EADSG Guidelines: Insulin Therapy in Diabetes.

PubMed

Silver, Bahendeka; Ramaiya, Kaushik; Andrew, Swai Babu; Fredrick, Otieno; Bajaj, Sarita; Kalra, Sanjay; Charlotte, Bavuma M; Claudine, Karigire; Makhoba, Anthony

2018-04-01

A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A). Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A). Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin. Two or three premixed insulin injections per day may be used (A). The target glycated hemoglobin A1c (HbA1c) for all children with T1DM, including preschool children, is recommended to be < 7.5% (< 58 mmol/mol). The target is chosen aiming at minimizing hyperglycemia, severe hypoglycemia, hypoglycemic unawareness, and reducing the likelihood of development of long-term complications (B). For patients prone to glycemic variability, glycemic control is best evaluated by a combination of results with self-monitoring of blood glucose (SMBG) (B). Indications for exogenous insulin therapy in patients with type 2 diabetes mellitus (T2DM) include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy (B). In T2DM patients, with regards to achieving glycemic goals, insulin is considered alone or in combination with oral agents when HbA1c is ≥ 7.5% (≥ 58 mmol/mol); and is essential for treatment in those with HbA1c ≥ 10% (≥ 86 mmol/mol), when diet, physical activity, and other antihyperglycemic agents have been optimally used (B). The preferred method of insulin initiation in T2DM is to begin by adding a long-acting (basal) insulin or once-daily premixed/co-formulation insulin or twice-daily premixed insulin, alone or in combination with glucagon-like peptide-1 receptor agonist (GLP-1 RA) or in combination with other oral antidiabetic

GAIN Premix Facility: an innovative approach for improving access to quality vitamin and mineral premix in fortification initiatives.

PubMed

Guinot, Philippe; Jallier, Vincent; Blasi, Alessandro; Guyondet, Christophe; Van Ameringen, Marc

2012-12-01

Vitamin and mineral premix is one of the most significant recurring input costs for large-scale food fortification programs. A number of barriers exist to procuring adequate quality premix, including accessing suppliers, volatile prices for premix, lack of quality assurance and monitoring of delivered products, and lack of funds to purchase premix. To develop and test a model to procure premix through a transparent and efficient process in which an adequate level of quality is guaranteed and a financial mechanism is in place to support countries or specific target groups when there are insufficient resources to cover the cost of premix. Efforts focused on premixes used to fortify flour, such as wheat or maize (iron, zinc, B vitamins, and vitamin A), edible oils (vitamins A and D), and other food vehicles, such as fortified complementary foods, complementary food supplements, and condiments. A premix procurement model was set up with three distinct components: a certification process that establishes industry-wide standards and guidelines for premix, a procurement facility that makes premix more accessible to countries and private industry engaged in fortification, and a credit facility mechanism that helps projects finance premix purchases. After three years of operation, 15 premix suppliers and 29 micronutrient manufacturers have been certified, and more than US$23 million worth of premix that met quality standards has been supplied in 34 countries in Africa, Central and Southern Asia, and Eastern Europe, reaching an estimated 242 million consumers. The Premix Facility demonstrated its effectiveness in ensuring access to high-quality premixes, therefore enabling the success of various fortification programs.

Subject-driven titration of biphasic insulin aspart 30 twice daily is non-inferior to investigator-driven titration in Chinese patients with type 2 diabetes inadequately controlled with premixed human insulin: A randomized, open-label, parallel-group, multicenter trial.

PubMed

Yang, Wenying; Zhu, Lvyun; Meng, Bangzhu; Liu, Yu; Wang, Wenhui; Ye, Shandong; Sun, Li; Miao, Heng; Guo, Lian; Wang, Zhanjian; Lv, Xiaofeng; Li, Quanmin; Ji, Qiuhe; Zhao, Weigang; Yang, Gangyi

2016-01-01

The present study was to compare the efficacy and safety of subject-driven and investigator-driven titration of biphasic insulin aspart 30 (BIAsp 30) twice daily (BID). In this 20-week, randomized, open-label, two-group parallel, multicenter trial, Chinese patients with type 2 diabetes inadequately controlled by premixed/self-mixed human insulin were randomized 1:1 to subject-driven or investigator-driven titration of BIAsp 30 BID, in combination with metformin and/or α-glucosidase inhibitors. Dose adjustment was decided by patients in the subject-driven group after training, and by investigators in the investigator-driven group. Eligible adults (n = 344) were randomized in the study. The estimated glycated hemoglobin (HbA1c) reduction was 14.5 mmol/mol (1.33%) in the subject-driven group and 14.3 mmol/mol (1.31%) in the investigator-driven group. Non-inferiority of subject-titration vs investigator-titration in reducing HbA1c was confirmed, with estimated treatment difference -0.26 mmol/mol (95% confidence interval -2.05, 1.53) (-0.02%, 95% confidence interval -0.19, 0.14). Fasting plasma glucose, postprandial glucose increment and self-measured plasma glucose were improved in both groups without statistically significant differences. One severe hypoglycemic event was experienced by one subject in each group. A similar rate of nocturnal hypoglycemia (events/patient-year) was reported in the subject-driven (1.10) and investigator-driven (1.32) groups. There were 64.5 and 58.1% patients achieving HbA1c <53.0 mmol/mol (7.0%), and 51.2 and 45.9% patients achieving the HbA1c target without confirmed hypoglycemia throughout the trial in the subject-driven and investigator-driven groups, respectively. Subject-titration of BIAsp 30 BID was as efficacious and well-tolerated as investigator-titration. The present study supported patients to self-titrate BIAsp 30 BID under physicians' supervision.

Utilization patterns of insulin therapy and healthcare services among Japanese insulin initiators during their first year: a descriptive analysis of administrative hospital data.

PubMed

Ikeda, Shunya; Crawford, Bruce; Sato, Masayo

2016-01-12

Type 2 diabetes poses an increasing healthcare burden in Japan. Although insulin treatment has diversified in recent years, the literature on the utilization of healthcare services among patients with type 2 diabetes undergoing different insulin therapy regimens is scarce. The current study aimed to characterize the real-world insulin treatment patterns and associated utilization of healthcare services among patients with type 2 diabetes who initiated insulin therapy during the study period. We examined data from a hospital-based database consisting of administrative and laboratory data from 121 acute-phase hospitals throughout Japan from April 2008 to August 2012. Patients diagnosed with type 2 diabetes and receiving continuous insulin therapy, defined by three insulin claims or more, were included in the analysis. Of the 2,145 insulin initiators, at initiation 46.5% received rapid-acting insulin alone, 36.6% received an intensive regimen, 11.4% received long-acting insulin alone, and 5.5% received pre-mixed insulin alone. Patients treated with rapid-acting insulin alone were older, experienced more comorbid conditions, had lower HbA1c, and more often had initiated their insulin treatment at inpatient admission, compared to patients treated with other types of insulin. Inpatient admission was more common and longer for patients taking rapid-acting insulin and an intensive regimen than those taking long-acting or pre-mixed insulin, and most were readmitted within 1 year. Utilization of outpatient clinics was approximately once per month, and emergency department visits were observed to be rare. This retrospective observational descriptive study found varied treatment and healthcare service utilization patterns, as well as disparities in patient characteristics across insulin regimens. Future research should assess the basis for these various utilization patterns associated with insulin to conduct robust analyses of clinical and economic outcomes.

Intranasal insulin improves memory in humans.

PubMed

Benedict, Christian; Hallschmid, Manfred; Hatke, Astrid; Schultes, Bernd; Fehm, Horst L; Born, Jan; Kern, Werner

2004-11-01

Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.

Fuel premixing module for gas turbine engine combustor

NASA Technical Reports Server (NTRS)

Chin, Jushan (Inventor); Rizk, Nader K. (Inventor); Razdan, Mohan K. (Inventor); Marshall, Andre W. (Inventor)

2005-01-01

A fuel-air premixing module is designed to reduce emissions from a gas turbine engine. In one form, the premixing module includes a central pilot premixer module with a main premixer module positioned thereround. Each of the portions of the fuel-air premixing module include an axial inflow swirler with a plurality of fixed swirler vanes. Fuel is injected into the main premixer module between the swirler vanes of the axial inflow swirler and at an acute angle relative to the centerline of the premixing module.

Premixed Turbulent Flame Propagation in Microgravity

NASA Technical Reports Server (NTRS)

Menon, S.; Disseau, M.; Chakravarthy, V. K.; Jagoda, J.

1997-01-01

Papers included address the following topics: (1) Turbulent premixed flame propagation in microgravity; (2) The effect of gravity on turbulent premixed flame propagation - a preliminary cold flow study; and (3) Characteristics of a subgrid model for turbulent premixed combustion.

Multiple tube premixing device

DOEpatents

Uhm, Jong Ho; Naidu, Balachandar; Ziminksy, Willy Steve; Kraemer, Gilbert Otto; Yilmaz, Ertan; Lacy, Benjamin; Stevenson, Christian; Felling, David

2013-08-13

The present application provides a premixer for a combustor. The premixer may include a fuel plenum with a number of fuel tubes and a burner tube with a number of air tubes. The fuel tubes extend about the air tubes.

Multiple tube premixing device

DOEpatents

Uhm, Jong Ho; Varatharajan, Balachandar; Ziminsky, Willy Steve; Kraemer, Gilbert Otto; Yilmaz, Ertan; Lacy, Benjamin; Stevenson, Christian; Felling, David

2012-12-11

The present application provides a premixer for a combustor. The premixer may include a fuel plenum with a number of fuel tubes and a burner tube with a number of air tubes. The fuel tubes extend about the air tubes.

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

PubMed

Vora, J P; Owens, D R; Dolben, J; Atiea, J A; Dean, J D; Kang, S; Burch, A; Brange, J

1988-11-12

To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. Study in normal people at a diabetes research unit and a university department of medical physics. Seven healthy male volunteers aged 20-39 not receiving any other drugs. After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U/kg respectively. The response of glucagon substantiated the earlier and

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

PubMed Central

Vora, J. P.; Owens, D. R.; Dolben, J.; Atiea, J. A.; Dean, J. D.; Kang, S.; Burch, A.; Brange, J.

1988-01-01

OBJECTIVE--To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. DESIGN--Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. SETTING--Study in normal people at a diabetes research unit and a university department of medical physics. SUBJECTS--Seven healthy male volunteers aged 20-39 not receiving any other drugs. INTERVENTIONS--After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. END POINT--To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U

Recombinant Human Insulin in Global Diabetes Management – Focus on Clinical Efficacy

PubMed Central

Mbanya, Jean Claude; Sandow, Juergen; Landgraf, Wolfgang

2017-01-01

Abstract Biosynthetic human insulin and insulin analogues are the mainstay of insulin therapy for both type 1 and type 2 diabetes although access to human insulin at affordable prices remains a global issue. The world is experiencing an exponential rise in the prevalence of diabetes presenting an urgent need to establish effective diabetes therapy in countries burdened by inadequate health care budgets, malnutrition and infectious diseases. Recombinant human insulin has replaced animal insulins and animal-based semisynthetic human insulin thereby available in sufficient quantities and at affordable prices able to provide global access to insulin therapy. In many patients, analog insulins can offer additional clinical benefit, although at a considerably higher price thus severely restricting availability in low income countries. The approval process for recombinant human insulins (i.e. biosimilars) and analogue insulins is highly variable in the developing countries in contrast to Europe and in North America, where it is well established within a strict regulatory framework. This review aims to discuss the future access to human insulin therapy in a global context with an ever increasing burden of diabetes and significant economic implications. PMID:29632602

In vivo response of Mesocestoides vogae to human insulin.

PubMed

Canclini, L; Esteves, A

2009-02-01

Successful host invasion by parasitic helminths involves detection and appropriate response to a range of host-derived signals. Insulin signal response pathways are ancient and highly-conserved throughout the metazoans. However, very little is known about helminth insulin signalling and the potential role it may play in host-parasite interactions. The response of Mesocestoides vogae (Cestoda: Cyclophyllidea) larvae to human insulin was investigated, focusing on tyrosine-phosphorylation status, glucose content, survival and asexual reproduction rate. Parasite larvae were challenged with different levels of insulin for variable periods. The parameters tested were influenced by human insulin, and suggested a host-parasite molecular dialogue.

Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans

PubMed Central

Byrne, Loretta M.; Yu, Chang; Wang, Thomas J.; Brown, Nancy J.

2014-01-01

Context: Interruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear. Objective: To test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans. Design: We conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high-sodium diet. Setting: Academic clinical research center. Participants: Healthy, nondiabetic, normotensive volunteers. Interventions: Infusion of exogenous aldosterone (0.7 μg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5–7 days. Main Outcome Measures: Change in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle. Results: A low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose-stimulated insulin (−16.0 ± 5.6%; P = .007) and C-peptide responses (−21.8 ± 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (−1.0 ± 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 ± 4.8%; P = .72) or insulin sensitivity index (+2.0 ± 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion. Conclusions: Low dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity. PMID:25029426

Optimization of Premix Powders for Tableting Use.

PubMed

Todo, Hiroaki; Sato, Kazuki; Takayama, Kozo; Sugibayashi, Kenji

2018-05-08

Direct compression is a popular choice as it provides the simplest way to prepare the tablet. It can be easily adopted when the active pharmaceutical ingredient (API) is unstable in water or to thermal drying. An optimal formulation of preliminary mixed powders (premix powders) is beneficial if prepared in advance for tableting use. The aim of this study was to find the optimal formulation of the premix powders composed of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) by using statistical techniques. Based on the "Quality by Design" concept, a (3,3)-simplex lattice design consisting of three components, LAC, CS, and MCC was employed to prepare the model premix powders. Response surface method incorporating a thin-plate spline interpolation (RSM-S) was applied for estimation of the optimum premix powders for tableting use. The effect of tablet shape identified by the surface curvature on the optimization was investigated. The optimum premix powder was effective when the premix was applied to a small quantity of API, although the function of premix was limited in the case of the formulation of large amount of API. Statistical techniques are valuable to exploit new functions of well-known materials such as LAC, CS, and MCC.

Gas turbine premixing systems

DOEpatents

Kraemer, Gilbert Otto; Varatharajan, Balachandar; Evulet, Andrei Tristan; Yilmaz, Ertan; Lacy, Benjamin Paul

2013-12-31

Methods and systems are provided for premixing combustion fuel and air within gas turbines. In one embodiment, a combustor includes an upstream mixing panel configured to direct compressed air and combustion fuel through premixing zone to form a fuel-air mixture. The combustor includes a downstream mixing panel configured to mix additional combustion fuel with the fule-air mixture to form a combustion mixture.

Lean premixed/prevaporized combustion

NASA Technical Reports Server (NTRS)

Lefebvre, A. H. (Editor)

1977-01-01

Recommendations were formulated on the status and application of lean premixed/prevaporized combustion to the aircraft gas turbine for the reduction of pollutant emissions. The approach taken by the NASA Stratospheric Cruise Emission Reduction Program (SCERP) in pursuing the lean premixed/prevaporized combustion technique was also discussed. The proceedings contains an overview of the SCERP program, the discussions and recommendations of the participants, and an overall summary.

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes.

PubMed

Kristensen, P L; Tarnow, L; Bay, C; Nørgaard, K; Jensen, T; Parving, H-H; Perrild, H; Beck-Nielsen, H; Christiansen, J S; Thorsteinsson, B; Pedersen-Bjergaard, U

2017-05-01

To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA 1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia. © 2017 Diabetes UK.

Trends in Medicaid Reimbursements for Insulin From 1991 Through 2014.

PubMed

Luo, Jing; Avorn, Jerry; Kesselheim, Aaron S

2015-10-01

Insulin is a vital medicine for patients with diabetes mellitus. Newer, more expensive insulin products and the lack of generic insulins in the United States have increased costs for patients and insurers. To examine Medicaid payment trends for insulin products. Cost information is available for all 50 states and has been recorded since the 1990s. A time-series analysis comparing reimbursements and prices. Using state- and national-level Medicaid data from 1991 to 2014, we identified all patients who used 1 or more of the 16 insulin products that were continuously available in the United States between 2006 and 2014. Insulin products were classified into rapid-acting and long-acting analogs, short-acting, intermediate, and premixed insulins based on American Diabetes Association Guidelines. Inflation-adjusted payments made to pharmacies by Medicaid per 1 mL (100 IU) of insulin in 2014 US dollars. Since 1991, Medicaid reimbursement per unit (1 mL) of insulin dispensed has risen steadily. In the 1990s, Medicaid reimbursed pharmacies between $2.36 and $4.43 per unit. By 2014, reimbursement for short-acting insulins increased to $9.64 per unit; intermediate, $9.22; premixed, $14.79; and long-acting, $19.78. Medicaid reimbursement for rapid-acting insulin analogs rose to $19.81 per unit. The rate of increase in reimbursement was higher for insulins with patent protection ($0.20 per quarter) than without ($0.05 per quarter) (P<.001).Total Medicaid reimbursements peaked at $407.4 million dollars in quarter 2 of 2014. Total volume peaked at 29.9 million units in quarter 4 of 2005 and was 21.2 million units in quarter 2 of 2014. Between 1991 and 2014, there was a near-exponential upward trend in Medicaid payments on a per-unit basis for a wide variety of insulin products regardless of formulation, duration of action, and whether the product was patented. Although reimbursements for newer, patent-protected insulin analogs increased at a faster rate than reimbursements for

Multidimensional flamelet-generated manifolds for partially premixed combustion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Phuc-Danh; Vervisch, Luc; Subramanian, Vallinayagam

2010-01-15

Flamelet-generated manifolds have been restricted so far to premixed or diffusion flame archetypes, even though the resulting tables have been applied to nonpremixed and partially premixed flame simulations. By using a projection of the full set of mass conservation species balance equations into a restricted subset of the composition space, unsteady multidimensional flamelet governing equations are derived from first principles, under given hypotheses. During the projection, as in usual one-dimensional flamelets, the tangential strain rate of scalar isosurfaces is expressed in the form of the scalar dissipation rates of the control parameters of the multidimensional flamelet-generated manifold (MFM), which ismore » tested in its five-dimensional form for partially premixed combustion, with two composition space directions and three scalar dissipation rates. It is shown that strain-rate-induced effects can hardly be fully neglected in chemistry tabulation of partially premixed combustion, because of fluxes across iso-equivalence-ratio and iso-progress-of-reaction surfaces. This is illustrated by comparing the 5D flamelet-generated manifold with one-dimensional premixed flame and unsteady strained diffusion flame composition space trajectories. The formal links between the asymptotic behavior of MFM and stratified flame, weakly varying partially premixed front, triple-flame, premixed and nonpremixed edge flames are also evidenced. (author)« less

Responses to acute insulin-induced hypoglycaemia in diabetic patients: a comparison of short-acting human and porcine insulins.

PubMed

Fisher, B M; Gray, C E; Beastall, G H; Frier, B M

1988-05-01

A comparison was made of the metabolic, hormonal, haemodynamic and symptomatic responses to acute hypoglycaemia induced by short-acting porcine and human insulins in 16 fasting, insulin-dependent diabetic patients, 8 of whom had diabetes for less than 5 years (Group A) and 8 of whom had diabetes for greater than 15 years (Group B). Each patient received an intravenous injection of 0.2 units/kg of insulin on two separate occasions. No differences were found between the groups in the rate of fall of blood glucose or the blood glucose nadir with either insulin, but in Group B, glucose recovery was more rapid after human insulin (p less than 0.01). No differences in the responses of blood lactate, plasma free fatty acids, glucagon or prolactin were observed between the groups. In Group B the rises of growth hormone and cortisol occurred more rapidly following human insulin (p less than 0.01), while the rise in adrenaline was greater following porcine insulin. Haemodynamic changes were identical following each species of insulin in both diabetic groups. A questionnaire was used to score 18 symptoms of hypoglycaemia on a 7 point scale. No significant differences were found in the mean scores of each symptom of hypoglycaemia or in the total symptom score. Thus recovery of blood glucose from hypoglycaemia was slightly more rapid after administration of human insulin to diabetic patients of long duration, but it is unlikely that these marginal differences would confer any clinical advantage in this subgroup.

Insulin therapy at onset of type 2 diabetes mellitus--a new concept.

PubMed

Sahay, B K

2011-04-01

In this study, insulin therapy was initiated at onset of disease in patients whose fasting blood glucose was more than 250 mg/dl. All enrolled subjects were treated with human premixed insulin (30/70) administered subcutaneously twice daily before breakfast and before dinner. A total of 113 subjects entered the study fulfilling the inclusion criteria. Good glycaemic control was achieved in a few days. The dosage requirement of insulin came down gradually after control was achieved as manifest by hypoglycaemia--leading to withdrawal of insulin. Some of them were managed with diet and exercise alone. Others required small doses of oral antidiabetic agents (OAD). There were no cases of secondary failure to OADs. Ten cases are on average duration of follow-up of 10 years. Two cases are under good control with diet and exercise alone, seven on treatment with oral hypoglycemic agents and one of them requiring insulin to maintain HbAlc below 7%. Thus insulin therapy at onset provides an opportunity to correct all the underlying pathogenic mechanisms, i.e., glucotoxicity, lipotoxicity and prevents beta cell apoptosis and suppresses inflammation, leading to beta cell protection. Such timely intervention provides long term benefits, laying the foundation for the concept of beta cell preservation rather that only replacing beta cell function. Hence we propose that all patients with type 2 diabetes should be offered insulin therapy at the onset of their diabetes for a period of 2-4 weeks.

Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.

PubMed

Carrasco-Benso, Maria P; Rivero-Gutierrez, Belen; Lopez-Minguez, Jesus; Anzola, Andrea; Diez-Noguera, Antoni; Madrid, Juan A; Lujan, Juan A; Martínez-Augustin, Olga; Scheer, Frank A J L; Garaulet, Marta

2016-09-01

In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P < 0.00001). Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. © FASEB.

Frequency of blood glucose testing among insulin-treated diabetes mellitus patients in the United Kingdom.

PubMed

Lee, Won Chan; Smith, Elise; Chubb, Barrie; Wolden, Michael Lyng

2014-03-01

Through a retrospective database analysis, this study seeks to provide an understanding of the utilization of SMBG by insulin therapy and diabetes type and to estimate healthcare costs of blood glucose monitoring in the UK diabetes population. Data were obtained from the IMS LifeLink Electronic Medical Record-Europe (EMR-EU) Database, a longitudinal database containing anonymized patient records from physician-practice data systems of office-based physicians in the UK. Depending on the insulin types used for type 1 and type 2 diabetes, patients were sub-categorized into one of four insulin regimen groups (basal, bolus, pre-mixed, or basal-bolus). Frequency of blood glucose testing was assessed descriptively throughout the 12-month post-index period, and generalized linear models were used to evaluate the effect of baseline characteristics, including insulin type, on the likelihood of blood glucose test utilization. Healthcare resource utilization and costs for all-cause services were assessed by insulin type. This study identified 8322 type 1 and type 2 diabetes patients with two insulin pharmacy records between January 1, 2009 and December 31, 2010. After applying study inclusion and exclusion criteria, a total of 2676 (32.2%) insulin-treated diabetes mellitus patients in the UK were identified, with the number of pharmacy blood glucose test strips averaging 771.1 (median 600). The glucose testing frequency was lowest among basal-only insulin patients and pre-mixed insulin patients (mean=576.2 [median=450] and mean=599.5 [median=500], respectively; non-significantly different) compared to other insulin types. Although the data did not capture the glucose frequency comprehensively, it varied significantly by insulin types, and was higher than what is recommended in the guidelines for patients with type 2 diabetes.

Fully Premixed Low Emission, High Pressure Multi-Fuel Burner

NASA Technical Reports Server (NTRS)

Nguyen, Quang-Viet (Inventor)

2012-01-01

A low-emissions high-pressure multi-fuel burner includes a fuel inlet, for receiving a fuel, an oxidizer inlet, for receiving an oxidizer gas, an injector plate, having a plurality of nozzles that are aligned with premix face of the injector plate, the plurality of nozzles in communication with the fuel and oxidizer inlets and each nozzle providing flow for one of the fuel and the oxidizer gas and an impingement-cooled face, parallel to the premix face of the injector plate and forming a micro-premix chamber between the impingement-cooled face and the in injector face. The fuel and the oxidizer gas are mixed in the micro-premix chamber through impingement-enhanced mixing of flows of the fuel and the oxidizer gas. The burner can be used for low-emissions fuel-lean fully-premixed, or fuel-rich fully-premixed hydrogen-air combustion, or for combustion with other gases such as methane or other hydrocarbons, or even liquid fuels.

Comparison of insulin analogue B9AspB27Glu and soluble human insulin in insulin-treated diabetes.

PubMed

Kang, S; Owens, D R; Vora, J P; Brange, J

1990-02-10

Postprandial plasma glucose excursions and plasma levels of free insulin after subcutaneous bolus injection of a rapidly absorbed monomeric insulin analogue (B9AspB27Glu) or soluble human insulin ('Actrapid HM' U100) were studied in six insulin-treated diabetic subjects. 10 U actrapid or an equimolar amount of the analogue were injected, in random order with an interval of 1 week, immediately before a 500 kcal test meal. Basal insulin levels were similar on the 2 study days (mean 74.1 [SE 5.1] pmol/l, actrapid; 79.7 [13.0] pmol/l, analogue). After injection of actrapid plasma free insulin levels rose slowly, reaching a plateau by 105 min at 222 (19) pmol/l. Injection of the analogue resulted in a rapid early peak at 30 min (798 [112] pmol/l), and levels were significantly higher than those after actrapid between 15 and 210 min. The more physiological plasma insulin levels achieved with the analogue were accompanied by a substantial reduction in postprandial plasma glucose excursions; the integrated area under the incremental plasma glucose curve was 45% lower after the analogue than after actrapid.

LEM-CF Premixed Tool Kit

DOE Office of Scientific and Technical Information (OSTI.GOV)

2015-01-19

The purpose of LEM-CF Premixed Tool Kit is to process premixed flame simulation data from the LEM-CF solver (https://fileshare.craft-tech.com/clusters/view/lem-cf) into a large-eddy simulation (LES) subgrid model database. These databases may be used with a user-defined-function (UDF) that is included in the Tool Kit. The subgrid model UDF may be used with the ANSYS FLUENT flow solver or other commercial flow solvers.

Choice of Insulin in Type 2 Diabetes: A Southeast Asian Perspective.

PubMed

Kalra, Sanjay; Thai, Hong Quang; Deerochanawong, Chaicharn; Su-Yen, Goh; Mohamed, Mafauzy; Latt, Tint Swe; Aye, Than Than; Latif, Zafar Ahmed; Katulanda, Prasad; Khun, Touch; Satha, Sum; Vongvandy, Vadsana

2017-01-01

Southeast Asia faces a diabetes epidemic, which has created significant challenges for health care. The unique Asian diabetes phenotype, coupled with peculiar lifestyle, diet, and healthcare-seeking behavior, makes it imperative to develop clinical pathways and guidelines which address local needs and requirements. From an insulin-centric viewpoint, the preparations prescribed in such pathways should be effective, safe, well tolerated, nonintrusive, and suitable for the use in multiple clinical situations including initiation and intensification. This brief communication describes the utility of premixed or dual action insulin in such clinical pathways and guidelines.

Choice of Insulin in Type 2 Diabetes: A Southeast Asian Perspective

PubMed Central

Kalra, Sanjay; Thai, Hong Quang; Deerochanawong, Chaicharn; Su-Yen, Goh; Mohamed, Mafauzy; Latt, Tint Swe; Aye, Than Than; Latif, Zafar Ahmed; Katulanda, Prasad; Khun, Touch; Satha, Sum; Vongvandy, Vadsana

2017-01-01

Southeast Asia faces a diabetes epidemic, which has created significant challenges for health care. The unique Asian diabetes phenotype, coupled with peculiar lifestyle, diet, and healthcare-seeking behavior, makes it imperative to develop clinical pathways and guidelines which address local needs and requirements. From an insulin-centric viewpoint, the preparations prescribed in such pathways should be effective, safe, well tolerated, nonintrusive, and suitable for the use in multiple clinical situations including initiation and intensification. This brief communication describes the utility of premixed or dual action insulin in such clinical pathways and guidelines. PMID:28553609

Gas turbine premixer with internal cooling

DOEpatents

York, William David; Johnson, Thomas Edward; Lacy, Benjamin Paul; Stevenson, Christian Xavier

2012-12-18

A system that includes a turbine fuel nozzle comprising an air-fuel premixer. The air-fuel premixed includes a swirl vane configured to swirl fuel and air in a downstream direction, wherein the swirl vane comprises an internal coolant path from a downstream end portion in an upstream direction through a substantial length of the swirl vane.

The Renin Angiotensin Aldosterone System and Insulin Resistance in Humans

PubMed Central

Underwood, Patricia C

2012-01-01

Alterations in the renin angiotensin aldosterone system (RAAS) contribute to the underlying pathophysiology of insulin resistance in humans; however, individual differences in the treatment response of insulin resistance to RAAS blockade persist. Thus, understanding inter-individual differences in the relationship between the RAAS and insulin resistance may provide insights into improved personalized treatments and improved outcomes. The effects of the systemic RAAS on blood pressure regulation and glucose metabolism have been studied extensively; however, recent discoveries on the influence of local tissue RAAS in the skeletal muscle, heart, vasculature, adipocytes, and pancreas have led to an improved understanding of how activated tissue RAAS influences the development of insulin resistance and diabetes in humans. Angiotensin II (ANGII) is the predominant RAAS component contributing to insulin resistance; however, other players such as aldosterone, renin, and ACE2 are also involved. This review examines the role of local ANGII activity on insulin resistance development in skeletal muscle, adipocytes, and pancreas, followed by a discussion of the other RAAS components implicated in insulin resistance, including ACE2, Ang1-7, renin, and aldosterone. PMID:23242734

Effect of lipopolysaccharide on inflammation and insulin action in human muscle.

PubMed

Liang, Hanyu; Hussey, Sophie E; Sanchez-Avila, Alicia; Tantiwong, Puntip; Musi, Nicolas

2013-01-01

Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR)4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM)] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP) concentrations. Plasma LPS (r = -0.46, P = 0.005) and LBP (r = -0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals.

Sequence-specific 1H-NMR assignments for the aromatic region of several biologically active, monomeric insulins including native human insulin.

PubMed

Roy, M; Lee, R W; Kaarsholm, N C; Thøgersen, H; Brange, J; Dunn, M F

1990-06-12

The aromatic region of the 1H-FT-NMR spectrum of the biologically fully-potent, monomeric human insulin mutant, B9 Ser----Asp, B27 Thr----Glu has been investigated in D2O. At 1 to 5 mM concentrations, this mutant insulin is monomeric above pH 7.5. Coupling and amino acid classification of all aromatic signals is established via a combination of homonuclear one- and two-dimensional methods, including COSY, multiple quantum filters, selective spin decoupling and pH titrations. By comparisons with other insulin mutants and with chemically modified native insulins, all resonances in the aromatic region are given sequence-specific assignments without any reliance on the various crystal structures reported for insulin. These comparisons also give the sequence-specific assignments of most of the aromatic resonances of the mutant insulins B16 Tyr----Glu, B27 Thr----Glu and B25 Phe----Asp and the chemically modified species des-(B23-B30) insulin and monoiodo-Tyr A14 insulin. Chemical dispersion of the assigned resonances, ring current perturbations and comparisons at high pH have made possible the assignment of the aromatic resonances of human insulin, and these studies indicate that the major structural features of the human insulin monomer (including those critical to biological function) are also present in the monomeric mutant.

Studies of Premixed Laminar and Turbulent Flames at Microgravity

NASA Technical Reports Server (NTRS)

Abid, M.; Aung, K.; Ronney, P. D.; Sharif, J. A.; Wu, M.-S.

1999-01-01

Several topics relating to combustion limits in premixed flames at reduced gravity have been studied. These topics include: (1) flame balls; (2) numerical simulation of flame ball and planar flame structure and stability; (3) experimental simulation of buoyancy effects in premixed flames using aqueous autocatalytic reactions; and (4) premixed flame propagation in Hele-Shaw cells.

Posology of insulins: A review of standard textbooks and product inserts.

PubMed

Bhutani, Garima; Kalra, Sanjay

2015-01-01

The study is aimed to assess whether the information contained in standard pharmacology, endocrinology, and diabetology textbooks regarding timings of administration, frequency and dose of various insulins is adequate and also to see whether the information contained in these texts is concordant with product inserts. Four standard textbooks of pharmacology, two of diabetology and three of endocrinology were assessed for the published information regarding dose, timing, and frequency of insulin administration. The product inserts of commonly available insulins in India were also studied for the same. Various omissions and disparities could be seen in the coverage of insulins in standard textbooks. Posology information about premixed insulins and basal insulins have been omitted by the majority of the textbooks. Details about dose, frequency and timings of ultra-short acting insulins have also not been covered by all textbooks. Some discrepancies regarding prescribing information was also noted in product inserts, especially in case of newer insulins. Thus, this article stresses upon the need of a uniform source of information for providing adequate and standardized knowledge regarding timing, frequency, and dose of insulins.

Insulin stimulates synthesis and release of human chorionic gonadotropin by choriocarcinoma cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, S.G.; Braunstein, G.D.

1991-03-01

Recent studies have shown that insulin regulates placental lactogen, progesterone, and estrogen production from human trophoblast cells. This study was performed to examine whether insulin also regulates the production of hCG by this type of cell. After 24-36 h of preincubation, JEG-3 and JAR cells (2-3 x 10(5) cells/ml.well) or human term trophoblast cells (1 x 10(6) cells/ml.well) were exposed to the test hormone in serum-free Dulbecco's Modified Eagle's Medium for 24-96 h. Secretion of hCG from JEG-3 cells was stimulated by human insulin, human proinsulin, or porcine insulin in a dose-dependent manner, with lowest effective doses of 6.7, 96,more » and 53 mg/L, respectively. Time-course studies showed that hCG secretion peaked at 72-96 h with insulin exposure; in contrast, no decernable peak was seen without insulin in serum-free media. Exposure of JEG-3 cells for 24 h to 209 mg/liter insulin stimulated hCG synthesis, with 40 +/- 3% more immunoreactive intracellular hCG (P less than 0.05). Cells grown in the presence of insulin and (35S)methionine had 47 +/- 21% more labeled intracellular hCG and 56 +/- 13% more immunoprecipitable (35S)methionine-hCG secreted into the medium than the control cultures (P less than 0.05). During this time period, human placental lactogen release and total trichloroacetice acid-precipitable (35S)methionine protein were not increased. The insulin-induced stimulation of hCG synthesis was inhibited by cycloheximide. Additionally, insulin did not significantly affect total intracellular protein during 24-96 h of incubation. Insulin also increased hCG release from JAR cells, but not from human term trophoblast cells. A mouse monoclonal antibody to the IGF-I receptor inhibited the stimulation of insulin in JEG-3 cells.« less

Colorimetric determination of selenium in mineral premixes .

PubMed

Hurlbut, J A; Burkepile, R G; Geisler, C A; Kijak, P J; Rummel, N G

1997-01-01

A method is described for determination of sodium selenite or sodium selenate in mineral-based premixes. It is based on the formation of intense-yellow piazselenol by Se(IV) and 3,3'-diaminobenzidine. Mineral premixes typically contain calcium carbonate as a base material and magnesium carbonate, silicon dioxide, and iron(III) oxide as minor components or additives. In this method, the premix is digested briefly in nitric acid, diluted with water, and filtered to remove any Iron(III) oxide. Ethylenediaminetetraacetic acid and HCl are added to the filtrate, which is heated to near boiling for 1 h to convert any selenate to selenite. After heating, the solution is buffered between pH 2 and 3 with NaOH and formic acid and treated with NH2OH and EDTA; any Se present forms a complex with 3,3'-diaminobenzidine at 60 degrees C. The solution is made basic with NH4OH, and the piazselenol is extracted into toluene. The absorbance of the complex in dried toluene is measured at 420 nm. The method was validated independently by 2 laboratories. Samples analyzed included calcium carbonate fortified with 100, 200, and 300 micrograms Se in the form of sodium selenite or sodium selenate, a calcium carbonate premix containing sodium selenite, a calcium carbonate premix containing sodium selenate, and a commercial premix; 5 replicates of each sample type were analyzed by each laboratory. Average recoveries ranged from 89 to 109% with coefficients of variation from 1.2 to 13.6%.

Effect of Lipopolysaccharide on Inflammation and Insulin Action in Human Muscle

PubMed Central

Liang, Hanyu; Hussey, Sophie E.; Sanchez-Avila, Alicia; Tantiwong, Puntip; Musi, Nicolas

2013-01-01

Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR)4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM)] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP) concentrations. Plasma LPS (r = −0.46, P = 0.005) and LBP (r = −0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals. PMID:23704966

Effects of pasteurization on adiponectin and insulin concentrations in donor human milk.

PubMed

Ley, Sylvia H; Hanley, Anthony J; Stone, Debbie; O'Connor, Deborah L

2011-09-01

Although pasteurization is recommended before distributing donor human milk in North America, limited data are available on its impact on metabolic hormones in milk. We aimed to investigate the effects of pasteurization on adiponectin and insulin concentrations in donor human milk. The study investigates concentrations of components in donor human milk before and after Holder pasteurization. After the guidelines of the Human Milk Bank Association of North America, human milk samples were pooled to produce 17 distinct batches (4 individuals per batch) and pasteurized at 62.5°C for 30 min. Adiponectin, insulin, energy, fat, total protein, and glucose concentrations were measured pre- and postpasteurization. Pasteurization reduced milk adiponectin and insulin by 32.8 and 46.1%, respectively (both p < 0.0001). Adiponectin and insulin were significantly correlated with energy and fat milk composition (r = 0.36-0.47; all p < 0.05). Pasteurization effects on milk hormone concentrations remained significant after adjusting for fat and energy (beta ± SEE: -4.11 ± 1.27, p = 0.003 for adiponectin; -70.0 ± 15.0, p < 0.0001 for insulin). Holder pasteurization reduced adiponectin and insulin concentrations in donor human milk. In view of emerging knowledge on the importance of milk components, continued work to find the optimal pasteurization process that mitigates risks but promotes retention of bioactive components is needed.

Consensus on Insulin Dose and Titration Algorithms in Ambulatory Care of Type 2 Diabetes in India.

PubMed

Kovil, Rajiv; Chawla, Manoj; Rajput, Rajesh; Singh, A K; Sinha, Binayak; Ghosal, Samit; Ballani, Piya; Gupta, Sunil; Tanna, Snehal; Bandukwala, S M; Shah, Tejas; Negalur, Vijay; Bhoraskar, Anil; Aravind, S R; Zargar, Abdul H; Kesavadev, Jothydev; Das, Ashok Kumar

2017-02-01

Insulin is the oldest of the currently available treatment options in Type 2 diabetes mellitus (T2DM) and is considered as the most effective glucose lowering agent. Despite this, decision on starting insulin therapy is often delayed in India as well as worldwide due to various barriers at both patient and physician levels. Appropriate insulin dosing and titration is also critical to the successful achievement of tight glycaemic control. To provide simple and easily implementable guidelines to primary care physicians on appropriate insulin dosing and titration of various insulin regimens for both initiation and intensification. Each insulin regimen (once daily [OD] basal, OD, twice daily and thrice daily premixed, basal-plus and basal-bolus) was presented and evaluated for dosing and titration based on established guidelines, data from approved pack inserts, and published scientific literature. These evaluations were then factored into the national context based on the expert committee representatives patient-physician experience in their clinical practice and common therapeutic practices followed in India. Recommendations for dosing and titration of basal, basal-plus, premixed and basal-bolus insulins were developed. The key recommendations are that insulin doses can be adjusted once or twice weekly; adjustment can be based on lowest/mean of three recent self-monitoring of plasma glucose pre-meal/fasting plasma glucose (FPG) values. The titration should be based on FPG or pre-meal value of 80-130 mg/dL and the dose should be reduced by 10-20% for patients reporting hypoglycaemia(<70mg/dL). The consensus based recommendations mentioned in this paper will be a useful reference tool for health care practitioners, to initiate, optimise and intensify insulin therapy and to successfully achieve optimal glucose control.

Human primary myoblast cell cultures from non-diabetic insulin resistant subjects retain defects in insulin action.

PubMed Central

Thompson, D B; Pratley, R; Ossowski, V

1996-01-01

Insulin resistance is a predictor of the development of noninsulin-dependent diabetes mellitus (NIDDM) in humans. It is unclear whether insulin resistance is a primary defect leading to NIDDM or the result of hyperinsulinemia and hyperglycemia. To determine if insulin resistance is the result of extrinsic factors such as hyperinsulinemia primary skeletal muscle cell cultures were established from muscle biopsies from Pima Indians with differing in vivo insulin sensitivities. These cell cultures expressed a variety of muscle-specific phenotypes including the proteins alpha-actinin and myosin, muscle-specific creatine kinase activity, and RNA encoding GLUT4, MYF5, MYOD1, and MYOGENIN. Labeled glucose was used to measure the insulin-stimulated conversion of glucose to glycogen in these cultures. The in vivo rates of insulin-stimulated glycogen production (insulin resistance) were correlated with in vitro measures of glycogen production (P = 0.007, r = 0.58). This defect in insulin action is stable in a uniform culture environment and is retained over time. The retention of insulin resistance in myoblast derived cell cultures is consistent with the expression of an underlying biochemical defect in insulin resistant skeletal muscle. PMID:8941652

Insulin in human milk and the prevention of type 1 diabetes.

PubMed

Shehadeh, N; Shamir, R; Berant, M; Etzioni, A

2001-12-01

Although controversial, exclusive breast milk feeding was shown to exert a protective effect in preventing type 1 diabetes. In contrast, an early introduction of cow's milk-based formula in young infants may enhance the risk of disease, especially in genetically susceptible children, presumably by an increase of intestinal permeability to macromolecules such as bovine serum albumin and beta-casein, which may arouse autoimmunity. We have shown that human milk contains insulin in substantial concentrations, while insulin is barely detectable (if at all) in infant formulas. Orally administered insulin was demonstrated to promote gut maturation and to reduce intestinal permeability to macromolecules. Furthermore, oral insulin may induce tolerance to insulin and protect against the development of type 1 diabetes. We herewith raise a hypothesis that human milk is protective against the development of type 1 diabetes by virtue of the effects of its substantial content of insulin.

New Basal Insulins: a Clinical Perspective of Their Use in the Treatment of Type 2 Diabetes and Novel Treatment Options Beyond Basal Insulin.

PubMed

Frias, Patrick F; Frias, Juan Pablo

2017-08-18

The purpose of this review was to review advances in basal insulin formulations and new treatment options for patients with type 2 diabetes not achieving glycemic targets despite optimized basal insulin therapy. Advances in basal insulin formulations have resulted in products with increasingly favorable pharmacokinetic and pharmacodynamic properties, including flatter, peakless action profiles, less inter- and intra-patient variability, and longer duration of activity. These properties have translated to significantly reduced risk of hypoglycemia (particularly during the night) compared with previous generation basal insulins. When optimized basal insulin therapy is not sufficient to obtain or maintain glycemic goals, various options exist to improve glycemic control, including intensification of insulin therapy with the addition of prandial insulin or changing to pre-mixed insulin and, more recently, the addition of a GLP-1 receptor agonist, either as a separate injection or as a component of one of the new fixed-ratio combinations of a basal insulin and GLP-1 RA. New safer and often more convenient basal insulins and fixed ratio combinations containing basal insulin (and GLP-1 receptor agonist) are available today for patients with type 2 diabetes not achieving glycemic goals. Head-to-head studies comparing the latest generation basal insulins are underway, and future studies assessing the fixed-ratio combinations will be important to better understand their differentiating features.

Annular fuel and air co-flow premixer

DOEpatents

Stevenson, Christian Xavier; Melton, Patrick Benedict; York, William David

2013-10-15

Disclosed is a premixer for a combustor including an annular outer shell and an annular inner shell. The inner shell defines an inner flow channel inside of the inner shell and is located to define an outer flow channel between the outer shell and the inner shell. A fuel discharge annulus is located between the outer flow channel and the inner flow channel and is configured to inject a fuel flow into a mixing area in a direction substantially parallel to an outer airflow through the outer flow channel and an inner flow through the inner flow channel. Further disclosed are a combustor including a plurality of premixers and a method of premixing air and fuel in a combustor.

Safety, cost, and clinical considerations for the use of premixed parenteral nutrition.

PubMed

Hall, Jacob W

2015-06-01

Premixed parenteral nutrition (PN) can be used for PN therapy in place of traditional compounded or customized PN. Premixed PN may have a number of advantages over compounded PN such as decreased costs, decreased compounding time, reduced chance for error, and reduced incidence of bloodstream infections. However, premixed PN may not be appropriate for all patients and may have other additional costs associated with its use. This article discusses the data available with regard to the use of premixed PN, focusing on the potential advantages and disadvantages of using premixed PN, and also discusses the implementation of premixed PN in a large tertiary cancer center. © 2015 American Society for Parenteral and Enteral Nutrition.

[Desensitization to human recombinant DNA insulin in an adolescent with insulin-dependent diabetes mellitus].

PubMed

Rosas Vargas, M A; Alvarez Amador, M; Alvarez Amador, L M; del Río Navarro, B E; Avila Castanón, L; Sienra Monge, J J

2001-01-01

Adverse reactions to drugs have increased in the last years, about 15% of all side effects are thought to be immune mediated according to the Coombs and Gell classification they can be type I (immediate) hypersensitivity, type II (cytotoxic) type III (immune complex mediated) or type IV (delay). Allergy to insulin is defined as an immunological response type I, and type II or III to exogenous insulin solutions occurring the 0.1% and 0.2% of the patients. A 13 year old female with a 4-year history of insulin-dependent diabetes mellitus who presented hypersensitivity against recombinant DNA (rDNA) insulin manifested with urticaria and itching. We used a premedication therapy without good response and impossibility to use alternative therapy for her metabolic control, so she needed desensitization with insulin. Skin prick testing with rapid insulin preparations 1:10 W/V dilution were positive. IgE antibodies to insulin weren't presented. IgE serum values were normal. We began the desensitization with a rapid 1:1000 UI insulin solution by intradermal route, than by subcutaneous route until reaching the accumulated doses necessary per day. During the process it appeared a papular rash and itching which were treated with an intravenous antihistaminic without troubles. The patient tolerated the desensitization procedure very well. For the past 14 months she has been treated uneventfully by subcutaneous administration of rDNA insulin. The desensitization against drugs is not a frequently process it only has to be used when it is impossible to substitute the treatment. Our patient showed probably hypersensitivity type 1 to insulin. However, we have to take into account the cytotoxic reaction caused by IgG or IgM antibodies or by immune complex. The desensitization finally was tolerated, 14 months after our patient accepts correctly her daily dose of human recombinant insulin.

Studies of Premixed Laminar and Turbulent Flames at Microgravity

NASA Technical Reports Server (NTRS)

Kwon, O. C.; Abid, M.; Porres, J.; Liu, J. B.; Ronney, P. D.; Struk, P. M.; Weiland, K. J.

