxes of glucose and free fatty acids (FFA) and is one main site of their reciprocal regulation. Acute exposure to hyperglycemia and hyperinsulinemia has been shown to reduce splanchnic beta-oxidation in healthy humans. We investigated whether a spontaneous condition of chronic mild hyperglycemia and hyperinsulinemia affects liver FFA uptake. Hepatic FFA influx rate constant (LKi) was measured after a 12-15-h fast in 10 patients with impaired glucose tolerance (IGT) and eight control subjects using positron emission tomography in combination with the long-chain FFA analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Compared with controls, IGT patients had higher serum insulin, glucose, and triglyceride levels (1.71 +/- 0.24 vs. 0.59 +/- 0.06 mmol/liter, P < 0.001), lower high-density lipoprotein (1.04 +/- 0.11 vs. 1.42 +/- 0.13 mmol/liter, P < 0.05), and similar FFA levels (0.59 +/- 0.06 vs. 0.56 +/- 0.05 mmol/liter(-1), P = not significant). LKi was significantly reduced in IGT (0.288 +/- 0.014 min(-1)) compared with control subjects (0.341 +/- 0.014 min(-1), P < 0.02). LKi was negatively correlated with plasma glucose (r = 0.51, P < 0.03), glycosylated hemoglobin (r = 0.55, P < 0.02), and blood lactate levels (r = 0.52, P < 0.03). We conclude that, in IGT patients, the ability of the liver to extract FFA from the circulation appears to be impaired. The reciprocal relationship between hepatic FFA extraction and glucose/lactate flux may derive from intrahepatic substrate competition.
Boudry, Gaëlle; Lallès, Jean-Paul; Malbert, Charles Henri; Grøndahl, Marie Louise; Unmack, Martin Andreas; Skadhauge, Erik
Recent evidence indicates that soybean, which is widely used in animal nutrition, could directly alter intestinal ion and nutrient transport. However, the mechanisms involved are still unknown. The aim of the study was to investigate the effect of three differently treated soybean products on the glucose and Cl- transport capacity in porcine small intestine by the Ussing chamber technique. Jejunal and ileal piglet epithelial tissues were pre-incubated with extracts of raw soybean flour (RSF), heated soybean flour (HSF), or ethanol heat-treated soybean protein concentrate (SPC). The Na(+)-dependent glucose co-absorption capacity was then measured as an increase in the short-circuit current (ISC) after luminal addition of D-glucose. The effect of the soybean products on cAMP-dependent Cl- secretion was measured as the increase in ISC after the addition of the phosphodiesterase inhibitor, theophylline, while nervous regulation of Cl- secretion was investigated by the addition of the enteric neurotransmitters; 5-hydroxytryptamine (5-HT), substance P and vasoactive intestinal polypeptide (VIP). Incubation with RSF and HSF induced a 30% decrease of the Na(+)-dependent glucose absorption capacity in the jejunum. The effect was similar for RSF in the ileum. Theophylline-induced secretion was decreased by 30% after incubation with RSF, HSF and SPC but only in the jejunum. 5-HT-, substance P- and VIP-induced secretion were not altered by incubation with soybean extracts except in the HSF-incubated where the substance P-induced secretion was significantly reduced. In conclusion, soybean contains ethanol-sensitive heat-insensitive compounds impairing Na(+)-dependent glucose absorption in the jejunum and ileum, and ethanol- and heat-insensitive compounds causing an acute impairment of cAMP-dependent jejunal secretion.
Lerat, Hervé; Imache, Mohamed Rabah; Polyte, Jacqueline; Gaudin, Aurore; Mercey, Marion; Donati, Flora; Baudesson, Camille; Higgs, Martin R; Picard, Alexandre; Magnan, Christophe; Foufelle, Fabienne; Pawlotsky, Jean-Michel
Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
To access the effects of life style interventions on impaired glucose regulation (IGR) in Shanghai urban communities, China. Two communities were randomly cluster-sampled to be carried out epidemiological intervention trial. Totally, 232 subjects with IGR were randomly allocated into 4 groups: control group,sports intervention group, diet intervention group, and sports and diet intervention group with the physical examinations in the baseline and end of this study respectively. Tests for fasting blood glucose, OGTT, HbA1c, total cholesterol,etc. were done. Data statistical analysis was occupied in SPSS 16.0. Compared to subjects of control group,fasting blood glucose, OGTT, HbAlc,total cholesterol,BMI,waist hip ratio and blood pressures were significantly decreased among subjects with three interventions (P < 0.05). Triglyceride were significantly decreased among subjects with sports intervention and sports and diet intervention (P < 0.05). High density lipids was significantly increased among subjects with sports and diet intervention (P < 0.05). There was a significant difference in 6 months cumulative incidence of diabetes mellitus between control group and interventions groups (8.6% vs. 0, Fisher' s exact P = 0.002), and the rate of transferring into normal blood glucose levels (fasting blood glucose < 5.6 mmol/L and 2 hours OGTT < 7.8 mmol/L) in control group was lower than those in three interventions group (3.4% vs. 8.6%, 14.0% and 16.9%, respectively) but only significant difference was observed between control group and sports and diet intervention group (OR = 5.74, 95% CI 1. 19-27. 64, P = 0.029). The life style interventions could decrease the risk of diabetes mellitus, help their transferring into normal blood glucose, and improve diabetic measures for the IGR population in Shanghai urban communities.
Krzyzanowska, K; Schnack, C; Mittermayer, F; Kopp, H P; Hofer, M; Kann, T; Schernthaner, G
Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.
Background. The effects of bed rest on the dysregulation of fatty acid and glucose metabolism have not been addressed in the older population. Objective. We examined the effect of 10 days of bed rest on fatty acid kinetics and hepatic and peripheral insulin resistance in aging. Methods. We utilized an octreotide, basal glucagon replacement, multistage insulin infusion, and the concomitant infusion of [6,6 2H2]glucose to derive insulin-mediated suppression of glucose production and insulin-stimulated glucose disposal in nine older, overweight individuals (body mass index 28.1 ± 1.7 kg m−2; 39.9% ± 1.9% fat). During the multistage insulin infusion, we also infused [1-13C]palmitate to examine free fatty acid rate of appearance (R a). Results. Body weight, % body fat, and energy metabolism did not change with bed rest. There was a significant decrease (−2291 ± 316cm3) in visceral fat, and no change in abdominal subcutaneous fat with bed rest. Insulin-mediated suppression of glucose production was modest prior to bed rest and was further reduced (>15% ± 2%) by bed rest. There was also a minor decrease in the insulin-mediated suppression of free fatty acid R a after bed rest and, as a consequence, a small variation in plasma free fatty acid from pre- to post-bed rest in the first stage of the multistage insulin infusion. There was also a significant bed rest–induced decline (>2.0 ± 0.6 mg kg FFM−1 min− 1) in insulin-stimulated glucose disposal. Conclusions. Preexisting impairments in insulin sensitivity are worsened by bed rest and seem linked to alterations in the regulation of free fatty acid in older, overweight individuals. PMID:23902932
Teichert, Tom; Hellwig, Anne; Peßler, Annette; Hellwig, Michael; Vossoughi, Mohammad; Sugiri, Dorothea; Vierkötter, Andrea; Schulte, Thomas; Freund, Juliane; Roden, Michael; Hoffmann, Barbara; Schikowski, Tamara; Luckhaus, Christian; Krämer, Ursula; Henle, Thomas; Herder, Christian
Advanced glycation end products (AGEs) may contribute to the development of type 2 diabetes and related complications, whereas their role in the early deterioration of glycaemia is unknown. While previous studies used antibody-based methods to quantify AGEs, data from tandem mass spectrometry coupled liquid chromatography (LC-MS/MS)-based measurements are limited to patients with known diabetes. Here, we used the LC-MS/MS method to test the hypothesis that plasma AGE levels are higher in individuals with impaired fasting glucose (IFG) than in those with normal fasting glucose (NFG). Secondary aims were to assess correlations of plasma AGEs with quantitative markers of glucose metabolism and biomarkers of subclinical inflammation. This study included on 60 women with NFG or IFG (n = 30 each, mean age 74 years) from the German SALIA cohort. Plasma levels of free metabolites (3-deoxyfructose, 3-deoxypentosone, 3-deoxypentulose), two hydroimidazolones, oxidised adducts (carboxymethyllysine, carboxyethyllysine, methionine sulfoxide) and Nε-fructosyllysine were measured using LC-MS/MS. Plasma concentrations of all tested AGEs did not differ between the NFG and IFG groups (all p>0.05). Associations between plasma levels of AGEs and fasting glucose, insulin and HOMA-IR as a measure of insulin resistance were weak (r between -0.2 and 0.2, all p>0.05). The association between 3-deoxyglucosone-derived hydroimidazolone with several proinflammatory biomarkers disappeared upon adjustment for multiple testing. In conclusion, plasma AGEs assessed by LC-MS/MS were neither increased in IFG nor associated with parameters of glucose metabolism and subclinical inflammation in our study. Thus, these data argue against strong effects of AGEs in the early stages of deterioration of glucose metabolism. PMID:26018950
Harrison, Neil A; Doeller, Christian F; Voon, Valerie; Burgess, Neil; Critchley, Hugo D
Inflammation impairs cognitive performance and is implicated in the progression of neurodegenerative disorders. Rodent studies demonstrated key roles for inflammatory mediators in many processes critical to memory, including long-term potentiation, synaptic plasticity, and neurogenesis. They also demonstrated functional impairment of medial temporal lobe (MTL) structures by systemic inflammation. However, human data to support this position are limited. Sequential fluorodeoxyglucose positron emission tomography together with experimentally induced inflammation was used to investigate effects of a systemic inflammatory challenge on human MTL function. Fluorodeoxyglucose positron emission tomography scanning was performed in 20 healthy participants before and after typhoid vaccination and saline control injection. After each scanning session, participants performed a virtual reality spatial memory task analogous to the Morris water maze and a mirror-tracing procedural memory control task. Fluorodeoxyglucose positron emission tomography data demonstrated an acute reduction in human MTL glucose metabolism after inflammation. The inflammatory challenge also selectively compromised human spatial, but not procedural, memory; this effect that was independent of actions on motivation or psychomotor response. Effects of inflammation on parahippocampal and rhinal glucose metabolism directly mediated actions of inflammation on spatial memory. These data demonstrate acute sensitivity of human MTL to mild peripheral inflammation, giving rise to associated functional impairment in the form of reduced spatial memory performance. Our findings suggest a mechanism for the observed epidemiologic link between inflammation and risk of age-related cognitive decline and progression of neurodegenerative disorders including Alzheimer's disease. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Ma, Dan; Shield, Julian P.H.; Dean, Wendy; Leclerc, Isabelle; Knauf, Claude; Burcelin, Rémy; Rutter, Guy A.; Kelsey, Gavin
Transient neonatal diabetes mellitus (TNDM) is a rare inherited diabetic syndrome apparent in the first weeks of life and again during early adulthood. The relative contributions of reduced islet β cell number and impaired β cell function to the observed hypoinsulinemia are unclear. The inheritance pattern of this imprinted disorder implicates overexpression of one or both genes within the TNDM locus: ZAC, which encodes a proapoptotic zinc finger protein, and HYMAI, which encodes an untranslated mRNA. To investigate the consequences for pancreatic function, we have developed a high-copy transgenic mouse line, TNDM29, carrying the human TNDM locus. TNDM29 neonates display hyperglycemia, and older adults, impaired glucose tolerance. Neonatal hyperglycemia occurs only on paternal transmission, analogous to paternal dependence of TNDM in humans. Embryonic pancreata of TNDM29 mice showed reductions in expression of endocrine differentiation factors and numbers of insulin-staining structures. By contrast, β cell mass was normal or elevated at all postnatal stages, whereas pancreatic insulin content in neonates and peak serum insulin levels after glucose infusion in adults were reduced. Expression of human ZAC and HYMAI in these transgenic mice thus recapitulates key features of TNDM and implicates impaired development of the endocrine pancreas and β cell function in disease pathogenesis. PMID:15286800
Valentino, Giovanna; Kramer, Verónica; Orellana, Lorena; Bustamante, María José; Casasbellas, Cinthia; Adasme, Marcela; Salazar, Alejandra; Navarrete, Carlos; Acevedo, Mónica
Background. Impaired fasting glucose (IFG) through the nondiabetic range (100–125 mg/dL) is not considered in the cardiovascular (CV) risk profile. Aim. To compare the clustering of CV risk factors (RFs) in nondiabetic subjects with normal fasting glucose (NFG) and IFG. Material and Methods. Cross-sectional study in 3739 nondiabetic subjects. Demographics, medical history, and CV risk factors were collected and lipid profile, fasting glucose levels (FBG), C-reactive protein (hsCRP), blood pressure (BP), anthropometric measurements, and aerobic capacity were determined. Results. 559 (15%) subjects had IFG: they had a higher mean age, BMI, waist circumference, non-HDL cholesterol, BP, and hsCRP (p < 0.0001) and lower HDL (p < 0.001) and aerobic capacity (p < 0.001). They also had a higher prevalence of hypertension (34% versus 25%; p < 0.001), dyslipidemia (79% versus 74%; p < 0.001), and obesity (29% versus 16%; p < 0.001) and a higher Framingham risk score (8% versus 6%; p < 0.001). The probability of presenting 3 or more CV RFs adjusted by age and gender was significantly higher in the top quintile of fasting glucose (≥98 mg/dL; OR = 2.02; 1.62–2.51). Conclusions. IFG in the nondiabetic range is associated with increased cardiovascular RF clustering. PMID:26504260
Gustavsson, Natalia; Lao, Ye; Maximov, Anton; Chuang, Jen-Chieh; Kostromina, Elena; Repa, Joyce J.; Li, Cai; Radda, George K.; Südhof, Thomas C.; Han, Weiping
Vertebrates express at least 15 different synaptotagmins with the same domain structure but diverse localizations and tissue distributions. Synaptotagmin-1,-2, and -9 act as calcium sensors for the fast phrase of neurotransmitter release, and synaptotagmin-12 acts as a calcium-independent modulator of release. The exact functions of the remaining 11 synaptotagmins, however, have not been established. By analogy to the role of synaptotagmin-1, -2, and -9 in neurotransmission, these other synaptotagmins may serve as Ca2+ transducers regulating other Ca2+-dependent membrane processes, such as insulin secretion in pancreatic β-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic β-cells. To determine whether synaptotagmin-7 regulates Ca2+-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor controlling insulin secretion in pancreatic β cells. PMID:18308938
Gustavsson, Natalia; Lao, Ye; Maximov, Anton; Chuang, Jen-Chieh; Kostromina, Elena; Repa, Joyce J; Li, Cai; Radda, George K; Südhof, Thomas C; Han, Weiping
Vertebrates express at least 15 different synaptotagmins with the same domain structure but diverse localizations and tissue distributions. Synaptotagmin-1,-2, and -9 act as calcium sensors for the fast phrase of neurotransmitter release, and synaptotagmin-12 acts as a calcium-independent modulator of release. The exact functions of the remaining 11 synaptotagmins, however, have not been established. By analogy to the role of synaptotagmin-1, -2, and -9 in neurotransmission, these other synaptotagmins may serve as Ca(2+) transducers regulating other Ca(2+)-dependent membrane processes, such as insulin secretion in pancreatic beta-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic beta-cells. To determine whether synaptotagmin-7 regulates Ca(2+)-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor controlling insulin secretion in pancreatic beta cells.
Thambisetty, Madhav; Beason-Held, Lori L; An, Yang; Kraut, Michael; Metter, Jeffrey; Egan, Josephine; Ferrucci, Luigi; O'Brien, Richard; Resnick, Susan M
We investigated whether individuals with impaired glucose tolerance (IGT) in midlife subsequently show regionally specific longitudinal changes in regional cerebral blood flow (rCBF) relative to those with normal glucose tolerance (NGT). Sixty-four cognitively normal participants in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging underwent serial (15)O-water positron emission tomography scans (age at first scan, 69.6 ± 7.5 years) and oral glucose tolerance tests 12 years earlier (age at first oral glucose tolerance test, 57.2 ± 11.1 years). Using voxel-based analysis, we compared changes in rCBF over an 8-year period between 15 participants with IGT in midlife and 49 with NGT. Significant differences were observed in longitudinal change in rCBF between the IGT and NGT groups. The predominant pattern was greater rCBF decline in the IGT group in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife is associated with subsequent longitudinal changes in brain function during aging even in cognitively normal older individuals.
Andries, Magdalene; Glintborg, Dorte; Andersen, Marianne
Hirsutism is a common disorder affecting 5-20% of women in reproductive age. Only limited follow-up data exist regarding the prognosis for glucose tolerance and metabolic risk factors in hirsutism. Sixty-nine Caucasian hirsute women underwent a clinical examination and an oral glucose tolerance test (OGTT) during 1997-2002 (baseline) and during 2003-2004 (re-evaluation). The observation period was (median; range) 4 (2-7) years. During re-evaluation, body mass index (BMI) was 24.9 (22.4-29.0) kg/m(2) and total Ferriman-Gallwey score was 10 (7-15) (median; 25-75% quartile). The women had unchanged BMI compared to baseline but increased fasting and 2 hour glucose levels. Impaired OGTT outcome during follow-up was seen in 14/66 (21.2%) women, 5/66 (7.6%) developed diabetes. Women who took oral contraceptives had a significantly decreased area under the curve (AUC) for insulin during follow-up, whereas AUC glucose levels increased. The present data supported a high risk of diabetes in only moderately overweight hirsute women.
Asghar, Zeenat A; Cusumano, Andrew; Yan, Zihan; Remedi, Maria S; Moley, Kelle H
Increased sugar consumption, particularly fructose, in the form of sweetened beverages and sweeteners in our diet adversely affects metabolic health. Because these effects are associated with features of the metabolic syndrome in humans, the direct effect of fructose on pancreatic islet function is unknown. Therefore, we examined the islet phenotype of mice fed excess fructose. Fructose-fed mice exhibited fasting hyperglycemia and glucose intolerance but not hyperinsulinemia, dyslipidemia, or hyperuricemia. Islet function was impaired, with decreased glucose-stimulated insulin secretion and increased glucagon secretion and high fructose consumption leading to α-cell proliferation and upregulation of the fructose transporter GLUT5, which was localized only in α-cells. Our studies demonstrate that excess fructose consumption contributes to hyperglycemia by affecting both β- and α-cells of islets in mice. Copyright © 2017 the American Physiological Society.
Weiss, Ram; Dufour, Sylvie; Taksali, Sara E; Tambortlane, William V; Petersen, Kitt F; Bonadonna, Riccardo C; Boselli, Linda; Barbetta, Gina; Alle, Karin; Rife, Francis; Savoye, Mary; Dziura, James; Sherwin, Robert; Shulman, Gerald I; Caprio, Sonia
Summary Background Impaired glucose tolerance is common among obese adolescents, but the changes in insulin sensitivity and secretion that lead to this prediabetic state are unknown. We investigated whether altered partitioning of myocellular and abdominal fat relates to abnormalities in glucose homoeostasis in obese adolescents with prediabetes. Methods We studied 14 obese children with impaired glucose tolerance and 14 with normal glucose tolerance, of similar ages, sex distribution, and degree of obesity. Insulin sensitivity and secretion were assessed by the euglycaemichyperinsulinaemic clamp and the hyperglycaemic clamp. Intramyocellular lipid was assessed by proton nuclear magnetic resonance spectroscopy and abdominal fat distribution by magnetic resonance imaging. Findings Peripheral glucose disposal was significantly lower in individuals with impaired than in those with normal glucose tolerance (mean 35·4 [SE 4·0] vs 60·6 [7·2] μmoles per kg lean body mass per min; p=0·023) owing to a reduction in non-oxidative glucose disposal metabolism (storage). Individuals with impaired glucose tolerance had higher intramyocellular lipid content (3·04 [0·43] vs 1·99 [0·19]%, p=0·03), lower abdominal subcutaneous fat (460  vs 626  cm2, p=0·04), and slightly higher visceral fat than the controls (70  vs 47  cm2, p=0·065), resulting in a higher ratio of visceral to subcutaneous fat (0·15 [0·02] vs 0·07 [0·01], p=0·002). Intramyocellular and visceral lipid contents were inversely related to the glucose disposal and non-oxidative glucose metabolism and positively related to the 2 h plasma glucose concentration. Interpretation In obese children and adolescents with prediabetes, intramyocellular and intra-abdominal lipid accumulation is closely linked to the development of severe peripheral insulin resistance. PMID:14511928
Weiss, Ram; Dufour, Sylvie; Taksali, Sara E; Tamborlane, William V; Petersen, Kitt F; Bonadonna, Riccardo C; Boselli, Linda; Barbetta, Gina; Allen, Karin; Rife, Francis; Savoye, Mary; Dziura, James; Sherwin, Robert; Shulman, Gerald I; Caprio, Sonia
Impaired glucose tolerance is common among obese adolescents, but the changes in insulin sensitivity and secretion that lead to this prediabetic state are unknown. We investigated whether altered partitioning of myocellular and abdominal fat relates to abnormalities in glucose homoeostasis in obese adolescents with prediabetes. We studied 14 obese children with impaired glucose tolerance and 14 with normal glucose tolerance, of similar ages, sex distribution, and degree of obesity. Insulin sensitivity and secretion were assessed by the euglycaemic-hyperinsulinaemic clamp and the hyperglycaemic clamp. Intramyocellular lipid was assessed by proton nuclear magnetic resonance spectroscopy and abdominal fat distribution by magnetic resonance imaging. Peripheral glucose disposal was significantly lower in individuals with impaired than in those with normal glucose tolerance (mean 35.4 [SE 4.0] vs 60.6 [7.2] micromoles per kg lean body mass per min; p=0.023) owing to a reduction in non-oxidative glucose disposal metabolism (storage). Individuals with impaired glucose tolerance had higher intramyocellular lipid content (3.04 [0.43] vs 1.99 [0.19]%, p=0.03), lower abdominal subcutaneous fat (460  vs 626  cm2, p=0.04), and slightly higher visceral fat than the controls (70  vs 47  cm2, p=0.065), resulting in a higher ratio of visceral to subcutaneous fat (0.15 [0.02] vs 0.07 [0.01], p=0.002). Intramyocellular and visceral lipid contents were inversely related to the glucose disposal and non-oxidative glucose metabolism and positively related to the 2 h plasma glucose concentration. In obese children and adolescents with prediabetes, intramyocellular and intra-abdominal lipid accumulation is closely linked to the development of severe peripheral insulin resistance.
Rancoule, Chloé; Dusaulcy, Rodolphe; Tréguer, Karine; Grès, Sandra; Attané, Camille; Saulnier-Blache, Jean Sébastien
Autotaxin (ATX) is a secreted lysophospholipase D involved in synthesis of lysophosphatidic acid (LPA), a phospholipid growth factor acting via specific receptors (LPA1R to LPA6R) and involved in several pathologies including obesity. ATX is secreted by adipocytes and contributes to circulating LPA. ATX expression is up-regulated in obese patients and mice in relationship with insulin resistance and impaired glucose tolerance. LPA1R is the most abundant subtype in adipose tissue. Its expression is higher in non-adipocyte cells than in adipocytes and is not altered in obesity. ATX increases and LPA1R decreases while preadipocytes differentiate into adipocytes (adipogenesis). LPA inhibits adipogenesis through down-regulation of the pro-adipogenic transcription factor PPARγ2. Adipocyte-specific knockout (FATX-KO) mice or mice treated with the LPAR antagonist Ki16425 gain more weight and accumulate more adipose tissue than wild type or control mice fed a high fat diet (HFD). These observations suggest that LPA (via LPA1R) exerts a tonic inhibitory effect on adipose tissue expansion that could, at least in part, result from the anti-adipogenic activity of LPA. A possible negative impact of LPA on insulin-sensitivity might also be considered. Despite being more sensitive to nutritional obesity, FATX-KO and Ki16425-treated mice fed a HFD show improved glucose tolerance when compared to wild type mice. Moreover, exogenously injected LPA acutely impairs glucose tolerance and insulin secretion. These observations show that LPA exerts a tonic deleterious impact on glucose homeostasis. In conclusion, ATX and LPA1R represent potential interesting pharmacological targets for the treatment of obesity-associated metabolic diseases. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
Uslan, Mark M.; Burton, Darren M.; Clements, Charles W.
Blood glucose meters (BGMs) that can be used nonvisually or with a visual limitation were introduced in the mid-1990s, but it was not until 2006 and 2007 that a new set of meters with accessibility features were introduced: Prodigy, Prodigy Autocode, and Prodigy Voice (Diagnostic Devices, Charlotte, NC), and Advocate and Advocate Redi-Code (TaiDoc, Taiwan). Accessibility attributes of the newly introduced BGMs were tabulated, and product design features were examined and documented. The Prodigy Voice was found to be the only one of these new BGMs that is fully usable by blind and visually impaired persons. PMID:19885356
Caesar, Robert; Reigstad, Christopher S; Bäckhed, Helene Kling; Reinhardt, Christoph; Ketonen, Maria; Lundén, Gunnel Östergren; Cani, Patrice D; Bäckhed, Fredrik
Obesity is associated with accumulation of macrophages in white adipose tissue (WAT), which contribute to the development of insulin resistance. Germ-free (GF) mice have reduced adiposity and are protected against diet-induced obesity, To investigate whether the gut microbiota and, specifically, gut-derived lipopolysaccharide (LPS) promote WAT inflammation and contribute to impaired glucose metabolism. Macrophage composition and expression of proinflammatory and anti-inflammatory markers were compared in WAT of GF, conventionally raised and Escherichia coli-monocolonised mice. Additionally, glucose and insulin tolerance in these mice was determined. The presence of a gut microbiota resulted in impaired glucose metabolism and increased macrophage accumulation and polarisation towards the proinflammatory M1 phenotype in WAT. Monocolonisation of GF mice for 4 weeks with E. coli W3110 or the isogenic strain MLK1067 (which expresses LPS with reduced immunogenicity) resulted in impaired glucose and insulin tolerance and promoted M1 polarisation of CD11b cells in WAT. However, colonisation with E. coli W3110 but not MLK1067 promoted macrophage accumulation and upregulation of proinflammatory and anti-inflammatory gene expression as well as JNK phosphorylation. Gut microbiota induced LPS-dependent macrophage accumulation in WAT, whereas impairment of systemic glucose metabolism was not dependent on LPS. These results indicate that macrophage accumulation in WAT does not always correlate with impaired glucose metabolism.
Donmoyer, C M; Ejiofor, J; Lacy, D B; Chen, S S; McGuinness, O P
During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) and net hepatic lactate release (NHLR) are markedly reduced (downward arrow approximately 45 and approximately 65%, respectively) with infection. Because small quantities of fructose are known to augment hepatic glucose uptake and lactate release in normal fasted animals, the aim of this work was to determine whether acute fructose infusion with TPN could correct the impairments in NHGU and NHLR during infection. Chronically catheterized conscious dogs received TPN for 5 days via the inferior vena cava at a rate designed to match daily basal energy requirements. On the third day of TPN administration, a sterile (SHAM, n = 12) or Escherichia coli-containing (INF, n = 11) fibrin clot was implanted in the peritoneal cavity. Forty-two hours later, somatostatin was infused with intraportal replacement of insulin (12 +/- 2 vs. 24 +/- 2 microU/ml, SHAM vs. INF, respectively) and glucagon (24 +/- 4 vs. 92 +/- 5 pg/ml) to match concentrations previously observed in sham and infected animals. After a 120-min basal period, animals received either saline (Sham+S, n = 6; Inf+S, n = 6) or intraportal fructose (0.7 mg x kg(-1) x min(-1); Sham+F, n = 6; Inf+F, n = 5) infusion for 180 min. Isoglycemia of 120 mg/dl was maintained with a variable glucose infusion. Combined tracer and arteriovenous difference techniques were used to assess hepatic glucose metabolism. Acute fructose infusion with TPN augmented NHGU by 2.9 +/- 0.4 and 2.5 +/- 0.3 mg x kg(-1) x min(-1) in Sham+F and Inf+F, respectively. The majority of liver glucose uptake was stored as glycogen, and NHLR did not increase substantially. Therefore, despite an infection-induced impairment in NHGU and different hormonal environments, small amounts of fructose enhanced NHGU similarly in sham and infected animals. Glycogen storage, not lactate release, was the preferential fate of the fructose-induced increase in hepatic glucose disposal in
Bethel, M Angelyn; Chacra, Antonio R; Deedwania, Prakash; Fulcher, Gregory R; Holman, Rury R; Jenssen, Trond; Kahn, Steven E; Levitt, Naomi S; McMurray, John J V; Califf, Robert M; Raptis, Sotirios A; Thomas, Laine; Sun, Jie-Lena; Haffner, Steven M
We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests. Copyright © 2013 Elsevier Inc. All rights reserved.
Baan, C A; Stolk, R P; Grobbee, D E; Witteman, J C; Feskens, E J
The authors carried out a study to investigate the association between different indicators of physical activity and the prevalence of impaired glucose tolerance (IGT) and newly diagnosed diabetes (nDM) in a population-based cohort of elderly men and women in the Netherlands. A sample of participants of the Rotterdam Study (n = 1,016) aged 55-75 years who were not known to have diabetes mellitus underwent an oral glucose tolerance test. Physical activity was assessed by means of a self-administered questionnaire and expressed as time spent on activities per week. Associations with the prevalence of IGT and nDM were assessed by logistic regression analysis after adjustment for age, body mass index, waist-hip ratio, family history of diabetes, and smoking. A total of 745 subjects had normal glucose tolerance, 153 IGT, and 118 nDM. The total amount of time spent on physical activity decreased with increasing glucose intolerance. Adjusted for main confounders, vigorous activities such as bicycling (men: odds ratio (OR) = 0.26, 95% confidence interval (CI) 0.14-0.49; women: OR = 0.37, 95% CI 0.18-0.78) and sports (men: OR = 0.28, 95% CI 0.11-0.74) showed an inverse association with the presence of nDM. For IGT, the associations pointed in the same direction but did not reach statistical significance. These results indicate that physical inactivity and glucose intolerance are associated among older adults similar to the way they are associated among middle-aged adults.
Vaidya, Anand; Cui, Liufu; Sun, Lixia; Lu, Bing; Chen, Shuohua; Liu, Xing; Zhou, Yong; Liu, Xiurong; Xie, Xiaobing; Hu, Frank B.; Wu, Shouling; Gao, Xiang
Abstract The worldwide prevalence and incidence of diabetes and obesity are increasing in pandemic proportions. This is particularly relevant for China, where an extremely large population is growing, aging, and urbanizing. We thus conducted a prospective study to examine the prevalence and incidence of impaired fasting glucose (IFG) and diabetes, the rate at which fasting blood glucose rises, and the major modifiable risk factors associated with these outcomes in a large Chinese population from the Kailuan prospective study. A prospective cohort included 100,279 Chinese participants, aged 18 years or more, who had available information on fasting blood glucose concentrations at the start of the study (2006). Examination surveys were conducted every 2 years in 2008 and 2010. For the analyses of incident diabetes, we included 76,869 participants who were free of diabetes, cardiovascular disease, and cancer at the baseline and participants in the 2008 and/or 2010 follow-up. Diabetes was defined by a fasting blood glucose concentration ≥7 mmol/L, self-reported history, or active treatment with insulin or any oral hypoglycemic agent. IFG was defined by a fasting blood glucose concentration between 5.6 and 6.9 mmol/L. During the 4-year study, the prevalence of diabetes and IFG rose from 6.6% to 7.7%, and 17.3% to 22.6%, respectively. There were 17,811 incident cases of IFG and 4867 incident cases of diabetes. The age-standardized incident rate of IFG and diabetes were 62.6/1000 person-years (51.2/1000 person-years in women and 73.8/1000 person-years in men) and 10.0/1000 person-years (7.8/1000 person-years in women and 12.1/1000 person-years in men), respectively. We observed steady increases in fasting blood glucose with body anthropometrics and in every defined category of body mass index, including in those traditionally considered to be well within the “normal” range. In this large longitudinal study of Chinese adults, we observed a high prevalence and
Kim, Ji Won; Lee, Min Ho; Park, Ji Eun; Yoon, Tae Ki; Lee, Woo Sik; Shim, Sung Han
Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age. The pro-inflammatory cytokine, interleukin (IL)-18, is associated with metabolic syndrome, and elevated serum IL-18 levels are related to obesity and insulin resistance in PCOS patients. However, the role of IL-18 in the PCOS remains unclear. So we examined whether or not two functional polymorphisms in the IL-18 gene, -137G>C and +183A>G, are associated with PCOS itself or glucose intolerance in Korean women with PCOS. The IL-18 genotypes of 126 women with PCOS and 113 controls were determined and their serum levels of lipid and hormone profiles measured. The insulin resistance index was calculated from the glucose and insulin concentrations obtained by oral glucose tolerance tests. There were no statistically significant differences in the distribution of -137 G>C polymorphisms among the women classified according to presence or absence of PCOS and obesity. However, the -137G/G allele was more frequent in the PCOS+impaired glucose regulation (IGR) group than PCOS+normal glucose tolerance group (X(2)=7.637, p(Bonf)=0.022). The PCOS group with only the -137G allele had a significantly increased risk of IGR compared to the PCOS group with the -137C allele (92 vs. 8%, odds ratio=6.325, 95% confidence interval=1.403-28.519). In the PCOS patients, the mean fasting and 2-h post-prandial plasma glucose level of patients with only the -137G allele was significantly higher than those of the patients with the -137C allele (88.87 ± 9.49 vs. 84.37 ± 6.19, p=0.002 and 120.07 ± 34.53 vs. 107.54 ± 27.13, p=0.038). Only one woman was heterozygous for the +183A>G polymorphism and the other 224 subjects were homozygous for the polymorphism (A/A). The IL-18 -137G allele could play a role in the predisposition to glucose intolerance in Korean women with PCOS, and the +183G allele of IL-18 is not associated with the Korean population. Copyright Â© 2011 Elsevier Ireland Ltd. All
Vaidya, Anand; Cui, Liufu; Sun, Lixia; Lu, Bing; Chen, Shuohua; Liu, Xing; Zhou, Yong; Liu, Xiurong; Xie, Xiaobing; Hu, Frank B; Wu, Shouling; Gao, Xiang
The worldwide prevalence and incidence of diabetes and obesity are increasing in pandemic proportions. This is particularly relevant for China, where an extremely large population is growing, aging, and urbanizing. We thus conducted a prospective study to examine the prevalence and incidence of impaired fasting glucose (IFG) and diabetes, the rate at which fasting blood glucose rises, and the major modifiable risk factors associated with these outcomes in a large Chinese population from the Kailuan prospective study.A prospective cohort included 100,279 Chinese participants, aged 18 years or more, who had available information on fasting blood glucose concentrations at the start of the study (2006). Examination surveys were conducted every 2 years in 2008 and 2010. For the analyses of incident diabetes, we included 76,869 participants who were free of diabetes, cardiovascular disease, and cancer at the baseline and participants in the 2008 and/or 2010 follow-up. Diabetes was defined by a fasting blood glucose concentration ≥7 mmol/L, self-reported history, or active treatment with insulin or any oral hypoglycemic agent. IFG was defined by a fasting blood glucose concentration between 5.6 and 6.9 mmol/L.During the 4-year study, the prevalence of diabetes and IFG rose from 6.6% to 7.7%, and 17.3% to 22.6%, respectively. There were 17,811 incident cases of IFG and 4867 incident cases of diabetes. The age-standardized incident rate of IFG and diabetes were 62.6/1000 person-years (51.2/1000 person-years in women and 73.8/1000 person-years in men) and 10.0/1000 person-years (7.8/1000 person-years in women and 12.1/1000 person-years in men), respectively. We observed steady increases in fasting blood glucose with body anthropometrics and in every defined category of body mass index, including in those traditionally considered to be well within the "normal" range.In this large longitudinal study of Chinese adults, we observed a high prevalence and incidence of IFG
Zheng, Fenping; Lu, Weina; Jia, Chengfang; Li, Hong; Wang, Zhou; Jia, Weiping
The effect of glucose excursions on oxidative stress is an important topic in diabetes research. We investigated this relationship by analyzing markers of oxidative stress and glycemic data from a continuous glucose monitoring system (CGMS) in 30 individuals with normal glucose regulation (NGR), 27 subjects with impaired glucose regulation (IGR), and 27 patients with newly diagnosed type 2 diabetes (T2DM). We compared the mean amplitude of glycemic excursion (MAGE), mean postprandial glucose excursion (MPPGE), and mean postprandial incremental area under the curve (IAUC) with plasma levels of oxidative stress markers 8-iso-PGF2α, 8-OH-dG, and protein carbonyl content in the study subjects. Patients with T2DM or IGR had significantly higher glucose excursions and plasma levels of oxidative stress markers compared to normal controls (P < 0.01 or 0.05). Multiple linear regression analyses showed significant relationships between MAGE and plasma 8-iso-PGF2α, and between MPPGE and plasma 8-OH-dG in patients with IGR or T2DM (P < 0.01 or 0.05). Furthermore, 2h-postprandial glucose level and IAUC were related to plasma protein carbonyl content in the study cohort including T2DM and IGR (P < 0.01). We demonstrate that glucose excursions in subjects with IGR and T2DM trigger the activation of oxidative stress.
Cheng, Licai; Yu, Yinghua; Szabo, Alexander; Wu, Yizhen; Wang, Hongqin; Camer, Danielle; Huang, Xu-Feng
The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. Copyright © 2015 Elsevier Inc. All rights reserved.
Fang, Qichen; Li, Huating; Song, Qianqian; Yang, Wenjing; Hou, Xuhong; Ma, Xiaojing; Lu, Junxi; Xu, Aimin; Jia, Weiping
OBJECTIVE Fibroblast growth factor 19 (FGF19), a hormone secreted from the small intestine, has recently been shown to stimulate glycogen synthesis and inhibit gluconeogenesis through insulin-independent pathways. This study investigated the change of FGF19 in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM) and explored the association of serum FGF19 levels with parameters of glucose metabolism in Chinese subjects. RESEARCH DESIGN AND METHODS Fasting serum FGF19 levels were determined by ELISA in 81 normal glucose tolerance (NGT), 91 impaired fasting glucose (IFG), 93 impaired glucose tolerance (IGT), and 104 newly diagnosed T2DM subjects, and their association with parameters of glucose metabolism was studied. An ordinal logistic regression analysis was performed in subjects with NGT, IFG, and T2DM. Serum FGF19 levels at 2 h after a 75-g oral glucose tolerance test in the different glucose tolerance categories were studied in a subgroup. RESULTS Fasting serum FGF19 levels in subjects with IFG (210 pg/mL [142–327]) (median [interquartile range]) and T2DM (196 pg/mL [137–280]) were significantly lower than those in NGT subjects (289 pg/mL [224–393]) (both P < 0.001). However, no significant difference in fasting FGF19 levels was observed between IGT (246 pg/mL [138–379]) and NGT subjects. Fasting serum FGF19 levels were negatively associated with fasting plasma glucose and independently associated with the deterioration of glucometabolic status from NGT to IFG and T2DM. CONCLUSIONS Fasting serum FGF19 levels were decreased in Chinese subjects with IFG and inversely associated with fasting glucose levels. PMID:23628619
Feigh, Michael; Andreassen, Kim V; Hjuler, Sara T; Nielsen, Rasmus H; Christiansen, Claus; Henriksen, Kim; Karsdal, Morten A
Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations. For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation. Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.
Nussbaumerova, Barbora; Rosolova, Hana; Krizek, Miroslav; Sefrna, Frantisek; Racek, Jaroslav; Müller, Ludek; Sindberg, Christian
Chromium (Cr) is considered as an important mineral, involved in biochemical reactions in human metabolic pathways. Organically bound Cr supplementation has been suggested to improve glycemia especially in patients with type 2 diabetes mellitus, but there are conflicting reports on efficacy. Effect of Cr is not clear in prediabetes status. Seventy patients with metabolic syndrome and impaired glucose tolerance (IGT), who are observed and treated in the Center of Preventive Cardiology of the University Hospital in Pilsen, were included in the prospective, randomized, double-blind, and placebo-controlled clinical study. Effect of Cr-enriched yeast (200 μg of elementary Cr in the morning and 100 μg in the evening) on glucose, lipid metabolism, fat tissue hormones, oxidative stress, and DNA damage markers was analyzed. There were no significant changes in glucose and lipid parameters, oxidative stress, or other laboratory markers. Only resting heart rate was significantly reduced in patients treated by Cr yeast, reflecting reduced sympathetic activity. This could represent an important cardiovascular risk reduction in patients with high cardiometabolic risk.
Gadad, Pramod C; Matthews, Kerr H; Knott, Rachel M
Reduced oxygen tension combined with high glucose concentration leads to chronic wounds in diabetic patients. Delayed wound healing is due in part to impaired angiogenesis as a result of reduced endothelial cell migration. Topical applications, in the form of sterile lyophilised wafers hold promise for the treatment of chronic diabetic wounds. In this study wafers containing silymarin were prepared using xanthan gum and sterilised with 25 and 40 kGy gamma radiation. The rheological properties of xanthan gels, before and after lyophilisation, were measured and it was concluded that an increased dose of gamma rays (40 kGy) increased the viscosity coefficient and yield stress of silymarin wafers. HPLC analysis indicated that 89-90% of silymarin was retained in the wafers after irradiation. Dermal microvascular cell migration studies in the presence of high glucose and reduced oxygen tension levels, using novel radial migration and wound healing assays developed 'in house', were also undertaken. Silymarin, when formulated as a lyophilised wafer, successfully retained its ability to overcome the high glucose induced reduction in endothelial cell migration. Copyright © 2013 Elsevier B.V. All rights reserved.
Cisternas, Pedro; Inestrosa, Nibaldo C
The brain is an organ that has a high demand for glucose. In the brain, glucose is predominantly used in energy production, with almost 70% of the energy used by neurons. The importance of the energy requirement in neurons is clearly demonstrated by the fact that all neurodegenerative disorders exhibit a critical metabolic impairment that includes decreased glucose uptake/utilization and decreased mitochondrial activity, with a consequent diminution in ATP production. In fact, in Alzheimer's disease, the measurement of the general metabolic rate of the brain has been reported to be an accurate tool for diagnosis. Additionally, the administration of metabolic activators such as insulin/glucagon-like peptide 1 can improve memory/learning performance. Despite the importance of energy metabolism in the brain, little is known about the cellular pathways involved in the regulation of this process. Several reports postulate a role for Wnt signaling as a general metabolic regulator. Thus, in the present review, we discuss the antecedents that support the relationship between Wnt signaling and energy metabolism in the Alzheimer's disease. Copyright © 2017. Published by Elsevier Ltd.
Yun, Hye Eun; Han, Mi-ah; Kim, Ki Soon; Park, Jong; Kang, Myeng Guen; Ryu, So Yeon
This study was performed to investigate the prevalence of impaired fasting glucose (IFG) and its related characteristics among healthy adults in some Korean rural areas. We conducted a cross-sectional study using the data from 1352 adults who were over the age 40 and under the age 70 and who were free of diabetes mellitus (DM), cardiovascular diseases and other diseases and who participated in a survey conducted as part of the Korean Rural Genomic Cohort Study. IFG was defined as a serum fasting glucose level between 100 and 125 mg/dL. The prevalence of IFG was 20.4% in men, 15.5% in women and 12.7% overall. Multivariate logistic regression analysis demonstrated that the independent risk factors for IFG were male gender, having a family history of DM, the quartiles of gamma glutamyltransferase and high sensitive C-reactive protein and the waist circumference. The homeostatis model assessment for insulin resistance was very strongly associated with IFG. The prevalence of metabolic syndrome (MS) and MS components was higher in the subjects with IFG then in those with normal fasting glucose (NFG). The result of study could supply evidence to find the high risk population and to determine a strategy for treating IFG. Further research is needed to explain the causal relationship and mechanisms of IFG.
Wu, Dongmei; Qiu, Yifu; Gao, Xiang; Yuan, Xiao-Bing; Zhai, Qiwei
SIRT1 plays crucial roles in glucose and lipid metabolism, and has various functions in different tissues including brain. The brain-specific SIRT1 knockout mice display defects in somatotropic signaling, memory and synaptic plasticity. And the female mice without SIRT1 in POMC neuron are more sensitive to diet-induced obesity. Here we created transgenic mice overexpressing SIRT1 in striatum and hippocampus under the control of CaMKIIα promoter. These mice, especially females, exhibited increased fat accumulation accompanied by significant upregulation of adipogenic genes in white adipose tissue. Glucose tolerance of the mice was also impaired with decreased Glut4 mRNA levels in muscle. Moreover, the SIRT1 overexpressing mice showed decreased energy expenditure, and concomitantly mitochondria-related genes were decreased in muscle. In addition, these mice showed unusual spontaneous physical activity pattern, decreased activity in open field and rotarod performance. Further studies demonstrated that SIRT1 deacetylated IRS-2, and upregulated phosphorylation level of IRS-2 and ERK1/2 in striatum. Meanwhile, the neurotransmitter signaling in striatum and the expression of endocrine hormones in hypothalamus and serum T3, T4 levels were altered. Taken together, our findings demonstrate that SIRT1 in forebrain regulates lipid/glucose metabolism and motor function. PMID:21738790
Jung, Su Yon; Sobel, Eric M; Papp, Jeanette C; Crandall, Carolyn J; Fu, Alan N; Zhang, Zuo-Feng
Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP-glucose variations. We used regression analysis plus stratification and graphic approaches. Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants' effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism-relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women. © 2016 WILEY PERIODICALS, INC.
Jung, Su Yon; Sobel, Eric M.; Papp, Jeanette C.; Crandall, Carolyn J.; Fu, Alan N.; Zhang, Zuo-Feng
Purpose Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. Methods With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP–glucose variations. We used regression analysis plus stratification and graphic approaches. Results Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants’ effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). Conclusions Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism–relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women. PMID:27377425
Kumar, Dommati Anand; Sweeya, Pisupati S. R.; Shukla, Srishti; Anusha, Sanga Venkata; Akshara, Dasari; Madhusudana, Kuncha; Tiwari, Ashok Kumar
Objective: The objective was to explore the effect of Dosakaya (DK) (Cucumis melo var. chito) juice on sucrose induced dysglycemia and disturbances in antioxidant defense in rats. Materials and Methods: Rats were preconditioned with DK juice before administration of sucrose beverage continuously for 1-month. Blood glucose tolerance test and glutathione (GSH) homeostasis pathways in kidney were analyzed in different group of animals at the end of the study. Results: DK juice diffused (P < 0.001) hypertriglyceridemia inducing effect of sucrose and arrested sucrose induced weight gain. It improved glucose tolerance ability by significantly reducing (P < 0.05) first-hour glycemic excursion and decreasing 2 h glycemic load (P < 0.05) following oral glucose tolerance test in sucrose fed animals. Furthermore, disturbances in antioxidant defense mechanisms in terms of GSH homeostasis in kidney were restored due to juice feeding. DK juice administration checked reduction in GSH-S-transferase and glyoxalase-I activity, thus, significantly mitigated lipid peroxidation (P < 0.05), and formation of advanced glycation end-products (P < 0.001) in kidney and serum (P < 0.01). Quantitative analysis of juice found it a rich source of protein and polyphenols. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed the presence of multiple protein bands in whole fruit juice. Therefore, SDS-PAGE protein fingerprint of DK juice may serve as a quality control tool for standardization of juice. Conclusion: The whole fruit juice of DK may become cost-effective, affordable health beverage in extenuating ill-health effects of sugar consumption. This is the first report identifying DK juice in preventing development dysglycemia, dyslipidemia, and oxidative stress induced due to chronic sucrose feeding in rats. SUMMARY Chronic sucrose consumption induced development of dysglycemia and also impaired antioxidant defense mechanism in rats. The oral administration of
Kumar, Dommati Anand; Sweeya, Pisupati S R; Shukla, Srishti; Anusha, Sanga Venkata; Akshara, Dasari; Madhusudana, Kuncha; Tiwari, Ashok Kumar
The objective was to explore the effect of Dosakaya (DK) (Cucumis melo var. chito) juice on sucrose induced dysglycemia and disturbances in antioxidant defense in rats. Rats were preconditioned with DK juice before administration of sucrose beverage continuously for 1-month. Blood glucose tolerance test and glutathione (GSH) homeostasis pathways in kidney were analyzed in different group of animals at the end of the study. DK juice diffused (P < 0.001) hypertriglyceridemia inducing effect of sucrose and arrested sucrose induced weight gain. It improved glucose tolerance ability by significantly reducing (P < 0.05) first-hour glycemic excursion and decreasing 2 h glycemic load (P < 0.05) following oral glucose tolerance test in sucrose fed animals. Furthermore, disturbances in antioxidant defense mechanisms in terms of GSH homeostasis in kidney were restored due to juice feeding. DK juice administration checked reduction in GSH-S-transferase and glyoxalase-I activity, thus, significantly mitigated lipid peroxidation (P < 0.05), and formation of advanced glycation end-products (P < 0.001) in kidney and serum (P < 0.01). Quantitative analysis of juice found it a rich source of protein and polyphenols. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed the presence of multiple protein bands in whole fruit juice. Therefore, SDS-PAGE protein fingerprint of DK juice may serve as a quality control tool for standardization of juice. The whole fruit juice of DK may become cost-effective, affordable health beverage in extenuating ill-health effects of sugar consumption. This is the first report identifying DK juice in preventing development dysglycemia, dyslipidemia, and oxidative stress induced due to chronic sucrose feeding in rats. Chronic sucrose consumption induced development of dysglycemia and also impaired antioxidant defense mechanism in rats. The oral administration of Dosakaya juice prior to sucrose feeding however, mitigated the
Lhamo, Sherpa Y; Supamai, Soonthornpun; Virasakdi, Chongsuvivatwong
The aim of this study was to determine the prevalence of impaired glucose regulation status in Sherpa adults living in the Everest area and in Kathmandu valley. A cross-sectional survey was conducted in Chaurikharka village (Everest area) and Kathmandu city on 119 and 121 randomly selected individuals, aged 30-70 years. They were assessed on conventional risk factors for diabetes, and an oral glucose tolerance test was performed. Based on the 2003 American Diabetes Association criteria, the prevalence in the Kathmandu city and Everest region of any impaired glucose regulation (IGR), isolated impaired fasting plasma glucose (isolated IFG), isolated impaired glucose tolerance (isolated IGT), and combined isolated IFG and isolated IGT were 55.4% vs. 23.5%, 42.1% vs. 14.3%, 1.7% vs. 0.8%, 11.6 vs. 8.4%, respectively. Using the subjects with normal glucose tolerance as the referent group and after adjusting for age, sex, physical activity, calories, and waist circumference, the odds ratios for isolated IFG and combined isolated IFG and isolated IGT of living in the highland region were 0.19 (0.08-0.44) and 0.33 (0.09-1.18), respectively. Isolated IFG was more common among the lowland Sherpas. Unlike combined isolated IFG and isolated IGT, this isolated IFG difference could not be explained by the difference of conventional diabetes mellitus risk factors.
Renner, Simone; Fehlings, Christiane; Herbach, Nadja; Hofmann, Andreas; von Waldthausen, Dagmar C.; Kessler, Barbara; Ulrichs, Karin; Chodnevskaja, Irina; Moskalenko, Vasiliy; Amselgruber, Werner; Göke, Burkhard; Pfeifer, Alexander; Wanke, Rüdiger; Wolf, Eckhard
OBJECTIVE The insulinotropic action of the incretin glucose-dependent insulinotropic polypeptide (GIP) is impaired in type 2 diabetes, while the effect of glucagon-like peptide-1 (GLP-1) is preserved. To evaluate the role of impaired GIP function in glucose homeostasis and development of the endocrine pancreas in a large animal model, we generated transgenic pigs expressing a dominant-negative GIP receptor (GIPRdn) in pancreatic islets. RESEARCH DESIGN AND METHODS GIPRdn transgenic pigs were generated using lentiviral transgenesis. Metabolic tests and quantitative stereological analyses of the different endocrine islet cell populations were performed, and β-cell proliferation and apoptosis were quantified to characterize this novel animal model. RESULTS Eleven-week-old GIPRdn transgenic pigs exhibited significantly reduced oral glucose tolerance due to delayed insulin secretion, whereas intravenous glucose tolerance and pancreatic β-cell mass were not different from controls. The insulinotropic effect of GIP was significantly reduced, whereas insulin secretion in response to the GLP-1 receptor agonist exendin-4 was enhanced in GIPRdn transgenic versus control pigs. With increasing age, glucose control deteriorated in GIPRdn transgenic pigs, as shown by reduced oral and intravenous glucose tolerance due to impaired insulin secretion. Importantly, β-cell proliferation was reduced by 60% in 11-week-old GIPRdn transgenic pigs, leading to a reduction of β-cell mass by 35% and 58% in 5-month-old and 1- to 1.4-year-old transgenic pigs compared with age-matched controls, respectively. CONCLUSIONS The first large animal model with impaired incretin function demonstrates an essential role of GIP for insulin secretion, proliferation of β-cells, and physiological expansion of β-cell mass. PMID:20185813
Herzog, Nina; Jauch-Chara, Kamila; Hyzy, Franziska; Richter, Annekatrin; Friedrich, Alexia; Benedict, Christian; Oltmanns, Kerstin M
Shortened nocturnal sleep impairs morning glucose tolerance. The underlying mechanism of this effect is supposed to involve a reduced fraction of slow wave sleep (SWS). However, it remains unanswered if impaired glucose tolerance occurs due to specific SWS reduction or a general disturbance of sleep. Sixteen healthy men participated in three experimental conditions in a crossover design: SWS suppression, rapid eye movement (REM)-sleep disturbance, and regular sleep. Selective sleep stage disturbance was performed by means of an acoustic tone (532Hz) with gradually rising sound intensity. Blood concentrations of glucoregulatory parameters were measured upon an oral glucose tolerance test the next morning. Our data show that morning plasma glucose and serum insulin responses were significantly increased after selective SWS suppression. Moreover, SWS suppression reduced postprandial insulin sensitivity up to 20%, as determined by Matsuda Index. Contrastingly, disturbed REM-sleep did not affect glucose homeostasis. We conclude that specifically SWS reduction is critically involved in the impairment of glucose tolerance associated with disturbed sleep. Therefore, glucose metabolism in subjects predisposed to reduced SWS (e.g. depression, aging, obstructive sleep apnea, pharmacological treatment) should be thoroughly monitored.
Khunti, K.; Bull, F.; Gorely, T.; Davies, M. J.
Although physical activity is widely reported to reduce the risk of type 2 diabetes in individuals with prediabetes, few studies have examined this issue independently of other lifestyle modifications. The aim of this review is to conduct a systematic review of controlled trials to determine the independent effect of exercise on glucose levels and risk of type 2 diabetes in people with prediabetes (IGT and/or IFG). A detailed search of MEDLINE (1966–2006) and EMBASE (1980–2006) found 279 potentially relevant studies, eight of which met the inclusion criteria for this review. All eight studies were controlled trials in individuals with impaired glucose tolerance. Seven studies used a multi-component lifestyle intervention that included exercise, diet and weight loss goals and one used a structured exercise training intervention. Four studies used the incidence of diabetes over the course of the study as an outcome variable and four relied on 2-h plasma glucose as an outcome measure. In the four studies that measured the incidence of diabetes as an outcome, the risk of diabetes was reduced by approximately 50% (range 42–63%); as these studies reported only small changes in physical activity levels, the reduced risk of diabetes is likely to be attributable to factors other than physical activity. In the remaining four studies, only one reported significant improvements in 2-h plasma glucose even though all but one reported small to moderate increases in maximal oxygen uptake. These results indicate that the contribution of physical activity independent of dietary or weight loss changes to the prevention of type 2 diabetes in people with prediabetes is equivocal. PMID:17415549
Background Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure. Methods In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). Results 100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients
Morris, Ken A; Gold, Paul E
Epinephrine enhances memory in young adult rats, in part, by increasing blood glucose levels needed to modulate memory. In old rats, epinephrine is deficient at raising blood glucose levels and thus is only moderately effective at enhancing memory. In contrast, systemic glucose injections improve memory in old rats, with resulting memory performance equal to that of young rats. The diminished response of glucose to training in old rats may blunt downstream neurochemical and molecular mechanisms needed to upregulate memory processes. In the first experiment, young adult and old rats were trained on an inhibitory avoidance task with immediate post-training injections of aCSF or glucose into the dorsal hippocampus. Old rats had significant memory impairments compared to young rats 7 days after training. Intrahippocampal injections of glucose reversed age-related deficits, improving memory scores in old rats to values seen in young rats. A second experiment examined age-related changes in activation of the transcription factor CREB, which is widely implicated in memory formation and may act downstream of hormonal and metabolic signals. Activation was assessed in response to training with systemic injections of epinephrine and glucose at doses known to enhance memory. Young adult and old rats were trained on inhibitory avoidance with immediate post-training systemic injections of saline, epinephrine, or glucose. After training, old rats had significant impairments in CREB phosphorylation in area CA1 and the dentate gyrus region of the hippocampus, and in the basolateral and lateral amygdala. Epinephrine and glucose attenuated age-related deficits in CREB phosphorylation, but were more effective in the amygdala and hippocampus, respectively. Together, these results support the view that age-related changes in blood glucose responses to epinephrine contribute to memory impairments, which may be related to alterations in regional patterns of CREB phosphorylation.
Morris, Ken A.; Gold, Paul E.
Epinephrine enhances memory in young adult rats, in part, by increasing blood glucose levels needed to modulate memory. In old rats, epinephrine is deficient at raising blood glucose levels and thus is only moderately effective at enhancing memory. In contrast, systemic glucose injections improve memory in old rats, with resulting memory performance equal to that of young rats. The diminished response of glucose to training in old rats may blunt downstream neurochemical and molecular mechanisms needed to upregulate memory processes. In the first experiment, young adult and old rats were trained on an inhibitory avoidance task with immediate post-training injections of aCSF or glucose into the dorsal hippocampus. Old rats had significant memory impairments compared to young rats 7 days after training. Intrahippocampal injections of glucose reversed age-related deficits, improving memory scores in old rats to values seen in young rats. A second experiment examined age-related changes in activation of the transcription factor CREB, which is widely implicated in memory formation and may act downstream of hormonal and metabolic signals. Activation was assessed in response to training with systemic injections of epinephrine and glucose at doses known to enhance memory. Young adult and old rats were trained on inhibitory avoidance with immediate post-training systemic injections of saline, epinephrine, or glucose. After training, old rats had significant impairments in CREB phosphorylation in area CA1 and the dentate gyrus region of the hippocampus, and in the basolateral and lateral amygdala. Epinephrine and glucose attenuated age-related deficits in CREB phosphorylation, but were more effective in the amygdala and hippocampus, respectively. Together, these results support the view that age-related changes in blood glucose responses to epinephrine contribute to memory impairments, which may be related to alterations in regional patterns of CREB phosphorylation. PMID
Leopold, Jane A.; Dam, Aamir; Maron, Bradley A.; Scribner, Anne W.; Liao, Ronglih; Handy, Diane E.; Stanton, Robert C.; Pitt, Bertram; Loscalzo, Joseph
Hyperaldosteronism is associated with impaired vascular reactivity; however, the mechanism by which aldosterone promotes endothelial dysfunction remains unknown. Glucose-6-phosphate dehydrogenase (G6pd), the principal source of Nadph, modulates vascular function by limiting oxidant stress to preserve bioavailable nitric oxide (NO•). In these studies, we show that aldosterone (10−9-10−7 mol/l) decreases endothelial G6pd expression and activity in vitro resulting in increased oxidant stress and decreased cGMP levels similar to what is observed in G6pd-deficient cells. Aldosterone decreases G6pd expression by protein kinase A activation to increase expression of Crem, which interferes with Creb binding to the G6pd promoter. In vivo, infusion of aldosterone decreases vascular G6pd expression and impairs vascular reactivity. These effects are abrogated by spironolactone or vascular gene transfer of G6pd. These studies demonstrate that aldosterone induces a G6pd-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6pd activity. PMID:17273168
Strawbridge, Andrew B.; Elmendorf, Jeffrey S.
Endothelin-1 (ET-1) disrupts insulin-regulated glucose transporter GLUT4 trafficking. Since the negative consequence of chronic ET-1 exposure appears to be independent of signal disturbance along the insulin receptor substrate-1/phosphatidylinositol (PI) 3-kinase (PI3K)/Akt-2 pathway of insulin action, we tested if ET-1 altered GLUT4 regulation engaged by osmotic shock, a PI3K-independent stimulus that mimics insulin action. Regulation of GLUT4 by hyperosmotic stress was impaired by ET-1. Because of the mutual disruption of both insulin- and hyperosmolarity-stimulated GLUT4 translocation, we tested whether shared signaling and/or key phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated cytoskeletal events of GLUT4 trafficking were targets of ET-1. Both insulin and hyperosmotic stress signaling to Cbl were impaired by ET-1. Also, plasma membrane PIP2 and cortical actin levels were reduced in cells exposed to ET-1. Exogenous PIP2, but not PI 3,4,5-bisphosphate, restored actin structure, Cbl activation, and GLUT4 translocation. These data show that ET-1-induced PIP2/actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity. In addition to showing for the first time the important role of PIP2-regulated cytoskeletal events in GLUT4 regulation by stimuli other than insulin, these studies reveal a novel function of PIP2/actin structure in signal transduction. PMID:16240321
Strawbridge, Andrew B; Elmendorf, Jeffrey S
Endothelin-1 (ET-1) disrupts insulin-regulated glucose transporter GLUT4 trafficking. Since the negative consequence of chronic ET-1 exposure appears to be independent of signal disturbance along the insulin receptor substrate-1/phosphatidylinositol (PI) 3-kinase (PI3K)/Akt-2 pathway of insulin action, we tested if ET-1 altered GLUT4 regulation engaged by osmotic shock, a PI3K-independent stimulus that mimics insulin action. Regulation of GLUT4 by hyperosmotic stress was impaired by ET-1. Because of the mutual disruption of both insulin- and hyperosmolarity-stimulated GLUT4 translocation, we tested whether shared signaling and/or key phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated cytoskeletal events of GLUT4 trafficking were targets of ET-1. Both insulin and hyperosmotic stress signaling to Cbl were impaired by ET-1. Also, plasma membrane PIP2 and cortical actin levels were reduced in cells exposed to ET-1. Exogenous PIP2, but not PI 3,4,5-bisphosphate, restored actin structure, Cbl activation, and GLUT4 translocation. These data show that ET-1-induced PIP2/actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity. In addition to showing for the first time the important role of PIP2-regulated cytoskeletal events in GLUT4 regulation by stimuli other than insulin, these studies reveal a novel function of PIP2/actin structure in signal transduction. 2005 Wiley-Liss, Inc.
Swithers, Susan E; Laboy, Alycia F; Clark, Kiely; Cooper, Stephanie; Davidson, T L
Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety.
Swithers, Susan E.; Laboy, Alycia F.; Clark, Kiely; Cooper, Stephanie; Davidson, T.L.
Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety. PMID:22561130
Kadota, Yoshihiro; Kazama, Shunsuke; Bajotto, Gustavo; Kitaura, Yasuyuki; Shimomura, Yoshiharu
It has been reported that branched-chain amino acid (BCAA) administration stimulates glucose uptake into muscles and whole body glucose oxidation in rats. The authors examined the effect of decreased plasma BCAA concentrations induced by clofibrate treatment on glucose tolerance in rats. Since clofibrate, a drug for hyperlipidemia (high serum triglyceride concentration), is a potent inhibitor of the branched-chain α-keto acid dehydrogenase kinase, clofibrate treatment (0.2 g/kg body weight) activated the hepatic branched-chain α-keto acid dehydrogenase complex, resulting in decreased plasma BCAA concentrations by 30% to 50% from the normal level. An intraperitoneal glucose tolerance test was conducted after clofibrate administration, and the results showed that peak plasma glucose concentration and the area under the curve of glucose concentration during the intraperitoneal glucose tolerance test were significantly higher in clofibrate-treated rats than in control rats. This impaired glucose tolerance in the clofibrate-treated rats was ameliorated by administration of BCAAs (0.45 g/kg body weight, leucine:isoleucine:valine = 2:1:1), which kept plasma BCAA concentrations at normal levels during the intraperitoneal glucose tolerance test. These results suggest that plasma BCAAs play an important role in maintaining normal glucose tolerance in rats.
Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue and increased vulnerability to fractures. Osteoporosis may result from disease, dietary or hormonal deficiency ...
Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue and increased vulnerability to fractures. Osteoporosis may result from disease, dietary or hormonal deficiency ...
Hsu, Tzu-Fang; Kise, Mitsuo; Wang, Ming-Fu; Ito, Yukihiko; Yang, Mei-Due; Aoto, Hiromichi; Yoshihara, Rie; Yokoyama, Jyunichi; Kunii, Daisuke; Yamamoto, Shigeru
White rice (WR) is made by polishing brown rice (BR) and has lost various nutrients; however, most people prefer it to BR, maybe because of the hardness of BR. Pre-germinated brown rice (PGBR) improves the problem of BR. It is made by soaking BR kernels in water to germinate and becomes softer than BR. In this study we compared the effects of WR and PGBR on blood glucose and lipid concentrations in the impaired fasting glucose (IFG) or type 2 diabetes patients. Six men and 5 women with impaired fasting glucose (IFG) or type 2 diabetes were randomly allocated to 6 wk on WR or PGBR diet separated by a 2 wk washout interval in a crossover design. Each subject was instructed to consume 3 packs of cooked WR or PGBR (180 g/pack) daily in each intervention phase. Blood samples were collected 4 times (in study weeks 0, 6, 8 and 14) for biochemical examination. Blood concentrations of fasting blood glucose, fructosamine, serum total cholesterol and triacylglycerol levels were favorably improved on the PGBR diet (p<0.01), but not on the WR diet. The present results suggest that diets including PGBR may be useful to control blood glucose level.
Short-term glucose metabolism and gut hormone modulations after Billroth II gastrojejunostomy in nonobese gastric cancer patients with type 2 diabetes mellitus, impaired glucose tolerance and normal glucose tolerance.
Zhang, Xiao-juan; Xiao, Zhu; Yu, Hong-ling; Zhang, Xiang-xun; Cheng, Zhong; Tian, Hao-ming
Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.
Ma, Lan; Aijima, Reona; Hoshino, Yoshihiro; Yamaza, Haruyoshi; Tomoda, Erika; Tanaka, Yosuke; Sonoda, Soichiro; Song, Guangtai; Zhao, Wei; Nonaka, Kazuaki; Shi, Songtao; Yamaza, Takayoshi
Secondary osteoporosis is common in systemic lupus erythematosus and leads to a reduction in quality of life due to fragility fractures, even in patients with improvement of the primary disorder. Systemic transplantation of mesenchymal stem cells could ameliorate bone loss and autoimmune disorders in a MRL/lpr mouse systemic lupus erythematosus model, but the detailed therapeutic mechanism of bone regeneration is not fully understood. In this study, we transplanted human bone marrow mesenchymal stem cells (BMMSCs) and stem cells from exfoliated deciduous teeth (SHED) into MRL/lpr mice and explored their therapeutic mechanisms in secondary osteoporotic disorders of the systemic lupus erythematosus model mice. The effects of systemic human mesenchymal stem cell transplantation on bone loss of MRL/lpr mice were analyzed in vivo and ex vivo. After systemic human mesenchymal stem cell transplantation, recipient BMMSC functions of MRL/lpr mice were assessed for aspects of stemness, osteogenesis and osteoclastogenesis, and a series of co-culture experiments under osteogenic or osteoclastogenic inductions were performed to examine the efficacy of interleukin (IL)-17-impaired recipient BMMSCs in the bone marrow of MRL/lpr mice. Systemic transplantation of human BMMSCs and SHED recovered the reduction in bone density and structure in MRL/lpr mice. To explore the mechanism, we found that impaired recipient BMMSCs mediated the negative bone metabolic turnover by enhanced osteoclastogenesis and suppressed osteoblastogenesis in secondary osteoporosis of MRL/lpr mice. Moreover, IL-17-dependent hyperimmune conditions in the recipient bone marrow of MRL/lpr mice damaged recipient BMMSCs to suppress osteoblast capacity and accelerate osteoclast induction. To overcome the abnormal bone metabolism, systemic transplantation of human BMMSCs and SHED into MRL/lpr mice improved the functionally impaired recipient BMMSCs through IL-17 suppression in the recipient bone marrow and then
Francini, Flavio; Castro, María C; Gagliardino, Juan J; Massa, María L
We evaluated the relative role of different regulatory mechanisms, particularly 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFK2/FBPase-2), in liver glucokinase (GK) activity in intact animals with fructose-induced insulin resistance and impaired glucose and lipid metabolism. We measured blood glucose, triglyceride and insulin concentration, glucose tolerance, liver triglyceride content, GK activity, and GK and PFK2 protein and gene expression in fructose-rich diet (FRD) and control rats. After 3 weeks, FRD rats had significantly higher blood glucose, insulin and triglyceride levels, and liver triglyceride content, insulin resistance, and impaired glucose tolerance. FRD rats also had significantly higher GK activity in the cytosolic fraction (18.3 +/- 0.35 vs. 11.27 +/- 0.34 mU/mg protein). Differences in GK protein concentration (116% and 100%) were not significant, suggesting a potentially impaired GK translocation in FRD rats. Although GK transcription level was similar, PFK2 gene expression and protein concentration were 4- and 5-fold higher in the cytosolic fraction of FRD animals. PFK2 immunological blockage significantly decreased GK activity in control and FRD rats; in the latter, this blockage decreased GK activity to control levels. Results suggest that increased liver GK activity might participate in the adaptative response to fructose overload to maintain glucose/triglyceride homeostasis in intact animals. Under these conditions, PFK2 increase would be the main enhancer of GK activity.
Yanagisawa, Rie; Koike, Eiko; Win-Shwe, Tin-Tin; Yamamoto, Megumi; Takano, Hirohisa
Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. Yanagisawa R, Koike E, Win-Shwe TT, Yamamoto M, Takano H. 2014. Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet. Environ Health Perspect 122:277-283; http://dx.doi.org/10.1289/ehp.1307421.
Koike, Eiko; Win-Shwe, Tin-Tin; Yamamoto, Megumi; Takano, Hirohisa
Background: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. Objectives: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). Methods: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. Results: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. Conclusions: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. Citation: Yanagisawa R, Koike E, Win-Shwe TT, Yamamoto M, Takano H. 2014. Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet. Environ Health
Smirnova, Elena; Podtaev, Sergey; Mizeva, Irina; Loran, Evgenia
The objective of this study is to explore changes in microvascular tone during a contralateral cold pressor test and to compare the results obtained in healthy subjects and in patients with impaired glucose tolerance (IGT) and type 2 diabetes. Low-amplitude fluctuations of skin temperature in the appropriate frequency ranges were used as a characteristic for the mechanism for vascular tone regulation. In total, 13 adults with type 2 diabetes aged 40-67 years and 18 adults with IGT aged 31-60 years participated in this pilot study. The control group included 12 healthy men and women aged 39-60 years. The response to the cold pressor test in patients with type 2 diabetes and with IGT differs essentially from that of healthy subjects in the endothelial frequency range. Endothelial dysfunction occurs in the preclinical stage of diabetes and manifests, in particular, as a disturbance of the endothelial part of vascular tone regulation.
Mitrou, P; Petsiou, E; Papakonstantinou, E; Maratou, E; Lambadiari, V; Dimitriadis, P; Spanoudi, F; Raptis, S A; Dimitriadis, G
Previous studies support the glucose-lowering effect of vinegar. However, the effect of vinegar on muscle glucose metabolism and endothelial function has not been studied in humans. This open, randomized, crossover, placebo-controlled study aims to investigate the effects of vinegar on muscle glucose metabolism, endothelial function and circulating lipid levels in subjects with impaired glucose tolerance (IGT) using the arteriovenous difference technique. Eight subjects with IGT (4 males, age 46±10 years, body mass index 30±5) were randomised to consume 0.50 mmol vinegar (6% acetic acid) or placebo before a mixed meal. Plasma samples were taken for 300 min from the radial artery and the forearm vein for measurements of glucose, insulin, triglycerides, non-esterified fatty acids (NEFAs) and glycerol. Muscle blood flow was measured with strain gauge plethysmography. Glucose flux was calculated as the arteriovenous difference of glucose multiplied by the blood flow rates. Vinegar compared with placebo: (1) decreased arterial plasma insulin (Poverall<0.001; P75 min=0.014, β=-42), (2) increased forearm blood flow (Poverall<0.001; P240 min=0.011, β=1.53; P300 min=0.023, β=1.37), (3) increased muscle glucose uptake (Poverall<0.001; P60 min=0.029, β=2.78) and (4) decreased arterial plasma triglycerides (Poverall=0.005; P240 min<0.001, β=-344; P300 min<0.001, β=-373), without changing NEFA and glycerol. In individuals with IGT, vinegar ingestion before a mixed meal results in an enhancement of muscle blood flow, an improvement of glucose uptake by the forearm muscle and a reduction of postprandial hyperinsulinaemia and hypertriglyceridaemia. From this point of view, vinegar may be considered beneficial for improving insulin resistance and metabolic abnormalities in the atherogenic prediabetic state.
Gebe, John A.; Unrath, Kellee A.; Yue, Betty B.; Miyake, Tom; Falk, Ben A.; Nepom, Gerald T.
A human TcR derived from an autoreactive T cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TCR was a CD4+ TH1+T cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2o/o/I-Abo/o/B6 background exhibited a CD4+ infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555–567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1 percent of CD4+ T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555–567 responsive T cells secrete IFN-γ, minimal IL2 and TNFα and no IL4, IL5, IL10, or IL17, consistent with a TH1 profile. These data demonstrate that CD4+ T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D. PMID:17949947
Molfino, Alessio; Cascino, Antonia; Conte, Caterina; Ramaccini, Cesarina; Rossi Fanelli, Filippo; Laviano, Alessandro
Reduced circulating and tissue carnitine levels, possibly leading to impaired mitochondrial function, have been postulated to be involved in the pathogenesis of insulin resistance. However, whether L-carnitine administration may improve insulin sensitivity in patients with impaired fasting glucose (IFG) or type 2 diabetes mellitus (DM-2) is still controversial. The aim of the study was to explore the role of L-carnitine supplementation in influencing insulin sensitivity. A randomized controlled study involving adult outpatients was designed. Adult patients referred to the outpatient clinic and within 10 days of the diagnosis of IFG or DM-2 were consecutively enrolled. Exclusion criteria were concomitant antidiabetic therapy and modifications of lifestyle during the previous 4 weeks. Patients were randomly assigned to receive a hypocaloric diet for 10 days (group C; n = 8) or the same dietetic regimen in addition to oral L-carnitine (2 g twice daily) supplementation (group LC; n = 8). Oral glucose tolerance test (OGTT), fasting plasma insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed at the beginning and end of the study. Data were statistically analyzed using the Student t test for paired and unpaired data. OGTT at 2 hours improved in both groups. Only in the L-carnitine-supplemented group did plasma insulin levels and HOMA-IR significantly decrease when compared to baseline values. Considering the role of caloric restriction in increasing the intestinal uptake of carnitine, the results suggest that oral L-carnitine administration, when associated with a hypocaloric feeding regimen, improves insulin resistance and may represent an adjunctive treatment for IFG and DM-2.
Lokhov, Petr G; Trifonova, Oxana P; Maslov, Dmitry L; Balashova, Elena E; Archakov, Alexander I; Shestakova, Ekaterina A; Shestakova, Marina V; Dedov, Ivan I
The goal of this study was to evaluate the capacity for mass spectrometry of blood plasma to diagnose impaired glucose tolerance (IGT). For this study, blood plasma samples from control subjects (n = 30) and patients with IGT (n = 20) were treated with methanol and low molecular weight fraction were then analyzed by direct infusion mass spectrometry. A total of 51 metabolite ions strongly associated with IGT were detected. The area under a receiver operating characteristic (ROC) curve (AUC) for diagnosing IGT that was based on an analysis of all these metabolites was 0.93 (accuracy 90%, specificity 90%, and sensitivity 90%). The associated reproducibility was 85%. The metabolites identified were also consistent with risk factors previously associated with the development of diabetes. Thus, direct infusion mass spectrometry of blood plasma metabolites represents a rapid, single-step, and reproducible method for the analysis of metabolites. Moreover, this method has the potential to serve as a prototype for clinical analyses that could replace the currently used glucose tolerance test with a more patient-friendly assay.
Lokhov, Petr G.; Trifonova, Oxana P.; Maslov, Dmitry L.; Balashova, Elena E.; Archakov, Alexander I.; Shestakova, Ekaterina A.; Shestakova, Marina V.; Dedov, Ivan I.
The goal of this study was to evaluate the capacity for mass spectrometry of blood plasma to diagnose impaired glucose tolerance (IGT). For this study, blood plasma samples from control subjects (n = 30) and patients with IGT (n = 20) were treated with methanol and low molecular weight fraction were then analyzed by direct infusion mass spectrometry. A total of 51 metabolite ions strongly associated with IGT were detected. The area under a receiver operating characteristic (ROC) curve (AUC) for diagnosing IGT that was based on an analysis of all these metabolites was 0.93 (accuracy 90%, specificity 90%, and sensitivity 90%). The associated reproducibility was 85%. The metabolites identified were also consistent with risk factors previously associated with the development of diabetes. Thus, direct infusion mass spectrometry of blood plasma metabolites represents a rapid, single-step, and reproducible method for the analysis of metabolites. Moreover, this method has the potential to serve as a prototype for clinical analyses that could replace the currently used glucose tolerance test with a more patient-friendly assay. PMID:25202985
Klemens, Patrick A W; Patzke, Kathrin; Trentmann, Oliver; Poschet, Gernot; Büttner, Michael; Schulz, Alexander; Marten, Irene; Hedrich, Rainer; Neuhaus, H Ekkehard
Arabidopsis vacuoles harbor, besides sugar transporter of the TMT-type, an early response to dehydration like 6 (ERDL6) protein involved in glucose export into the cytosol. However, the mode of transport of ERDL6 and the plant's feedback to overexpression of its activity on essential properties such as, for example, seed germination or freezing tolerance, remain unexplored. Using patch-clamp studies on vacuoles expressing AtERDL6 we demonstrated directly that this carrier operates as a proton-driven glucose exporter. Overexpression of BvIMP, the closest sugar beet (Beta vulgaris) homolog to AtERDL6, in Arabidopsis leads surprisingly to impaired seed germination under both conditions, sugar application and low environmental temperatures, but not under standard conditions. Upon cold treatment, BvIMP overexpressor plants accumulated lower quantities of monosaccharides than the wild-type, a response in line with the reduced frost tolerance of the transgenic Arabidopsis plants, and the fact that cold temperatures inhibits BvIMP transcription in sugar beet leaves. With these findings we show that the tight control of vacuolar sugar import and export is a key requisite for cold tolerance and seed germination of plants.
Katsoulieris, Elias N.; Drossopoulou, Garyfalia I.; Kotsopoulou, Eleni S.; Vlahakos, Dimitrios V.; Lianos, Elias A.; Tsilibary, Effie C.