2003-01-01

Several topics relating to premixed flame behavior at reduced gravity have been studied. These topics include: (1) flame balls; (2) flame structure and stability at low Lewis number; (3) experimental simulation of buoyancy effects in premixed flames using aqueous autocatalytic reactions; and (4) premixed flame propagation in Hele-Shaw cells. Because of space limitations, only topic (1) is discussed here, emphasizing results from experiments on the recent STS-107 Space Shuttle mission, along with numerical modeling efforts.

Large eddy simulation of bluff body stabilized premixed and partially premixed combustion

NASA Astrophysics Data System (ADS)

Porumbel, Ionut

Large Eddy Simulation (LES) of bluff body stabilized premixed and partially premixed combustion close to the flammability limit is carried out in this thesis. The main goal of the thesis is the study of the equivalence ratio effect on flame stability and dynamics in premixed and partially premixed flames. An LES numerical algorithm able to handle the entire range of combustion regimes and equivalence ratios is developed for this purpose. The algorithm has no ad-hoc adjustable model parameters and is able to respond automatically to variations in the inflow conditions, without user intervention. Algorithm validation is achieved by conducting LES of reactive and non-reactive flow. Comparison with experimental data shows good agreement for both mean and unsteady flow properties. In the reactive flow, two scalar closure models, Eddy Break-Up (EBULES) and Linear Eddy Mixing (LEMLES), are used and compared. Over important regions, the flame lies in the Broken Reaction Zone regime. Here, the EBU model assumptions fail. In LEMLES, the reaction-diffusion equation is not filtered, but resolved on a linear domain and the model maintains validity. The flame thickness predicted by LEMLES is smaller and the flame is faster to respond to turbulent fluctuations, resulting in a more significant wrinkling of the flame surface when compared to EBULES. As a result, LEMLES captures better the subtle effects of the flame-turbulence interaction, the flame structure shows higher complexity, and the far field spreading of the wake is closer to the experimental observations. Three premixed (φ = 0.6, 0.65, and 0.75) cases are simulated. As expected, for the leaner case (φ = 0.6) the flame temperature is lower, the heat release is reduced and vorticity is stronger. As a result, the flame in this case is found to be unstable. In the rich case (φ = 0.75), the flame temperature is higher, and the spreading rate of the wake is increased due to the higher amount of heat release. The ignition

Bovine and human insulin adsorption at lipid monolayers: a comparison

NASA Astrophysics Data System (ADS)

Mauri, Sergio; Pandey, Ravindra; Rzeznicka, Izabela; Lu, Hao; Bonn, Mischa; Weidner, Tobias

2015-07-01

Insulin is a widely used peptide in protein research and it is utilised as a model peptide to understand the mechanics of fibril formation, which is believed to be the cause of diseases such as Alzheimer and Creutzfeld-Jakob syndrome. Insulin has been used as a model system due to its biomedical relevance, small size and relatively simple tertiary structure. The adsorption of insu lin on a variety of surfaces has become the focus of numerous studies lately. These works have helped in elucidating the consequence of surface/protein hydrophilic/hydrophobic interaction in terms of protein refolding and aggregation. Unfortunately, such model surfaces differ significantly from physiological surfaces. Here we spectroscopically investigate the adsorption of insulin at lipid monolayers, to further our understanding of the interaction of insulin with biological surfaces. In particular we study the effect of minor mutations of insulin’s primary amino acid sequence on its interaction with 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) model lipid layers. We probe the structure of bovine and human insulin at the lipid/water interface using sum frequency generation spectroscopy (SFG). The SFG experiments are complemented with XPS analysis of Langmuir-Schaefer deposited lipid/insulin films. We find that bovine and human insulin, even though very similar in sequence, show a substantially different behavior when interacting with lipid films.

Large eddy simulation of premixed and non-premixed combustion in a Stagnation Point Reverse Flow combustor

NASA Astrophysics Data System (ADS)

Undapalli, Satish

A new combustor referred to as Stagnation Point Reverse Flow (SPRF) combustor has been developed at Georgia Tech to meet the increasingly stringent emission regulations. The combustor incorporates a novel design to meet the conflicting requirements of low pollution and high stability in both premixed and non-premixed modes. The objective of this thesis work is to perform Large Eddy Simulations (LES) on this lab-scale combustor and elucidate the underlying physics that has resulted in its excellent performance. To achieve this, numerical simulations have been performed in both the premixed and non-premixed combustion modes, and velocity field, species field, entrainment characteristics, flame structure, emissions, and mixing characteristics have been analyzed. Simulations have been carried out first for a non-reactive case to resolve relevant fluid mechanics without heat release by the computational grid. The computed mean and RMS quantities in the non-reacting case compared well with the experimental data. Next, the simulations were extended for the premixed reactive case by employing different sub-grid scale combustion chemistry closures: Eddy Break Up (EBU), Artificially Thickened Flame (TF) and Linear Eddy Mixing (LEM) models. Results from the EBU and TF models exhibit reasonable agreement with the experimental velocity field. However, the computed thermal and species fields have noticeable discrepancies. Only LEM with LES (LEMLES), which is an advanced scalar approach, has been able to accurately predict both the velocity and species fields. Scalar mixing plays an important role in combustion, and this is solved directly at the sub-grid scales in LEM. As a result, LEM accurately predicts the scalar fields. Due to the two way coupling between the super-grid and sub-grid quantities, the velocity predictions also compare very well with the experiments. In other approaches, the sub-grid effects have been either modeled using conventional approaches (EBU) or need

LIF measurements and chemical kinetic analysis of methylidyne formation in high-pressure counter-flow partially premixed and non-premixed flames

NASA Astrophysics Data System (ADS)

Naik, S. V.; Laurendeau, N. M.

2004-11-01

We report quantitative, spatially resolved, linear laser-induced fluorescence (LIF) measurements of methylidyne concentration ([CH]) in laminar, methane air, counter-flow partially premixed and non-premixed flames using excitation near 431.5 nm in the A X (0,0) band. For partially premixed flames, fuel-side equivalence ratios (ϕB) of 1.45, 1.6 and 2.0 are studied at pressures of 1, 3, 6, 9 and 12 atm. For non-premixed flames, the fuel-side mixture consists of 25% CH4 and 75% N2; measurements are obtained at pressures of 1, 2, 3, 4, 5, 6, 9 and 12 atm. The quantitative CH measurements are compared with predictions from an opposed-flow flame code utilizing two GRI chemical kinetic mechanisms (versions 2.11 and 3.0). LIF measurements of [CH] are corrected for variations in the quenching rate coefficient by using major species concentrations and temperatures generated by the code along with suitable quenching cross sections for CH available from the literature. A pathway analysis provides relative contributions from important elementary reactions to the total amount of CH produced at various pressures. Key reactions controlling peak CH concentrations are also identified by using a sensitivity analysis. For the partially premixed flames, measured CH profiles are reproduced reasonably well by GRI 3.0, although some quantitative disagreement exists at all pressures. Two CH radical peaks are observed for ϕB=1.45 and ϕB=1.6 at pressures above 3 atm. Peak CH concentrations for the non-premixed flames are significantly underpredicted by GRI 3.0. The latter agrees with previously reported NO concentrations, which are also underpredicted in these same high-pressure counter-flow diffusion flames.

Treating Type 1 Diabetes Mellitus with a Rapid-Acting Analog Insulin Regimen vs. Regular Human Insulin in Germany: A Long-Term Cost-Effectiveness Evaluation.

PubMed

Valentine, William J; Van Brunt, Kate; Boye, Kristina S; Pollock, Richard F

2018-06-01

The aim of the present study was to evaluate the cost effectiveness of rapid-acting analog insulin relative to regular human insulin in adults with type 1 diabetes mellitus in Germany. The PRIME Diabetes Model, a patient-level, discrete event simulation model, was used to project long-term clinical and cost outcomes for patients with type 1 diabetes from the perspective of a German healthcare payer. Simulated patients had a mean age of 21.5 years, duration of diabetes of 8.6 years, and baseline glycosylated hemoglobin of 7.39%. Regular human insulin and rapid-acting analog insulin regimens reduced glycosylated hemoglobin by 0.312 and 0.402%, respectively. Compared with human insulin, hypoglycemia rate ratios with rapid-acting analog insulin were 0.51 (non-severe nocturnal) and 0.80 (severe). No differences in non-severe diurnal hypoglycemia were modeled. Discount rates of 3% were applied to future costs and clinical benefits accrued over the 50-year time horizon. In the base-case analysis, rapid-acting analog insulin was associated with an improvement in quality-adjusted life expectancy of 1.01 quality-adjusted life-years per patient (12.54 vs. 11.53 quality-adjusted life-years). Rapid-acting analog insulin was also associated with an increase in direct costs of €4490, resulting in an incremental cost-effectiveness ratio of €4427 per quality-adjusted life-year gained vs. human insulin. Sensitivity analyses showed that the base case was driven predominantly by differences in hypoglycemia; abolishing these differences reduced incremental quality-adjusted life expectancy to 0.07 quality-adjusted life-years, yielding an incremental cost-effectiveness ratio of €74,622 per quality-adjusted life-year gained. Rapid-acting analog insulin is associated with beneficial outcomes in patients with type 1 diabetes and is likely to be considered cost effective in the German setting vs. regular human insulin.

The structure of partially-premixed methane/air flames under varying premixing

NASA Astrophysics Data System (ADS)

Kluzek, Celine; Karpetis, Adonios

2008-11-01

The present work examines the spatial and scalar structure of laminar, partially premixed methane/air flames with the objective of developing flamelet mappings that capture the effect of varying premixture strength (air addition in fuel.) Experimental databases containing full thermochemistry measurements within laminar axisymmetric flames were obtained at Sandia National Laboratories, and the measurements of all major species and temperature are compared to opposed-jet one-dimensional flow simulation using Cantera and the full chemical kinetic mechanism of GRI 3.0. Particular emphasis is placed on the scalar structure of the laminar flames, and the formation of flamelet mappings that capture all of the salient features of thermochemistry in a conserved scalar representation. Three different premixture strengths were examined in detail: equivalence ratios of 1.8, 2.2, and 3.17 resulted in clear differences in the flame scalar structure, particularly in the position of the rich premixed flame zone and the attendant levels of major and intermediate species (carbon monoxide and hydrogen).

Insulin Human Inhalation

MedlinePlus

... insulin and therefore cannot control the amount of sugar in the blood). It is also used in ... normally and, therefore, cannot control the amount of sugar in the blood) who need insulin to control ...

Skeletal muscle phosphatidylcholine fatty acids and insulin sensitivity in normal humans.

PubMed

Clore, J N; Li, J; Gill, R; Gupta, S; Spencer, R; Azzam, A; Zuelzer, W; Rizzo, W B; Blackard, W G

1998-10-01

The fatty acid composition of skeletal muscle membrane phospholipids (PL) is known to influence insulin responsiveness in humans. However, the contribution of the major PL of the outer (phosphatidylcholine, PC) and inner (phosphatidylethanolamine, PE) layers of the sarcolemma to insulin sensitivity is not known. Fatty acid composition of PC and PE from biopsies of vastus lateralis from 27 normal men and women were correlated with insulin sensitivity determined by the hyperinsulinemic euglycemic clamp technique at insulin infusion rates of 0.4, 1.0, and 10.0 mU . kg-1 . min-1. Significant variation in the half-maximal insulin concentration (ED50) was observed in the normal volunteers (range 24.0-146.0 microU/ml), which correlated directly with fasting plasma insulin (r = 0.75, P < 0.0001). ED50 was inversely correlated with the degree of membrane unsaturation (C20-C22 polyunsaturated fatty acids; r = 0. 58, P < 0.01) and directly correlated with fatty acid elongation (ratio of 16:0 to 18:0, r = 0.45, P < 0.05) in PC. However, no relationship between fatty acid composition and insulin sensitivity was observed in PE (NS). These studies suggest that the fatty acid composition of PC may be of particular importance in the relationship between fatty acids and insulin sensitivity in normal humans.

Insulin in human milk and the use of hormones in infant formulas.

PubMed

Shamir, Raanan; Shehadeh, Naim

2013-01-01

Human milk contains a substantial number of hormones and growth factors. Studies in animal models show that some of these peptides (e.g. insulin, insulin-like growth factor 1, IGF-1, epidermal growth factors) have an effect on the small intestine after orogastric administration. Recently, two efforts were made to incorporate growth factors into infant formulas. One of these efforts included the incorporation of IGF-1, and the second is an ongoing effort to evaluate the safety and efficacy of incorporating insulin into infant formulas. The rational and current evidence for adding insulin to infant formulas (presence in human milk, effects of orally administrated insulin on gut maturation, intestinal permeability, systemic effects and preliminary encouraging results of supplementing insulin to a preterm infant formula) is detailed in this review. If the addition of insulin to preterm infant formulas indeed results in better growth and accelerated intestinal maturation, future studies will need to address the supplementation of insulin in term infants and assess the efficacy of such supplementation in enhancing gut maturation and prevention of later noncommunicable diseases such as allergy, autoimmune diseases and obesity. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.

A single-islet microplate assay to measure mouse and human islet insulin secretion.

PubMed

Truchan, Nathan A; Brar, Harpreet K; Gallagher, Shannon J; Neuman, Joshua C; Kimple, Michelle E

2015-01-01

One complication to comparing β-cell function among islet preparations, whether from genetically identical or diverse animals or human organ donors, is the number of islets required per assay. Islet numbers can be limiting, meaning that fewer conditions can be tested; other islet measurements must be excluded; or islets must be pooled from multiple animals/donors for each experiment. Furthermore, pooling islets negates the possibility of performing single-islet comparisons. Our aim was to validate a 96-well plate-based single islet insulin secretion assay that would be as robust as previously published methods to quantify glucose-stimulated insulin secretion from mouse and human islets. First, we tested our new assay using mouse islets, showing robust stimulation of insulin secretion 24 or 48 h after islet isolation. Next, we utilized the assay to quantify mouse islet function on an individual islet basis, measurements that would not be possible with the standard pooled islet assay methods. Next, we validated our new assay using human islets obtained from the Integrated Islet Distribution Program (IIDP). Human islets are known to have widely varying insulin secretion capacity, and using our new assay we reveal biologically relevant factors that are significantly correlated with human islet function, whether displayed as maximal insulin secretion response or fold-stimulation of insulin secretion. Overall, our results suggest this new microplate assay will be a useful tool for many laboratories, expert or not in islet techniques, to be able to precisely quantify islet insulin secretion from their models of interest.

Generation of insulin-producing human mesenchymal stem cells using recombinant adeno-associated virus.

PubMed

Kim, Jeong Hwan; Park, Si-Nae; Suh, Hwal

2007-02-28

The purpose of current experiment is the generation of insulin-producing human mesenchymal stem cells as therapeutic source for the cure of type 1 diabetes. Type 1 diabetes is generally caused by insulin deficiency accompanied by the destruction of islet beta-cells. In various trials for the treatment of type 1 diabetes, cell-based gene therapy using stem cells is considered as one of the most useful candidate for the treatment. In this experiment, human mesenchymal stem cells were transduced with AAV which is containing furin-cleavable human preproinsulin gene to generate insulin-producing cells as surrogate beta-cells for the type 1 diabetes therapy. In the rAAV production procedure, rAAV was generated by transfection of AD293 cells. Human mesenchymal stems cells were transduced using rAAV with a various multiplicity of infection. Transduction of recombinant AAV was also tested using beta-galactosidse expression. Cell viability was determined by using MTT assay to evaluate the toxicity of the transduction procedure. Expression and production of Insulin were tested using reverse transcriptase-polymerase chain reaction and immunocytochemistry. Secretion of human insulin and C-peptide from the cells was assayed using enzyme-linked immunosorbent assay. Production of insulin and C-peptide from the test group represented a higher increase compared to the control group. In this study, we examined generation of insulin-producing cells from mesenchymal stem cells by genetic engineering for diabetes therapy. This work might be valuable to the field of tissue engineering for diabetes treatment.

Comparison of medication adherence in diabetes mellitus patients on human versus analogue insulins.

PubMed

Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro; Echeverri-Cataño, Luis Felipe

2017-02-01

Objetive: This study evaluated the results of treatment adherence scales in two cohorts of patients with diabetes mellitus treated either with human or analogue insulins. A cohort study was conducted in diabetes mellitus patients older than 18 that were being treated with human or analogue insulins. Two instruments were applied to each patient [medication possession ratio, Morisky-Green test] to evaluate treatment adherence. A total of 238 patients, were included. The majority (69.4%) of the subjects had human insulin and 30.6% had insulin analogue prescriptions. Out of the total, 163 (68.5%) cases were classified as adherent to therapy, according to the type of insulin, as follows: 69.9% for conventional and 65.3% for analogues; without differences between the groups (CI95%:0.450-1.458). The adherence to treatment was more probable in patients with elementary-secondary education (OR:2.341; CI95%:1.199-4.568) and less probable for those in the age range of 31-45 years (OR:0.427; CI95%:0.187-0.971). The results of this study show that there are no significant statistical differences in adherence when comparing human with analogue insulin therapy. Strategies to improve treatment adherence are particularly important since they improve the clinical results.

A bolus/basal multiple injection regimen in type I diabetes. A multicentre trial using a new 'fountain-pen' device for short-acting human insulin as well as long-acting human insulin.

PubMed

Distiller, L A; Robertson, L I; Moore, R; Bonnici, F

1987-06-20

A trial was undertaken to ascertain the effect and acceptability of a multiple insulin injection regimen (MII) in patients with insulin-dependent diabetes mellitus using short-acting monocomponent human soluble insulin (Actrapid HM; Novo) for pre-meal bolus injections with the NovoPen injection device (Novo) and long-acting human insulin (Ultratard HM; Novo) at bedtime. Fifty-four patients, all previously on twice-daily short/intermediate-acting human insulin (Monotard HM; Novo) and Actrapid HM, were randomly selected. There was a significant overall improvement in diabetic control over the 12 weeks of the trial, the glycosylated haemoglobin (Hb A1) dropping from a mean of 9.8 +/- 2.2% to 8.6 +/- 1.7% (P less than 0.05). MII, using the NovoPen, was found to be more convenient than conventional insulin administration by 92% of the subjects. It is concluded that the NovoPen is a useful and convenient means of administering pre-meal boluses in an MII regimen, with a very high rate of acceptance by patients of all ages.

St. John’s Wort inhibits insulin signaling in murine and human adipocytes

PubMed Central

Richard, Allison J.; Amini, Zhaleh J.; Ribnicky, David M.; Stephens, Jacqueline M.

2012-01-01

Adipocytes are insulin-sensitive cells that play a major role in energy homeostasis. Obesity is the primary disease of fat cells and a major risk factor for the development of Type 2 diabetes, cardiovascular disease, and metabolic syndrome. The use of botanicals in the treatment of metabolic diseases is an emerging area of research. In previous studies, we screened over 425 botanical extracts for their ability to modulate adipogenesis and insulin sensitivity. We identified St. John’s Wort (SJW) extracts as inhibitors of adipogenesis of 3T3-L1 cells and demonstrated that these extracts also inhibited insulin-sensitive glucose uptake in mature fat cells. In these follow-up studies we have further characterized the effects of SJW on insulin action in both murine and human fat cells. We have shown that SJW also attenuates insulin-sensitive glucose uptake in human adipocytes. Moreover, SJW inhibits IRS-1 tyrosine phosphorylation in both murine and human fat cells. Botanical extracts are complex mixtures. Many bioactive compounds have been identified in SJW, including hypericin (HI) and hyperforin (HF). We have examined the ability of HI and HF, purified from SJW, to modulate adipocyte development and insulin action in mature adipocytes. Our novel studies indicate that the profound effects of SJW on adipogenesis, IRS-1 activation, and insulin-stimulated glucose uptake are not mediated by HI and/or HF. Nonetheless, we propose that extracts of SJW may contribute to adipocyte related diseases by limiting differentiation of preadipocytes and significantly inducing insulin resistance in mature fat cells. PMID:22198320

Soot Formation in Freely-Propagating Laminar Premixed Flames

NASA Technical Reports Server (NTRS)

Lin, K.-C.; Hassan, M. I.; Faeth, G. M.

1997-01-01

Soot formation within hydrocarbon-fueled flames is an important unresolved problem of combustion science. Thus, the present study is considering soot formation in freely-propagating laminar premixed flames, exploiting the microgravity environment to simplify measurements at the high-pressure conditions of interest for many practical applications. The findings of the investigation are relevant to reducing emissions of soot and continuum radiation from combustion processes, to improving terrestrial and spacecraft fire safety, and to developing methods of computational combustion, among others. Laminar premixed flames are attractive for studying soot formation because they are simple one-dimensional flows that are computationally tractable for detailed numerical simulations. Nevertheless, studying soot-containing burner-stabilized laminar premixed flames is problematical: spatial resolution and residence times are limited at the pressures of interest for practical applications, flame structure is sensitive to minor burner construction details so that experimental reproducibility is not very good, consistent burner behavior over the lengthy test programs needed to measure soot formation properties is hard to achieve, and burners have poor durability. Fortunately, many of these problems are mitigated for soot-containing, freely-propagating laminar premixed flames. The present investigation seeks to extend work in this laboratory for various soot processes in flames by observing soot formation in freely-propagating laminar premixed flames. Measurements are being made at both Normal Gravity (NG) and MicroGravity (MG), using a short-drop free-fall facility to provide MG conditions.

Dynamics and structure of turbulent premixed flames

NASA Technical Reports Server (NTRS)

Bilger, R. W.; Swaminathan, N.; Ruetsch, G. R.; Smith, N. S. A.

1995-01-01

In earlier work (Mantel & Bilger, 1994) the structure of the turbulent premixed flame was investigated using statistics based on conditional averaging with the reaction progress variable as the conditioning variable. The DNS data base of Trouve and Poinsot (1994) was used in this investigation. Attention was focused on the conditional dissipation and conditional axial velocity in the flame with a view to modeling these quantities for use in the conditional moment closure (CMC) approach to analysis of kinetics in premixed flames (Bilger, 1993). Two remarkable findings were made: there was almost no acceleration of the axial velocity in the flame front itself; and the conditional scalar dissipation remained as high, or higher, than that found in laminar premixed flames. The first finding was surprising since in laminar flames all the fluid acceleration occurs through the flame front, and this could be expected also for turbulent premixed flames at the flamelet limit. The finding gave hope of inventing a new approach to the dynamics of turbulent premixed flames through use of rapid distortion theory or an unsteady Bernoulli equation. This could lead to a new second order closure for turbulent premixed flames. The second finding was contrary to our measurements with laser diagnostics in lean hydrocarbon flames where it is found that conditional scalar dissipation drops dramatically below that for laminar flamelets when the turbulence intensity becomes high. Such behavior was not explainable with a one-step kinetic model, even at non-unity Lewis number. It could be due to depletion of H2 from the reaction zone by preferential diffusion. The capacity of the flame to generate radicals is critically dependent on the levels of H2 present (Bilger, et al., 1991). It seemed that a DNS computation with a multistep reduced mechanism would be worthwhile if a way could be found to make this feasible. Truly innovative approaches to complex problems often come only when there is the

Leucine modulates dynamic phosphorylation events in insulin signaling pathway and enhances insulin-dependent glycogen synthesis in human skeletal muscle cells

PubMed Central

2014-01-01

Background Branched-chain amino acids, especially leucine, are known to interact with insulin signaling pathway and glucose metabolism. However, the mechanism by which this is exerted, remain to be clearly defined. In order to examine the effect of leucine on muscle insulin signaling, a set of experiments was carried out to quantitate phosphorylation events along the insulin signaling pathway in human skeletal muscle cell cultures. Cells were exposed to insulin, leucine or both, and phosphorylation events of key insulin signaling molecules were tracked over time so as to monitor time-related responses that characterize the signaling events and could be missed by a single sampling strategy limited to pre/post stimulus events. Results Leucine is shown to increase the magnitude of insulin-dependent phosphorylation of protein kinase B (AKT) at Ser473 and glycogen synthase kinase (GSK3β) at Ser21-9. Glycogen synthesis follows the same pattern of GSK3β, with a significant increase at 100 μM leucine plus insulin stimulus. Moreover, data do not show any statistically significant increase of pGSK3β and glycogen synthesis at higher leucine concentrations. Leucine is also shown to increase the magnitude of insulin-mediated extracellularly regulated kinase (ERK) phosphorylation; however, differently from AKT and GSK3β, ERK shows a transient behavior, with an early peak response, followed by a return to the baseline condition. Conclusions These experiments demonstrate a complementary effect of leucine on insulin signaling in a human skeletal muscle cell culture, promoting insulin-activated GSK3β phosphorylation and glycogen synthesis. PMID:24646332

Lean, premixed, prevaporized combustion for aircraft gas turbine engines

NASA Technical Reports Server (NTRS)

Mularz, E. J.

1979-01-01

The application of lean, premixed, prevaporized combustion to aircraft turbine engine systems can result in benefits in terms of superior combustion performance, improved combustor and turbine durability, and environmentally acceptable pollutant emissions. Lean, premixed prevaporized combustion is particularly attractive for reducing the oxides of nitrogen emissions during high altitude cruise. The NASA stratospheric cruise emission reduction program will evolve and demonstrate lean, premixed, prevaporized combustion technology for aircraft engines. This multiphased program is described. In addition, the various elements of the fundamental studies phase of the program are reviewed, and results to date of many of these studies are summarized.

Turbulent flame propagation in partially premixed flames

NASA Technical Reports Server (NTRS)

Poinsot, T.; Veynante, D.; Trouve, A.; Ruetsch, G.

1996-01-01

Turbulent premixed flame propagation is essential in many practical devices. In the past, fundamental and modeling studies of propagating flames have generally focused on turbulent flame propagation in mixtures of homogeneous composition, i.e. a mixture where the fuel-oxidizer mass ratio, or equivalence ratio, is uniform. This situation corresponds to the ideal case of perfect premixing between fuel and oxidizer. In practical situations, however, deviations from this ideal case occur frequently. In stratified reciprocating engines, fuel injection and large-scale flow motions are fine-tuned to create a mean gradient of equivalence ratio in the combustion chamber which provides additional control on combustion performance. In aircraft engines, combustion occurs with fuel and secondary air injected at various locations resulting in a nonuniform equivalence ratio. In both examples, mean values of the equivalence ratio can exhibit strong spatial and temporal variations. These variations in mixture composition are particularly significant in engines that use direct fuel injection into the combustion chamber. In this case, the liquid fuel does not always completely vaporize and mix before combustion occurs, resulting in persistent rich and lean pockets into which the turbulent flame propagates. From a practical point of view, there are several basic and important issues regarding partially premixed combustion that need to be resolved. Two such issues are how reactant composition inhomogeneities affect the laminar and turbulent flame speeds, and how the burnt gas temperature varies as a function of these inhomogeneities. Knowledge of the flame speed is critical in optimizing combustion performance, and the minimization of pollutant emissions relies heavily on the temperature in the burnt gases. Another application of partially premixed combustion is found in the field of active control of turbulent combustion. One possible technique of active control consists of pulsating

Insulin lispro 25/75 and insulin lispro 50/50 as starter insulin in Japanese patients with type 2 diabetes: subanalysis of the CLASSIFY randomized trial.

PubMed

Watada, Hirotaka; Imori, Makoto; Li, Pengfei; Iwamoto, Noriyuki

2017-07-28

In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.

Methods for quantifying adipose tissue insulin resistance in overweight/obese humans.

PubMed

Ter Horst, K W; van Galen, K A; Gilijamse, P W; Hartstra, A V; de Groot, P F; van der Valk, F M; Ackermans, M T; Nieuwdorp, M; Romijn, J A; Serlie, M J

2017-08-01

Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3- 2 H 5 ]glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50±11 years; body mass index 38±7 kg m -2 ). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r=0.960, P<0.001), (2) suppression of plasma non-esterified fatty acid (NEFA) concentrations (r=0.899, P<0.001), (3) the Adipose tissue Insulin Resistance (Adipo-IR) index (fasting plasma insulin-NEFA product; r=-0.526, P<0.001), (4) the fasting plasma insulin-glycerol product (r=-0.467, P<0.001), (5) the Adipose Tissue Insulin Resistance Index (fasting plasma insulin-basal lipolysis product; r=0.460, P<0.001), (6) the Quantitative Insulin Sensitivity Check Index (QUICKI)-NEFA index (r=0.621, P<0.001), and (7) the QUICKI-glycerol index (r=0.671, P<0.001). Bland-Altman plots showed no systematic errors for the suppression indices but proportional errors for all fasting indices. Receiver-operator characteristic curves confirmed that all indices were able to detect adipose tissue insulin resistance (area

Premixed polymer concrete overlays.

DOT National Transportation Integrated Search

1990-01-01

The results of a study undertaken to evaluate premixed polymer concrete overlays (PMPCO) over a 3-year period are presented. The PMPCO evaluated were constructed with polyester amide para resin and silica sand 1;. polyester styrene resin 1 and silica...

The Novel Endocrine Disruptor Tolylfluanid Impairs Insulin Signaling in Primary Rodent and Human Adipocytes through a Reduction in Insulin Receptor Substrate-1 Levels

PubMed Central

Sargis, Robert M.; Neel, Brian A.; Brock, Clifton O.; Lin, Yuxi; Hickey, Allison T.; Carlton, Daniel A.; Brady, Matthew J.

2012-01-01

Emerging data suggest that environmental endocrine disrupting chemicals (EDCs) may contribute to the pathophysiology of obesity and diabetes. In prior work, the phenylsulfamide fungicide tolylfluanid (TF) was shown to augment adipocyte differentiation, yet its effects on mature adipocyte metabolism remain unknown. Because of the central role of adipose tissue in global energy regulation, the present study tested the hypothesis that TF modulates insulin action in primary rodent and human adipocytes. Alterations in insulin signaling in primary mammalian adipocytes were determined by the phosphorylation of Akt, a critical insulin signaling intermediate. Treatment of primary murine adipose tissue in vitro with 100 nM TF for 48 h markedly attenuated acute insulin-stimulated Akt phosphorylation in a strain- and species-independent fashion. Perigonadal, perirenal, and mesenteric fat were all sensitive to TF-induced insulin resistance. A similar TF-induced reduction in insulin-stimulated Akt phosphorylation was observed in primary human subcutaneous adipose tissue. TF-treatment led to a potent and specific reduction in insulin receptor substrate-1 (IRS-1) mRNA and protein levels, a key upstream mediator of insulin’s diverse metabolic effects. In contrast, insulin receptor-β, phosphatidylinositol 3-kinase, and Akt expression were unchanged, indicating a specific abrogation of insulin signaling. Additionally, TF-treated adipocytes exhibited altered endocrine function with a reduction in both basal and insulin-stimulated leptin secretion. These studies demonstrate that TF induces cellular insulin resistance in primary murine and human adipocytes through a reduction of IRS-1 expression and protein stability, raising concern about the potential for this fungicide to disrupt metabolism and thereby contribute to the pathogenesis of diabetes. PMID:22387882

Premixed direct injection nozzle

DOEpatents

Zuo, Baifang [Simpsonville, SC; Johnson, Thomas Edward [Greer, SC; Lacy, Benjamin Paul [Greer, SC; Ziminsky, Willy Steve [Simpsonville, SC

2011-02-15

An injection nozzle having a main body portion with an outer peripheral wall is disclosed. The nozzle includes a plurality of fuel/air mixing tubes disposed within the main body portion and a fuel flow passage fluidly connected to the plurality of fuel/air mixing tubes. Fuel and air are partially premixed inside the plurality of the tubes. A second body portion, having an outer peripheral wall extending between a first end and an opposite second end, is connected to the main body portion. The partially premixed fuel and air mixture from the first body portion gets further mixed inside the second body portion. The second body portion converges from the first end toward said second end. The second body portion also includes cooling passages that extend along all the walls around the second body to provide thermal damage resistance for occasional flame flash back into the second body.

Chemical stability and cytotoxicity of human insulin loaded in cationic DPPC/CTA/DDAB liposomes.

PubMed

Manosroi, Aranya; Khositsuntiwong, Narinthorn; Komno, Chonlada; Manosroi, Worapaka; Werner, Rolf G; Manosoi, Jiradej

2011-04-01

Liposomes were prepared from DPPC (dipalmitoyl phosphatidyl choline) mixed with Chol (cholesterol) and CTA [cholest-5-en-3-ol(3beta)(trimethylammonio) acetate] or DDAB (dioctadecyl dimethyl ammonium bromide) at various molar ratios by chloroform film method with sonication. The most physical stable (no sedimentation with an average zeta potential value of 47.7+/-1.44 mV) liposomal formulation (DPPC/CTA/DDAB at 7:2:1 molar ratio) was selected to load with human insulin (0.45 mg/mL) by the freeze dried empty liposomes (FDELs) method with the entrapment efficiency of human insulin of 62.72% (determined by gel filtration). Liposomes were spherical shape with unilamellar structure and an average size of 2.26+/-0.87 microm determined by TEM. The percentages of insulin remaining in liposomes when stored at 4+/-2, 30+/-2 and 45+/-2 degrees C for 4 months were 26.21, 36.86 and 15.75% which were higher than human insulin solution of 6.13, 11.31 and 2.61 times, respectively. The percentages of entrapment of human insulin were 62.72 at initial and at 31.72, 64.10 and 8.10 when kept at 4+/-2, 30+/-2 and 45+/-2 degrees C, respectively, for 4 months. The synthesized cationic lipid, CTA, and the DPPC/Chol/CTA liposomes loaded with human insulin demonstrated no cytotoxicity on normal human skin fibroblast but some cytotoxic effects on mouth epidermal cancer cell line. This study has demonstrated the enhancement of chemical stability of human insulin with no cytotoxicity when loaded this protein in cationic DPPC/CTA/DDAB liposomes. The results indicated the potential application of this cationic liposomal formulation for topical therapeutic use.

Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans.

PubMed

Gancheva, Sofiya; Koliaki, Chrysi; Bierwagen, Alessandra; Nowotny, Peter; Heni, Martin; Fritsche, Andreas; Häring, Hans-Ulrich; Szendroedi, Julia; Roden, Michael

2015-06-01

Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery have provided conflicting results. In this randomized controlled crossover trial, we investigated the effects of intranasal insulin on hepatic insulin sensitivity (HIS) and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCLs), ATP, and inorganic phosphate concentrations with (1)H/(31)P magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin levels followed by a gradual lowering of blood glucose in CON only. Fasting HIS index was not affected by intranasal insulin in CON and patients. HCLs decreased by 35% in CON only, whereas absolute hepatic ATP concentration increased by 18% after 3 h. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCLs without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes. © 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.

Human milk insulin is related to maternal plasma insulin and BMI: but other components of human milk do not differ by BMI.

PubMed

Young, B E; Patinkin, Z; Palmer, C; de la Houssaye, B; Barbour, L A; Hernandez, T; Friedman, J E; Krebs, N F

2017-09-01

The impact of maternal BMI and insulin sensitivity on bioactive components of human milk (HM) is not well understood. As the prevalence of obesity and diabetes rises, it is increasingly critical that we understand how maternal BMI and hormones associated with metabolic disease relate to concentrations of bioactive components in HM. This longitudinal cohort design followed 48 breastfeeding mothers through the first four months of lactation, collecting fasting morning HM samples at 2-weeks and 1, 2, 3 and 4-months, and fasting maternal blood at 2-weeks and 4-months. Insulin, glucose, adipokines leptin and adiponectin, appetite regulating hormone ghrelin, marker of oxidative stress 8OHdG and inflammatory cytokines (IL-6, IL-8, and TNF-a) were measured in HM and maternal plasma. A total of 26 normal weight (NW) (BMI=21.4±2.0 kg/m 2 ) and 22 overweight/obese (OW/Ob) (BMI=30.4±4.2 kg/m 2 ) were followed. Of all HM analytes measured, only insulin and leptin were different between groups - consistently higher in the OW/Ob group (leptin: P<0.001; insulin: P<0.03). HM insulin was 98% higher than maternal plasma insulin at 2-weeks and 32% higher at 4-months (P<0.001). Maternal fasting plasma insulin and HOMA-IR were positively related to HM insulin at 2-weeks (P<0.001, R 2 ⩾0.38, n=31), and 4-months (P⩽0.005, R 2 ⩾0.20, n=38). The concentrations of insulin in HM are higher than in maternal plasma and are related to maternal BMI and insulin sensitivity. With the exception of leptin, there were minimal other differences observed in HM composition across a wide range in maternal BMI.

Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet

PubMed Central

Molina, Judith; Rodriguez-Diaz, Rayner; Fachado, Alberto; Jacques-Silva, M. Caroline

2014-01-01

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeostasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is primarily a paracrine signal released from α-cells rather than primarily a neural signal as in rodent islets. In this study, we demonstrate that the effects acetylcholine produces in the human islet are different and more complex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcholine not only stimulates the insulin-secreting β-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting δ-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin secretion, we hypothesized that cholinergic input to the δ-cell indirectly regulates β-cell function. Indeed, when all muscarinic signaling was blocked, somatostatin secretion decreased and insulin secretion unexpectedly increased, suggesting a reduced inhibitory input to β-cells. Endogenous cholinergic signaling therefore provides direct stimulatory and indirect inhibitory input to β-cells to regulate insulin secretion from the human islet. PMID:24658304

The cost effectiveness of rapid-acting insulin aspart compared with human insulin in type 2 diabetes patients: an analysis from the Japanese third-party payer perspective.

PubMed

Pollock, R F; Valentine, W J; Pilgaard, T; Nishimura, H

2011-01-01

The Nippon Ultra-Rapid Insulin and Diabetic Complication Evaluation Study (NICE Study) (NCT00575172) was a 5-year, open-label, randomised controlled trial which compared cardiovascular outcomes in Japanese type 2 diabetes patients intensively treated with regular human insulin or insulin aspart (NovoRapid; Novo Nordisk A/S, Bagsvaerd, Denmark), a rapid-acting insulin analogue. The aim of the present analysis was to evaluate the cost effectiveness of insulin aspart versus regular human insulin from the perspective of a Japanese third-party healthcare payer. A discrete event-simulation model was developed in Microsoft Excel to assess the within-trial cost effectiveness and make longer-term clinical projections in patients treated with regular human insulin or insulin aspart. In addition to severe hypoglycaemia, the model captured myocardial and cerebral infarction events and percutaneous coronary intervention and coronary artery bypass graft procedures. Within-trial mortality, incidence of severe hypoglycaemia and cardiovascular event probabilities were derived from the annual rates observed during the trial period, while post-trial outcomes were calculated using the event rates from the trial, adjusted for increasing patient age. Event costs were accounted from the healthcare payer perspective and expressed in 2008 Japanese yen (JPY), while health-related quality of life (HRQoL) was captured using event and state utilities. Future costs and clinical benefits were discounted at 3% annually. Life expectancy, quality-adjusted life expectancy, cardiovascular event rates and costs were evaluated over 5- and 10-year time horizons and sensitivity analyses were performed to assess variability in model outcomes. Over 5 years of treatment, insulin aspart dominated human insulin both in incremental life expectancy and in incremental quality-adjusted life-years (QALYS). Insulin aspart was associated with a small improvement in discounted life expectancy of 0.005 years (4.688 vs

Numerical evaluation of equivalence ratio measurement using OH{sup *} and CH{sup *} chemiluminescence in premixed and non-premixed methane-air flames

DOE Office of Scientific and Technical Information (OSTI.GOV)

Panoutsos, C.S.; Hardalupas, Y.; Taylor, A.M.K.P.

This work presents results from detailed chemical kinetics calculations of electronically excited OH (A{sup 2}{sigma}, denoted as OH{sup *}) and CH (A{sup 2}{delta}, denoted as CH{sup *}) chemiluminescent species in laminar premixed and non-premixed counterflow methane-air flames, at atmospheric pressure. Eight different detailed chemistry mechanisms, with added elementary reactions that account for the formation and destruction of the chemiluminescent species OH{sup *} and CH{sup *}, are studied. The effects of flow strain rate and equivalence ratio on the chemiluminescent intensities of OH{sup *}, CH{sup *} and their ratio are studied and the results are compared to chemiluminescent intensity ratio measurementsmore » from premixed laminar counterflow natural gas-air flames. This is done in order to numerically evaluate the measurement of equivalence ratio using OH{sup *} and CH{sup *} chemiluminescence, an experimental practise that is used in the literature. The calculations reproduced the experimental observation that there is no effect of strain rate on the chemiluminescent intensity ratio of OH{sup *} to CH{sup *}, and that the ratio is a monotonic function of equivalence ratio. In contrast, the strain rate was found to have an effect on both the OH{sup *} and CH{sup *} intensities, in agreement with experiment. The calculated OH{sup *}/CH{sup *} values showed that only five out of the eight mechanisms studied were within the same order of magnitude with the experimental data. A new mechanism, proposed in this work, gave results that agreed with experiment within 30%. It was found that the location of maximum emitted intensity from the excited species OH{sup *} and CH{sup *} was displaced by less than 65 and 115 {mu}m, respectively, away from the maximum of the heat release rate, in agreement with experiments, which is small relative to the spatial resolution of experimental methods applied to combustion applications, and, therefore, it is expected that

Blood glucose and serum insulin responses to breakfast including guar gum and cooked or uncooked milk in type 2 (non-insulin-dependent) diabetic patients.

PubMed

Uusitupa, M; Aro, A; Korhonen, T; Tuunainen, A; Sarlund, H; Penttilä, I

1984-06-01

The post-prandial blood glucose and serum insulin responses to test meals, each including 300 ml fat-free milk taken separately with the meal or premixed before cooking into the meal consisting of oatmeal porridge, were studied in 10 diet-treated Type 2 (non-insulin-dependent) diabetic subjects. The modifying effect of guar gum on the responses was also studied by supplementing both types of test meals with 5 g granulated guar gum taken at the beginning of the meal. The blood glucose response was higher after the meal which contained cooked milk than after the respective meal with milk taken separately. The guar gum supplementation attenuated the blood glucose response after the meals, but the effect was more pronounced after the meal containing cooked milk. Post-prandial serum insulin responses were similar after all test meals. The results suggest that cooking may facilitate the absorption of lactose from milk-containing foods, and that supplementation with guar gum may counteract this response.

Insulin Restores Gestational Diabetes Mellitus–Reduced Adenosine Transport Involving Differential Expression of Insulin Receptor Isoforms in Human Umbilical Vein Endothelium

PubMed Central

Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Puebla, Carlos; Guzmán-Gutiérrez, Enrique; Cifuentes, Fredi; Leiva, Andrea; Casanello, Paola; Sobrevia, Luis

2011-01-01

OBJECTIVE To determine whether insulin reverses gestational diabetes mellitus (GDM)–reduced expression and activity of human equilibrative nucleoside transporters 1 (hENT1) in human umbilical vein endothelium cells (HUVECs). RESEARCH DESIGN AND METHODS Primary cultured HUVECs from full-term normal (n = 44) and diet-treated GDM (n = 44) pregnancies were used. Insulin effect was assayed on hENT1 expression (protein, mRNA, SLC29A1 promoter activity) and activity (initial rates of adenosine transport) as well as endothelial nitric oxide (NO) synthase activity (serine1177 phosphorylation, l-citrulline formation). Adenosine concentration in culture medium and umbilical vein blood (high-performance liquid chromatography) as well as insulin receptor A and B expression (quantitative PCR) were determined. Reactivity of umbilical vein rings to adenosine and insulin was assayed by wire myography. Experiments were in the absence or presence of l-NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) or ZM-241385 (an A2A-adenosine receptor antagonist). RESULTS Umbilical vein blood adenosine concentration was higher, and the adenosine- and insulin-induced NO/endothelium-dependent umbilical vein relaxation was lower in GDM. Cells from GDM exhibited increased insulin receptor A isoform expression in addition to the reported NO–dependent inhibition of hENT1-adenosine transport and SLC29A1 reporter repression, and increased extracellular concentration of adenosine and NO synthase activity. Insulin reversed all these parameters to values in normal pregnancies, an effect blocked by ZM-241385 and l-NAME. CONCLUSIONS GDM and normal pregnancy HUVEC phenotypes are differentially responsive to insulin, a phenomenon where insulin acts as protecting factor for endothelial dysfunction characteristic of this syndrome. Abnormal adenosine plasma levels, and potentially A2A-adenosine receptors and insulin receptor A, will play crucial roles in this phenomenon in GDM. PMID:21515851

Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium.

PubMed

Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Puebla, Carlos; Guzmán-Gutiérrez, Enrique; Cifuentes, Fredi; Leiva, Andrea; Casanello, Paola; Sobrevia, Luis

2011-06-01

To determine whether insulin reverses gestational diabetes mellitus (GDM)-reduced expression and activity of human equilibrative nucleoside transporters 1 (hENT1) in human umbilical vein endothelium cells (HUVECs). Primary cultured HUVECs from full-term normal (n = 44) and diet-treated GDM (n = 44) pregnancies were used. Insulin effect was assayed on hENT1 expression (protein, mRNA, SLC29A1 promoter activity) and activity (initial rates of adenosine transport) as well as endothelial nitric oxide (NO) synthase activity (serine(1177) phosphorylation, l-citrulline formation). Adenosine concentration in culture medium and umbilical vein blood (high-performance liquid chromatography) as well as insulin receptor A and B expression (quantitative PCR) were determined. Reactivity of umbilical vein rings to adenosine and insulin was assayed by wire myography. Experiments were in the absence or presence of l-N(G)-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) or ZM-241385 (an A(2A)-adenosine receptor antagonist). Umbilical vein blood adenosine concentration was higher, and the adenosine- and insulin-induced NO/endothelium-dependent umbilical vein relaxation was lower in GDM. Cells from GDM exhibited increased insulin receptor A isoform expression in addition to the reported NO-dependent inhibition of hENT1-adenosine transport and SLC29A1 reporter repression, and increased extracellular concentration of adenosine and NO synthase activity. Insulin reversed all these parameters to values in normal pregnancies, an effect blocked by ZM-241385 and l-NAME. GDM and normal pregnancy HUVEC phenotypes are differentially responsive to insulin, a phenomenon where insulin acts as protecting factor for endothelial dysfunction characteristic of this syndrome. Abnormal adenosine plasma levels, and potentially A(2A)-adenosine receptors and insulin receptor A, will play crucial roles in this phenomenon in GDM.

Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme

PubMed Central

Bailey, Lucas J; Tan, Yong Zi; Wei, Hui; Wang, Andrew; Farcasanu, Mara; Woods, Virgil A; McCord, Lauren A; Lee, David; Shang, Weifeng; Deprez-Poulain, Rebecca; Deprez, Benoit; Liu, David R; Koide, Akiko; Koide, Shohei; Kossiakoff, Anthony A

2018-01-01

Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies. PMID:29596046

Chaos in an imperfectly premixed model combustor.