Objective Chronic hyperglycaemia, as seen in type II diabetes, results in both morphological and functional impairments of podocytes in the kidney. We investigated the effects of high glucose (HG) on the insulin signaling pathway, focusing on cell survival and apoptotic markers, in immortalized human glomerular cells (HGEC; podocytes) and isolated glomeruli from healthy rats. Methods and Findings HGEC and isolated glomeruli were cultured for various time intervals under HG concentrations in the presence or absence of insulin. Our findings indicated that exposure of HGEC to HG led to downregulation of all insulin signaling markers tested (IR, p-IR, IRS-1, p-Akt, p-Fox01,03), as well as to increased sensitivity to apoptosis (as seen by increased PARP cleavage, Casp3 activation and DNA fragmentation). Short insulin pulse caused upregulation of insulin signaling markers (IR, p-IR, p-Akt, p-Fox01,03) in a greater extent in normoglycaemic cells compared to hyperglycaemic cells and for the case of p-Akt, in a PI3K-dependent manner. IRS-1 phosphorylation of HG-treated podocytes was negatively regulated, favoring serine versus tyrosine residues. Prolonged insulin treatment caused a significant decrease of IR levels, while alterations in glucose concentrations for various time intervals demonstrated changes of IR, p-IR and p-Akt levels, suggesting that the IR signaling pathway is regulated by glucose levels. Finally, HG exerted similar effects in isolated glomeruli. Conclusions These results suggest that HG compromises the insulin signaling pathway in the glomerulus, promoting a proapoptotic environment, with a possible critical step for this malfunction lying at the level of IRS-1 phosphorylation; thus we herein demonstrate glomerular insulin signaling as another target for investigation for the prevention and/ or treatment of diabetic nephropathy. PMID:27434075
Wang, Ting; Xu, Dandan; Fan, Qiming; Rong, Weifeng; Zheng, Jiewei; Gao, Chen; Li, Guoliang; Zeng, Ni; Guo, Tao; Zeng, Lihai; Wang, Fei; Xiao, Chen; Cai, Li; Tang, Shangqing; Deng, Xinlei; Yin, Xiao; Huang, Manqi; Lu, Fengrong; Hu, Qiansheng; Chen, Wen; Huang, Zhenlie; Wang, Qing
Excessive exposure to 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to liver dysfunction. To fully explore the mechanism of 1,2-DCE-induced hepatic abnormalities, 30 male National Institutes of Health (NIH) Swiss mice were exposed to 0, 350, or 700mg/m(3) of 1,2-DCE, via inhalation, 6h/day for 28days. Increased liver/body weight ratios, as well as serum AST and serum ALT activity were observed in the 350 and 700mg/m(3) 1,2-DCE exposure group mice, compared with the control group mice. In addition, decreased body weights were observed in mice exposed to 700mg/m(3) 1,2-DCE, compared with control mice. Exposure to 350 and 700mg/m(3) 1,2-DCE also led to significant accumulation of hepatic glycogen, free fatty acids (FFA) and triglycerides, elevation of blood triglyceride and FFA levels, and decreases in blood glucose levels. Results from microarray analysis indicated that the decreases in glucose-6-phosphatase catalytic subunit (G6PC) and liver glycogen phosphorylase (PYGL) expression, mediated by the activation of AKT serine/threonine kinase 1 (Akt1), might be responsible for the hepatic glycogen accumulation and steatosis. Further in vitro study demonstrated that 2-chloroacetic acid (1,2-DCE metabolite), rather than 1,2-DCE, up-regulated Akt1 phosphorylation and suppressed G6PC and PYGL expression, resulting in hepatocellular glycogen accumulation. These results suggest that hepatic glucose and lipid homeostasis are impaired by 1,2-DCE exposure via down-regulation of PYGL and G6PC expression, which may be primarily mediated by the 2-chloroacetic acid-activated Akt1 pathway.
De Feo, P; Gallai, V; Mazzotta, G; Crispino, G; Torlone, E; Perriello, G; Ventura, M M; Santeusanio, F; Brunetti, P; Bolli, G B
To establish the glycemic threshold for onset of neuroglycopenia (impaired cognitive function, measured by the latency of the P300 wave), activation of hormonal counterregulation and hypoglycemic symptoms, 12 normal subjects were studied either under conditions of insulin-induced, glucose-controlled plasma glucose decrements, or during maintenance of euglycemia. A decrement in plasma glucose concentration from 88 +/- 3 to 80 +/- 1 mg/dl for 150 min did not result in changes in the latency of the P300 wave nor in an activation of counterregulatory hormonal response. In contrast, a greater decrement in plasma glucose concentration from 87 +/- 3 to 72 +/- 1 mg/dl for 120 min caused an increase in the latency of the P300 wave (from 301 +/- 12 to 348 +/- 20 ms, P less than 0.01), a subsequent increase in all counterregulatory hormones but no hypoglycemic symptoms. Finally, when plasma glucose concentration was decreased in a stepwise manner from 88 +/- 2 to 50 +/- 1 mg/dl within 75 min, the increase in the latency of the P300 wave was correlated with the corresponding plasma glucose concentration (r = -0.76, P less than 0.001). The glycemic threshold for hypoglycemic symptoms was 49 +/- 2 mg/dl. Thus, in normal man the glycemic threshold for neuroglycopenia (72 +/- 1 mg/dl) is greater than currently thought; the hormonal counterregulation follows the onset of neuroglycopenia; the hypoglycemic symptoms are a late indicator of advanced neuroglycopenia. PMID:3403713
Palatini, Paolo; Benetti, Elisabetta; Mos, Lucio; Garavelli, Guido; Mazzer, Adriano; Cozzio, Susanna; Fania, Claudio; Casiglia, Edoardo
Whether and how coffee use influences glucose metabolism is still a matter for debate. We investigated whether baseline coffee consumption is longitudinally associated with risk of impaired fasting glucose in a cohort of 18-to-45 year old subjects screened for stage 1 hypertension and whether CYP1A2 polymorphism modulates this association. A total of 1,180 nondiabetic patients attending 17 hospital centers were included. Seventy-four percent of our subjects drank coffee. Among the coffee drinkers, 87% drank 1-3 cups/day (moderate drinkers), and 13% drank over 3 cups/day (heavy drinkers). Genotyping of CYP1A2 SNP was performed by real time PCR in 639 subjects. At the end of a median follow-up of 6.1 years, impaired fasting glucose was found in 24.0% of the subjects. In a multivariable Cox regression coffee use was a predictor of impaired fasting glucose at study end, with a hazard ratio (HR) of 1.3 (95% CI 0.97-1.8) in moderate coffee drinkers and of 2.3 (1.5-3.5) in heavy drinkers compared to abstainers. Among the subjects stratified by CYP1A2 genotype, heavy coffee drinkers carriers of the slow *1F allele (59%) had a higher adjusted risk of impaired fasting glucose (HR 2.8, 95% CI 1.3-5.9) compared to abstainers whereas this association was of borderline statistical significance among the homozygous for the A allele (HR 1.7, 95% CI 0.8-3.8). These data show that coffee consumption increases the risk of impaired fasting glucose in hypertension particularly among carriers of the slow CYP1A2 *1F allele.
Sakane, Naoki; Sato, Juichi; Tsushita, Kazuyo; Tsujii, Satoru; Kotani, Kazuhiko; Tominaga, Makoto; Kawazu, Shoji; Sato, Yuzo; Usui, Takeshi; Kamae, Isao; Yoshida, Toshihide; Kiyohara, Yutaka; Sato, Shigeaki; Tsuzaki, Kokoro; Nirengi, Shinsuke; Takahashi, Kaoru; Kuzuya, Hideshi; Group, JDPP Research
Background Limited evidence is available about the relationship of lifestyle factors with glycated hemoglobin (HbA1c) in subjects with impaired glucose tolerance. The aim of study was to identify such determinant factors of HbA1c in subjects with impaired glucose tolerance. Methods This cross-sectional study included 121 men and 124 women with impaired glucose tolerance, who were diagnosed based on a 75-g oral glucose tolerance test. Demographic and biochemical parameters, including the body mass index (BMI), fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and HbA1c, were measured. The pancreatic β-cell function and insulin resistance were assessed using homeostasis model assessment (HOMA-β). Dietary intake was assessed by a food frequency questionnaire. Results The levels of FPG, 2-h PG, and carbohydrate intake were correlated with the HbA1c level in men, while the FPG and 2-h PG levels were correlated with the HbA1c level in women. In multiple regression analyses, BMI, FPG, 2-h PG, and white rice intake were associated with HbA1c levels in men, while BMI, FPG, HOMA-β, and bread intake were associated with HbA1c levels in women. Conclusions The present findings suggest that a substantial portion of HbA1c may be composed of not only glycemic but also several lifestyle factors in men with impaired glucose tolerance. These factors can be taken into consideration as modifiable determinants in assessing the HbA1c level for the diagnosis and therapeutic monitoring of the disease course. PMID:28270897
Goldberg, Allon; Russell, James William; Alexander, Neil Burton
Type 2 diabetes mellitus (T2DM) and pre-diabetes or impaired glucose tolerance (IGT) affect a large segment of the population. Peripheral neuropathy (PN) is a common complication of T2DM, leading to sensory and motor deficits. While T2DM-related PN often results in balance- and mobility-related dysfunction which manifests as gait instability and falls, little is known about balance capabilities in patients who have evidence of PN related to IGT (IGT-PN). We evaluated patients with IGT-PN on commonly-used clinical balance and mobility tests as well as a new test of trunk position sense and balance impairment, trunk repositioning errors (TREs). Eight participants aged 50-72 years with IGT-PN, and eight age- and gender-matched controls underwent balance, mobility and trunk repositioning accuracy tests at a university neurology clinic and mobility research laboratory. Compared to controls, IGT-PN participants had as much as twice the magnitude of TREs and stood approximately half as long on the single leg balance test. People with IGT-PN exhibit deficits in standing balance and trunk position sense. Furthermore, there was a significant association between performance on commonly-used clinical balance and mobility tests, and electrophysiological and clinical measures of neuropathy in IGT-PN participants. Because IGT-related neuropathy represents the earliest stage of diabetic neuropathy, deficits in IGT-PN participants highlight the importance of early screening in the dysglycemic process for neuropathy and associated balance deficits.
Hosking, Joanne; Metcalf, Brad S; Jeffery, Alison N; Streeter, Adam J; Voss, Linda D; Wilkin, Terence J
An HbA1c threshold of ≥ 6.5% has recently been adopted for the diagnosis of diabetes in adults, and of ≥ 5.7% to identify adults at risk. Little,however, is known of HbA1c's behaviour or diagnostic value in youth. Our aim was to describe the course of HbA1c during childhood, and its association with fasting glucose. HbA1c and glucose were measured every year in a cohort of 326 healthy children (162 boys) from 5 to 15 years. Mixed effects modelling was used to establish the determinants of HbA1c and its development over time. ROC analysis was used to determine the diagnostic value of HbA1c in the 55 individuals who showed impaired fasting glucose(IFG – glucose ≥ 5.6 mmol/L). Glucose rose progressively from 4.3 mmol/L at 5 years to 5.1 mmol/Lat 15 years, and although there were positive associations between HbA1c and glucose, from 10 to 13 years, HbA1c fell while glucose continued to rise. IFG developed in 55 children, but HbA1c exceeded 5.7% in only 16 of them. The maximum area under the ROC curve was 0.71 at the age of 14 (p<0.001), and the sensitivity and specificity were optimal at 50 and 80% respectively,corresponding to HbA1c of 5.4%. Although HbA1c retains a positive association with glucose throughout childhood, it is weak, and their trends diverge from 10 years,suggesting that factors other than glycaemia systematically influence the variance of HbA1c in youth. These findings therefore limit the interpretation of HbA1c for the diagnosis of IFG during childhood.
Huang, Yan-Qin; Yang, Qing-Feng; Wang, Hua; Xu, Yun-Sheng; Peng, Wei; Jiang, Yue-Hua
To evaluate the long-term clinical effect of Tangyiping Granules (, TYP) on patients with impaired glucose tolerance (IGT) to achieve normal glucose tolerance (NGT) and hence preventing them from conversion to diabetes mellitus (DM). In total, 127 participants with IGT were randomly assigned to the control (63 cases, 3 lost to follow-up) and treatment groups (64 cases, 4 lost to follow-up) according to the random number table. The control group received lifestyle intervention alone, while the patients in the treatment group took orally 10 g of TYP twice daily in addition to lifestyle intervention for 12 weeks. The rates of patients achieving NGT or experiencing conversion to DM as main outcome measure were observed at 3, 12, and 24 months after TYP treatment. The secondary outcome measures included fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-h insulin (2hINS), homeostatic model assessment of insulin resistance (HOMA-IR), blood lipid and patients' complains of Chinese medicine (CM) symptoms before and after treatment. A higher proportion of the treatment group achieved NGT compared with the control group after 3-, 12- and 24-month follow-up (75.00% vs. 43.33%, 58.33% vs. 35.00%, 46.67% vs. 26.67%, respectively, P<0.05). The IGT to DM conversion rate of the treatment group was significantly lower than that of the control group at the end of 24-month follow-up (16.67% vs. 31.67%, P<0.05). Before treatment, FPG, 2hPG, HbA1c, FINS, 2hINS, HOMA-IR, triglyceride (TG), total cholesterol, low- and high-density lipoprotein cholesterol levels had no statistical difference between the two groups (P>0.05). After treatment, the 2hPG, HbA1c, HOMA-IR, and TG levels of the treatment group decreased significantly compared with those of the control group (P<0.05). CM symptoms such as exhaustion, irritability, chest tightness and breathless, spontaneous sweating, constipation, and dark thick and
González-Yanes, Carmen; Serrano, Antonia; Bermúdez-Silva, Francisco Javier; Hernández-Dominguez, María; Páez-Ochoa, María Angeles; Rodríguez de Fonseca, Fernando; Sánchez-Margalet, Víctor
Oleylethanolamide (OEA) is a lipid mediator that inhibits food intake and body weight gain and also exhibits hypolipemiant actions. OEA exerts its anorectic effects peripherally through the stimulation of C-fibers. OEA is synthesized in the intestine in response to feeding, increasing its levels in portal blood after the meal. Moreover, OEA is produced by adipose tissue, and a lipolytic effect has been found. In this work, we have examined the effect of OEA on glucose metabolism in rats in vivo and in isolated adipocytes. In vivo studies showed that acute administration (30 min and 6 h) of OEA produced glucose intolerance without decreasing insulin levels. Ex vivo, we found that 10 min of preincubation with OEA inhibited 30% insulin-stimulated glucose uptake in isolated adipocytes. Maximal effect was achieved at 1 microM OEA. The related compounds palmitylethanolamide and oleic acid had no effect, suggesting a specific mechanism. Insulin-stimulated GLUT4 translocation was not affected, but OEA promoted Ser/Thr phosphorylation of GLUT4, which may impair transport activity. This phosphorylation may be partly mediated by p38 and JNK kinases, since specific inhibitors (SB-203580 and SP-600125) partly reverted the inhibitory effect of OEA on insulin-stimulated glucose uptake. These results suggest that the lipid mediator OEA inhibits insulin action in the adipocyte, impairing glucose uptake via p38 and JNK kinases, and these effects may at least in part explain the glucose intolerance produced in rats in vivo. These effects of OEA may contribute to the anorectic effects induced by this mediator, and they might be also relevant for insulin resistance in adipose tissue.
Vukovic, R; Mitrovic, K; Milenkovic, T; Todorovic, S; Zdravkovic, D
An increase in the prevalence of pediatric type 2 diabetes mellitus (T2DM) has been reported by numerous studies in the United States during the past two decades. Available data from Europe are scarce, but also suggest the rising prevalence of this disease in overweight children. The aim of this study was to determine the prevalence of previously undiagnosed T2DM, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a clinic cohort of otherwise healthy overweight and obese Caucasian children and adolescents living in Serbia. The study group consisted of 301 subjects (176 girls, 125 boys) aged 5.2-18.9 years, with body mass index >90th percentile. Oral glucose tolerance test was performed in all subjects. Previously undiagnosed T2DM was discovered in 0.3% (n=1) and impaired glucose regulation in 15.9% (n=48) of the subjects. Isolated IFG was detected in 4.3% (n=13), isolated IGT in 8.3% (n=25) and combined IFG and IGT in 3.3% (n=10) of the subjects. Disturbances of glucose metabolism were present in a substantial number of the subjects, which emphasizes the need for prevention and treatment of childhood obesity.
Kuhlow, Doreen; Zarse, Kim; Voigt, Anja; Schulz, Tim J; Petzke, Klaus J; Schomburg, Lutz; Pfeiffer, Andreas F H; Ristow, Michael
Both dietary fat and dietary sucrose are major components of Western diets that may differentially affect the risk for body mass gain, diabetes mellitus, and cardiovascular disease. We have phenotypically analyzed mice with ubiquitously impaired expression of mitochondrial frataxin protein that were challenged with diets differing in macronutrient content, namely high-sucrose/low-fat and high-saturated fat/low-sugar diets. We find here that a high-sucrose/low-fat diet has especially detrimental effects in mice with impaired mitochondrial metabolism promoting several independent cardiovascular risk factors, including impaired glucose metabolism, fasting hyperinsulinemia, reduced glucose-stimulated insulin secretion, increased serum triglycerides, and elevated cholesterol levels due to increased expression of HMG-CoA reductase. In contrast, a high-saturated fat/low-sugar diet protects mice with impaired mitochondrial metabolism from diet-induced obesity by increasing total energy expenditure and increasing expression of ACAA2, a rate-limiting enzyme of mitochondrial beta-oxidation, whereas no concomitant improvement of glucose metabolism was observed. Taken together, our results suggest that mitochondrial dysfunction may cause sucrose to become a multifunctional cardiovascular risk factor, whereas low-sugar diets high in saturated fat may prevent weight gain without improving glucose metabolism.
Zhang, Jing; Li, Huating; Zhou, Hu; Fang, Li; Xu, Jingjing; Yan, Han; Chen, Shuqin; Song, Qianqian; Zhang, Yinan; Xu, Aimin; Fang, Qichen; Ye, Yang; Jia, Weiping
The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated-impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects. After OGTT, serum FGF19 peaked at 120 min in all subjects. Glycine conjugated BAs peaked at 30 min, while free BAs did not elevated significantly. Consistent with the decrease trend in FGF19 levels, fasting serum CDCA levels in subjects with I-IFG, CGI and T2DM were significantly lower than NGT subjects (P < 0.05). Fasting serum CDCA was independently associated with FGF19. CDCA strongly upregulated FGF19 mRNA levels in LS174T cells in a dose- and time-dependent manner. These results suggest that the decrease of FGF19 in subjects with I-IFG was at least partially due to their decrease of CDCA acting via FXR.
Hidalgo, J; Flores, C; Hidalgo, M A; Perez, M; Yañez, A; Quiñones, L; Caceres, D D; Burgos, R A
The impetus of our study was to investigate the effects of a nutritional supplement Delphinol®, an extract of maqui berries (Aristotelia chilensis) standardised to ≥25% delphinidins and ≥35% total anthocyanins, on postprandial blood glucose and insulin levels and identify the physiologic mechanism involved. Postprandial blood glucose and insulin were investigated in double-blind, placebo-controlled, cross-over fashion in ten volunteers with moderate glucose intolerance. Longer term effects on blood sugar levels were investigated in streptozotocin-diabetic rats over a four months period. Effects of maqui berry delphinidins on sodium-glucose symport were examined in rodent jejenum of the small intestine. Delphinol® intake prior to rice consumption statistical significantly lowered post prandial blood glucose and insulin as compared to placebo. We identified an inhibition of Na+-dependant glucose transport by delphinidin, the principal polyphenol to which Delphinol® is standardised. In a diabetic rat model the daily oral application of Delphinol® over a period of four months significantly lowered fasting blood glucose levels and reached values indistinguishable from healthy non-diabetic rats. Our results suggest a potential use of Delphinol® for naturally controlling post-prandial blood glucose owed to inhibition of sodium glucose co-transporter in small intestine.
Hellgren, Margareta; Daka, Bledar; Larsson, Charlotte
An HbA1c threshold of ≥ 42 mmol/mol has been proposed to diagnose prediabetes. The sensitivity, specificity and positive predictive value of the proposed threshold for detection of individuals with prediabetes was examined in a study of 573 randomly selected individuals from Vara and Skövde. In addition, the utility of the FINDRISC questionnaire and of a fasting glucose test in combination with three short questions concerning BMI, heredity for type 2 diabetes and known hypertension was examined. Results from an oral glucose tolerance test were used as reference. The sensitivity of HbA1c and FINDRISC to detect individuals with IGT was 16 and 26 per cent respectively. Questions regarding BMI, heredity and hypertension together with a fasting glucose test yielded a sensitivity of 50%, but a lower specificity and positive predictive value. We conclude that HbA1c inefficiently detected individuals with impaired glucose tolerance and that oral glucose tolerance tests can still preferably be recommended.
Yatsuya, Hiroshi; Kawaguchi, Leo; Aoyama, Atsuko
Abstract Objective To assess differences between men and women in the prevalence of diabetes mellitus, impaired fasting glycaemia and impaired glucose tolerance in sub-Saharan Africa. Methods In September 2011, the PubMed and Web of Science databases were searched for community-based, cross-sectional studies providing sex-specific prevalences of any of the three study conditions among adults living in parts of sub-Saharan Africa (i.e. in Eastern, Middle and Southern Africa according to the United Nations subregional classification for African countries). A random-effects model was then used to calculate and compare the odds of men and women having each condition. Findings In a meta-analysis of the 36 relevant, cross-sectional data sets that were identified, impaired fasting glycaemia was found to be more common in men than in women (OR: 1.56; 95% confidence interval, CI: 1.20–2.03), whereas impaired glucose tolerance was found to be less common in men than in women (OR: 0.84; 95% CI: 0.72–0.98). The prevalence of diabetes mellitus – which was generally similar in both sexes (OR: 1.01; 95% CI: 0.91–1.11) – was higher among the women in Southern Africa than among the men from the same subregion and lower among the women from Eastern and Middle Africa and from low-income countries of sub-Saharan Africa than among the corresponding men. Conclusion Compared with women in the same subregions, men in Eastern, Middle and Southern Africa were found to have a similar overall prevalence of diabetes mellitus but were more likely to have impaired fasting glycaemia and less likely to have impaired glucose tolerance. PMID:24101783
Sun, Shichao; Pan, Yuesong; Zhao, Xingquan; Liu, Liping; Li, Hao; He, Yan; Guo, Li; Wang, Yilong; Wang, Yongjun
This study aimed at observing the influence of impaired glucose regulation (IGR) on 1-year outcomes in patients with intracerebral hemorrhage (ICH). Patients hospitalized for ICH from 2008 to 2009 were recruited consecutively at 35 centres across China. A standard oral glucose tolerance test at day 14 ± 3 after stroke onset or before discharge was performed to identify IGR. The outcomes were death (modified Rankin scale [mRS] score of 6), dependency (mRS score of 2 to 5) and poor outcome (mRS score of 2 to 6) at 1 year. Cox proportion hazard model for death and logistic regression model for dependency and poor outcome were performed to investigate the influence of IGR on 1-year outcomes. A total of 288 non-diabetic ICH patients were included in this analysis, among which 150 (52.1%) were IGR. IGR was associated with 1-year dependency (adjusted odds ratio [OR] 2.18, 95% confidence interval [CI], 1.19–3.99; P = 0.01) and poor outcome (adjusted OR 2.17; 95% CI, 1.24–3.80; P = 0.007) of patients with ICH. However, IGR showed no significant association with 1-year death (adjusted hazard ratio 1.49, 95% CI, 0.60–3.67; P = 0.39). IGR was independently associated with 1-year poor outcome of ICH in Chinese patients, with more important influence on dependency than death. PMID:27796374
Tuomilehto, J; Lindström, J; Eriksson, J G; Valle, T T; Hämäläinen, H; Ilanne-Parikka, P; Keinänen-Kiukaanniemi, S; Laakso, M; Louheranta, A; Rastas, M; Salminen, V; Uusitupa, M
Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle. Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.
Bächle, C; Claessen, H; Andrich, S; Brüne, M; Dintsios, C M; Slomiany, U; Roggenbuck, U; Jöckel, K H; Moebus, S; Icks, A
Objective For the first time, this population-based study sought to analyze healthcare utilization and associated costs in people with normal fasting glycemia (NFG), impaired fasting glycemia (IFG), as well as previously undetected diabetes and previously diagnosed diabetes linking data from the prospective German Heinz Nixdorf Recall (HNR) study with individual claims data from German statutory health insurances. Research design and methods A total of 1709 participants of the HNR 5-year follow-up (mean age (SD) 64.9 (7.5) years, 44.5% men) were included in the study. Age-standardized and sex-standardized healthcare utilization and associated costs (reported as € for the year 2008, perspective of the statutory health insurance) were stratified by diabetes stage defined by the participants' self-report and fasting plasma glucose values. Cost ratios (CRs) were estimated using two-part regression models, adjusting for age, sex, sociodemographic variables and comorbidity. Results The mean total direct healthcare costs for previously diagnosed diabetes, previously undetected diabetes, IFG, and NFG were €2761 (95% CI 2378 to 3268), €2210 (1483 to 4279), €2035 (1732 to 2486) and €1810 (1634 to 2035), respectively. Corresponding age-adjusted and sex-adjusted CRs were 1.53 (1.30 to 1.80), 1.16 (0.91 to 1.47), and 1.09 (0.95 to 1.25) (reference: NFG). Inpatient, outpatient and medication costs varied in order between people with IFG and those with previously undetected diabetes. Conclusions The study provides claims-based detailed cost data in well-defined glucose metabolism subgroups. CRs of individuals with IFG and previously undetected diabetes were surprisingly low. Data are important for the model-based evaluation of screening programs and interventions that are aimed either to prevent diabetes onset or to improve diabetes therapy as well. PMID:27252871
Suzuki, Keishi; Takano, Hitoshi; Kubota, Yoshiaki; Inui, Keisuke; Nakamura, Shunichi; Tokita, Yukichi; Kato, Koji; Asai, Kuniya; Shimizu, Wataru
Background Impaired glucose tolerance (IGT) patients are known to have a high risk of cardiovascular events and their prognosis has been reported to be poor. The present study aimed to compare coronary plaque characteristics among coronary artery disease (CAD) patients with normal glucose tolerance (NGT), those with IGT, and those with diabetes mellitus (DM) by using optical coherence tomography (OCT). Methods The present study included 101 coronary artery disease patients (mean age, 67.9 ± 10.4 years; 82.4% male). OCT was performed for target and non-target vessels during percutaneous coronary intervention. The patients were divided into the following 3 groups: the NGT, IGT, and DM groups. Results A total of 136 non-target residual plaques were found in 101 patients (27, 30, and 44 in the NGT, IGT, and DM groups, respectively). The size of the lipid core expressed as the mean angle of the lipid arc was significantly greater in the IGT and DM groups than in the NGT group (163.0 ± 58.7°, 170.1 ± 59.3°, and 130.9 ± 37.7°, respectively, P < 0.05). The fibrous cap covering the lipid core was significantly thinner in the IGT group than in the NGT group (77.0 ± 23.4 μm vs. 105.6 ± 47.0 μm, P = 0.040). Conclusion The coronary plaques in CAD patients are more vulnerable when having IGT compared to those with NGT, and similar to those with DM. This finding may explain the high risk of cardiovascular events in CAD patients with IGT. PMID:27936195
Wang, Yaqin; Yang, Pingting; Cao, Xia; Liu, Meilin; Chen, Zhiheng
To investigate the change of diabetic cardiomyopathy in patients with impaired glucose tolerance (IGT) and Type 2 diabetes (T2DM) and its influencing factors. Patients with IGT and T2DM were divided into an IGT group (n=314), a T2DM group (n=368) and an NC group (400 normal subjects). The left ventricular ejection fractions (LVEF) and the interventricular septal depth (IVSd) were measured by Doppler echocardiography. The general information and blood biochemistry were also collected during the corresponding time period. Compared with the NC group, waist circumference (WC), bodymass index (BMI), premature family history of cardiovascular disease, the serum levels of fasting plasma glucose (FPG), HbA1c, TC, TG, hyperlipidemia, BUN and Cr significantly increased (P<0.01) in the IGT and T2DM groups. Compared with the NC group and the IGT group, the LVEF significantly decreased (P<0.01) and the IVSd significantly increased (P<0.01) in the T2DM group. The LVEF and IVSd did not have obvious difference between the NC group and the IGT group. Pearson correlation analysis showed a negative correlation between LVEF and HbA1c, TC and duration of disease (P<0.01); but a positive correlation between IVSd and WC, BMI, HbA1c and duration of disease, and a negative correlation between IVSd and HDL (P<0.05). In the multiple linear stepwise regression, HbA1c and duration of disease showed a significant association with both LVEF and IVSd (P<0.05). T2DM has a close association with cardiomyopathy. HbA1c and duration of disease are the independent predictors for LVEF and IVSd.
Ford, Earl S; Abbasi, Fahim; Reaven, Gerald M
We sought to evaluate the effect of the new definition of impaired fasting glucose (IFG = fasting glucose concentration 100-125 mg/dL among people without diabetes) on the ability to identify insulin resistance, as well as the prevalence of the metabolic syndrome in apparently healthy individuals. From the Stanford General Clinical Research Center data-base, we used data from 230 men and 260 women aged 19-79 years who had had an insulin suppression test to measure insulin resistance. From the Third National Health and Nutrition Examination Survey (1988-1994), we used data from 8814 participants aged > or =20 years to estimate the impact of adopting the new IFG criteria on the prevalence of the metabolic syndrome. Among the 490 participants, the prevalence of IFG increased from 5.5% under the old definition of IFG to 20.4% under the new definition. Using the old definition of IFG, the sensitivity, specificity, and positive predictive value (PPV) of IFG of identifying an individual as being insulin resistant were 10%, 97%, and 63%, respectively. Using the new definition, these parameters were 33%, 88%, and 61%, respectively. If the new IFG criteria were adopted, the prevalence of the metabolic syndrome would increase from 21.8% to 26.3%. The new definition of IFG expands the population with insulin resistance by almost four-fold and could expand the population with the metabolic syndrome by about 20%. The clinical and public health implications of the new IFG definition remain to be elucidated.
Hagman, E; Reinehr, T; Kowalski, J; Ekbom, A; Marcus, C; Holl, R W
Impaired fasting glucose (IFG), a pre-stage to type 2 diabetes in adults, is also present in obese children. A large variation of the occurrence has been recorded, but the true prevalence is unknown due to lack of larger representative cohort studies. This study was implemented to investigate the prevalence of IFG in two nationwide cohorts of obese children and to find factors that affect the risk of IFG. A cross-sectional study based on data collected from two nationwide registers of obese children in Germany and Sweden, respectively. Subjects included were 2-18 years old. 32,907 subjects with fasting glucose were eligible in Germany and 2726 in Sweden. Two cutoff limits for IFG were used: 5.6-6.9 mmol l(-1) according to the American Diabetes Association (ADA) and 6.1-6.9 mmol l(-1)according to the World Health Organization (WHO). Variables collected were gender, age and degree of obesity. Logistic regression was used to calculate odds ratios. The total prevalence of IFG among obese children in the German cohort according to the ADA was 5.7% and according to the WHO it was 1.1%. In Sweden, the corresponding prevalence was 17.1% and 3.9%, respectively. IFG risk was correlated with increasing age, male sex and degree of obesity. IFG is highly prevalent among obese children. Age and degree of obesity are positively correlated with the risk of having IFG. There are large regional differences. After adjustments, obese children in Sweden, due to unknown reasons, have a 3.4- to 3.7-fold higher risk of having IFG than obese children in Germany.
Nakajima, Mayuka; Arimatsu, Kei; Minagawa, Takayoshi; Matsuda, Yumi; Sato, Keisuke; Takahashi, Naoki; Nakajima, Takako; Yamazaki, Kazuhisa
Periodontitis has been implicated as a risk factor for metabolic disorders associated with insulin resistance. Recently, we have demonstrated that orally administered Porphyromonas gingivalis, a representative periodontopathic bacterium, induces endotoxemia via reduced gut barrier function coupled with changes in gut microbiota composition, resulting in systemic inflammation and insulin resistance. Propolis, a resinous substance collected by honeybees from leaf buds and cracks in the bark of various plants, can positively affect metabolic disorders in various experimental models. In this study, we thus aimed to clarify the effect of propolis on impaired glucose and lipid metabolism induced by P. gingivalis administration. Eight-week-old male C57BL/6 mice were orally administered P. gingivalis strain W83, propolis ethanol extract powder with P. gingivalis, or vehicle. We then analyzed the expression profile of glucose and lipid metabolism-related genes in the liver and adipose tissues. Serum endotoxin levels were also evaluated by a limulus amebocyte lysate test. In addition, we performed histological analysis of the liver and quantified alveolar bone loss by measuring the root surface area on the lower first molar. Oral administration of P. gingivalis induced downregulation of genes that improve insulin sensitivity in adipose tissue (C1qtnf9, Irs1, and Sirt1), but upregulation of genes associated with lipid droplet formation and gluconeogenesis (Plin2, Acox, and G6pc). However, concomitant administration of propolis abrogated these adverse effects of P. gingivalis. Consistent with gene expression, histological analysis showed that administered propolis suppressed hepatic steatosis induced by P. gingivalis. Furthermore, propolis inhibited the elevation of serum endotoxin levels induced by P. gingivalis administration. Contrary to the systemic effects, propolis had no beneficial effect on alveolar bone loss. These results suggest that administration of propolis may
Hao, C; Zhang, C; Chen, W; Shi, Z
To investigate the prevalence and risk factors of diabetes and impaired fasting glucose among urban university applicants in Eastern China. The study uses data from the annual health examination among all students finishing high school who applied for university entrance in Changzhou City in 2012. In total, 6716 students aged 17-19 years had fasting blood glucose, alanine transaminase, height, weight and blood pressure measured. Impaired fasting glucose and diabetes were defined as fasting blood glucose ≥ 5.6 mmol/l (but < 7 mmol/l) and ≥ 7 mmol/l, respectively. The overall prevalence of impaired fasting glucose and diabetes was 2.40% and 0.13%, respectively (3.67% and 0.09% in boys; 1.09% and 0.18% in girls). In total, 20.9% of boys and 10.6% of girls were overweight/obese. High socio-economic status was associated with an increased risk of diabetes/impaired fasting glucose, but the association was significant only among boys (adjusted odds ratio 1.94, 95% CI 1.26-2.98). Alanine transaminase levels were significantly and positively related to diabetes/impaired fasting glucose risk. Overweight/obesity was significantly associated with increased risk of impaired fasting glucose/diabetes in girls, but not in boys. Moreover, the number of the above-mentioned risk factors (i.e. overweight/obesity, elevated alanine transaminase, pre-hypertension) was significantly and positively related to diabetes/impaired fasting glucose among both boys and girls. Impaired fasting glucose was prevalent among urban university applicants, in particular boys and those of high socio-economic status in eastern China. Elevated levels of liver function enzyme appear to be the strongest risk factor for diabetes/impaired fasting glucose. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.
Bonnet, Fabrice; Patel, Sheila; Laville, Martine; Balkau, Beverley; Favuzzi, Angela; Monti, Lucilla D; Lalic, Nebojsa; Walker, Mark
Recent studies suggested that the blockade of the renin-angiotensin system (RAS) may be associated with metabolic benefits. However, data about the potential influence of the ACE insertion/deletion (I/D) genotype on insulin resistance have been contradictory with studies of limited sample sizes. The purpose of this study was to investigate the relationship between the ACE gene I/D polymorphism and both insulin sensitivity and glucose intolerance in a large cohort of healthy subjects. A total of 1,286 participants in the Relationship Between Insulin Sensitivity and Cardiovascular Disease Risk Study had a 75-g oral glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess whole-body insulin sensitivity. Age, BMI, waist, fat-free mass (ffm), and physical activity did not differ by ACE genotype. Fasting glucose and insulin were similar among genotypes, but 2-h glucose levels were higher in DD than in ID and II subjects (DD: 5.9 +/- 1.7; ID: 5.7 +/- 1.5; II: 5.6 +/- 1.5 mmol/l) (P = 0.004). Participants with the DD genotype were more likely to have impaired glucose tolerance than those with the ID and II genotypes (13.1 vs. 8.7%; P = 0.02). Insulin sensitivity was lower in participants with the DD genotype than in those with the II genotype (136 +/- 63 vs. 147 +/- 65 micromol x min(-1)x kg ffm(-1) x mmol(-1) x l(-1); P = 0.02). The presence of the D allele was associated with a trend, albeit not significant, for reduced insulin secretion during the oral glucose tolerance test (P = 0.07). The ACE I/D polymorphism is associated with whole-body insulin sensitivity and with impaired glucose tolerance in our healthy population. These findings confirm potential interactions between the RAS and glucose metabolism.
Leung, Chung-Ming; Stone, William S; Lee, Edwin Ho-Ming; Seidman, Larry J; Chen, Eric Yu-Hai
Studies in healthy individuals show that exerting self-control consumes cognitive resources, which reduces subsequent self-control performance. Restoring the availability of blood glucose eliminates this impairment. Patients with schizophrenia are found to have self-regulatory dysfunctions. This study aims to investigate whether patient's (a) glucose facilitation effects will be impaired, and (b) will have exaggerated depletion in a self-control task. 40 patients with schizophrenia-spectrum disorders and 40 normal controls were recruited. A two drinks (glucose vs. placebo)×two depleting phases (self-control depleted vs. non-depleted) between-groups design was used. We examined the blood glucose levels before and after the selfcontrol depletion phase and the subsequent performances in two self-control tasks (handgrip and Stroop tests) after the drink condition. The four groups (depleting×glucose, depleting×placebo, non-depleting×glucose and nondepleting×placebo) of both patients and normal controls were comparable on a number of characteristics. The change in blood glucose level in the depleting group was significantly different from those in the non-depleting group. Two×two between-subjects ANOVAs were carried out to test the performances in the handgrip and Stroop tasks. Significant interactions were found in healthy controls regarding both tasks. However, a significant interaction was only found in patients regarding the handgrip task but not the Stroop task. This study demonstrated an abnormal glucose facilitation effect in patients during a cognitive self-control task but not during a physical self-control task. The findings also suggested for the first time that a self-control depletion effect is intact in patients with schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.
Panazzolo, Diogo G; Sicuro, Fernando L; Clapauch, Ruth; Maranhão, Priscila A; Bouskela, Eliete; Kraemer-Aguiar, Luiz G
We aimed to evaluate the multivariate association between functional microvascular variables and clinical-laboratorial-anthropometrical measurements. Data from 189 female subjects (34.0 ± 15.5 years, 30.5 ± 7.1 kg/m2), who were non-smokers, non-regular drug users, without a history of diabetes and/or hypertension, were analyzed by principal component analysis (PCA). PCA is a classical multivariate exploratory tool because it highlights common variation between variables allowing inferences about possible biological meaning of associations between them, without pre-establishing cause-effect relationships. In total, 15 variables were used for PCA: body mass index (BMI), waist circumference, systolic and diastolic blood pressure (BP), fasting plasma glucose, levels of total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), insulin, C-reactive protein (CRP), and functional microvascular variables measured by nailfold videocapillaroscopy. Nailfold videocapillaroscopy was used for direct visualization of nutritive capillaries, assessing functional capillary density, red blood cell velocity (RBCV) at rest and peak after 1 min of arterial occlusion (RBCV(max)), and the time taken to reach RBCV(max) (TRBCV(max)). A total of 35% of subjects had metabolic syndrome, 77% were overweight/obese, and 9.5% had impaired fasting glucose. PCA was able to recognize that functional microvascular variables and clinical-laboratorial-anthropometrical measurements had a similar variation. The first five principal components explained most of the intrinsic variation of the data. For example, principal component 1 was associated with BMI, waist circumference, systolic BP, diastolic BP, insulin, TG, CRP, and TRBCV(max) varying in the same way. Principal component 1 also showed a strong association among HDL-c, RBCV, and RBCV(max), but in the opposite way. Principal component 3 was associated only with microvascular
Ameri, Pietro; Bruzzone, Santina; Mannino, Elena; Sociali, Giovanna; Andraghetti, Gabriella; Salis, Annalisa; Ponta, Monica Laura; Briatore, Lucia; Adami, Giovanni F.; Ferraiolo, Antonella; Venturini, Pier Luigi; Maggi, Davide; Cordera, Renzo; Murialdo, Giovanni; Zocchi, Elena
The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8–12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8–12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control. PMID:25723556
Ameri, Pietro; Bruzzone, Santina; Mannino, Elena; Sociali, Giovanna; Andraghetti, Gabriella; Salis, Annalisa; Ponta, Monica Laura; Briatore, Lucia; Adami, Giovanni F; Ferraiolo, Antonella; Venturini, Pier Luigi; Maggi, Davide; Cordera, Renzo; Murialdo, Giovanni; Zocchi, Elena
The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8-12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8-12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control.
Fitzenberger, Elena; Deusing, Dorothé Jenni; Wittkop, Anette; Kler, Adolf; Kriesl, Erwin; Bonnländer, Bernd; Wenzel, Uwe
Enhanced blood glucose levels are a hallmark of diabetes and are associated with diabetic complications and a reduction of lifespan. In order to search for plant extracts that display preventive activities in such a scenario, we tested 16 extracts used in human nutrition for their survival enhancing activities in the nematode Caenorhabditis elegans. Nematodes were exposed for 48 h to 10 mM glucose in the absence or presence of 0.1% extract. Thereafter, survival was measured at 37 °C. Extracts made from coffee, kola, rooibos and cinnamon, did not influence the glucose-induced reduction of survival. Those made from ginseng, camomile, lime blossom, paraguay tea, balm, rhodiola, black tea, or knotgrass all extended the lifespan of the glucose-treated nematodes significantly but did not rescue survival completely. Extracts from the leaves of blackberries, from hibiscus, elderberries, or jiaogulan completely countered the glucose-induced survival reduction. A potent activation of the proteasome was shown for the most preventive extracts suggesting a more efficient degradation of proteins impaired by glucose. In conclusion, we present a simple animal model to screen for plant extracts with potency to reverse glucose toxicity. Extracts from blackberry leaves, hibiscus, elderberries, and jiaogulan were identified as very potent in this regard whose exact mechanisms of action appear worthwile to investigate at the molecular level.
Ozsari, L; Karadurmus, N; Sahin, M; Uckaya, G; Ural, A U; Kutlu, M
Diabetes mellitus (DM) is a complex disease that affects many systems. The most important cells of the immune system are lymphomononuclear (LMN) cells. Here, we aimed to evaluate the energy metabolism of LMN cells in patients with diabetes and impaired glucose tolerance. We measured LMN cell energy metabolism in patients with type 2 diabetes mellitus, impaired glucose tolerance (IGT) and healthy subjects. Cells were freshly isolated from peripheral blood and the subgroups were determined by flow cytometric method. Lactate production and glycogen utilization were significantly increased in the LMN cells of patients with type 2 DM and IGT when compared with healthy volunteers. No statistical difference was observed between the patients with type 2 DM and IGT. There was a significant correlation between fasting plasma glucose and lactate production in LMN cells. LMN cells changed their energy pathway in a diabetic state and preferred anaerobic glycolysis. Prediabetic range also affected energy metabolism in LMN cells. This abnormal energy production might cause dysfunction in LMN cells and the immune system in diabetic and prediabetic patients. In conclusion, we concluded that impaired glucose metabolism could change energy metabolism.
De Souza, L R; Berger, H; Retnakaran, R; Vlachou, P A; Maguire, J L; Nathens, A B; Connelly, P W; Ray, J G
Hepatic fat and abdominal adiposity individually reflect insulin resistance, but their combined effect on glucose homeostasis in mid-pregnancy is unknown. A cohort of 476 pregnant women prospectively underwent sonographic assessment of hepatic fat and visceral (VAT) and total (TAT) adipose tissue at 11–14 weeks' gestation. Logistic regression was used to assess the relation between the presence of maternal hepatic fat and/or the upper quartile (Q) of either VAT or TAT and the odds of developing the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus at 24–28 weeks' gestation, based on a 75 g OGTT. Upon adjusting for maternal age, ethnicity, family history of DM and body mass index (BMI), the co-presence of hepatic fat and quartile 4 (Q4) of VAT (adjusted odds ratio (aOR) 6.5, 95% CI: 2.3–18.5) or hepatic fat and Q4 of TAT (aOR 7.8 95% CI 2.8–21.7) were each associated with the composite outcome, relative to women with neither sonographic feature. First-trimester sonographic evidence of maternal hepatic fat and abdominal adiposity may independently predict the development of impaired glucose homeostasis and GDM in mid-pregnancy. PMID:27643724
Liu, Shing-Hwa; Cai, Fang-Ying; Chiang, Meng-Tsan
This study was designed to investigate the effects of long-term feeding of chitosan on plasma glucose and lipids in rats fed a high-fructose (HF) diet (63.1%). Male Sprague-Dawley rats aged seven weeks were used as experimental animals. Rats were divided into three groups: (1) normal group (normal); (2) HF group; (3) chitosan + HF group (HF + C). The rats were fed the experimental diets and drinking water ad libitum for 21 weeks. The results showed that chitosan (average molecular weight was about 3.8 × 10⁵ Dalton and degree of deacetylation was about 89.8%) significantly decreased body weight, paraepididymal fat mass, and retroperitoneal fat mass weight, but elevated the lipolysis rate in retroperitoneal fats of HF diet-fed rats. Supplementation of chitosan causes a decrease in plasma insulin, tumor necrosis factor (TNF)-α, Interleukin (IL)-6, and leptin, and an increase in plasma adiponectin. The HF diet increased hepatic lipids. However, intake of chitosan reduced the accumulation of hepatic lipids, including total cholesterol (TC) and triglyceride (TG) contents. In addition, chitosan elevated the excretion of fecal lipids in HF diet-fed rats. Furthermore, chitosan significantly decreased plasma TC, low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), the TC/high-density lipoprotein cholesterol (HDL-C) ratio, and increased the HDL-C/(LDL-C + VLDL-C) ratio, but elevated the plasma TG and free fatty acids concentrations in HF diet-fed rats. Plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected by the HF diet, but it was significantly increased in chitosan-supplemented, HF-diet-fed rats. The high-fructose diet induced an increase in plasma glucose and impaired glucose tolerance, but chitosan supplementation decreased plasma glucose and improved impairment of glucose tolerance and insulin tolerance. Taken together, these results indicate that supplementation with chitosan can improve the impairment of
Sol, E-ri M; Hovsepyan, Meri; Bergsten, Peter
Background Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion The identified altered proteins indicate mechanism important for altered β-cell function in T2DM. PMID:19607692
Venojärvi, Mika; Aunola, Sirkka; Puhke, Raivo; Marniemi, Jukka; Hämäläinen, Helena; Halonen, Jukka-Pekka; Lindström, Jaana; Rastas, Merja; Hällsten, Kirsti; Nuutila, Pirjo; Hänninen, Osmo; Atalay, Mustafa
Insulin resistance and diabetes are associated with increased oxidative stress and impairment of cellular defence systems. Our purpose was to investigate the interaction between glucose metabolism, antioxidative capacity and heat shock protein (HSP) defence in different skeletal muscle phenotypes among middle-aged obese subjects during a long-term exercise and dietary intervention. As a sub-study of the Finnish Diabetes Prevention Study (DPS), 22 persons with impaired glucose tolerance (IGT) taking part in the intervention volunteered to give samples from the vastus lateralis muscle. Subjects were divided into two sub-groups (IGTslow and IGTfast) on the basis of their baseline myosin heavy chain profile. Glucose metabolism, oxidative stress and HSP expressions were measured before and after the 2-year intervention. Exercise training, combined with dietary counselling, increased the expression of mitochondrial chaperones HSP60 and glucose-regulated protein 75 (GRP75) in the vastus lateralis muscle in the IGTslow group and that of HSP60 in the IGTfast group. In cytoplasmic chaperones HSP72 or HSP90 no changes took place. In the IGTslow group, a significant positive correlation between the increased muscle content of HSP60 and the oxygen radical absorbing capacity values and, in the IGTfast group, between the improved VO2max value and the increased protein expression of GRP75 were found. Serum uric acid concentrations decreased in both sub-groups and serum protein carbonyl concentrations decreased in the IGTfast group. The 2-year intervention up-regulated mitochondrial HSP expressions in middle-aged subjects with impaired glucose tolerance. These improvements, however, were not correlated directly with enhanced glucose tolerance.
Venojärvi, Mika; Aunola, Sirkka; Puhke, Raivo; Marniemi, Jukka; Hämäläinen, Helena; Halonen, Jukka-Pekka; Lindström, Jaana; Rastas, Merja; Hällsten, Kirsti; Nuutila, Pirjo; Hänninen, Osmo; Atalay, Mustafa
Background Insulin resistance and diabetes are associated with increased oxidative stress and impairment of cellular defence systems. Our purpose was to investigate the interaction between glucose metabolism, antioxidative capacity and heat shock protein (HSP) defence in different skeletal muscle phenotypes among middle-aged obese subjects during a long-term exercise and dietary intervention. As a sub-study of the Finnish Diabetes Prevention Study (DPS), 22 persons with impaired glucose tolerance (IGT) taking part in the intervention volunteered to give samples from the vastus lateralis muscle. Subjects were divided into two sub-groups (IGTslow and IGTfast) on the basis of their baseline myosin heavy chain profile. Glucose metabolism, oxidative stress and HSP expressions were measured before and after the 2-year intervention. Results Exercise training, combined with dietary counselling, increased the expression of mitochondrial chaperones HSP60 and glucose-regulated protein 75 (GRP75) in the vastus lateralis muscle in the IGTslow group and that of HSP60 in the IGTfast group. In cytoplasmic chaperones HSP72 or HSP90 no changes took place. In the IGTslow group, a significant positive correlation between the increased muscle content of HSP60 and the oxygen radical absorbing capacity values and, in the IGTfast group, between the improved VO2max value and the increased protein expression of GRP75 were found. Serum uric acid concentrations decreased in both sub-groups and serum protein carbonyl concentrations decreased in the IGTfast group. Conclusion The 2-year intervention up-regulated mitochondrial HSP expressions in middle-aged subjects with impaired glucose tolerance. These improvements, however, were not correlated directly with enhanced glucose tolerance. PMID:18371210
Wong, Martin CS; Jiang, Johnny Y; Fung, H; Griffiths, Sian; Mercer, Stewart
Background There is a scarcity of studies addressing the factors associated with impaired fasting glucose in Chinese patients with uncomplicated hypertension. We included 1,218 patients newly prescribed a single antihypertensive drug in the public primary healthcare setting in Hong Kong, where their fasting glucose levels were measured 6–7 weeks after the first-ever antihypertensive prescription. Methods The odds ratios of having above borderline (≥ 6.1 mmol/l) and adverse (≥ 7.0 mmol/l) glucose levels, respectively, were studied according to patient age, gender, socioeconomic status, clinic types and antihypertensive drug classes by multivariable regression analyses. Results The fasting glucose levels were statistically similar (p = 0.786) among patients prescribed thiazide diuretics (5.48 mmol/l, 95%, 5.38, 5.59), calcium channel blockers (5.46 mmol/l, 95% C.I. 5.37, 5.54), β-blockers (5.42 mmol/l, 95% C.I. 5.34, 5.51) and drugs acting on the renin angiotensin system (RAS) [5.41 mmol/l, 95% C.I. 5.20, 5.61]. Multivariate analyses reported no significant associations between antihypertensive drug class and impaired fasting glucose. Elderly patients and male gender were significantly more likely to present with above borderline and adverse readings respectively. Conclusion Clinicians should be aware of the increased risk of impaired fasting glucose in these groups, and use of thiazides should not in itself deter its use as a first-line antihypertensive agent among ethnic Chinese patients. PMID:18783618
Pal, Krishnendu; Cao, Ying; Gaisina, Irina N.; Bhattacharya, Santanu; Dutta, Shamit K.; Wang, Enfeng; Gunosewoyo, Hendra; Kozikowski, Alan P.; Billadeau, Daniel D.; Mukhopadhyay, Debabrata
Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases including Type II diabetes, Alzheimer's disease, bipolar disorder, inflammation and cancer. Consequently it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacological and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent anti-proliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The anti-proliferative activity is most likely caused by G0–G1 and G2-M phase arrest as evident from cell cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. Additionally, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft RCC tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells. PMID:24327518
Zhang, Meilin; Zhu, Yufeng; Li, Ping; Chang, Hong; Wang, Xuan; Liu, Weiqiao; Zhang, Yuwen; Huang, Guowei
Few studies have examined the association between Asian dietary pattern and prediabetes, in particular, the Chinese diet. We conducted a cross-sectional study to identify dietary patterns associated with impaired fasting glucose (IFG) which considered a state of prediabetes in Chinese men. The study included 1495 Chinese men aged 20 to 75 years. Information about diet was obtained using an 81-item food frequency questionnaire (FFQ), and 21 predefined food groups were considered in a factor analysis. Three dietary patterns were generated by factor analysis: (1) a vegetables-fruits pattern; (2) an animal offal-dessert pattern; and (3) a white rice-red meat pattern. The multivariate-adjusted odds ratio (OR) of IFG for the highest tertile of the animal offal-dessert pattern in comparison with the lowest tertile was 3.15 (95% confidence intervals (CI): 1.87–5.30). The vegetables-fruits dietary pattern was negatively associated with the risk of IFG, but a significant association was observed only in the third tertile. There was no significant association between IFG and the white rice-red meat pattern. Our findings indicated that the vegetables-fruits dietary pattern was inversely associated with IFG, whereas the animal offal-dessert pattern was associated with an increased risk of IFG in Chinese men. Further prospective studies are needed to elucidate the diet-prediabetes relationships. PMID:26402695
Zhang, Meilin; Zhu, Yufeng; Li, Ping; Chang, Hong; Wang, Xuan; Liu, Weiqiao; Zhang, Yuwen; Huang, Guowei
Few studies have examined the association between Asian dietary pattern and prediabetes, in particular, the Chinese diet. We conducted a cross-sectional study to identify dietary patterns associated with impaired fasting glucose (IFG) which considered a state of prediabetes in Chinese men. The study included 1495 Chinese men aged 20 to 75 years. Information about diet was obtained using an 81-item food frequency questionnaire (FFQ), and 21 predefined food groups were considered in a factor analysis. Three dietary patterns were generated by factor analysis: (1) a vegetables-fruits pattern; (2) an animal offal-dessert pattern; and (3) a white rice-red meat pattern. The multivariate-adjusted odds ratio (OR) of IFG for the highest tertile of the animal offal-dessert pattern in comparison with the lowest tertile was 3.15 (95% confidence intervals (CI): 1.87-5.30). The vegetables-fruits dietary pattern was negatively associated with the risk of IFG, but a significant association was observed only in the third tertile. There was no significant association between IFG and the white rice-red meat pattern. Our findings indicated that the vegetables-fruits dietary pattern was inversely associated with IFG, whereas the animal offal-dessert pattern was associated with an increased risk of IFG in Chinese men. Further prospective studies are needed to elucidate the diet-prediabetes relationships.
Rachner, Tilman D.; Khosla, Sundeep; Hofbauer, Lorenz C.
Summary Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic impact of osteoporosis in general and postmenopausal osteoporosis in particular, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Based on this, therapeutic strategies have been developed aimed at (I) inhibiting excessive bone resorption and by (II) increasing bone formation. The most promising novel treatments include denosumab, a monoclonal antibody against receptor activator of NF-κB ligand, a key osteoclast cytokine, odanacatib, a specific inhibitor of the osteoclast protease cathepsin K, and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This review provides an overview on these novel therapies and explains their underlying physiology. PMID:21450337
Alvestrand, A; Mujagic, M; Wajngot, A; Efendic, S
Glucose tolerance and tissue sensitivity to insulin were examined in 19 renal failure patients on chronic regular hemodialysis (group U) and in 6 matched control subjects with normal renal function (group A). Based on glucose tolerance as assessed by an oral glucose tolerance test (OGTT), glucose tolerance was normal in 5 (group U:N), borderline in 5 (group U:BL) and decreased in 9 uremic subjects (group U:D). Compared with group A the uremics demonstrated significantly (p less than 0.01) impaired insulin sensitivity as assessed by a continuous mixed infusion of somatostatin, insulin and glucose (SIGIT). In addition 19 non-diabetic subjects with normal fasting blood glucose and normal renal function, matching the uremic patients with respect to glucose tolerance as assessed by OGTT, were studied (group B). In group B impairments in both insulin secretion and insulin sensitivity tended to be more pronounced in subjects with decreased OGTT as compared with those with borderline OGTT. In contrast, insulin resistance was present to a similar degree in uremic subjects of group U:N, U:BL and U:D. During SIGIT endogenous insulin, glucagon and growth hormone (GH) were suppressed in both uremic and control subjects. This implies that insulin resistance in uremia is most likely not due to hyperglucagonemia or abnormal GH metabolism. During OGTT subjects of group U:N had significantly higher insulin response than subjects of group U:BL (p less than 0.02) and group U:D (p less than 0.01). Insulinogenic index was significantly higher in group U:N than in group U:BL (p less than 0.02) and group U:D (p = 0.01) and was higher in group U:BL than in group U:D (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Hussain, M; Janghorbani, M; Schuette, S; Considine, RV; Chisholm, RL; Mather, KJ
Objective To evaluate whether the augmented insulin and glucose response to a glucose challenge is sufficient to compensate for defects in glucose utilization in obesity and type 2 diabetes, using a breath test measurement of integrated glucose metabolism. Methods Non-obese, obese normoglycemic and obese Type 2 diabetic subjects were studied on 2 consecutive days. A 75g oral glucose load spiked with 13C-glucose was administered, measuring exhaled breath 13CO2 as an integrated measure of glucose metabolism and oxidation. A hyperinsulinemic euglycemic clamp was performed, measuring whole body glucose disposal rate. Body composition was measured by DEXA. Multivariable analyses were performed to evaluate the determinants of the breath 13CO2. Results Breath 13CO2 was reduced in obese and type 2 diabetic subjects despite hyperglycemia and hyperinsulinemia. The primary determinants of breath response were lean mass, fat mass, fasting FFA concentrations, and OGTT glucose excursion. Multiple approaches to analysis showed that hyperglycemia and hyperinsulinemia were not sufficient to compensate for the defect in glucose metabolism in obesity and diabetes. Conclusions Augmented insulin and glucose responses during an OGTT are not sufficient to overcome the underlying defects in glucose metabolism in obesity and diabetes. PMID:25511878
Ren, Xingxing; Han, Tingting; Chen, Yawen; Qiu, Huiying; Wu, Peihong; Zheng, Jun; Wang, Lihua; Liu, Wei; Hu, Yaomin
Aims To investigate the associations of dyslipidemia with insulin resistance and β cell function in individuals with normal glucose tolerance (NGT) and different categories of impaired glucose regulation (IGR). Methods 544 subjects (365 with dyslipidemia and/or IGR and 179 with normal lipid and glucose tolerance) were enrolled in the study. All subjects underwent oral glucose tolerance test (OGTT). HOMA-IR was used to evaluate insulin sensitivity. Disposition index (DI) was used to evaluate β cell function. Multiple linear regression analysis was performed to assess correlations among lipid profiles, insulin resistance and β cell function. Results Among subjects with NGT, those with dyslipidemia had higher level of HOMA-IR but lower level of DI. While among subjects with different categories of IGR, those with dyslipidemia and CGI had significantly decreased DI. No obvious differences of insulin resistance or β cell function were found in IFG or IGT subjects with or without dyslipidemia. TG and HDL-C were correlated with HOMA-IR (β = 0.79, p <0.001; β = -0.38, p = 0.027, respectively, compared with subjects in the low level groups). Moreover, TG and TC were negatively correlated with DI (β = -2.17, p = 0.013; β = -2.01, p = 0.034 respectively, compared with subjects in the low level groups) after adjusting for confounding parameters. Conclusions Dyslipidemia induces insulin resistance and impaired β cell response to insulin resistance in individuals with NGT. Furthermore, dyslipidemia diminishes β cell function in subjects with CGI. TG and HDL-C were correlated with insulin resistance, and TG, TC were negatively correlated with β cell response to insulin resistance in non-diabetic individuals. PMID:28199386
Cicero, Arrigo Francesco Giuseppe; Fogacci, Federica; Morbini, Martino; Colletti, Alessandro; Bove, Marilisa; Veronesi, Maddalena; Giovannini, Marina; Borghi, Claudio
A number of natural compounds have individually demonstrated to improve glucose and lipid levels in humans. To evaluate the short-term glucose and lipid-lowering activity in subjects with impaired fasting glucose. To assess the effects of a combination of nutraceuticals based on Lagerstroemia speciosa, Berberis aristata, Curcuma longa, Alpha-lipoic acid, Chrome picolinate and Folic acid, we performed a double-blind, parallel group, placebo-controlled, randomized clinical trial in 40 adults affected by impaired fasting glucose (FPG = 100-125 mg/dL) in primary prevention of cardiovascular disease. After a period of 2 weeks of dietary habits correction only, patients continued the diet and began a period of 8 weeks of treatment with nutraceutical or placebo. Data related to lipid pattern, insulin resistance, liver function and hsCRP were obtained at the baseline and at the end of the study. No side effects were detected in both groups of subjects. After the nutraceutical treatment, and compared to the placebo-treated group, the enrolled patients experienced a significant improvement in TG (-34.7%), HDL-C (+13.7), FPI (-13.4%), and HOMA-Index (-25%) versus the baseline values. No significant changes were observed in the other investigated parameters in both groups (Body Mass Index, LDL-C, hsCRP). The tested combination of nutraceuticals showed clinical efficacy in the improvement of TG, HDL-C, FPI and HOMA-Index, with an optimal tolerability profile. Further confirmation is needed to verify these observations on the middle and long term with a larger number of subjects.
Napoli, R; Davalli, A M; Hirshman, M F; Weitgasser, R; Weir, G C; Horton, E S
Chronic insulin therapy improves but does not restore impaired insulin-mediated muscle glucose uptake in human diabetes or muscle glucose uptake, transport, and transporter translocation in streptozocin diabetic rats. To determine whether this inability is due to inadequate insulin replacement, we studied fasted streptozocin-induced diabetic Lewis rats either untreated or after islet transplantation under the kidney capsule. Plasma glucose was increased in untreated diabetics and normalized by the islet transplantation (110 +/- 5, 452 +/- 9, and 102 +/- 3 mg/dl in controls, untreated diabetics, and transplanted diabetics, respectively). Plasma membrane and intracellular microsomal membrane vesicles were prepared from hindlimb skeletal muscle of basal and maximally insulin-stimulated rats. Islet transplantation normalized plasma membrane carrier-mediated glucose transport Vmax, plasma membrane glucose transporter content, and insulin-induced transporter translocation. There were no differences in transporter intrinsic activity (Vmax/Ro) among the three groups. Microsomal membrane GLUT4 content was reduced by 30% in untreated diabetic rats and normal in transplanted diabetics, whereas the insulin-induced changes in microsomal membrane GLUT4 content were quantitatively similar in the three groups. There were no differences in plasma membrane GLUT1 among the groups and between basal and insulin stimulated states. Microsomal membrane GLUT1 content was increased 60% in untreated diabetics and normalized by the transplantation. In conclusion, an adequate insulin delivery in the peripheral circulation, obtained by islet transplantation, fully restores the muscle glucose transport system to normal in streptozocin diabetic rats. PMID:8617870
Diab, Dima L; Watts, Nelson B
The aim of this study is to provide a thorough updated review of the diagnosis and treatment of postmenopausal osteoporosis. There have been several important findings in the field of postmenopausal osteoporosis over the past 1-2 years. Fewer morphometric vertebral fractures were found in women treated for 6 years with zoledronic acid compared with those who stopped treatment after 3 years. Longer duration of bisphosphonate therapy is associated with a higher risk of atypical femur fractures. Combination therapy with teriparatide and denosumab appears to increase bone mineral density to a greater extent than either therapy alone in postmenopausal women at high risk for fracture. There are several novel therapies under investigation for the treatment of osteoporosis, which are in various stages of development. Nonadherence to osteoporosis therapies continues to be a major problem in clinical practice. There are numerous effective pharmacologic treatment options for postmenopausal osteoporosis. Bisphosphonate drug holidays continue to be an area of significant debate.
Gupta, Akhil; March, Lyn
summary Osteoporotic fractures are common resulting in increased morbidity and mortality. Exercise can help prevent osteoporosis. It can also benefit patients with osteoporosis, but the exercises must be tailored to the patient. Most Australians should be able to obtain adequate calcium in their diet and vitamin D from the sun. Supplements may be needed in some patients and they are recommended for use with other drugs for osteoporosis. Bisphosphonates, and in some patients denosumab, are first-line drugs for osteoporosis. Raloxifene and strontium ranelate can be considered in patients who cannot take bisphosphonates or denosumab. Teriparatide is reserved for patients with severe osteoporosis and the use of strontium ranelate is declining because of cardiovascular safety concerns. PMID:27340321
Sheu, Angela; Diamond, Terry
SUMMARY Secondary osteoporosis is less common than primary osteoporosis. It may be suspected in patients who present with a fragility fracture despite having no risk factors for osteoporosis. In addition, secondary osteoporosis should be considered if the bone density Z-score is –2.5 or less. Consider the fracture site and presence of other clinical clues to guide investigations for an underlying cause. The tests to use are those that are indicated for the suspected cause. Baseline investigations include tests for bone and mineral metabolism (calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone), liver and kidney function, full blood count and thyroid-stimulating hormone. More detailed testing may be required in patients with severe osteoporosis. PMID:27346916
Fu, Jingqi; Cui, Qi; Yang, Bei; Hou, Yongyong; Wang, Huihui; Xu, Yuanyuan; Wang, Difei; Zhang, Qiang; Pi, Jingbo
Type 2 diabetes (T2D) is a progressive disease characterized by sustained hyperglycemia and is frequently accompanied by hyperlipidemia. Deterioration of β-cell function in T2D patients may be caused, in part, by long-term exposure to high concentrations of glucose and/or lipids. We developed systems to study how chronic glucotoxicity and lipotoxicity might be linked to the impairment of glucose-stimulated insulin secretion (GSIS) machinery in pancreatic β-cells. INS-1 (832/13) were exposed to glucose and/or palmitate for up to 10 weeks. Chronic high glucose and/or palmitate exposure resulted in impaired GSIS accompanied by a dramatic increase in oxidative stress, as determined by basal intracellular peroxide levels. In addition, the GSIS-associated reactive oxygen species (ROS) signals, assessed as glucose-stimulated peroxide accumulation positively correlated with GSIS in glucose- and/or palmitate-exposed cells, as well as glucose-stimulated reductions in GSH/GSSG ratios. Furthermore, the impairment of GSIS caused by chronic high glucose and/or palmitate exposures were attributed to the induction of adaptive antioxidant response and mitochondrial uncoupling, which negatively regulates glucose-derived ROS generation. Taken together, persistent glucotoxicity- and/or lipotoxicity-mediated oxidative stress and subsequent adaptive antioxidant response impair glucose-derived ROS signaling and GSIS in pancreatic β-cells. Copyright © 2016 Elsevier Ltd. All rights reserved.
Donovan, Lois; Parkins, Vicky M; Mahalingham, Aishling
Thyrotoxic periodic paralysis (TPP) is an unusual presentation of hyperthyroidism in women. The occurrence of this condition in the context of pregnancy is even more uncommon. Impaired glucose tolerance, pregnancy, and TPP impact overall management of thyrotoxicosis. There is little guidance in the literature for management under this constellation of circumstances. This is a case report of a previously healthy 36-year-old Filipino female presenting at 15 weeks gestation with tetraparesis, hypokalemia, and new onset Graves' disease with impaired glucose tolerance. Normal thyroid function was achieved in the mother without further episodes of TPP and a healthy, euthyroid male was delivered at 38 weeks gestation. Acute and long-term management strategies used in this case are described in detail. A synthesis of the available literature allowed development of a practical management strategy applicable to a variety of situations involving TPP in pregnancy.
Pillai, Renjitha; Paglialunga, Sabina; Hoang, Monica; Cousteils, Katelyn; Prentice, Kacey J; Bombardier, Eric; Huang, Mei; Gonzalez, Frank J; Tupling, A Russell; Wheeler, Michael B; Joseph, Jamie W
It has been suggested that the transcription factor ARNT/HIF1β is critical for maintaining in vivo glucose homeostasis and pancreatic beta cell glucose-stimulated insulin secretion (GSIS). Our goal was to gain more insights into the metabolic defects seen after the loss of ARNT/HIF1β in beta cells. The in vivo and in vitro consequences of the loss of ARNT/HIF1β were investigated in beta cell specific Arnt/Hif1β knockout mice (β-Arnt (fl/fl/Cre) mice). The only in vivo defects found in β-Arnt (fl/fl/Cre) mice were significant increases in the respiratory exchange ratio and in vivo carbohydrate oxidation, and a decrease in lipid oxidation. The mitochondrial oxygen consumption rate was unaltered in mouse β-Arnt (fl/fl/Cre) islets upon glucose stimulation. β-Arnt (fl/fl/Cre) islets had an impairment in the glucose-stimulated increase in Ca(2+) signalling and a reduced insulin secretory response to glucose in the presence of KCl and diazoxide. The glucose-stimulated increase in the NADPH/NADP(+) ratio was reduced in β-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in β-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1β in human islets also inhibited GSIS. These results suggest that the regulation of GSIS by the KATP channel-dependent and -independent pathways is affected by the loss of ARNT/HIF1β in islets. This study provides three new insights into the role of ARNT/HIF1β in beta cells: (1) ARNT/HIF1β deletion in mice impairs GSIS ex vivo; (2) β-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1β is required for GSIS in human islets.
Kornfeld, Jan-Wilhelm; Baitzel, Catherina; Könner, A Christine; Nicholls, Hayley T; Vogt, Merly C; Herrmanns, Karolin; Scheja, Ludger; Haumaitre, Cécile; Wolf, Anna M; Knippschild, Uwe; Seibler, Jost; Cereghini, Silvia; Heeren, Joerg; Stoffel, Markus; Brüning, Jens C
Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism. MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr(db/db) mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.
Yadav, Anitha; Carey, Elizabeth J
Osteoporosis is a common skeletal complication seen in patients with chronic liver disease. Osteoporosis is usually asymptomatic and, if untreated, can result in fractures and impaired quality of life. For this review, we performed a systematic search of the PubMed database, and all recent peer-reviewed articles regarding the prevalence, pathophysiology, diagnosis, and management of osteoporosis in chronic liver disease were included. The prevalence of osteoporosis varies between 11% and 58% in patients with chronic liver disease and in transplant recipients. The etiology of osteoporosis is multifactorial and only partially understood. Various factors linked to the pathogenesis of bone loss are vitamin D, calcium, insulin growth factor-1, receptor activation of nuclear factor-κB ligand (RANKL), bilirubin, fibronectin, leptin, proinflammatory cytokines, and genetic polymorphisms. Management of osteoporosis involves early diagnosis, identifying and minimizing risk factors, general supportive care, nutrition therapy, and pharmacotherapy. Osteoporosis is diagnosed based on the bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry scan. Measurement of BMD should be considered in all patients with advanced liver disease and in transplant recipients. Vitamin D and calcium supplementation is recommended for all patients with osteoporosis. Specific agents used for treatment of osteoporosis include bisphosphonates, calcitonin, hormonal therapy, and raloxifene. Bisphosphonates have become the mainstay of therapy for osteoporosis prevention and treatment. Prolonged suppression of bone remodeling resulting in atypical fractures has emerged as a significant complication with long-term use of bisphosphonates. Newer treatment agents and better fracture prevention strategies are necessary to prevent and treat osteoporosis.
Jansen, Anna M.; Jin, Chunyu; Rickhag, Mattias; Lund, Viktor K.; Jensen, Morten; Bhatia, Vikram; Sørensen, Gunnar; Madsen, Andreas N.; Xue, Zhichao; Møller, Siri K.; Woldbye, David; Qvortrup, Klaus; Huganir, Richard; Stamou, Dimitrios; Kjærulff, Ole; Gether, Ulrik
Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine
Holst, Birgitte; Madsen, Kenneth L; Jansen, Anna M; Jin, Chunyu; Rickhag, Mattias; Lund, Viktor K; Jensen, Morten; Bhatia, Vikram; Sørensen, Gunnar; Madsen, Andreas N; Xue, Zhichao; Møller, Siri K; Woldbye, David; Qvortrup, Klaus; Huganir, Richard; Stamou, Dimitrios; Kjærulff, Ole; Gether, Ulrik
Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine
Yarar-Fisher, Ceren; Bickel, C. Scott; Windham, Samuel T.; McLain, Amie B.
The mechanisms underlying poor glucose tolerance in persons with spinal cord injury (SCI), along with its improvement after several weeks of neuromuscular electrical stimulation-induced resistance exercise (NMES-RE) training, remain unclear, but presumably involve the affected skeletal musculature. We, therefore, investigated skeletal muscle signaling pathways associated with glucose transporter 4 (GLUT-4) translocation at rest and shortly after a single bout of NMES-RE in SCI (n = 12) vs. able-bodied (AB, n = 12) men. Subjects completed an oral glucose tolerance test during visit 1 and ≈90 NMES-RE isometric contractions of the quadriceps during visit 2. Muscle biopsies were collected before, and 10 and 60 min after, NMES-RE. We assessed transcript levels of GLUT-4 by quantitative PCR and protein levels of GLUT-4 and phosphorylated- and total AMP-activated protein kinase (AMPK)-α, CaMKII, Akt, and AS160 by immunoblotting. Impaired glucose tolerance in SCI was confirmed by higher (P < 0.05) plasma glucose concentrations than AB at all time points after glucose ingestion, despite equivalent insulin responses to the glucose load. GLUT-4 protein content was lower (P < 0.05) in SCI vs. AB at baseline. Main group effects revealed higher phosphorylation in SCI of AMPK-α, CaMKII, and Akt (P < 0.05), and Akt phosphorylation increased robustly (P < 0.05) following NMES-RE in SCI only. In SCI, low skeletal muscle GLUT-4 protein concentration may, in part, explain poor glucose tolerance, whereas heightened phosphorylation of relevant signaling proteins (AMPK-α, CaMKII) suggests a compensatory effort. Finally, it is encouraging to find (based on Akt) that SCI muscle remains both sensitive and responsive to mechanical loading (NMES-RE) even ≈22 yr after injury. PMID:23766505
Tuomilehto, Henri; Peltonen, Markku; Partinen, Markku; Lavigne, Gilles; Eriksson, Johan G.; Herder, Christian; Aunola, Sirkka; Keinänen-Kiukaanniemi, Sirkka; Ilanne-Parikka, Pirjo; Uusitupa, Matti; Tuomilehto, Jaakko; Lindström, Jaana
OBJECTIVE Both short and long sleep duration have frequently been found to be associated with an increased risk for diabetes. The aim of the present exploratory analysis was to examine the association between sleep duration and type 2 diabetes after lifestyle intervention in overweight individuals with impaired glucose tolerance in a 7-year prospective follow-up. RESEARCH DESIGN AND METHODS A total of 522 individuals (aged 40–64 years) were randomly allocated either to an intensive diet-exercise counseling group or to a control group. Diabetes incidence during follow-up was calculated according to sleep duration at baseline. Sleep duration was obtained for a 24-h period. Physical activity, dietary intakes, body weight, and immune mediators (C-reactive protein and interleukin-6) were measured. RESULTS Interaction between sleep duration and treatment group was statistically significant (P = 0.003). In the control group, the adjusted hazard ratios (HRs) (95% CI) for diabetes were 2.29 (1.38–3.80) and 2.74 (1.67–4.50) in the sleep duration groups 9–9.5 h and ≥10 h, respectively, compared with for that of the 7–8.5 h group. In contrast, sleep duration did not influence the incidence of diabetes in the intervention group; for sleep duration groups 9–9.5 h and ≥10 h, the adjusted HRs (95% CI) were 1.10 (0.60–2.01) and 0.73 (0.34–1.56), respectively, compared with that in the reference group (7–8.5 h sleep). Lifestyle intervention resulted in similar improvement in body weight, insulin sensitivity, and immune mediator levels regardless of sleep duration. CONCLUSIONS Long sleep duration is associated with increased type 2 diabetes risk. Lifestyle intervention with the aim of weight reduction, healthy diet, and increased physical activity may ameliorate some of this excess risk. PMID:19651919
Pedro-Botet, Juan; Barrios, Vivencio; Pascual, Vicente; Ascaso, Juan F; Cases, Aleix; Millán, Jesús; Serrano, Adalberto; Pintó, Xavier
The aim of the present study was to develop a multidisciplinary consensus based on the Delphi system to establish clinical recommendations for the management of dyslipidaemia when hyperglycaemia is present, and the relevant factors that should be taken into consideration when prescribing and monitoring treatment with statins. The questionnaire developed by the scientific committee included four blocks of questions about dyslipidaemia in patients with impaired glucose metabolism. The results of the first two blocks are presented here: a) management of dyslipidaemia; b) relevant factors that should be taken into consideration when prescribing and monitoring treatment with statins. Among the 497 experts who participated in the study, an agreement of over 90% was attained for recommending screening for dyslipidaemia in patients with diabetes or pre-diabetes and/or cardiovascular disease or a family history and/or abdominal obesity and/or hypertension. There was a high degree of agreement that a statin is the lipid-lowering treatment of choice, and that it should be switched when side effects develop. Also, the choice of statin and dose should be made according to baseline LDL cholesterol levels, the target to achieve, and the possible drug-drug interactions. The screening of dyslipidaemia is primarily conducted in patients with cardiovascular disease, or any major cardiovascular risk factor. When prescribing a statin, physicians mainly focus on the ability to reduce LDL cholesterol and the risk of drug interactions. Copyright © 2016 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.
Bermúdez, Valmore; Salazar, Juan; Rojas, Joselyn; Calvo, María; Rojas, Milagros; Chávez-Castillo, Mervin; Añez, Roberto; Cabrera, Mayela
To determine the predictive power of various anthropometric indices for the identification of dysglycemic states in Maracaibo, Venezuela. A cross-sectional study with randomized, multi-staged sampling was realized in 2230 adult subjects of both genders who had their body mass index (BMI), waist circumference (WC) and waist-height ratio (WHR) determined. Diagnoses of type 2 diabetes mellitus (DM2) and impaired fasting glucose (IFG) were made following ADA 2015 criteria. ROC curves were used to evaluate the predictive power of each anthropometric parameter. Area under the curve (AUC) values were compared through Delong's test. Of the total 2230 individuals (52.6 % females), 8.4 % were found to have DM2, and 19.5 % had IFG. Anthropometric parameters displayed greater predictive power regarding newly diagnosed diabetics, where WHR was the most important predictor in both females (AUC = 0.808; CI 95 % 0.715-0.900. Sensitivity: 82.8 %; specificity: 76.2 %) and males (AUC = 0.809; CI 95 % 0.736-0.882. Sensitivity: 78.6 %; specificity: 68.1 %), although all three parameters appeared to have comparable predictive power in this subset. In previously diagnosed diabetic subjects, WHR was superior to both WC and BMI in females, and WHR and WC were both superior to BMI in males. Lower predictive values were found for IFG in both genders. Accumulation of various altered anthropometric measurements was associated with increased odds ratios for both newly and previously diagnosed DM2. The predictive power of anthropometric measurements was greater for DM2 than IFG. We suggest assessment of as many available parameters as possible in the clinical setting.