PubMed

Kabiraj, Lipika; Saurabh, Aditya; Karimi, Nader; Sailor, Anna; Mastorakos, Epaminondas; Dowling, Ann P; Paschereit, Christian O

2015-02-01

This article reports nonlinear bifurcations observed in a laboratory scale, turbulent combustor operating under imperfectly premixed mode with global equivalence ratio as the control parameter. The results indicate that the dynamics of thermoacoustic instability correspond to quasi-periodic bifurcation to low-dimensional, deterministic chaos, a route that is common to a variety of dissipative nonlinear systems. The results support the recent identification of bifurcation scenarios in a laminar premixed flame combustor (Kabiraj et al., Chaos: Interdiscip. J. Nonlinear Sci. 22, 023129 (2012)) and extend the observation to a practically relevant combustor configuration.

Human blood-brain barrier insulin-like growth factor receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duffy, K.R.; Pardridge, W.M.; Rosenfeld, R.G.

1988-02-01

Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefoldmore » greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of /sup 125/I-IGF-1, /sup 125/I-IGF-2, and /sup 125/I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin.« less

Study on Combustion Oscillation of Premixed Flame with Pilot Fuel at Elevated Pressures

NASA Astrophysics Data System (ADS)

Ohtsuka, Masaya; Yoshida, Shohei; Hirata, Yoshitaka; Kobayashi, Nariyoshi

Acoustically-coupled combustion oscillation is studied for premixed flame with pilot fuel to be used in gas turbine combustors. Premixed gas is passed through swirl vanes and burnt with the centrally injected pilot fuel. The dependencies of pressure, fuel to air ratio, premixed fuel rate, inlet velocity and air temperature on the combustion oscillation are investigated. Two kinds of oscillation modes of ˜100Hz and ˜350Hz are activated according to inlet velocities. Fluctuating pressures are amplified when the premixed fuel rate is over ˜80% at elevated pressures. The fluctuating pressure peak moves to a higher premixed fuel ratio region with increased pressure or fuel to air ratio for the Helmholz type mode. Combustion oscillation occurs when the pilot fuel velocity is changed proportionally with the flame length.

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

PubMed

Home, Philip D; Dain, Marie-Paule; Freemantle, Nick; Kawamori, Ryuzo; Pfohl, Martin; Brette, Sandrine; Pilorget, Valérie; Scherbaum, Werner A; Vespasiani, Giacomo; Vincent, Maya; Balkau, Beverley

2015-05-01

It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.

PubMed

Aye, Irving L M H; Jansson, Thomas; Powell, Theresa L

2013-12-05

Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10pg/ml) for 24h. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth. Published by Elsevier Ireland Ltd.

Interleukin-1β Inhibits Insulin Signaling and Prevents Insulin-Stimulated System A Amino Acid Transport in Primary Human Trophoblasts

PubMed Central

Aye, Irving L. M. H.; Jansson, Thomas; Powell, Theresa L.

2013-01-01

Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10 pg/ml) for 24 hours. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth. PMID:23891856

Laminar Premixed and Diffusion Flames (Ground-Based Study)

NASA Technical Reports Server (NTRS)

Dai, Z.; El-Leathy, A. M.; Lin, K.-C.; Sunderland, P. B.; Xu, F.; Faeth, G. M.; Urban, D. L. (Technical Monitor); Yuan, Z.-G. (Technical Monitor)

2000-01-01

Ground-based studies of soot processes in laminar flames proceeded in two phases, considering laminar premixed flames and laminar diffusion flames, in turn. The test arrangement for laminar premixed flames involved round flat flame burners directed vertically upward at atmospheric pressure. The test arrangement for laminar jet diffusion flames involved a round fuel port directed vertically upward with various hydrocarbon fuels burning at atmospheric pressure in air. In both cases, coflow was used to prevent flame oscillations and measurements were limited to the flame axes. The measurements were sufficient to resolve soot nucleation, growth and oxidation rates, as well as the properties of the environment needed to evaluate mechanisms of these processes. The experimental methods used were also designed to maintain capabilities for experimental methods used in corresponding space-based experiments. This section of the report will be limited to consideration of flame structure for both premixed and diffusion flames.

Induction of insulin-producing cells from human pancreatic progenitor cells.

PubMed

Noguchi, H; Naziruddin, B; Shimoda, M; Fujita, Y; Chujo, D; Takita, M; Peng, H; Sugimoto, K; Itoh, T; Tamura, Y; Olsen, G S; Kobayashi, N; Onaca, N; Hayashi, S; Levy, M F; Matsumoto, S

2010-01-01

We previously established a mouse pancreatic stem cell line without genetic manipulation. In this study, we sought to identify and isolate human pancreatic stem/progenitor cells. We also tested whether growth factors and protein transduction of pancreatic and duodenal homeobox factor-1 (PDX-1) and BETA2/NeuroD into human pancreatic stem/progenitor cells induced insulin or pancreas-related gene expressions. Human pancreata from brain-dead donors were used for islet isolation with the standard Ricordi technique modified by the Edmonton protocol. The cells from a duct-rich population were cultured in several media, based on those designed for mouse pancreatic or for human embryonic stem cells. To induce cell differentiation, cells were cultured for 2 weeks with exendin-4, nicotinamide, keratinocyte growth factor, PDX-1 protein, or BETA2/NeuroD protein. The cells in serum-free media showed morphologies similar to a mouse pancreatic stem cell line, while the cells in the medium for human embryonic stem cells formed fibroblast-like morphologies. The nucleus/cytoplasm ratios of the cells in each culture medium decreased during the culture. The cells stopped dividing after 30 days, suggesting that they had entered senescence. The cells treated with induction medium differentiated into insulin-producing cells, expressing pancreas-related genes. Duplications of cells from a duct-rich population were limited. Induction therapy with several growth factors and transduction proteins might provide a potential new strategy for induction of transplantable insulin-producing cells. Copyright 2010 Elsevier Inc. All rights reserved.

Decision analysis applied to the purchase of frozen premixed intravenous admixtures.

PubMed

Witte, K W; Eck, T A; Vogel, D P

1985-04-01

A structured decision-analysis model was used to evaluate frozen premixed cefazolin admixtures. Decision analysis is a process of stating the desired outcome, establishing and weighting evaluation criteria, identifying options for reaching the outcome, evaluating and numerically ranking each option for each criterion, multiplying the ranking by the weight for each criterion, and calculating total points for each option. It was used to compare objectively frozen premixed cefazolin admixtures with batch reconstitution from vials and reconstitution of lyophilized, ready-to-mix containers. In this institution the model numerically demonstrated a distinct preference for the premixed frozen admixture over these other alternatives. A comparison of these results with the total cost impact of each option resulted in a decision to purchase the frozen premixed solution. The advantages of the frozen premixed solution that contributed most to this decision were decreased waste and personnel time. The latter was especially important since it allowed for the reallocation of personnel resources to other potentially cost-reducing clinical functions. Decision analysis proved to be an effective tool for formalizing the process of selecting among various alternatives to reach a desired outcome in this hospital pharmacy.

Turbulent transport in premixed flames

NASA Technical Reports Server (NTRS)

Rutland, C. J.; Cant, R. S.

1994-01-01

Simulations of planar, premixed turbulent flames with heat release were used to study turbulent transport. Reynolds stress and Reynolds flux budgets were obtained and used to guide the investigation of important physical effects. Essentially all pressure terms in the transport equations were found to be significant. In the Reynolds flux equations, these terms are the major source of counter-gradient transport. Viscous and molecular terms were also found to be significant, with both dilatational and solenoidal terms contributing to the Reynolds stress dissipation. The BML theory of premixed turbulent combustion was critically examined in detail. The BML bimodal pdf was found to agree well with the DNS data. All BML decompositions, through the third moments, show very good agreement with the DNS results. Several BML models for conditional terms were checked using the DNS data and were found to require more extensive development.

Quantification of trace metals in infant formula premixes using laser-induced breakdown spectroscopy

NASA Astrophysics Data System (ADS)

Cama-Moncunill, Raquel; Casado-Gavalda, Maria P.; Cama-Moncunill, Xavier; Markiewicz-Keszycka, Maria; Dixit, Yash; Cullen, Patrick J.; Sullivan, Carl

2017-09-01

Infant formula is a human milk substitute generally based upon fortified cow milk components. In order to mimic the composition of breast milk, trace elements such as copper, iron and zinc are usually added in a single operation using a premix. The correct addition of premixes must be verified to ensure that the target levels in infant formulae are achieved. In this study, a laser-induced breakdown spectroscopy (LIBS) system was assessed as a fast validation tool for trace element premixes. LIBS is a promising emission spectroscopic technique for elemental analysis, which offers real-time analyses, little to no sample preparation and ease of use. LIBS was employed for copper and iron determinations of premix samples ranging approximately from 0 to 120 mg/kg Cu/1640 mg/kg Fe. LIBS spectra are affected by several parameters, hindering subsequent quantitative analyses. This work aimed at testing three matrix-matched calibration approaches (simple-linear regression, multi-linear regression and partial least squares regression (PLS)) as means for precision and accuracy enhancement of LIBS quantitative analysis. All calibration models were first developed using a training set and then validated with an independent test set. PLS yielded the best results. For instance, the PLS model for copper provided a coefficient of determination (R2) of 0.995 and a root mean square error of prediction (RMSEP) of 14 mg/kg. Furthermore, LIBS was employed to penetrate through the samples by repetitively measuring the same spot. Consequently, LIBS spectra can be obtained as a function of sample layers. This information was used to explore whether measuring deeper into the sample could reduce possible surface-contaminant effects and provide better quantifications.

PREMIX: PRivacy-preserving EstiMation of Individual admiXture.

PubMed

Chen, Feng; Dow, Michelle; Ding, Sijie; Lu, Yao; Jiang, Xiaoqian; Tang, Hua; Wang, Shuang

2016-01-01

In this paper we proposed a framework: PRivacy-preserving EstiMation of Individual admiXture (PREMIX) using Intel software guard extensions (SGX). SGX is a suite of software and hardware architectures to enable efficient and secure computation over confidential data. PREMIX enables multiple sites to securely collaborate on estimating individual admixture within a secure enclave inside Intel SGX. We implemented a feature selection module to identify most discriminative Single Nucleotide Polymorphism (SNP) based on informativeness and an Expectation Maximization (EM)-based Maximum Likelihood estimator to identify the individual admixture. Experimental results based on both simulation and 1000 genome data demonstrated the efficiency and accuracy of the proposed framework. PREMIX ensures a high level of security as all operations on sensitive genomic data are conducted within a secure enclave using SGX.

Premix formulation for making the Indonesian otak-otak

NASA Astrophysics Data System (ADS)

Tawali, A. B.; Wakiah, N.; Ramli, A. R.; Mahendradatta, M.; Tawali, S.; Made, S.

2018-05-01

Otak-otak is one indigenous foods from Indonesia which made from fish paste, tapioca flour and spices. The aim of this research was to produce premix flour for making otak-otak using mackerel surimi, tapioca flour and spices and to evaluate their chemical properties and sensory acceptability of the product. Mackerel surimi was first dried, miled into powder form then mixed with tapioca flour and spices. The result showed that, otak-otak which made from Premix-B formula (40% mackerel surimi powder and 60% tapioca flour) was the best result for all sensory attributes. It presented “like moderately” for hedonic score. Protein, ash, moisture, carbohydrate, and fat contents of the premix-B formula were 23.51%, 2.44%, 7.31%, 71.02%, 4.28%, respectively, which met the SNI requirements. Overall, this study clearly showed that it was possible to make otak-otak with less complicated process and the product did not have any negative results on sensory perception.

Use of Piggyback Electrolytes for Patients Receiving Individually Prescribed vs Premixed Parenteral Nutrition.

PubMed

Busch, Rebecca A; Curtis, Caitlin S; Leverson, Glen E; Kudsk, Kenneth A

2015-07-01

Parenteral nutrition (PN) is available as individualized prescriptions frequently prepared with an automated compounding device or as commercially prepared premixed solutions. Our institution exclusively used individualized PN until an amino acid shortage forced a temporary switch to premixed solutions. In general, premixed solutions contain lower electrolyte levels than individualized formulations prescribed for patients with normal organ function. We aimed to quantify supplemental intravenous piggyback (IVPB) electrolyte use in adult patients receiving individualized and premixed PN and to quantify any effect on difference in the cost of therapy. We compared use of supplemental IVPB electrolytes administered to patients receiving PN during consecutive periods prior to and during the amino acid shortage. Electrolyte IVPBs tabulated were potassium chloride, 10 and 20 mEq; magnesium sulfate, 2 g and 4 g; potassium phosphate, 7.5 and 15 mmol; and sodium phosphate, 7.5 and 15 mmol IVPB. There was no statistical difference in the number of PN formulations administered per day during each period (14.7 ± 3.9 vs 14.0 ± 2.6, individualized vs premixed, respectively). Total IVPB electrolytes prescribed per day increased significantly from the individualized PN period to the premixed PN period (7.03 ± 3.8 vs 13.8 ± 6.8; P < .0001). The additional IVPB electrolyte supplementation required in patients receiving premixed PN was associated with an additional $11,855.74 cost per 30 days of therapy compared with those who received individualized PN. Inpatient use of premixed PN results in a significant increase in IVPB electrolyte supplementation and cost compared with individualized PN use. © 2014 American Society for Parenteral and Enteral Nutrition.

Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus.

PubMed

Fullerton, Birgit; Siebenhofer, Andrea; Jeitler, Klaus; Horvath, Karl; Semlitsch, Thomas; Berghold, Andrea; Plank, Johannes; Pieber, Thomas R; Gerlach, Ferdinand M

2016-06-30

Short-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates. To assess the effects of short-acting insulin analogues versus regular human insulin in adults with type 1 diabetes. We carried out the electronic searches through Ovid simultaneously searching the following databases: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 14 April 2015), EMBASE (1988 to 2015, week 15), the Cochrane Central Register of Controlled Trials (CENTRAL; March 2015), ClinicalTrials.gov and the European (EU) Clinical Trials register (both March 2015). We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues with regular human insulins in the treatment of adults with type 1 diabetes who were not pregnant. Two review authors independently extracted data and assessed trials for risk of bias, and resolved differences by consensus. We graded overall study quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. We used random-effects models for the main analyses and presented the results as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes. We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in

Studies of Premixed Laminar and Turbulent Flames at Microgravity

NASA Technical Reports Server (NTRS)

Ronney, Paul D.

1993-01-01

The work of the Principal Investigator (PI) has encompassed four topics related to the experimental and theoretical study of combustion limits in premixed flames at microgravity, as discussed in the following sections. These topics include: (1) radiation effects on premixed gas flames; (2) flame structure and stability at low Lewis number; (3) flame propagation and extinction is cylindrical tubes; and (4) experimental simulation of combustion processes using autocatalytic chemical reactions.

Trends in the use and cost of human and analogue insulins in a Colombian population, 2011-2015.

PubMed

Torres, D R; Portilla, A; Machado-Duque, M E; Machado-Alba, J E

2017-12-01

Diabetes mellitus is a common disease among the general population and imposes considerable costs on health care systems. Insulin is used to treat type 1 diabetes mellitus and as an adjuvant to oral agents in advanced stages of type 2 diabetes mellitus. The objective was to describe the trends in use and cost of human and analogue insulins for Colombian patients. Descriptive retrospective analysis of prescriptions of human and analogue insulins on a monthly basis for the period from July 1, 2011 to February 2, 2015. Information was collected for the database population of two insurance companies. Frequencies and proportions were calculated; estimated economic impact was expressed as net cost and cost per thousand inhabitants per day. During the observation period, there was continuous growth in use of insulin, mainly in analogue forms (34.0% growth). At the start of the study, 10.4% of subjects were using an analogue insulin; this figure was 62.6% at the end of the study. In 2012, the average cost per 1000 inhabitants/day was US$1.7 for analogue and US$0.8 for human insulins. At the end of the observation period these costs had risen to US$9.2 for analogue (441.1% increase) and fallen to US$0.5 for human insulin (58.3% decrease). There has been an increase in the unit cost and frequency of use of insulin analogues for anti-diabetic therapy in Colombian patients. Moreover, there is controversy over whether insulin analogues are a more cost-effective treatment than human insulins for the general diabetic population. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Gravity Effects Observed In Partially Premixed Flames

NASA Technical Reports Server (NTRS)

Puri, Ishwar K.; Aggarwal, Suresh K.; Lock, Andrew J.; Gauguly, Ranjan; Hegde, Uday

2003-01-01

Partially premixed flames (PPFs) contain a rich premixed fuel air mixture in a pocket or stream, and, for complete combustion to occur, they require the transport of oxidizer from an appropriately oxidizer-rich (or fuel-lean) mixture that is present in another pocket or stream. Partial oxidation reactions occur in fuel-rich portions of the mixture and any remaining unburned fuel and/or intermediate species are consumed in the oxidizer-rich portions. Partial premixing, therefore, represents that condition when the equivalence ratio (phi) in one portion of the flowfield is greater than unity, and in another section its value is less than unity. In general, for combustion to occur efficiently, the global equivalence ratio is in the range fuel-lean to stoichiometric. These flames can be established by design by placing a fuel-rich mixture in contact with a fuel-lean mixture, but they also occur otherwise in many practical systems, which include nonpremixed lifted flames, turbulent nonpremixed combustion, spray flames, and unwanted fires. Other practical applications of PPFs are reported elsewhere. Although extensive experimental studies have been conducted on premixed and nonpremixed flames under microgravity, there is a absence of previous experimental work on burner stabilized PPFs in this regard. Previous numerical studies by our group employing a detailed numerical model showed gravity effects to be significant on the PPF structure. We report on the results of microgravity experiments conducted on two-dimensional (established on a Wolfhard-Parker slot burner) and axisymmetric flames (on a coannular burner) that were investigated in a self-contained multipurpose rig. Thermocouple and radiometer data were also used to characterize the thermal transport in the flame.

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

PubMed Central

Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish K.; Labbe, Sebastien M.; Hurren, Nicholas M.; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal

2014-01-01

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans. PMID:25056438

Flow-combustion interactions in ducted flameholder-stabilized premixed flames

NASA Astrophysics Data System (ADS)

Soteriou, Marios; Arienti, Marco; Erickson, Robert

2006-11-01

Turbulent premixed combustion is present in many power generation and propulsion systems due to its large energy conversion rate (as compared to non-premixed combustion) and its potential for reduced emissions (at the lean limit). As a result, the study of turbulent premixed flames has received substantial attention in the past through experiment, analysis and simulation. In the recent past, unsteady Computational Fluid Dynamics (CFD) based models have been increasingly leveraged towards the in depth study of the physics of turbulent premixed flames. The bulk of this effort focuses on the response of the flame to turbulence. In contrast, we focus on the opposite problem, i.e. the modification of the turbulent flowfield by the flame. This topic has also received some attention but with a strong emphasis on planar (in the mean), flames propagating normal to the flow. Instead, we focus on flameholder-stabilized ducted flames, i.e. ones in which the flame is confined and substantially inclined to the incoming flow. The fundamental mechanisms by which the flame impacts the flow, i.e. dilatation, baroclinic vorticity generation and molecular diffusion enhancement are discussed in detail and their relative impact quantified. Limitations of modeling these mechanisms in current state of the art CFD models are also addressed.

Ingested human insulin inhibits the mosquito NF-¿B-dependent immune response to Plasmodium falciparum

USDA-ARS?s Scientific Manuscript database

We showed previously that ingested human insulin activates the insulin/IGF-1 signaling pathway in Anopheles stephensi and increases the susceptibility of these mosquitoes to Plasmodium falciparum. In other organisms insulin can alter immune responsiveness through regulation of NF-kB transcription fa...

Differentiation of human-induced pluripotent stem cells into insulin-producing clusters.

PubMed

Shaer, Anahita; Azarpira, Negar; Vahdati, Akbar; Karimi, Mohammad Hosein; Shariati, Mehrdad

2015-02-01

In diabetes mellitus type 1, beta cells are mostly destroyed; while in diabetes mellitus type 2, beta cells are reduced by 40% to 60%. We hope that soon, stem cells can be used in diabetes therapy via pancreatic beta cell replacement. Induced pluripotent stem cells are a kind of stem cell taken from an adult somatic cell by "stimulating" certain genes. These induced pluripotent stem cells may be a promising source of cell therapy. This study sought to produce isletlike clusters of insulin-producing cells taken from induced pluripotent stem cells. A human-induced pluripotent stem cell line was induced into isletlike clusters via a 4-step protocol, by adding insulin, transferrin, and selenium (ITS), N2, B27, fibroblast growth factor, and nicotinamide. During differentiation, expression of pancreatic β-cell genes was evaluated by reverse transcriptase-polymerase chain reaction; the morphologic changes of induced pluripotent stem cells toward isletlike clusters were observed by a light microscope. Dithizone staining was used to stain these isletlike clusters. Insulin produced by these clusters was evaluated by radio immunosorbent assay, and the secretion capacity was analyzed with a glucose challenge test. Differentiation was evaluated by analyzing the morphology, dithizone staining, real-time quantitative polymerase chain reaction, and immunocytochemistry. Gene expression of insulin, glucagon, PDX1, NGN3, PAX4, PAX6, NKX6.1, KIR6.2, and GLUT2 were documented by analyzing real-time quantitative polymerase chain reaction. Dithizone-stained cellular clusters were observed after 23 days. The isletlike clusters significantly produced insulin. The isletlike clusters could increase insulin secretion after a glucose challenge test. This work provides a model for studying the differentiation of human-induced pluripotent stem cells to insulin-producing cells.

Glucose metabolism in pigs expressing human genes under an insulin promoter.

PubMed

Wijkstrom, Martin; Bottino, Rita; Iwase, Hayoto; Hara, Hidetaka; Ekser, Burcin; van der Windt, Dirk; Long, Cassandra; Toledo, Frederico G S; Phelps, Carol J; Trucco, Massimo; Cooper, David K C; Ayares, David

2015-01-01

Xenotransplantation of porcine islets can reverse diabetes in non-human primates. The remaining hurdles for clinical application include safe and effective T-cell-directed immunosuppression, but protection against the innate immune system and coagulation dysfunction may be more difficult to achieve. Islet-targeted genetic manipulation of islet-source pigs represents a powerful tool to protect against graft loss. However, whether these genetic alterations would impair islet function is unknown. On a background of α1,3-galactosyltransferase gene-knockout (GTKO)/human (h)CD46, additional genes (hCD39, human tissue factor pathway inhibitor, porcine CTLA4-Ig) were inserted in different combinations under an insulin promoter to promote expression in islets (confirmed by immunofluorescence). Seven pigs were tested for baseline and glucose/arginine-challenged levels of glucose, insulin, C-peptide, and glucagon. This preliminary study did not show definite evidence of β-cell deficiencies, even when three transgenes were expressed under the insulin promoter. Of seven animals, all were normoglycemic at fasting, and five of seven had normal glucose disposal rates after challenge. All animals exhibited insulin, C-peptide, and glucagon responses to both glucose and arginine challenge; however, significant interindividual variation was observed. Multiple islet-targeted transgenic expression was not associated with an overtly detrimental effect on islet function, suggesting that complex genetic constructs designed for islet protection warrants further testing in islet xenotransplantation models. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects.

PubMed

Kang, S; Creagh, F M; Peters, J R; Brange, J; Vølund, A; Owens, D R

1991-07-01

To compare postprandial glucose excursions and plasma free insulin-analogue levels after subcutaneous injection of three novel human insulin analogues (AspB10; AspB9, GluB27; and AspB28) with those after injection of soluble human insulin (Actrapid HM U-100). Six male subjects with insulin-dependent diabetes, at least 1 wk apart and after an overnight fast and basal insulin infusion, received 72 nmol (approximately 12 U) s.c. of soluble human insulin 30 min before, or 72 nmol of each of the three analogues immediately before, a standard 500-kcal meal. Mean basal glucoses were similar on the 4 study days. Compared to human insulin (6.3 +/- 0.8 mM), mean +/- SE peak incremental glucose rises were similar after analogues AspB10 (5.4 +/- 0.8 mM) and AspB9, GluB27 (5.4 +/- 0.7 mM) and significantly lower after analogue AspB28 (3.6 +/- 1.2 mM, P less than 0.02). Relative to soluble human insulin (100% +/- SE21), incremental areas under the glucose curve between 0 and 240 min were 79% +/- 34 (AspB10, NS), 70% +/- 29 (AspB9, GluB27, NS), and 43% +/- 23 (AspB28, P less than 0.02). Basal plasma free insulin levels were similar on the 4 study days. Plasma free insulin-analogue levels rose rapidly to peak 30 min after injection at 308 +/- 44 pM (AspB10); 1231 +/- 190 pM (AspB9, GluB27) and 414 +/- 42 pM (AspB28) and were significantly higher than corresponding (i.e., 30 min postmeal) plasma free insulin levels of 157 +/- 15 pM (P less than 0.02 in each case). Plasma profiles of the insulin analogues were more physiological than that of human insulin after subcutaneous injection. All three analogues given immediately before the meal are at least as effective as soluble human insulin given 30 min earlier. These analogues are promising potential candidates for short-acting insulins of the future.

Glucose responsive insulin production from human embryonic germ (EG) cell derivatives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, Gregory O.; Yochem, Robert L.; Axelman, Joyce

2007-05-11

Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term complications such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and {beta}-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation ofmore » preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivatives may eventually serve as a source of insulin producing cells for the treatment of diabetes.« less

Glucose responsive insulin production from human embryonic germ (EG) cell derivatives.

PubMed

Clark, Gregory O; Yochem, Robert L; Axelman, Joyce; Sheets, Timothy P; Kaczorowski, David J; Shamblott, Michael J

2007-05-11

Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term complications such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and beta-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation of preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivatives may eventually serve as a source of insulin producing cells for the treatment of diabetes.

Insulin Exhibits an Antiproliferative and Hypertrophic Effect in First Trimester Human Extravillous Trophoblasts.

PubMed

Silva, Cláudia; Nunes, Catarina; Correia-Branco, Ana; Araújo, João R; Martel, Fátima

2017-04-01

Our aim was to investigate the effect of high levels of glucose, insulin, leptin, and tumor necrosis factor alpha, biomarkers of diabetes in pregnancy, in the process of placentation, using as a cell model a first trimester extravillous human trophoblast cell line (HTR8/SVneo cells). Exposure of HTR8/SVneo cells for 24 hours to either glucose (20 mmol/L) or leptin (25-100 ng/mL) did not cause significant changes in cell proliferation and viability. Tumor necrosis factor alpha (24 hours; 10-100 ng/L) caused a small decrease (10%) in cell proliferation and an increase (9%) in cell viability; however, both effects disappeared when exposure time was increased. Insulin (24 hours; 1-10 nmol/L) caused a concentration- and time-dependent decrease (10%-20%) in cell proliferation; the effect of insulin (10 nmol/L) was more pronounced after a 48 hours exposure (35%). In contrast, exposure to insulin (10 nmol/L; 48 hours) showed no significant effect on cell viability, apoptosis, and migration capacity. Insulin appears to cause hypertrophy of HTR8/SVneo cells as it reduces the cell mitotic index while increasing the culture protein content. The antiproliferative effect of insulin seems to involve activation of mammalian target of rapamycin, phosphoinositide 3-kinase, and p38 mitogen-activated protein kinase. Finally, simvastatin and the polyphenol quercetin potentiated the antiproliferative effect of insulin; on the contrary, the polyphenol resveratrol, the polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids, and folic acid were not able to change it. In conclusion, we show that insulin has an antiproliferative and hypertrophic effect on a first trimester extravillous human trophoblast cell line. So insulin might affect the process of placentation.

Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion.

PubMed

Mizgier, Maria L; Cataldo, Luis R; Gutierrez, Juan; Santos, José L; Casas, Mariana; Llanos, Paola; Contreras-Ferrat, Ariel E; Moro, Cedric; Bouzakri, Karim; Galgani, Jose E

2017-01-01

Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle) glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines). We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS). In conditioned media from human myotubes incubated with/without insulin (100 nmol/L) for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets ( p < 0.05). Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets.

Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion

PubMed Central

Cataldo, Luis R.; Gutierrez, Juan; Santos, José L.; Casas, Mariana; Contreras-Ferrat, Ariel E.; Moro, Cedric; Bouzakri, Karim

2017-01-01

Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle) glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines). We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS). In conditioned media from human myotubes incubated with/without insulin (100 nmol/L) for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets (p < 0.05). Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets. PMID:28286777

Preparation of lipid nanoemulsions by premix membrane emulsification with disposable materials.

PubMed

Gehrmann, Sandra; Bunjes, Heike

2016-09-25

The possibility to prepare nanoemulsions as drug carrier systems on small scale was investigated with disposable materials. For this purpose premix membrane emulsification (premix ME) as a preparation method for nanoemulsions with narrow particle size distributions on small scale was used. The basic principle of premix ME is that the droplets of a coarse pre-emulsion get disrupted by the extrusion through a porous membrane. In order to implement the common preparation setup for premix ME with disposable materials, the suitability of different syringe filters (made from polyethersulfone, cellulose acetate, cellulose ester and nylon) and different pharmaceutically relevant emulsifiers (phospholipids, polysorbate 80 and sucrose laurate) for the preparation of nanoemulsions was investigated. Already the preparation of the premix could be realized by emulsification with the help of two disposable syringes. As shown for a phospholipid-stabilized emulsion, the polyethersulfone filter was the most appropriate one and was used for the study with different emulsifiers. With this syringe filter, the median particle size of all investigated emulsions was below 500nm after 21 extrusion cycles through a 200nm filter and a subsequent extrusion cycle through a 100nm filter. Furthermore, the particle size distribution of the polysorbate 80- and sucrose laurate-stabilized emulsions prepared this way was very narrow (span value of 0.7). Copyright © 2016 Elsevier B.V. All rights reserved.

Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice.

PubMed

Jansson, L; Eizirik, D L; Pipeleers, D G; Borg, L A; Hellerström, C; Andersson, A

1995-08-01

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.

Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice.

PubMed Central

Jansson, L; Eizirik, D L; Pipeleers, D G; Borg, L A; Hellerström, C; Andersson, A

1995-01-01

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

21 CFR 170.60 - Nitrites and/or nitrates in curing premixes.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Nitrites and/or nitrates in curing premixes. 170... and Decisions § 170.60 Nitrites and/or nitrates in curing premixes. (a) Nitrites and/or nitrates are.... (b) Nitrites and/or nitrates, when packaged separately from flavoring and seasoning in curing...

21 CFR 170.60 - Nitrites and/or nitrates in curing premixes.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Nitrites and/or nitrates in curing premixes. 170... and Decisions § 170.60 Nitrites and/or nitrates in curing premixes. (a) Nitrites and/or nitrates are.... (b) Nitrites and/or nitrates, when packaged separately from flavoring and seasoning in curing...

21 CFR 170.60 - Nitrites and/or nitrates in curing premixes.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Nitrites and/or nitrates in curing premixes. 170... and Decisions § 170.60 Nitrites and/or nitrates in curing premixes. (a) Nitrites and/or nitrates are.... (b) Nitrites and/or nitrates, when packaged separately from flavoring and seasoning in curing...

Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans.

PubMed

Tubbs, Emily; Chanon, Stéphanie; Robert, Maud; Bendridi, Nadia; Bidaux, Gabriel; Chauvin, Marie-Agnès; Ji-Cao, Jingwei; Durand, Christine; Gauvrit-Ramette, Daphné; Vidal, Hubert; Lefai, Etienne; Rieusset, Jennifer

2018-04-01

Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently shown to be involved in the control of hepatic insulin action and glucose homeostasis, but with conflicting results. Whereas skeletal muscle is the primary site of insulin-mediated glucose uptake and the main target for alterations in insulin-resistant states, the relevance of MAM integrity in muscle insulin resistance is unknown. Deciphering the importance of MAMs on muscle insulin signaling could help to clarify this controversy. Here, we show in skeletal muscle of different mice models of obesity and type 2 diabetes (T2D) a marked disruption of ER-mitochondria interactions as an early event preceding mitochondrial dysfunction and insulin resistance. Furthermore, in human myotubes, palmitate-induced insulin resistance is associated with a reduction of structural and functional ER-mitochondria interactions. Importantly, experimental increase of ER-mitochondria contacts in human myotubes prevents palmitate-induced alterations of insulin signaling and action, whereas disruption of MAM integrity alters the action of the hormone. Lastly, we found an association between altered insulin signaling and ER-mitochondria interactions in human myotubes from obese subjects with or without T2D compared with healthy lean subjects. Collectively, our data reveal a new role of MAM integrity in insulin action of skeletal muscle and highlight MAM disruption as an essential subcellular alteration associated with muscle insulin resistance in mice and humans. Therefore, reduced ER-mitochondria coupling could be a common alteration of several insulin-sensitive tissues playing a key role in altered glucose homeostasis in the context of obesity and T2D. © 2018 by the American Diabetes Association.

Premixed Turbulent Flame Propagation in Microgravity

NASA Technical Reports Server (NTRS)

Menon, Suresh

1999-01-01

A combined numerical-experimental study has been carried out to investigate the structure and propagation characteristics of turbulent premixed flames with and without the influence of buoyancy. Experimentally, the premixed flame characteristics are studied in the wrinkled regime using a Couette flow facility and an isotropic flow facility in order to resolve the scale of flame wrinkling. Both facilities were chosen for their ability to achieve sustained turbulence at low Reynolds number. This implies that conventional diagnostics can be employed to resolve the smallest scales of wrinkling. The Couette facility was also built keeping in mind the constraints imposed by the drop tower requirements. Results showed that the flow in this Couette flow facility achieves full-developed turbulence at low Re and all turbulence statistics are in good agreement with past measurements on large-scale facilities. Premixed flame propagation studies were then carried out both using the isotropic box and the Couette facility. Flame imaging showed that fine scales of wrinkling occurs during flame propagation. Both cases in Ig showed significant buoyancy effect. To demonstrate that micro-g can remove this buoyancy effect, a small drop tower was built and drop experiments were conducted using the isotropic box. Results using the Couette facility confirmed the ability to carry out these unique reacting flow experiments at least in 1g. Drop experiments at NASA GRC were planned but were not completed due to termination of this project.

Experimental Investigation of Premixed Turbulent Hydrocarbon/Air Bunsen Flames

NASA Astrophysics Data System (ADS)

Tamadonfar, Parsa

Through the influence of turbulence, the front of a premixed turbulent flame is subjected to the motions of eddies that leads to an increase in the flame surface area, and the term flame wrinkling is commonly used to describe it. If it is assumed that the flame front would continue to burn locally unaffected by the stretch, then the total turbulent burning velocity is expected to increase proportionally to the increase in the flame surface area caused by wrinkling. When the turbulence intensity is high enough such that the stretch due to hydrodynamics and flame curvature would influence the local premixed laminar burning velocity, then the actual laminar burning velocity (that is, flamelet consumption velocity) should reflect the influence of stretch. To address this issue, obtaining the knowledge of instantaneous flame front structures, flame brush characteristics, and burning velocities of premixed turbulent flames is necessary. Two axisymmetric Bunsen-type burners were used to produce premixed turbulent flames, and three optical measurement techniques were utilized: Particle image velocimetry to measure the turbulence statistics; Rayleigh scattering method to measure the temperature fields of premixed turbulent flames, and Mie scattering method to visualize the flame front contours of premixed turbulent flames. Three hydrocarbons (methane, ethane, and propane) were used as the fuel in the experiments. The turbulence was generated using different perforated plates mounted upstream of the burner exit. A series of comprehensive parameters including the thermal flame front thickness, characteristic flame height, mean flame brush thickness, mean volume of the turbulent flame region, two-dimensional flame front curvature, local flame front angle, two-dimensional flame surface density, wrinkled flame surface area, turbulent burning velocity, mean flamelet consumption velocity, mean turbulent flame stretch factor, mean turbulent Markstein length and number, and mean

Roles of circulating WNT-signaling proteins and WNT-inhibitors in human adiposity, insulin resistance, insulin secretion, and inflammation.

PubMed

Almario, R U; Karakas, S E

2015-02-01

Wingless-type MMTV integration site family member (WNT) signaling and WNT-inhibitors have been implicated in regulation of adipogenesis, insulin resistance, pancreatic function, and inflammation. Our goal was to determine serum proteins involved in WNT signaling (WNT5 and WISP2) and WNT inhibition (SFRP4 and SFRP5) as they relate to obesity, serum adipokines, insulin resistance, insulin secretion, and inflammation in humans. Study population comprised 57 insulin resistant women with polycystic ovary syndrome (PCOS) and 27 reference women. In a cross-sectional study, blood samples were obtained at fasting, during oral, and frequently sampled intravenous glucose tolerance tests. Serum WNT5, WISP2, and SFRP4 concentrations did not differ between PCOS vs. reference women. Serum WNT5 correlated inversely with weight both in PCOS and reference women, and correlated directly with insulin response during oral glucose tolerance test in PCOS women. Serum WISP2 correlated directly with fatty acid binding protein 4. Serum SFRP5 did not differ between obese (n=32) vs. nonobese (n=25) PCOS women, but reference women had lower SFRP5 (p<5×10(-6) as compared to both PCOS groups). Serum SFRP5 correlated inversely with IL-1β, TNF-α, cholesterol, and apoprotein B. These findings demonstrated that WNT5 correlated inversely with adiposity and directly with insulin response, and the WNT-inhibitor SFRP5 may be anti-inflammatory. Better understanding of the role of WNT signaling in obesity, insulin resistance, insulin secretion, lipoprotein metabolism, and inflammation is important for prevention and treatment of metabolic syndrome, diabetes and cardiovascular disease. © Georg Thieme Verlag KG Stuttgart · New York.

Ancestral genomic duplication of the insulin gene in tilapia: An analysis of possible implications for clinical islet xenotransplantation using donor islets from transgenic tilapia expressing a humanized insulin gene.

PubMed

Hrytsenko, Olga; Pohajdak, Bill; Wright, James R

2016-07-03

Tilapia, a teleost fish, have multiple large anatomically discrete islets which are easy to harvest, and when transplanted into diabetic murine recipients, provide normoglycemia and mammalian-like glucose tolerance profiles. Tilapia insulin differs structurally from human insulin which could preclude their use as islet donors for xenotransplantation. Therefore, we produced transgenic tilapia with islets expressing a humanized insulin gene. It is now known that fish genomes may possess an ancestral duplication and so tilapia may have a second insulin gene. Therefore, we cloned, sequenced, and characterized the tilapia insulin 2 transcript and found that its expression is negligible in islets, is not islet-specific, and would not likely need to be silenced in our transgenic fish.

Ancestral genomic duplication of the insulin gene in tilapia: An analysis of possible implications for clinical islet xenotransplantation using donor islets from transgenic tilapia expressing a humanized insulin gene

PubMed Central

Hrytsenko, Olga; Pohajdak, Bill; Wright, James R.

2016-01-01

ABSTRACT Tilapia, a teleost fish, have multiple large anatomically discrete islets which are easy to harvest, and when transplanted into diabetic murine recipients, provide normoglycemia and mammalian-like glucose tolerance profiles. Tilapia insulin differs structurally from human insulin which could preclude their use as islet donors for xenotransplantation. Therefore, we produced transgenic tilapia with islets expressing a humanized insulin gene. It is now known that fish genomes may possess an ancestral duplication and so tilapia may have a second insulin gene. Therefore, we cloned, sequenced, and characterized the tilapia insulin 2 transcript and found that its expression is negligible in islets, is not islet-specific, and would not likely need to be silenced in our transgenic fish. PMID:27222321

A Human Anti-Insulin IgG Autoantibody Apparently Arises Through Clonal Selection from an Insulin-Specific “Germ-Line” Natural Antibody Template

PubMed Central

Ichiyoshi, Yuji; Zhou, Min; Casali, Paolo

2015-01-01

We analyzed the structural correlates underlying the insulin-dependent selection of the specific anti-insulin IgG1 κ mAb13-producing cell clone, derived from a patient with insulin-dependent diabetes mellitus treated with recombinant human insulin. First, we cloned the germ-line genes that putatively gave rise to the expressed VH and Vκ segments and used them to generate the full (unmutated) “germ-line revertant” of the “wild-type” (somatically mutated) mAb13, using recombinant PCR methods and an in vitro human Cγ1 and Cκ expression system. The full “germ-line revertant” bound insulin specifically and in a dose-saturable fashion, but with a relative avidity (Avrel) more than three-fold lower than that of its wild-type counterpart (Avrel, 1.69 × 10−8 vs 4.91 × 10−9 g/μl). Second, we established, by reassorting wild-type and germ-line revertant forms of the mAb13 VH and Vκ segments, that the increased Avrel for insulin of mAb13 when compared with its full “germ-line revertant” counterpart was entirely dependent on the mutations in the VH not those in the Vκ chain. Third, we determined, by site-directed mutagenesis experiments, that of the three mutations in the mAb13 VH segment (Ser→Gly, Ser→Thr, and Ser→Arg at positions 31, 56, and 58, respectively), only Arg58 was crucial in increasing the mAb13 Avrel (from 1.44 × 10−8 to 5.14 × 10−9 g/μl) and affinity (Kd, from 189 to 59 nM) for insulin. The affinity enhancement mediated by the VH segment Arg58 residue reflected about a threefold decrease in dissociation rate constant (Koff, from 4.92 × 10−3 to 1.54 × 10−3 s−1)but not an increase in association rate constant (Kon, from 2.60 × 104 to 2.61 × 104 M−1 s−1), and it contrasted with the complete loss of insulin binding resulting from the substitution of the VH segment Asn52 by Lys. The present findings suggest that human insulin, a self Ag, has the potential to recruit a natural autoantibody-producing cell precursor

Differences in glucose-stimulated insulin secretion in vitro of islets from human, nonhuman primate and porcine origin

PubMed Central

Mueller, Kate R; Balamurugan, A.N.; Cline, Gary W; Pongratz, Rebecca L; Hooper, Rebecca L; Weegman, Bradley P; Kitzmann, Jennifer P; Taylor, Michael J; Graham, Melanie L; Schuurman, Henk-Jan; Papas, Klearchos K

2014-01-01

Background Porcine islet xenotransplantation is considered a potential cell-based therapy for type 1 diabetes. It is currently being evaluated in diabetic nonhuman primates (NHP) to assess safety and efficacy of the islet product. However, due to a variety of distinct differences between the respective species, including the insulin secretory characteristics of islets, the suitability and predictive value of the preclinical model in the extrapolation to the clinical setting remains a critical issue. Methods Islets isolated from human (n=3), NHP (n=2), adult pig (AP, n=3) and juvenile pig (JP, n=3) pancreata were perifused with medium at basal glucose (2.5mM) followed by high glucose (16.7mM) concentrations. The total glucose-stimulated insulin secretion (GSIS) was calculated from generated insulin secretion profiles. Results NHP islets exhibited GSIS 3-fold higher than human islets, while AP and JP islets exhibited GSIS 1/3 and 1/16 of human islets, respectively. The insulin content of NHP and AP islets was similar to that of human islets, whereas that of JP islets was 1/3 of human islets. Conclusion Despite the fact that human, NHP, and AP islets contain similar amounts of insulin, the much higher GSIS for NHP islets than for human, AP and JP islets suggests the need for increased dosing of islets from JP and AP in pig-to-NHP transplantation which may be substantially higher than that required for humans. Finally, porcine islet xenotransplantation to humans may require significantly higher dosing given the lower GSIS of AP islets compared to human islets. PMID:23384163

Generation of high-yield insulin producing cells from human bone marrow mesenchymal stem cells.

PubMed

Jafarian, Arefeh; Taghikhani, Mohammad; Abroun, Saeid; Pourpak, Zahra; Allahverdi, Amir; Soleimani, Masoud

2014-07-01

Allogenic islet transplantation is a most efficient approach for treatment of diabetes mellitus. However, the scarcity of islets and long term need for an immunosuppressant limits its application. Recently, cell replacement therapies that generate of unlimited sources of β cells have been developed to overcome these limitations. In this study we have described a stage specific differentiation protocol for the generation of insulin producing islet-like clusters from human bone marrow mesenchymal stem cells (hBM-MSCs). This specific stepwise protocol induced differentiation of hMSCs into definitive endoderm, pancreatic endoderm and pancreatic endocrine cells that expressed of sox17, foxa2, pdx1, ngn3, nkx2.2, insulin, glucagon, somatostatin, pancreatic polypeptide, and glut2 transcripts respectively. In addition, immunocytochemical analysis confirmed protein expression of the above mentioned genes. Western blot analysis discriminated insulin from proinsulin in the final differentiated cells. In derived insulin producing cells (IPCs), secreted insulin and C-peptide was in a glucose dependent manner. We have developed a protocol that generates effective high-yield human IPCs from hBM-MSCs in vitro. These finding suggest that functional IPCs generated by this procedure can be used as a cell-based approach for insulin dependent diabetes mellitus.

Characterization of the growth of murine fibroblasts that express human insulin receptors. II. Interaction of insulin with other growth factors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Randazzo, P.A.; Jarett, L.

1990-09-01

The effects of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin on DNA synthesis were studied in murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental NIH 3T3 cells. In NIH 3T3/HIR cells, individual growth factors in serum-free medium stimulated DNA synthesis with the following relative efficacies: insulin greater than or equal to 10% fetal calf serum greater than PDGF greater than IGF-1 much greater than EGF. In comparison, the relative efficacies of these factors in stimulating DNA synthesis by NIH 3T3 cells were 10% fetalmore » calf serum greater than PDGF greater than EGF much greater than IGF-1 = insulin. In NIH 3T3/HIR cells, EGF was synergistic with 1-10 ng/ml insulin but not with 100 ng/ml insulin or more. Synergy of PDGF or IGF-1 with insulin was not detected. In the parental NIH 3T3 cells, insulin and IGF-1 were found to be synergistic with EGF (1 ng/ml), PDGF (100 ng/ml), and PDGF plus EGF. In NIH 3T3/HIR cells, the lack of interaction of insulin with other growth factors was also observed when the percentage of cells synthesizing DNA was examined. Despite insulin's inducing only 60% of NIH 3T3/HIR cells to incorporate thymidine, addition of PDGF, EGF, or PDGF plus EGF had no further effect. In contrast, combinations of growth factors resulted in 95% of the parental NIH 3T3 cells synthesizing DNA. The independence of insulin-stimulated DNA synthesis from other mitogens in the NIH 3T3/HIR cells is atypical for progression factor-stimulated DNA synthesis and is thought to be partly the result of insulin receptor expression in an inappropriate context or quantity.« less

Premixed calcium silicate cement for endodontic applications

PubMed Central

Persson, Cecilia; Engqvist, Håkan

2011-01-01

Calcium silicate-based materials (also called MTA) are increasingly being used in endodontic applications. However, the handling properties of MTA are not optimal when it comes to injectability and cohesion. Premixing the cements using glycerol avoids these issues. However, there is a lack of data on the effect of common cement variables on important properties of premixed cements for endodontic applications. In this study, the effects of liquid-to-powder ratio, amount of radiopacifier and amount of calcium sulfate (added to control the setting time) were screened using a statistical model. In the second part of the study, the liquid-to-powder ratio was optimized for cements containing three different amounts of radiopacifier. Finally, the effect of using glycerol rather than water was evaluated in terms of radiopacity. The setting time was found to increase with the amount of radiopacifier when the liquid-to-powder ratio was fixed. This was likely due to the higher density of the radiopacifier in comparison to the calcium silicate, which gave a higher liquid-to-powder ratio in terms of volume. Using glycerol rather than water to mix the cements led to a decrease in radiopacity of the cement. In conclusion, we were able to produce premixed calcium silicate cements with acceptable properties for use in endodontic applications. PMID:23507729

Destabilization of Human Insulin Fibrils by Peptides of Fruit Bromelain Derived From Ananas comosus (Pineapple).