Battram, D S; Graham, T E; Dela, F
Caffeine (CAF) impedes insulin-mediated glucose disposal (IMGD) and increases plasma adrenaline concentrations ([ADR]; 0.6 nm). While the antagonism of ADR abolishes the CAF effect, infusion of ADR (0.75 nm) has no effect on IMGD. We have now examined CAF and ADR in concert to determine whether or not they elicit an additive response on IMGD. We hypothesized that CAF + ADR would elicit a greater effect than either CAF or ADR alone (i.e. that CAF effects would not be solely attributed to ADR). Subjects (n = 8) completed four trials in a randomized manner. An isoglycaemic–hyperinsulinaemic clamp was performed 30 min after the following treatments were administered: (1) placebo capsules and saline infusion ([ADR]= 0.29 nm) (PL trial), (2) CAF capsules (dose = 5 mg kg−1) and saline infusion ([ADR]= 0.62 nm) (CAF trial), (3) PL capsules and ADR infusion ([ADR]= 1.19 nm) (ADR trial), and (4) CAF capsules (dose = 5 mg kg−1) and ADR infusion ([ADR]= 0.93 nm) (CAF + ADR trial). As expected, CAF, ADR and CAF + ADR decreased (P ≤ 0.05) IMGD compared to PL. CAF + ADR resulted in a more pronounced decrease in IMGD versus PL (42%) compared to CAF (26%) or ADR (24%) alone; however, the effect was not fully additive (P = 0.08). Furthermore, CAF decreased IMGD to a similar magnitude as ADR despite a 50% lower [ADR]. In summary, while ADR contributes to the CAF-induced impairment in IMGD, it is not solely responsible for caffeine's effects. PMID:17656440
Mansur, Rodrigo B; Santos, Camila M; Rizzo, Lucas B; Asevedo, Elson; Cunha, Graccielle R; Noto, Mariane N; Pedrini, Mariana; Zeni-Graiff, Maiara; Cordeiro, Quirino; Vinberg, Maj; Kapczinski, Flavio; McIntyre, Roger S; Brietzke, Elisa
The neurotrophin brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker in bipolar disorder (BD). However, current evidence is limited and results have been highly heterogeneous. This study aimed to assess the moderating effect of impaired glucose metabolism (IGM) on plasma levels of BDNF in individuals with BD, and on the relationship between BDNF and variables of illness course. We measured and compared the plasma levels of BDNF in individuals with BD (n=57) and healthy controls (n=26). IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. Information related to current and past psychiatric/medical history, as well as prescription of pharmacological treatments was also captured. Individuals with BD had lower levels of BDNF, relative to healthy controls, after adjustment for age, gender, current medications, smoking, alcohol use, and IGM (P=.046). There was no effect of IGM (P=.860) and no interaction between BD diagnosis and IGM (P=.893). Peripheral BDNF levels were positively correlated with lifetime depressive episodes (P<.001), psychiatric hospitalizations (P=.001) and suicide attempts (P=.021). IGM moderated the association between BDNF and the number of previous mood episodes (P<.001), wherein there was a positive correlation in euglycemic participants and a negative correlation in individuals with IGM. BD is independently associated with lower levels of BDNF; IGM may modify the relationship between BDNF and BD course, suggesting an interactive effect of BDNF with metabolic status on illness progression. © 2016 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Mansur, Rodrigo B; Rizzo, Lucas B; Santos, Camila M; Asevedo, Elson; Cunha, Graccielle R; Noto, Mariane N; Pedrini, Mariana; Zeni, Maiara; Cordeiro, Quirino; McIntyre, Roger S; Brietzke, Elisa
The longitudinal course of bipolar disorder (BD) is highly heterogeneous, and is moderated by the presence of general medical comorbidities. This study aimed to investigate the moderating effects of impaired glucose metabolism (IGM) on variables of illness course and severity in a BD population. Fifty-five patients with BD were evaluated. All subjects were evaluated with respect to current and past psychiatric and medical disorders, as well as lifetime use of any medication. Body mass index (BMI) and metabolic parameters were obtained. IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. Thirty (54.5%) individuals had IGM. After adjustment for age, gender, ethnicity, alcohol use, smoking, BMI and past and current exposure to psychotropic medications, individuals with IGM, when compared to euglycemic participants, had an earlier age of onset (RR: 0.835, p=0.024), longer illness duration (RR: 1.754, p=0.007), a higher number of previous manic/hypomanic episodes (RR: 1.483, p=0.002) and a higher ratio of manic/hypomanic to depressive episodes (RR: 1.753, p=0.028). Moreover, we observed a moderating effect of IGM on the association between number of mood episodes and other variables of illness course, with the correlation between lifetime mood episodes and frequency of episodes being significantly greater in the IGM subgroup (RR: 1.027, p=0.029). All associations observed herein remained significant after adjusting for relevant confounding factors (e.g. age, alcohol and tobacco use, exposure to psychotropic agents, BMI). Cross-sectional design, small sample size. Comorbid IGM may be a key moderator of illness progression in BD. Copyright © 2016 Elsevier B.V. All rights reserved.
Dai, Chunhua; Lustig, Mary E.; Bonner, Jeffrey S.; Mayes, Wesley H.; Mokshagundam, Shilpa; James, Freyja D.; Thompson, Courtney S.; Lin, Chien-Te; Perry, Christopher G.R.; Anderson, Ethan J.; Neufer, P. Darrell; Wasserman, David H.; Powers, Alvin C.
Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2+/+) and heterozygous knockout mice (sod2+/−) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2+/− and sod2+/+ but was markedly decreased in HF-fed sod2+/−. Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2+/− was associated with increased ROS, such as superoxide ion. Surprisingly, insulin action determined by HI clamps did not differ between sod2+/− and sod2+/+ of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2+/− was due to increased glucose effectiveness. Increased GLUT-1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2+/− support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action. PMID:24947366
Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Knip, Mikael; Koski, Katriina; Koski, Matti; Härkönen, Taina; Ryhänen, Samppa; Hämäläinen, Anu-Maaria; Ormisson, Anne; Peet, Aleksandr; Tillmann, Vallo; Ulich, Valentina; Kuzmicheva, Elena; Mokurov, Sergei; Markova, Svetlana; Pylova, Svetlana; Isakova, Marina; Shakurova, Elena; Petrov, Vladimir; Dorshakova, Natalya V.; Karapetyan, Tatyana; Varlamova, Tatyana; Ilonen, Jorma; Kiviniemi, Minna; Alnek, Kristi; Janson, Helis; Uibo, Raivo; Salum, Tiit; von Mutius, Erika; Weber, Juliane; Ahlfors, Helena; Kallionpää, Henna; Laajala, Essi; Lahesmaa, Riitta; Lähdesmäki, Harri; Moulder, Robert; Nieminen, Janne; Ruohtula, Terhi; Vaarala, Outi; Honkanen, Hanna; Hyöty, Heikki; Kondrashova, Anita; Oikarinen, Sami; Harmsen, Hermie J. M.; De Goffau, Marcus C.; Welling, Gjalt; Alahuhta, Kirsi; Virtanen, Suvi M.
Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. PMID:25480564
Blesson, Chellakkan S; Sathishkumar, Kunju; Chinnathambi, Vijayakumar; Yallampalli, Chandrasekhar
Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet-exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet-fed rats gained less weight than controls during pregnancy. Male pups from LP diet-fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor
Jiang, Hua; Feng, Jueping; Du, Zhongxia; Zhen, Hui; Lin, Mei; Jia, Shaohui; Li, Tao; Huang, Xinyuan; Ostenson, Claes-Goran; Chen, Zhengwang
Vglycin, a natural 37-residue polypeptide isolated from pea seeds in which six half-cysteine residues are embedded in three pairs of disulfide bonds, is resistant to digestive enzymes and has antidiabetic potential. To investigate the pharmacological activity of Vglycin in vivo and to examine the mechanisms involved, the therapeutic effect of Vglycin in diabetic rats was examined. Diabetes was induced in Wistar rats by high-fat diet and multiple streptozotocin intraperitoneal injections. Diabetic rats were treated daily with Vglycin for 4 weeks. Body weight, food intake, fasting plasma glucose and insulin levels were assayed weekly. Glucose and insulin tolerance tests were conducted on Day 29. Subsequently, levels of p-Akt in the liver and pancreas and cleaved PARP, Pdx-1 and insulin in the pancreas were detected by immunoblotting. The morphology of the pancreas and the insulin expression in the pancreas were analyzed by hematoxylin-eosin staining and immunohistochemistry, respectively. Furthermore, human liver-derived cell lines were used to explore the in vitro effects of Vglycin on insulin sensitivity and glucose uptake. Chronic treatment with Vglycin normalized fasting glucose levels in diabetic rats. The improvement in glucose homeostasis and the increased insulin sensitivity mediated by restored insulin signaling likely contributed to decreased food intake and reduced body weight. Vglycin protected pancreatic cells from damage by streptozotocin. Although insulin synthesis and secretion in impaired β-cell were not significantly elevated, islets morphology was improved in the Vglycin-treated groups. These results suggest that Vglycin could be useful in Type 2 diabetes for restoring impaired insulin signaling, glucose tolerance and pancreatic function.
Due to its incidence and clinical consequences osteoporosis followed by vertebral, hip, and forearm fractures represents an outstanding problem of nowadays' health care. Because of its high mortality rate hip fractures are of special interest. The number of fractures caused by postmenopausal osteoporosis increases with age. Costs of examinations and treatment of women with postmenopausal osteoporosis and fractures are also increasing and represent a significant amount all over the world. Organization of Osteoporosis Centres in Hungary was founded in 1995 and has been since functioning, however, only the one-sixth of osteoporotic patients are treated. Several risk factors are known in the pathogenesis of osteoporosis, first of all the lack of sufficient calcium and vitamin D intake, age, genetic factors, and circumstances known to predispose falling. Estrogen deficiency is the most likely cause of postmenopausal osteoporosis. Osteodensitometry by DEXA is the most important method to evaluate osteoporosis, since decrease in bone mineral density strongly correlates with fracture incidence. Physical, radiologic, and laboratory examination are also required at the first visit and during follow-up. The quantity of bone can hardly be influenced after the 35th year of age, thus prevention of osteoporosis has special significance: appropriate calcium and vitamin D supplementation, weight-bearing sports and physical activity can prevent fractures. According to the results from studies fulfilling the criteria of evidence-based medicine, first choice treatment of osteoporosis involves hormone replacement therapy, bisphosphonates, the tissue specific tibolone, raloxifen and calcitonin. Calcium and vitamin D supplementation are always necessary to be added to any antiporotic treatment. Other combinations of different antiporotic drugs are useless and make the treatment more expensive. Other treatments like massage, physiotherapy, hip-protecting pants, etc. as well as
Oh, Jeong-Ah; Kim, Hee-Seung; Park, Min-Jeong; Shim, Hye-Sun
The purpose of this study was to investigate the effectiveness of an educational intervention that used both cellular phones and the Internet to provide a short messaging service (SMS) relating to blood glucose, blood pressure, and serum lipid levels in postmenopausal women with impaired fasting glucose (IFG). Twenty-eight postmenopausal women were assigned to an intervention group and twenty-one postmenopausal women to a control group. The intervention was provided for 12 weeks. Patients in the intervention group were asked to access a web site by using a cellular phone or to use the Internet directly and input their blood glucose and blood pressure levels weekly. Participants were sent the optimal recommendations weekly by both cellular phone and Internet. The intervention group had a mean decrease in systolic blood pressure (SBP) level of 8.1 mmHg but changes for the control group were not significant. There was a significant mean change in diastolic blood pressure (DBP) level for the intervention group (-7.7 mmHg). The mean change in the control group was not significant. This educational intervention using the Internet and a SMS by cellular phone improved levels of SBP and DBP in postmenopausal women with IFG.
Pais, Ramona; Zietek, Tamara; Hauner, Hans; Daniel, Hannelore; Skurk, Thomas
Type 2 diabetes is associated with elevated circulating levels of the chemokine RANTES and with decreased plasma levels of the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 is a peptide secreted from intestinal L-cells upon nutrient ingestion. It enhances insulin secretion from pancreatic β-cells and protects from β-cell loss but also promotes satiety and weight loss. In search of chemokines that may reduce GLP-1 secretion we identified RANTES and show that it reduces glucose-stimulated GLP-1 secretion in the human enteroendocrine cell line NCI-H716, blocked by the antagonist Met-RANTES, and in vivo in mice. RANTES exposure to mouse intestinal tissues lowers transport function of the intestinal glucose transporter SGLT1, and administration in mice reduces plasma GLP-1 and GLP-2 levels after an oral glucose load and thereby impairs insulin secretion. These data show that RANTES is involved in altered secretion of glucagon-like peptide hormones most probably acting through SGLT1, and our study identifies the RANTES-receptor CCR1 as a potential target in diabetes therapy.
Hickson, DeMarc A; Burchfiel, Cecil M; Liu, Jiankang; Petrini, Marcy F; Harrison, Kimystian; White, Wendy B; Sarpong, Daniel F
The objectives of this study were to test the hypothesis that diabetes and impaired glucose tolerance (IGT), diabetes control and diabetes duration, and metabolic biomarkers in adults with normal glucose tolerance (NGT) are inversely associated with spirometry-measured lung function. We conducted a cross-sectional observational cohort study that included nonsmoking African American adults (n = 2,945; mean age = 52.5 ± 12.6 years; 69.2% female), who were free of cardiovascular disease, from the Jackson Heart Study. The interventions were diabetes, metabolic biomarkers and lung function. We measured the associations of glycemia with forced expiratory volume (FEV) in 1 s, FEV in 6 s, and vital capacity. Multivariable adjusted mean lung function values were lower among adults with diabetes and IGT (in women only, but not after adjustment for waist circumference) than adults with NGT. Among adults with diabetes, no associations were observed between lung function and diabetes control or duration. In women with NGT, lower lung function was consistently associated with higher glucose levels and less consistently with higher insulin levels and insulin resistance. Lower lung function was consistently associated with higher insulin levels and insulin resistance and less consistently associated with insulin and hemoglobin A1c in men with NGT. Overall, our findings generally support the hypothesis that diabetes, IGT, and increased levels of metabolic biomarkers in individuals with NGT are inversely associated with lung function in African Americans, independent of adiposity.
Li, Qiang; Cai, Yuxi; Huang, Jing; Yu, Xiaolan; Sun, Jun; Yang, Zaiqing; Zhou, Lei
Type 2 diabetes mellitus (T2DM) is a chronic disease which is now affecting the health of more and more people in the world. Resistin, discovered in 2001, is considered to be closely related to metabolic dysfunction and obesity. Previous study showed that hyperglycemia is always accompanied by a high serum resistin concentration. We therefore investigated whether resistin can mediate glucose transfer across the blood-tissue barrier. Here, we employed a transwell system to analyze glucose permeability in EA.hy926 human endothelial cells treated without or with human resistin. In EA.hy926 cells treated with resistin, the permeability to glucose was heavily impaired. This was due to the down-regulation of GLUT1 expression as a result of the treatment, rather than regulation of tight junctions. In addition, overexpression of GLUT1 in EA.hy926 cells was able to recover the blocking effect of resistin on glucose permeability. We further found that resistin could inhibit the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and consequently impede the transcription of GLUT1. The results of the present study suggested that resistin could cause glucose retention in serum and thus result in hyperglycemia. This provides a novel explanation for hyperglycemia and a potential new way of treating type 2 diabetes mellitus.
Zambrowicz, Brian; Lapuerta, Pablo; Strumph, Paul; Banks, Phillip; Wilson, Alan; Ogbaa, Ike; Sands, Arthur; Powell, David
We sought to assess the efficacy and safety profile of LX4211, a dual inhibitor of sodium-glucose cotransporter1 (SGLT1) and SGLT2, in patients with type 2 diabetes and renal impairment. Thirty-one patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) were randomly assigned to receive 400 mg of LX4211 or placebo for 7 days. The primary end point was the change from baseline to day 7 in postprandial glucose (PPG) levels. Other end points included changes in fasting plasma glucose levels, glucagon-like peptide 1 levels, urinary glucose excretion (UGE), and blood pressure. LX4211 therapy significantly reduced PPG levels relative to placebo in the total population and in patients with an eGFR <45 mL/min/1.73 m(2), with a placebo-adjusted decrease in incremental AUCpredose-4 of 73.5 mg·h/dL (P = 0.009) and 137.2 mg·h/dL (P = 0.001) for the total population and the eGFR <45 mL/min/1.73 m(2) subgroup, respectively. There was a significant reduction in fasting plasma glucose levels relative to baseline of -27.1 mg/dL (P < 0.001). Total and active glucagon-like peptide 1 levels were significantly elevated relative to placebo with LX4211 dosing, and UGE was significantly elevated with placebo-subtracted measures of 38.7, 53.5, and 20.4 g/24 h (P ≤ 0.007 for all 3) in the total population, eGFR 45 to 59 mL/min/1.73 m(2), and eGFR <45 mL/min/1.73 m(2) subgroups, respectively. The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m(2) despite the expected reduction in UGE, suggesting that dual SGLT1 and SGLT2 inhibition with LX4211 could prove useful for the treatment of patients with type 2 diabetes and renal impairment. ClinicalTrials.gov identifier: NCT01555008. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.
Irimia, Jose M; Meyer, Catalina M; Peper, Caron L; Zhai, Lanmin; Bock, Cheryl B; Previs, Stephen F; McGuinness, Owen P; DePaoli-Roach, Anna; Roach, Peter J
Conversion to glycogen is a major fate of ingested glucose in the body. A rate-limiting enzyme in the synthesis of glycogen is glycogen synthase encoded by two genes, GYS1, expressed in muscle and other tissues, and GYS2, primarily expressed in liver (liver glycogen synthase). Defects in GYS2 cause the inherited monogenic disease glycogen storage disease 0. We have generated mice with a liver-specific disruption of the Gys2 gene (liver glycogen synthase knock-out (LGSKO) mice), using Lox-P/Cre technology. Conditional mice carrying floxed Gys2 were crossed with mice expressing Cre recombinase under the albumin promoter. The resulting LGSKO mice are viable, develop liver glycogen synthase deficiency, and have a 95% reduction in fed liver glycogen content. They have mild hypoglycemia but dispose glucose less well in a glucose tolerance test. Fed, LGSKO mice also have a reduced capacity for exhaustive exercise compared with mice carrying floxed alleles, but the difference disappears after an overnight fast. Upon fasting, LGSKO mice reach within 4 h decreased blood glucose levels attained by control floxed mice only after 24 h of food deprivation. The LGSKO mice maintain this low blood glucose for at least 24 h. Basal gluconeogenesis is increased in LGSKO mice, and insulin suppression of endogenous glucose production is impaired as assessed by euglycemic-hyperinsulinemic clamp. This observation correlates with an increase in the liver gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression and activity. This mouse model mimics the pathophysiology of glycogen storage disease 0 patients and highlights the importance of liver glycogen stores in whole body glucose homeostasis.
Holness, Mark J; Greenwood, Gemma K; Smith, Nicholas D; Sugden, Mary C
The aim of the study was to investigate the impact of hyperthyroidism on the characteristics of the islet insulin secretory response to glucose, particularly the consequences of competition between thyroid hormone and peroxisome proliferator-activated receptor (PPAR)alpha in the regulation of islet adaptations to starvation and dietary lipid-induced insulin resistance. Rats maintained on standard (low-fat/high-carbohydrate) diet or high-fat/low-carbohydrate diet were rendered hyperthyroid (HT) by triiodothyronine (T(3)) administration (1 mg.kg body wt(-1).day(-1) sc, 3 days). The PPARalpha agonist WY14643 (50 mg/kg body wt ip) was administered 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed during hyperglycemic clamps or after acute glucose bolus injection in vivo and with step-up and step-down islet perifusions. Hyperthyroidism decreased the glucose responsiveness of GSIS, precluding sufficient enhancement of insulin secretion for the degree of insulin resistance, in rats fed either standard diet or high-fat diet. Hyperthyroidism partially opposed the starvation-induced increase in the glucose threshold for GSIS and decrease in glucose responsiveness. WY14643 administration restored glucose tolerance by enhancing GSIS in fed HT rats and relieved the impact of hyperthyroidism to partially oppose islet starvation adaptations. Competition between thyroid hormone receptor (TR) and PPARalpha influences the characteristics of GSIS, such that hyperthyroidism impairs GSIS while PPARalpha activation (and increased dietary lipid) opposes TR signaling and restores GSIS in the fed hyperthyroid state. Increased islet PPARalpha signaling and decreased TR signaling during starvation facilitates appropriate modification of islet function.
Betzlbacher, Anna-Franziska; Grady, Katherine; Savas, Linda; Cotterill, Sarah; Boaden, Ruth; Summers, Lucinda; Gibson, Martin
To develop, implement and compare two lifestyle services for people at risk of developing type 2 diabetes. Two localities were selected to implement two different service delivery models, telephone-based and face-to-face, supporting people at risk of developing type 2 diabetes. Impact was assessed by comparing weight, fasting plasma glucose and oral glucose tolerance test (OGTT) results at baseline and six months later. Both services were associated with an improvement in OGTT 2-h plasma glucose and weight. In the telephone intervention, 47.3% of participants who completed the project achieved both normal fasting plasma glucose (≤6.0 mmol/l) and normal plasma glucose levels (≤7.7 mmol/l). Participants had a mean weight loss of 3.3 kg (SD 4.3), equating to 3.4% of body weight (p < 0.001). In the face-to-face intervention, 46.3% of participants achieved normal plasma glucose (≤7.7 mmol/l) and a mean weight loss of 2.9 kg (SD 4.5), equating to 3.1% of bodyweight (p < 0.001). Local health providers can adapt existing service provision and tailor it to provide lifestyle programmes for people with impaired glucose tolerance. Both service delivery models offer effective diabetes prevention although each model may cater for different population needs and a choice of services might be the preferred option. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
Aguirre, Luis G; Urrunaga-Pastor, Diego; Moncada-Mapelli, Enrique; Guarnizo-Poma, Mirella; Lazaro-Alcantara, Herbert; Benites-Zapata, Vicente A
To assess the association between elevated serum ferritin levels and the presence of insulin resistance (IR) or impaired glucose tolerance (IGT) in a population of individuals with no endocrine or metabolic disorders background. Analytical cross-sectional study, carried out in adults of both sexes with no medical history of type 2 diabetes mellitus (T2DM) or other metabolic or endocrine disorder, who attended the outpatient service of a private clinic in Lima-Peru during 2012-2014 period. Impaired serum ferritin levels were defined as serum ferritin values >300μg/L in men and >200μg/L in women. IR was defined as a Homeostasis Model Assessment (HOMA-IR) value ≥3.8 and IGT was defined as an oral glucose tolerance test (OGTT) value between 126mg/dL and 199mg/dL. The reported association measure was the prevalence ratio (PR) with their respective 95% confidence intervals (95% CI). We analyzed 213 participants, the average age was 35.8±11.1years and 35.7% were males. The prevalence of impaired serum ferritin levels, IR and IGT in the population was 12.7%, 33.3% and 9.9% respectively. In the adjusted Poisson regression models, the prevalence of IR was higher among the group with impaired serum ferritin levels (PR=1.74; 95%CI:1.18-2.56); however, we found no association between impaired serum ferritin levels and IGT (PR=1.42; 95%CI:0.47-4.30). Impaired levels of serum ferritin are associated with IR, nevertheless, not with IGT in a metabolically healthy population. Serum ferritin could be considered as an early marker of IR prior to the onset of glycaemia disorders. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Bhargava, Santosh K.; Sachdev, Harshpal Singh; Fall, Caroline H.D.; Osmond, Clive; Lakshmy, Ramakrishnan; Barker, David J.P.; Biswas, Sushant K. Dey; Ramji, Siddharth; Prabhakaran, Dorairaj; Reddy, Kolli Srinath
BACKGROUND The risk of type 2 diabetes mellitus is increased in people who have low birth weights and who subsequently become obese as adults. Whether their obesity originates in childhood and, if so, at what age are unknown. Understanding the origin of obesity may be especially important in developing countries, where type 2 diabetes is rapidly increasing yet public health messages still focus on reducing childhood “undernutrition.” METHODS We evaluated glucose tolerance and plasma insulin concentrations in 1492 men and women 26 to 32 years of age who had been measured at birth and at intervals of three to six months throughout infancy, childhood, and adolescence in a prospective, population-based study. RESULTS The prevalence of impaired glucose tolerance was 10.8 percent, and that of diabetes was 4.4 percent. Subjects with impaired glucose tolerance or diabetes typically had a low body-mass index up to the age of two years, followed by an early adiposity rebound (the age after infancy when body mass starts to rise) and an accelerated increase in body-mass index until adulthood. However, despite an increase in body-mass index between the ages of 2 and 12 years, none of these subjects were obese at the age of 12 years. The odds ratio for disease associated with an increase in the body-mass index of 1 SD from 2 to 12 years of age was 1.36 (95 percent confidence interval, 1.18 to 1.57; P<0.001). CONCLUSIONS There is an association between thinness in infancy and the presence of impaired glucose tolerance or diabetes in young adulthood. Crossing into higher categories of body-mass index after the age of two years is also associated with these disorders. PMID:14985484
Chikani, U N; Ibekwe, M U; Oguonu, T; Mungai, L; Bisi-Onyemaechi, A I; Ugege, O M; Ogbonna, I F; de Beaufort, Carine
Glucocorticoid (referred to from here on as simply steroid) is used for effective treatment of various inflammatory disorders since its discovery in 1940s. However, these useful drugs cause important side effects, such as impairment of glucose tolerance. We sought to determine the prevalence of steroid-induced impairment of glucose tolerance in pediatric patients on long-term steroid use. A cross-sectional, descriptive and hospital-based study. Consenting subjects who met the inclusion criteria were screened with random glucometer measurements repeated twice. An average of both readings obtained from the initial measurement of their random blood glucose (RBG) and a repeat during the next clinic visit was taken as the RBG. Hundred patients were studied, 66 males/34 females. Subjects with nephrotic syndrome were 61 while 39 had asthma. Mean age of 10.13 years (range: 0.5-18 years); mean body mass index (BMI): 18.2 kg/m(2) (range: 6.6 to 26.30 kg/m(2) ). The subjects with nephrotic syndrome were on oral prednisolone while the asthmatics were on inhaled fluticasone, budesonide and oral methylprednisolone. Mean (range) duration of steroid use was 9.74 (0.5-72) months. Mean (range) RBG was 3.49 (3.3-7.5) mmol/L. None of the subjects showed abnormal RBG. However, the RBG was further categorized into low, moderate and high normal RBG. A positive correlation between longer duration of steroid use as well as high doses of both oral and inhaled steroids, and high normal RBG existed (P = .015). No statistically significant relationship existed between body mass index (BMI) percentile and RBG (P = .437). Low to moderate doses of oral and inhaled steroids should be used when indicated as they are associated with lesser risk of impairment of glucose tolerance in the pediatric population. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Korompilias, Anastasios V; Karantanas, Apostolos H; Lykissas, Marios G; Beris, Alexandros E
Transient osteoporosis is characterized primarily by bone marrow edema. The disease most commonly affects the hip, knee, and ankle in middle-aged men. Its cause remains unknown. The hallmark that separates transient osteoporosis from other conditions presenting with a bone marrow edema pattern is its self-limited nature. Laboratory tests usually do not contribute to the diagnosis. Plain radiographs may reveal regional osseous demineralization. Magnetic resonance imaging is used primarily for early diagnosis and monitoring disease progression. Early differentiation from more aggressive conditions with long-term sequelae is essential to avoid unnecessary treatment. Clinical entities such as transient osteoporosis of the hip and regional migratory osteoporosis are spontaneously resolving conditions. However, early differential diagnosis and surgical treatment are crucial for the patient with osteonecrosis of the hip or knee.
Moisey, Lesley L; Kacker, Sita; Bickerton, Andrea C; Robinson, Lindsay E; Graham, Terry E
The ingestion of caffeine (5 mg/kg body weight) and a 75-g oral glucose load has been shown to elicit an acute insulin-insensitive environment in healthy and obese individuals and in those with type 2 diabetes. In this study we investigated whether a similar impairment in blood glucose management exists when coffee and foods typical of a Western diet were used in a similar protocol. Ten healthy men underwent 4 trials in a randomized order. They ingested caffeinated (5 mg/kg) coffee (CC) or the same volume of decaffeinated coffee (DC) followed 1 h later by either a high or low glycemic index (GI) cereal (providing 75 g of carbohydrate) mixed meal tolerance test. CC with the high GI meal resulted in 147%, 29%, and 40% greater areas under the curve for glucose (P < 0.001), insulin (NS), and C-peptide (P < 0.001), respectively, compared with the values for DC. Similarly, with the low GI treatment, CC elicited 216%, 44%, and 36% greater areas under the curve for glucose (P < 0.001), insulin (P < 0.01), and C-peptide (P < 0.01), respectively. Insulin sensitivity was significantly reduced (40%) with the high GI treatment after CC was ingested compared with DC; with the low GI treatment, CC ingestion resulted in a 29% decrease in insulin sensitivity, although this difference was not significant. The ingestion of CC with either a high or low GI meal significantly impairs acute blood glucose management and insulin sensitivity compared with ingestion of DC. Future investigations are warranted to determine whether CC is a risk factor for insulin resistance.
Oliveira, Lindomar Guimarães; Guimarães, Mara Lucia Rassi
ABSTRACT Population aging is a reality that is being faced worldwide, and Brazil is no different. Osteoporosis was considered to be a postmenopausal women's disease for many years. Men have many development and hormonal factors that differentiate their skeletal maturation, which affects the incidence of osteoporosis and fractures. An up-to-date review of the specific literature within the Medline system is presented. PMID:27022584
Yin, Yutian; Han, Weiqing; Wang, Yuhan; Zhang, Yue; Wu, Shili; Zhang, Huiping; Jiang, Lingling; Wang, Rui; Zhang, Peng; Yu, Yaqin; Li, Bo
Besides genetic factors, the occurrence of diabetes is influenced by lifestyles and environmental factors as well as trace elements in diet materials. Subjects with impaired fasting glucose (IFG) have an increased risk of developing diabetes mellitus (DM). This study aimed to explore risk factors affecting IFG and diabetes in patients from Northeast China. A population-based, cross-sectional survey of chronic diseases and related risk factors was conducted in Jilin Province of Northeast China. All adult residents, aged 18-79, were invited to participate in this survey using the method of multistage stratified random cluster sampling. One hundred thirty-four patients with IFG or DM and 391 healthy control subjects were recruited. We compared demographic factors, body size measurements, healthy-related behaviors, and hair metallic element contents between IFG/diabetes patients and healthy individuals. IFG/diabetes patients had a greater weight, waist, hip, and body mass index (BMI) than control subjects. Significant differences in the content of zinc (Zn), potassium (K), copper (Ca), and sodium (Na) as well as Cu/Zn ratios between IFG or DM patients and control subjects (p < 0.05) were also observed. Hair Cu, selenium (Se), and Na contents were positively correlated with blood glucose levels (Cu: rs = 0.135, p = 0.002; Se: rs = 0.110, p = 0.012; Na: rs = 0.091, p = 0.038). Polytomous logistic regression adjusting for age, sex, family history of diabetes and BMI, showed that subjects with high BMI were more likely to develop IFG and DM (IFG: OR = 1.15, OR 95% CI = 1.02-1.29; DM: OR = 1.15, OR 95% CI = 1.01-1.33). Moreover, rarely or never eating fruits was a risk factor for DM (OR = 5.46, OR 95% CI = 1.87-15.98) but not for IFG (OR = 1.70, OR 95% CI = 0.72-4.02). Subjects with abdominal obesity or DM history were more susceptible to DM (abdominal obesity: OR = 2.99, OR 95% CI = 1.07-8.37; DM history: OR = 2.69, OR 95% CI = 1.01-7.20). We found that subjects living in
Hu, Xia; Reaven, Peter D; Saremi, Aramesh; Liu, Ninghao; Abbasi, Mohammad Ali; Liu, Huan; Migrino, Raymond Q
Prediabetes is a major epidemic and is associated with adverse cardio-cerebrovascular outcomes. Early identification of patients who will develop rapid progression of atherosclerosis could be beneficial for improved risk stratification. In this paper, we investigate important factors impacting the prediction, using several machine learning methods, of rapid progression of carotid intima-media thickness in impaired glucose tolerance (IGT) participants. In the Actos Now for Prevention of Diabetes (ACT NOW) study, 382 participants with IGT underwent carotid intima-media thickness (CIMT) ultrasound evaluation at baseline and at 15-18 months, and were divided into rapid progressors (RP, n = 39, 58 ± 17.5 μM change) and non-rapid progressors (NRP, n = 343, 5.8 ± 20 μM change, p < 0.001 versus RP). To deal with complex multi-modal data consisting of demographic, clinical, and laboratory variables, we propose a general data-driven framework to investigate the ACT NOW dataset. In particular, we first employed a Fisher Score-based feature selection method to identify the most effective variables and then proposed a probabilistic Bayes-based learning method for the prediction. Comparison of the methods and factors was conducted using area under the receiver operating characteristic curve (AUC) analyses and Brier score. The experimental results show that the proposed learning methods performed well in identifying or predicting RP. Among the methods, the performance of Naïve Bayes was the best (AUC 0.797, Brier score 0.085) compared to multilayer perceptron (0.729, 0.086) and random forest (0.642, 0.10). The results also show that feature selection has a significant positive impact on the data prediction performance. By dealing with multi-modal data, the proposed learning methods show effectiveness in predicting prediabetics at risk for rapid atherosclerosis progression. The proposed framework demonstrated utility in outcome prediction in a typical
Espinoza, Sara E; Wang, Chen-Pin; Tripathy, Devjit; Clement, Stephen C; Schwenke, Dawn C; Banerji, Mary Ann; Bray, George A; Buchanan, Thomas A; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Stentz, Frankie B; Reaven, Peter D; DeFronzo, Ralph A; Musi, Nicolas
To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). β cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 μg/mL [2.7-fold] vs. 12.7 ± 1.4 μg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm(2)). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.
... your browser. Home Osteoporosis Osteoporosis Basics What Is Osteoporosis? Fast Facts: An Easy-to-Read Series of ... in the hip, spine, and wrist. Who Gets Osteoporosis? In the United States, millions of people either ...
Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao
Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction.
Watanabe, Reiko; Inoue, Daisuke
Recent epidemiological studies have revealed that osteoporosis is closely associated with common chronic diseases including diabetes, hypertension, chronic kidney disorders, and chronic obstructive pulmonary disease (COPD). COPD is a chronic inflammatory airway disease but now well known to be associated with various systemic comorbidities including osteoporosis. Osteoporosis and osteoporotic fractures are extremely common in COPD patients, which have significant impacts on their quality of life (QOL), activities of daily life (ADL), respiratory function, and possibly their prognosis. COPD-associated osteoporosis is however extremely under-recognized, hence undertreated. Recent studies have suggested that both decreased bone mineral density (BMD) and impaired bone quality compromise bone strength causing fractures in COPD. In COPD patients, various general clinical risk factors for osteoporosis are present including smoking, older age, low body weight, and physical inactivity. In addition, disease-related risk factors such as decreased pulmonary function, inflammation, glucocorticoid use and vitamin D deficiency/insufficiency have been linked to the development of osteoporosis in COPD. Increased awareness of osteoporosis in COPD, especially that of high prevalence of vertebral fractures is called upon among general physicians as well as pulmonologists. Routine screening for osteoporosis and risk assessment of fractures will enable physicians to diagnose COPD patients with comorbid osteoporosis at an early stage. Timely prevention of developing osteoporosis together with appropriate treatment of established osteoporosis may improve QOL and ADL of the COPD patients, preserve their lung function and eventually result in better prognosis in these patients. PMID:27622174
Devineni, Damayanthi; Curtin, Christopher R; Marbury, Thomas C; Smith, William; Vaccaro, Nicole; Wexler, David; Vandebosch, An; Rusch, Sarah; Stieltjes, Hans; Wajs, Ewa
Canagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. Participants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7-9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR ≥80 mL/min]; mild [CLCR 50 to <80 mL/min], moderate [CLCR 30 to <50 mL/min], or severe [CLCR <30 mL/min] renal impairment; and end-stage renal disease [ESRD]) and received a single oral dose of canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin's pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0-∞ values differed by <11% between the group with normal hepatic function and those with mild and moderate hepatic impairment. In the renal study, the mean Cmax values were 13%, 29%, and 29% higher and the mean AUC0-∞ values were 17%, 63%, and 50% higher in participants with mild, moderate, and severe renal impairment, respectively; values were similar in the ESRD group relative to the group with normal
Biljes, Daniel; Hammerschmidt-Kamper, Christiane; Kadow, Stephanie; Diel, Patrick; Weigt, Carmen; Burkart, Volker; Esser, Charlotte
Disturbed homeostasis of glucose and lipid metabolism are dominant features of the so-called metabolic syndrome (MetS) and can increase the risk for the development of type 2 diabetes (T2D), a severe metabolic disease. T2D prevalence increases with age. The aryl hydrocarbon receptor (AHR) is a sensor of small molecules including dietary components. AHR has been identified as potential regulator of glucose homeostasis and lipid metabolism. Epidemiologically, exposure to xenobiotic AHR ligands such as polycyclic aromatic hydrocarbons is linked to T2D. We assess here the potential role of the AHR in disturbances of glucose and lipid metabolism in young (age 2-5 months) and old (age > 1,5 years) AHR-deficient (AHR KO) mice. Fasted young wildtype (WT) and AHR-KO mice displayed similar blood glucose kinetics after challenge with intra-peritoneal glucose injection. However, old AHR-KO mice showed lower tolerance than WT to i.p. administered glucose, i.e. glucose levels rose higher and returned more slowly to normal levels. Old mice had overall higher insulin levels than young mice, and old AHR-KO had a somewhat disturbed insulin kinetic in the serum after glucose challenge. Surprisingly, young AHR-KO mice had significantly lower triglycerides, cholesterol, high density lipoprotein values than WT, i.e., a dyslipidemic profile. With ageing, AHR-KO and WT mice did not differ in these lipid levels, except for slightly reduced levels of triglycerides and cholesterol. In conclusion, our findings in AHR KO mice suggest that AHR expression is relevant for the maintenance of glucose and lipid homeostasis in old mice. PMID:26664351
Stochmal, Anna; Jasiak-Tyrkalska, Bozena; Stochmal, Ewa; Huszno, Bohdan; Kawecka-Jaszcz, Kalina
Body mass reduction and regular physical training form part of a strategy to treat disorders of carbohydrate metabolism associated with obesity. Evidence shows that even a slight reduction in body mass may improve carbohydrate tolerance, lipid profile and insulin resistance, reduce insulin levels and finally delay or reduce risk of diabetes mellitus. Multiple studies, including prospective studies confirm the independent protective effects of physical training against future development of type 2 diabetes mellitus. Myocardial infarction is a severe complication of atherosclerosis. Patients with glucose intolerance have a 2-fold higher risk of dying. Impaired glucose tolerance is negatively associated with prognosis in patients after myocardial infarction. Glucose intolerance accompanies hyperinsulinemia, a major indicator of insulin resistance. The aim of the study was to analyze the effect of physical training on hyperinsulinemia/ insulin resistance in patients after myocardial infarction (MI) with impaired glucose tolerance (IGT). 31 men aged 37-69 years (mean 51 +/- 7.4) with IGT 3.5 years after MI, in NYHA class I and II participated in the study. Group A (n=16 men) underwent supervised physical training and group B (n=15) received standard information on physical training. Tissue glucose disposal using normoglycemic glucose clamp technique, fasting insulinemia, glycemia during OGTT, lipid profile, BMI and body mass composition were obtained in all patients. The groups were matched for age. There were no differences in BMI, percent fat content, blood pressure, diet, smoking status and pharmacotherapy. Glycemia during baseline OGTT did not differentiate the groups, either. Analysis of insulinemia and glycemia during OGTT at baseline and at 12 weeks after regular physical training showed lower levels of insulinemia and glycemia compared with baseline levels in group A (fasting glycemia 6.41+/-0.46 vs. 4.8+/-0.32 mmol/l, p<0.001; fasting insulinemia 59
Background Red ginseng is prepared by steaming raw ginseng, a process believed to increase the pharmacological efficacy. Further bioconversion of red ginseng through fermentation is known to increase its intestinal absorption and bioactivity, and bioconversion diminishes the toxicity of red ginseng’s metabolite. This study was conducted to investigate the effects of daily supplementation with fermented red ginseng (FRG) on glycemic status in subjects with impaired fasting glucose or type 2 diabetes. Methods This study was a four-week long, randomized, double-blind, placebo-controlled trial. Forty-two subjects with impaired fasting glucose or type 2 diabetes were randomly allocated to two groups assigned to consume either the placebo or fermented red ginseng (FRG) three times per day for four weeks. Fasting and postprandial glucose profiles during meal tolerance tests were assessed before and after the intervention. Results FRG supplementation led to a significant reduction in postprandial glucose levels and led to an increase in postprandial insulin levels compared to the placebo group. There was a consistently significant improvement in the glucose area under the curve (AUC) in the FRG group. However, fasting glucose, insulin, and lipid profiles were not different from the placebo group. Conclusion Daily supplementation with FRG lowered postprandial glucose levels in subjects with impaired fasting glucose or type 2 diabetes. Trial registration ClinicalTrials.gov: NCT01826409 PMID:25015735
Yoshimura, Noriko; Muraki, Shigeyuki; Nakamura, Kozo; Tanaka, Sakae
Although locomotive organ disorders are major causes of disability and require support, little information is available regarding their epidemiology. Prevalence and co-existence of locomotive organ disorders including knee osteoarthritis (KOA), lumbar spondylosis (LS), hip osteoarthritis, and osteoporosis have been determined from baseline results of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study. KOA, LS, and hip osteoarthritis overlap in the population, while KOA and LS co-exist in 42.0% of people. Mutual associations between locomotive organ disorders, metabolic syndrome components, and mild cognitive impairment were found using baseline and 3-year follow-up data from the ROAD study. Logistic regression analysis showed that hypertension, impaired glucose tolerance, and mild cognitive impairment increase the risk of KOA. Osteoporosis at L2-4 was significantly influenced by the presence of femoral neck osteoporosis, and vice versa. In turn, excess weight was inversely associated with the occurrence of femoral neck osteoporosis. Finally, data from the 3rd survey (7-year follow-up) were used to calculate the prevalence of the locomotive syndrome using tests proposed by the Japanese Orthopaedic Association for assessing the risk of developing locomotive syndrome. Subsequently, the age-sex prevalence of stage 1 and stage 2 locomotive syndrome was estimated at 69.8% and 25.1%, respectively.
Vierucci, Francesco; Saggese, Giuseppe; Cimaz, Rolando
The aim of this review is to highlight recent findings in prevention, diagnosis, and treatment of pediatric osteoporosis. Several genes are involved in bone mass acquisition, and various monogenic bone disorders characterized by reduced bone mineral density and increased bone fragility have been recently described. Moreover, many chronic diseases and/or their treatment have been associated with impaired bone mass acquisition. Pediatric osteoporosis should be adequately suspected and properly diagnosed in children at risk of fractures. Particularly, detection of vertebral fracture allows the diagnosis regardless of densitometric evaluation. Dual X-ray absorptiometry remains the most widely used densitometric technique in childhood, but interpretation of results should be made with caution because of different confounding factors. Bisphosphonates represent one of the main medical treatments of pediatric osteoporosis, and many different protocols have been proposed. Bisphosphonates administration should be characterized by a first phase, followed by a period of maintenance. Optimal route of administration, duration of therapy, and long-term safety of bisphosphonates treatment require further investigation. Careful monitoring of children at risk of fractures is essential to pose early diagnosis of osteoporosis. In children with persistent risk factors and reduced probability of spontaneous recovery, medical treatment with bisphosphonates should be considered.
Barlow, D H
The Position Statement from the International Menopause Society (IMS) in 2004 recommends the use of hormone therapy for the 'avoidance of bone-wasting and fractures'. It also states that 'prevention, not treatment, is the most feasible goal'. In updating the Statement, this paper considers the relevance of Osteoporosis Guidelines. Relevant documents will be of two broad types. These may be consensus statements/position statements that summarize the 'state of the art' for practitioners, based on the work of expert groups, or they may be formal Guidelines generated through formal 'evidence-based' methodology. The former approach is generally used by Societies and can be generated through relatively efficient consensus processes. The latter approach will normally involve extensive work and cost, necessarily becomes very detailed, involving systematic review and technology appraisal and can lead to highly specific recommendations on intervention thresholds. For the revision of the general IMS Position Statement, the specific IMS Paper on Postmenopausal Osteoporosis (2005) must be a key reference document. This provides a description of the international consensus on the management of osteoporosis up to late 2004 and which remains relevant today. Additionally, other consensus statements and systematic guidelines need to be considered. Across these documents providing guidance, the substantial influence of the International Osteoporosis Foundation/National Osteoporosis Foundation Position Paper, defining a 'New approach to the development of assessment guidelines for osteoporosis', can be seen. This flagged the importance of a shift from guidance, tying the diagnostic threshold to the intervention threshold, and instead advised linking the intervention threshold to estimated fracture risk probability. This moves the intervention decision away from a simple bone density threshold to a more complex, but more realistic, threshold estimate, taking into account a range of
This paper aims to study the abnormal patterns of brain glucose metabolism co-variations in Alzheimer disease (AD) and Mild Cognitive Impairment (MCI) patients compared to Normal healthy controls (NC) using the Alzheimer Disease Neuroimaging Initiative (ADNI) database. The local cerebral metabolic rate for glucose (CMRgl) in a set of 90 structures belonging to the AAL atlas was obtained from Fluro-Deoxyglucose Positron Emission Tomography data in resting state. It is assumed that brain regions whose CMRgl values are significantly correlated are functionally associated; therefore, when metabolism is altered in a single region, the alteration will affect the metabolism of other brain areas with which it interrelates. The glucose metabolism network (represented by the matrix of the CMRgl co-variations among all pairs of structures) was studied using the graph theory framework. The highest concurrent fluctuations in CMRgl were basically identified between homologous cortical regions in all groups. Significant differences in CMRgl co-variations in AD and MCI groups as compared to NC were found. The AD and MCI patients showed aberrant patterns in comparison to NC subjects, as detected by global and local network properties (global and local efficiency, clustering index, and others). MCI network’s attributes showed an intermediate position between NC and AD, corroborating it as a transitional stage from normal aging to Alzheimer disease. Our study is an attempt at exploring the complex association between glucose metabolism, CMRgl covariations and the attributes of the brain network organization in AD and MCI. PMID:23894356
Zhang, Quan; Ramracheya, Reshma; Lahmann, Carolina; Tarasov, Andrei; Bengtsson, Martin; Braha, Orit; Braun, Matthias; Brereton, Melissa; Collins, Stephan; Galvanovskis, Juris; Gonzalez, Alejandro; Groschner, Lukas N.; Rorsman, Nils J.G.; Salehi, Albert; Travers, Mary E.; Walker, Jonathan N.; Gloyn, Anna L.; Gribble, Fiona; Johnson, Paul R.V.; Reimann, Frank; Ashcroft, Frances M.; Rorsman, Patrik
Summary Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na+ channels involved in action potential firing that, via reduced action potential height and Ca2+ entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes. PMID:24315372
Kato, Takayuki; Nakayama, Noriyuki; Yasokawa, Yuto; Okumura, Ayumi; Shinoda, Jun; Iwama, Toru
The aim of this study was to explore the regional cerebral glucose metabolism (rCM) in patients with chronic stage traumatic brain injury (TBI) compared with normal controls. We also investigated the relationship between regional cerebral glucose metabolism and cognitive function. We performed 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) study using statistical parametric mapping (SPM) analysis in 36 diffuse axonal injury (DAI) patients (mean age +/- SD, 36.3 +/- 9.8 years). At 6 months or more after head injury, all patients underwent FDG-PET study and neuropsychological batteries to assess cognitive function. Thirty healthy, gender-matched control subjects who were comparable in age were also studied. Between the TBI patients and normal controls, group comparisons showed regional metabolic decreases in the bilateral frontal lobes, temporal lobes, thalamus, as well as the right cerebellum in the TBI group. Only full-scale Intelligence Quotient (IQ) (mean +/- SD, 78.5 +/- 11.9) correlated positively with rCM in the right cingulate gyrus and the bilateral medial frontal gyrus. In other examinations, the correlation was not provided. DAI may induce functional disconnection and decreased neuronal activity, and finally lead to diffuse glucose hypometabolism. Low full-scale IQ scores may be related to significantly different underlying cognitive impairment. In supporting cognitive function following TBI, which showed diffuse cerebral metabolic reduction compared with normal controls, medial prefrontal cortex and anterior cingulate cortex may be an important component.
Ziemer, David C; Kolm, Paul; Weintraub, William S; Vaccarino, Viola; Rhee, Mary K; Caudle, Jane M; Irving, Jade M; Koch, David D; Narayan, K M Venkat; Phillips, Lawrence S
Age, BMI, and race/ethnicity are used in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and American Diabetes Association (ADA) guidelines to prompt screening for pre-diabetes and diabetes, but cutoffs have not been evaluated rigorously. Random plasma glucose (RPG) was measured and 75-g oral glucose tolerance tests were performed in 1,139 individuals without known diabetes. Screening performance was assessed by logistic regression and area under the receiver operating characteristic curve (AROC). NIDDK/ADA indicators age >45 years and BMI >25 kg/m(2) provided significant detection of both diabetes and dysglycemia (both AROCs 0.63), but screening was better with continuous-variable models of age, BMI, and race and better still with models of age, BMI, race, sex, and family history (AROC 0.78 and 0.72). However, screening was even better with RPG alone (AROCs 0.81 and 0.72). RPG >125 mg/dl could be used to prompt further evaluation with an OGTT. Use of age, BMI, and race/ethnicity in guidelines for screening to detect diabetes and pre-diabetes may be less important than evaluation of RPG. RPG should be investigated further as a convenient, inexpensive screen with good predictive utility.
Valencia, Ana Lucia; Bustamante, Jesus; Mendiluce, Alicia; Floege, Jürgen
Background Hypoglycemia is a serious complication following the administration of insulin for hyperkalemia. We determined the incidence of hypoglycemia and severe hypoglycemia (blood glucose <70 or ≤40 mg/dl, respectively) in a cohort of AKI and non-dialysis dependent CKD patients who received an intravenous infusion of insulin plus glucose to treat hyperkalemia. Methods We retrospectively reviewed charts of all AKI and non-dialysis dependent CKD patients who received 10 U of insulin plus 50 g glucose to treat hyperkalemia from December 1, 2013 to May 31, 2015 at our Department. Results One hundred sixty four episodes of hyperkalemia were treated with insulin plus glucose and were eligible for analysis. Serum potassium levels dropped by 1.18 ± 1.01 mmol/l. Eleven treatments (6.1%) resulted in hypoglycemia and two (1.2%) in severe hypoglycemia. A lower pretreatment blood glucose tended to associate with a higher subsequent risk of hypoglycemia. Age, sex, renal function, an established diagnosis of diabetes or previous treatment were not associated with the development of this complication. We did not register any significant adverse events. Conclusion Our intravenous regimen combining an infusion of insulin plus glucose effectively reduced serum potassium levels compared to previous studies and associated a low risk of symptomatic hypoglycemia and other complications. PMID:28245289
Coca, Armando; Valencia, Ana Lucia; Bustamante, Jesus; Mendiluce, Alicia; Floege, Jürgen
Hypoglycemia is a serious complication following the administration of insulin for hyperkalemia. We determined the incidence of hypoglycemia and severe hypoglycemia (blood glucose <70 or ≤40 mg/dl, respectively) in a cohort of AKI and non-dialysis dependent CKD patients who received an intravenous infusion of insulin plus glucose to treat hyperkalemia. We retrospectively reviewed charts of all AKI and non-dialysis dependent CKD patients who received 10 U of insulin plus 50 g glucose to treat hyperkalemia from December 1, 2013 to May 31, 2015 at our Department. One hundred sixty four episodes of hyperkalemia were treated with insulin plus glucose and were eligible for analysis. Serum potassium levels dropped by 1.18 ± 1.01 mmol/l. Eleven treatments (6.1%) resulted in hypoglycemia and two (1.2%) in severe hypoglycemia. A lower pretreatment blood glucose tended to associate with a higher subsequent risk of hypoglycemia. Age, sex, renal function, an established diagnosis of diabetes or previous treatment were not associated with the development of this complication. We did not register any significant adverse events. Our intravenous regimen combining an infusion of insulin plus glucose effectively reduced serum potassium levels compared to previous studies and associated a low risk of symptomatic hypoglycemia and other complications.
Galbo, Thomas; Olsen, Grith Skytte; Quistorff, Bjørn; Nishimura, Erica
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
Wong-McClure, Roy; Gregg, Edward W; Barcelo, Alberto; Sanabria-Lopez, Laura; Lee, Kahye; Abarca-Gomez, Leandra; Cervantes-Loaiza, Marvin; Luman, Elizabeth T
The projected rising prevalence of diabetes and impaired fasting glucose (IFG) in developing countries warrants careful monitoring. The aim of this study was to present the results of the Costa Rican National Cardiovascular Risk Factors Surveillance System, which provides the first national estimates of diabetes and IFG prevalence among adults in Costa Rica. A cross-sectional survey of 3653 non-institutionalized adults aged ≥20 years (87.8% response rate) following the World Health Organization STEPwise approach was built on a probabilistic sample of the non-institutionalized population during 2010. Known diabetes was defined as self-reported diagnosis, the use of insulin, or hypoglycemic oral treatment as consequence of diabetes during at least the previous 2 weeks before the survey. Unknown diabetes was defined no self-reported diabetes but with venous blood concentrations of fasting glucose >125 mg/dL determined by laboratory testing. Impaired fasting glucose was defined as fasting glucose between 100 and 125 mg/dL among those without diabetes. The prevalence of diabetes and IFG prevalence was estimated according gender, body mass index (BMI), waist circumference (WC), educational level, and physical activity level. Overall diabetes prevalence was 10.8% (9.5% known and 1.3% unknown diabetes) and IFG prevalence was 16.5%. The prevalence of known diabetes was higher among women >65 years compared with men of the same age group. Both known and unknown diabetes were significantly associated with higher BMI, increased WC, and low education level (P = 0.01). The prevalence of diabetes and IFG in Costa Rica is comparable to that in developed countries and indicates an urgent need for effective preventive interventions. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.
Hämäläinen, H; Rönnemaa, T; Virtanen, A; Lindström, J; Eriksson, J G; Valle, T T; Ilanne-Parikka, P; Keinänen-Kiukaanniemi, S; Rastas, M; Aunola, S; Uusitupa, M; Tuomilehto, J
The aim of this study was to investigate the effects of lifestyle intervention on the levels of plasminogen activator inhibitor (PAI-1) and fibrinogen in subjects participating in the Finnish Diabetes Prevention Study (DPS). In five DPS centres, 321 subjects with impaired glucose tolerance (intervention group, n=163; control group, n=158) had their PAI-1 and fibrinogen levels measured at baseline and at the 1-year follow-up. Additional 3-year follow-up assessments were carried out in a sample of 97 subjects in one of the DPS centres (Turku). The intervention programme included an intensive lifestyle intervention aiming at weight reduction, healthy diet and increased physical activity. During the first intervention year, PAI-1 decreased by 31% in the intervention group but showed no change in the control group (p<0.0001). In the Turku subgroup, the decrease in PAI-1 persisted throughout the 3-year follow-up. Changes in PAI-1 were associated with the number of lifestyle changes made during the first year (p=0.008). Weight reduction was the most important factor explaining the decrease in PAI-1. Changes in fibrinogen levels did not differ between the groups. In addition to the previously reported reduction in the risk of type 2 diabetes in DPS participants with impaired glucose tolerance, the intensive dietary and exercise intervention had beneficial long-term effects on fibrinolysis as indicated by the reduced levels of PAI-1. These results suggest that elevated PAI-1 levels in obese subjects with impaired glucose tolerance are mostly reversible by lifestyle changes, especially those geared to weight reduction.
Kang, Li; Dai, Chunhua; Lustig, Mary E; Bonner, Jeffrey S; Mayes, Wesley H; Mokshagundam, Shilpa; James, Freyja D; Thompson, Courtney S; Lin, Chien-Te; Perry, Christopher G R; Anderson, Ethan J; Neufer, P Darrell; Wasserman, David H; Powers, Alvin C
Elevated reactive oxygen species (ROS) are linked to insulin resistance and islet dysfunction. Manganese superoxide dismutase (SOD2) is a primary defense against mitochondrial oxidative stress. To test the hypothesis that heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion (GSIS) and insulin action, wild-type (sod2(+/+)) and heterozygous knockout mice (sod2(+/-)) were fed a chow or high-fat (HF) diet, which accelerates ROS production. Hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI) clamps were performed to assess GSIS and insulin action in vivo. GSIS during HG clamps was equal in chow-fed sod2(+/-) and sod2(+/+) but was markedly decreased in HF-fed sod2(+/-). Remarkably, this impairment was not paralleled by reduced HG glucose infusion rate (GIR). Decreased GSIS in HF-fed sod2(+/-) was associated with increased ROS, such as superoxide ion. Surprisingly, insulin action determined by HI clamps did not differ between sod2(+/-) and sod2(+/+) of either diet. Since insulin action was unaffected, we hypothesized that the unchanged HG GIR in HF-fed sod2(+/-) was due to increased glucose effectiveness. Increased GLUT-1, hexokinase II, and phospho-AMPK protein in muscle of HF-fed sod2(+/-) support this hypothesis. We conclude that heterozygous SOD2 deletion in mice, a model that mimics SOD2 changes observed in diabetic humans, impairs GSIS in HF-fed mice without affecting insulin action. © 2014 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.
Priebe, Steffen; Menzel, Uwe; Zarse, Kim; Groth, Marco; Platzer, Matthias; Ristow, Michael; Guthke, Reinhard
Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably. To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family. The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding. By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis.
Priebe, Steffen; Menzel, Uwe; Zarse, Kim; Groth, Marco; Platzer, Matthias; Ristow, Michael; Guthke, Reinhard
Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably. To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family. The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding. By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis. PMID:24204961
Eastell, Richard; O'Neill, Terence W; Hofbauer, Lorenz C; Langdahl, Bente; Reid, Ian R; Gold, Deborah T; Cummings, Steven R
Osteoporosis is a metabolic bone disorder that is characterized by low bone mass and micro-architectural deterioration of bone tissue. Fractures of the proximal femur, the vertebrae and the distal radius are the most frequent osteoporotic fractures, although most fractures in the elderly are probably at least partly related to bone fragility. The incidence of fractures varies greatly by country, but on average up to 50% of women >50 years of age are at risk of fractures. Fractures severely affect the quality of life of an individual and are becoming a major public health problem owing to the ageing population. Postmenopausal osteoporosis, resulting from oestrogen deficiency, is the most common type of osteoporosis. Oestrogen deficiency results in an increase in bone turnover owing to effects on all types of bone cells. The imbalance in bone formation and resorption has effects on trabecular bone (loss of connectivity) and cortical bone (cortical thinning and porosity). Osteoporosis is diagnosed using bone density measurements of the lumbar spine and proximal femur. Preventive strategies to improve bone health include diet, exercise and abstaining from smoking. Fractures may be prevented by reducing falls in high-risk populations. Several drugs are licensed to reduce fracture risk by slowing down bone resorption (such as bisphosphonates and denosumab) or by stimulating bone formation (such as teriparatide). Improved understanding of the cellular basis for osteoporosis has resulted in new drugs targeted to key pathways, which are under development.
Vyssoulis, Gregory P; Liakos, Charalampos I; Karpanou, Eva A; Triantafyllou, Athanasios I; Michaelides, Andreas P; Tzamou, Vanessa E; Markou, Maria I; Stefanadis, Christodoulos I
Arterial hypertension (AH) and diabetes mellitus (DM) are established cardiovascular risk factors. Impaired glucose homeostasis (IGH; impaired fasting glucose or/and impaired glucose tolerance) or pre-diabetes, obesity, and DM family history identify individuals at risk for type 2 DM in whom preventive interventions are necessary. The aim of this study was to determine the glycemic profile in non-diabetic Greek adult hypertensive men and women according to DM family history and the obesity status. Diabetes family history, obesity markers (waist-to-hip ratio, WHR; body mass index, BMI), glycemic parameters (fasting and 2-hour post-load plasma glucose, if necessary; glycated hemoglobin, HbA1c; fasting insulin), insulin resistance indices (homeostasis model assessment, HOMA; quantitative insulin sensitivity check index, QUICKI; Bennett; McAuley), and IGH prevalence were determined in a large cohort of 11,540 Greek hypertensives referred to our institutions. Positive DM family history was associated with elevated fasting glucose (98.6 ± 13.1 vs 96.5 ± 12.3 mg/dL), HbA1c (5.58% ± 0.49% vs 5.50% ± 0.46%), fasting insulin (9.74 ± 4.20 vs 9.21 ± 3.63 μU/mL) and HOMA (2.43 ± 1.19 vs 2.24 ± 1.01) values, lower QUICKI (0.342 ± 0.025 vs 0.345 ± 0.023), Bennett (0.285 ± 0.081 vs 0.292 ± 0.078) and McAuley (6.73 ± 3.43 vs 6.95 ± 3.44) values, and higher IGH prevalence (45.3% vs 38.7%); P < .01 for all comparisons. The difference in the prevalence of IGH according to DM family history was significant (P < .01) in both genders and every WHR and BMI subgroup (except for women with BMI <20 kg/m(2)). Non-diabetic hypertensives with positive DM family history present with higher IGH prevalence and worse glycemic indices levels compared with those with negative family history, especially in the higher WHR/BMI subgroups. Copyright © 2013 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
Jia, Qian; Liu, Gaifen; Zheng, Huaguang; Zhao, Xingquan; Wang, Chunxue; Wang, Yilong; Liu, Liping; Wang, Yongjun
It remains uncertain if impaired glucose regulation (IGR) as a predictor for stroke outcomes. This study aimed at observing the effect of IGR on the 1-year outcomes in Chinese patients with ischemic stroke. Patients with acute ischemic stroke were recruited consecutively in multihospitals across China. Oral glucose tolerance test was performed to identify IGR. Cox proportion hazard model was performed to investigate the effect of IGR on 1-year mortality or stroke recurrence in patients with ischemic stroke. The study recruited 2639 patients with ischemic stroke. IGR was shown as an independent risk factor for the mortality of patients with ischemic stroke (hazard ratio [95% confidence interval], 3.088 [1.386-6.884]; P=0.006). However, IGR showed no significant effects on the dependency or stroke recurrence of patients (P=0.540 and 0.618, respectively). IGR was an independent predictor for the mortality of patients with ischemic stroke. IGR should be highlighted and intervened actively in the patients with ischemic stroke.
Background Developing countries are undergoing an epidemiological transition, from Communicable or Infectious to 'Non-Communicable' diseases (NCDs), such that cardiovascular disease, chronic respiratory diseases, cancer, and diabetes were responsible for 60% of all deaths globally in 2005, with more than 75% of these deaths occurring in developing countries. A survey was conducted to determine among other objectives the prevalence of diabetes and its association with physical fitness and biological factors. Methods A cross sectional study utilizing a modified World Health Organization's STEPwise approach to surveillance of NCDs was conducted in Lusaka district, Zambia. A multi-stage cluster sampling technique was used to select study participants of age 25 years or older. All eligible members of a household that was selected were invited to participate in the study. Unadjusted odds ratios (OR), and adjusted odds ratios (AOR) together with their 95% Confidence Intervals (CI) were obtained using Complex samples logistic regression Results A total of 1928 individuals participated in the survey, of which 33.0% were males. About half of the participants were of age 25-34 years (53.2%), and about a third of the respondents had attained secondary level of education (35.8%). The combined prevalence for impaired glucose level or diabetes was 4.0%. Age and mild hypertension were significantly associated with impaired levels of glucose or diabetes. Compared to participants in the age group 25-34 years, older participants were more likely to have impaired glucose level or diabetes (AOR = 2.49 (95%CI [1.35, 2.92]) for 35-44 years age group, and AOR = 3.80 (95%CI [2.00, 7.23]) for 45 + years age group). Mild hypertension was associated with impaired glucose level or diabetes (AOR = 2.57) (95%CI [1.44, 4.57])). Conclusions The prevalence of diabetes in Lusaka district has not reached an alarming level and it is now that interventions targeting the younger age group 25-34 years
Shin, Su-Kyung; Kwon, Joong-Ho; Jeong, Yong-Jin; Jeon, Seon-Min; Choi, Ji-Young; Choi, Myung-Sook
This study was conducted to investigate the plasma lipid profile and blood glucose-lowering effects of cheonggukjang (CH) and red ginseng CH (RGCH) in 45 subjects (men:women = 27:18; mean age, 44.9 ± 3.1 years) with impaired fasting glucose (IFG). Subjects were randomly divided into three groups: control (starch, 2 g/day), CH (20 g/day), and RGCH (20 g/day). Each volunteer received his or her daily doses for 8 weeks. The supplementation with CH and RGCH significantly decreased the plasma total cholesterol about 30.0 mg/mL and 37.7 mg/mL, respectively, compared to the initial value. The plasma low-density lipoprotein-cholesterol concentration was also significantly reduced by 29.66% and 23.42% in the CH and RGCH groups, respectively, compared to the initial value. The concentration of plasma non-high-density lipoprotein-cholesterol (107.9 mg/mL) was significantly lowered in the RGCH group compared to the initial value (139.1 mg/mL). The level of erythrocyte thiobarbituric acid-reactive substances was significantly lowered in the CH (6.5 nmol/mL) and RGCH (6.6 nmol/mL) groups compared to the initial value (7.9 nmol/mL and 8.0 nmol/mL, respectively). The ratio of apolipoprotein B and apolipoprotein A-1 concentrations (2.5) was significantly reduced in the CH group compared to the initial value (3.0). The concentration of fasting blood glucose (FBG) was significantly lower in the CH- and RGCH-supplemented groups compared to the initial value. These results suggest that CH and RGCH can lower the FBG concentration and improve the plasma lipid profile in subjects with IFG.
Ferrara, C M; Goldberg, A P
Insulin resistance (IR) in older individuals is associated with risk factors for coronary artery disease. The glucose clamp measures IR directly, but the homeostasis model assessment (HOMA) of IR, referred to here as HOMA-IR, is based on fasting glucose and insulin and is less invasive and labor intensive. This method requires validation in the elderly. We assessed the validity of HOMA-IR as an index of IR by comparing it to glucose infusion rates (GIRs) measured by a glucose clamp (600 pmol x m(-2) x min(-1)) in 45 obese men (61 +/- 8 years of age, mean +/- SD) with normal glucose tolerance (NGT) (n = 21) or impaired glucose tolerance (IGT) (n = 24). We also evaluated relationships between body composition, exercise capacity, and IR. Subjects with NGT had lower BMI (28 +/- 3 vs. 31 +/- 3 kg/m2), waist circumference (97 +/- 9 vs. 105 +/- 9 cm), waist-to-hip ratio (WHR) (0.93 +/- 0.06 vs. 0.97 +/- 0.05), and percent body fat (25 +/- 6 vs. 30 +/- 6) than subjects with IGT. Subjects with NGT also had lower areas above basal during the 2-h oral glucose tolerance test for glucose (274 +/- 95 vs. 419 +/- 124 mmol x min/l) and insulin (38,142 +/- 18,206 vs. 58,383 +/- 34,408 pmol x min/l) and lower HOMA-IR values (2.2 +/- 0.8 vs. 4.2 +/- 2.6) than subjects with IGT. GIR (micromol x kg(-1) FFM x min(-1)) was higher in subjects with NGT than in subjects with IGT (53 +/- 11 vs. 43 +/- 14). HOMA-IR correlated with GIR in subjects with NGT (r = -0.59), but not in subjects with IGT (r = -0.13). GIR correlated with VO2max in subjects with NGT (r = 0.58) and IGT (r = 0.42), but with WHR only in subjects with NGT (r = -0.53). HOMA-IR correlated with VO2max (r = -0.57) and waist circumference (r = 0.54) in subjects with NGT, but with percent body fat in subjects with IGT (r = 0.54). These findings indicate that HOMA-IR should not be used as an index of IR in older individuals who may be at risk for IGT, and suggest that lifestyle changes that increase VO2max and decrease body fat
Dean, B; Thomas, N; Scarr, E; Udawela, M
Studies using central nervous system tissue obtained postmortem suggest pathways involved in energy and metabolism contribute to the pathophysiology of schizophrenia; neuroimaging studies suggesting glucose metabolism is particularly affected in the striatum. To gain information on the status of pathways involved in glucose metabolism in the striatum, we measured levels of glucose, pyruvate, acetyl-CoA and lactate as well as the β subunit of pyruvate dehydrogenase, a rate limiting enzyme, in the postmortem tissue from subjects with schizophrenia and age/sex-matched controls. The subjects with schizophrenia were made up of two subgroups, which could be divided because they either had (muscarinic receptor deficit schizophrenia (MRDS)), or did not have (non-MRDS), a marked deficit in cortical muscarinic receptors. Compared to controls, levels of β subunit of pyruvate dehydrogenase were lower (Δ mean=−20%) and levels of pyruvate (Δ mean=+47%) and lactate (Δ mean=+15%) were significantly higher in the striatum from subjects with schizophrenia. Notably, in subjects with non-MRDS, striatal levels of β subunit of pyruvate dehydrogenase were lower (Δ mean=−29%), whereas levels of pyruvate (Δ mean=−66%), acetyl-CoA (Δ mean=−28%) and glucose (Δ mean=-27%) were higher, whereas levels of lactate (Δ mean=+17%) were higher in MRDS. Finally, discriminate analyses using levels the β subunit of pyruvate dehydrogenase and glucose, or better still, β subunit of pyruvate dehydrogenase and glucose in combination with pyruvate, lactate or acetyl-CoA could separate subjects with non-MRDS from controls with high levels of specificity (up to 93%) and selectivity (up to 91%). Our data show the benefit of being able to study defined subgroups within the syndrome of schizophrenia as such an approach has revealed that changes in glucose metabolism may be a significant contributor to the pathophysiology of non-MRDS. PMID:27845781
Ismail, Muhammad-Al-Mustafa; Mateos, Laura; Maioli, Silvia; Merino-Serrais, Paula; Ali, Zeina; Lodeiro, Maria; Westman, Eric; Leitersdorf, Eran; Gulyás, Balázs; Olof-Wahlund, Lars; Winblad, Bengt; Savitcheva, Irina; Björkhem, Ingemar; Cedazo-Mínguez, Angel
Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced (18)F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)-mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders.
Chen, Xiaoqiang; Wang, Yuefei; Wu, Yalin; Han, Baoyu; Zhu, Yuejin; Tang, Xiaolin; Sun, Qinglei
Hot-water extracts of low-grade green tea were precipitated with ethanol, deproteinized with trichloroacetic acid, neutralized with NaOH and fractionated by DEAE-cellulose DE-52 column chromatography to yield three (3) of unexplored polysaccharide-conjugate fractions termed gTPC1, gTPC2 and gTPC3. Monosaccharide and amino acid composition, contents of total neutral sugars, proteins and moistures, HPGPC distribution and Zeta potentials of gTPC1-3 were investigated. Exposure of human umbilical vein endothelial (HUVE) cells to high glucose (33 mM) for 12h significantly decreased cell viability relative to normal glucose control (p<0.001). As compared with cell injury group, gTPC1-3 at all of three dose levels (50, 150 and 300 μg/mL) were found to possess remarkably protective effects on HUVE cells against impairments induced by high glucose in a dose-dependent manner (p<0.05, p<0.001). To contribute toward our understanding of the cell-based protection mechanism of gTPC1-3, the latter were subjected to self-oxidation of 1,2,3-phentriol assay, and their scavenging effects were observed as 55.1%, 47.6% and 47.9% at the concentration of 300 μg/mL, respectively. On the basis of the fact that high glucose-induced endothelial dysfunction involves in the overproduction of reactive oxygen species (ROS) and contributes to the vascular complications in patients with diabetes, inhibitory effects of gTPC1-3 on high glucose-mediated HUVE cell loss are, at least in part, correlated with their potential scavenging potency of ROS. Taken together, gTPC1-3 could be developed as non-cytotoxic candidates of therapeutic agent for diabetic vascular complications. Copyright © 2011 Elsevier B.V. All rights reserved.
Li, Xinli; Chen, Younan; Liu, Jingping; Yang, Guang; Zhao, Jiuming; Liao, Guangneng; Shi, Meimei; Yuan, Yujia; He, Sirong; Lu, Yanrong; Cheng, Jingqiu
Dyslipidemia caused by 'Western-diet pattern' is a strong risk factor for the onset of diabetes. This study aimed to disclose the relationship between the serum metabolite changes induced by habitual intake of high-fat and high-cholesterol (HFHC) diet and the development of impaired glucose tolerance (IGT) and insulin resistance through animal models of Macaca mulatta. Sixteen M. mulatta (six months old) were fed a control diet or a HFHC diet for 18 months. The diet effect on serum metabolic profiles was investigated by longitudinal research. Islet function was assessed by intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp test. Metabonomics were determined by (1)H proton nuclear magnetic resonance spectroscopy. Prolonged diet-dependent hyperlipidemia facilitated visceral fat accumulation in liver and skeletal muscle and disorder of glucose homeostasis in juvenile monkeys. Glucose disappearance rate (K(Glu)) and insulin response to the glucose challenge effects in HFHC monkeys were significantly lower than in control monkeys. Otherwise, serum trimethylamine-N-oxide (TMAO), lactate and leucine/isoleucine were significantly higher in HFHC monkeys. Sphingomyelin and choline were the most positively correlated with K(Glu) (R(2) = 0.778), as well as negative correlation (R(2) = 0.64) with total cholesterol. The HFHC diet induced visceral fat, abnormal lipid metabolism and IGT prior to weight gain and body fat content increase in juvenile monkeys. We suggest that increased serum metabolites, such as TMAO, lactate, branched-chain amino acids and decreased sphingomyelin and choline, may serve as possible predictors for the evaluation of IGT and insulin resistance risks in the prediabetic state.
Most premenopausal women with low trauma fracture(s) or low bone mineral density have a secondary cause of osteoporosis or bone loss. Where possible, treatment of the underlying cause should be the focus of management. Premenopausal women with an ongoing cause of bone loss and those who have had, or continue to have, low trauma fractures may require pharmacologic intervention. Clinical trials provide evidence of benefits of bisphosphonates and teriparatide for bone mineral density in several types of premenopausal osteoporosis, but studies are small and do not provide evidence regarding fracture risk reduction.
Uebelhart, B; Rizzoli, R
As for any chronic disease, adherence to osteoporosis treatment is low. Folates and vitamin B12 decrease hip fracture risk in elderly Japanese with stroke. Raloxifene (Evista) decreases the incidence of positive estrogen receptor breast cancer and could prevent cardiovascular events in patients at high risk. Strontium ranelate (Protélos) prevents hip fracture in elderly women. The action of alendronate (Fosamax) on bone mineral density and markers of bone remodelling is of higher amplitude than that of risedronate (Actonel). Once monthly ibandronate (Bonviva) increases bone mineral density in post menopausal women with osteoporosis. Excessive suppression of bone remodelling and osteonecrosis of the yaws could be related to bisphosphonate intake.
Korol, A M; Rosso, O A; Martín, M T; D'Arrigo, M; Riquelme, B D
This study investigates the effects produced by an increased concentration of glucose in a suspending medium on the erythrocytes Information Theory quantifiers. Erythrocytes, which were obtained from eight healthy volunteers, were washed and incubated in vitro with glucose solutions at different concentrations. The measured Wavelet-based Information Theory quantifiers include the Relative Wavelet Energy (RWE), the Normalized Total Wavelet Shannon Entropy (NTWS), MPR-Statistical Complexity Measure (SCM) and entropy-complexity plane. The results show that the increase in glucose concentration does not produce significant changes on the RWE, while significant ones on the NTSE, which combined with SCM values allow to identify different behaviour for all the different populations in the entropy-complexity plane. Modification in the hemorheological properties of cells could be clearly detected with these Wavelet-based Information Theory quantifiers.
D'souza, Anna M; Asadi, Ali; Johnson, James D; Covey, Scott D; Kieffer, Timothy J
Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of β-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 μg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance.
Faure, Cécile; Charlot, Keyne; Henri, Stéphane; Hardy-Dessources, Marie-Dominique; Hue, Olivier; Antoine-Jonville, Sophie
A high demand on thermoregulatory processes may challenge homoeostasis, particularly regarding glucose regulation. This has been understudied, although it might concern millions of humans. The objective of this project was to examine the isolated and combined effects of experimental short-term mild heat exposure and metabolic level on glucoregulation. Two experimental randomized crossover studies were conducted. Ten healthy young men participated in study A, which comprises four sessions in a fasting state at two metabolic levels [rest and exercise at 60% of maximal oxygen uptake (O2) for 40 min] in two environmental temperatures (warm: 31°C and control: 22°C). Each session ended with an ad libitum meal, resulting in similar energy intake across sessions. In study B, 12 healthy young men underwent two 3 h oral glucose tolerance tests (OGTTs) in warm and control environmental temperatures. Venous blood was sampled at several time points. In study A, repeated measure ANOVAs revealed higher postprandial serum glucose and insulin levels with heat exposure. Glycaemia following the OGTT was higher in the warm temperature compared with control. The kinetics of the serum glucose response to the glucose load was also affected by the environmental temperature (temperature-by-time interaction, P=0.030), with differences between the warm and control conditions observed up to 90 min after the glucose load (all P<0.033). These studies provide evidence that heat exposure alters short-term glucoregulation. The implication of this environmental factor in the physiopathology of Type 2 diabetes has yet to be investigated.
Yildirim, Pinar; Ceken, Cinar; Hassanpour, Reza; Esmelioglu, Sadik; Tolun, Mehmet Resit
In this paper, we consider the importance of osteoporosis disease in terms of medical research and pharmaceutical industry and we introduce a knowledge discovery approach regarding the treatment of osteoporosis from a historical perspective. Osteoporosis is a systemic skeletal disease in which osteoporotic fractures are associated with substantial morbidity and mortality and impaired quality of life. Osteoporosis has also higher costs, for example, longer hospital stays than many other diseases such as diabetes and heart attack and it is an attractive market for pharmaceutical companies. We use a freely available biomedical search engine leveraging text-mining technology to extract the drug names used in the treatment of osteoporosis from MEDLINE articles. We conclude that alendronate (Fosamax) and raloxifene (Evista) have the highest number of articles in MEDLINE and seem the dominating drugs for the treatment of osteoporosis in the last decade.
Beall, Craig; Piipari, Kaisa; Al-Qassab, Hind; Smith, Mark A.; Parker, Nadeene; Carling, David; Viollet, Benoit; Withers, Dominic J.; Ashford, Michael L. J.
AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic β-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in β-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPKα2 in β-cells and a population of hypothalamic neurons (RIPCreα2KO mice) and RIPCreα2KO mice lacking AMPKα1 (α1KORIPCreα2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured β-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCreα2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in α1KORIPCreα2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCreα2KO and α1KORIPCreα2KO mice, and conversely GSIS was impaired. β-Cells lacking AMPKα2 or expressing a kinase-dead AMPKα2 failed to hyperpolarize in response to low glucose, although KATP (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCreα2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse β-cell hyperpolarization, mimicking the effect of AMPKα2 loss. These results show that AMPKα2 activity is necessary to maintain normal pancreatic β-cell glucose sensing, possibly by maintaining high β-cell levels of UCP2. PMID:20465544
Mitchell, B D; Valdez, R; Hazuda, H P; Haffner, S M; Monterrosa, A; Stern, M P
To determine whether diabetes risk is influenced by which parent (a parental history of diabetes is a well-documented risk factor for NIDDM) is reported to have diabetes. We compared the prevalence of NIDDM and IGT for 4914 subjects according to their parental history of diabetes (mother only, father only, both parents, neither parent). Subjects were drawn from the San Antonio Heart Study, a population-based survey of diabetes and cardiovascular risk factors conducted in Mexican American and non-Hispanic white individuals between 1979-1988. Men with a parental history of diabetes had a higher prevalence of both NIDDM and impaired glucose tolerance than men reporting no parental history of diabetes. Prevalence was equally high regardless of which parent, or whether both parents, had diabetes. In contrast, in women, only a maternal history of diabetes was associated with a higher prevalence of NIDDM and impaired glucose tolerance. Virtually no difference in NIDDM prevalence was found between women with a paternal-only history of diabetes and women with no parental history of diabetes. Results differed markedly between men and women. The reason for this sex difference is unclear. It may represent a measurement bias, a sex-specific environmental effect, or a genetic effect that is expressed or transmitted differently between the sexes.
glucose tolerance (IGT), diabetes mellitus (DM), use of oral hypoglycemic agents, or use of insulin for the period 1988 to 1992. The paper reviewed the...incidence and prevalence of diabetes mellitus in Army aviators. The study tabulated the incidence and age-specific annual rates of diabetes mellitus and
Objective: To determine the effects of an aqueous extract of cinnamon on antioxidant status of obese subjects. Methods: Twenty-two obese subjects with elevated blood glucose were enrolled in a double-blind placebo-controlled trial. Subjects were given either a placebo or 250 mg of an aqueous extract...
In response to food intake, glucagon-like peptide-2 (GLP-2) with GLP-1 is co-secreted from enteroendocrine L cells in the gut. GLP-2 receptor (GLP-2R) is expressed in the hypothalamus, a key tissue to integrate energy signals to regulate energy balance and glucose homeostasis. However, the physiolog...
McCarthy, Alicia M.; Spisak, Kristen O.; Brozinick, Joseph T.; Elmendorf, Jeffrey S.