PubMed

Das, Sromona; Bhattacharyya, Debasish

2017-12-01

Deposition of insulin aggregates in human body leads to dysfunctioning of several organs. Effectiveness of fruit bromelain from pineapple in prevention of insulin aggregate was investigated. Proteolyses of bromelain was done as par human digestive system and the pool of small peptides was separated from larger peptides and proteins. Under conditions of growth of insulin aggregates from its monomers, this pool of peptides restricted the reaction upto formation of oligomers of limited size. These peptides also destabilized preformed insulin aggregates to oligomers. These processes were followed fluorimetrically using Thioflavin T and 1-ANS, size-exclusion HPLC, dynamic light scattering, atomic force microscopy, and transmission electron microscopy. Sequences of insulin (A and B chains) and bromelain were aligned using Clustal W software to predict most probable sites of interactions. Synthetic tripeptides corresponding to the hydrophobic interactive sites of bromelain showed disaggregation of insulin suggesting specificity of interactions. The peptides GG and AAA serving as negative controls showed no potency in destabilization of aggregates. Disaggregation potency of the peptides was also observed when insulin was deposited on HepG2 liver cells where no formation of toxic oligomers occurred. Amyloidogenic des-octapeptide (B23-B30 of insulin) incapable of cell signaling showed cytotoxicity similar to insulin. This toxicity could be neutralized by bromelain derived peptides. FT-IR and far-UV circular dichroism analysis indicated that disaggregated insulin had structure distinctly different from that of its hexameric (native) or monomeric states. Based on the stoichiometry of interaction and irreversibility of disaggregation, the mechanism/s of the peptides and insulin interactions has been proposed. J. Cell. Biochem. 118: 4881-4896, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Challenges constraining insulin access in Nepal-a country with no local insulin production.

PubMed

Sharma, Abhishek; Bhandari, Parash Mani; Neupane, Dipika; Kaplan, Warren A; Mishra, Shiva Raj

2018-05-01

Nepal is facing an increasing burden of diabetes and relies almost entirely on insulin imported through India. We employed a modified version of the WHO/Health Action International standard survey to assess insulin availability and prices, along with qualitative interviews with insulin retailers (pharmacists) and wholesalers in the Kathmandu Valley, Nepal. The mean availability of the two human insulins listed on the 2011 Nepal Essential Medicine List were 14.3% and 42.85% in the surveyed private- and public-sector pharmacies, respectively, compared with the WHO target of 80% availability. The median consumer price of human insulin cartridges, analogue insulin cartridges and pens was, respectively, 2.1, 4.6 and 5.3 times that of human insulin vials (US$5.54). The insulin cartridges made in India were less expensive (p<0.001) than those made elsewhere. The lowest-paid worker would need to spend between 3 and 17 days' wages to purchase a monthly insulin supply out of pocket. Insulin access is limited in Kathmandu owing to low availability and the highly unaffordable price. Insulin access could improve with the government exploring additional suppliers, pooling insulin tenders, auditing insulin utilization and developing independent prescribing guidelines. Furthermore, there is a need to educate physicians and develop a consensus statement on insulin initiation to curb the growing analogue use and promote rational use.

Premixed calcium phosphate cements: synthesis, physical properties, and cell cytotoxicity.

PubMed

Xu, Hockin H K; Carey, Lisa E; Simon, Carl G; Takagi, Shozo; Chow, Laurence C

2007-04-01

Calcium phosphate cement (CPC) is a promising material for dental, periodontal, and craniofacial repairs. However, its use requires on-site powder-liquid mixing that increases the surgical placement time and raises concerns of insufficient and inhomogeneous mixing. The objective of this study was to determine a formulation of premixed CPC (PCPC) with rapid setting, high strength, and good in vitro cell viability. PCPCs were formulated from CPC powder+non-aqueous liquid+gelling agent+hardening accelerator. Five PCPCs were thus developed: PCPC-Tartaric, PCPC-Malonic, PCPC-Citric, PCPC-Glycolic, and PCPC-Malic. Formulations and controls were compared for setting time, diametral tensile strength, and osteoblast cell compatibility. Setting time (mean+/-S.D.; n=4) for PCPC-Tartaric was 8.2+/-0.8 min, significantly less than the 61.7+/-1.5 min for the Premixed Control developed previously (p<0.001). On 7th day immersion, the diametral tensile strength of PCPC-Tartaric reached 6.5+/-0.8 MPa, higher than 4.5+/-0.8 MPa of Premixed Control (p=0.036). Osteoblast cells displayed a polygonal morphology and attached to the nano-hydroxyapatite crystals in the PCPCs. All cements had similar live cell density values (p=0.126), indicating that the new PCPCs were as cell compatible as a non-premixed CPC control known to be biocompatible. Each of the new PCPCs had a cell viability that was not significantly different (p>0.1) from that of the non-premixed CPC control. PCPCs will eliminate the powder-liquid mixing during surgery and may also improve the cement performance. The new PCPCs supported cell attachment and yielded a high cell density and viability. Their mechanical strengths approached the reported strengths of sintered porous hydroxyapatite implants and cancellous bone. These nano-crystalline hydroxyapatite cements may be useful in dental, periodontal, and craniofacial repairs.

Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation

PubMed Central

Fritzen, Andreas M.; Madsen, Agnete B.; Kleinert, Maximilian; Treebak, Jonas T.; Lundsgaard, Anne‐Marie; Jensen, Thomas E.; Richter, Erik A.; Wojtaszewski, Jørgen; Kiens, Bente

2016-01-01

Key points Regulation of autophagy in human muscle in many aspects differs from the majority of previous reports based on studies in cell systems and rodent muscle.An acute bout of exercise and insulin stimulation reduce human muscle autophagosome content.An acute bout of exercise regulates autophagy by a local contraction‐induced mechanism.Exercise training increases the capacity for formation of autophagosomes in human muscle.AMPK activation during exercise seems insufficient to regulate autophagosome content in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagy‐inhibiting effect of insulin. Abstract Studies in rodent muscle suggest that autophagy is regulated by acute exercise, exercise training and insulin stimulation. However, little is known about the regulation of autophagy in human skeletal muscle. Here we investigate the autophagic response to acute one‐legged exercise, one‐legged exercise training and subsequent insulin stimulation in exercised and non‐exercised human muscle. Acute one‐legged exercise decreased (P<0.01) lipidation of microtubule‐associated protein 1A/1B‐light chain 3 (LC3) (∼50%) and the LC3‐II/LC3‐I ratio (∼60%) indicating that content of autophagosomes decreases with exercise in human muscle. The decrease in LC3‐II/LC3‐I ratio did not correlate with activation of 5′AMP activated protein kinase (AMPK) trimer complexes in human muscle. Consistently, pharmacological AMPK activation with 5‐aminoimidazole‐4‐carboxamide riboside (AICAR) in mouse muscle did not affect the LC3‐II/LC3‐I ratio. Four hours after exercise, insulin further reduced (P<0.01) the LC3‐II/LC3‐I ratio (∼80%) in muscle of the exercised and non‐exercised leg in humans. This coincided with increased Ser‐757 phosphorylation of Unc51 like kinase 1 (ULK1), which is suggested as a mammalian target of rapamycin complex 1 (mTORC1) target. Accordingly, inhibition of mTOR signalling in mouse muscle prevented the

Association of hypoglycaemia severity with clinical, patient‐reported and economic outcomes in US patients with type 2 diabetes using basal insulin

PubMed Central

Lee, Lulu K.; Gupta, Shaloo; Preblick, Ron

2018-01-01

Aims To evaluate the clinical and patient‐reported outcomes and healthcare utilization and costs associated with patient‐reported hypoglycaemia in US adults with type 2 diabetes (T2D) treated with basal insulin. Materials and methods This was an observational, cross‐sectional, survey‐based study of adults with T2D on basal insulin ± oral antidiabetes drugs (OADs) or rapid‐acting/premixed insulin, who had in the past ever experienced hypoglycaemia, using US data from the National Health and Wellness Survey. Eligible patients were categorized as having no hypoglycaemia (38.7%), non‐severe hypoglycaemia (55.1%), or severe hypoglycaemia (6.2%) in the preceding 3 months. Outcomes included health‐related quality of life (HRQoL), work productivity and activity impairment, healthcare resource utilization, and estimated direct and indirect costs. Multivariable regression models were performed to control for patient characteristics. Results Patients who experienced severe hypoglycaemia had significantly (P < .05) lower HRQoL scores, greater overall impairment of work productivity and activity, greater healthcare resource utilization, and higher costs compared with those who experienced non‐severe or no hypoglycaemia. Patients with non‐severe hypoglycaemia also reported an impact on the number of provider visits, indirect costs, and HRQoL. Conclusions Patients with T2D using basal insulin ± OADs or rapid‐acting/premixed insulin in the United States who experienced severe hypoglycaemia had greater impairment of activity and work productivity, utilized more healthcare resources, and incurred higher associated costs than those with non‐severe or no hypoglycaemia. The study also demonstrated the impact that non‐severe hypoglycaemic events have on economic and HRQoL outcomes. Reducing the incidence and severity of hypoglycaemia could lead to clinically meaningful improvements in HRQoL and may result in lower healthcare utilization and associated costs

Spectral kinetic energy transfer in turbulent premixed reacting flows.

PubMed

Towery, C A Z; Poludnenko, A Y; Urzay, J; O'Brien, J; Ihme, M; Hamlington, P E

2016-05-01

Spectral kinetic energy transfer by advective processes in turbulent premixed reacting flows is examined using data from a direct numerical simulation of a statistically planar turbulent premixed flame. Two-dimensional turbulence kinetic-energy spectra conditioned on the planar-averaged reactant mass fraction are computed through the flame brush and variations in the spectra are connected to terms in the spectral kinetic energy transport equation. Conditional kinetic energy spectra show that turbulent small-scale motions are suppressed in the burnt combustion products, while the energy content of the mean flow increases. An analysis of spectral kinetic energy transfer further indicates that, contrary to the net down-scale transfer of energy found in the unburnt reactants, advective processes transfer energy from small to large scales in the flame brush close to the products. Triadic interactions calculated through the flame brush show that this net up-scale transfer of energy occurs primarily at spatial scales near the laminar flame thermal width. The present results thus indicate that advective processes in premixed reacting flows contribute to energy backscatter near the scale of the flame.

Three-Dimensional Direct Numerical Simulation of Methane-Air Turbulent Premixed Flames with Reduced Kinetic Mechanism

NASA Astrophysics Data System (ADS)

Tanahashi, Mamoru; Kikuta, Satoshi; Miyauchi, Toshio

2004-11-01

Three-dimensional DNS of methane-air turbulent premixed flames have been conducted to investigate local extinction mechanism of turbulent premixed flames. A reduced kinetic mechanism (MeCH-19), which is created from GRI-Mech. 2.11 and includes 23 reactive species and 19 step reactions, are used to simulate CH_4-O_2-N2 reaction in turbulence. The effectiveness of this reduced kinetic mechanism has been conformed by preliminary two-dimensional DNS with the reduced kinetic mechanism and two detailed kinetic mechanisms; GRI-Mech. 2.11 and Miller & Bowman. Flame structures of methane-air turbulent premixed flames are compared with those of hydrogen-air turbulent premixed flames which have been obtained by 3D-DNS with a detailed kinetic mechanism in our previous study. Local extinctions occur in methane-air turbulent premixed flames, whereas no extinction is observed for hydrogen-air flames in nearly same turbulence condition. The local extinction mechanism is discussed based on eddy/flame interaction in small scales.

Insulin regimens and glycemic control in different parts of Europe over 4years after starting insulin in people with type 2 diabetes: Data from the CREDIT non-interventional study.

PubMed

Blonde, Lawrence; Marre, Michel; Vincent, Maya; Brette, Sandrine; Pilorget, Valerie; Danchin, Nicholas; Vespasiani, Giacomo; Home, Philip

2017-11-01

A number of insulin regimens are used in type 2 diabetes. This analysis aims to better understand the evolution of insulin therapy in different regions of Europe. Data from people starting any insulin were collected in eastern Europe (EEur: Croatia, Russia, Ukraine), northern Europe (NEur: Finland, Germany, UK) and southern Europe (SEur: France, Italy, Portugal, Spain). Retrospective data on starting insulin and prospective follow-up data were extracted from clinical records. At 4years, 1699 (76.0%) of 2236 eligible people had data. EEur participants were mostly female, younger and had shorter diabetes duration on starting insulin, yet had highest baseline HbA1c and more micro-/macrovascular disease. A majority (60%-64%) in all regions started on basal insulin alone, declining to 30%-38% at 4years, with most switching to basal+mealtime insulin regimen (24%-40%). Higher baseline (28%) and 4-year use (34%) of premix insulin was observed in NEur. Change in HbA1c (SD) ranged from -1.2 (2.1)% (-13 [23]mmol/mol) in NEur to -2.4 (2.0)% (-26 [22]mmol/mol) in EEur. Weight change ranged from +1.9 (8.3) kg in NEur to +3.2 (7.0) kg in SEur. Overall documented hypoglycemia ranged from 0.3 (1.3) to 1.3 (4.4) events/person/6-months (NEur vs. EEur, respectively) and was stable with time. Severe hypoglycemia rates remained low. When starting insulin, HbA1c and prevalence of complications were higher in EEur. Regional differences exist in choice of insulin regimens in Europe. However, people starting insulin improved and sustained their glycemic control regardless of regional differences or insulin regimens used. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

The Effects of Insulin Resistance on Individual Tissues: An Application of a Mathematical Model of Metabolism in Humans.

PubMed

Pearson, Taliesin; Wattis, Jonathan A D; King, John R; MacDonald, Ian A; Mazzatti, Dawn J

2016-06-01

Whilst the human body expends energy constantly, the human diet consists of a mix of carbohydrates and fats delivered in a discontinuous manner. To deal with this sporadic supply of energy, there are transport, storage and utilisation mechanisms, for both carbohydrates and fats, around all tissues of the body. Insulin-resistant states such as type 2 diabetes and obesity are characterised by reduced efficiency of these mechanisms. Exactly how these insulin-resistant states develop, for example whether there is an order in which tissues become insulin resistant, is an active area of research with the hope of gaining a better overall understanding of insulin resistance. In this paper, we use a previously derived system of 12 first-order coupled differential equations that describe the transport between, and storage in, different tissues of the human body. We briefly revisit the derivation of the model before parametrising the model to account for insulin resistance. We then solve the model numerically, separately simulating each individual tissue as insulin resistant, and discuss and compare these results, drawing three main conclusions. The implications of these results are in accordance with biological intuition. First, insulin resistance in a tissue creates a knock-on effect on the other tissues in the body, whereby they attempt to compensate for the reduced efficiency of the insulin-resistant tissue. Second, insulin resistance causes a fatty liver, and the insulin resistance of tissues other than the liver can cause fat to accumulate in the liver. Finally, although insulin resistance in individual tissues can cause slightly reduced skeletal muscle metabolic flexibility, it is when the whole body is insulin resistant that the biggest effect on skeletal muscle flexibility is seen.

Effects of insulin detemir and NPH insulin on body weight and appetite-regulating brain regions in human type 1 diabetes: a randomized controlled trial.

PubMed

van Golen, Larissa W; Veltman, Dick J; IJzerman, Richard G; Deijen, Jan Berend; Heijboer, Annemieke C; Barkhof, Frederik; Drent, Madeleine L; Diamant, Michaela

2014-01-01

Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli. ClinicalTrials.gov NCT00626080.

Statistics of premixed flame cells

NASA Technical Reports Server (NTRS)

Noever, David A.

1991-01-01

The statistics of random cellular patterns in premixed flames are analyzed. Agreement is found with a variety of topological relations previously found for other networks, namely, Lewis's law and Aboav's law. Despite the diverse underlying physics, flame cells are shown to share a broad class of geometric properties with other random networks-metal grains, soap foams, bioconvection, and Langmuir monolayers.

Combustion-acoustic stability analysis for premixed gas turbine combustors

NASA Technical Reports Server (NTRS)

Darling, Douglas; Radhakrishnan, Krishnan; Oyediran, Ayo; Cowan, Lizabeth

1995-01-01

Lean, prevaporized, premixed combustors are susceptible to combustion-acoustic instabilities. A model was developed to predict eigenvalues of axial modes for combustion-acoustic interactions in a premixed combustor. This work extends previous work by including variable area and detailed chemical kinetics mechanisms, using the code LSENS. Thus the acoustic equations could be integrated through the flame zone. Linear perturbations were made of the continuity, momentum, energy, chemical species, and state equations. The qualitative accuracy of our approach was checked by examining its predictions for various unsteady heat release rate models. Perturbations in fuel flow rate are currently being added to the model.

The Investigation of ADAMTS16 in Insulin-Induced Human Chondrosarcoma Cells.

PubMed

Cakmak, Ozlem; Comertoglu, Ismail; Firat, Ridvan; Erdemli, Haci Kemal; Kursunlu, S Fatih; Akyol, Sumeyya; Ugurcu, Veli; Altuntas, Aynur; Adam, Bahattin; Demircan, Kadir

2015-08-01

A disintegrin-like metalloproteinase with thrombospondin motifs (ADAMTS) is a group of proteins that have enzymatic activity secreted by cells to the outside extracellular matrix. Insulin induces proteoglycan biosynthesis in chondrosarcoma chondrocytes. The purpose of the present in vitro study is to assess the time course effects of insulin on ADAMTS16 expression in OUMS-27 (human chondrosarcoma) cell line to examine whether insulin regulates ADAMTS16 expression as well as proteoglycan biosynthesis with multifaceted properties or not. Chondrosarcoma cells were cultured in Dulbecco's modified Eagle's medium having either 10 μg/mL insulin or not. While the experiment was going on, the medium containing insulin had been changed every other day. Cells were harvested at 1st, 3rd, 7th, and 11th days; subsequently, RNA and proteins were isolated in every experimental group according to their time interval. RNA expression of ADAMTS was estimated by quantitative real-time polymerase chain reaction (qRT-PCR) by using primers. Immunoreactive protein levels were encountered by the western blot protein detection technique by using proper anti-ADAMTS16 antibodies. ADAMTS16 mRNA expression level of chondrosarcoma cells was found to be insignificantly decreased in chondrosarcoma cells induced by insulin detected by the qRT-PCR instrument. On the other hand, there was a gradual decrease in immune-reactant ADAMTS16 protein amount by the time course in insulin-treated cell groups when compared with control cells. It has been suggested that insulin might possibly regulate ADAMTS16 levels/activities in OUMS-27 chondrosarcoma cells taking a role in extracellular matrix turnover.

Theoretical and experimental investigation of turbulent premixed flames

NASA Astrophysics Data System (ADS)

Azzazy, M. T. F.

1982-11-01

A model is proposed to describe the propagation of a plane oblique flame into a turbulent flow of premixed reactants. The model incorporates a transport equation for the single or joint PDF's of passive scalers, in addition to the conservation equations of mass, momentum, energy and K.E. of turbulence. In the first phase of developing the model, the reaction mechanism was treated as a single step irreversible exothermic reaction. In this case, the PDF of the progress variable was parameterized and solved with the conservation equations. The second phase considered a two step reaction mechanism in an attempt to explore the role played by the radicals in the propagation of turbulent premixed flames. For both the two phases, the flame speed and angle are eigenvalues of the solution. Laser induced fluorescence spectroscopy (LIFS) was used to measure the PDF of OH concentration in a laboratory scale burner simulating the flame studied by the model. The premixed methane-air flame is stabilized on a rod flame holder downstream of a turbulence producing grid. The experimentally observed PDF's of the hydroxil radical concentration, and the statistical moments, used to describe and compare the PDF's and moments of the two reaction model.

The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro.

PubMed

Pingitore, Attilio; Chambers, Edward S; Hill, Thomas; Maldonado, Inmaculada Ruz; Liu, Bo; Bewick, Gavin; Morrison, Douglas J; Preston, Tom; Wallis, Gareth A; Tedford, Catriona; Castañera González, Ramón; Huang, Guo C; Choudhary, Pratik; Frost, Gary; Persaud, Shanta J

2017-02-01

Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on β-cell function in humans and the direct effects of propionate on isolated human islets in vitro. For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon. Acute insulin, GLP-1 and non-esterified fatty acid (NEFA) levels were quantified pre- and post-supplementation in response to a mixed meal test. Expression of the SCFA receptor FFAR2 in human islets was determined by western blotting and immunohistochemistry. Dynamic insulin secretion from perifused human islets was quantified by radioimmunoassay and islet apoptosis was determined by quantification of caspase 3/7 activities. Colonic propionate delivery in vivo was associated with improved β-cell function with increased insulin secretion that was independent of changes in GLP-1 levels. Human islet β-cells expressed FFAR2 and propionate potentiated dynamic glucose-stimulated insulin secretion in vitro, an effect that was dependent on signalling via protein kinase C. Propionate also protected human islets from apoptosis induced by the NEFA sodium palmitate and inflammatory cytokines. Our results indicate that propionate has beneficial effects on β-cell function in vivo, and in vitro analyses demonstrated that it has direct effects to potentiate glucose-stimulated insulin release and maintain β-cell mass through inhibition of apoptosis. These observations support ingestion of propiogenic dietary fibres to maintain healthy glucose homeostasis. © 2016 John Wiley & Sons Ltd.

Comparison Between Premixed and Compounded Parenteral Nutrition Solutions in Hospitalized Patients Requiring Parenteral Nutrition.

PubMed

Beattie, Colleen; Allard, Johane; Raman, Maitreyi

2016-04-01

Parenteral nutrition (PN) may be provided through compounded or premixed solutions. To determine the proportion of stable custom-compounded PN prescriptions that would fit within a 20% deviance of an existing premixed PN solution. A retrospective study design was used. Inpatients who received PN in non-critical care units in the preceding year were screened for eligibility. Results are reported descriptively as means (95% confidence intervals) and proportions. We reviewed 97 PN prescriptions that met inclusion criteria. Stable hospital PN prescriptions compared with the reference premixed prescription provided 1838 (1777-1898) vs 1843 (1781-1905) kcal/d, P = .43; dextrose, 266 (254-277) vs 225 (216-234) g/d, P < .001; amino acids, 100 (95.9-104) vs 95.2 (91.7-98.7) g/d, P < .001; and lipids, 53.2 (51.3-55.1) vs 76.5 (73.8-79.2) g/d, P < .001. Fifty-eight of 97 (59.8%) matched for 2 of 3 macronutrients. Hospital compared with premixed lipid was lower 53.6 (43-64.2) g/d vs 75.5 (60.5-90.5) g/d, P < .001. Electrolytes differed between hospital and premixed solutions: sodium, 98.6 (95.0-102) vs 66.9 (64.6-69.9) mmol/L, P < .001; potassium, 93.7 (89.0-98.3) vs 57.4 (55.4-59.4) mmol/L, P < .001; and magnesium, 5.4 (4.8-5.4) vs 7.6 (7.4-7.9) mmol/L. Calories and protein were remarkably similar, but dextrose, lipid, and electrolytes differed between hospital PN and the reference premixed prescription. We believe that there may be a role for premixed solutions in quaternary centers in stable non-critically ill patients. © 2016 American Society for Parenteral and Enteral Nutrition.

Enzymatic amplification of a flow-injected thermometric enzyme-linked immunoassay for human insulin.

PubMed

Mecklenburg, M; Lindbladh, C; Li, H; Mosbach, K; Danielsson, B

1993-08-01

A flow-injected thermometric enzyme linked immunoassay for human insulin which employs the lactate dehydrogenase/lactate oxidase (LDH/LOD) substrate recycling system for signal amplification is described. The system is composed of two columns, an immunosorbent column containing immobilized anti-insulin antibodies for sensing and a recycling column containing immobilized LDH/LOD/Catalase for detection. The effect of flow rates, conjugate concentrations, and chromatographic support material upon the sensitivity of the assay are investigated. The assay has a detection limit of 0.025 microgram/ml and a linear range from 0.05 to 2 micrograms/ml. This corresponds to a 10-fold increase in sensitivity over the unamplified system. A recombinant human insulin-proinsulin conjugate was also tested. The results show that enzymatic amplification can be employed to increase the sensitivity and reproducibility of flow injection assay-based biosensors. The implications of these results upon on-line analysis are discussed.

Differences in glucose-stimulated insulin secretion in vitro of islets from human, nonhuman primate, and porcine origin.

PubMed

Mueller, Kate R; Balamurugan, A N; Cline, Gary W; Pongratz, Rebecca L; Hooper, Rebecca L; Weegman, Bradley P; Kitzmann, Jennifer P; Taylor, Michael J; Graham, Melanie L; Schuurman, Henk-Jan; Papas, Klearchos K

2013-01-01

Porcine islet xenotransplantation is considered a potential cell-based therapy for type 1 diabetes. It is currently being evaluated in diabetic nonhuman primates (NHP) to assess safety and efficacy of the islet product. However, due to a variety of distinct differences between the respective species, including the insulin secretory characteristics of islets, the suitability and predictive value of the preclinical model in the extrapolation to the clinical setting remain a critical issue. Islets isolated from human (n = 3), NHP (n = 2), adult pig (AP, n = 3), and juvenile pig (JP, n = 4) pancreata were perifused with medium at basal glucose (2.5 mm) followed by high glucose (16.7 mm) concentrations. The total glucose-stimulated insulin secretion (GSIS) was calculated from generated insulin secretion profiles. Nonhuman primate islets exhibited GSIS 3-fold higher than AP islets, while AP and JP islets exhibited GSIS 1/3 and 1/30 of human islets, respectively. The insulin content of NHP and AP islets was similar to that of human islets, whereas that of JP islets was 1/5 of human islets. Despite the fact that human, NHP, and AP islets contain similar amounts of insulin, the much higher GSIS for NHP islets than for AP and JP islets suggests the need for increased dosing of islets from JP and AP in pig-to-NHP transplantation. Porcine islet xenotransplantation to humans may require significantly higher dosing given the lower GSIS of AP islets compared to human islets. © 2013 John Wiley & Sons A/S.

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.

PubMed

Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj; Hermann, Thomas; Køber, Lars; Torp-Pedersen, Christian

2003-10-14

Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. These results support the concept that TNF-alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

Analyses of insulin-potentiating fragments of human growth hormone by computative simulation; essential unit for insulin-involved biological responses.

PubMed

Ohkura, K; Hori, H

2000-07-01

We analyzed the structural features of insulin-potentiating fragments of human growth hormone by computative simulations. The peptides were designated from the N-terminus sequences of the hormone positions at 1-15 (hGH(1-15); H2N-Phe1-Pro2-Thr3-Ile4-Pro5-Leu6-Ser7-Arg8-L eu9-Phe10-Asp11-Asn12-Ala13-Met14-Leu15 -COOH), 6-13 (hGH(6-13)), 7-13 (hGH(7-13)) and 8-13 (hGH(8-13)), which enhanced insulin-producing hypoglycemia. In these peptide molecules, ionic bonds were predicted to form between 8th-arginyl residue and 11th-aspartic residue, and this intramolecular interaction caused the formation of a macrocyclic structure containing a tetrapeptide Arg8-Leu9-Phe10-Asp11. The peptide positions at 6-10 (hGH(6-10)), 9-13 (hGH(9-13)) and 10-13 (hGH(10-13)) did not lead to a macrocyclic formation in the molecules, and had no effect on the insulin action. Although beta-Ala13hGH(1-15), in which the 13th-alanine was replaced by a beta-alanyl residue, had no effect on insulin-producing hypoglycemia, the macrocyclic region (Arg8-Leu9-Phe10-Asp11) was observed by the computative simulation. An isothermal vibration analysis of both of beta-Ala13hGH(1-15) and hGH(1-15) peptide suggested that beta-Ala13hGH(1-15) is molecule was more flexible than hGH(1-15); C-terminal carboxyl group of Leu15 easily accessed to Arg8 and inhibited the ionic bond formation between Arg8 and Asp11 in beta-Ala13hGH(1-15). The peptide of hGH(8-13) dose-dependently enhanced the insulin-involved fatty acid synthesis in rat white adipocytes, and stabilized the C6-NBD-PC (1-acyl-2-[6-[(7-nitro-2,1,3benzoxadiazol-4-yl)amino]-caproyl]-sn- glycero-3-phosphatidylcholine) model membranes. In contrast, hGH(9-13) had no effect both on the fatty acid synthesis and the membrane stability. In the same culture conditions as the fatty acid synthesis assay, hGH(8-13) had no effect on the transcript levels of glucose transporter isoforms (GLUT 1, 4) and hexokinase isozymes (HK I, II) in rat white adipocytes. Judging from

Production of human insulin in an E. coli system with Met-Lys-human proinsulin as the expressed precursor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin-Qiu Chen; Hong-Tao Zhang; Mei-Hao Hu

1995-10-01

The construction of a gene encoding Lys-human proinsulin, its direct expression in E.coli, and the simple purification procedure are described here. The temperature inducible promotor was employed for induction in a very short time. The expression level could reach 20-30%. After a simple downstream processing and only one step of Sephadex G50 purification, 150 mg recombinant Lys-human proinsulin with a purity of up to 90% could be obtained easily from 1 L of high density fermentation medium. The obtained product is in the form of Met-Lys-human proinsulin because of the failure of the bacterial host to remove the initiator methioninemore » residue. The Lys-human proinsulin could be changed into human insulin by tryspin and carboxypeptidase B treatment in later steps. After separation with DEAE Sephadex A25, human insulin with expected amino acid composition and full native biological activity could be obtained with a yield of 50 mg/L fermentation medium. 20 refs., 5 figs., 4 tabs.« less

Insulin released from titanium discs with insulin coatings-Kinetics and biological activity.

PubMed

Malekzadeh, B Ö; Ransjo, M; Tengvall, P; Mladenovic, Z; Westerlund, A

2017-10-01

Local administration of insulin from a titanium surface has been demonstrated to increase bone formation in non-diabetic rats. The authors hypothesized that insulin was released from the titanium surface and with preserved biological activity after the release. Thus, in the present in vitro study, human recombinant insulin was immobilized onto titanium discs, and the insulin release kinetics was evaluated using Electro-chemiluminescence immunoassay. Neutral Red uptake assay and mineralization assay were used to evaluate the biological effects of the released insulin on human osteoblast-like MG-63 cells. The results confirmed that insulin was released from titanium surfaces during a six-week period. Etching the disc prior to insulin coating, thickening of the insulin coating and incubation of the discs in serum-enriched cell culture medium increased the release. However, longer storage time decreased the release of insulin. Furthermore, the released insulin had retained its biological activity, as demonstrated by the significant increase in cell number and a stimulated mineralization process, upon exposure to released insulin. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1847-1854, 2017. © 2016 Wiley Periodicals, Inc.

Differential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples.

PubMed

Chan, Elizabeth S; Chen, Christopher; Soong, Tuck Wah; Wong, Boon-Seng

2018-03-01

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), where inheritance of this isoform predisposes development of AD in a gene dose-dependent manner. Although the mode of action of ApoE4 on AD onset and progression remains unknown, we have previously shown that ApoE4, and not ApoE3 expression, resulted in insulin signaling deficits in the presence of amyloid beta (Aβ). However, these reports were not conducted with clinical samples that more accurately reflect human disease. In this study, we investigated the effect of ApoE genotype on the insulin signaling pathway in control and AD human brain samples. We found that targets of the insulin signaling pathway were attenuated in AD cases, regardless of ApoE isoform. We also found a decrease in GluR1 subunit expression, and an increase NR2B subunit expression in AD cases, regardless of ApoE isoform. Lastly, we observed that more insulin receptor (IR) was immunoprecipitated in control cases, and more Aβ was immunoprecipitated with AD cases. But, when comparing among AD cases, we found that more IR was immunoprecipitated with ApoE3 than ApoE4, and more Aβ was immunoprecipitated with ApoE4 than ApoE3. Our results suggest that the difference in IR binding and effect on protein expression downstream of the IR may affect onset and progression of AD.

Pseudoislet formation enhances gene expression, insulin secretion and cytoprotective mechanisms of clonal human insulin-secreting 1.1B4 cells.

PubMed

Green, Alastair D; Vasu, Srividya; McClenaghan, Neville H; Flatt, Peter R

2015-10-01

We have studied the effects of cell communication on human beta cell function and resistance to cytotoxicity using the novel human insulin-secreting cell line 1.1B4 configured as monolayers and pseudoislets. Incubation with the incretin gut hormones GLP-1 and GIP caused dose-dependent stimulation of insulin secretion from 1.1B4 cell monolayers and pseudoislets. The secretory responses were 1.5-2.7-fold greater than monolayers. Cell viability (MTT), DNA damage (comet assay) and apoptosis (acridine orange/ethidium bromide staining) were investigated following 2-h exposure of 1.1B4 monolayers and pseudoislets to ninhydrin, H2O2, streptozotocin, glucose, palmitate or cocktails of proinflammatory cytokines. All agents tested decreased viability and increased DNA damage and apoptosis in both 1.1B4 monolayers and pseudoislets. However, pseudoislets exhibited significantly greater resistance to cytotoxicity (1.5-2.7-fold increases in LD50) and lower levels of DNA damage (1.3-3.4-fold differences in percentage tail DNA and olive tail moment) and apoptosis (1.3-1.5-fold difference) compared to monolayers. Measurement of gene expression by reverse-transcription, real-time PCR showed that genes involved with insulin secretion (INS, PDX1, PCSK1, PCSK2, GLP1R and GIPR), cell-cell communication (GJD2, GJA1 and CDH1) and antioxidant defence (SOD1, SOD2, GPX1 and CAT) were significantly upregulated in pseudoislets compared to monolayers, whilst the expression of proapoptotic genes (NOS2, MAPK8, MAPK10 and NFKB1) showed no significant differences. In summary, these data indicate cell-communication associated with three-dimensional islet architecture is important both for effective insulin secretion and for protection of human beta cells against cytotoxicity.

Differential roles of MAPK-Erk1/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells.

PubMed

Seto-Young, D; Avtanski, D; Varadinova, M; Park, A; Suwandhi, P; Leiser, A; Parikh, G; Poretsky, L

2011-06-01

Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis. © Georg Thieme Verlag KG Stuttgart · New York.

Effects of Insulin Detemir and NPH Insulin on Body Weight and Appetite-Regulating Brain Regions in Human Type 1 Diabetes: A Randomized Controlled Trial

PubMed Central

van Golen, Larissa W.; Veltman, Dick J.; IJzerman, Richard G.; Deijen, Jan Berend; Heijboer, Annemieke C.; Barkhof, Frederik; Drent, Madeleine L.; Diamant, Michaela

2014-01-01

Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli. Trial Registration ClinicalTrials.gov NCT00626080

An Investigation of a Hybrid Mixing Model for PDF Simulations of Turbulent Premixed Flames

NASA Astrophysics Data System (ADS)

Zhou, Hua; Li, Shan; Wang, Hu; Ren, Zhuyin

2015-11-01

Predictive simulations of turbulent premixed flames over a wide range of Damköhler numbers in the framework of Probability Density Function (PDF) method still remain challenging due to the deficiency in current micro-mixing models. In this work, a hybrid micro-mixing model, valid in both the flamelet regime and broken reaction zone regime, is proposed. A priori testing of this model is first performed by examining the conditional scalar dissipation rate and conditional scalar diffusion in a 3-D direct numerical simulation dataset of a temporally evolving turbulent slot jet flame of lean premixed H2-air in the thin reaction zone regime. Then, this new model is applied to PDF simulations of the Piloted Premixed Jet Burner (PPJB) flames, which are a set of highly shear turbulent premixed flames and feature strong turbulence-chemistry interaction at high Reynolds and Karlovitz numbers. Supported by NSFC 51476087 and NSFC 91441202.

Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan.

PubMed

Hassanein, Mohamed; Echtay, Akram Salim; Malek, Rachid; Omar, Mahomed; Shaikh, Shehla Sajid; Ekelund, Magnus; Kaplan, Kadriye; Kamaruddin, Nor Azmi

2018-01-01

To compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. In this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ± oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8-20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30-50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose <3.1 mmol/L [56 mg/dL]), nocturnal (00:01-05:59) or severe (requiring assistance of another person). During the treatment period, IDegAsp (n = 131) had significantly lower overall and nocturnal hypoglycaemia rates with similar glycaemic efficacy, versus BIAsp 30 (n = 132). During Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: -0.54 mmol/L [-1.02; -0.07] 95% CI , p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. IDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue. Copyright © 2017. Published by Elsevier B.V.

Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

PubMed

Langkjaer, L; Brange, J; Grodsky, G M; Guy, R H

1998-01-23

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

Premixed calcium phosphate cements: Synthesis, physical properties, and cell cytotoxicity

PubMed Central

Xu, Hockin H.K.; Carey, Lisa E.; Simon, Carl G.; Takagi, Shozo; Chow, Laurence C.

2009-01-01

Objectives Calcium phosphate cement (CPC) is a promising material for dental, periodontal, and craniofacial repairs. However, its use requires on-site powder–liquid mixing that increases the surgical placement time and raises concerns of insufficient and inhomogeneous mixing. The objective of this study was to determine a formulation of premixed CPC (PCPC) with rapid setting, high strength, and good in vitro cell viability. Methods PCPCs were formulated from CPC powder + non-aqueous liquid + gelling agent + hardening accelerator. Five PCPCs were thus developed: PCPC-Tartaric, PCPC-Malonic, PCPC-Citric, PCPC-Glycolic, and PCPC-Malic. Formulations and controls were compared for setting time, diametral tensile strength, and osteoblast cell compatibility. Results Setting time (mean ± S.D.; n = 4) for PCPC-Tartaric was 8.2 ± 0.8 min, significantly less than the 61.7 ± 1.5 min for the Premixed Control developed previously (p < 0.001). On 7th day immersion, the diametral tensile strength of PCPC-Tartaric reached 6.5 ± 0.8 MPa, higher than 4.5 ± 0.8 MPa of Premixed Control (p = 0.036). Osteoblast cells displayed a polygonal morphology and attached to the nano-hydroxyapatite crystals in the PCPCs. All cements had similar live cell density values (p = 0.126), indicating that the new PCPCs were as cell compatible as a non-premixed CPC control known to be biocompatible. Each of the new PCPCs had a cell viability that was not significantly different (p > 0.1) from that of the non-premixed CPC control. Significance PCPCs will eliminate the powder–liquid mixing during surgery and may also improve the cement performance. The new PCPCs supported cell attachment and yielded a high cell density and viability. Their mechanical strengths approached the reported strengths of sintered porous hydroxyapatite implants and cancellous bone. These nano-crystalline hydroxyapatite cements may be useful in dental, periodontal, and craniofacial repairs. PMID:16678895

Design of a Premixed Gaseous Rocket Engine Injector for Ethylene and Oxygen

DTIC Science & Technology

2006-12-01

and uniform combustion zone. An engine will benefit by having a greater characteristic exhaust velocity efficiency (ηc*), less soot production and...the challenges of designing a premixed injector. The design requirements for the engine are to provide a wide range of combustion pressure... Engineering Original Premixed Injector1 Downstream of the three inch combustion chamber a bolt-on conical nozzle was attached. This nozzle had a

WNT5A-JNK regulation of vascular insulin resistance in human obesity.

PubMed

Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

2016-12-01

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m 2 ) and five metabolically normal non-obese (BMI 26±2 kg/m 2 ) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. © The Author(s) 2016.

WNT5A-JNK regulation of vascular insulin resistance in human obesity

PubMed Central

Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

2017-01-01

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. PMID:27688298

Degradation of insulin by human fibroblasts: effects of inhibitors of pinocytosis and lysosomal activity.

PubMed

Kooistra, T; Lloyd, J B

1985-01-01

The role of the pinosome-lysosome pathway in the degradation of 125I-labelled bovine insulin by cultured human fibroblasts was examined by comparing the effects of various known inhibitors of pinocytosis and lysosomal degradation on the uptake and degradation of 125I-labelled polyvinylpyrrolidone, formaldehyde-denatured bovine serum albumin and bovine insulin by these cells. Fibroblasts incubated with polyvinylpyrrolidone steadily accumulate this substrate, whereas incubations with insulin or denatured albumin led to the progressive appearance in the culture medium of [125I]iodotyrosine. Inhibitors of pinocytosis (bacitracin, colchicine and monensin), metabolic inhibitors (2,4-dinitrophenol and NaF), lysosomotropic agents (chloroquine and NH4Cl) and an inhibitor of cysteine-proteinases (leupeptin) decreased the rate of uptake of polyvinylpyrrolidone and denatured albumin very similarly, but only bacitracin had an effect on the processing of insulin. Chloroquine, NH4Cl and leupeptin strongly inhibited the digestion of denatured albumin, but not of insulin. The different responses to the modifiers, with polyvinylpyrrolidone and denatured albumin on the one hand and insulin on the other, suggest that insulin degradation can occur by a non-lysosomal pathway. The very strong inhibitory effect of bacitracin on insulin processing by fibroblasts may point to an important role of plasma membrane proteinases in insulin degradation.

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy.

PubMed

Goldenberg, Ronald M; Berard, Lori

2018-01-01

Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM. Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov. Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia. The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).

Theoretical and experimental investigation of turbulent premixed flames

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azzazy, M.T.F.

1982-01-01

A model is proposed to describe the propagation of a plane oblique flame into a turbulent flow of premixed reactants. The model incorporates a transport equation for the single or joint PDF's of passive scalers, in addition to the conservation equations of mass, momentum, energy and K.E. of turbulence. In the first phase of developing the model, the reaction mechanism was treated as a single step irreversible exothermic reaction. In this case, the PDF of the progress variable was parameterized and solved with the conservation equations. The second phase considered a two step reaction mechanism in an attempt to exploremore » the role played by the radicals in the propagation of turbulent premixed flames. For both the two phases, the flame speed and angle are Eigenvalues of the solution. Laser Induced Fluoresence Spectroscopy (LIFS) was used to measure the PDF of OH concentration in a laboratory scale burner simulating the flame studied by the model. The premixed Methane-Air flame was stabilized on a rod flame holder downstream of a turbulence producing grid. Measurements in both the streamwise and transverse directions were made for a variety of flow conditions. The experimentally observed PDF's of the hydroxil radical concentration, and the statistical moments, were used to describe and compare the PDF's and moments of the two reaction model.« less

Reprogramming human gallbladder cells into insulin-producing β-like cells

PubMed Central

Benedetti, Eric; Wang, Yuhan; Pelz, Carl; Schug, Jonathan; Kaestner, Klaus H.; Grompe, Markus

2017-01-01

The gallbladder and cystic duct (GBCs) are parts of the extrahepatic biliary tree and share a common developmental origin with the ventral pancreas. Here, we report on the very first genetic reprogramming of patient-derived human GBCs to β-like cells for potential autologous cell replacement therapy for type 1 diabetes. We developed a robust method for large-scale expansion of human GBCs ex vivo. GBCs were reprogrammed into insulin-producing pancreatic β-like cells by a combined adenoviral-mediated expression of hallmark pancreatic endocrine transcription factors PDX1, MAFA, NEUROG3, and PAX6 and differentiation culture in vitro. The reprogrammed GBCs (rGBCs) strongly induced the production of insulin and pancreatic endocrine genes and these responded to glucose stimulation in vitro. rGBCs also expressed an islet-specific surface marker, which was used to enrich for the most highly reprogrammed cells. More importantly, global mRNA and microRNA expression profiles and protein immunostaining indicated that rGBCs adopted an overall β-like state and these rGBCs engrafted in immunodeficient mice. Furthermore, comparative global expression analyses identified putative regulators of human biliary to β cell fate conversion. In summary, we have developed, for the first time, a reliable and robust genetic reprogramming and culture expansion of primary human GBCs—derived from multiple unrelated donors—into pancreatic β-like cells ex vivo, thus showing that human gallbladder is a potentially rich source of reprogrammable cells for autologous cell therapy in diabetes. PMID:28813430

Dry low NOx combustion system with pre-mixed direct-injection secondary fuel nozzle

DOEpatents

Zuo, Baifang; Johnson, Thomas; Ziminsky, Willy; Khan, Abdul

2013-12-17

A combustion system includes a first combustion chamber and a second combustion chamber. The second combustion chamber is positioned downstream of the first combustion chamber. The combustion system also includes a pre-mixed, direct-injection secondary fuel nozzle. The pre-mixed, direct-injection secondary fuel nozzle extends through the first combustion chamber into the second combustion chamber.

Swozzle based burner tube premixer including inlet air conditioner for low emissions combustion

DOEpatents

Tuthill, Richard Sterling; Bechtel, II, William Theodore; Benoit, Jeffrey Arthur; Black, Stephen Hugh; Bland, Robert James; DeLeonardo, Guy Wayne; Meyer, Stefan Martin; Taura, Joseph Charles; Battaglioli, John Luigi

2002-01-01

A burner for use in a combustion system of a heavy-duty industrial gas turbine includes a fuel/air premixer having an air inlet, a fuel inlet, and an annular mixing passage. The fuel/air premixer mixes fuel and air into a uniform mixture for injection into a combustor reaction zone. The burner also includes an inlet flow conditioner disposed at the air inlet of the fuel/air premixer for controlling a radial and circumferential distribution of incoming air. The pattern of perforations in the inlet flow conditioner is designed such that a uniform air flow distribution is produced at the swirler inlet annulus in both the radial and circumference directions. The premixer includes a swozzle assembly having a series of preferably air foil shaped turning vanes that impart swirl to the airflow entering via the inlet flow conditioner. Each air foil contains internal fuel flow passages that introduce natural gas fuel into the air stream via fuel metering holes that pass through the walls of the air foil shaped turning vanes. By injecting fuel in this manner, an aerodynamically clean flow field is maintained throughout the premixer. By injecting fuel via two separate passages, the fuel/air mixture strength distribution can be controlled in the radial direction to obtain optimum radial concentration profiles for control of emissions, lean blow outs, and combustion driven dynamic pressure activity as machine and combustor load are varied.