Study has demonstrated an essential role of cortical filamentous actin (F-actin) in insulin-regulated glucose uptake by skeletal muscle. Here, we tested whether perturbations in F-actin contributed to impaired insulin responsiveness provoked by hyperinsulinemia. In L6 myo-tubes stably expressing GLUT4 that carries an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased GLUT4myc translocation and glucose uptake by ~2-fold. In contrast, a hyperinsulinemic state, induced by inclusion of 5 nM insulin in the medium for 12 h decreased the ability of insulin to stimulate these processes. Defects in insulin signaling did not readily account for the observed disruption. In contrast, hyperinsulinemia reduced cortical F-actin. This occurred concomitant with a loss of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2), a lipid involved in cytoskeletal regulation. Restoration of plasma membrane PIP2 in hyperinsulinemic cells restored F-actin and insulin responsiveness. Consistent with these in vitro observations suggesting that the hyperinsulinemic state negatively affects cortical F-actin structure, epitrochlearis skeletal muscle from insulin-resistant hyperinsulinemic Zucker fatty rats displayed a similar loss of F-actin structure compared with that in muscle from lean insulin-sensitive littermates. We propose that a component of insulin-induced insulin resistance in skeletal muscle involves defects in PIP2/F-actin structure essential for insulin-regulated glucose transport. PMID:16774991
McCarthy, Alicia M; Spisak, Kristen O; Brozinick, Joseph T; Elmendorf, Jeffrey S
Study has demonstrated an essential role of cortical filamentous actin (F-actin) in insulin-regulated glucose uptake by skeletal muscle. Here, we tested whether perturbations in F-actin contributed to impaired insulin responsiveness provoked by hyperinsulinemia. In L6 myotubes stably expressing GLUT4 that carries an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased GLUT4myc translocation and glucose uptake by approximately 2-fold. In contrast, a hyperinsulinemic state, induced by inclusion of 5 nM insulin in the medium for 12 h decreased the ability of insulin to stimulate these processes. Defects in insulin signaling did not readily account for the observed disruption. In contrast, hyperinsulinemia reduced cortical F-actin. This occurred concomitant with a loss of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)), a lipid involved in cytoskeletal regulation. Restoration of plasma membrane PIP(2) in hyperinsulinemic cells restored F-actin and insulin responsiveness. Consistent with these in vitro observations suggesting that the hyperinsulinemic state negatively affects cortical F-actin structure, epitrochlearis skeletal muscle from insulin-resistant hyperinsulinemic Zucker fatty rats displayed a similar loss of F-actin structure compared with that in muscle from lean insulin-sensitive littermates. We propose that a component of insulin-induced insulin resistance in skeletal muscle involves defects in PIP(2)/F-actin structure essential for insulin-regulated glucose transport.
Wang, Yi; Simar, David; Fiatarone Singh, Maria A
The aim of this investigation was to review morphological and metabolic adaptations within skeletal muscle to exercise training in adults with type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). A comprehensive, systematic database search for manuscripts was performed from 1966 to March 2008 using computerized databases, including Medline, Premedline, CINAHL, AMED, EMBASE and SportDiscus. Three reviewers independently assessed studies for potential inclusion (exposure to exercise training, T2DM or IGT, muscle biopsy performed). A total of 18 exercise training studies were reviewed. All morphological and metabolic outcomes from muscle biopsies were collected. The metabolic outcomes were divided into six domains: glycogen, glucose facilitated transporter 4 (GLUT4) and insulin signalling, enzymes, markers of inflammation, lipids metabolism and so on. Beneficial adaptations to exercise were seen primarily in muscle fiber area and capillary density, glycogen, glycogen synthase and GLUT4 protein expressions. Few randomized controlled trials including muscle biopsy data existed, with a small number of subjects involved. More trials, especially robustly designed exercise training studies, are needed in this field. Future research should focus on the insulin signalling pathway to better understand the mechanism of the improvements in insulin sensitivity and glucose homeostasis in response to various modalities and doses of exercise in this cohort.
Zheng, Ze; Xu, Xiaohua; Zhang, Xuebao; Wang, Aixia; Zhang, Chunbin; Hüttemann, Maik; Grossman, Lawrence I.; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong
Background Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters < 2.5 μm (PM2.5) to the development of metabolic diseases. In this study, we investigated the effect of PM2.5 exposure on liver pathogenesis and the mechanism by which ambient PM2.5 modulates hepatic pathways and glucose homeostasis. Methods Using “Ohio’s Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1”, we performed whole-body exposure of mice to concentrated ambient PM2.5 for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM2.5 exposure promotes liver pathogenesis. Results Mice exposed to PM2.5 for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. Mice after PM2.5 exposure displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM2.5 led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4) but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM2.5 exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR) γ and PPARα in the liver. Conclusions Our study suggests that PM2.5 exposure represents a significant “hit” that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders. PMID:22902548
Zheng, Ze; Xu, Xiaohua; Zhang, Xuebao; Wang, Aixia; Zhang, Chunbin; Hüttemann, Maik; Grossman, Lawrence I; Chen, Lung Chi; Rajagopalan, Sanjay; Sun, Qinghua; Zhang, Kezhong
Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters<2.5 μm (PM(2.5)) to the development of metabolic diseases. In this study, we investigated the effect of PM(2.5) exposure on liver pathogenesis and the mechanism by which ambient PM(2.5) modulates hepatic pathways and glucose homeostasis. Using "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1", we performed whole-body exposure of mice to concentrated ambient PM(2.5) for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM(2.5) exposure promotes liver pathogenesis. Mice exposed to PM(2.5) for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM(2.5) exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM(2.5) led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM(2.5) exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)γ and PPARα in the liver. Our study suggests that PM(2.5) exposure represents a significant "hit" that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Wein, P; Beischer, N; Harris, C; Permezel, M
Women with impaired glucose tolerance are at high risk of developing noninsulin dependent diabetes mellitus (NIDDM). The Mercy Hospital for Women has a long-term follow-up programme for women with gestational diabetes, which identifies many women with impaired glucose tolerance. Two hundred of these women were entered into a randomized controlled trial of intensive versus routine dietary advice. Seven women were lost to follow-up. The annual incidence rates of diabetes mellitus for the 2 groups were 6.1% (intervention) and 7.3% (control), an incident rate ratio of 0.83, 95% confidence interval 0.47-1.48, p = 0.50. Overall, there was a return to normal glucose tolerance in 44% of patients. Multivariate analysis showed that body mass index, fasting and 2-hour plasma glucose levels at trial entry were significantly associated with an increased risk of diabetes mellitus. Impaired glucose tolerance is an important condition that should be treated with advice about lifestyle modification (diet and/or exercise). We consider that future trials in the management of women with previous gestational diabetes who have impaired glucose tolerance should investigate the effect of pharmacological intervention in addition to diet and/or exercise, the latter providing a therapy that it would be unethical to exclude on the evidence presently available.
Zhang, Ruxue; Zhou, Jun; Li, Maoxing; Ma, Haigang; Qiu, Jianguo; Luo, Xiaohong; Jia, Zhengping
The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with high-fat diet. The rats were fed by a high-fat diet and simultaneously stimulated by chronic stress over 5 weeks. Body weight, fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), plasma lipids, gluconeogenesis test (GGT), glycogen content, and corticosterone, insulin and leptin levels were measured. The results showed that ROS administration (100, 200 mg/kg, i.g.) for 5 weeks exerted the effects of increasing the organ weights of thymus and spleen, lowering the fasting plasma glucose level, improving impaired glucose tolerance, increasing the contents of liver and muscle glycogen, decreasing the gluconeogenesis ability, plasma-free fatty acid's level, as well as plasma triglyceride and total cholesterol levels in chronic stress and high-fat fed rats, especially in the group of 200mg/kg; while the plasma corticosterone level was decreased, and plasma leptin level was increased. These results suggest that ROS exert an ameliorating effect of impaired glucose metabolism in chronic stress rats fed with high-fat diet, and the potential mechanism may be mediated through rebuilding the glucose homeostasis in the neuroendocrine immuno-modulation (NIM) network through multilinks and multitargets. Copyright © 2013 Elsevier GmbH. All rights reserved.
Karcaaltincaba, Deniz; Buyukkaragoz, Bahar; Kandemir, Omer; Yalvac, Serdar; Kıykac-Altınbaş, Sadiman; Haberal, Ali
The aim of this study was to determine the prevalence of gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (GIGT) in adolescent pregnancies, associated risk factors, and pregnancy complications. Retrospective study. Community-based teaching hospital. Results of 1653 pregnant women age ≤ 19 years in 2005-2007 were reviewed. All pregnant women screened with 50-g glucose challenge test (GCT) and patients with a GCT result ≥ 140 mg/dl underwent a 3-hour 100-g oral glucose tolerance test (OGTT). GDM was diagnosed with at least two abnormal results and GIGT was diagnosed with one abnormal result. GDM and GIGT cases were evaluated for the presence of any associated risk factors and effects of presence of risk factors on pregnancy outcomes. The prevalence of GDM was 0.85% (95% CI, 0.41-1.29), GIGT was 0.5% (95% CI, 0.15-0.81) and GDM+GIGT was 1.35% (95% CI, 0.78-1.88) by Carpenter and Coustan criteria. 68% of patients had at least one of the risk factors including body mass index ≥ 25, family history of diabetes and polycystic ovary syndrome (PCOS). Only 9.1% (n = 2) of them required insulin for glucose regulation during pregnancy with 9.1% (n = 2) macrosomia rate. All patients were primiparous and cesarean delivery rate was 27.3% (n = 6). We could not find any effect of presence of risk factors on pregnancy outcomes in GDM and GIGT cases. We demonstrated that GDM and GIGT are strongly associated with high BMI before pregnancy, PCOS, and family history of diabetes. Since GDM is a state of prediabetes, it is important to diagnose in adolescent pregnancies considering their life expectancy to take preventive measures to avoid diabetes mellitus. Copyright © 2011 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.
Background The purpose of this study is to investigate the association of metabolic syndrome (MS) and its components with the risk of impaired glucose tolerance (IGT) in high risk urban professionals. The goal is to improve the selection of candidates who would most benefit from an oral glucose tolerance test (OGTT). Methods This is a cross sectional study in which MS was identified by both the definitions proposed by the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF). Results There were 928 eligible subjects in the study, and 23.9% of them failed in OGTT. The odds ratio of IGT was increased 3.16-fold for MS defined by the NCEP criteria and 2.79-fold for the hyperglycemia factor alone. Both MS and hyperglycemia were shown to be acceptable measures to discriminate subjects with IGT from those with normal glucose tolerance (NGT). The clustering of any 1, 2, or ≥3 metabolic components resulted in increased odds ratios for IGT: i.e., 1.71, 2.38 and 5.92, respectively. Even without hyperglycemia in the cluster, an increased odds ratio was still observed. The risk of IGT increased dramatically when the fasting plasma glucose and waist circumference were both at their highest defined level. Conclusions MS and its components are associated with the increased risk of IGT. People with MS, one of its components, especially hyperglycemia and central obesity, or a cluster of its components are strong candidates for an OGTT in order to achieve early cost-effective detection of IGT. PMID:24499585
Kratochvílová, Simona; Škoch, Antonín; Wohl, Petr; Švehlíková, Eva; Dezortová, Monika; Hill, Martin; Hájek, Milan; Pelikánová, Terezie
Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and (1)H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFα (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways. Copyright © 2015 Elsevier Inc. All rights reserved.
Eussen, Simone J P M; van Dongen, Martien C J M; Wijckmans, Nicole; den Biggelaar, Louise; Oude Elferink, Stefanie J W H; Singh-Povel, Cécile M; Schram, Miranda T; Sep, Simone J S; van der Kallen, Carla J; Koster, Annemarie; Schaper, Nicolaas; Henry, Ronald M A; Stehouwer, Coen D A; Dagnelie, Pieter C
Observational studies suggest an inverse association between total dairy product intake and diabetes risk. However, there is a lack of information on the relationship of specific dairy products with impaired glucose metabolism (IGM) and type 2 diabetes mellitus (T2DM). Individuals aged 40-75 years were recruited for the Maastricht Study. All the participants filled out a 253-food item FFQ, covering fifty specific dairy items that captured differences between full-fat, semi-skimmed and skimmed products, as well as fermented and non-fermented products. Glucose metabolism status was assessed by an oral glucose tolerance test, and participants were informed on their glucose metabolism status after returning the FFQ. Data of 2391 individuals were available to estimate OR (95 % CI) for IGM (n 470) and newly diagnosed (ND) T2DM (n 125), with adjustment for age, sex, BMI, physical activity, smoking status, education, energy intake and intakes of vegetables, fruits, meat and fish. For IGM, fully adjusted analyses revealed inverse associations, with OR comparing the highest with the lowest tertile of intake of 0·73 (95 % CI 0·55, 0·96) for skimmed products and 0·74 (95 % CI 0·54, 0·99) for fermented products. These dairy products were not associated with ND T2DM. In contrast, full-fat products were positively associated with ND T2DM (OR 2·01; 95 % CI 1·16, 3·47), whereas total dairy product intake was inversely associated with ND T2DM (OR 0·50; 95 % CI 0·26, 0·93). In conclusion, individuals with a high consumption of skimmed and fermented products had lower odds of having IGM, and individuals with a high consumption of total dairy products had lower odds of having ND T2DM. High intake of full-fat products was not related to IGM but was positively related to ND T2DM.
Robertson, Tracey M; Clifford, Michael N; Penson, Simon; Chope, Gemma; Robertson, M Denise
Previous studies regarding the acute effects of coffee on glycaemic control have used a single large dose of coffee, typically containing the caffeine equivalent of 2-4 servings of coffee. This study investigates whether the acute effects of coffee are dose-dependent, starting with a single serving. A total of ten healthy overweight males participated in a two-part randomised double-blind cross-over study. In the first part, they ingested 2, 4 or 8 g instant decaffeinated coffee (DC) dissolved in 400 ml water with caffeine added in proportion to the DC (total 100, 200 or 400 mg caffeine) or control (400 ml water) all with 50 g glucose. In the second part, they ingested the same amounts of DC (2, 4, 8 g) or control, but with a standard 100 mg caffeine added to each. Capillary blood samples were taken every 15 min for 2 h after each drink and glucose and insulin levels were measured. Repeated measures ANOVA on glucose results found an effect when caffeine was varied in line with DC (P=0·008). Post hoc analysis revealed that both 2 and 4 g DC with varied caffeine content increased the glycaemic response v. There was no effect of escalating doses of DC when caffeine remained constant at 100 mg. These results demonstrate that one standard serving of coffee (2 g) is sufficient to affect glucose metabolism. Furthermore, the amount of caffeine found in one serving (100 mg) is sufficient to mask any potential beneficial effects of increasing other components. No dose-dependent effect was found.
Engelbrecht, B; Mattern, Y; Scheibler, S; Tschoepe, D; Gawlowski, T; Stratmann, B
Methylglyoxal (MG) is a highly reactive dicarbonyl compound derived mainly from glucose degradation pathways, but also from protein and fatty acid metabolism. MG modifies structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic complications. Hyperglycemia-associated accumulation of MG might be associated with generation of oxidative stress and subsequently insulin resistance. Therefore, the effects of MG on insulin signaling and on translocation of glucose transporter 4 (GLUT4) were investigated in the rat skeletal muscle cell line L6-GLUT4myc stably expressing myc-tagged GLUT4. Twenty four-hour MG treatment resulted in elevated GLUT4 presentation on the surface of L6 myoblasts and in an increased uptake of glucose even without insulin stimulation. Exogenously added MG neither effected IRS-1 expression nor IRS-1 phosphorylation. A decreased expression of Akt1 but not Akt2 and concomitantly increased apoptosis were detected following MG treatment. To exclude that oxidative stress caused by MG treatment leads to increased GLUT4 translocation, effects of pretreatment with 2 antioxidants were investigated. The antioxidant and MG scavenger NAC prevented the MG-induced GLUT4 translocation. In contrast, tiron, a well-known antioxidant that does not exert MG-scavenger function, had no impact on MG-induced GLUT4 translocation supporting the hypothesis of a direct effect of MG on GLUT4 trafficking. In conclusion, prolonged treatment with MG augments GLUT4 level on the surface of L6 myoblasts, at least in part through a higher translocation of GLUT4 from the intracellular compartment as well as a reduction of GLUT4 internalization, resulting in increased glucose uptake.
Xiao, Bo; Liu, Huazhen; Gu, Zeyun; Liu, Sining; Ji, Cheng
Cell transplantation of neural stem cells (NSCs) is a promising approach for neurological recovery both structurally and functionally. However, one big obstacle is to promote differentiation of NSCs into neurons and the followed maturation. In the present study, we aimed to investigate the protective effect of taurine on the differentiation of NSCs and subsequent maturation of their neuronal lineage, when exposed to oxygen-glucose deprivation (OGD). The results suggested that taurine (5-20 mM) promoted the viability and proliferation of NSCs, and it protected against 8 h of OGD induced impairments. Furthermore, 20 mM taurine promoted NSCs to differentiate into neurons after 7 days of culture, and it also protected against the suppressive impairments of 8 h of OGD. Consistently, taurine (20 mM) promoted the neurite sprouting and outgrowth of the NSC differentiated neurons after 14 days of differentiation, which were significantly inhibited by OGD (8 h). At D21, the mushroom spines and spine density were promoted or restored by 20 mM taurine. Taken together, the enhanced viability and proliferation of NSCs, more differentiated neurons and the promoted maturation of neurons by 20 mM taurine support its therapeutic application during stem cell therapy to enhance neurological recovery. Moreover, it protected against the impairments induced by OGD, which may highlight its role for a more direct therapeutic application especially in an ischemic stroke environment.
Ren, Hongxia; Lu, Taylor Y.; McGraw, Timothy E.
The central nervous system (CNS) uses glucose independent of insulin. Nonetheless, insulin receptors and insulin-responsive glucose transporters (Glut4) often colocalize in neurons (Glut4 neurons) in anatomically and functionally distinct areas of the CNS. The apparent heterogeneity of Glut4 neurons has thus far thwarted attempts to understand their function. To answer this question, we used Cre-dependent, diphtheria toxin–mediated cell ablation to selectively remove basal hypothalamic Glut4 neurons and investigate the resulting phenotypes. After Glut4 neuron ablation, mice demonstrate altered hormone and nutrient signaling in the CNS. Accordingly, they exhibit negative energy balance phenotype characterized by reduced food intake and increased energy expenditure, without locomotor deficits or gross neuronal abnormalities. Glut4 neuron ablation affects orexigenic melanin-concentrating hormone neurons but has limited effect on neuropeptide Y/agouti-related protein and proopiomelanocortin neurons. The food intake phenotype can be partially normalized by GABA administration, suggesting that it arises from defective GABAergic transmission. Glut4 neuron–ablated mice show peripheral metabolic defects, including fasting hyperglycemia and glucose intolerance, decreased insulin levels, and elevated hepatic gluconeogenic genes. We conclude that Glut4 neurons integrate hormonal and nutritional cues and mediate CNS actions of insulin on energy balance and peripheral metabolism. PMID:25187366
Jansson, L; Eizirik, D L; Pipeleers, D G; Borg, L A; Hellerström, C; Andersson, A
Hyperglycemia-induced beta-cell dysfunction may be an important component in the pathogenesis of non-insulin-dependent diabetes mellitus. However, most available data in this field were obtained from rodent islets. To investigate the relevance of this hypothesis for human beta-cells in vivo, human pancreatic islets were transplanted under the renal capsule of nude mice. Experimental groups were chosen so that grafted islets were exposed to either hyper- or normoglycemia or combinations of these for 4 or 6 wk. Grafts of normoglycemic recipients responded with an increased insulin release to a glucose stimulus during perfusion, whereas grafts of hyperglycemic recipients failed to respond to glucose. The insulin content of the grafts in the latter groups was only 10% of those observed in controls. Recipients initially hyperglycemic (4 wk), followed by 2 wk of normoglycemia regained a normal graft insulin content, but a decreased insulin response to glucose remained. No ultrastructural signs of beta-cell damage were observed, with the exception of increased glycogen deposits in animals hyperglycemic at the time of killing. It is concluded that prolonged exposure to a diabetic environment induces a long-term secretory defect in human beta-cells, which is not dependent on the size of the islet insulin stores.
Jansson, L; Eizirik, D L; Pipeleers, D G; Borg, L A; Hellerström, C; Andersson, A
Hyperglycemia-induced beta-cell dysfunction may be an important component in the pathogenesis of non-insulin-dependent diabetes mellitus. However, most available data in this field were obtained from rodent islets. To investigate the relevance of this hypothesis for human beta-cells in vivo, human pancreatic islets were transplanted under the renal capsule of nude mice. Experimental groups were chosen so that grafted islets were exposed to either hyper- or normoglycemia or combinations of these for 4 or 6 wk. Grafts of normoglycemic recipients responded with an increased insulin release to a glucose stimulus during perfusion, whereas grafts of hyperglycemic recipients failed to respond to glucose. The insulin content of the grafts in the latter groups was only 10% of those observed in controls. Recipients initially hyperglycemic (4 wk), followed by 2 wk of normoglycemia regained a normal graft insulin content, but a decreased insulin response to glucose remained. No ultrastructural signs of beta-cell damage were observed, with the exception of increased glycogen deposits in animals hyperglycemic at the time of killing. It is concluded that prolonged exposure to a diabetic environment induces a long-term secretory defect in human beta-cells, which is not dependent on the size of the islet insulin stores. Images PMID:7635965
Prasain, Jeevan K.; Peng, Ning; Rajbhandari, Rajani; Wyss, J. Michael
The incidence of type 2 diabetes and metabolic disease is rapidly increasing, but effective therapies for their prevention and treatment have been poorly tolerated or minimally effective. In this study, chronic administration of kudzu root extract (8 months, 0.2% w/w in diet) decreased baseline fasting plasma glucose (183±14 vs 148±11 mg/dl) and improved glucose and insulin tolerance in C57BL/6J ob/ob mice (1.67±0.17 ng/ml [kudzu treated] vs. 2.35±0.63 ng/ml [control]), but such treatment did not alter these parameters in lean control mice. Among the mice on the kudzu supplementation, plasma levels of isoflavone metabolites were significantly higher in ob/ob versus lean control mice, and unmetabolized puerarin (11.50±5.63 ng/gram) was found in adipose tissue only in the treated mice. Together, these data demonstrate that a puerarin containing kudzu diet improves glucose and insulin responsiveness in ob/ob mice, suggesting that puerarin may be a beneficial adjuvant for treating metabolic disease. PMID:23123226
Prasain, Jeevan K; Peng, Ning; Rajbhandari, Rajani; Wyss, J Michael
The incidence of type 2 diabetes and metabolic disease is rapidly increasing, but effective therapies for their prevention and treatment have been poorly tolerated or minimally effective. In this study, chronic administration of kudzu root extract (8 months, 0.2%, w/w, in diet) decreased baseline fasting plasma glucose (183±14 vs. 148±11 mg/dl) and improved glucose and insulin tolerance in C57BL/6J ob/ob mice (1.67±0.17 ng/ml [kudzu treated] vs. 2.35±0.63 ng/ml [control]), but such treatment did not alter these parameters in lean control mice. Among the mice on the kudzu supplementation, plasma levels of isoflavone metabolites were significantly higher in ob/ob versus lean control mice, and unmetabolized puerarin (11.50±5.63 ng/g) was found in adipose tissue only in the treated mice. Together, these data demonstrate that a puerarin containing kudzu diet improves glucose and insulin responsiveness in ob/ob mice, suggesting that puerarin may be a beneficial adjuvant for treating metabolic disease. Copyright © 2012 Elsevier GmbH. All rights reserved.
Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R; Barr, David; Herndon, David N
Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months postburn. The purpose of this study was to measure insulin sensitivity in severely burned children before discharge when wounds are 95% healed. Twenty-four children, aged 4 to 17 years, with burns > or = 40% TBSA underwent a 2-hour oral glucose tolerance test before discharge from the acute pediatric burn unit. Plasma glucose and insulin levels as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared with published oral glucose tolerance test data from healthy, nonburned children. There was a significant difference between severely burned children and nonburned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53 +/- 1.62 compared with the value in nonburned, healthy children of 1.28 +/- 0.16 (P < .05). Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury.
Ren, Hongxia; Lu, Taylor Y; McGraw, Timothy E; Accili, Domenico
The central nervous system (CNS) uses glucose independent of insulin. Nonetheless, insulin receptors and insulin-responsive glucose transporters (Glut4) often colocalize in neurons (Glut4 neurons) in anatomically and functionally distinct areas of the CNS. The apparent heterogeneity of Glut4 neurons has thus far thwarted attempts to understand their function. To answer this question, we used Cre-dependent, diphtheria toxin-mediated cell ablation to selectively remove basal hypothalamic Glut4 neurons and investigate the resulting phenotypes. After Glut4 neuron ablation, mice demonstrate altered hormone and nutrient signaling in the CNS. Accordingly, they exhibit negative energy balance phenotype characterized by reduced food intake and increased energy expenditure, without locomotor deficits or gross neuronal abnormalities. Glut4 neuron ablation affects orexigenic melanin-concentrating hormone neurons but has limited effect on neuropeptide Y/agouti-related protein and proopiomelanocortin neurons. The food intake phenotype can be partially normalized by GABA administration, suggesting that it arises from defective GABAergic transmission. Glut4 neuron-ablated mice show peripheral metabolic defects, including fasting hyperglycemia and glucose intolerance, decreased insulin levels, and elevated hepatic gluconeogenic genes. We conclude that Glut4 neurons integrate hormonal and nutritional cues and mediate CNS actions of insulin on energy balance and peripheral metabolism.
Mamas, Mamas A; Deaton, Christi; Rutter, Martin K; Yuille, Martin; Williams, Simon G; Ray, Simon G; New, John; Gibson, J Martin; Neyses, Ludwig
A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear. The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR. We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients. Copyright 2010 Elsevier Inc. All rights reserved.
O3 is associated with adverse cardiopulmonary health effects in humans and is thought to produce metabolic effects, such as insulin resistance. Recently, we showed that episodic O3 exposure increased insulin levels in aged rats. We hypothesized that O3 exposure could impair gluc...
Berlanga-Acosta, Jorge; Schultz, Gregory S.; López-Mola, Ernesto; Guillen-Nieto, Gerardo; García-Siverio, Marianela; Herrera-Martínez, Luis
Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia is the proximal detonator of systemic and local toxic effectors including proinflammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis deficiency weakens wounds' anabolism and predisposes to inflammation. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. These factors in concert hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflammed, procatabolic, and an additional source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic fibroblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation figures. PMID:23484099
O3 is associated with adverse cardiopulmonary health effects in humans and is thought to produce metabolic effects, such as insulin resistance. Recently, we showed that episodic O3 exposure increased insulin levels in aged rats. We hypothesized that O3 exposure could impair gluc...
Kodama, Norihiro; Tahara, Nobuhiro; Tahara, Atsuko; Honda, Akihiro; Nitta, Yoshikazu; Mizoguchi, Minori; Kaida, Hayato; Ishibashi, Masatoshi; Abe, Toshi; Ikeda, Hisao; Narula, Jagat; Fukumoto, Yoshihiro; Yamagishi, Sho-ichi; Imaizumi, Tsutomu
Excess visceral fat is associated with chronic systemic inflammation and cardiovascular complications. Pioglitazone has been reported to variably influence visceral fat volume; however, its effect on metabolic activity of the visceral fat remains uncharacterized. The aim of this study was to assess the effects of pioglitazone on glucose metabolism of fat tissue by using (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and computed tomography imaging. FDG-PET and computed tomography imaging were performed in 56 patients with impaired glucose tolerance or type 2 diabetes mellitus; lipid and glycemic profiles and inflammatory biomarkers were obtained in all patients. These patients were randomized to treatment with either pioglitazone or glimepiride for 16 weeks. The metabolic activity of the visceral fat tissues as assessed by FDG uptake was expressed as a target-to-background ratio (TBR) of blood-normalized standardized uptake value. The study was completed in 32 pioglitazone-treated and 21 glimepiride-treated patients (40 men and 13 women; mean age, 67.7 ± 8.1 y; body mass index, 25.0 ± 3.6 kg/m(2); glycated hemoglobin, 6.78 ± 0.70%). Both treatments were well-tolerated and comparably improved glycemic control. At baseline, visceral fat exhibited a higher TBR value than subcutaneous fat (0.55 ± 0.14 vs 0.30 ± 0.07, P < .001). Pioglitazone, but not glimepiride, significantly decreased the visceral fat volume (130.5 ± 53.0 to 122.1 ± 51.0 cm(2), P = .013) and TBR values (0.57 ± 0.16 to 0.50 ± 0.11, P = .007). Neither pioglitazone nor glimepiride treatment showed any effect on the volume or TBR values of subcutaneous fat. After 16 weeks of treatment with pioglitazone, reduction in visceral fat TBR was correlated to the increase in high-density lipoprotein cholesterol levels. Our study indicated that pioglitazone decreased the visceral fat volume and its metabolic activity in patients with impaired glucose tolerance or type 2 diabetes mellitus
Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.
Dagenais, G R; Gerstein, H C; Holman, R; Budaj, A; Escalante, A; Hedner, T; Keltai, M; Lonn, E; McFarlane, S; McQueen, M; Teo, K; Sheridan, P; Bosch, J; Pogue, J; Yusuf, S
Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84-1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75-1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60-31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68-0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.
Noncardiovascular deaths are more common than cardiovascular deaths in patients with cardiovascular disease or cardiovascular risk factors and impaired glucose tolerance: Insights from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.
Sharma, Abhinav; de Souza Brito, Flávio; Sun, Jie-Lena; Thomas, Laine; Haffner, Steven; Holman, Rury R; Lopes, Renato D
Patients with impaired glucose tolerance have an elevated risk of cardiovascular (CV) death; however, the causes and risk factors associated with non-CV deaths are poorly understood. The NAVIGATOR trial enrolled 9,306 participants with impaired glucose tolerance and CV disease or at high CV risk, with a median follow-up of 6.4years. Using this population, we identified (1) the proportion of deaths attributed to CV, non-CV, and unknown causes, and (2) the risk factors associated with non-CV death. During the NAVIGATOR trial follow-up, 622 patients died. Investigators reported 244 (39.2%) CV deaths, 313 (50.3%) non-CV deaths, and 65 (10.5%) deaths of unknown cause. Myocardial infarction was the leading cause of investigator-reported death (57/622 [9.2%]). Among non-CV deaths, the most commonly identified cause related to malignancy (177/313 [56.5%]). Using adjudicated causes of death, Cox proportional hazard models identified 3 independent prognostic markers that increased the risk of non-CV death: history of non-melanoma skin cancer (hazard ratio 2.67 [95% CI 1.65-4.33]; P<.0001), white blood cell count (1 unit >5000/mm(3); 1.10 [1.02-1.18]; P=.011), and serum potassium levels (per 1mmol/L above any value; 1.67 [1.302.15]; P<.0001). Despite the high baseline CV risk among patients in the NAVIGATOR trial, the most common cause of death was non-CV. The high burden of non-CV death in this population has potential implications for future CV event-driven trials. Copyright © 2016 Elsevier Inc. All rights reserved.
Gray, Laura J; Khunti, Kamlesh; Williams, Sian; Goldby, Stephanie; Troughton, Jacqui; Yates, Thomas; Gray, Alastair; Davies, Melanie J
The prevention of type 2 diabetes is a globally recognised health care priority, but there is a lack of rigorous research investigating optimal methods of translating diabetes prevention programmes, based on the promotion of a healthy lifestyle, into routine primary care. The aim of the study is to establish whether a pragmatic structured education programme targeting lifestyle and behaviour change in conjunction with motivational maintenance via the telephone can reduce the incidence of type 2 diabetes in people with impaired glucose regulation (a composite of impaired glucose tolerance and/or impaired fasting glucose) identified through a validated risk score screening programme in primary care. Cluster randomised controlled trial undertaken at the level of primary care practices. Follow-up will be conducted at 12, 24 and 36 months. The primary outcome is the incidence of type 2 diabetes. Secondary outcomes include changes in HbA1c, blood glucose levels, cardiovascular risk, the presence of the Metabolic Syndrome and the cost-effectiveness of the intervention. The study consists of screening and intervention phases within 44 general practices coordinated from a single academic research centre. Those at high risk of impaired glucose regulation or type 2 diabetes are identified using a risk score and invited for screening using a 75 g-oral glucose tolerance test. Those with screen detected impaired glucose regulation will be invited to take part in the trial. Practices will be randomised to standard care or the intensive arm. Participants from intensive arm practices will receive a structured education programme with motivational maintenance via the telephone and annual refresher sessions. The study will run from 2009-2014. This study will provide new evidence surrounding the long-term effectiveness of a diabetes prevention programme conducted within routine primary care in the United Kingdom. Clinicaltrials.gov NCT00677937.
Invernizzi, Marco; Carda, Stefano; Viscontini, Giovanni Sguazzini; Cisari, Carlo
Patients affected by Parkinson's disease are at a high risk for fractures, mainly of the hip. These fractures are caused by falls due to postural imbalance, neurological impairment and reduced bone mass. The purpose of this study was (1) to investigate the correlations and the pathophysiological mechanisms underlying bone loss in Parkinson's disease and appraise bone loss or fracture risk reduction interventions; (2) to develop a research agenda that informs the design and development of risk reduction strategies. Osteoporosis and osteopenia are very common findings in patients with Parkinson's disease, affecting up to 91% of women and 61% of men. Reduced bone mass in Parkinsonian patients seems to be caused mainly by reduced mobility through a mechanism similar to that observed in other neurological diseases. Endocrine (such as vitamin D deficiency), nutritional and iatrogenic factors also play an important role in bone mass depletion. Female gender, disease duration and severity (Hoehn and Yahr stages III and IV), old age and low body mass index are related to more severe osteoporosis. Vitamin D supplementation and bisphosphonates seem to be effective in reducing the risk of nonvertebral fractures in patients affected by Parkinson's disease. Prevention and evaluation of osteoporosis through bone mass density assessment should be considered in all patients with Parkinson's disease.
Almurdhi, M M; Brown, S J; Bowling, F L; Boulton, A J M; Jeziorska, M; Malik, R A; Reeves, N D
To investigate alterations in walking strategy and dynamic sway (unsteadiness) in people with impaired glucose tolerance and people with Type 2 diabetes in relation to severity of neuropathy and vitamin D levels. A total of 20 people with Type 2 diabetes, 20 people with impaired glucose tolerance and 20 people without either Type 2 diabetes or impaired glucose tolerance (control group) underwent gait analysis using a motion analysis system and force platforms, and detailed assessment of neuropathy and serum 25 hydroxy-vitamin D levels. Ankle strength (P = 0.01) and power (P = 0.003) during walking and walking speed (P = 0.008) were preserved in participants with impaired glucose tolerance but significantly lower in participants with Type 2 diabetes compared with control participants; however, step width (P = 0.005) and dynamic medio-lateral sway (P = 0.007) were significantly higher and posterior maximal movement (P = 0.000) was lower in participants with impaired glucose tolerance, but preserved in those with Type 2 diabetes compared with the control group. Dynamic medio-lateral sway correlated with corneal nerve fibre length (P = 0.001) and corneal nerve branch density (P = 0.001), but not with vibration perception threshold (P = 0.19). Serum 25 hydroxy-vitamin D levels did not differ significantly among the groups (P = 0.10) and did not correlate with any walking variables or measures of dynamic sway. Early abnormalities in walking strategy and dynamic sway were evident in participants with impaired glucose tolerance, whilst there was a reduction in ankle strength, power and walking speed in participants with Type 2 diabetes. Unsteadiness correlated with small-, but not large-fibre neuropathy and there was no relationship between vitamin D levels and walking variables. © 2017 Diabetes UK.
Barnard, Katharine; Peveler, Robert C.; Holt, Richard I.G.
OBJECTIVE Antidepressant use has risen sharply over recent years. Recent concerns that antidepressants may adversely affect glucose metabolism require investigation. Our aim was to assess the risk of type 2 diabetes associated with antidepressants through a systematic review. RESEARCH DESIGN AND METHODS Data sources were MEDLINE, Embase, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of the European Association for the Study of Diabetes, American Diabetes Association, and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, U.K. Clinical Research Network, scrutiny of bibliographies of retrieved articles, and contact with relevant experts. Relevant studies of antidepressant effects were included. Key outcomes were diabetes incidence and change in blood glucose (fasting and random). RESULTS Three systemic reviews and 22 studies met the inclusion criteria. Research designs included 1 case series and 21 observational studies comprising 4 cross-sectional, 5 case-control, and 12 cohort studies. There was evidence that antidepressant use is associated with type 2 diabetes. Causality is not established, but rather, the picture is confused, with some antidepressants linked to worsening glucose control, particularly with higher doses and longer duration, others linked with improved control, and yet more with mixed results. The more recent, larger studies, however, suggest a modest effect. Study quality was variable. CONCLUSIONS Although evidence exists that antidepressant use may be an independent risk factor for type 2 diabetes, long-term prospective studies of the effects of individual antidepressants rather than class effects are required. Heightened alertness to potential risks is necessary until these are complete. PMID:24065841
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age and is associated with various metabolic risk factors, in addition to chronic anovulation and factors related to androgen excess. Women with PCOS have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, resulting in a higher risk of type 2 diabetes mellitus, subclinical atherosclerosis, vascular dysfunction, and apparently cardiovascular disease and mortality. The aim of the present article was to summarize current knowledge with focus on a suggestion to the clinical approach and handling of these metabolic risk factors.
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Mirza, Rabeea; Ishaq, Saliha; Amjad, Hira
Transient Osteoporosis of Hip (TOH) is an uncommon disorder of idiopathic nature, particularly in the Asian population. It has been described to mostly occur in middle aged men and women in their third trimester of pregnancy. A distinctive hallmark of this condition is that it is self limiting and resolves in a few months. The patient presents to the physician with pain on movement and impaired mobility of the affected joint, developing without any history of trauma. MRI is the main diagnostic tool. We report herein a case of a forty five year old male, who developed transient osteoporosis of the hip, and was managed conservatively.
Giusti, A; Bianchi, G
As a result of population ageing worldwide, osteoporotic fractures are becoming a serious problem in the western world. Osteoporotic fractures are associated with a significant burden in terms of morbidity, mortality, and economic costs. Although less frequent than in women, male osteoporosis is also a relatively common problem. Since bone loss and fragility fractures in men have been recognized as a serious medical condition, over the last two decades several studies have investigated a number of aspects related to the pathogenesis, diagnosis and assessment, prevention and treatment of male osteoporosis. A better understanding of factors underlying increased bone fragility in men has led to the definition of appropriate screening and diagnostic strategies, and the development of treatments that have shown to improve bone mineral density and, in some cases, reduce fracture risk in men as well as in women. This review will summarize recent findings on male osteoporosis with a particular focus on risk factors and causes of bone loss, and available therapeutic options.
Sambrook, P; Lane, N E
Corticosteroids are widely used and effective agents for the control of many inflammatory diseases, but corticosteroid osteoporosis is a common problem associated with their long term high dose use. Prevention of corticosteroid osteoporosis is preferable to treatment of established corticosteroid bone loss. Several large double-blind controlled clinical trials in patients with corticosteroid osteoporosis have recently been published that provide new insights into its treatment. Based upon available evidence, the rank order of choice for prophylaxis would be a bisphosphonate followed by a vitamin D metabolite or an oestrogen type medication. Calcium alone appears to be unable to prevent rapid bone loss in patients starting corticosteroids, especially with prednisolone doses at 10 mg a day or greater. If an active vitamin D metabolite is used, calcium supplementation should be avoided unless dietary calcium intake is low. Hormone replacement therapy should be considered if hypogonadism is present. Since vertebral fracture is a common and important complication of high dose corticosteroid therapy, these findings suggest that rapid bone loss and hence fractures, can be prevented by prophylactic treatment. Although the follow-up data is limited, it is likely that such therapy needs to be continued beyond 12 months whilst patients continue significant doses of corticosteroid therapy.