A retrospective database analysis of insulin use patterns in insulin-naïve patients with type 2 diabetes initiating basal insulin or mixtures

PubMed Central

Bonafede, Machaon MK; Kalsekar, Anupama; Pawaskar, Manjiri; Ruiz, Kimberly M; Torres, Amelito M; Kelly, Karen R; Curkendall, Suellen M

2010-01-01

Objective: To describe insulin persistence among patients with type 2 diabetes initiating insulin therapy with basal insulin or insulin mixtures and determine factors associated with nonpersistence. Research design and methods: The Thomson Reuters MarketScan® databases were used to retrospectively analyze insulin-naïve patients with type 2 diabetes by initiating insulin therapy. Insulin use was described using a variety of measures. The persistence to insulin was described using both a gap-based measure and the number of claims measure. Results: Patients in the basal insulin cohort (N = 15,255) primarily used insulin analogs (88.1%) and vial and syringe (97%). Patients in the mixture cohort (N = 2,732) were more likely to initiate on human insulin mixtures (62.5%) and vial and syringe (68.1%). Average time between insulin refills was 80 and 71 days for basal and mixture initiators, respectively. Nearly, 75% of basal insulin initiators and 65% of insulin mixture initiators had a 90-day gap in insulin prescriptions. More than half of all the patients had at least one insulin prescription per quarter. Patients initiating with insulin analogs were more likely to be persistent compared with those initiating with human insulin across both cohorts and measures of persistence (P < 0.001). Conclusion: Persistence to insulin therapy is poorer than one would anticipate, but appears to be higher in users of insulin analogs and insulin mixtures. PMID:20622915

Partially Premixed Flame (PPF) Research for Fire Safety

NASA Technical Reports Server (NTRS)

Puri, Ishwar K.; Aggarwal, Suresh K.; Lock, Andrew J.; Hegde, Uday

2004-01-01

Incipient fires typically occur after the partial premixing of fuel and oxidizer. The mixing of product species into the fuel/oxidizer mixture influences flame stabilization and fire spread. Therefore, it is important to characterize the impact of different levels of fuel/oxidizer/product mixing on flame stabilization, liftoff and extinguishment under different gravity conditions. With regard to fire protection, the agent concentration required to achieve flame suppression is an important consideration. The initial stage of an unwanted fire in a microgravity environment will depend on the level of partial premixing and the local conditions such as air currents generated by the fire itself and any forced ventilation (that influence agent and product mixing into the fire). The motivation of our investigation is to characterize these impacts in a systematic and fundamental manner.

Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways.

PubMed

Lambernd, S; Taube, A; Schober, A; Platzbecker, B; Görgens, S W; Schlich, R; Jeruschke, K; Weiss, J; Eckardt, K; Eckel, J

2012-04-01

Obesity is closely associated with muscle insulin resistance and is a major risk factor for the pathogenesis of type 2 diabetes. Regular physical activity not only prevents obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. We sought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. Contracting human skeletal muscle cell cultures were established by applying electrical pulse stimulation. To induce insulin resistance, skeletal muscle cells were incubated with human adipocyte-derived conditioned medium, monocyte chemotactic protein (MCP)-1 and chemerin. Similarly to in exercising skeletal muscle in vivo, electrical pulse stimulation induced contractile activity in human skeletal muscle cells, combined with the formation of sarcomeres, activation of AMP-activated protein kinase (AMPK) and increased IL-6 secretion. Insulin-stimulated glucose uptake was substantially elevated in contracting cells compared with control. The incubation of skeletal muscle cells with adipocyte-conditioned media, chemerin and MCP-1 significantly reduced the insulin-stimulated phosphorylation of Akt. This effect was abrogated by concomitant pulse stimulation of the cells. Additionally, pro-inflammatory signalling by adipocyte-derived factors was completely prevented by electrical pulse stimulation of the myotubes. We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion. In our model, muscle contractile activity eliminates insulin resistance by blocking pro-inflammatory signalling pathways. This novel model therefore provides a unique tool for investigating the molecular mechanisms that mediate the beneficial effects of muscle

Lean Premixed Combustion Stabilized by Low Swirl a Promising Concept for Practical Applications

NASA Technical Reports Server (NTRS)

Cheng, R. K.

1999-01-01

Since its inception, the low-swirl burner (LSB) has shown to be a useful laboratory apparatus for fundamental studies of premixed turbulent flames. The LSB operates under wide ranges of equivalence ratios, flow rates, and turbulence intensities. Its flame is lifted and detached from the burner and allows easy access for laser diagnostics. The flame brush is axisymmetric and propagates normal to the incident reactants. Therefore, the LSB is well suited for investigating detailed flame structures and empirical coefficients such as flame speed, turbulence transport, and flame generated turbulence. Due to its capability to stabilize ultra-lean premixed turbulent flames (phi approx. = 0.55), the LSB has generated interest from the gas appliance industry for use as an economical low-NO(x) burner. Lean premixed combustion emits low levels of NO(x), due primarily to the low flame temperature. Therefore, it is a very effective NO(x) prevention method without involving selective catalytic reduction (SCR), fuel-air staging, or flue gas recirculation (FGR). En the gas turbine industry, substantial research efforts have already been undertaken and engines with lean premixed combustors are already in use. For commercial and residential applications, premixed pulsed combustors and premixed ceramic matrix burners are commercially available. These lean premixed combustion technologies, however, tend to be elaborate but have relatively limited operational flexibility, and higher capital, operating and maintenance costs. Consequently, these industries are continuing the development of lean premixed combustion technologies as well as exploring new concepts. This paper summarizes the research effects we have undertaken in the past few years to demonstrate the feasibility of applying the low-swirl flame stabilization method for a wide range of heating and power generation systems. The principle of flame stabilization by low-swirl is counter to the conventional high-swirl methods that

Clinical utility of insulin and insulin analogs

PubMed Central

Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

2013-01-01

Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells.

PubMed

Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-Ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

2013-11-19

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001.

Internalization and localization of basal insulin peglispro in cells.

PubMed

Moyers, Julie S; Volk, Catherine B; Cao, Julia X C; Zhang, Chen; Ding, Liyun; Kiselyov, Vladislav V; Michael, M Dodson

2017-10-15

Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a large hydrodynamic size compared with insulin lispro. It has a prolonged duration of action, which is related to a delay in insulin absorption and a reduction in clearance. Given the different physical properties of BIL compared with native insulin and insulin lispro, it is important to assess the cellular internalization characteristics of the molecule. Using immunofluorescent confocal imaging, we compared the cellular internalization and localization patterns of BIL, biosynthetic human insulin, and insulin lispro. We assessed the effects of BIL on internalization of the insulin receptor (IR) and studied cellular clearance of BIL. Co-localization studies using antibodies to either insulin or PEG, and the early endosomal marker EEA1 showed that the overall internalization and subcellular localization pattern of BIL was similar to that of human insulin and insulin lispro; all were rapidly internalized and co-localized with EEA1. During ligand washout for 4 h, concomitant loss of insulin, PEG methoxy group, and PEG backbone immunostaining was observed for BIL, similar to the loss of insulin immunostaining observed for insulin lispro and human insulin. Co-localization studies using an antibody to the lysosomal marker LAMP1 did not reveal evidence of lysosomal localization for insulin lispro, human insulin, BIL, or PEG using either insulin or PEG immunostaining reagents. BIL and human insulin both induced rapid phosphorylation and internalization of human IR. Our findings show that treatment of cells with BIL stimulates internalization and localization of IR to early endosomes. Both the insulin and PEG moieties of BIL undergo a dynamic cellular process of rapid internalization and transport to early endosomes followed by loss of cellular immunostaining in a manner similar to that of insulin lispro and human insulin. The rate of clearance for the insulin lispro portion of BIL was slower than

Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

NASA Astrophysics Data System (ADS)

Zalzman, Michal; Gupta, Sanjeev; Giri, Ranjit K.; Berkovich, Irina; Sappal, Baljit S.; Karnieli, Ohad; Zern, Mark A.; Fleischer, Norman; Efrat, Shimon

2003-06-01

Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.

Protein crystal growth in microgravity review of large scale temperature induction method: Bovine insulin, human insulin and human α-interferon

NASA Astrophysics Data System (ADS)

Long, Marianna M.; Bishop, John Bradford; Delucas, Lawrence J.; Nagabhushan, Tattanhalli L.; Reichert, Paul; Smith, G. David

1997-01-01

The Protein Crystal Growth Facility (PCF) is space-flight hardware that accommodates large scale protein crystal growth experiments using temperature change as the inductive step. Recent modifications include specialized instrumentation for monitoring crystal nucleation with laser light scattering. This paper reviews results from its first seven flights on the Space Shuttle, the last with laser light scattering instrumentation in place. The PCF's objective is twofold: (1) the production of high quality protein crystals for x-ray analysis and subsequent structure-based drug design and (2) preparation of a large quantity of relatively contaminant free crystals for use as time-release protein pharmaceuticals. The first three Shuttle flights with bovine insulin constituted the PCF's proof of concept, demonstrating that the space-grown crystals were larger and diffracted to higher resolution than their earth-grown counterparts. The later four PCF missions were used to grow recombinant human insulin crystals for x-ray analysis and continue productions trials aimed at the development of a processing facility for crystalline recombinant a-interferon.

Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells.

PubMed

Prabakar, Kamalaveni R; Domínguez-Bendala, Juan; Molano, R Damaris; Pileggi, Antonello; Villate, Susana; Ricordi, Camillo; Inverardi, Luca

2012-01-01

We sought to assess the potential of human cord blood-derived mesenchymal stem cells (CB-MSCs) to derive insulin-producing, glucose-responsive cells. We show here that differentiation protocols based on stepwise culture conditions initially described for human embryonic stem cells (hESCs) lead to differentiation of cord blood-derived precursors towards a pancreatic endocrine phenotype, as assessed by marker expression and in vitro glucose-regulated insulin secretion. Transplantation of these cells in immune-deficient animals shows human C-peptide production in response to a glucose challenge. These data suggest that human cord blood may be a promising source for regenerative medicine approaches for the treatment of diabetes mellitus.

Improving influence of insulin on cognitive functions in humans.

PubMed

Kern, W; Peters, A; Fruehwald-Schultes, B; Deininger, E; Born, J; Fehm, H L

2001-10-01

Insulin receptors have been identified in limbic brain structures, but their functional relevance is still unclear. In order to characterize some of their effects, we evaluated auditory evoked brain potentials (AEP) in a vigilance task, behavioral measures of memory (recall of words) and selective attention (Stroop test) during infusion of insulin. The hormone was infused at two different rates (1.5 mU/kg x min, "low insulin", and 15 mU/kg x min, "high insulin"), inducing respectively serum levels of 543 +/- 34 and 24,029 +/- 1,595 pmol/l. This experimental design allowed to compare cognitive parameters under two conditions presenting markedly different insulin levels, but with minimal incidence on blood glucose concentrations since these were kept constant by glucose infusion. A "no insulin treatment" group was not included in order to avoid leaving patients infused with glucose without insulin treatment. Measures were taken during a baseline phase preceding insulin infusion and every 90 min during the 360 min of insulin infusion. Compared with "low insulin", "high insulin" induced a slow negative potential shift in the AEP over the frontal cortex (average amplitude, high insulin: 0.27 +/- 0.48 microV; low insulin: 1.87 +/- 0.48 microV, p < 0.005), which was paralleled by enhanced memory performance (words recalled, high insulin: 22.04 +/- 0.93; low insulin: 19.29 +/- 0.92, p < 0.05). Also, during "high insulin" subjects displayed enhanced performance on the Stroop test (p < 0.05) and expressed less difficulty in thinking than during "low insulin" (p < 0.03). Results indicate an improving effect of insulin on cognitive function, and may provide a frame for further investigations of neurobehavioral effects of insulin in patients with lowered or enhanced brain insulin, i.e., patients with Alzheimer's disease or diabetes mellitus. Copyright 2001 S. Karger AG, Basel

A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design

PubMed Central

2012-01-01

Background Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. Methods/design The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. Discussion In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996. PMID:22727048

Common Genetic Variation in the Human FNDC5 Locus, Encoding the Novel Muscle-Derived ‘Browning’ Factor Irisin, Determines Insulin Sensitivity

PubMed Central

Staiger, Harald; Böhm, Anja; Scheler, Mika; Berti, Lucia; Machann, Jürgen; Schick, Fritz; Machicao, Fausto; Fritsche, Andreas; Stefan, Norbert; Weigert, Cora; Krook, Anna; Häring, Hans-Ulrich; de Angelis, Martin Hrabě

2013-01-01

Aims/hypothesis Recently, the novel myokine irisin was described to drive adipose tissue ‘browning’, to increase energy expenditure, and to improve obesity and insulin resistance in high fat-fed mice. Here, we assessed whether common single nucleotide polymorphisms (SNPs) in the FNDC5 locus, encoding the irisin precursor, contribute to human prediabetic phenotypes (overweight, glucose intolerance, insulin resistance, impaired insulin release). Methods A population of 1,976 individuals was characterized by oral glucose tolerance tests and genotyped for FNDC5 tagging SNPs. Subgroups underwent hyperinsulinaemic-euglycaemic clamps, magnetic resonance imaging/spectroscopy, and intravenous glucose tolerance tests. From 37 young and 14 elderly participants recruited in two different centres, muscle biopsies were obtained for the preparation of human myotube cultures. Results After appropriate adjustment and Bonferroni correction for the number of tested variants, SNPs rs16835198 and rs726344 were associated with in vivo measures of insulin sensitivity. Via interrogation of publicly available data from the Meta-Analyses of Glucose and Insulin-related traits Consortium, rs726344’s effect on insulin sensitivity was replicated. Moreover, novel data from human myotubes revealed a negative association between FNDC5 expression and appropriately adjusted in vivo measures of insulin sensitivity in young donors. This finding was replicated in myotubes from elderly men. Conclusions/interpretation This study provides evidence that the FNDC5 gene, encoding the novel myokine irisin, determines insulin sensitivity in humans. Our gene expression data point to an unexpected insulin-desensitizing effect of irisin. PMID:23637927

A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro.

PubMed

Al-Romaiyan, A; Liu, B; Asare-Anane, H; Maity, C R; Chatterjee, S K; Koley, N; Biswas, T; Chatterji, A K; Huang, G-C; Amiel, S A; Persaud, S J; Jones, P M

2010-09-01

Many plant-based products have been suggested as potential antidiabetic agents, but few have been shown to be effective in treating the symptoms of Type 2 diabetes mellitus (T2DM) in human studies, and little is known of their mechanisms of action. Extracts of Gymnema sylvestre (GS) have been used for the treatment of T2DM in India for centuries. The effects of a novel high molecular weight GS extract, Om Santal Adivasi, (OSA(R)) on plasma insulin, C-peptide and glucose in a small cohort of patients with T2DM are reported here. Oral administration of OSA(R) (1 g/day, 60 days) induced significant increases in circulating insulin and C-peptide, which were associated with significant reductions in fasting and post-prandial blood glucose. In vitro measurements using isolated human islets of Langerhans demonstrated direct stimulatory effects of OSA(R) on insulin secretion from human ß-cells, consistent with an in vivo mode of action through enhancing insulin secretion. These in vivo and in vitro observations suggest that OSA(R) may provide a potential alternative therapy for the hyperglycemia associated with T2DM. Copyright 2010 John Wiley & Sons, Ltd.

Enhanced skeletal muscle lipid oxidative efficiency in insulin-resistant vs insulin-sensitive nondiabetic, nonobese humans.

PubMed

Galgani, Jose E; Vasquez, Karla; Watkins, Guillermo; Dupuy, Aude; Bertrand-Michel, Justine; Levade, Thierry; Moro, Cedric

2013-04-01

Skeletal muscle insulin resistance is proposed to result from impaired skeletal muscle lipid oxidative capacity. However, there is no evidence indicating that muscle lipid oxidative capacity is impaired in healthy otherwise insulin-resistant individuals. The objective of the study was to assess muscle lipid oxidative capacity in young, nonobese, glucose-tolerant, insulin-resistant vs insulin-sensitive individuals. In 13 insulin-sensitive [by Matsuda index (MI) (22.6 ± 0.6 [SE] kg/m(2)); 23 ± 1 years; MI 5.9 ± 0.1] and 13 insulin-resistant (23.2 ± 0.6 kg/m(2); 23 ± 3 years; MI 2.2 ± 0.1) volunteers, skeletal muscle biopsy, blood extraction before and after an oral glucose load, and dual-energy x-ray absorptiometry were performed. Skeletal muscle mitochondrial to nuclear DNA ratio, oxidative phosphorylation protein content, and citrate synthase and β-hydroxyacyl-CoA dehydrogenase activities were assessed. Muscle lipids and palmitate oxidation ((14)CO2 and (14)C-acid soluble metabolites production) at 4 [1-(14)C]palmitate concentrations (45-520 μM) were also measured. None of the muscle mitochondrial measures showed differences between groups, except for a higher complex V protein content in insulin-resistant vs insulin-sensitive volunteers (3.5 ± 0.4 vs 2.2 ± 0.4; P = .05). Muscle ceramide content was significantly increased in insulin-resistant vs insulin-sensitive individuals (P = .04). Total palmitate oxidation showed a similar concentration-dependent response in both groups (P = .69). However, lipid oxidative efficiency (CO2 to (14)C-acid soluble metabolites ratio) was enhanced in insulin-resistant vs insulin-sensitive individuals, particularly at the highest palmitate concentration (0.24 ± 0.04 vs 0.12 ± 0.02; P = .02). We found no evidence of impaired muscle mitochondrial oxidative capacity in young, nonobese, glucose-tolerant, otherwise insulin-resistant vs insulin-sensitive individuals. Enhanced muscle lipid oxidative efficiency in insulin

The human insulin mRNA is partly translated via a cap- and eIF4A-independent mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fred, Rikard G., E-mail: Rikard.Fred@mcb.uu.se; Sandberg, Monica; Pelletier, Jerry

Highlights: {yields} The polypyrimidine tract binding protein binds to the 5'-UTR of the insulin mRNA. {yields} Insulin mRNA can be translated via a cap-independent mechanism. {yields} The fraction cap-independent insulin synthesis increases during conditions of stress. {yields} The {beta}-cell is able to uphold basal insulin biosynthesis under conditions of stress. -- Abstract: The aim of this study was to investigate whether cap-independent insulin mRNA translation occurs in human pancreatic islets at basal conditions, during stimulation at a high glucose concentration and at conditions of nitrosative stress. We also aimed at correlating cap-independent insulin mRNA translation with binding of the IRESmore » trans-acting factor polypyrimidine tract binding protein (PTB) to the 5'-UTR of insulin mRNA. For this purpose, human islets were incubated for 2 h in the presence of low (1.67 mM) or high glucose (16.7 mM). Nitrosative stress was induced by addition of 1 mM DETA/NO and cap-dependent mRNA translation was inhibited with hippuristanol. Insulin biosynthesis rates were determined by radioactive labeling and immunoprecipitation. PTB affinity to insulin mRNA 5'-UTR was assessed by a magnetic micro bead pull-down procedure. We observed that in the presence of 1.67 mM glucose, approximately 70% of the insulin mRNA translation was inhibited by hippuristanol. Corresponding value from islets incubated at 16.7 mM glucose was 93%. DETA/NO treatment significantly decreased the translation of insulin by 85% in high glucose incubated islets, and by 50% at a low glucose concentration. The lowered insulin biosynthesis rates of DETA/NO-exposed islets were further suppressed by hippuristanol with 55% at 16.7 mM glucose but not at 1.67 mM glucose. Thus, hippuristanol-induced inhibition of insulin biosynthesis was less pronounced in DETA/NO-treated islets as compared to control islets. We observed also that PTB bound specifically to the insulin mRNA 5'-UTR in vitro, and that

Expression of human choline kinase in NIH 3T3 fibroblasts increases the mitogenic potential of insulin and insulin-like growth factor I.

PubMed

Chung, T; Huang, J S; Mukherjee, J J; Crilly, K S; Kiss, Z

2000-05-01

In mammalian cells, growth factors, oncogenes, and carcinogens stimulate phosphocholine (PCho) synthesis by choline kinase (CK), suggesting that PCho may regulate cell growth. To validate the role of PCho in mitogenesis, we determined the effects of insulin, insulin-like growth factor I (IGF-I), and other growth factors on DNA synthesis in NIH 3T3 fibroblast sublines highly expressing human choline kinase (CK) without increasing phosphatidylcholine synthesis. In serum-starved CK expressor cells, insulin and IGF-I stimulated DNA synthesis, p70 S6 kinase (p70 S6K) activity, phosphatidylinositol 3-kinase (PI3K) activity, and activating phosphorylation of p42/p44 mitogen-activated protein kinases (MAPK) to greater extents than in the corresponding vector control cells. Furthermore, the CK inhibitor hemicholinium-3 (HC-3) inhibited insulin- and IGF-I-induced DNA synthesis in the CK overexpressors, but not in the vector control cells. The results indicate that high cellular levels of PCho potentiate insulin- and IGF-I-induced DNA synthesis by MAPK- and p70 S6K-regulated mechanisms.

Computations of turbulent lean premixed combustion using conditional moment closure

NASA Astrophysics Data System (ADS)

Amzin, Shokri; Swaminathan, Nedunchezhian

2013-12-01

Conditional Moment Closure (CMC) is a suitable method for predicting scalars such as carbon monoxide with slow chemical time scales in turbulent combustion. Although this method has been successfully applied to non-premixed combustion, its application to lean premixed combustion is rare. In this study the CMC method is used to compute piloted lean premixed combustion in a distributed combustion regime. The conditional scalar dissipation rate of the conditioning scalar, the progress variable, is closed using an algebraic model and turbulence is modelled using the standard k-ɛ model. The conditional mean reaction rate is closed using a first order CMC closure with the GRI-3.0 chemical mechanism to represent the chemical kinetics of methane oxidation. The PDF of the progress variable is obtained using a presumed shape with the Beta function. The computed results are compared with the experimental measurements and earlier computations using the transported PDF approach. The results show reasonable agreement with the experimental measurements and are consistent with the transported PDF computations. When the compounded effects of shear-turbulence and flame are strong, second order closures may be required for the CMC.

Implementation of Premixed Equilibrium Chemistry Capability in OVERFLOW

NASA Technical Reports Server (NTRS)

Olsen, M. E.; Liu, Y.; Vinokur, M.; Olsen, T.

2003-01-01

An implementation of premixed equilibrium chemistry has been completed for the OVERFLOW code, a chimera capable, complex geometry flow code widely used to predict transonic flowfields. The implementation builds on the computational efficiency and geometric generality of the solver.

Implementation of Premixed Equilibrium Chemistry Capability in OVERFLOW

NASA Technical Reports Server (NTRS)

Olsen, Mike E.; Liu, Yen; Vinokur, M.; Olsen, Tom

2004-01-01

An implementation of premixed equilibrium chemistry has been completed for the OVERFLOW code, a chimera capable, complex geometry flow code widely used to predict transonic flowfields. The implementation builds on the computational efficiency and geometric generality of the solver.

Effects of the beta-carbolines, harmane and pinoline, on insulin secretion from isolated human islets of Langerhans.

PubMed

Cooper, E Jane; Hudson, Alan L; Parker, Christine A; Morgan, Noel G

2003-12-15

It is well known that certain imidazoline compounds can stimulate insulin secretion and this has been attributed to the activation of imidazoline I(3) binding sites in the pancreatic beta-cell. Recently, it has been proposed that beta-carbolines may be endogenous ligands having activity at imidazoline sites and we have, therefore, studied the effects of beta-carbolines on insulin secretion. The beta-carbolines harmane, norharmane and pinoline increased insulin secretion two- to threefold from isolated human islets of Langerhans. The effects of harmane and pinoline were dose-dependent (EC(50): 5 and 25 microM, respectively) and these agents also blocked the inhibitory effects of the potassium channel agonist, diazoxide, on glucose-induced insulin release. Stimulation of insulin secretion by harmane was glucose-dependent but, unlike the imidazoline I(3) receptor agonist efaroxan, it increased the rate of insulin release beyond that elicited by 20 mM glucose (20 mM glucose alone: 253+/-34% vs. basal; 20 mM glucose plus 100 microM harmane: 327+/-15%; P<0.01). Stimulation of insulin secretion by harmane was attenuated by the imidazoline I(3) receptor antagonist KU14R (2 (2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole) and was reduced when islets were treated with efaroxan for 18 h, prior to the addition of harmane. The results reveal that beta-carbolines can potentiate the rate of insulin secretion from human islets and suggest that these agents may be useful prototypes for the development of novel insulin secretagogues.

Study of premixing phase of steam explosion with JASMINE code in ALPHA program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moriyama, Kiyofumi; Yamano, Norihiro; Maruyama, Yu

Premixing phase of steam explosion has been studied in ALPHA Program at Japan Atomic Energy Research Institute (JAERI). An analytical model to simulate the premixing phase, JASMINE (JAERI Simulator for Multiphase Interaction and Explosion), has been developed based on a multi-dimensional multi-phase thermal hydraulics code MISTRAL (by Fuji Research Institute Co.). The original code was extended to simulate the physics in the premixing phenomena. The first stage of the code validation was performed by analyzing two mixing experiments with solid particles and water: the isothermal experiment by Gilbertson et al. (1992) and the hot particle experiment by Angelini et al.more » (1993) (MAGICO). The code predicted reasonably well the experiments. Effectiveness of the TVD scheme employed in the code was also demonstrated.« less

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract.

PubMed

Eichler, Tad E; Becknell, Brian; Easterling, Robert S; Ingraham, Susan E; Cohen, Daniel M; Schwaderer, Andrew L; Hains, David S; Li, Birong; Cohen, Ariel; Metheny, Jackie; Tridandapani, Susheela; Spencer, John David

2016-09-01

Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. Because the impact of diabetes on RNase 7 expression and function are unknown, we investigated the effects of insulin on RNase 7 using human urine specimens. The urinary RNase 7 concentrations were measured in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared with controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, the mechanisms by which insulin stimulates RNase 7 synthesis were next explored. Insulin induced RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, uropathogenic E. coli suppressed PI3K/AKT activity and RNase 7 production. Thus, insulin and PI3K/AKT signaling are essential for RNase 7 expression and increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. Our data may provide unique insight into novel urinary tract infection therapeutic strategies in at-risk populations. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines.

PubMed

Norouzi, Shaghayegh; Adulcikas, John; Sohal, Sukhwinder Singh; Myers, Stephen

2018-01-01

Zinc is a metal ion that is an essential cell signaling molecule. Highlighting this, zinc is an insulin mimetic, activating cellular pathways that regulate cellular homeostasis and physiological responses. Previous studies have linked dysfunctional zinc signaling with several disease states including cancer, obesity, cardiovascular disease and type 2 diabetes. The present study evaluated the insulin-like effects of zinc on cell signaling molecules including tyrosine, PRSA40, Akt, ERK1/2, SHP-2, GSK-3β and p38, and glucose oxidation in human and mouse skeletal muscle cells. Insulin and zinc independently led to the phosphorylation of these proteins over a 60-minute time course in both mouse and human skeletal muscle cells. Similarly, utilizing a protein array we identified that zinc could active the phosphorylation of p38, ERK1/2 and GSK-3B in human and ERK1/2 and GSK-3B in mouse skeletal muscle cells. Glucose oxidation assays were performed on skeletal muscle cells treated with insulin, zinc, or a combination of both and resulted in a significant induction of glucose consumption in mouse (p<0.01) and human (p<0.05) skeletal muscle cells when treated with zinc alone. Insulin, as expected, increased glucose oxidation in mouse (p<0.001) and human (0.001) skeletal muscle cells, however the combination of zinc and insulin did not augment glucose consumption in these cells. Zinc acts as an insulin mimetic, activating key molecules implicated in cell signaling to maintain glucose homeostasis in mouse and human skeletal muscle cells. Zinc is an important metal ion implicated in several biological processes. The role of zinc as an insulin memetic in activating key signaling molecules involved in glucose homeostasis could provide opportunities to utilize this ion therapeutically in treating disorders associated with dysfunctional zinc signaling.

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients.

PubMed

Hu, Xiaolei; Chen, Fengling

2018-01-01

Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. © 2018 The authors.

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients

PubMed Central

Hu, Xiaolei

2018-01-01

Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. PMID:29233817

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

NASA Astrophysics Data System (ADS)

Stump, Craig S.; Short, Kevin R.; Bigelow, Maureen L.; Schimke, Jill M.; Sreekumaran Nair, K.

2003-06-01

Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P < 0.01) i.v. infused with insulin (1.5 milliunits/kg of fat-free mass per min) while clamping glucose, amino acids, glucagon, and growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164-180%) encoding mitochondrial proteins (P < 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P < 0.05). Further studies demonstrated no effect of low to high insulin levels on muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16-26% (P < 0.02) when four different substrate combinations were used. In conclusion, insulin stimulates mitochondrial oxidative phosphorylation in skeletal muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels. cytochrome c oxidase | NADH dehydrogenase subunit IV | amino acids | citrate synthase

Gravitational Influences on Flame Propagation through Non-Uniform, Premixed Gas Systems

NASA Technical Reports Server (NTRS)

Miller, Fletcher J.; Easton, John; Ross, Howard D.; Marchese, Anthony; Perry, David; Kulis, Michael

2001-01-01

Flame propagation through non-uniformly premixed (or layered) gases has importance both in useful combustion systems and in unintentional fires. As summarized previously, non-uniform premixed gas combustion receives scant attention compared to the more usual limiting cases of diffusion or uniformly premixed flames, especially regarding the role gravity plays. This paper summarizes our progress on furthering the knowledge of layered combustion, in which a fuel concentration gradient exists normal to the direction of flame spread. We present experimental and numerical results for flame spread through propanol-air layers formed near the flash point temperature (25 C) or near the stoichiometric temperature (33 C). Both the model and experimental results show that the removal of gravity results in a faster spreading flame, by as much as 80% depending on conditions. This is exactly the opposite effect as that predicted by an earlier model reported. We also found that having a gallery lid results in faster flame spread, an effect more pronounced at normal gravity, demonstrating the importance of enclosure geometry. Also reported here is the beginning of our spectroscopic measurements of fuel vapor.

Direct numerical simulations of premixed autoignition in compressible uniformly-sheared turbulence

NASA Astrophysics Data System (ADS)

Towery, Colin; Darragh, Ryan; Poludnenko, Alexei; Hamlington, Peter

2017-11-01

High-speed combustion systems, such as scramjet engines, operate at high temperatures and pressures, extremely short combustor residence times, very high rates of shear stress, and intense turbulent mixing. As a result, the reacting flow can be premixed and have highly-compressible turbulence fluctuations. We investigate the effects of compressible turbulence on the ignition delay time, heat-release-rate (HRR) intermittency, and mode of autoignition of premixed Hydrogen-air fuel in uniformly-sheared turbulence using new three-dimensional direct numerical simulations with a multi-step chemistry mechanism. We analyze autoignition in both the Eulerian and Lagrangian reference frames at eight different turbulence Mach numbers, Mat , spanning the quasi-isentropic, linear thermodynamic, and nonlinear compressibility regimes, with eddy shocklets appearing in the nonlinear regime. Results are compared to our previous study of premixed autoignition in isotropic turbulence at the same Mat and with a single-step reaction mechanism. This previous study found large decreases in delay times and large increases in HRR intermittency between the linear and nonlinear compressibility regimes and that detonation waves could form in both regimes.

Large Eddy Simulation of High-Speed, Premixed Ethylene Combustion

NASA Technical Reports Server (NTRS)

Ramesh, Kiran; Edwards, Jack R.; Chelliah, Harsha; Goyne, Christopher; McDaniel, James; Rockwell, Robert; Kirik, Justin; Cutler, Andrew; Danehy, Paul

2015-01-01

A large-eddy simulation / Reynolds-averaged Navier-Stokes (LES/RANS) methodology is used to simulate premixed ethylene-air combustion in a model scramjet designed for dual mode operation and equipped with a cavity for flameholding. A 22-species reduced mechanism for ethylene-air combustion is employed, and the calculations are performed on a mesh containing 93 million cells. Fuel plumes injected at the isolator entrance are processed by the isolator shock train, yielding a premixed fuel-air mixture at an equivalence ratio of 0.42 at the cavity entrance plane. A premixed flame is anchored within the cavity and propagates toward the opposite wall. Near complete combustion of ethylene is obtained. The combustor is highly dynamic, exhibiting a large-scale oscillation in global heat release and mass flow rate with a period of about 2.8 ms. Maximum heat release occurs when the flame front reaches its most downstream extent, as the flame surface area is larger. Minimum heat release is associated with flame propagation toward the cavity and occurs through a reduction in core flow velocity that is correlated with an upstream movement of the shock train. Reasonable agreement between simulation results and available wall pressure, particle image velocimetry, and OH-PLIF data is obtained, but it is not yet clear whether the system-level oscillations seen in the calculations are actually present in the experiment.

A stochastic multi-scale method for turbulent premixed combustion

NASA Astrophysics Data System (ADS)

Cha, Chong M.

2002-11-01

The stochastic chemistry algorithm of Bunker et al. and Gillespie is used to perform the chemical reactions in a transported probability density function (PDF) modeling approach of turbulent combustion. Recently, Kraft & Wagner have demonstrated a 100-fold gain in computational speed (for a 100 species mechanism) using the stochastic approach over the conventional, direct integration method of solving for the chemistry. Here, the stochastic chemistry algorithm is applied to develop a new transported PDF model of turbulent premixed combustion. The methodology relies on representing the relevant spatially dependent physical processes as queuing events. The canonical problem of a one-dimensional premixed flame is used for validation. For the laminar case, molecular diffusion is described by a random walk. For the turbulent case, one of two different material transport submodels can provide the necessary closure: Taylor dispersion or Kerstein's one-dimensional turbulence approach. The former exploits ``eddy diffusivity'' and hence would be much more computationally tractable for practical applications. Various validation studies are performed. Results from the Monte Carlo simulations compare well to asymptotic solutions of laminar premixed flames, both with and without high activation temperatures. The correct scaling of the turbulent burning velocity is predicted in both Damköhler's small- and large-scale turbulence limits. The effect of applying the eddy diffusivity concept in the various regimes is discussed.

Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells

PubMed Central

Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

2013-01-01

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001 PMID:24252877

Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture.

PubMed

Pandolfi, A; Iacoviello, L; Capani, F; Vitacolonna, E; Donati, M B; Consoli, A

1996-12-01

Hyperglycaemia and hyperinsulinaemia have both been related to accelerated atherosclerosis in non-insulin-dependent diabetes mellitus (NIDDM). Plasma fibrinolytic potential is reduced in NIDDM and it is known that glucose and insulin can modulate plasminogen activator inhibitor (PAI-1) and tissue-plasminogen activator (t-PA) secretion and can therefore regulate local fibrinolysis. Vascular smooth muscle cells (vSMC) play an important role in the development of atherosclerotic lesions; however, the role of insulin and glucose in regulating PAI-1 and t-PA production in vSMC is presently not known. Therefore, we cultured arterial vSMC explanted from human umbilical cords and exposed them to increasing concentrations of glucose (5, 12, 20, 27, 35 mmol/l) or insulin (0.1, 0.5, 1, 10 nmol/l) in a serum free medium. After 24 h, PAI-1 and t-PA antigens and activity were evaluated in the culture medium; in cells exposed to 20 mmol/l glucose and to 0.5 nmol/l insulin PAI-1 gene expression was also evaluated. An increase in PAI-1 antigen was observed at each glucose concentration (by 138, 169, 251 and 357% as compared to 5 mmol/l glucose) which was paralleled by an increase in PAI-1 activity. t-PA concentration was also increased by glucose but its activity was sharply reduced. An increase in PAI-1 antigen was detected at each insulin level (by 121, 128, 156 and 300% as compared to no insulin). PAI-1 activity was slightly increased at the lowest insulin concentrations but markedly increased by 10 nmol/l insulin. t-PA antigen was also increased by insulin; however, its activity was markedly reduced at each concentration. As compared to control cells, PAI-1 mRNA was increased by 2.5 and 2.0 fold by 20 mmol/l glucose and 0.5 nmol/l insulin, respectively. We conclude that in human vSMC both glucose and insulin can affect the fibrinolytic balance so as to reduce fibrinolytic potential. This might contribute to decreased local fibrinolysis and thereby might accelerate the

Insulin and the PI3K/AKT Signaling Pathway Regulate Ribonuclease 7 Expression in the Human Urinary Tract

PubMed Central

Eichler, Tad; Becknell, Brian; Easterling, Robert S.; Ingraham, Susan E.; Cohen, Daniel M.; Schwaderer, Andrew; Hains, David S.; Li, Birong; Cohen, Ariel; Metheny, Jackie; Trindandapani, Susheela; Spencer, John David

2017-01-01

Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site of infection. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. The impact of diabetes on RNase 7 expression and function are unknown. Here, we investigate the effects of insulin on RNase 7. Using human urine specimens, we measured urinary RNase 7 concentrations in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared to controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, we explored the mechanisms by which insulin induces RNase 7. Insulin induces RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, we show that uropathogenic E. coli suppresses PI3K/AKT and RNase 7. Together, these results indicate that insulin and PI3K/AKT signaling are essential for RNase 7 expression. They also suggest that increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. These data may provide unique insight into novel UTI therapeutic strategies in at risk populations. PMID:27401534

Characterization of Insulin-Immunoreactive Cells and Endocrine Cells Within the Duct System of the Adult Human Pancreas.

PubMed

Li, Rong; Zhang, Xiaoxi; Yu, Lan; Zou, Xia; Zhao, Hailu

2016-01-01

The adult pancreatic duct system accommodates endocrine cells that have the potential to produce insulin. Here we report the characterization and distribution of insulin-immunoreactive cells and endocrine cells within the ductal units of adult human pancreas. Sequential pancreas sections from 12 nondiabetic adults were stained with biomarkers of ductal epithelial cells (cytokeratin 19), acinar cells (amylase), endocrine cells (chromogranin A; neuron-specific enolase), islet hormones (insulin, glucagon, somatostatin, pancreatic polypeptide), cell proliferation (Ki-67), and neogenesis (CD29). The number of islet hormone-immunoreactive cells increased from large ducts to the terminal branches. The insulin-producing cells outnumbered endocrine cells reactive for glucagon, somatostatin, or pancreatic polypeptide. The proportions of insulin-immunoreactive count compared with local islets (100% as a baseline) were 1.5% for the main ducts, 7.2% for interlobular ducts, 24.8% for intralobular ducts, 67.9% for intercalated ducts, and 348.9% for centroacinar cells. Both Ki-67- and CD29-labeled cells were predominantly localized in the terminal branches around the islets. The terminal branches also showed cells coexpressing islet hormones and cytokeratin 19. The adult human pancreatic ducts showed islet hormone-producing cells. The insulin-reactive cells predominantly localized in terminal branches where they may retain potential capability for β-cell neogenesis.

Intrauterine-like growth rates can be achieved with premixed parenteral nutrition solution in preterm infants.

PubMed

Rigo, Jacques; Senterre, Thibault

2013-12-01

Growth failure in neonatal intensive care units is a major challenge for pediatricians and neonatologists. The use of early "aggressive" parenteral nutrition (PN), with >2.5 g/(kg ·d) of amino acids and at least 40 kcal/(kg ·d) of energy from the first day of life, has been shown to provide nutritional intakes in the range recommended by international guidelines, reducing nutritional deficit and the incidence of postnatal growth restriction in preterm infants. However, nutritional practices and adherence to recommendations may vary in different hospitals. Two ready-to-use (RTU), premixed parenteral solutions (PSs) designed for preterm infants have been prospectively evaluated: a binary RTU premixed PS from our hospital pharmacy and a commercially premixed 3-chamber bag (Baxter Healthcare). These premixed PSs provide nitrogen and energy intakes in the range of the most recent recommendations, reducing or eliminating the early cumulative nutritional deficit in very-low-birth-weight infants, and avoiding the development of postnatal growth restriction. A further rationale for RTU premixed PSs is that preterm infants require balanced PN that contains not only amino acids and energy but also minerals and electrolytes from the first day of life in order to reduce the incidence of metabolic disorders frequently reported in extremely-low-birth-weight infants during the early weeks of life.

A human model of dietary saturated fatty acid induced insulin resistance.

PubMed

Koska, Juraj; Ozias, Marlies K; Deer, James; Kurtz, Julie; Salbe, Arline D; Harman, S Mitchell; Reaven, Peter D

2016-11-01

Increased consumption of high-fat diets is associated with the development of insulin resistance and type 2 diabetes. Current models to study the mechanisms of high-fat diet-induced IR in humans are limited by their long duration or low efficacy. In the present study we developed and characterized an acute dietary model of saturated fatty acid-enriched diet induced insulin resistance. High caloric diets enriched with saturated fatty acids (SFA) or carbohydrates (CARB) were evaluated in subjects with normal and impaired glucose tolerance (NGT or IGT). Both diets were compared to a standard eucaloric American Heart Association (AHA) control diet in a series of crossover studies. Whole body insulin resistance was estimated as steady state plasma glucose (SSPG) concentrations during the last 30min of a 3-h insulin suppression test. SSPG was increased after a 24-h SFA diet (by 83±74% vs. control, n=38) in the entire cohort, which was comprised of participants with NGT (92±82%, n=22) or IGT (65±55%, n=16) (all p<0.001). SSPG was also increased after a single SFA breakfast (55±32%, p=0.008, n=7). The increase in SSPG was less pronounced after an overnight fast following a daylong SFA diet (24±31%, p=0.04, n=10), and further attenuated 24h after returning to the control diet (19±35%, p=0.09, n=11). SSPG was not increased after a 24-h CARB diet (26±50%, p=0.11, n=12). A short-term SFA-enriched diet induced whole body insulin resistance in both NGT and IGT subjects. Insulin resistance persisted overnight after the last SFA meal and was attenuated by one day of a healthy diet. This model offers opportunities for identifying early mechanisms and potential treatments of dietary saturated fat induced insulin resistance. Published by Elsevier Inc.

Subetta increases phosphorylation of insulin receptor β-subunit alone and in the presence of insulin

PubMed Central

Gorbunov, E A; Nicoll, J; Kachaeva, E V; Tarasov, S A; Epstein, O I

2015-01-01

It has been previously shown that Subetta (a drug containing released-active forms of antibodies to the insulin receptor β-subunit and antibodies to endothelial nitric oxide synthase) stimulated insulin-induced adiponectin production by mature human adipocytes in the absence of insulin. Therefore, it was assumed that Subetta could activate the insulin receptor. To confirm this hypothesis, the capacity of Subetta to activate the insulin receptor in mature human adipocytes in the absence or presence of the insulin was investigated. Cells were incubated either with Subetta or with vehicle, or with basal medium for 3 days. Then, adipocytes were treated with water or insulin (100 nm) for 15 min. Following treatment, lysates were prepared and phosphorylation of insulin receptor β-subunits was analyzed by western blot analysis. It was shown that Subetta significantly increased (P<0.001) the ‘phosphorylated-insulin receptor β-subunit/total insulin receptor β-subunit' ratios in both the presence and the absence of insulin. These results support previously published data and indicate that Subetta could activate the insulin receptor through the effect on its β-subunits, whose conformational state is essential for insulin receptor activation. This action might serve as one of the primary mechanisms of the drug's antidiabetic effect. PMID:26148148

Comparison of insulin lispro mix 25 with insulin lispro mix 50 as insulin starter in Chinese patients with type 2 diabetes mellitus (CLASSIFY study): Subgroup analysis of a Phase 4 open-label randomized trial.

PubMed

Su, Qing; Liu, Chao; Zheng, Hongting; Zhu, Jun; Li, Peng Fei; Qian, Lei; Yang, Wen Ying

2017-06-01

Premixed insulins are recommended starter insulins in Chinese patients after oral antihyperglycemic medication (OAM) failure. In the present study, we compared the efficacy and safety of insulin lispro mix 25 (LM25) twice daily (b.i.d.) and insulin lispro mix 50 (LM50) b.i.d. as a starter insulin regimen in Chinese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with OAMs. The primary efficacy outcome in the present open-label parallel randomized clinical trial was change in HbA1c from baseline to 26 weeks. Patients were randomized in a ratio of 1:  1 to LM25 (n = 80) or LM50 (n = 76). A mixed-effects model with repeated measures was used to analyze continuous variables. The Cochran-Mantel-Haenszel test with stratification factor was used to analyze categorical variables. At the end of the study, LM50 was more efficacious than LM25 in reducing mean HbA1c levels (least-squares [LS] mean difference 0.48; 95 % confidence interval [CI] 0.22, 0.74; P < 0.001). More subjects in the LM50 than LM25 group achieved HbA1c targets of <7.0 % (72.4 % vs 45.0 %; P = 0.001) or ≤6.5 % (52.6 % vs 20.0 %; P < 0.001). Furthermore, LM50 was more effective than LM25 at reducing HbA1c in patients with baseline HbA1c, blood glucose excursion, and postprandial glucose greater than or equal to median levels (P ≤ 0.001). The rate and incidence of hypoglycemic episodes and increase in weight at the end of the study were similar between treatment groups. In Chinese patients with T2DM, LM50 was more efficacious than LM25 as a starter insulin. © 2016 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.

miR-375 induces human decidua basalis-derived stromal cells to become insulin-producing cells.

PubMed

Shaer, Anahita; Azarpira, Negar; Vahdati, Akbar; Karimi, Mohammad Hosein; Shariati, Mehrdad

2014-09-01

This paper focuses on the development of renewable sources of isletreplacement tissue for the treatment of type I diabetes mellitus. Placental tissue-derived mesenchymal stem cells (MSCs) are a promising source for regenerative medicine due to their plasticity and easy availability. They have the potential to differentiate into insulin-producing cells. miR-375 is a micro RNA that is expressed in the pancreas and involved in islet development. Human placental decidua basalis MSCs (PDB-MSCs) were cultured from full-term human placenta. The immunophenotype of the isolated cells was checked for CD90, CD105, CD44, CD133 and CD34 markers. The MSCs (P3) were chemically transfected with hsa-miR-375. Total RNA was extracted 4 and 6 days after transfection. The expressions of insulin, NGN3, GLUT2, PAX4, PAX6, KIR6.2, NKX6.1, PDX1, and glucagon genes were evaluated using real-time qPCR. On day 6, we tested the potency of the clusters in response to the high glucose challenge and assessed the presence of insulin and NGN3 proteins via immunocytochemistry. Flow cytometry analysis confirmed that more than 90% of the cells were positive for CD90, CD105 and CD44 and negative for CD133 and CD34. Morphological changes were followed from day 2. Cell clusters formed during day 6. Insulin-producing clusters showed a deep red color with DTZ. The expression of pancreatic-specific transcription factors increased remarkably during the four days after transfection and significantly increased on day 7. The clusters were positive for insulin and NGN3 proteins, and C-peptide and insulin secretion increased in response to changes in the glucose concentration (2.8 mM and 16.7 mM). In conclusion, the MSCs could be programmed into functional insulin-producing cells by transfection of miR-375.

Partially premixed prevalorized kerosene spray combustion in turbulent flow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chrigui, M.; Ahmadi, W.; Sadiki, A.

2010-04-15

A detailed numerical simulation of kerosene spray combustion was carried out on a partially premixed, prevaporized, three-dimensional configuration. The focus was on the flame temperature profile dependency on the length of the pre-vaporization zone. The results were analyzed and compared to experimental data. A fundamental study was performed to observe the temperature variation and flame flashback. Changes were made to the droplet diameter, kerosene flammability limits, a combustion model parameter and the location of the combustion initialization. Investigations were performed for atmospheric pressure, inlet air temperature of 90 C and a global equivalence ratio of 0.7. The simulations were carriedmore » out using the Eulerian Lagrangian procedure under a fully two-way coupling. The Bray-Moss-Libby model was adjusted to account for the partially premixed combustion. (author)« less

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

PubMed

Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

2017-12-01

Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans.

PubMed

Carpentier, André C; Frisch, Frédérique; Brassard, Pascal; Lavoie, François; Bourbonnais, Annie; Cyr, Denis; Giguère, Robert; Baillargeon, Jean-Patrice

2007-03-01

Insulin increases plasma nonesterified fatty acid (NEFA) clearance in humans, but whether this is independent of change in plasma NEFA appearance is currently unknown. Nine nondiabetic men (age: 28+/-3 yr, body mass index: 27.2+/-1.7 kg/m2) underwent euglycemic clamps to maintain low (LINS) vs. high (HINS) physiological insulin levels for 6 h. An intravenous infusion of heparin+Intralipid (HI) was performed during 4 of the 6 h of the clamps (in the last 4 h at LINS and in the first 4 h at HINS), whereas saline infusion (SAL) was administered in the remaining 2 h to modulate plasma NEFA levels independently of plasma insulin levels. Four experimental conditions were obtained in each individual: LINS with saline (LINS/SAL) and with HI infusion (LINS/HI) and HINS with saline (HINS/SAL) and with HI infusion (HINS/HI). Plasma palmitate appearance during HINS/SAL was lower than during the three other experimental conditions (P<0.05). In contrast, plasma linoleate appearance, as expected, was increased by HI independently of insulin level (P<0.02). Plasma palmitate clearance during HINS/SAL was higher than LINS/SAL and LINS/HI (P<0.008), and this increase was blunted during HINS/HI. We observed a linear decrease in plasma palmitate clearance with increasing plasma NEFA appearance independent of insulin levels. Plasma NEFA levels increased exponentially with increase in plasma NEFA appearance. We conclude that insulin stimulates plasma NEFA clearance by reducing the endogenous appearance rate of NEFA. The relationship between plasma NEFA level and appearance rate is nonlinear.

Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

PubMed

Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

2016-02-01

Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Novel recombinant insulin analogue with flexible C-terminus in B chain. NMR structure of biosynthetic engineered A22G-B31K-B32R human insulin monomer in water/acetonitrile solution.

PubMed

Borowicz, Piotr; Bocian, Wojciech; Sitkowski, Jerzy; Bednarek, Elżbieta; Mikiewicz-Syguła, Diana; Błażej-Sosnowska, Sylwia; Bogiel, Monika; Rusek, Dorota; Kurzynoga, Dariusz; Kozerski, Lech

2011-11-01

A tertiary structure of recombinant A22(G)-B31(K)-B32(R)-human insulin monomer (insulin GKR) has been characterized by (1)H, (13)C NMR at natural isotopic abundance using NOESY, TOCSY, (1)H/(13)C-GHSQC, and (1)H/(13)C-GHSQC-TOCSY spectra. Translational diffusion studies indicate the monomer structure in water/acetonitrile (65/35vol.%). CSI analysis confirms existence of secondary structure motifs present in human insulin standard (HIS). Both techniques allow to establish that in this solvent recombinant insulin GKR exists as a monomer. Starting from structures calculated by the program CYANA, two different refinement protocols used molecular dynamics simulated annealing with the program AMBER; in vacuum (AMBER_VC), and including a generalized Born solvent model (AMBER_GB). From these calculations an ensemble of 20 structures of lowest energy was chosen which represents the tertiary structure of studied insulin. Here we present novel insulin with added A22(G) amino acid which interacts with β-turn environment resulting in high flexibility of B chain C-terminus. Copyright © 2011 Elsevier B.V. All rights reserved.

Measurements and Modeling of Nitric Oxide Formation in Counterflow, Premixed CH4/O2/N2 Flames

NASA Technical Reports Server (NTRS)

Thomsen, D. Douglas; Laurendeau, Normand M.

2000-01-01

Laser-induced fluorescence (LIF) measurements of NO concentration in a variety of CH4/O2/N2 flames are used to evaluate the chemical kinetics of NO formation. The analysis begins with previous measurements in flat, laminar, premixed CH4/O2/N2 flames stabilized on a water-cooled McKenna burner at pressures ranging from 1 to 14.6 atm, equivalence ratios from 0.5 to 1.6, and volumetric nitrogen/oxygen dilution ratios of 2.2, 3.1 and 3.76. These measured results are compared to predictions to determine the capabilities and limitations of the comprehensive kinetic mechanism developed by the Gas Research Institute (GRI), version 2.11. The model is shown to predict well the qualitative trends of NO formation in lean-premixed flames, while quantitatively underpredicting NO concentration by 30-50%. For rich flames, the model is unable to even qualitatively match the experimental results. These flames were found to be limited by low temperatures and an inability to separate the flame from the burner surface. In response to these limitations, a counterflow burner was designed for use in opposed premixed flame studies. A new LIF calibration technique was developed and applied to obtain quantitative measurements of NO concentration in laminar, counterflow premixed, CH4/O2/N2 flames at pressures ranging from 1 to 5.1 atm, equivalence ratios of 0.6 to 1.5, and an N2/O2 dilution ratio of 3.76. The counterflow premixed flame measurements are combined with measurements in burner-stabilized premixed flames and counterflow diffusion flames to build a comprehensive database for analysis of the GRI kinetic mechanism. Pathways, quantitative reaction path and sensitivity analyses are applied to the GRI mechanism for these flame conditions. The prompt NO mechanism is found to severely underpredict the amount of NO formed in rich premixed and nitrogen-diluted diffusion flames. This underprediction is traced to uncertainties in the CH kinetics as well as in the nitrogen oxidation chemistry

Intravenous glucagon in a deliberate insulin overdose in an adolescent with type 1 diabetes mellitus.

PubMed

White, Mary; Zacharin, Margaret R; Werther, George A; Cameron, Fergus J

2016-02-01

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chassin, D.; Laurent, A.; Janneau, J.L.

1995-09-20

A new member of the insulin gene superfamily was identified by screening a subtracted cDNA library of first-trimester human placenta and, hence, was tentatively named early placenta insulin-like peptide (EPIL). In this paper, we report the cloning and sequencing of the EPIL cDNA and the EPIL gene (INSL4). Comparison of the deduced amino acid sequence of the early placenta insulin-like peptide revealed significant overall and structural homologies with members of the insulin-like hormone superfamily. Moreover, the organization of the early placenta insulin-like gene, which is composed of two exons and one intron, is similiar to that of insulin and relaxin.more » By in situ hybridization, the INSL4 gene was assigned to band p24 of the short arm of chromosome 9. RT-PCR analysis of EPIL tissue distribution revealed that its transcripts are expressed in the placenta and uterus. 22 refs., 3 figs.« less

Vortex combustor for low NOX emissions when burning lean premixed high hydrogen content fuel

DOEpatents

Steele, Robert C; Edmonds, Ryan G; Williams, Joseph T; Baldwin, Stephen P

2012-11-20

A trapped vortex combustor. The trapped vortex combustor is configured for receiving a lean premixed gaseous fuel and oxidant stream, where the fuel includes hydrogen gas. The trapped vortex combustor is configured to receive the lean premixed fuel and oxidant stream at a velocity which significantly exceeds combustion flame speed in a selected lean premixed fuel and oxidant mixture. The combustor is configured to operate at relatively high bulk fluid velocities while maintaining stable combustion, and low NOx emissions. The combustor is useful in gas turbines in a process of burning synfuels, as it offers the opportunity to avoid use of diluent gas to reduce combustion temperatures. The combustor also offers the possibility of avoiding the use of selected catalytic reaction units for removal of oxides of nitrogen from combustion gases exiting a gas turbine.

Vortex combustor for low NOx emissions when burning lean premixed high hydrogen content fuel

DOEpatents

Steele, Robert C [Woodinville, WA; Edmonds, Ryan G [Renton, WA; Williams, Joseph T [Kirkland, WA; Baldwin, Stephen P [Winchester, MA

2009-10-20

A trapped vortex combustor. The trapped vortex combustor is configured for receiving a lean premixed gaseous fuel and oxidant stream, where the fuel includes hydrogen gas. The trapped vortex combustor is configured to receive the lean premixed fuel and oxidant stream at a velocity which significantly exceeds combustion flame speed in a selected lean premixed fuel and oxidant mixture. The combustor is configured to operate at relatively high bulk fluid velocities while maintaining stable combustion, and low NOx emissions. The combustor is useful in gas turbines in a process of burning synfuels, as it offers the opportunity to avoid use of diluent gas to reduce combustion temperatures. The combustor also offers the possibility of avoiding the use of selected catalytic reaction units for removal of oxides of nitrogen from combustion gases exiting a gas turbine.

Changes in metformin use and other antihyperglycemic therapies after insulin initiation in patients with type 2 diabetes.

PubMed

Pilla, Scott J; Dotimas, James R; Maruthur, Nisa M; Clark, Jeanne M; Yeh, Hsin-Chieh

2018-05-01

When patients with type 2 diabetes initiate insulin, metformin should be continued while continuation of other antihyperglycemics has unclear benefit. We aimed to identify practice patterns in antihyperglycemic therapy during the insulin transition, and determine factors associated with metformin continuation. We performed a retrospective analysis of the Look AHEAD (Action for Health in Diabetes) trial which randomized overweight/obese adults under ambulatory care for type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. Among the 931 participants who initiated insulin over ten years, we described longitudinal changes in antihyperglycemic medications during the insulin transition, and performed multivariable logistic regression to estimate the association between patient characteristics and metformin continuation. Before insulin initiation, 81.0% of patients used multiple antihyperglycemics, the most common being metformin, sulfonylureas, and thiazolidinediones. After insulin initiation, metformin was continued in 80.3% of patients; other antihyperglycemics were continued less often, yet 58.0% of patients were treated with multiple non-insulin antihyperglycemics. Metformin continuation was inversely associated with age (fully adjusted (a) OR 0.60 per 10 years [0.42-0.86]), serum creatinine above safety thresholds (aOR 0.09 [0.02-0.36]), lower income (P = 0.025 for trend), taking more medications (aOR 0.92 per medication [0.86-0.98]), and initiating rapid, short, or premixed insulin (aOR 0.59 [0.39-0.89]). The vast majority of patients with type 2 diabetes continue metformin after insulin initiation, consistent with guidelines. Other antihyperglycemics are frequently continued along with insulin, and further research is needed to determine which, if any, patients may benefit from this. Copyright © 2018 Elsevier B.V. All rights reserved.

The conditional moment closure method for modeling lean premixed turbulent combustion

NASA Astrophysics Data System (ADS)

Martin, Scott Montgomery

Natural gas fired lean premixed gas turbines have become the method of choice for new power generation systems due to their high efficiency and low pollutant emissions. As emission regulations for these combustion systems become more stringent, the use of numerical modeling has become an important a priori tool in designing clean and efficient combustors. Here a new turbulent combustion model is developed in an attempt to improve the state of the art. The Conditional Moment Closure (CMC) method is a new theory that has been applied to non-premixed combustion with good success. The application of the CMC method to premixed systems has been proposed, but has not yet been done. The premixed CMC method replaces the species mass fractions as independent variables with the species mass fractions that are conditioned on a reaction progress variable (RPV). Conservation equations for these new variables are then derived and solved. The general idea behind the CMC method is that the behavior of the chemical species is closely coupled to the reaction progress variable. Thus, species conservation equations that are conditioned on the RPV will have terms involving the fluctuating quantities that are much more likely to be negligible. The CMC method accounts for the interaction between scalar dissipation (micromixing) and chemistry, while de-coupling the kinetics from the bulk flow (macromixing). Here the CMC method is combined with a commercial computational fluid dynamics program, which calculates the large-scale fluid motions. The CMC model is validated by comparison to 2-D reacting backward facing step data. Predicted species, temperature and velocity fields are compared to experimental data with good success. The CMC model is also validated against the University of Washington's 3-D jet stirred reactor (JSR) data, which is an idealized lean premixed combustor. The JSR results are encouraging, but not as good as the backward facing step. The largest source of error is from

The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes

PubMed Central

Inman, Taylor R.; Plyushko, Erika; Austin, Nicholas P.; Johnson, Jeremy L.

2018-01-01

The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications. PMID:29796245

The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes.

PubMed

Inman, Taylor R; Plyushko, Erika; Austin, Nicholas P; Johnson, Jeremy L

2018-05-01

The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications.

Gravitational Influences on Flame Propagation Through Non-Uniform, Premixed Gas Systems

NASA Technical Reports Server (NTRS)

Miller, Fletcher J.; Easton, John; Marchese, Anthony; Hovermann, Fred

2003-01-01

Flame propagation through non-uniformly premixed (or layered) gases has importance both in useful combustion systems and in unintentional fires. As summarized recently and in previous Microgravity Workshop papers, non-uniform premixed gas combustion receives scant attention compared to the more usual limiting cases of diffusion or uniformly premixed flames, especially regarding the role gravity plays. This paper summarizes our recent findings on gravitational effects on layered combustion along a floor, in which the fuel concentration gradient exists normal to the direction of flame spread. In an effort to understand the mechanism by which the flames spread faster in microgravity (and much faster, in laboratory coordinates, than the laminar burning velocity for uniform mixtures), we have begun making pressure measurements across the spreading flame front that are described here. Earlier researchers, testing in 1g, claimed that hydrostatic pressure differences could account for the rapid spread rates. Additionally, we present the development of a new apparatus to study flame spread in free (i.e., far from walls), non-homogeneous fuel layers formed in a flow tunnel behind an airfoil that has been tested in normal gravity.

Insulin acutely improves mitochondrial function of rat and human skeletal muscle by increasing coupling efficiency of oxidative phosphorylation.

PubMed

Nisr, Raid B; Affourtit, Charles

2014-02-01

Insulin is essential for the regulation of fuel metabolism and triggers the uptake of glucose by skeletal muscle. The imported glucose is either stored or broken down, as insulin stimulates glycogenesis and ATP synthesis. The mechanism by which ATP production is increased is incompletely understood at present and, generally, relatively little functional information is available on the effect of insulin on mitochondrial function. In this paper we have exploited extracellular flux technology to investigate insulin effects on the bioenergetics of rat (L6) and human skeletal muscle myoblasts and myotubes. We demonstrate that a 20-min insulin exposure significantly increases (i) the cell respiratory control ratio, (ii) the coupling efficiency of oxidative phosphorylation, and (iii) the glucose sensitivity of anaerobic glycolysis. The improvement of mitochondrial function is explained by an insulin-induced immediate decrease of mitochondrial proton leak. Palmitate exposure annuls the beneficial mitochondrial effects of insulin. Our data improve the mechanistic understanding of insulin-stimulated ATP synthesis, and reveal a hitherto undisclosed insulin sensitivity of cellular bioenergetics that suggests a novel way of detecting insulin responsiveness of cells. © 2013.

Insulin acutely improves mitochondrial function of rat and human skeletal muscle by increasing coupling efficiency of oxidative phosphorylation☆

PubMed Central

Nisr, Raid B.; Affourtit, Charles

2014-01-01

Insulin is essential for the regulation of fuel metabolism and triggers the uptake of glucose by skeletal muscle. The imported glucose is either stored or broken down, as insulin stimulates glycogenesis and ATP synthesis. The mechanism by which ATP production is increased is incompletely understood at present and, generally, relatively little functional information is available on the effect of insulin on mitochondrial function. In this paper we have exploited extracellular flux technology to investigate insulin effects on the bioenergetics of rat (L6) and human skeletal muscle myoblasts and myotubes. We demonstrate that a 20-min insulin exposure significantly increases (i) the cell respiratory control ratio, (ii) the coupling efficiency of oxidative phosphorylation, and (iii) the glucose sensitivity of anaerobic glycolysis. The improvement of mitochondrial function is explained by an insulin-induced immediate decrease of mitochondrial proton leak. Palmitate exposure annuls the beneficial mitochondrial effects of insulin. Our data improve the mechanistic understanding of insulin-stimulated ATP synthesis, and reveal a hitherto undisclosed insulin sensitivity of cellular bioenergetics that suggests a novel way of detecting insulin responsiveness of cells. PMID:24212054

Resveratrol ameliorates the chemical and microbial induction of inflammation and insulin resistance in human placenta, adipose tissue and skeletal muscle.

PubMed

Tran, Ha T; Liong, Stella; Lim, Ratana; Barker, Gillian; Lappas, Martha

2017-01-01

Gestational diabetes mellitus (GDM), which complicates up to 20% of all pregnancies, is associated with low-grade maternal inflammation and peripheral insulin resistance. Sterile inflammation and infection are key mediators of this inflammation and peripheral insulin resistance. Resveratrol, a stilbene-type phytophenol, has been implicated to exert beneficial properties including potent anti-inflammatory and antidiabetic effects in non-pregnant humans and experimental animal models of GDM. However, studies showing the effects of resveratrol on inflammation and insulin resistance associated with GDM in human tissues have been limited. In this study, human placenta, adipose (omental and subcutaneous) tissue and skeletal muscle were stimulated with pro-inflammatory cytokines TNF-α and IL-1β, the bacterial product lipopolysaccharide (LPS) and the synthetic viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) to induce a GDM-like model. Treatment with resveratrol significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, IL-1α, IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in human placenta and omental and subcutaneous adipose tissue. Resveratrol also significantly restored the defects in the insulin signalling pathway and glucose uptake induced by TNF-α, LPS and poly(I:C). Collectively, these findings suggest that resveratrol reduces inflammation and insulin resistance induced by chemical and microbial products. Resveratrol may be a useful preventative therapeutic for pregnancies complicated by inflammation and insulin resistance, like GDM.

Studies of premixed laminar and turbulent flames at microgravity

NASA Technical Reports Server (NTRS)

Ronney, Paul D.

1993-01-01

A two and one-half year experimental and theoretical research program on the properties of laminar and turbulent premixed gas flames at microgravity was conducted. Progress during this program is identified and avenues for future studies are discussed.

Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor

PubMed Central

2018-01-01

Insulin receptor (IR) signaling plays a critical role in the regulation of metabolism and growth in multicellular organisms. IRs are unique among receptor tyrosine kinases in that they exist exclusively as covalent (αβ)2 homodimers at the cell surface. Transmembrane signaling by the IR can therefore not be based on ligand-induced dimerization as such but must involve structural changes within the existing receptor dimer. In this study, using glycosylated full-length human IR reconstituted into lipid nanodiscs, we show by single-particle electron microscopy that insulin binding to the dimeric receptor converts its ectodomain from an inverted U-shaped conformation to a T-shaped conformation. This structural rearrangement of the ectodomain propagates to the transmembrane domains, which are well separated in the inactive conformation but come close together upon insulin binding, facilitating autophosphorylation of the cytoplasmic kinase domains. PMID:29453311

Implementation of subcutaneous insulin protocol for non-critically ill hospitalized patients in andalusian tertiary care hospitals.

PubMed

Martínez-Brocca, María Asunción; Morales, Cristóbal; Rodríguez-Ortega, Pilar; González-Aguilera, Beatriz; Montes, Cristina; Colomo, Natalia; Piédrola, Gonzalo; Méndez-Muros, Mariola; Serrano, Isabel; Ruiz de Adana, Maria Soledad; Moreno, Alberto; Fernández, Ignacio; Aguilar, Manuel; Acosta, Domingo; Palomares, Rafael

2015-02-01

In 2009, the Andalusian Society of Endocrinology and Nutrition designed a protocol for subcutaneous insulin treatment in hospitalized non-critically ill patients (HIP). To analyze implementation of HIP at tertiary care hospitals from the Andalusian Public Health System. A descriptive, multicenter study conducted in 8 tertiary care hospitals on a random sample of non-critically ill patients with diabetes/hyperglycemia (n=306) hospitalized for ≥48 hours in 5 non-surgical (SM) and 2 surgical (SQ) departments. Type 1 and other specific types of diabetes, pregnancy and nutritional support were exclusion criteria. 288 patients were included for analysis (62.5% males; 70.3±10.3 years; 71.5% SM, 28.5% SQ). A scheduled subcutaneous insulin regimen based on basal-bolus-correction protocol was started in 55.9% (95%CI: 50.5-61.2%) of patients, 63.1% SM vs. 37.8% SQ (P<.05). Alternatives to insulin regimen based on basal-bolus-correction included sliding scale insulin (43.7%), diet (31.3%), oral antidiabetic drugs (17.2%), premixed insulin (1.6%), and others (6.2%). For patients previously on oral antidiabetic drugs, in-hospital insulin dose was 0.32±0.1 IU/kg/day. In patients previously on insulin, in-hospital insulin dose was increased by 17% [-13-53], and in those on insulin plus oral antidiabetic drugs, in-hospital insulin dose was increased by 26.4% [-6-100]. Supplemental insulin doses used for<40 IU/day and 40-80 IU/day were 72.2% and 56.7% respectively. HbA1c was measured in 23.6% of patients (95CI%: 18.8-28.8); 27.7% SM vs. 13.3% SQ (P<.05). Strategies are needed to improve implementation of the inpatient subcutaneous insulin protocol, particularly in surgical departments. Sliding scale insulin is still the most common alternative to insulin regimen based on basal-bolus-correction scheduled insulin. Metabolic control assessment during hospitalization should be encouraged. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Insulin analogues with improved absorption characteristics.

PubMed

Brange, J; Hansen, J F; Langkjaer, L; Markussen, J; Ribel, U; Sørensen, A R

1992-01-01

The insulin preparations available today are not ideal for therapy as s.c. injection does not provide a physiological insulin profile. With the aim to improve the absorption properties recombinant DNA technology has been utilized to design novel insulin molecules with changed physico-chemical characteristics and hence altered subcutaneous absorption kinetics. Soluble, long-acting human insulin analogues in which the isoelectric point has been increased from 5.4 to approx. 7 are absorbed very slowly, providing a more constant basal insulin delivery with lower day-to-day variation than present protracted preparations. In addition they have better storage stability. Rapid-acting human insulin analogues with largely reduced self-association are absorbed substantially faster from subcutaneous tissue than current regular insulin and thus are better suited for bolus injection. The absorption kinetics of these analogues have been able to explain the mechanism behind the dose effect on insulin absorption rate.

Metformin and insulin receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vigneri, R.; Gullo, D.; Pezzino, V.

The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitromore » to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.« less

[Insulin resistance as a mechanism of adaptation during human evolution].

PubMed

Ricart, W; Fernández-Real, J M

2010-10-01

The recent application of concepts of evolution to human disease is proving useful to understand certain pathophysiological mechanisms of different entities that span genomic alterations of immunity, respiratory and hormone function, and the circulatory and neural systems. However, effort has concentrated on explaining the keys to adaptation that define human metabolism and, since the early 1960s, several theories have been developed. This article reviews some of the hypotheses postulated in recent years on the potential benefit of insulin resistance and discusses the most recent knowledge. The concept of the thrifty gene seems to have been definitively refuted by current knowledge. The current paradigm describes an interaction between the metabolic and the immune systems resulting from their coevolution, promoted by evolutionary pressures triggered by fasting, infection and intake of different foods. The activation and regulation of these ancient mechanisms in integrated and interdependent areas defines insulin resistance as a survival strategy that is critical during fasting and in the fight against infection. The relationship with some components of the diet and, particularly, with the symbiotic intestinal microflora points to new paradigms in understanding the pathophysiology of obesity, metabolic syndrome and type 2 diabetes mellitus. Copyright © 2010 SEEN. Published by Elsevier Espana. All rights reserved.

From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

NASA Astrophysics Data System (ADS)

Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

2005-05-01

Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

[Influence and mechanism of a tight control of blood glucose by intensive insulin therapy on human sepsis].

PubMed

Yu, Wen-kui; Li, Wei-qin; Wang, Xiao-dong; Yan, Xiao-wen; Qi, Xiao-ping; Li, Ning; Li, Jie-shou

2005-01-01

To investigate the effect of a tight control of blood glucose by intensive insulin therapy on human sepsis, and to explore the potential mechanism of the intensive insulin therapy. Eligible patients were randomized by a blinded pharmacist to receive tight control of blood glucose by intensive insulin therapy (maintenance of blood glucose at a level between 4.4 and 6.1 mmol/L) or to receive conventional treatment (maintenance of glucose at a level between 10.0 and 11.1 mmol/L). The expression of HLA-DR on peripheral monocytes was measured in 54 patients by flow cytometry on 24 h, 3 d, 5 d, 7 d, 10 d and 14 d of intensive care in parallel with serum c-reactive protein (CRP), severity of the disease (APACHE II score, SOFA score) and clinical data collection. Patients receiving intensive insulin therapy were less likely to require prolonged mechanical ventilation. Tight control of blood glucose significantly reduced the number of days during which leukopenia or leukocytosis and the days with hypo- or hyperthermia (P < 0.05). Hypoglycemia occurred in 3 patients (10.7%) in the tight control of blood glucose group. There were no instance of hemodynamic deterioration or convulsions. Compared with the conventional treatment, tight control of blood glucose also increased the HLA-DR expression of peripheral monocytes, and there were significantly difference on 3 d, 5 d and 7 d (P < 0.05). Whereas it suppressed the elevated serum CRP concentrations, there was significantly difference on 7 d (P < 0.05). Tight control of blood glucose by intensive insulin therapy expedited healing of human sepsis, and increased the HLA-DR expression of peripheral and suppressed the elevated serum CRP. So, it is necessary to use insulin to strict control the glucose levels in human sepsis.

Experimental Investigation of Turbulence-Chemistry Interaction in High-Reynolds-Number Turbulent Partially Premixed Flames

DTIC Science & Technology

2016-06-23

4 . TITLE AND SUBTITLE [U] Experimental investigation of turbulence-chemistry interaction in high-Reynolds-number 5a. CONTRACT NUMBER turbulent...nonpremixed/partially premixed flames and turbulence-chemistry interaction. Turbulent mixing of mixture fraction has been studied extensively [ 4 , 14]. In a...two-feed non-premixed flame, the mixture fraction is defined as: ξ = Y − Yo YF − Yo (1) where Y is a conserved quantity such as the mass fraction of any

Experimental study on flame propagation characteristics of Hydrogen premixed gas in gas pipeline

NASA Astrophysics Data System (ADS)

Ma, Danzhu; Li, Zhuang; Jia, Fengrui; Li, Zhou

2018-06-01

Hydrogen is the cleanest high-energy gas fuel, and also is the main industrial material. However, hydrogen is more explosive and more powerful than conventional gas fuels, which restricts its application. In particular, the expansion of premixed combustion under a strong constraint is more complicated, the reaction spreads faster. The flame propagation characteristics of premixed hydrogen/air were investigated by experiment. The mechanism of reaction acceleration is discussed, and then the speed of the flame propagation and the reaction pressure were tested and analysed.

On the suppression of plasma nonesterified fatty acids by insulin during enhanced intravascular lipolysis in humans.

PubMed

Carpentier, André C; Frisch, Frédérique; Cyr, Denis; Généreux, Philippe; Patterson, Bruce W; Giguère, Robert; Baillargeon, Jean-Patrice

2005-11-01

During the fasting state, insulin reduces nonesterified fatty acid (NEFA) appearance in the systemic circulation mostly by suppressing intracellular lipolysis in the adipose tissue. In the postprandial state, insulin may also control NEFA appearance through enhanced trapping into the adipose tissue of NEFA derived from intravascular triglyceride lipolysis. To determine the contribution of suppression of intracellular lipolysis in the modulation of plasma NEFA metabolism by insulin during enhanced intravascular triglyceride lipolysis, 10 healthy nonobese subjects underwent pancreatic clamps at fasting vs. high physiological insulin level with intravenous infusion of heparin plus Intralipid. Nicotinic acid was administered orally during the last 2 h of each 4-h clamp to inhibit intracellular lipolysis and assess insulin's effect on plasma NEFA metabolism independently of its effect on intracellular lipolysis. Stable isotope tracers of palmitate, acetate, and glycerol were used to assess plasma NEFA metabolism and total triglyceride lipolysis in each participant. The glycerol appearance rate was similar during fasting vs. high insulin level, but plasma NEFA levels were significantly lowered by insulin. Nicotinic acid significantly blunted the insulin-mediated suppression of plasma palmitate appearance and oxidation rates by approximately 60 and approximately 70%, respectively. In contrast, nicotinic acid did not affect the marked stimulation of palmitate clearance by insulin. Thus most of the insulin-mediated reduction of plasma NEFA appearance and oxidation can be explained by suppression of intracellular lipolysis during enhanced intravascular triglyceride lipolysis in healthy humans. Our results also suggest that insulin may affect plasma NEFA clearance independently of the suppression of intracellular lipolysis.

Effects of Inhibition of Interleukin-6 Signalling on Insulin Sensitivity and Lipoprotein (A) Levels in Human Subjects with Rheumatoid Diseases

PubMed Central

Schultz, Olaf; Oberhauser, Frank; Saech, Jasemine; Rubbert-Roth, Andrea; Hahn, Moritz; Krone, Wilhelm; Laudes, Matthias

2010-01-01

Background Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been found to be increased in type 2 diabetic subjects. However, it still remains unclear if these elevated IL-6 levels are co-incidental or if this cytokine is causally related to the development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin sensitivity, serum adipokine levels and lipid parameters in human subjects before and after treatment with the IL-6 receptor antibody Tocilizumab. Methodology/Principal Findings 11 non-diabetic patients with rheumatoid disease were included in the study. HOMA-IR was calculated and serum levels for leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) (Lp (a)) were measured before as well as one and three months after Tocilizumab treatment. The HOMA index for insulin resistance decreased significantly. While leptin concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased. Thus the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a significant decrease. Serum triglycerides, LDL-cholesterol and HDL-cholesterol tended to be increased whereas Lp (a) levels significantly decreased. Conclusions/Significance Inhibition of IL-6 signalling improves insulin sensitivity in humans with immunological disease suggesting that elevated IL-6 levels in type 2 diabetic subjects might be causally involved in the pathogenesis of insulin resistance. Furthermore, our data indicate that inhibition of IL-6 signalling decreases Lp (a) serum levels, which might reduce the cardiovascular risk of human subjects. PMID:21179199

Monomeric insulins and their experimental and clinical implications.

PubMed

Brange, J; Owens, D R; Kang, S; Vølund, A

1990-09-01

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier

Insulin Signaling in Type 2 Diabetes

PubMed Central

Brännmark, Cecilia; Nyman, Elin; Fagerholm, Siri; Bergenholm, Linnéa; Ekstrand, Eva-Maria; Cedersund, Gunnar; Strålfors, Peter

2013-01-01

Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time course data on signaling intermediaries, normally and in diabetes, we developed a dynamic mathematical model of insulin signaling. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor, (ii) reduced concentration of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable with experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and, using a multilevel model, at the whole body level. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis. PMID:23400783

1H NMR spectrum of the native human insulin monomer. Evidence for conformational differences between the monomer and aggregated forms.

PubMed

Roy, M; Lee, R W; Brange, J; Dunn, M F

1990-04-05

The effects of high dilution on the 1H Fourier transform NMR spectrum of native human insulin at pH* 8.0 and 9.3 have been examined at 500 MHz resolution. The dependence of the spectrum on concentration and comparison with the spectrum of a biologically highly potent monomeric insulin mutant (SerB9----Asp) establish that at 36 microM (pH* 9.3) or 18 microM (pH* 8) and no added buffer or salts, human insulin is monomeric. Under these conditions of dilution, ionic strength, and pH*, human insulin and the SerB9----Asp mutant exhibit nearly identical 1H NMR spectra. At higher concentrations (i.e. greater than 36 microM to 0.91 mM), native human insulin dimerizes, and this aggregation causes a change in insulin conformation. Although there are many changes in the spectrum, the TyrB26 ring H3,5 proton signals located at 6.63 ppm and the methyl signal located at 0.105 ppm (characteristics of monomeric insulin) are particularly distinct signatures of the conformation change that accompanies dimerization. Magnetization transfer experiments show that the 0.105 ppm methyl signal shifts downfield to a new position at 0.45 ppm. We conclude that the 0.105 ppm methyl signal is due to a conformation in which a Leu methyl group is centered over and in van der Waals contact with the ring of an aromatic side chain. Dimerization causes a conformation change that alters this interaction, thereby causing the downfield shift. Nuclear Overhauser studies indicate that the methyl group involved is located within a cluster of aromatic side chains and that the closest ring-methyl group interaction is with the ring of PheB24.

Circulating ApoJ is closely associated with insulin resistance in human subjects.

PubMed

Seo, Ji A; Kang, Min-Cheol; Ciaraldi, Theodore P; Kim, Sang Soo; Park, Kyong Soo; Choe, Charles; Hwang, Won Min; Lim, Dong Mee; Farr, Olivia; Mantzoros, Christos; Henry, Robert R; Kim, Young-Bum

2018-01-01

Insulin resistance is a major risk factor for type 2 diabetes. ApolipoproteinJ (ApoJ) has been implicated in altered pathophysiologic states including cardiovascular and Alzheimer's disease. However, the function of ApoJ in regulation of glucose homeostasis remains unclear. This study sought to determine whether serum ApoJ levels are associated with insulin resistance in human subjects and if they change after interventions that improve insulin sensitivity. Serum ApoJ levels and insulin resistance status were assessed in nondiabetic (ND) and type 2 diabetic (T2D) subjects. The impacts of rosiglitazone or metformin therapy on serum ApoJ levels and glucose disposal rate (GDR) during a hyperinsulinemic/euglycemic clamp were evaluated in a separate cohort of T2D subjects. Total ApoJ protein or that associated with the HDL and LDL fractions was measured by immunoblotting or ELISA. Fasting serum ApoJ levels were greatly elevated in T2D subjects (ND vs T2D; 100±8.3 vs. 150.6±8.5AU, P<0.0001). Circulating ApoJ levels strongly correlated with fasting glucose, fasting insulin, HOMA-IR, and BMI. ApoJ levels were significantly and independently associated with HOMA-IR, even after adjustment for age, sex, and BMI. Rosiglitazone treatment in T2D subjects resulted in a reduction in serum ApoJ levels (before vs. after treatment; 100±13.9 vs. 77±15.2AU, P=0.015), whereas metformin had no effect on ApoJ levels. The change in ApoJ levels during treatment was inversely associated with the change in GDR. Interestingly, ApoJ content in the LDL fraction was inversely associated with HOMA-IR. Serum ApoJ levels are closely correlated with the magnitude of insulin resistance regardless of obesity, and decrease along with improvement of insulin resistance in response only to rosiglitazone in type 2 diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanisms of combustion limits in premixed gas flames at microgravity

NASA Technical Reports Server (NTRS)

Ronney, Paul D.

1991-01-01

A three-year experimental and theoretical research program on the mechanisms of combustion limits of premixed gasflames at microgravity was conducted. Progress during this program is identified and avenues for future studies are discussed.

Study of Turbulent Premixed Flame Propagation using a Laminar Flamelet Model

NASA Technical Reports Server (NTRS)

Im, H. G.

1995-01-01

The laminar flamelet concept in turbulent reacting flows is considered applicable to many practical combustion systems (Linan & Williams 1993). For turbulent premixed combustion, the laminar flamelet regime is valid when turbulent Karlovitz number is less than unity, which is equivalent to stating that the characteristic thickness of the flame is less than that of a Kolmogorov eddy; this is known as the Klimov-Williams criterion (Williams 1985). In such a case, the flame maintains its laminar structure, and the effect of turbulent flow is merely to wrinkle and strain the flame front. The propagating wrinkled premixed flame can then be described as an infinitesimally thin surface dividing the unburnt fresh mixture and the burnt product.

Determination of human insulin in dog plasma by a selective liquid chromatography-tandem mass spectrometry method: Application to a pharmacokinetic study.

PubMed

Dong, Shiqi; Zeng, Yong; Wei, Guangli; Si, Duanyun; Liu, Changxiao

2018-03-01

A simple, sensitive and selective LC-MS/MS method for quantitative analysis of human insulin was developed and validated in dog plasma. Insulin glargine was used as the internal standard. After a simple step of solid-phase extraction, the chromatographic separation of human insulin was achieved by using InertSustain Bio C18 column with a mobile phase of acetonitrile containing 1% formic acid (A)-water containing 1% formic acid (B). The detection was performed by positive ion electrospray ionization in multiple-reaction monitoring (MRM) mode. Good linearity was observed in the concentration range of 1-1000 μIU/mL (r 2  > 0.99), and the lower limit of quantification was 1 μIU/mL (equal to 38.46 pg/mL). The intra- and inter-day precision (expressed as relative standard deviation, RSD) of human insulin were ≤12.1% and ≤13.0%, respectively, and the accuracy (expressed as relative error, RE) was in the range of -7.23-11.9%. The recovery and matrix effect were both within acceptable limits. This method was successfully applied for the pharmacokinetic study of human insulin in dogs after subcutaneous administration. Copyright © 2018 Elsevier B.V. All rights reserved.

Direct Numerical Simulation of a Cavity-Stabilized Ethylene/Air Premixed Flame

NASA Astrophysics Data System (ADS)

Chen, Jacqueline; Konduri, Aditya; Kolla, Hemanth; Rauch, Andreas; Chelliah, Harsha

2016-11-01

Cavity flame holders have been shown to be important for flame stabilization in scramjet combustors. In the present study the stabilization of a lean premixed ethylene/air flame in a rectangular cavity at thermo-chemical conditions relevant to scramjet combustors is simulated using a compressible reacting multi-block direct numerical simulation solver, S3D, incorporating a 22 species ethylene-air reduced chemical model. The fuel is premixed with air to an equivalence ratio of 0.4 and enters the computational domain at Mach numbers between 0.3 and 0.6. An auxiliary inert channel flow simulation is used to provide the turbulent velocity profile at the inlet for the reacting flow simulation. The detailed interaction between intense turbulence, nonequilibrium concentrations of radical species formed in the cavity and mixing with the premixed main stream under density variations due to heat release rate and compressibility effects is quantified. The mechanism for flame stabilization is quantified in terms of relevant non-dimensional parameters, and detailed analysis of the flame and turbulence structure will be presented. We acknowledge the sponsorship of the AFOSR-NSF Joint Effort on Turbulent Combustion Model Assumptions and the DOE Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences.

Modeling of Dissipation Element Statistics in Turbulent Non-Premixed Jet Flames

NASA Astrophysics Data System (ADS)

Denker, Dominik; Attili, Antonio; Boschung, Jonas; Hennig, Fabian; Pitsch, Heinz

2017-11-01

The dissipation element (DE) analysis is a method for analyzing and compartmentalizing turbulent scalar fields. DEs can be described by two parameters, namely the Euclidean distance l between their extremal points and the scalar difference in the respective points Δϕ . The joint probability density function (jPDF) of these two parameters P(Δϕ , l) is expected to suffice for a statistical reconstruction of the scalar field. In addition, reacting scalars show a strong correlation with these DE parameters in both premixed and non-premixed flames. Normalized DE statistics show a remarkable invariance towards changes in Reynolds numbers. This feature of DE statistics was exploited in a Boltzmann-type evolution equation based model for the probability density function (PDF) of the distance between the extremal points P(l) in isotropic turbulence. Later, this model was extended for the jPDF P(Δϕ , l) and then adapted for the use in free shear flows. The effect of heat release on the scalar scales and DE statistics is investigated and an extended model for non-premixed jet flames is introduced, which accounts for the presence of chemical reactions. This new model is validated against a series of DNS of temporally evolving jet flames. European Research Council Project ``Milestone''.

The Effect of Premixed Al-Cu Powder on the Stir Zone in Friction Stir Welding of AA3003-H18

NASA Astrophysics Data System (ADS)

Abnar, B.; Kazeminezhad, M.; Kokabi, A. H.

2015-02-01

In this research, 3-mm-thick AA3003-H18 non-heat-treatable aluminum alloy plates were joined by friction stir welding (FSW). It was performed by adding pure Cu and premixed Cu-Al powders at various rotational speeds of 800, 1000, and 1200 rpm and constant traveling speeds of 100 mm/min. At first, the powder was filled into the gap (0.2 or 0.4 mm) between two aluminum alloy plates, and then the FSW process was performed in two passes. The microstructure, mechanical properties, and formation of intermetallic compounds were investigated in both cases of using pure Cu and premixed Al-Cu powders. The results of using pure Cu and premixed Al-Cu powders were compared in the stir zone at various rotational speeds. The copper particle distribution and formation of Al-Cu intermetallic compounds (Al2Cu and AlCu) in the stir zone were desirable using premixed Al-Cu powder into the gap. The hardness values were significantly increased by formation of Al-Cu intermetallic compounds in the stir zone and it was uniform throughout the stir zone when premixed Al-Cu powder was used. Also, longitudinal tensile strength from the stir zone was higher when premixed Al-Cu powder was used instead of pure Cu powder.

UV-light exposure of insulin: pharmaceutical implications upon covalent insulin dityrosine dimerization and disulphide bond photolysis.

PubMed

Correia, Manuel; Neves-Petersen, Maria Teresa; Jeppesen, Per Bendix; Gregersen, Søren; Petersen, Steffen B

2012-01-01

In this work we report the effects of continuous UV-light (276 nm, ~2.20 W.m(-2)) excitation of human insulin on its absorption and fluorescence properties, structure and functionality. Continuous UV-excitation of the peptide hormone in solution leads to the progressive formation of tyrosine photo-product dityrosine, formed upon tyrosine radical cross-linkage. Absorbance, fluorescence emission and excitation data confirm dityrosine formation, leading to covalent insulin dimerization. Furthermore, UV-excitation of insulin induces disulphide bridge breakage. Near- and far-UV-CD spectroscopy shows that UV-excitation of insulin induces secondary and tertiary structure losses. In native insulin, the A and B chains are held together by two disulphide bridges. Disruption of either of these bonds is likely to affect insulin's structure. The UV-light induced structural changes impair its antibody binding capability and in vitro hormonal function. After 1.5 and 3.5 h of 276 nm excitation there is a 33.7% and 62.1% decrease in concentration of insulin recognized by guinea pig anti-insulin antibodies, respectively. Glucose uptake by human skeletal muscle cells decreases 61.7% when the cells are incubated with pre UV-illuminated insulin during 1.5 h. The observations presented in this work highlight the importance of protecting insulin and other drugs from UV-light exposure, which is of outmost relevance to the pharmaceutical industry. Several drug formulations containing insulin in hexameric, dimeric and monomeric forms can be exposed to natural and artificial UV-light during their production, packaging, storage or administration phases. We can estimate that direct long-term exposure of insulin to sunlight and common light sources for indoors lighting and UV-sterilization in industries can be sufficient to induce irreversible changes to human insulin structure. Routine fluorescence and absorption measurements in laboratory experiments may also induce changes in protein

Insulin-Increased L-Arginine Transport Requires A2A Adenosine Receptors Activation in Human Umbilical Vein Endothelium

PubMed Central

Guzmán-Gutiérrez, Enrique; Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

2012-01-01

Adenosine causes vasodilation of human placenta vasculature by increasing the transport of arginine via cationic amino acid transporters 1 (hCAT-1). This process involves the activation of A2A adenosine receptors (A2AAR) in human umbilical vein endothelial cells (HUVECs). Insulin increases hCAT-1 activity and expression in HUVECs, and A2AAR stimulation increases insulin sensitivity in subjects with insulin resistance. However, whether A2AAR plays a role in insulin-mediated increase in L-arginine transport in HUVECs is unknown. To determine this, we first assayed the kinetics of saturable L-arginine transport (1 minute, 37°C) in the absence or presence of nitrobenzylthioinosine (NBTI, 10 µmol/L, adenosine transport inhibitor) and/or adenosine receptors agonist/antagonists. We also determined hCAT-1 protein and mRNA expression levels (Western blots and quantitative PCR), and SLC7A1 (for hCAT-1) reporter promoter activity. Insulin and NBTI increased the extracellular adenosine concentration, the maximal velocity for L-arginine transport without altering the apparent K m for L-arginine transport, hCAT-1 protein and mRNA expression levels, and SLC7A1 transcriptional activity. An A2AAR antagonist ZM-241385 blocked these effects. ZM241385 inhibited SLC7A1 reporter transcriptional activity to the same extent in cells transfected with pGL3-hCAT-1−1606 or pGL3-hCAT-1−650 constructs in the presence of NBTI + insulin. However, SLC7A1 reporter activity was increased by NBTI only in cells transfected with pGL3-hCAT-1−1606, and the ZM-241385 sensitive fraction of the NBTI response was similar in the absence or in the presence of insulin. Thus, insulin modulation of hCAT-1 expression and activity requires functional A2AAR in HUVECs, a mechanism that may be applicable to diseases associated with fetal insulin resistance, such as gestational diabetes. PMID:22844517

Intraportal injection of insulin-producing cells generated from human bone marrow mesenchymal stem cells decreases blood glucose level in diabetic rats.

PubMed

Tsai, Pei-Jiun; Wang, Hwai-Shi; Lin, Chi-Hung; Weng, Zen-Chung; Chen, Tien-Hua; Shyu, Jia-Fwu

2014-01-01

We studied the process of trans-differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) into insulin-producing cells. Streptozotocin (STZ)-induced diabetic rat model was used to study the effect of portal vein transplantation of these insulin-producing cells on blood sugar levels. The BM-MSCs were differentiated into insulin-producing cells under defined conditions. Real-time PCR, immunocytochemistry and glucose challenge were used to evaluate in vitro differentiation. Flow cytometry showed that hBM-MSCs were strongly positive for CD44, CD105 and CD73 and negative for hematopoietic markers CD34, CD38 and CD45. Differentiated cells expressed C-peptide as well as β-cells specific genes and hormones. Glucose stimulation increased C-peptide secretion in these cells. The insulin-producing, differentiated cells were transplanted into the portal vein of STZ-induced diabetic rats using a Port-A catheter. The insulin-producing cells were localized in the liver of the recipient rat and expressed human C-peptide. Blood glucose levels were reduced in diabetic rats transplanted with insulin-producing cells. We concluded that hBM-MSCs could be trans-differentiated into insulin-producing cells in vitro. Portal vein transplantation of insulin-producing cells alleviated hyperglycemia in diabetic rats.

Dynamic properties of combustion instability in a lean premixed gas-turbine combustor.

PubMed

Gotoda, Hiroshi; Nikimoto, Hiroyuki; Miyano, Takaya; Tachibana, Shigeru

2011-03-01

We experimentally investigate the dynamic behavior of the combustion instability in a lean premixed gas-turbine combustor from the viewpoint of nonlinear dynamics. A nonlinear time series analysis in combination with a surrogate data method clearly reveals that as the equivalence ratio increases, the dynamic behavior of the combustion instability undergoes a significant transition from stochastic fluctuation to periodic oscillation through low-dimensional chaotic oscillation. We also show that a nonlinear forecasting method is useful for predicting the short-term dynamic behavior of the combustion instability in a lean premixed gas-turbine combustor, which has not been addressed in the fields of combustion science and physics.

Establishing bioequivalence of veterinary premixes (Type A medicated articles).