Orosz, Andrea; Baczkó, István; Nyiraty, Szabolcs; Körei, Anna E; Putz, Zsuzsanna; Takács, Róbert; Nemes, Attila; Várkonyi, Tamás T; Balogh, László; Ábrahám, György; Kempler, Péter; Papp, Julius Gy; Varró, András; Lengyel, Csaba
Prediabetic states and diabetes are important risk factors for cardiovascular morbidity and mortality. Determination of short-term QT interval variability (STVQT) is a non-invasive method for assessment of proarrhythmic risk. The aim of the study was to evaluate the STVQT in patients with impaired glucose tolerance (IGT). 18 IGT patients [age: 63 ± 11 years, body mass index (BMI): 31 ± 6 kg/m(2), fasting glucose: 6.0 ± 0.4 mmol/l, 120 min postload glucose: 9.0 ± 1.0 mmol/l, hemoglobin A1c (HbA1c): 5.9 ± 0.4%; mean ± SD] and 18 healthy controls (age: 56 ± 9 years, BMI: 27 ± 5 kg/m(2), fasting glucose: 5.2 ± 0.4 mmol/l, 120 min postload glucose: 5.5 ± 1.3 mmol/l, HbA1c: 5.4 ± 0.3%) were enrolled into the study. ECGs were recorded, processed, and analyzed off-line. The RR and QT intervals were expressed as the average of 30 consecutive beats, the temporal instability of beat-to-beat repolarization was characterized by calculating STVQT as follows: STVQT = Σ|QTn + 1 - QTn| (30x√2)(-1). Autonomic function was assessed by means of standard cardiovascular reflex tests. There were no differences between IGT and control groups in QT (411 ± 43 vs 402 ± 39 ms) and QTc (431 ± 25 vs 424 ± 19 ms) intervals or QT dispersion (44 ± 13 vs 42 ± 17 ms). However, STVQT was significantly higher in IGT patients (5.0 ± 0.7 vs 3.7 ± 0.7, P < 0.0001). The elevated temporal STVQT in patients with IGT may be an early indicator of increased instability of cardiac repolarization during prediabetic conditions.
Peltier, Amanda; Smith, A. Gordon; Russell, James W.; Sheikh, Kiran; Bixby, Billie; Howard, James; Goldstein, Jonathan; Song, Yanna; Wang, Lily; Feldman, Eva L.; Singleton, J. Robinson
Reproducible neurophysiological testing paradigms are critical to multi-center studies of neuropathy associated with impaired glucose regulation (IGR), yet the best methodologies and endpoints remain to be established. This study evaluates the reproducibility of neurophysiologic tests within a multi-center research setting. Twenty-three participants with neuropathy and IGR were studied. Reproducibility of QSART and QST (using the CASE IV system) were determined in a subset of patients at two sessions and calculated from intraclass correlation coefficients (ICC). QST (cold detection threshold ICC 0.80, vibration detection threshold ICC 0.75) was more reproducible than QSART (ICC foot 0.52). Performing multiple tests in one setting did not improve reproducibility of QST. QST reproducibility in IGR patients is similar to other patient groups studied. QSART reproducibility was significantly lower than QST. In this group of patients, the reproducibility of QSART was unacceptable for a secondary endpoint measure in clinical research trials. PMID:19260066
Ferroni, Patrizia; Riondino, Silvia; Buonomo, Oreste; Palmirotta, Raffaele; Guadagni, Fiorella; Roselli, Mario
Metabolic disorders, especially type 2 diabetes and its associated complications, represent a growing public health problem. Epidemiological findings indicate a close relationship between diabetes and many types of cancer (including breast cancer risk), which regards not only the dysmetabolic condition, but also its underlying risk factors and therapeutic interventions. This review discusses the advances in understanding of the mechanisms linking metabolic disorders and breast cancer. Among the proposed mechanisms to explain such an association, a major role is played by the dysregulated glucose metabolism, which concurs with a chronic proinflammatory condition and an associated oxidative stress to promote tumour initiation and progression. As regards the altered glucose metabolism, hyperinsulinaemia, both endogenous due to insulin-resistance and drug-induced, appears to promote tumour cell growth through the involvement of innate immune activation, platelet activation, increased reactive oxygen species, exposure to protumorigenic and proangiogenic cytokines, and increased substrate availability to neoplastic cells. In this context, understanding the relationship between metabolic disorders and cancer is becoming imperative, and an accurate analysis of these associations could be used to identify biomarkers able to predict disease risk and/or prognosis and to help in the choice of proper evidence-based diagnostic and therapeutic protocols. PMID:26171112
Fram, Ricki Y.; Cree, Melanie G.; Wolfe, Robert R.; Barr, David; Herndon, David N.
Objective Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months post burn. The purpose of this study was to measure insulin sensitivity in severely burned children prior to discharge when wounds are 95% healed. Methods Twenty-four children, aged 4–17 years, with burns ≥ 40% total body surface area (TBSA) underwent a 2 hour oral glucose tolerance test (OGTT) prior to discharge from the acute pediatric burn unit. Plasma glucose and insulin levels, as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared to published OGTT data from healthy, non-burned children. Results There was a significant difference between severely burned children and non-burned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53±1.62 compared to the value in non-burned healthy children was 1.28±0.16 (p<0.05). Conclusion Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury. PMID:20634704
Fernandez, Marina O; Sharma, Shweta; Kim, Sun; Rickert, Emily; Hsueh, Katherine; Hwang, Vicky; Olefsky, Jerrold M; Webster, Nicholas J G
The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3. Copyright © 2017 by the Endocrine Society.
Dong, Zhi; Luo, Yanji; Cai, Huasong; Zhang, Zhongwei; Peng, Zhenpeng; Jiang, Mengjie; Li, Yanbing; Li, Chang; Li, Zi-Ping; Feng, Shi-Ting
Abstract The aim of the study is to investigate if the fat content of the liver and pancreas may indicate impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM). A total of 83 subjects (34 men; aged 46.5 ± 13.5 years) were characterized as T2DM, IGT, or normal glucose tolerant (NGT). NGT individuals were stratified as <40 or ≥40 years. Standard laboratory tests were conducted for insulin resistance and β-cell dysfunction. The magnetic resonance imaging Dixon technique was used to determine fat distribution in the liver and pancreas. Correlations among liver and pancreatic fat volume fractions (LFVFs and PFVFs, respectively) and laboratory parameters were analyzed. Among the groups, fat distribution was consistent throughout sections of the liver and pancreas, and LFVFs closely correlated with PFVFs. LFVFs correlated more closely than PFVFs with insulin resistance and β-cell function. Both the LFVFs and PFVFs were the highest in the T2DM patients, less in the IGT, and least in the NGT; all differences were significant. The PFVFs of the NGT subjects ≥40 years were significantly higher than that of those <40 years. The fat content of the liver and pancreas, particularly the liver, may be a biomarker for IGT and T2DM. PMID:27281097
Liu, Zhi; Chen, Tian; Sun, Wenhua; Yuan, Zongyi; Yu, Mei; Chen, Guoqing; Guo, Weihua; Xiao, Jingang; Tian, Weidong
Diabetes mellitus, characterized by abnormally high blood glucose levels, gives rise to impaired bone remodeling. In response to high glucose (HG), the attenuated osteogenic differentiation capacity of human periodontal ligament stem cells (hPDLSCs) is associated with the loss of alveolar bone. Recently, DNA methylation was reported to affect osteogenic differentiation of stem cells in pathological states. However, the intrinsic mechanism linking DNA methylation to osteogenic differentiation ability in the presence of HG is still unclear. In this study, we found that diabetic rats with increased DNA methylation levels in periodontal ligaments exhibited reduced bone mass and density. In vitro application of 5-aza-2′-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to decrease DNA methylation levels in hPDLSCs, rescued the osteogenic differentiation capacity of hPDLSCs under HG conditions. Moreover, we demonstrated that the canonical Wnt signaling pathway was activated during this process and, under HG circumstances, the 5-aza-dC-rescued osteogenic differentiation capacity was blocked by Dickkopf-1, an effective antagonist of the canonical Wnt signaling pathway. Taken together, these results demonstrate for the first time that suppression of DNA methylation is able to facilitate the osteogenic differentiation capacity of hPDLSCs exposed to HG, through activation of the canonical Wnt signaling pathway. PMID:27273319
López-González, Ángel Arturo; Manzanero, Zoe; Vicente-Herrero, Ma Teófila; García-Agudo, Sheila; Gil-Llinás, María; Moreno-Morcillo, Francisco
The impaired fasting glucose (IFG) is an intermediate clinical situation between normal glucose and type 2 diabetes, it is known that 25% of people with IFG progress to type 2 diabetes. Descriptive study in 60,798 Spanish workers. The IFG was determined using the American Diabetes Association (ADA) criteria: 100-125 mg/dl and the World Health Organization (WHO) criteria: 110-125 mg/dl. The influence of sociodemographic variables (age, sex, social class, studies class) and healthy habits (tobacco, alcohol consumption, physical activity, feeding) were evaluated in the IFG prevalence. The IFG prevalence was 3.3% (1.8% in women and 4.5% in men) using the WHO criteria and 11.8% (7% in women and 15.4% in men) using the ADA criteria. The IFG is more common in men and increases with age. People with low socioeconomic status (social classes IV and V, blue collar and primary studies) and poor health habits (smokers, heavy alcohol consumption and low physical activity) have a higher prevalence. The sociodemographic variables and the healthy habits, except consumption of fruits and vegetables, influence the prevalence of IFG.
Iglesias, Cristina; Floridia, Ebel; Sartages, Miriam; Porteiro, Begoña; Fraile, María; Guerrero, Ana; Santos, Diana; Cuñarro, Juan; Tovar, Sulay; Nogueiras, Rubén; Pombo, Celia M; Zalvide, Juan
The identification of mediators in the pathogenesis of type 2 diabetes mellitus is essential for the full understanding of this disease. Protein kinases are especially important because of their potential as pharmacological targets. The goal of this study was to investigate whether mammalian sterile-20 3 (MST3/STK24), a stress-regulated kinase, is involved in metabolic alterations in obesity. Glucose regulation of Mst3 (also known as Stk24)-knockout mice was analysed both in 129;C57 mixed background mice and in C57/BL6J mice fed normally or with a high-fat diet (HFD). This work was complemented with an analysis of the insulin signalling pathway in cultured human liver cells made deficient in MST3 using RNA interference. MST3 is phosphorylated in the livers of mice subject to an obesity-promoting HFD, and its deficiency lowers the hyperglycaemia, hyperinsulinaemia and insulin resistance that the animals develop with this diet, an effect that is seen even without complete inactivation of the kinase. Lack of MST3 results in activation of the insulin signalling pathway downstream of IRS1, in both cultured liver cells and the liver of animals after HFD. This effect increases the inhibition of forkhead box (FOX)O1, with subsequent downregulation of the expression of gluconeogenic enzymes. MST3 inhibits the insulin signalling pathway and is important in the development of insulin resistance and impaired blood glucose levels after an HFD.
Guan, Yue; Cheng, Yan; Yin, Ying; Duan, Jialin; Wei, Guo; Weng, Yan; Guo, Chao; Zhu, Yanrong; Wang, Yanhua; Xi, Miaomiao; Wen, Aidong
Impaired glucose tolerance (IGT), known as the prediabetes stage, is usually induced by habits of life or environmental factors. Established IGT animal models are mostly conducted with chemical compounds such as streptozocin or genetic modification. However, the occasion of exposure to these factors in daily life is seldom. The objective of this study was to establish a new animal model of IGT induced by VE deficiency in diet and exposure to radiation. SD rats were treated individually or in combination of these two factors. In the combination group, the calculated insulin sensitivity index decreased; then HOMA-β value increased. Oxidative damage and IGT were observed. Insulin secretion level in perfusate from pancreas response to glucose was characterized by a rapid but reduced first phase and an obviously defective second phase upon pancreas perfusion. Histopathological images demonstrated the pathological changes. Western blotting analysis showed that the insulin signaling pathway was downregulated. The interaction of VE deficiency in diet and exposure to radiation could break the equilibrium of oxidation and antioxidation and result in IGT. More importantly, a new IGT model was successfully established which may be conducive to further research into development of drugs against human IGT. PMID:25954750
Song, Do Kyeong; Lee, Hyejin; Sung, Yeon-Ah
Purpose The triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio could be related to insulin resistance (IR). We previously reported that Korean women with polycystic ovary syndrome (PCOS) had a high prevalence of impaired glucose tolerance (IGT). We aimed to determine the cutoff value of the TG/HDL-C ratio for predicting IR and to examine whether the TG/HDL-C ratio is useful for identifying individuals at risk of IGT in young Korean women with PCOS. Materials and Methods We recruited 450 women with PCOS (24±5 yrs) and performed a 75-g oral glucose tolerance test (OGTT). IR was assessed by a homeostasis model assessment index over that of the 95th percentile of regular-cycling women who served as the controls (n=450, 24±4 yrs). Results The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in women with PCOS. Among the women with PCOS who had normal fasting glucose (NFG), the prevalence of IGT was significantly higher in the women with PCOS who had a high TG/HDL-C ratio compared with those with a low TG/HDL-C ratio (15.6% vs. 5.6%, p<0.05). Conclusion The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in young Korean women with PCOS, and women with NFG and a high TG/HDL-C ratio had a higher prevalence of IGT. Therefore, Korean women with PCOS with a TG/HDL-C ratio >2.5 are recommended to be administered an OGTT to detect IGT even if they have NFG. PMID:27593868
Song, Do Kyeong; Lee, Hyejin; Sung, Yeon Ah; Oh, Jee Young
The triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio could be related to insulin resistance (IR). We previously reported that Korean women with polycystic ovary syndrome (PCOS) had a high prevalence of impaired glucose tolerance (IGT). We aimed to determine the cutoff value of the TG/HDL-C ratio for predicting IR and to examine whether the TG/HDL-C ratio is useful for identifying individuals at risk of IGT in young Korean women with PCOS. We recruited 450 women with PCOS (24±5 yrs) and performed a 75-g oral glucose tolerance test (OGTT). IR was assessed by a homeostasis model assessment index over that of the 95th percentile of regular-cycling women who served as the controls (n=450, 24±4 yrs). The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in women with PCOS. Among the women with PCOS who had normal fasting glucose (NFG), the prevalence of IGT was significantly higher in the women with PCOS who had a high TG/HDL-C ratio compared with those with a low TG/HDL-C ratio (15.6% vs. 5.6%, p<0.05). The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in young Korean women with PCOS, and women with NFG and a high TG/HDL-C ratio had a higher prevalence of IGT. Therefore, Korean women with PCOS with a TG/HDL-C ratio >2.5 are recommended to be administered an OGTT to detect IGT even if they have NFG.
Irazola, Vilma; Rubinstein, Adolfo; Bazzano, Lydia; Calandrelli, Matias; Chung-Shiuan, Chen; Elorriaga, Natalia; Gutierrez, Laura; Lanas, Fernando; Manfredi, Jose A; Mores, Nora; Olivera, Hector; Poggio, Rosana; Ponzo, Jacqueline; Seron, Pamela; He, Jiang
To determine the prevalence, treatment and control of diabetes mellitus (DM) and impaired fasting glucose (IFG) as well as associated factors in the adult population of four cities of the Southern Cone of Latin America (SCLA). This is a cross-sectional population-based study that included 7407 adults between 35 and 74 years old in four cities of the SCLA: Temuco (Chile), Marcos Paz and Bariloche (Argentina), and Pando-Barros Blancos (Uruguay). DM was defined as fasting plasma glucose ≥126 mg/dL or self-reported history of diabetes. Awareness, treatment, and control of DM were defined as subjects self-reporting a DM previous diagnosis, the use of a prescription medication or nonpharmacological intervention for DM, and fasting plasma glucose <126 mg/dl, respectively. Prevalence of DM varied among cities, between 8.4% in Bariloche and 14.3% in Temuco. Prevalence of IFG varied at different sites, from 3.5% in Barros Blancos to 6.8% in Marcos Paz. Of the total number of people with diabetes, 20% were newly diagnosed at the time of the study. Overall, 79.8% of patients with diabetes were aware of their condition. The treatment and control rate were 58.8% and 46.2%, respectively. Older age, family history of diabetes, lower educational attainment, overweight, obesity, central obesity, low physical activity, hypertension, hypercholesterolemia and hypertriglyceridemia were all significantly associated with an increased risk of diabetes. The prevalence of DM and IFG in the adult population of the SCLA is high and varies among cities. These conditions represent a public health challenge since the rates of awareness, treatment, and control are still low.
Irazola, Vilma; Rubinstein, Adolfo; Bazzano, Lydia; Calandrelli, Matias; Chung-Shiuan, Chen; Elorriaga, Natalia; Gutierrez, Laura; Lanas, Fernando; Manfredi, Jose A.; Mores, Nora; Olivera, Hector; Poggio, Rosana; Ponzo, Jacqueline; Seron, Pamela; He, Jiang
Aims To determine the prevalence, treatment and control of diabetes mellitus (DM) and impaired fasting glucose (IFG) as well as associated factors in the adult population of four cities of the Southern Cone of Latin America (SCLA). Methods This is a cross-sectional population-based study that included 7407 adults between 35 and 74 years old in four cities of the SCLA: Temuco (Chile), Marcos Paz and Bariloche (Argentina), and Pando-Barros Blancos (Uruguay). DM was defined as fasting plasma glucose ≥126 mg/dL or self-reported history of diabetes. Awareness, treatment, and control of DM were defined as subjects self-reporting a DM previous diagnosis, the use of a prescription medication or nonpharmacological intervention for DM, and fasting plasma glucose <126 mg/dl, respectively. Results Prevalence of DM varied among cities, between 8.4% in Bariloche and 14.3% in Temuco. Prevalence of IFG varied at different sites, from 3.5% in Barros Blancos to 6.8% in Marcos Paz. Of the total number of people with diabetes, 20% were newly diagnosed at the time of the study. Overall, 79.8% of patients with diabetes were aware of their condition. The treatment and control rate were 58.8% and 46.2%, respectively. Older age, family history of diabetes, lower educational attainment, overweight, obesity, central obesity, low physical activity, hypertension, hypercholesterolemia and hypertriglyceridemia were all significantly associated with an increased risk of diabetes. Conclusions The prevalence of DM and IFG in the adult population of the SCLA is high and varies among cities. These conditions represent a public health challenge since the rates of awareness, treatment, and control are still low. PMID:28877254
Guo, Vivian YW; Yu, Esther YT; Wong, Carlos KH; Sit, Regina WS; Wang, Jenny HL; Ho, SY; Lam, Cindy LK
Background. In Hong Kong, fasting plasma glucose (FPG) is the most popular screening test for diabetes mellitus (DM) in primary care. Individuals with impaired fasting glucose (IFG) are commonly encountered. Objectives. To explore the determinants of regression to normoglycaemia among primary care patients with IFG based on non-invasive variables and to establish a nomogram for the prediction of regression from IFG. Methods. This cohort study consisted of 1197 primary care patients with IFG. These subjects were invited to repeat a FPG test and 75-g 2-hour oral glucose tolerance test (2h-OGTT) to determine the glycaemia change. Normoglycaemia was defined as FPG <5.6 mmol/L and 2h-OGTT <7.8 mmol/L. Stepwise logistic regression model was developed to predict the regression to normoglycaemia with non-invasive variables, using a randomly selected training dataset (810 subjects). The model was validated on the remaining testing dataset (387 subjects). Area under the receiver operating characteristic curve (AUC) and Hosmer–Lemeshow test were used to evaluate discrimination and calibration of the model. A nomogram was constructed based on the model. Results. After a mean follow-up period of 6.1 months, 180 subjects (15.0%) had normoglycaemia based on the repeated FPG and 2h-OGTT results at follow-up. Subjects without central obesity or hypertension, with moderate-to-high-level physical activity and a lower baseline FPG level, were more likely to regress to normoglycaemia. The prediction model had acceptable discrimination (AUC = 0.705) and calibration (P = 0.840). Conclusion. The simple-to-use nomogram could facilitate identification of subjects with low risk of progression to DM and thus aid in clinical decision making and resource prioritization in the primary care setting. PMID:27142313
Guo, Vivian Yw; Yu, Esther Yt; Wong, Carlos Kh; Sit, Regina Ws; Wang, Jenny Hl; Ho, S Y; Lam, Cindy Lk
In Hong Kong, fasting plasma glucose (FPG) is the most popular screening test for diabetes mellitus (DM) in primary care. Individuals with impaired fasting glucose (IFG) are commonly encountered. To explore the determinants of regression to normoglycaemia among primary care patients with IFG based on non-invasive variables and to establish a nomogram for the prediction of regression from IFG. This cohort study consisted of 1197 primary care patients with IFG. These subjects were invited to repeat a FPG test and 75-g 2-hour oral glucose tolerance test (2h-OGTT) to determine the glycaemia change. Normoglycaemia was defined as FPG <5.6 mmol/L and 2h-OGTT <7.8 mmol/L. Stepwise logistic regression model was developed to predict the regression to normoglycaemia with non-invasive variables, using a randomly selected training dataset (810 subjects). The model was validated on the remaining testing dataset (387 subjects). Area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow test were used to evaluate discrimination and calibration of the model. A nomogram was constructed based on the model. After a mean follow-up period of 6.1 months, 180 subjects (15.0%) had normoglycaemia based on the repeated FPG and 2h-OGTT results at follow-up. Subjects without central obesity or hypertension, with moderate-to-high-level physical activity and a lower baseline FPG level, were more likely to regress to normoglycaemia. The prediction model had acceptable discrimination (AUC = 0.705) and calibration (P = 0.840). The simple-to-use nomogram could facilitate identification of subjects with low risk of progression to DM and thus aid in clinical decision making and resource prioritization in the primary care setting. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: email@example.com.
Leandro, João G B; Espindola-Netto, Jair M; Vianna, Maria Carolina F; Gomez, Lilian S; DeMaria, Thaina M; Marinho-Carvalho, Monica M; Zancan, Patricia; Paula Neto, Heitor A; Sola-Penna, Mauro
Overweight and obesity have become epidemic worldwide and are linked to sedentary lifestyle and the consumption of processed foods and drinks. Citrate is a metabolite that plays central roles in carbohydrate and lipid metabolism. In addition, citrate is the additive most commonly used by the food industry, and therefore is highly consumed. Extracellular citrate can freely enter the cells via the constitutively expressed plasma membrane citrate transporter. Within the cytosol, citrate is readily metabolised by ATP-citrate lyase into acetyl-CoA - the metabolic precursor of endogenously produced lipids and cholesterol. We therefore hypothesised that the citrate ingested from processed foods and drinks could contribute to increased postprandial fat production and weight gain. To test our hypothesis, we administered citrate to mice through their drinking water with or without sucrose and monitored their weight gain and other metabolic parameters. Our results showed that mice receiving citrate or citrate+sucrose did not show increased weight gain or an increase in the weight of the liver, skeletal muscles or adipose tissues (AT). Moreover, the plasma lipid profiles (TAG, total cholesterol, LDL and HDL) were similar across all groups. However, the group receiving citrate+sucrose showed augmented fasting glycaemia, glucose intolerance and the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-10) in their AT. Therefore, our results suggest that citrate consumption contributes to increased AT inflammation and altered glucose metabolism, which is indicative of initial insulin resistance. Thus, citrate consumption could be a previously unknown causative agent for the complications associated with obesity.
Reviriego, Jesús; Vázquez, Luis Alberto; Goday, Albert; Cabrera, Martha; García-Margallo, María Teresa; Calvo, Eva
To report the prevalence of impaired fasting glucose (IFG), undiagnosed and diagnosed diabetes, and their association to occupational categories in a representative sample of working population in Spain. A cross-sectional study of workers who attended routine medical check-ups from January 2007 to December 2007. A structured questionnaire was completed, and physical examinations and routine serum biochemical tests were performed. IFG was defined as fasting glucose levels ranging from 100 to 125 mg/dl with no diagnosis of T1DM or T2DM; T1DM was defined as previous diagnosis of T1DM; and T2DM as previous diagnosis of T2DM, treatment with oral antidiabetic drugs or insulin or fasting glucose levels ≥126 mg/dl, according to ADA criteria. Of the 371,997 participants (median age 35 [interquartile range 29-44] years), 72.4% were male. Raw prevalence rates (95% CI) of IFG, undiagnosed (UKDM), and previously known type 2 (KDM2) and type 1 (KDM1) diabetes were 10.4% (10.3-10.5%), 1.3% (1.2-1.3%), 1.1% (1.1-1.2%), and 0.3% (0.3-0.3%), respectively. With the exception of KDM1, prevalence of these conditions increased with age and was greater among manual/blue-collar workers (12.1%, 1.5%, 1.3% and 0.3%, respectively) as compared to non-manual/white-collar workers (7.3%, 0.8%, 0.8% and 0.3%, respectively). Age- and sex-adjusted prevalence rates of IFG, UKDM and KDM2 were 13.1%, 2.0% and 2.4%, respectively. In this sample of Spanish working population, impaired glycemic profiles were common. Prevalence rates of IFG and T2DM were high among blue-collar workers (except for T1DM). These data emphasize the need for earlier structured preventive schemes. Copyright © 2016 SEEN. Published by Elsevier España, S.L.U. All rights reserved.
Manco, Melania; Grugni, Graziano; Di Pietro, Mario; Balsamo, Antonio; Di Candia, Stefania; Morino, Giuseppe Stefano; Franzese, Adriana; Di Bonito, Procolo; Maffeis, Claudio; Valerio, Giuliana
To identify metabolic phenotypes at increased risk of impaired glucose tolerance (IGT) in Italian overweight/obese children (n = 148, age 5-10 years) and adolescents (n = 531, age 10-17.9 year). Phenotypes were defined as follows: obesity by the 95th cut-points of the Center for Disease Control body mass index reference standards, impaired fasting glucose (fasting plasma glucose ≥100 mg/dl), high circulating triglycerides (TG), TG/HDL cholesterol ≥2.2, waist-to-height ratio (WTHR) >0.6, and combination of the latter with high TG or TG/HDL cholesterol ≥2.2. In the 148 obese children, TG/HDL-C ≥ 2.2 (OR 20.19; 95 % CI 2.50-163.28, p = 0.005) and the combination of TG/HDL-C ≥ 2.2 and WTHR > 0.60 (OR 14.97; 95 % CI 2.18-102.76, p = 0.006) were significantly associated with IGT. In the 531 adolescents, TG/HDL-C ≥ 2.2 (OR 1.991; 95 % CI 1.243-3.191, p = 0.004) and the combination with WTHR > 0.60 (OR 2.24; 95 % CI 1.29-3.87, p = 0.004) were associated with significantly increased risk of IGT. In the whole sample, having high TG levels according to the NIH National Heart, Lung and Blood Institute Expert Panel was not associated with an increased risk of presenting IGT. TG/HDL-C ratio can be useful, particularly in children, to identify obese young patients at risk of IGT. Its accuracy as screening tool in a general population needs to be verified. The combination of TG/HDL-C ratio and WTHR > 0.6 did not improve prediction. Having high TG according to the NIH definition was not associated with increased risk of developing IGT.
Zhang, Huaqiu; Schools, Gary P.; Lei, Ting; Wang, Wei; Kimelberg, Harold; Zhou, Min
Accumulating evidence indicates that the polyphenol resveratrol (trans-3, 5, 4′-trihydroxystibene, RVT) potently protects against cerebral ischemia neuronal damage due to its oxygen free radicals scavenging and antioxidant properties. However, it is unknown whether RVT can attenuate ischemia-induced early impairment of neuronal excitability. To address this question, we simulated ischemic conditions by applying oxygen-glucose deprivation (OGD) to acute rat hippocampal slices and examined the effect of RVT on OGD-induced pyramidal neuron excitability impairment using whole-cell patch clamp recording. 100 μM RVT largely inhibited the 15 min OGD-induced progressive membrane potential (Vm) depolarization and the reduction in evoked action potential frequency and amplitude in pyramidal neurons. In the parallel neuronal viability study using TO-PRO-3 iodide staining, 20 min OGD induced irreversible CA1 pyramidal neuronal death which was significantly reduced by 100 μM RVT. No similar effects were found with PQQ treatment, an antioxidant also showing potent neuroprotection in the rat rMCAO ischemia model. This suggests that antioxidant action per se, is unlikely accounting for the observed early effects of RVT. RVT also markedly reduced the frequency and amplitude of AMPA mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons, which is also an early consequence of OGD. RVT effects on neuronal excitability were inhibited by the large conductance potassium channel (BK channel) inhibitor paxilline. Together, these studies demonstrate that RVT attenuates OGD induced neuronal impairment occurring early in the simulated ischemia slice model by enhancing the activation of BK channel and reducing the OGD-enhanced AMPA/NMDA receptor mediated neuronal EPSCs. PMID:18495119
Totsuka, Kumiko; Maeno, Takami; Saito, Kazumi; Kodama, Satoru; Asumi, Mihoko; Yachi, Yoko; Hiranuma, Yuri; Shimano, Hitoshi; Yamada, Nobuhiro; Ono, Yukio; Naito, Takashi; Sone, Hirohito
We recorded self-reported eating patterns in 172 Japanese men and women who were subsequently followed for 3 years for the occurrence of impaired glucose tolerance (IGT). Incidence of IGT was significantly higher in those who reported eating fast. Self-reported eating fast is a potent risk factor for development of IGT.
Vigliotta, Giovanni; Miele, Claudia; Santopietro, Stefania; Portella, Giuseppe; Perfetti, Anna; Maitan, Maria Alessandra; Cassese, Angela; Oriente, Francesco; Trencia, Alessandra; Fiory, Francesca; Romano, Chiara; Tiveron, Cecilia; Tatangelo, Laura; Troncone, Giancarlo; Formisano, Pietro; Beguinot, Francesco
Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In vivo, insulin-stimulated glucose uptake was decreased by almost 50% in fat and muscle tissues of the ped/pea-15 transgenic mice, accompanied by protein kinase Calpha activation and block of insulin induction of protein kinase Czeta. These changes persisted in isolated adipocytes from the transgenic mice and were rescued by the protein kinase C inhibitor bisindolylmaleimide. In addition to insulin resistance, ped/pea-15 transgenic mice showed a 70% reduction in insulin response to glucose loading. Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase Calpha activation and a marked decline in glucose-stimulated insulin secretion. Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells. Thus, in vivo, overexpression of ped/pea-15 may lead to diabetes by impairing insulin secretion in addition to insulin action.
Chao, Louis Kuoping; Chang, Wen-Teng; Shih, Yuan-Wei; Huang, Jau-Shyang
Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.
Mantelmacher, Fernanda Dana; Fishman, Sigal; Cohen, Keren; Pasmanik Chor, Metsada; Yamada, Yuichiro; Zvibel, Isabel; Varol, Chen
The bone marrow (BM) contains controlled specialized microenvironments, or niches, that regulate the quiescence, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPC). The glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone that mediates postprandial insulin secretion and has anabolic effects on adipose tissue. Previous studies demonstrated altered bone microarchitecture in mice deficient for GIP receptor (Gipr(-/-) ), as well as the expression of high-affinity GIP receptor by distinct cells constructing the BM HSPC niche. Nevertheless, the involvement of GIP in the process of BM hematopoiesis remains elusive. In this article, we show significantly reduced representation and proliferation of HSPC and myeloid progenitors in the BM of Gipr(-/-) mice. This was further manifested by reduced levels of BM and circulating differentiated immune cells in young and old adult mice. Moreover, GIP signaling was required for the establishment of supportive BM HSPC niches during HSPC repopulation in radioablated BM chimera mice. Finally, molecular profiling of various factors involved in retention, survival, and expansion of HSPC revealed significantly lower expression of the Notch-receptor ligands Jagged 1 and Jagged 2 in osteoblast-enriched bone extracts from Gipr(-/-) mice, which are important for HSPC expansion. In addition, there was increased expression of CXCL12, a factor important for HSPC retention and quiescence, in whole-BM extracts from Gipr(-/-) mice. Collectively, our data suggest that the metabolic hormone GIP plays an important role in BM hematopoiesis.
Karbe, H; Szelies, B; Herholz, K; Heiss, W D
Twenty-six aphasic patients who had an ischaemic infarct in the territory of the left middle cerebral artery (MCA) were investigated. Cranial computed tomography (CT) showed various lesion sites: infarcts restricted to cortical structures in 12 patients, combined cortical and subcortical infarcts in 7 and isolated subcortical infarcts sparing the left cortex in another 7 cases. 18F-2-fluoro-2-deoxyglucose positron emission tomography revealed remote hypometabolism of the left convexity cortex and of the left basal ganglia, which was extended further than the morphological infarct zone in all cases. Types and degrees of aphasia were classified using the Aachener Aphasie Test (AAT): 10 patients had global aphasia, 2 Broca's, 5 Wernicke's, and 5 amnesic aphasia. Four patients suffered from minimal or residual aphasic symptoms. The AAT results were compared with the regional cerebral metabolic rates of glucose of the left hemisphere. Irrespective of the infarct location all five AAT subtests (Token test, repetition, written language, confrontation naming, auditory and reading comprehension) were closely correlated among each other and with left parieto-temporal metabolic rates, whereas left frontal and left basal ganglia metabolism showed no significant correlation. The close relation between left temporo-parietal functional activity and all five AAT subtests suggests that the different aspects of aphasia tested by AAT can be related to a common disorder of language processing in those areas.
Schneider, Hannah; Errede, Mariella; Ulrich, Nils H; Virgintino, Daniela; Frei, Karl; Bertalanffy, Helmut
Cerebral cavernous malformations (CCMs) often cause hemorrhages that can result in severe clinical manifestations, including hemiparesis and seizures. The underlying mechanisms of the aggressive behavior of CCMs are undetermined to date, but alterations of vascular matrix components may be involved. We compared the localization of the tight junction proteins (TJPs) in 12 CCM specimens and the expression of glucose transporter 1 (GLUT-1), which is sensitive to alterations in TJP levels, in 5 CCM specimens with those in 5 control temporal lobectomy specimens without CCM by immunofluorescence microscopy. The TJPs occludin, claudin-5, and zonula occludens ZO-1 were downregulated at intercellular contact sites and partly redistributed within the surrounding tissue in the CCM samples; there was also a marked reduction of GLUT-1 immunoreactivity compared with that in control specimens. Corresponding analysis using quantitative real-time reverse transcription polymerase chain reaction on 8 CCM and 8 control specimens revealed significant downregulation of mRNA expression of occludin, claudin-5, ZO-1, and GLUT-1. The altered expression and localization of the TJPs at interendothelial contact sites accompanied by a reduction of GLUT-1 expression in dilated CCM microvessels likely affect vascular matrix stability and may contribute to hemorrhages of CCMs.
Chao, Louis Kuoping; Chang, W.-T.; Shih, Y.-W.; Huang, J.-S.
Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.
Chen, Qiaoli; Xie, Bingxian; Zhu, Sangsang; Rong, Ping; Sheng, Yang; Ducommun, Serge; Chen, Liang; Quan, Chao; Li, Min; Sakamoto, Kei; MacKintosh, Carol; Chen, Shuai; Wang, Hong Yu
TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser(231), which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis. Whole-body glucose homeostasis and muscle glucose uptake were assayed in mice bearing a Tbc1d1 (Ser231Ala)-knockin mutation or harbouring skeletal muscle-specific Ampkα1/α2 (also known as Prkaa1/2) double-knockout mutations in response to an AMPK-activating agent, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Exercise-induced muscle glucose uptake and exercise capacity were also determined in the Tbc1d1 (Ser231Ala)-knockin mice. Skeletal muscle-specific deletion of Ampkα1/a2 in mice prevented AICAR-induced hypoglycaemia and muscle glucose uptake. The Tbc1d1 (Ser231Ala)-knockin mutation also attenuated the glucose-lowering effect of AICAR in mice. Glucose uptake and cell surface GLUT4 content were significantly lower in muscle isolated from the Tbc1d1 (Ser231Ala)-knockin mice upon stimulation with a submaximal dose of AICAR. However, this Tbc1d1 (Ser231Ala)-knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice. TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding partially mediates AMPK-governed glucose homeostasis and muscle glucose uptake in a context-dependent manner.
Farabi, Sarah S; Carley, David W; Smith, Donald; Quinn, Lauretta
We measured the effects of a single bout of exercise on diurnal and nocturnal oxidative stress and glycaemic variability in obese subjects with type 2 diabetes mellitus or impaired glucose tolerance versus obese healthy controls. Subjects (in random order) performed either a single 30-min bout of moderate-intensity exercise or remained sedentary for 30 min at two separate visits. To quantify glycaemic variability, standard deviation of glucose (measured by continuous glucose monitoring system) and continuous overlapping net glycaemic action of 1-h intervals (CONGA-1) were calculated for three 12-h intervals during each visit. Oxidative stress was measured by 15-isoprostane F(2t) levels in urine collections for matching 12-h intervals. Exercise reduced daytime glycaemic variability (ΔCONGA-1 = -12.62 ± 5.31 mg/dL, p = 0.04) and urinary isoprostanes (ΔCONGA-1 = -0.26 ± 0.12 ng/mg, p = 0.04) in the type 2 diabetes mellitus/impaired glucose tolerance group. Daytime exercise-induced change in urinary 15-isoprostane F(2t) was significantly correlated with both daytime standard deviation (r = 0.68, p = 0.03) and with subsequent overnight standard deviation (r = 0.73, p = 0.027) in the type 2 diabetes mellitus/impaired glucose tolerance group. Exercise significantly impacts the relationship between diurnal oxidative stress and nocturnal glycaemic variability in individuals with type 2 diabetes mellitus/impaired glucose tolerance. © The Author(s) 2015.
Blubaugh, Morgan V; Uslan, Mark M
The vast majority of diabetes-related self-management technology utilizes small visual displays (SVDs) that often produce a low level of contrast and suffer from high levels of reflection (glare). This is a major accessibility issue for the 3.5 million Americans with diabetes who have reduced vision. The purpose of this article is to gather comparative data on the key display attributes of the SVDs used in blood glucose meters (BGMs) and home blood pressure monitors (HBPMs) on the market today and determine which displays offer the best prospect for being accessible to people with reduced vision. Nine BGMs and eight HBPMs were identified for this study on the basis of amount of devices sold, fullfunctionality speech output, and advanced display technologies. An optical instrumentation system obtained contrast, reflection (glare), and font height measurements for all 17 displays. The contrast, reflection, and font-height values for the BGMs and HBPMs varied greatly between models. The Michelson contrast values for the BGMs ranged from 11% to 98% and font heights ranged 0.39-1.00 in. for the measurement results. The HBPMs had Michelson contrast values ranging 55-96% and font height ranging 0.28-0.94 in. for the measurement results. Due largely to the lack of display design standards for the technical requirements of SVDs, there is tremendous variability in the quality and readability of BGM and HBPM displays. There were two BGMs and one HBPM that exhibited high-contrast values and large font heights, but most of the devices exhibited either poor contrast or exceptionally high reflection.
Chao, Jung; Huo, Teh-Ia; Cheng, Hao-Yuan; Tsai, Jen-Chieh; Liao, Jiunn-Wang; Lee, Meng-Shiou; Qin, Xue-Mei; Hsieh, Ming-Tsuen; Pao, Li-Heng; Peng, Wen-Huang
Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more “holistic view” approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help
Shen, Lan; Shah, Bimal R; Reyes, Eric M; Thomas, Laine; Wojdyla, Daniel; Diem, Peter; Leiter, Lawrence A; Charbonnel, Bernard; Mareev, Viacheslav; Horton, Edward S; Haffner, Steven M; Soska, Vladimir; Holman, Rury; Bethel, M Angelyn; Schaper, Frank; Sun, Jie-Lena; McMurray, John J V; Califf, Robert M; Krum, Henry
To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. NAVIGATOR trial. Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant. ClinicalTrials.gov NCT00097786.
Yasunari, K; Kohno, M; Kano, H; Yokokawa, K; Minami, M; Yoshikawa, J
To explore the role of intracellular oxidative stress in high glucose-induced atherogenesis, we examined the effect of probucol and/or alpha-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). Chronic high-glucose-medium (22. 2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, [3H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/L+16.6 mmol/L mannose). Probucol and alpha-tocopherol significantly suppressed high glucose-induced increase in VSMC migration, cell number, and [3H]thymidine incorporation. Probucol and alpha-tocopherol suppressed hi