PubMed

Hunter, R P; Lees, P; Concordet, D; Toutain, P-L

2012-04-01

a) Key issues concerning Premix (Type A medicated articles) Bioequivalence evaluations: 1) This is a complex issue concerning both route of administration and formulation. 2) If the animal is not at the bunk/trough, the animal is not self-administering (eating medicated feed), thus there can be no drug absorption. b) Differing opinions among scientists and regulatory authorities/expert bodies regarding: 1) No harmonization on how to design, conduct, and interpret in vivo studies. 2) Applicability of biowaivers to Type A (premix) products. 3) Why are topdress and complete feed considered differently? Are they different formulations or different routes of administration? 4) Single dose vs. multi-dose studies. 5) What is the final formulation? c) What are the next steps: 1) Harmonize current bioequivalence guidelines through the VICH process. 2) Determine the applicability/non-applicability of the Biopharmaceutical Classification System (BCS). 3) Establish the Total Mixed Ration (i.e. formulation) effects. 4) Define the test subject (individual, pen, etc.). © 2012 Blackwell Publishing Ltd.

UV-Light Exposure of Insulin: Pharmaceutical Implications upon Covalent Insulin Dityrosine Dimerization and Disulphide Bond Photolysis

PubMed Central

Correia, Manuel; Neves-Petersen, Maria Teresa; Jeppesen, Per Bendix; Gregersen, Søren; Petersen, Steffen B.

2012-01-01

In this work we report the effects of continuous UV-light (276 nm, ∼2.20 W.m−2) excitation of human insulin on its absorption and fluorescence properties, structure and functionality. Continuous UV-excitation of the peptide hormone in solution leads to the progressive formation of tyrosine photo-product dityrosine, formed upon tyrosine radical cross-linkage. Absorbance, fluorescence emission and excitation data confirm dityrosine formation, leading to covalent insulin dimerization. Furthermore, UV-excitation of insulin induces disulphide bridge breakage. Near- and far-UV-CD spectroscopy shows that UV-excitation of insulin induces secondary and tertiary structure losses. In native insulin, the A and B chains are held together by two disulphide bridges. Disruption of either of these bonds is likely to affect insulin’s structure. The UV-light induced structural changes impair its antibody binding capability and in vitro hormonal function. After 1.5 and 3.5 h of 276 nm excitation there is a 33.7% and 62.1% decrease in concentration of insulin recognized by guinea pig anti-insulin antibodies, respectively. Glucose uptake by human skeletal muscle cells decreases 61.7% when the cells are incubated with pre UV-illuminated insulin during 1.5 h. The observations presented in this work highlight the importance of protecting insulin and other drugs from UV-light exposure, which is of outmost relevance to the pharmaceutical industry. Several drug formulations containing insulin in hexameric, dimeric and monomeric forms can be exposed to natural and artificial UV-light during their production, packaging, storage or administration phases. We can estimate that direct long-term exposure of insulin to sunlight and common light sources for indoors lighting and UV-sterilization in industries can be sufficient to induce irreversible changes to human insulin structure. Routine fluorescence and absorption measurements in laboratory experiments may also induce changes in protein

Endodermal differentiation of human pluripotent stem cells to insulin-producing cells in 3D culture

PubMed Central

Takeuchi, Hiroki; Nakatsuji, Norio; Suemori, Hirofumi

2014-01-01

Insulin-producing cells (IPCs) derived from human pluripotent stem cells (hPSCs) may be useful in cell therapy and drug discovery for diabetes. Here, we examined various growth factors and small molecules including those previously reported to develop a robust differentiation method for induction of mature IPCs from hPSCs. We established a protocol that induced PDX1-positive pancreatic progenitor cells at high efficiency, and further induced mature IPCs by treatment with forskolin, dexamethasone, Alk5 inhibitor II and nicotinamide in 3D culture. The cells that differentiated into INSULIN-positive and C-PEPTIDE-positive cells secreted insulin in response to glucose stimulation, indicating a functional IPC phenotype. We also found that this method was applicable to different types of hPSCs. PMID:24671046

Optimization of instant dalia dessert pre-mix production by using response surface methodology.

PubMed

Jha, Alok; Shalini, B N; Patel, Ashok Ambalal; Singh, Mithilesh; Rasane, Prasad

2015-02-01

Dalia, a wheat-based, particulate containing dairy dessert is popularly consumed as a breakfast food and is also considered as a health food. Though popular throughout Northern parts of the country, its limited shelf-life even under refrigeration imposes severe restrictions on its organized manufacture and marketing. In order to promote dalia dessert as a marketable product, in the present study, a process was developed for manufacture of instant dalia pre-mix, as a dry product with long shelf-life, which could be attractively packaged and easily reconstituted for consumption. During the investigation, the effect of different levels of milk solids and wheat solids was studied on dalia pre-mix quality by employing a central composite rotatable design (CCRD). The suggested formulation had 17.82 % milk solids and 2.87 % wheat solids. This formulation was found to be most appropriate for manufacture of instant dalia pre-mix with predicted sensory scores (Max. 100) of 85.35, 41.98 and 67.27 for mouthfeel, consistency and flavor, respectively; the viscosity of the product was 941.0 cp.

21 CFR 170.60 - Nitrites and/or nitrates in curing premixes.

Code of Federal Regulations, 2010 CFR

2010-04-01

... additives when combined in curing premixes with spices and/or other flavoring or seasoning ingredients that... hydrolyzed vegetable protein), oleoresins of spices, soy products, and spice extractives. Such food additives...

An Investigation of a Hybrid Mixing Timescale Model for PDF Simulations of Turbulent Premixed Flames

NASA Astrophysics Data System (ADS)

Zhou, Hua; Kuron, Mike; Ren, Zhuyin; Lu, Tianfeng; Chen, Jacqueline H.

2016-11-01

Transported probability density function (TPDF) method features the generality for all combustion regimes, which is attractive for turbulent combustion simulations. However, the modeling of micromixing due to molecular diffusion is still considered to be a primary challenge for TPDF method, especially in turbulent premixed flames. Recently, a hybrid mixing rate model for TPDF simulations of turbulent premixed flames has been proposed, which recovers the correct mixing rates in the limits of flamelet regime and broken reaction zone regime while at the same time aims to properly account for the transition in between. In this work, this model is employed in TPDF simulations of turbulent premixed methane-air slot burner flames. The model performance is assessed by comparing the results from both direct numerical simulation (DNS) and conventional constant mechanical-to-scalar mixing rate model. This work is Granted by NSFC 51476087 and 91441202.

The hybrid RANS/LES of partially premixed supersonic combustion using G/Z flamelet model

NASA Astrophysics Data System (ADS)

Wu, Jinshui; Wang, Zhenguo; Bai, Xuesong; Sun, Mingbo; Wang, Hongbo

2016-10-01

In order to describe partially premixed supersonic combustion numerically, G/Z flamelet model is developed and compared with finite rate model in hybrid RANS/LES simulation to study the strut-injection supersonic combustion flow field designed by the German Aerospace Center. A new temperature calculation method based on time-splitting method of total energy is introduced in G/Z flamelet model. Simulation results show that temperature predictions in partially premixed zone by G/Z flamelet model are more consistent with experiment than finite rate model. It is worth mentioning that low temperature reaction zone behind the strut is well reproduced. Other quantities such as average velocity and average velocity fluctuation obtained by developed G/Z flamelet model are also in good agreement with experiment. Besides, simulation results by G/Z flamelet also reveal the mechanism of partially premixed supersonic combustion by the analyses of the interaction between turbulent burning velocity and flow field.

Premixing quality and flame stability: A theoretical and experimental study

NASA Technical Reports Server (NTRS)

Radhakrishnan, K.; Heywood, J. B.; Tabaczynski, R. J.

1979-01-01

Models for predicting flame ignition and blowout in a combustor primary zone are presented. A correlation for the blowoff velocity of premixed turbulent flames is developed using the basic quantities of turbulent flow, and the laminar flame speed. A statistical model employing a Monte Carlo calculation procedure is developed to account for nonuniformities in a combustor primary zone. An overall kinetic rate equation is used to describe the fuel oxidation process. The model is used to predict the lean ignition and blow out limits of premixed turbulent flames; the effects of mixture nonuniformity on the lean ignition limit are explored using an assumed distribution of fuel-air ratios. Data on the effects of variations in inlet temperature, reference velocity and mixture uniformity on the lean ignition and blowout limits of gaseous propane-air flames are presented.

Protein Kinase-C Beta Contributes to Impaired Endothelial Insulin Signaling in Humans with Diabetes Mellitus

PubMed Central

Tabit, Corey E; Shenouda, Sherene M; Holbrook, Monica; Fetterman, Jessica L; Kiani, Soroosh; Frame, Alissa A; Kluge, Matthew A; Held, Aaron; Dohadwala, Mustali; Gokce, Noyan; Farb, Melissa; Rosenzweig, James; Ruderman, Neil; Vita, Joseph A; Hamburg, Naomi M

2013-01-01

Background Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling through the activity of protein kinase C-β (PKCβ) and nuclear factor κB (NFκB) reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus. Methods and Results We measured protein expression and insulin response in freshly isolated endothelial cells from patients with Type 2 diabetes mellitus (n=40) and non-diabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes (P=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in non-diabetic subjects but not in diabetic patients (P=0.003) consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients indicating endothelial oxidative stress. PKCβ expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=−0.541, P=0.02) Inhibition of PKCβ with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes. Endothelial NFκB activation was higher in diabetes and was reduced with PKCβ inhibition. Conclusions We provide evidence for the presence of altered eNOS activation, reduced insulin action and inflammatory activation in the endothelium of patients with diabetes. Our findings implicate PKCβ activity in endothelial insulin resistance. PMID:23204109

Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

PubMed Central

Ingelsson, Erik; Langenberg, Claudia; Hivert, Marie-France; Prokopenko, Inga; Lyssenko, Valeriya; Dupuis, Josée; Mägi, Reedik; Sharp, Stephen; Jackson, Anne U.; Assimes, Themistocles L.; Shrader, Peter; Knowles, Joshua W.; Zethelius, Björn; Abbasi, Fahim A.; Bergman, Richard N.; Bergmann, Antje; Berne, Christian; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Buchanan, Thomas A.; Bumpstead, Suzannah J.; Böttcher, Yvonne; Chines, Peter; Collins, Francis S.; Cooper, Cyrus C.; Dennison, Elaine M.; Erdos, Michael R.; Ferrannini, Ele; Fox, Caroline S.; Graessler, Jürgen; Hao, Ke; Isomaa, Bo; Jameson, Karen A.; Kovacs, Peter; Kuusisto, Johanna; Laakso, Markku; Ladenvall, Claes; Mohlke, Karen L.; Morken, Mario A.; Narisu, Narisu; Nathan, David M.; Pascoe, Laura; Payne, Felicity; Petrie, John R.; Sayer, Avan A.; Schwarz, Peter E. H.; Scott, Laura J.; Stringham, Heather M.; Stumvoll, Michael; Swift, Amy J.; Syvänen, Ann-Christine; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Tönjes, Anke; Valle, Timo T.; Williams, Gordon H.; Lind, Lars; Barroso, Inês; Quertermous, Thomas; Walker, Mark; Wareham, Nicholas J.; Meigs, James B.; McCarthy, Mark I.; Groop, Leif; Watanabe, Richard M.; Florez, Jose C.

2010-01-01

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. PMID:20185807

Laser-saturated fluorescence of nitric oxide and chemiluminescence measurements in premixed ethanol flames

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marques, Carla S.T.; Barreta, Luiz G.; Sbampato, Maria E.

In this study, nitric oxide laser-saturated fluorescence (LSF) measurements were acquired from premixed ethanol flames at atmospheric pressure in a burner. NO-LSF experimental profiles for fuel-rich premixed ethanol flames ({phi} = 1.34 and {phi} = 1.66) were determined through the excitation/detection scheme of the Q{sub 2}(26.5) rotational line in the A{sup 2}{sigma}{sup +} - X{sup 2}{pi} (0,0) vibronic band and {gamma}(0,1) emission band. A calibration procedure by NO doping into the flame was applied to establish the NO concentration profiles in these flames. Chemiluminescent emission measurements in the (0, 0) vibronic emission bands of the OH{sup *} (A{sup 2}{sigma}{sup +}more » - X{sup 2}{pi}) and CH{sup *}(A{sup 2}{delta} - X{sup 2}{pi}) radicals were also obtained with high spatial and spectral resolution for fuel-rich premixed ethanol flames to correlate them with NO concentrations. Experimental chemiluminescence profiles and the ratios of the integrated areas under emission spectra (A{sub CH*}/A{sub CH*}(max.) and A{sub CH*}/A{sub OH*}) were determined. The relationships between chemiluminescence and NO concentrations were established along the premixed ethanol flames. There was a strong connection between CH{sup *} radical chemiluminescence and NO formation and the prompt-NO was identified as the governing mechanism for NO production. The results suggest the optimum ratio of the chemiluminescence of two radicals (A{sub CH*}/A{sub OH*}) for NO diagnostic purposes. (author)« less

Combining insulins for optimal blood glucose control in type 1 and 2 diabetes: Focus on insulin glulisine

PubMed Central

Ulrich, Heather; Snyder, Benjamin; K Garg, Satish

2007-01-01

Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM)-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs) reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI). Insulin glulisine (Apidra®) is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs). The safety and tolerability profile of insulin glulisine is also comparable to that of insulin lispro or RHI in type 1 or 2 DM and it has been shown to be as safe and effective when used in a continuous subcutaneous insulin infusion (CSII). In summary, insulin glulisine is a safe, effective, and well tolerated rapid-acting insulin analogue across all BMIs and a worthy option for prandial

Release of skeletal muscle peptide fragments identifies individual proteins degraded during insulin deprivation in type 1 diabetic humans and mice.

PubMed

Robinson, Matthew M; Dasari, Surendra; Karakelides, Helen; Bergen, H Robert; Nair, K Sreekumaran

2016-09-01

Insulin regulates skeletal muscle protein degradation, but the types of proteins being degraded in vivo remain to be determined due to methodological limitations. We present a method to assess the types of skeletal muscle proteins that are degraded by extracting their degradation products as low-molecular weight (LMW) peptides from muscle samples. High-resolution mass spectrometry was used to identify the original intact proteins that generated the LMW peptides, which we validated in rodents and then applied to humans. We deprived insulin from insulin-treated streptozotocin (STZ) diabetic mice for 6 and 96 h and for 8 h in type 1 diabetic humans (T1D) for comparison with insulin-treated conditions. Protein degradation was measured using activation of autophagy and proteasome pathways, stable isotope tracers, and LMW approaches. In mice, insulin deprivation activated proteasome pathways and autophagy in muscle homogenates and isolated mitochondria. Reproducibility analysis of LMW extracts revealed that ∼80% of proteins were detected consistently. As expected, insulin deprivation increased whole body protein turnover in T1D. Individual protein degradation increased with insulin deprivation, including those involved in mitochondrial function, proteome homeostasis, nDNA support, and contractile/cytoskeleton. Individual mitochondrial proteins that generated more LMW fragment with insulin deprivation included ATP synthase subunit-γ (+0.5-fold, P = 0.007) and cytochrome c oxidase subunit 6 (+0.305-fold, P = 0.03). In conclusion, identifying LMW peptide fragments offers an approach to determine the degradation of individual proteins. Insulin deprivation increases degradation of select proteins and provides insight into the regulatory role of insulin in maintaining proteome homeostasis, especially of mitochondria. Copyright © 2016 the American Physiological Society.

Release of skeletal muscle peptide fragments identifies individual proteins degraded during insulin deprivation in type 1 diabetic humans and mice

PubMed Central

Robinson, Matthew M.; Dasari, Surendra; Karakelides, Helen; Bergen, H. Robert

2016-01-01

Insulin regulates skeletal muscle protein degradation, but the types of proteins being degraded in vivo remain to be determined due to methodological limitations. We present a method to assess the types of skeletal muscle proteins that are degraded by extracting their degradation products as low-molecular weight (LMW) peptides from muscle samples. High-resolution mass spectrometry was used to identify the original intact proteins that generated the LMW peptides, which we validated in rodents and then applied to humans. We deprived insulin from insulin-treated streptozotocin (STZ) diabetic mice for 6 and 96 h and for 8 h in type 1 diabetic humans (T1D) for comparison with insulin-treated conditions. Protein degradation was measured using activation of autophagy and proteasome pathways, stable isotope tracers, and LMW approaches. In mice, insulin deprivation activated proteasome pathways and autophagy in muscle homogenates and isolated mitochondria. Reproducibility analysis of LMW extracts revealed that ∼80% of proteins were detected consistently. As expected, insulin deprivation increased whole body protein turnover in T1D. Individual protein degradation increased with insulin deprivation, including those involved in mitochondrial function, proteome homeostasis, nDNA support, and contractile/cytoskeleton. Individual mitochondrial proteins that generated more LMW fragment with insulin deprivation included ATP synthase subunit-γ (+0.5-fold, P = 0.007) and cytochrome c oxidase subunit 6 (+0.305-fold, P = 0.03). In conclusion, identifying LMW peptide fragments offers an approach to determine the degradation of individual proteins. Insulin deprivation increases degradation of select proteins and provides insight into the regulatory role of insulin in maintaining proteome homeostasis, especially of mitochondria. PMID:27436610

In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor δ reflects donors' insulin sensitivity in vivo.

PubMed

Ordelheide, Anna-Maria; Heni, Martin; Thamer, Claus; Machicao, Fausto; Fritsche, Andreas; Stefan, Norbert; Häring, Hans-Ulrich; Staiger, Harald

2011-12-01

Peroxisome proliferator-activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity. Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR. Donors' insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp. Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0·0312 and P = 0·0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors' insulin sensitivity (P > 0·2, all). Treatment of myotubes with a selective high-affinity PPARδ agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13- and 16-fold, respectively (P < 0·0001, both). The individual PDK4 and ANGPTL4 expression levels reached upon GW501516 treatment were associated with donors' insulin sensitivity neither (P > 0·2, both). However, GW501516-mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARδ responsiveness, were positively associated with donors' insulin sensitivity derived from OGTT (P = 0·0182 and P = 0·0231, respectively) and hyperinsulinemic-euglycemic clamp (P = 0·0046 and P = 0·0258, respectively). Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARδ, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

Insulin Reverses D-Glucose–Increased Nitric Oxide and Reactive Oxygen Species Generation in Human Umbilical Vein Endothelial Cells

PubMed Central

González, Marcelo; Rojas, Susana; Avila, Pía; Cabrera, Lissette; Villalobos, Roberto; Palma, Carlos; Aguayo, Claudio; Peña, Eduardo; Gallardo, Victoria; Guzmán-Gutiérrez, Enrique; Sáez, Tamara; Salsoso, Rocío; Sanhueza, Carlos; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

2015-01-01

Vascular tone is controlled by the L-arginine/nitric oxide (NO) pathway, and NO bioavailability is strongly affected by hyperglycaemia-induced oxidative stress. Insulin leads to high expression and activity of human cationic amino acid transporter 1 (hCAT-1), NO synthesis and vasodilation; thus, a protective role of insulin on high D-glucose–alterations in endothelial function is likely. Vascular reactivity to U46619 (thromboxane A2 mimetic) and calcitonin gene related peptide (CGRP) was measured in KCl preconstricted human umbilical vein rings (wire myography) incubated in normal (5 mmol/L) or high (25 mmol/L) D-glucose. hCAT-1, endothelial NO synthase (eNOS), 42 and 44 kDa mitogen-activated protein kinases (p42/44mapk), protein kinase B/Akt (Akt) expression and activity were determined by western blotting and qRT-PCR, tetrahydrobiopterin (BH4) level was determined by HPLC, and L-arginine transport (0–1000 μmol/L) was measured in response to 5–25 mmol/L D-glucose (0–36 hours) in passage 2 human umbilical vein endothelial cells (HUVECs). Assays were in the absence or presence of insulin and/or apocynin (nicotinamide adenine dinucleotide phosphate-oxidase [NADPH oxidase] inhibitor), tempol or Mn(III)TMPyP (SOD mimetics). High D-glucose increased hCAT-1 expression and activity, which was biphasic (peaks: 6 and 24 hours of incubation). High D-glucose–increased maximal transport velocity was blocked by insulin and correlated with lower hCAT-1 expression and SLC7A1 gene promoter activity. High D-glucose–increased transport parallels higher reactive oxygen species (ROS) and superoxide anion (O2 •–) generation, and increased U46619-contraction and reduced CGRP-dilation of vein rings. Insulin and apocynin attenuate ROS and O2 •– generation, and restored vascular reactivity to U46619 and CGRP. Insulin, but not apocynin or tempol reversed high D-glucose–increased NO synthesis; however, tempol and Mn(III)TMPyP reversed the high D-glucose–reduced BH4

Effect of magnesium supplementation on insulin resistance in humans: A systematic review.

PubMed

Morais, Jennifer Beatriz Silva; Severo, Juliana Soares; de Alencar, Geórgia Rosa Reis; de Oliveira, Ana Raquel Soares; Cruz, Kyria Jayanne Clímaco; Marreiro, Dilina do Nascimento; Freitas, Betânia de Jesus E Silva de Almendra; de Carvalho, Cecília Maria Resende; Martins, Maria do Carmo de Carvalho E; Frota, Karoline de Macedo Gonçalves

2017-06-01

Recent studies have demonstrated that minerals play a role in glucose metabolism disorders in humans. Magnesium, in particular, is an extensively studied mineral that has been shown to function in the management of hyperglycemia, hyperinsulinemia, and insulin resistance (IR) action. The aim of this study was to investigate the effect of magnesium supplementation on IR in humans via systematic review of the available clinical trials. This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. A survey was conducted to select clinical trials related to the effects of this mineral in insulin sensitivity using the following databases: PubMed, SciVerse Scopus, ScienceDirect, and SciVerse Cochrane. After the selection process, 12 articles were identified as eligible, representing different clinical conditions and being free of restriction with regard to sex, age, ethnicity, and differential dosing/shape of magnesium. The results of eight clinical trials showed that supplementation with magnesium influences serum fasting glucose concentrations, and five trials determined an effect on fasting insulin levels. The results of seven studies demonstrated that mineral supplementation reduced homeostasis model assessment for IR values. The data of this systematic review provide evidence as to the benefits of magnesium supplementation in reducing IR in patients with hypomagnesemia presenting IR. However, new intervention studies are needed to elucidate the role of the nutrient in protection against this metabolic disorder, as well as the standardization of the type, dose, and time of magnesium supplementation. Copyright © 2017 Elsevier Inc. All rights reserved.

Insulin Delivery System

NASA Technical Reports Server (NTRS)

1988-01-01

When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

Insulin-producing cells could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells

PubMed Central

2013-01-01

Objective The aim of this study was to compare the difference between insulin-producing cells (IPCs) and normal human pancreatic beta cells both in physiological function and morphological features in cellular level. Methods The levels of insulin secretion were measured by enzyme-linked immunosorbent assay. The insulin gene expression was determined by real-time quantitative polymerase chain reaction. The morphological features were detected by atomic force microscopy (AFM) and laser confocal scanning microscopy. Results IPCs and normal human pancreatic beta cells were similar to each other under the observation in AFM with the porous structure features in the cytoplasm. Both number of membrane particle size and average roughness of normal human beta cells were higher than those of IPCs. Conclusions Our results firstly revealed that the cellular ultrastructure of IPCs was closer to that of normal human pancreatic beta cells, but they still could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells. PMID:23421382

Soot Formation in Laminar Premixed Methane/Oxygen Flames at Atmospheric Pressure

NASA Technical Reports Server (NTRS)

Xu, F.; Lin, K.-C.; Faeth, G. M.

1998-01-01

Flame structure and soot formation were studied within soot-containing laminar premixed mc1hane/oxygen flames at atmospheric pressure. The following measurements were made: soot volume fractions by laser extinction, soot temperatures by multiline emission, gas temperatures (where soot was absent) by corrected fine-wire thermocouples, soot structure by thermophoretic sampling and transmission electron microscope (TEM), major gas species concentrations by sampling and gas chromatography, and gas velocities by laser velocimetry. Present measurements of gas species concentrations were in reasonably good agreement with earlier measurements due to Ramer et al. as well as predictions based on the detailed mechanisms of Frenklach and co-workers and Leung and Lindstedt: the predictions also suggest that H atom concentrations are in local thermodynamic equilibrium throughout the soot formation region. Using this information, it was found that measured soot surface growth rates could be correlated successfully by predictions based on the hydrogen-abstraction/carbon-addition (HACA) mechanisms of both Frenklach and co-workers and Colket and Hall, extending an earlier assessment of these mechanisms for premixed ethylene/air flames to conditions having larger H/C ratios and acetylene concentrations. Measured primary soot particle nucleation rates were somewhat lower than the earlier observations for laminar premixed ethylene/air flames and were significantly lower than corresponding rates in laminar diffusion flames. for reasons that still must be explained.

Optimizing inpatient glycemic control with basal-bolus insulin therapy.

PubMed

Pollom, R Daniel

2010-11-01

Hyperglycemia is highly prevalent in the acute-care setting and is associated with an increased risk of morbidity and mortality. Evidence suggests that glycemic control in this population is suboptimal, due in part to continued use of nonphysiologic sliding-scale insulin strategies without scheduled basal insulin doses or prandial insulin with concomitant correction doses. Although the ineffectiveness and risks of sliding-scale insulin regimens have been criticized for decades, sliding-scale insulin is still the most commonly prescribed subcutaneous insulin regimen among inpatients. Improving inpatient management requires the use of scheduled basal-bolus insulin therapy that includes basal insulin, nutritional insulin, and supplemental, or correctional, insulin. Insulin analogs are the preferred insulins, as they provide a more physiologic action than human insulin regimens, are associated with a lower risk of hypoglycemia, and are more convenient to administer than human insulins. Standardized insulin protocols and subcutaneous insulin order sets are critical components of effective inpatient glycemic control. Although preliminary data have demonstrated that inpatient diabetes management programs involving basal-bolus insulin therapy are effective and well tolerated, more research is needed.

Regulation of Endogenous (Male) Rodent GLP-1 Secretion and Human Islet Insulin Secretion by Antagonism of Somatostatin Receptor 5.

PubMed

Farb, Thomas B; Adeva, Marta; Beauchamp, Thomas J; Cabrera, Over; Coates, David A; Meredith, Tamika DeShea; Droz, Brian A; Efanov, Alexander; Ficorilli, James V; Gackenheimer, Susan L; Martinez-Grau, Maria A; Molero, Victoriano; Ruano, Gema; Statnick, Michael A; Suter, Todd M; Syed, Samreen K; Toledo, Miguel A; Willard, Francis S; Zhou, Xin; Bokvist, Krister B; Barrett, David G

2017-11-01

Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Agents including sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit; however, their modes of action limit efficacy. Because somatostatin (SST) has been shown to suppress insulin and glucagonlike peptide-1 (GLP-1) secretion through the Gi-coupled SST receptor 5 (SSTR5) isoform in vitro, antagonism of SSTR5 may improve glycemic control via intervention in both pathways. Here, we show that a potent and selective SSTR5 antagonist reverses the blunting effects of SST on insulin secretion from isolated human islets, and demonstrate that SSTR5 antagonism affords increased levels of systemic GLP-1 in vivo. Knocking out Sstr5 in mice provided a similar increase in systemic GLP-1 levels, which were not increased further by treatment with the antagonist. Treatment of mice with the SSTR5 antagonist in combination with a DPP4i resulted in increases in systemic GLP-1 levels that were more than additive and resulted in greater glycemic control compared with either agent alone. In isolated human islets, the SSTR5 antagonist completely reversed the inhibitory effect of exogenous SST-14 on insulin secretion. Taken together, these data suggest that SSTR5 antagonism should increase circulating GLP-1 levels and stimulate insulin secretion (directly and via GLP-1) in humans, improving glycemic control in patients with diabetes. Copyright © 2017 Endocrine Society.

Design of insulin analogues for meal-related therapy.

PubMed

Brange, J

1993-01-01

The human insulin in replacement therapy has a hexameric structure. Hexamerization of the insulin molecule facilitates biosynthesis and beta-cell storage of insulin, but is unnecessary for biologic activity and appears to contribute to delayed absorption of exogenous insulin from the subcutis. Insulin analogues with reduced self-association that are produced through recombinant DNA techniques have been shown to have in vivo activity comparable to that of human insulin and absorption kinetics characterized by higher and more constant rates of disappearance from the subcutaneous injection site. In preliminary studies in patients receiving insulin therapy, monomeric insulin analogues have been found to provide glycemic control in the postprandial period that is at least equivalent to that of human insulin. Findings in these studies suggest that the use of such analogues may provide meal-related insulin effects closer to those observed in the physiologic state by limiting excessive postprandial glucose excursions and decreasing the risk of late hypoglycemia. Banting and Best revolutionized diabetes therapy 70 years ago with the extraction of insulin from animal pancreas glands (J Lab Clin Med 7:464-472, 1922). Since that time, many refinements of the therapeutic properties of pharmaceutical preparations of the hormone have been introduced. Until recently, however, such advances have been limited to improvements in insulin purity, insulin species, and adjustment of the composition of the vehicle with respect to auxiliary substances and other additives. With the advent of recombinant DNA techniques, it has become possible to optimize the insulin molecule itself for purposes of replacement therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermodynamic and kinetic studies of As2O3 toxicological effects on human insulin in generation diabetes mellitus

NASA Astrophysics Data System (ADS)

Mohsennia, Mohsen; Motaharinejad, Atieh; Rafiee-Pour, Hossain-Ali; Torabbeigi, Marzieh

2017-12-01

The interaction of arsenic trioxide with human insulin was investigated by circular dichroism (CD), cyclic voltammetry and electrophoresis techniques. The interfacial behavior of insulin in presence of As2O3 onto the Ag electrode surface was studied at 310 K in phosphate buffer solution (PBS). According to Far-UV CD spectroscopy results, As2O3 caused to decrease in structural compactness and variety of alpha helix into beta structures. Near-UV CD indicated that As2O3 dissociates disulfide linkage in insulin structure. The kinetic parameters, including charge-transfer coefficient and apparent heterogeneous electron transfer rate constant were also determined. The thermodynamic parameters of insulin denaturation in presence of arsenic trioxide were calculated and reported. The obtained results indicated strong adsorption of insulin in presence of arsenic trioxide onto the Ag surface via chemisorptions.

Human insulin polymorphism upon ligand binding and pH variation: the case of 4-ethylresorcinol.

PubMed

Fili, S; Valmas, A; Norrman, M; Schluckebier, G; Beckers, D; Degen, T; Wright, J; Fitch, A; Gozzo, F; Giannopoulou, A E; Karavassili, F; Margiolaki, I

2015-09-01

This study focuses on the effects of the organic ligand 4-ethylresorcinol on the crystal structure of human insulin using powder X-ray crystallography. For this purpose, systematic crystallization experiments have been conducted in the presence of the organic ligand and zinc ions within the pH range 4.50-8.20, while observing crystallization behaviour around the isoelectric point of insulin. High-throughput crystal screening was performed using a laboratory X-ray diffraction system. The most representative samples were selected for synchrotron X-ray diffraction measurements, which took place at the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS). Four different crystalline polymorphs have been identified. Among these, two new phases with monoclinic symmetry have been found, which are targets for the future development of microcrystalline insulin drugs.

Human insulin polymorphism upon ligand binding and pH variation: the case of 4-ethylresorcinol

PubMed Central

Fili, S.; Valmas, A.; Norrman, M.; Schluckebier, G.; Beckers, D.; Degen, T.; Wright, J.; Fitch, A.; Gozzo, F.; Giannopoulou, A. E.; Karavassili, F.; Margiolaki, I.

2015-01-01

This study focuses on the effects of the organic ligand 4-ethylresorcinol on the crystal structure of human insulin using powder X-ray crystallography. For this purpose, systematic crystallization experiments have been conducted in the presence of the organic ligand and zinc ions within the pH range 4.50–8.20, while observing crystallization behaviour around the isoelectric point of insulin. High-throughput crystal screening was performed using a laboratory X-ray diffraction system. The most representative samples were selected for synchrotron X-ray diffraction measurements, which took place at the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS). Four different crystalline polymorphs have been identified. Among these, two new phases with monoclinic symmetry have been found, which are targets for the future development of microcrystalline insulin drugs. PMID:26306195

Understanding and predicting soot generation in turbulent non-premixed jet flames.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Hai; Kook, Sanghoon; Doom, Jeffrey

2010-10-01

This report documents the results of a project funded by DoD's Strategic Environmental Research and Development Program (SERDP) on the science behind development of predictive models for soot emission from gas turbine engines. Measurements of soot formation were performed in laminar flat premixed flames and turbulent non-premixed jet flames at 1 atm pressure and in turbulent liquid spray flames under representative conditions for takeoff in a gas turbine engine. The laminar flames and open jet flames used both ethylene and a prevaporized JP-8 surrogate fuel composed of n-dodecane and m-xylene. The pressurized turbulent jet flame measurements used the JP-8 surrogatemore » fuel and compared its combustion and sooting characteristics to a world-average JP-8 fuel sample. The pressurized jet flame measurements demonstrated that the surrogate was representative of JP-8, with a somewhat higher tendency to soot formation. The premixed flame measurements revealed that flame temperature has a strong impact on the rate of soot nucleation and particle coagulation, but little sensitivity in the overall trends was found with different fuels. An extensive array of non-intrusive optical and laser-based measurements was performed in turbulent non-premixed jet flames established on specially designed piloted burners. Soot concentration data was collected throughout the flames, together with instantaneous images showing the relationship between soot and the OH radical and soot and PAH. A detailed chemical kinetic mechanism for ethylene combustion, including fuel-rich chemistry and benzene formation steps, was compiled, validated, and reduced. The reduced ethylene mechanism was incorporated into a high-fidelity LES code, together with a moment-based soot model and models for thermal radiation, to evaluate the ability of the chemistry and soot models to predict soot formation in the jet diffusion flame. The LES results highlight the importance of including an optically

NMR structure of biosynthetic engineered human insulin monomer B31(Lys)-B32(Arg) in water/acetonitrile solution. Comparison with the solution structure of native human insulin monomer.

PubMed

Bocian, Wojciech; Borowicz, Piotr; Mikołajczyk, Jerzy; Sitkowski, Jerzy; Tarnowska, Anna; Bednarek, Elzbieta; Głabski, Tadeusz; Tejchman-Małecka, Bozena; Bogiel, Monika; Kozerski, Lech

2008-10-01

A solution NMR-derived structure of a new long -acting, B31(Lys)-B32(Arg) (LysArg), engineered human insulin monomer, in H(2)O/CD(3)CN, 65/35 vol %, pH 3.6, is presented and compared with the available X-ray structure of a monomer that forms part of a hexamer (Smith, et al., Acta Crystallogr D 2003, 59, 474) and with NMR structure of human insulin in the same solvent (Bocian, et al., J Biomol NMR 2008, 40, 55-64). Detailed analysis using PFGSE NMR (Pulsed Field Gradient Spin Echo NMR) in dilution experiments and CSI analysis prove that the structure is monomeric in the concentration range 0.1-3 mM. The presence of long-range interstrand NOEs in a studied structure, relevant to the distances found in the crystal structure of the monomer, provides the evidence for conservation of the tertiary structure. Therefore the results suggest that this solvent system is a suitable medium for studying the native conformation of the protein, especially in situations (as found for insulins) in which extensive aggregation renders structure elucidations in water difficult or impossible. Starting from the structures calculated by the program CYANA, two different molecular dynamics (MD) simulated annealing refinement protocols were applied, either using the program AMBER in vacuum (AMBER_VC), or including a generalized Born solvent model (AMBER_GB). Here we present another independent evidence to the one presented recently by us (Bocian et al., J Biomol NMR 2008, 40, 55-64), that in water/acetonitrile solvent detailed structural and dynamic information can be obtained for important proteins that are naturally present as oligomers under native conditions. (c) 2008 Wiley Periodicals, Inc.

Direct numerical simulation of a high Ka CH 4/air stratified premixed jet flame

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Haiou; Hawkes, Evatt R.; Savard, Bruno

Here, direct numerical simulation (DNS) of a high Karlovitz number (Ka) CH 4/air stratified premixed jet flame was performed and used to provide insights into fundamentals of turbulent stratified premixed flames and their modelling implications. The flame exhibits significant stratification where the central jet has an equivalence ratio of 0.4, which is surrounded by a pilot flame with an equivalence ratio of 0.9. A reduced chemical mechanism for CH 4/air combustion based on GRI-Mech3.0 was used, including 268 elementary reactions and 28 transported species.

Direct numerical simulation of a high Ka CH 4/air stratified premixed jet flame

DOE PAGES

Wang, Haiou; Hawkes, Evatt R.; Savard, Bruno; ...

2018-04-24

Here, direct numerical simulation (DNS) of a high Karlovitz number (Ka) CH 4/air stratified premixed jet flame was performed and used to provide insights into fundamentals of turbulent stratified premixed flames and their modelling implications. The flame exhibits significant stratification where the central jet has an equivalence ratio of 0.4, which is surrounded by a pilot flame with an equivalence ratio of 0.9. A reduced chemical mechanism for CH 4/air combustion based on GRI-Mech3.0 was used, including 268 elementary reactions and 28 transported species.

Commercial premixed parenteral nutrition: Is it right for your institution?

PubMed

Miller, Sarah J

2009-01-01

Two-compartment premixed parenteral nutrition (PN) products are heavily promoted in the United States. These products may present safety advantages over PN solutions mixed by a local pharmacy, although clinical data to support this assertion are scarce. Multicompartment products can be labor-saving for pharmacy and therefore may be cost-effective for some institutions. Before adopting such products for use, an institution must determine that standardized PN solutions are acceptable for many or most of their patients compared with customized PN compounded specifically for individual patients. A larger selection of premixed products is available in Europe and some other parts of the world compared with the United States. Availability of a broader selection of products in the United States, including 3-compartment bags and a wider range of macronutrient concentrations and volumes, may make the use of such products more desirable in the future.

Premixed calcium silicate cement for endodontic applications: injectability, setting time and radiopacity.

PubMed

Persson, Cecilia; Engqvist, Håkan

2011-01-01

Calcium silicate-based materials (also called MTA) are increasingly being used in endodontic applications. However, the handling properties of MTA are not optimal when it comes to injectability and cohesion. Premixing the cements using glycerol avoids these issues. However, there is a lack of data on the effect of common cement variables on important properties of premixed cements for endodontic applications. In this study, the effects of liquid-to-powder ratio, amount of radiopacifier and amount of calcium sulfate (added to control the setting time) were screened using a statistical model. In the second part of the study, the liquid-to-powder ratio was optimized for cements containing three different amounts of radiopacifier. Finally, the effect of using glycerol rather than water was evaluated in terms of radiopacity. The setting time was found to increase with the amount of radiopacifier when the liquid-to-powder ratio was fixed. This was likely due to the higher density of the radiopacifier in comparison to the calcium silicate, which gave a higher liquid-to-powder ratio in terms of volume. Using glycerol rather than water to mix the cements led to a decrease in radiopacity of the cement. In conclusion, we were able to produce premixed calcium silicate cements with acceptable properties for use in endodontic applications.

On the Structure and Stabilization Mechanisms of Planar and Cylindrical Premixed Flames

NASA Technical Reports Server (NTRS)

Eng, James A.; Zhu, Delin; Law, Chung K.

1993-01-01

The configurational simplicity of the stationary one-dimensional flames renders them intrinsically attractive for fundamental flame structure studies. The possibility and fidelity of studies of such flames on earth, however, have been severely restricted by the unidirectional nature of the gravity vector. To demonstrate these complications, let us first consider the premixed flame. Here a stationary, one-dimensional flame can be established by using the flat-flame burner. We next consider nonpremixed flames. First it may be noted that in an unbounded gravity-free environment, the only stationary one-dimensional flame is the spherical flame. Indeed, this is a major motivation for the study of microgravity droplet combustion, in which the gas-phase processes can be approximated to be quasi-steady because of the significant disparity between the gas and liquid densities for subcritical combustion. In view of the above considerations, an experimental and theoretical program on cylindrical and spherical premixed and nonpremixed flames in microgravity has been initiated. For premixed flames, we are interested in: (1) assessing the heat loss versus flow divergence as the dominant stabilization mechanism; (2) determining the laminar flame speed by using this configuration; and (3) understanding the development of flamefront instability and the effects of the flame curvature on the burning intensity.

Development of Criteria for Flameholding Tendencies within Premixer Passages for High Hydrogen Content Fuels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, Elliot Sullivan-; McDonell, Vincent G.

Due to increasingly stringent air quality requirements stationary power gas turbines have moved to lean-premixed operation, which reduces pollutant emissions but can result in flashback. Flashback can cause serious damage to the premixer hardware. Curtailing flashback can be difficult with hydrocarbon fuels and becomes even more challenging when hydrogen is used as the fuel. The two main approaches for coping with flashback are either to design a combustor that is resistant to flashback, or to design a premixer that will not anchor a flame if flashback occurs. Even with a well-designed combustor flashback can occur under certain circumstances, thus itmore » is necessary to determine how to avoid flameholding within the premixer passageways of a gas turbine. To this end, an experiment was designed that would determine the flameholding propensities at elevated pressures and temperatures of three different classes of geometric features commonly found in gas turbine premixers, with both natural gas and hydrogen fuel. Experiments to find the equivalence ratio at blow off were conducted within an optically accessible test apparatus with four flameholders: 0.25 and 0.50 inch diameter cylinders, a reverse facing step with a height of 0.25 inches, and a symmetric airfoil with a thickness of 0.25 inches and a chord length of one inch. Tests were carried out at temperatures between 300 K and 750 K, at pressures up to 9 atmospheres. Typical bulk velocities were between 40 and 100 m/s. The effect of airfoil’s angle of rotation was also investigated. Blow off for hydrogen flames was found to occur at much lower adiabatic flame temperatures than natural gas flames. Additionally it was observed that at high pressures and high turbulence intensities, reactant velocity does not have a noticeable effect on the point of blow off due in large part to corresponding increases in turbulent flame speed. Finally a semi empirical correlation was developed that predicts flame extinction

Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance

PubMed Central

Hoeks, Joris; van Herpen, Noud A.; Mensink, Marco; Moonen-Kornips, Esther; van Beurden, Denis; Hesselink, Matthijs K.C.; Schrauwen, Patrick

2010-01-01

OBJECTIVE Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function. RESEARCH DESIGN AND METHODS While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry. RESULTS Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density. CONCLUSIONS These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible

An Information Theoretical Analysis of Human Insulin-Glucose System Toward the Internet of Bio-Nano Things.

PubMed

Abbasi, Naveed A; Akan, Ozgur B

2017-12-01

Molecular communication is an important tool to understand biological communications with many promising applications in Internet of Bio-Nano Things (IoBNT). The insulin-glucose system is of key significance among the major intra-body nanonetworks, since it fulfills metabolic requirements of the body. The study of biological networks from information and communication theoretical (ICT) perspective is necessary for their introduction in the IoBNT framework. Therefore, the objective of this paper is to provide and analyze for the first time in the literature, a simple molecular communication model of the human insulin-glucose system from ICT perspective. The data rate, channel capacity, and the group propagation delay are analyzed for a two-cell network between a pancreatic beta cell and a muscle cell that are connected through a capillary. The results point out a correlation between an increase in insulin resistance and a decrease in the data rate and channel capacity, an increase in the insulin transmission rate, and an increase in the propagation delay. We also propose applications for the introduction of the system in the IoBNT framework. Multi-cell insulin glucose system models may be based on this simple model to help in the investigation, diagnosis, and treatment of insulin resistance by means of novel IoBNT applications.

Insulin Action is Blocked by a Monoclonal Antibody That Inhibits the Insulin Receptor Kinase

NASA Astrophysics Data System (ADS)

Morgan, David O.; Ho, Lisa; Korn, Laurence J.; Roth, Richard A.

1986-01-01

Thirty-six monoclonal antibodies to the human insulin receptor were produced. Thirty-four bound the intracellular domain of the receptor β subunit, the domain containing the tyrosine-specific kinase activity. Of these 34 antibodies, 33 recognized the rat receptor and 1 was shown to precipitate the receptors from mice, chickens, and frogs with high affinity. Another of the antibodies inhibited the kinase activities of the human and frog receptors with equal potencies. This antibody inhibited the kinase activities of these receptors by more than 90%, whereas others had no effect on either kinase activity. Microinjection of the inhibiting antibody into Xenopus oocytes blocked the ability of insulin to stimulate oocyte maturation. In contrast, this inhibiting antibody did not block the ability of progesterone to stimulate the same response. Furthermore, control immunoglobulin and a noninhibiting antibody to the receptor β subunit did not block this response to insulin. These results strongly support a role for the tyrosine-specific kinase activity of the insulin receptor in mediating this biological effect of insulin.

Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

PubMed Central

Colombo, Carlo; Porzio, Ottavia; Liu, Ming; Massa, Ornella; Vasta, Mario; Salardi, Silvana; Beccaria, Luciano; Monciotti, Carla; Toni, Sonia; Pedersen, Oluf; Hansen, Torben; Federici, Luca; Pesavento, Roberta; Cadario, Francesco; Federici, Giorgio; Ghirri, Paolo; Arvan, Peter; Iafusco, Dario; Barbetti, Fabrizio

2008-01-01

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM. PMID:18451997

Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women.

PubMed

Kullmann, Stephanie; Frank, Sabine; Heni, Martin; Ketterer, Caroline; Veit, Ralf; Häring, Hans-Ulrich; Fritsche, Andreas; Preissl, Hubert

2013-01-01

There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy. Copyright © 2012 S. Karger AG, Basel.

The route of liquid precursor to ZnO nanoparticles in premixed combustion spray pyrolysis

NASA Astrophysics Data System (ADS)

Widiyastuti, W.; Machmudah, Siti; Nurtono, Tantular; Winardi, Sugeng

2018-04-01

Zinc oxide nanoparticles had been successfully synthesized by premixed combustion spray pyrolysis. Zinc acetate was dissolved in distilled water was selected as a liquid precursor. Zinc nitrate was also used for comparison the effect of precursor type on the generated particles morphology and the crystallinity. The premixed combustion reaction used liquefied petroleum gas (LPG) mainly consisting of butane and propane as a fuel and compressed air used as an oxidizer. The liquid precursor was atomized using a custom two fluid nozzle to generate droplets. Then, the droplets were sprayed by the flow of air as a carrier gas into the premixed combustion reactor. The zinc precursor was decomposed to zinc oxide due to the high temperature as a result of combustion reaction inside the reactor resulting in nanoparticles formation. The particle size decreased with the increase of the fuel flow rate. In addition, it can be found that at the same flow rate of fuel, the particle size of zinc oxide synthesized using zinc nitrate is larger than that of the use of zinc acetate as a precursor.

Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity

PubMed Central

Díaz-Ruiz, Alberto; Guzmán-Ruiz, Rocío; Moreno, Natalia R.; García-Rios, Antonio; Delgado-Casado, Nieves; Membrives, Antonio; Túnez, Isaac; El Bekay, Rajaa; Fernández-Real, José M.; Tovar, Sulay; Diéguez, Carlos; Tinahones, Francisco J.; Vázquez-Martínez, Rafael; López-Miranda, José

2015-01-01

Abstract Aims: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. Results: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. Innovation: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. Conclusion: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity. Antioxid. Redox Signal. 23, 597–612. PMID:25714483

Effects of Non-Equilibrium Plasmas on Low-Pressure, Premixed Flames. Part 1: CH* Chemiluminescence, Temperature, and OH

DTIC Science & Technology

2018-01-16

1    Effects of Non -Equilibrium Plasmas on Low-Pressure, Premixed Flames. Part 1: CH* Chemiluminescence, Temperature, and OH Ting Li, Igor V...investigate the effects of nanosecond, repetitively-pulsed, non -equilibrium plasma discharges on laminar, low-pressure, premixed burner-stabilized hydrogen/O2...sources, both of which generate uniform, low-temperature, volumetric, non -equilibrium plasma discharges, are used to study changes in

Insulin Resistance and Mitochondrial Dysfunction.

PubMed

Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

2017-01-01

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

Familial hyperinsulinemia associated with secretion of an abnormal insulin, and coexistence of insulin resistance in the propositus.

PubMed

Vinik, A I; Seino, S; Funakoshi, A; Schwartz, J; Matsumoto, M; Schteingart, D E; Fu, Z Z; Tsai, S T

1986-04-01

A 45-yr-old muscular nonobese white man who had a 9-yr history of syncopal episodes was studied on several occasions between April 1979 and August 1984. Fasting glucose concentrations ranged between 74-115 mg/dl, and those of insulin ranged between 14-64 microU/ml. Reactive hypoglycemia 3-4 h after ingestion of glucose occurred in the first 2 yr. Glucose tolerance was impaired in 1979, from February 1982 through September 1983, and again in August 1984. The maximum plasma insulin response to glucose ranged between 475-1630 microU/ml. When studied in November 1982, insulin (0.1 U/kg) caused a fall in blood glucose concentration of only 25% (normal, greater than 50%), and maximal glucose utilization during the euglycemic hyperinsulinemic clamp was 7.5 mg/kg . min (normal, greater than 12 mg/kg . min). Plasma counterregulatory hormone concentrations were normal, and antibodies to insulin and the insulin receptor were absent. Binding of exogenous insulin to the patient's cellular receptors (monocytes, red blood cells, and skin fibroblasts) was normal. Insulin was purified from plasma by immunoaffinity and molecular sieve chromatography and was found to elute later than human insulin on reversed phase high performance liquid chromatography. It was more hydrophobic than normal human insulin and had only 10% of the activity of normal insulin in terms of ability to bind to and stimulate glucose metabolism in isolated rat adipocytes. The abnormal insulin was identified in two of three sons and a sister, but not in the mother, brother, or niece. Sensitivity to insulin was normal in the two sons who had abnormal insulin. These results suggest that in this family the abnormal insulin was due to a biosynthetic defect, inherited as an autosomal dominant trait. The hyperinsulinemia was not associated with diabetes in family members who had no insulin resistance.

Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle.

PubMed

Treebak, J T; Frøsig, C; Pehmøller, C; Chen, S; Maarbjerg, S J; Brandt, N; MacKintosh, C; Zierath, J R; Hardie, D G; Kiens, B; Richter, E A; Pilegaard, H; Wojtaszewski, J F P

2009-05-01

TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. Insulin stimulation increased glucose uptake in both legs, with greater effects (approximately 80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.

Large Eddy Simulation of Flame Flashback in Swirling Premixed Flames

NASA Astrophysics Data System (ADS)

Lietz, Christopher; Raman, Venkatramanan

2014-11-01

In the design of high-hydrogen content gas turbines for power generation, flashback of the turbulent flame by propagation through the low velocity boundary layers in the premixing region is an operationally dangerous event. Predictive models that could accurately capture the onset and subsequent behavior of flashback would be indispensable in gas turbine design. The large eddy simulation (LES) approach is used here to model this process. The goal is to examine the validity of a probability distribution function (PDF) based model in the context of a lean premixed flame in a confined geometry. A turbulent swirling flow geometry and corresponding experimental data is used for validation. A suite of LES calculations are performed on a large unstructured mesh for varying fuel compositions operating at several equivalence ratios. It is shown that the PDF based method can predict some statistical properties of the flame front, with improvement over other models in the same application.

Evaluation of fuel preparation systems for lean premixing-prevaporizing combustors

NASA Technical Reports Server (NTRS)

Dodds, W. J.; Ekstedt, E. E.

1985-01-01

A series of experiments was carried out in order to produce design data for a premixing prevaporizing fuel-air mixture preparation system for aircraft gas turbine engine combustors. The fuel-air mixture uniformity of four different system design concepts was evaluated over a range of conditions representing the cruise operation of a modern commercial turbofan engine. Operating conditions including pressure, temperature, fuel-to-air ratio, and velocity, exhibited no clear effect on mixture uniformity of systems using pressure-atomizing fuel nozzles and large-scale mixing devices. However, the performance of systems using atomizing fuel nozzles and large-scale mixing devices was found to be sensitive to operating conditions. Variations in system design variables were also evaluated and correlated. Mixing uniformity was found to improve with system length, pressure drop, and the number of fuel injection points per unit area. A premixing system capable of providing mixing uniformity to within 15 percent over a typical range of cruise operating conditions is demonstrated.

Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice.

PubMed

Sengupta, Anshuman; Patel, Peysh A; Yuldasheva, Nadira Y; Mughal, Romana S; Galloway, Stacey; Viswambharan, Hema; Walker, Andrew M N; Aziz, Amir; Smith, Jessica; Ali, Noman; Mercer, Ben N; Imrie, Helen; Sukumar, Piruthivi; Wheatcroft, Stephen B; Kearney, Mark T; Cubbon, Richard M

2018-05-15

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We asked whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor haploinsufficient mice (IRKO) were crossed with mice expressing a human insulin receptor transgene in the endothelium (hIRECO), to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO in glucose- and insulin-tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild-type littermates. These phenotypic changes were associated with enhanced basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro, but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

Human Recombinant Insulin 1g - ug

NASA Technical Reports Server (NTRS)

2004-01-01

Proteins are the building blocks of our bodies and the living world around us. Within our bodies proteins make it possible for red blood cells to carry oxygen throughout the body. Others help transmit nerve impulses so we can hear, smell and feel the world around us. While others play a crucial role in preventing or causing disease. If the structure of a protein is known, then companies can develop new or improved drugs to fight the disease of which the protein is a part. To determine protein structure, researchers must grow near-perfect crystals of the protein. On Earth convection currents, sedimentation and other gravity-induced phenomena hamper crystal growth efforts. In microgravity researchers can grow near-perfect crystals in an environment free of these effects. Because of the enormous potential for new pharmaceutical products the Center for Macromolecular Crystallography--the NASA Commercial Space Center responsible for commercial protein crystal growth efforts has more than fifty major industry and academic partners. Research on crystals of human insulin could lead to improved treatments for diabetes.

Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans.

PubMed

Newsom, Sean A; Brozinick, Joseph T; Kiseljak-Vassiliades, Katja; Strauss, Allison N; Bacon, Samantha D; Kerege, Anna A; Bui, Hai Hoang; Sanders, Phil; Siddall, Parker; Wei, Tao; Thomas, Melissa; Kuo, Ming Shang; Nemkov, Travis; D'Alessandro, Angelo; Hansen, Kirk C; Perreault, Leigh; Bergman, Bryan C

2016-06-01

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D (P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH (P < 0.05), tended to be elevated in OB vs. ATH (P = 0.07), and was inversely related to insulin sensitivity among the entire cohort (r = -0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio. Copyright © 2016 the American Physiological Society.

Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans

PubMed Central

Newsom, Sean A.; Brozinick, Joseph T.; Kiseljak-Vassiliades, Katja; Strauss, Allison N.; Bacon, Samantha D.; Kerege, Anna A.; Bui, Hai Hoang; Sanders, Phil; Siddall, Parker; Wei, Tao; Thomas, Melissa; Kuo, Ming Shang; Nemkov, Travis; D'Alessandro, Angelo; Hansen, Kirk C.; Perreault, Leigh

2016-01-01

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D (P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH (P < 0.05), tended to be elevated in OB vs. ATH (P = 0.07), and was inversely related to insulin sensitivity among the entire cohort (r = −0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio. PMID:27032901

Lowest Glucose Variability and Hypoglycemia Are Observed With the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study).

PubMed

Bajaj, Harpreet S; Venn, Karri; Ye, Chenglin; Patrick, Avril; Kalra, Shivani; Khandwala, Hasnain; Aslam, Nadeem; Twum-Barima, David; Aronson, Ronnie

2017-02-01

There is a dearth of published literature comparing glucose variability (GV) between different insulin regimens in type 2 diabetes. This cohort study compares GV using continuous glucose monitoring (CGM) in patients with well-controlled type 2 diabetes using four common insulin regimens: basal insulin + oral drugs (BO), basal insulin + glucagon-like peptide 1 receptor agonist (GLP-1 RA) (BGLP), premixed insulin (PM), and basal-bolus insulin (BB). Consecutive patients from three endocrinology clinics who met study criteria-type 2 diabetes, age 18 to 80 years, BMI ≤ 45 kg/m 2 , stable insulin regimen for a minimum of 6 months, and stable A1C value ≤7.5% (58 mmol/mol) before study enrollment-underwent 6-day masked CGM. Hypoglycemia was defined as a sensor glucose concentration <70 mg/dL on CGM. A total of 160 patients with comparable baseline characteristics formed four equal insulin regimen cohorts. The daily glucose SD (the primary outcome) was significantly lower in the BGLP cohort versus the BO, PM, and BB cohorts (P = 0.03, P = 0.01, and P < 0.01, respectively), and remained so after adjusting for age, BMI, type 2 diabetes duration, and A1C. Similarly, daily hypoglycemia outcomes on CGM were least for the BGLP cohort. The lowest GV and lowest hypoglycemia were observed in patients using the combination of basal insulin with a GLP-1 RA, supporting the complementary glycemic action of these agents in type 2 diabetes. These observed benefits in GV and hypoglycemia may contribute to the cardiovascular outcome reduction seen with GLP-1 RA therapy and should be investigated further. © 2017 by the American Diabetes Association.

Amino group of salicylic acid exhibits enhanced inhibitory potential against insulin amyloid fibrillation with protective aptitude toward amyloid induced cytotoxicity.

PubMed

Zaman, Masihuz; Khan, Mohsin Vahid; Zakariya, Syed Mohammad; Nusrat, Saima; Meeran, Syed Mustapha; Alam, Parvez; Ajmal, Mohammad Rehan; Wahiduzzaman, Wahiduzzaman; Shahein, Yasser E; Abouelella, Amira M; Khan, Rizwan Hasan

2018-05-01

Protein misfolding and aggregation lead to amyloid generation that in turn may induce cell membrane disruption and leads to cell apoptosis. In an effort to prevent or treat amyloidogenesis, large number of studies has been paying attention on breakthrough of amyloid inhibitors. In the present work, we aim to access the effect of two drugs, that is, acetylsalicylic acid and 5-amino salicylic acid on insulin amyloids by using various biophysical, imaging, cell viability assay, and computational approaches. We established that both drugs reduce the turbidity, light scattering and fluorescence intensity of amyloid indicator dye thioflavin T. Premixing of drugs with insulin inhibited the nucleation phase and inhibitory potential was boosted by increasing the concentration of the drug. Moreover, addition of drugs at the studied concentrations attenuated the insulin fibril induced cytotoxicity in breast cancer cell line MDA-MB-231. Our results highlight the amino group of salicylic acid exhibited enhanced inhibitory effects on insulin fibrillation in comparison to acetyl group. It may be due to presence of amino group that helps it to prolong the nucleation phase with strong binding as well as disruption of aromatic and hydrophobic stacking that plays a key role in amyloid progression. © 2017 Wiley Periodicals, Inc.

Assessment of implantable infusion pumps for continuous infusion of human insulin in rats: potential for group housing.

PubMed

Jensen, Vivi Flou Hjorth; Mølck, Anne-Marie; Mårtensson, Martin; Strid, Mette Aagaard; Chapman, Melissa; Lykkesfeldt, Jens; Bøgh, Ingrid Brück

2017-06-01

Group housing is considered to be important for rats, which are highly sociable animals. Single housing may impact behaviour and levels of circulating stress hormones. Rats are typically used in the toxicological evaluation of insulin analogues. Human insulin (HI) is frequently used as a reference compound in these studies, and a comparator model of persistent exposure by HI infusion from external pumps has recently been developed to support toxicological evaluation of long-acting insulin analogues. However, this model requires single housing of the animals. Developing an insulin-infusion model which allows group housing would therefore greatly improve animal welfare. The aim of the present study was to investigate the suitability of implantable infusion pumps for HI infusion in group-housed rats. Group housing of rats implanted with a battery-driven pump proved to be possible. Intravenous infusion of HI lowered blood glucose levels persistently for two weeks, providing a comparator model for use in two-week repeated-dose toxicity studies with new long-acting insulin analogues, which allows group housing, and thereby increasing animal welfare compared with an external infusion model.

Albert Renold Memorial Lecture: Molecular Background of Nutritionally Induced Insulin Resistance Leading to Type 2 Diabetes – From Animal Models to Humans

PubMed Central

Shafrir, Eleazar

2001-01-01

Albert Renold strived to gain insight into the abnormalities of human diabetes by defining the pathophysiology of the disease peculiar to a given animal. He investigated the Israeli desert-derived spiny mice (Acomys cahirinus), which became obese on fat-rich seed diet. After a few months hyperplasia and hypertrophy of β-cells occurred leading to a sudden rupture, insulin loss and ketosis. Spiny mice were low insulin responders, which is probably a characteristic of certain desert animals, protecting against insulin oversecretion when placed on an abundant diet. We have compared the response to overstimulation of several mutant diabetic species and nutritionally induced nonmutant animals when placed on affluent diet. Some endowed with resilient β-cells sustain long-lasting oversecretion, compensating for the insulin resistance, without lapsing into overt diabetes. Some with labile beta cells exhibit apoptosis and lose their capacity of coping with insulin resistance after a relatively short period. The wide spectrum of response to insulin resistance among different diabetes prone species seems to represent the varying response of human beta cells among the populations. In search for the molecular background of insulin resistance resulting from overnutrition we have studied the Israeli desert gerbil Psammomys obesus (sand rat), which progresses through hyperinsulinemia, followed by hyperglycemia and irreversible beta cell loss. Insulin resistance was found to be the outcome of reduced activation of muscle insulin receptor tyrosine kinase by insulin, in association with diminished GLUT4 protein and DNA content and overexpression of PKC isoenzymes, notably of PKCε. This overexpression and translocation to the membrane was discernible even prior to hyperinsulinemia and may reflect the propensity to diabetes in nondiabetic species and represent a marker for preventive action. By promoting the phosphorylation of serine/threonine residues on certain proteins of the

Differentiation of PDX1 gene-modified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro.

PubMed

He, Dongmei; Wang, Juan; Gao, Yangjun; Zhang, Yuan

2011-12-01

Mesenchymal stem cells (MSCs) have significant advantages over other stem cell types, and greater potential for immediate clinical application. MSCs would be an interesting cellular source for treatment of type 1 diabetes. In this study, MSCs from human umbilical cord were differentiated into functional insulin-producing cells in vitro by introduction of the pancreatic and duodenal homeobox factor 1 (PDX1) and in the presence of induction factors. The expressions of cell surface antigens were detected by flow cytometry. After induction in an adipogenic medium or an osteogenic medium, the cells were observed by Oil Red O staining and alkaline phosphatase staining. Recombinant adenovirus carrying the PDX1 gene was constructed and MSCs were infected by the recombinant adenovirus, then treated with several inducing factors for differentiation into islet β-like cells. The expression of the genes and protein related to islet β-cells was detected by immunocytochemistry, RT-PCR and Western blot analysis. Insulin and C-peptide secretion were assayed. Our results show that the morphology and immunophenotype of MSCs from human umbilical cord were similar to those present in human bone marrow. The MSCs could be induced to differentiate into osteocytes and adipocytes. After induction by recombined adenovirus vector with induction factors, MSCs were aggregated and presented islet-like bodies. Dithizone staining of these cells was positive. The genes' expression related to islet β-cells was found. After induction, insulin and C-peptide secretion in the supernatant were significantly increased. In conclusion, our results demonstrated that PDX1 gene-modified human umbilical cord mesenchymal stem cells could be differentiated into insulin-producing cells in vitro.

Insulin Aspart in the Management of Diabetes Mellitus: 15 Years of Clinical Experience.

PubMed

Hermansen, Kjeld; Bohl, Mette; Schioldan, Anne Grethe

2016-01-01

Limiting excessive postprandial glucose excursions is an important component of good overall glycemic control in diabetes mellitus. Pharmacokinetic studies have shown that insulin aspart, which is structurally identical to regular human insulin except for the replacement of a single proline amino acid with an aspartic acid residue, has a more physiologic time-action profile (i.e., reaches a higher peak and reaches that peak sooner) than regular human insulin. As expected with this improved pharmacokinetic profile, insulin aspart demonstrates a greater glucose-lowering effect compared with regular human insulin. Numerous randomized controlled trials and a meta-analysis have also demonstrated improved postprandial control with insulin aspart compared with regular human insulin in patients with type 1 or type 2 diabetes, as well as efficacy and safety in children, pregnant patients, hospitalized patients, and patients using continuous subcutaneous insulin infusion. Studies have demonstrated that step-wise addition of insulin aspart is a viable intensification option for patients with type 2 diabetes failing on basal insulin. Insulin aspart has shown a good safety profile, with no evidence of increased receptor binding, mitogenicity, stimulation of anti-insulin antibodies, or hypoglycemia compared with regular human insulin. In one meta-analysis, there was evidence of a lower rate of nocturnal hypoglycemia compared with regular human insulin and, in a trial that specifically included patients with a history of recurrent hypoglycemia, a significantly lower rate of severe hypoglycemic episodes. The next generation of insulin aspart (faster-acting insulin aspart) is being developed with a view to further improving on these pharmacokinetic/pharmacodynamic properties.

Branched chain amino acid suppressed insulin-initiated proliferation of human cancer cells through induction of autophagy.

PubMed

Wubetu, Gizachew Yismaw; Utsunomiya, Tohru; Ishikawa, Daichi; Ikemoto, Tetsuya; Yamada, Shinichiro; Morine, Yuji; Iwahashi, Shuichi; Saito, Yu; Arakawa, Yusuke; Imura, Satoru; Arimochi, Hideki; Shimada, Mitsuo

2014-09-01

Branched chain amino acid (BCAA) dietary supplementation inhibits activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis in diabetic animal models. However, the in vitro effect of BCAA on human cancer cell lines under hyper-insulinemic conditions remains unclear. Colon (HCT-116) and hepatic (HepG2) tumor cells were treated with varying concentrations of BCAA with or without fluorouracil (5-FU). The effect of BCAA on insulin-initiated proliferation was determined. Gene and protein expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. BCAA supplementation had no significant effect on cell proliferation and did not show significant synergistic or antagonistic effects with 5-FU. However, BCAA significantly decreased insulin-initiated proliferation of human colon and hepatic cancer cell lines in vitro. BCAA supplementation caused a marked decrease in activated IGF-IR expression and significantly enhanced both mRNA and protein expression of LC3-II and BECN1 (BECLIN-1). BCAA could be a useful chemopreventive modality for cancer in hyperinsulinemic conditions. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Inhibition of Insulin Degrading Enzyme and Insulin Degradation by UV-Killed Lactobacillus acidophilus.

PubMed

Neyazi, Nadia; Motevaseli, Elahe; Khorramizadeh, Mohammad Reza; Mohammadi Farsani, Taiebeh; Nouri, Zahra; Nasli Esfahani, Ensieh; Ghahremani, Mohammad Hossein

2018-05-11

Probiotics have beneficial effects on management of type 2 diabetes (T2D). The major hallmarks of T2D are insulin deficiency and insulin resistance which emphasize insulin therapy in onset of disease. Lactobacilli such as Lactobacillus acidophilus ( L. acidophilus ) have well known properties on prevention of T2D and insulin resistance but not on insulin degradation. Insulin-degrading enzyme (IDE) degrades insulin in the human body. We studied the effects of cell-free supernatant (CFS) and ultraviolet (UV)-killed L. acidophilus (ATCC 314) on IDE activity and insulin degradation in vitro. Cell growth inhibition by CFS and UV-killed L. acidophilus (ATCC 314) was studied and Western blotting and a fluoregenic assay was performed to determine IDE expression and its activity, respectively. Insulin degradation was evaluated by sandwich enzyme-linked immunosorbent assay(ELISA). IDE expression and activity was reduced by CFS and UV-killed L. acidophilus (ATCC 314). Although, decreased enzyme expression and activity was not significant for CFS in contrast to MRL (MRS with same pH as CFS). Also, reduction in IDE activity was not statistically considerable when compared to IDE expression. Insulin degradation was increased by CFS but decreased by UV-killed L. acidophilus (ATCC 314).

Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control.

PubMed

Chisalita, Simona I; Lindström, Torbjörn; Eson Jennersjö, Pär; Paulsson, Johan F; Westermark, Gunilla T; Olsson, Anders G; Arnqvist, Hans J

2009-03-01

Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

An Evolutionary Perspective on Basal Insulin in Diabetes Treatment: Role of Insulin Therapy In Diabetes.

PubMed

Rodbard, Helena W

2016-10-01

The availability of human insulin and subsequently insulin analogs that more closely mimic the body's physiology have contributed to increased safety in patients with diabetes and a greater role in patients with T2DM. This greater role is supported by clear evidence that early use of insulin in T2DM results in long-term improvements in glycemic control and beta-cell function compared with oral agents.

Comparison of the impact of human vs analogue insulins on glycosylated haemoglobin in a population with diabetes mellitus.

PubMed

Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro

2016-12-01

To compare the effect on metabolic control of treatment with conventional and analogue insulins for patients with diabetes mellitus. Retrospective cohort study held in cities of Colombia (Pereira and Manizales). People insured by the paid healthcare system, who were diagnosed with diabetes mellitus type 1 and 2, and treated with conventional and analogue insulin for at least 6 months prior to the start of the study were sampled and followed up for 18 months. Data were collected from clinical records for each patient. Treatment groups were compared according to the type of insulin received. A total of 313 patients were included; overall, 56.9% were women and the mean age was 57.3 years. No statistically significant difference was found in glycosylated haemoglobin reduction at 3, 6 and 18 months when comparing patients receiving glargine vs NPH insulin (P=.403) and NPH plus zinc crystalline insulin vs glargine plus glulisine (P=.514). The percentage of patients with metabolic control increased from 27.8% to 34.2% during follow-up with all types of insulin. Insulin analogues were not superior to human insulin for glycaemic control. A significant proportion of patients did not attain the treatment goals; therefore, it is necessary to implement measures to improve the monitoring and control of diabetes mellitus. © 2016 John Wiley & Sons Ltd.

An Audit of Insulin Usage and Insulin Injection Practices in a Large Indian Cohort

PubMed Central

Baruah, Manash P.; Kalra, Sanjay; Bose, Saptarshi; Deka, Jumi

2017-01-01

Introduction: Insulin remains the cornerstone of therapy in a substantial number of patients with type 2 diabetes mellitus (T2DM). Inadequate knowledge regarding insulin usage is likely to influence its acceptance and adherence, and outcome of therapy, underscoring great need to investigate knowledge, attitude, and practice of insulin usage in patients with T2DM. Methodology: A cross-sectional registry-based retrospective study analyzed data collected from 748 respondents (male: 466, female: 282), mostly from high or middle economic status, who were enrolled as outpatient in a referral clinic during last 10 years (2006–2016), to assess the general characteristics of patients with type 2 diabetes and their baseline knowledge, attitude, and practice of insulin usage and injection practices. Results: Mean ± standard deviation (SD) of duration of diabetes was 12.24 ± 7.60 years and mean ± SD duration of insulin therapy was 3.42 ± 4.18 years, which was initiated after a mean ± SD diabetes duration of 8.80 ± 6.42 years. Mean insulin dose per kilogram of body weight/day was 0.51 ± 0.27 units. Total daily dose of insulin was 33.36 ± 18.44 units and number of injections/day (mean ± SD) was 2.06 ± 0.73. Among the respondents, 58.96% were on human insulin and 35.70% were on analog insulin. Pen devices were used by 66.08% of the population whereas 31.76% used insulin syringes. The prevalence of lipohypertrophy (LH) was 12.57%, which was significantly (P < 0.001) associated with wrong technique with regard to injection angle (10.45% vs. 23.02%), site of injection (7.00% vs. 30.51%), rotation of site of injection (0.88% vs. 17.66%), and reuse of needle (5.77% vs. 15.19%). LH was also significantly (P < 0.05) associated with the use of human (14.74%) compared to analog insulin (8.24%). Conclusion: The current study highlights the unique patterns of insulin usage and associated high prevalence of LH among insulin users in India. PMID:28553603

Structure of the Soot Growth Region of Laminar Premixer Methane/Oxygen Flames

NASA Technical Reports Server (NTRS)

Xu, F.; Faeth, G. M.

1999-01-01

Soot is a dominant feature of hydrocarbon/air flames, affecting their reaction mechanisms and structure. As a result, soot processes affect capabilities for computational combustion as well as predictions of flame radiation and pollution emissions. Motivated by these observations, the present investigation extended past work on soot growth in laminar premixed flames, seeking to evaluate model predictions of flame structure. Xu et al. report direct measurements of soot residence times, soot concentrations, soot structure, gas temperatures and gas compositions for premixed flames similar to those studied by Harris and Weiner and Ramer et al. respectively. It was found that predictions of major stable gas species concentrations based on mechanisms of Leung and Lindstedt and Frenklach and coworkers, were in good agreement with the measurements. The results were also used to evaluate the hydrogen-abstraction/carbon-addition (HACA) soot growth mechanisms of Frenklach and coworkers and Colket and Hall. It was found that these mechanisms were effective using quite reasonable correlations for the steric factors appearing in the theories. The successful evaluation of the HACA mechanism of soot growth in Refs. 1 and 2 is encouraging but one aspect of this evaluation is a concern. In particular, H-atom concentrations play a crucial role in the HACA mechanism and it was necessary to estimate these concentrations because they were not measured directly. These estimates were made assuming local thermodynamic equilibrium between H, and H based on measured temperatures and H2 concentrations and the equilibrium constant data of Kee et al.. This approach was justified by the flame structure predictions; nevertheless, direct evaluation of equilibrium estimates of H-atom concentrations in the soot growth regions of laminar premixed flames is needed to provide more convincing proof of this behavior. Thus, the objective of the present investigation was to complete new measurements of the

Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin.

PubMed

Khunti, K; Nikolajsen, A; Thorsted, B L; Andersen, M; Davies, M J; Paul, S K

2016-04-01

To investigate whether clinical inertia, the failure to intensify treatment regimens when required, exists in people with type 2 diabetes treated with basal insulin. This was a retrospective cohort study involving patients with type 2 diabetes in the UK Clinical Practice Research Datalink database between January 2004 and December 2011, with follow-up until December 2013. A total of 11 696 patients were included in the analysis. Among all patients, 36.5% had their treatment intensified during the study period; of these, the treatment of 50.0, 42.5 and 7.4% was intensified with bolus or premix insulin or glucagon-like peptide-1 receptor agonists, respectively. The median time from initiation of basal insulin to treatment intensification was 4.3 years [95% confidence interval (CI) 4.1, 4.6]. Among patients clinically eligible for treatment intensification [glycated haemoglobin (HbA1c) ≥7.5% (58 mmol/mol)], 30.9% had their treatment regimen intensified. The median time to intensification in this group was 3.7 years (95% CI 3.4, 4.0). Increasing age, duration of diabetes, oral antihyperglycaemic agent usage and Charlson comorbidity index score were associated with a significant delay in the time to intensification (p < 0.05). Among patients with HbA1c ≥7.5% (58 mmol/mol), 32.1% stopped basal insulin therapy. Strategies should be developed to increase the number of patients undergoing therapy intensification and to reduce the delay in intensifying therapy for suitable patients on basal insulin. Initiatives to support patients continuing on insulin are also required. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Interaction of turbulent premixed flames with combustion products: Role of stoichiometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coriton, Bruno Rene Leon; Frank, Jonathan H.; Gomez, Alessandro

Stabilization methods of turbulent flames often involve mixing of reactants with hot products of combustion. The stabilizing effect of combustion product enthalpy has been long recognized, but the role played by the chemical composition of the product gases is typically overlooked. We employ a counterflow system to pinpoint the effects of the combustion product stoichiometry on the structure of turbulent premixed flames under conditions of both stable burning and local extinction. To that end, a turbulent jet of lean-to-rich, CH 4/O 2/N 2-premixed reactants at a turbulent Reynolds number of 1050 was opposed to a stream of hot products ofmore » combustion that were generated in a preburner. While the combustion product stream temperature was kept constant, its stoichiometry was varied independently from that of the reactant stream, leading to reactant-to-product stratification of relevance to practical combustion systems. The detailed structure of the turbulent flame front was analyzed in two series of experiments using laser-induced fluorescence (LIF): joint CH 2O LIF and OH LIF measurements and joint CO LIF and OH LIF measurements. Results revealed that a decrease in local CH 2O+OH and CO+OH reaction rates coincide with the depletion of OH radicals in the vicinity of the combustion product stream. These critical combustion reaction rates were more readily quenched in the presence of products of combustion from a stoichiometric flame, whereas they were favored by lean combustion products. As a result, stoichiometric combustion products contributed to a greater occurrence of local extinction. Furthermore, they limited the capacity of premixed reactants to ignite and of the turbulent premixed flames to stabilize. In contrast, lean and rich combustion products facilitated flame ignition and stability and reduced the rate of local extinction. The influence of the combustion product stream on the turbulent flame front was limited to a zone of approximately two

Interaction of turbulent premixed flames with combustion products: Role of stoichiometry

DOE PAGES

Coriton, Bruno Rene Leon; Frank, Jonathan H.; Gomez, Alessandro

2016-05-30

Stabilization methods of turbulent flames often involve mixing of reactants with hot products of combustion. The stabilizing effect of combustion product enthalpy has been long recognized, but the role played by the chemical composition of the product gases is typically overlooked. We employ a counterflow system to pinpoint the effects of the combustion product stoichiometry on the structure of turbulent premixed flames under conditions of both stable burning and local extinction. To that end, a turbulent jet of lean-to-rich, CH 4/O 2/N 2-premixed reactants at a turbulent Reynolds number of 1050 was opposed to a stream of hot products ofmore » combustion that were generated in a preburner. While the combustion product stream temperature was kept constant, its stoichiometry was varied independently from that of the reactant stream, leading to reactant-to-product stratification of relevance to practical combustion systems. The detailed structure of the turbulent flame front was analyzed in two series of experiments using laser-induced fluorescence (LIF): joint CH 2O LIF and OH LIF measurements and joint CO LIF and OH LIF measurements. Results revealed that a decrease in local CH 2O+OH and CO+OH reaction rates coincide with the depletion of OH radicals in the vicinity of the combustion product stream. These critical combustion reaction rates were more readily quenched in the presence of products of combustion from a stoichiometric flame, whereas they were favored by lean combustion products. As a result, stoichiometric combustion products contributed to a greater occurrence of local extinction. Furthermore, they limited the capacity of premixed reactants to ignite and of the turbulent premixed flames to stabilize. In contrast, lean and rich combustion products facilitated flame ignition and stability and reduced the rate of local extinction. The influence of the combustion product stream on the turbulent flame front was limited to a zone of approximately two

Production of functional human insulin-like growth factor binding proteins (IGFBPs) using recombinant expression in HEK293 cells.

PubMed

Wanscher, Anne Sofie Molsted; Williamson, Michael; Ebersole, Tasja Wainani; Streicher, Werner; Wikström, Mats; Cazzamali, Giuseppe

2015-04-01

Insulin-like growth factor binding proteins (IGFBPs) display many functions in humans including regulation of the insulin-like growth factor (IGF) signaling pathway. The various roles of human IGFBPs make them attractive protein candidates in drug discovery. Structural and functional knowledge on human proteins with therapeutic relevance is needed to design and process the next generation of protein therapeutics. In order to conduct structural and functional investigations large quantities of recombinant proteins are needed. However, finding a suitable recombinant production system for proteins such as full-length human IGFBPs, still remains a challenge. Here we present a mammalian HEK293 expression method suitable for over-expression of secretory full-length human IGFBP-1 to -7. Protein purification of full-length human IGFBP-1, -2, -3 and -5 was conducted using a two-step chromatography procedure and the final protein yields were between 1 and 12mg protein per liter culture media. The recombinant IGFBPs contained PTMs and exhibited high-affinity interactions with their natural ligands IGF-1 and IGF-2. Copyright © 2014 Elsevier Inc. All rights reserved.

Adipokines and Hepatic Insulin Resistance

PubMed Central

Hassan, Waseem

2013-01-01

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-α, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarification of the regulatory processes about hepatic insulin resistance by adipokines in rodents and human would seem essential in order to understand the mechanism of type 2 diabetes and for developing novel therapeutic strategies to treat it. PMID:23762871

Cross-reactivity of insulin analogues with three insulin assays.

PubMed

Dayaldasani, A; Rodríguez Espinosa, M; Ocón Sánchez, P; Pérez Valero, V

2015-05-01

Immunometric assays have recently shown higher specificity in the detection of human insulin than radioimmunoassays with almost no cross-reaction with proinsulin or C peptide. The introduction of the new insulin analogues on the market, however, has raised the need to define their cross-reactivity in these assays. Several studies have been published in this regard with different results. The analogues studied were insulins lispro, aspart, glargine, detemir, and glulisine. Insulin concentrations were measured in Immulite(®) 2000 and Advia Centaur(®) XP (Siemens Healthcare Diagnostics), and Elecsys(®) Modular Analytics E170 (Roche). All samples were processed 15 times in the same analytical run following a random sequence. Those samples which showed statistically and clinically significant changes in insulin concentration were reprocessed using increasing concentrations of analogue, and this was done twice, using two different serum pools, one with a low concentration of insulin and one with a high concentration of insulin. In the Elecsys(®) E170 analyser, glargine showed statistical changes (comparison of mean concentrations with p < 0.05) and clinically significant changes in measured insulin (percentage difference 986.2% > reference change value: 59.8%), and the interference increased with increasing concentrations of analogue; the differences were not significant in the case of the other analogues. In the Advia Centaur(®) and Immulite(®) 2000 only the results for glulisine did not present significance (percentage difference 44.7% < reference change value 103.5%). Increasing concentrations of aspart, glargine, and lispro showed increased interference in Immulite(®) 2000. In the Elecsys(®) E170 assay, relevant cross-reactivity was only detected with insulin glargine, whereas in the other analysers all analogues except glulisine showed significant interference. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Lean, Premixed-Prevaporized (LPP) combustor conceptual design study

NASA Technical Reports Server (NTRS)

Dickman, R. A.; Dodds, W. J.; Ekstedt, E. E.

1979-01-01

Four combustion systems were designed and sized for the energy efficient engine. A fifth combustor was designed for the cycle and envelope of the twin-spool, high bypass ratio, high pressure ratio turbofan engine. Emission levels, combustion performance, life, and reliability assessments were made for these five combustion systems. Results of these design studies indicate that cruise NOx emission can be reduced by the use of lean, premixed-prevaporaized combustion and airflow modulation.

Studying the Hurdles of Insulin Prescription (SHIP©): development, scoring and initial validation of a new self-administered questionnaire

PubMed Central

Martinez, Luc; Consoli, Silla M; Monnier, Louis; Simon, Dominique; Wong, Olivier; Yomtov, Bernard; Guéron, Béatrice; Benmedjahed, Khadra; Guillemin, Isabelle; Arnould, Benoit

2007-01-01

Background Although insulin therapy is well-accepted by symptomatic diabetic patients, it is still often delayed in less severe patients, in whom injectable insulin remains under-used. A better understanding of patients' perception of insulin would eventually help physicians to adopt the most appropriate dialogue when having to motivate patients to initiate or to intensify insulin injection. Methods The 'Studying the Hurdles of Insulin Prescription' (SHIP) questionnaire was developed based on a list of concepts derived from three diabetic patients' focus groups, and was included into two cross-sectional studies with similar design: SHIP Oral study and SHIP Premix study. Diabetic patients treated with oral hypoglycaemic agents (OHA; n = 1,494) and patients already treated with insulin (n = 1,150) completed the questionnaire at baseline, 6- and 12 months. Psychometric properties were assessed: 1) structure analysis by Principal Component Analysis (PCA) with Varimax rotation, 2) internal consistency reliability (Cronbach's alpha), and 3) concurrent validity (Spearman correlation coefficients with the Fear of Self-Injecting (FSI) score of the Diabetes Fear of Injecting and Self-testing Questionnaire. Reluctance/motivation towards insulin was assessed. Scores' ability to predict patients' insulin injection reluctance/motivation and initiation/intensification was evaluated with the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC). Results PCA analysis confirmed the structure of the 14 items grouped into 3 dimensions: 'acceptance and motivation', 'fear and constraints', and 'restraints and barriers' towards insulin injection. Internal consistency reliability was excellent (Cronbach's alpha > 0.70); concurrent validity was good. The three scores were significantly predictive of patients' reluctance/motivation towards insulin injection initiation, as they were of patients' actual switch, except for the 'restraints and barriers' dimension. 'Acceptance and

The effect of stratification on premixed swirl-flame flashback by using porous center-body injection

NASA Astrophysics Data System (ADS)

McCaslin, Andrew; Ranjan, Rakesh; Clemens, Noel

2016-11-01

Boundary layer flashback must be prevented in order to stably operate stationary gas turbines. One strategy to avoid flashback is to create equivalence-ratio stratification, such as by reducing the fuel/air ratio in the boundary layer below the flammability limit. Typically, stratification is achieved by using radially non-uniform fuel injection. The goal of the current study is to reduce the propensity of flashback in a premixed annular swirl combustor that uses a premix section with center-body. A porous metal center-body (10 micron pore size) is used to bleed air directly into the boundary layer and thus locally reduce the equivalence ratio. Planar laser-induced fluorescence imaging of anisole-seeded flow is carried out to assess the stratification in the flow. Time-resolved PIV and chemiluminescence imaging are used to investigate flashback at atmospheric pressure conditions. A comparative study between fully premixed and stratified flame flashback is conducted to determine how stratification influences flashback physics. This work was sponsored by the DOE NETL under Grant DEFC2611-FE0007107. This source of funding is gratefully acknowledged.

Insulin analogs with improved pharmacokinetic profiles.

PubMed

Brange; Vølund

1999-02-01

The aim of insulin replacement therapy is to normalize blood glucose in order to reduce the complications of diabetes. The pharmacokinetics of the traditional insulin preparations, however, do not match the profiles of physiological insulin secretion. The introduction of the rDNA technology 20 years ago opened new ways to create insulin analogs with altered properties. Fast-acting analogs are based on the idea that an insulin with less tendency to self-association than human insulin would be more readily absorbed into the systemic circulation. Protracted-acting analogs have been created to mimic the slow, steady rate of insulin secretion in the fasting state. The present paper provides a historical review of the efforts to change the physicochemical and pharmacological properties of insulin in order to improve insulin therapy. The available clinical studies of the new insulins are surveyed and show, together with modeling results, that new strategies for optimal basal-bolus treatment are required for utilization of the new fast-acting analogs.

Pdf modeling for premixed turbulent combustion based on the properties of iso-concentration surfaces

NASA Technical Reports Server (NTRS)

Vervisch, L.; Kollmann, W.; Bray, K. N. C.; Mantel, T.

1994-01-01

In premixed turbulent flames the presence of intense mixing zones located in front of and behind the flame surface leads to a requirement to study the behavior of iso-concentration surfaces defined for all values of the progress variable (equal to unity in burnt gases and to zero in fresh mixtures). To support this study, some theoretical and mathematical tools devoted to level surfaces are first developed. Then a database of direct numerical simulations of turbulent premixed flames is generated and used to investigate the internal structure of the flame brush, and a new pdf model based on the properties of iso-surfaces is proposed.

Exocyst sec5 regulates exocytosis of newcomer insulin granules underlying biphasic insulin secretion.

PubMed

Xie, Li; Zhu, Dan; Kang, Youhou; Liang, Tao; He, Yu; Gaisano, Herbert Y

2013-01-01

The exocyst complex subunit Sec5 is a downstream effector of RalA-GTPase which promotes RalA-exocyst interactions and exocyst assembly, serving to tether secretory granules to docking sites on the plasma membrane. We recently reported that RalA regulates biphasic insulin secretion in pancreatic islet β cells in part by tethering insulin secretory granules to Ca(2+) channels to assist excitosome assembly. Here, we assessed β cell exocytosis by patch clamp membrane capacitance measurement and total internal reflection fluorescence microscopy to investigate the role of Sec5 in regulating insulin secretion. Sec5 is present in human and rodent islet β cells, localized to insulin granules. Sec5 protein depletion in rat INS-1 cells inhibited depolarization-induced release of primed insulin granules from both readily-releasable pool and mobilization from the reserve pool. This reduction in insulin exocytosis was attributed mainly to reduction in recruitment and exocytosis of newcomer insulin granules that undergo minimal docking time at the plasma membrane, but which encompassed a larger portion of biphasic glucose stimulated insulin secretion. Sec5 protein knockdown had little effect on predocked granules, unless vigorously stimulated by KCl depolarization. Taken together, newcomer insulin granules in β cells are more sensitive than predocked granules to Sec5 regulation.

Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin

PubMed Central

Holden, Sarah E; Poole, Chris D; Morgan, Christopher Ll

2011-01-01

Introduction Insulin analogues have become increasingly popular despite their greater cost compared with human insulin. The aim of this study was to calculate the incremental cost to the National Health Service (NHS) of prescribing analogue insulin preparations instead of their human insulin alternatives. Methods Open-source data from the four UK prescription pricing agencies from 2000 to 2009 were analysed. Cost was adjusted for inflation and reported in UK pounds at 2010 prices. Results Over the 10-year period, the NHS spent a total of £2732 million on insulin. The total annual cost increased from £156 million to £359 million, an increase of 130%. The annual cost of analogue insulin increased from £18.2 million (12% of total insulin cost) to £305 million (85% of total insulin cost), whereas the cost of human insulin decreased from £131 million (84% of total insulin cost) to £51 million (14% of total insulin cost). If it is assumed that all patients using insulin analogues could have received human insulin instead, the overall incremental cost of analogue insulin was £625 million. Conclusion Given the high marginal cost of analogue insulin, adherence to prescribing guidelines recommending the preferential use of human insulin would have resulted in considerable financial savings over the period. PMID:22021891

Ex vivo generation of glucose sensitive insulin secreting mesenchymal stem cells derived from human adipose tissue.

PubMed

Dave, Shruti D; Vanikar, Aruna V; Trivedi, Hargovind L

2012-03-01

Diabetics are incapable of producing insulin/have autoimmune mechanisms making it ineffective to control glucose secretion. We present a prospective study of glucose-sensitive insulin-secreting mesenchymal stem cells (IS-MSC) generated from human adipose tissue (h-AD) sans xenogenic material. Ten grams h-AD from donor anterior abdominal wall was collected in proliferation medium composed of α-Minimum Essential Media (α-MEM), albumin, fibroblast-growth factor and antibiotics, minced, incubated in collagenase-I at 37°C with shaker and centrifuged. Supernatant and pellets were separately cultured in proliferation medium on cell+ plates at 37°C with 5% CO(2) for 10 days. Cells were harvested by trypsinization, checked for viability, sterility, counts, flow-cytometry (CD45(-)/90(+)/73(+)), and differentiated into insulin-expressing cells using medium composed of DMEM, gene expressing up-regulators and antibiotics for 3 days. They were studied for transcriptional factors Pax-6, Isl-1, pdx-1 (immunofluorescence). C-peptide and insulin were measured by chemiluminescence. In vitro glucose sensitivity assay was carried out by measuring levels of insulin and C-peptide secretion in absence of glucose followed by 2 hours incubation after glucose addition. Mean IS-AD-MSC quantum was 3.21 ml, cell count, 1.5 ×10(3) cells/μl), CD45(-)/90(+)/73(+) cells were 44.37% /25.52%. All of them showed presence of pax-6, pdx-1, and Isl-1. Mean C-Peptide and insulin levels were 0.36 ng/ml and 234 μU/ml, respectively, pre-glucose and 0.87 ng/ml and 618.3 μU/ml post-glucose additions. The mean rise in secretion levels was 2.42 and 2.65 fold, respectively. Insulin-secreting h-AD-MSC can be generated safely and effectively showing in vitro glucose responsive alteration in insulin and C-peptide secretion levels.

Probiotic supplementation prevents high-fat, overfeeding-induced insulin resistance in human subjects.

PubMed

Hulston, Carl J; Churnside, Amelia A; Venables, Michelle C

2015-02-28

The purpose of the present study was to determine whether probiotic supplementation (Lactobacillus casei Shirota (LcS)) prevents diet-induced insulin resistance in human subjects. A total of seventeen healthy subjects were randomised to either a probiotic (n 8) or a control (n 9) group. The probiotic group consumed a LcS-fermented milk drink twice daily for 4 weeks, whereas the control group received no supplementation. Subjects maintained their normal diet for the first 3 weeks of the study, after which they consumed a high-fat (65 % of energy), high-energy (50 % increase in energy intake) diet for 7 d. Whole-body insulin sensitivity was assessed by an oral glucose tolerance test conducted before and after overfeeding. Body mass increased by 0·6 (SE 0·2) kg in the control group (P< 0·05) and by 0·3 (SE 0·2) kg in the probiotic group (P>0·05). Fasting plasma glucose concentrations increased following 7 d of overeating (control group: 5·3 (SE 0·1) v. 5·6 (SE 0·2) mmol/l before and after overfeeding, respectively, P< 0·05), whereas fasting serum insulin concentrations were maintained in both groups. Glucose AUC values increased by 10 % (from 817 (SE 45) to 899 (SE 39) mmol/l per 120 min, P< 0·05) and whole-body insulin sensitivity decreased by 27 % (from 5·3 (SE 1·4) to 3·9 (SE 0·9), P< 0·05) in the control group, whereas normal insulin sensitivity was maintained in the probiotic group (4·4 (SE 0·8) and 4·5 (SE 0·9) before and after overeating, respectively (P>0·05). These results suggest that probiotic supplementation may be useful in the prevention of diet-induced metabolic diseases such as type 2 diabetes.

Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timper, Katharina; Seboek, Dalma; Eberhardt, Michael

2006-03-24

Mesenchymal stem cells (MSC) from mouse bone marrow were shown to adopt a pancreatic endocrine phenotype in vitro and to reverse diabetes in an animal model. MSC from human bone marrow and adipose tissue represent very similar cell populations with comparable phenotypes. Adipose tissue is abundant and easily accessible and could thus also harbor cells with the potential to differentiate in insulin producing cells. We isolated human adipose tissue-derived MSC from four healthy donors. During the proliferation period, the cells expressed the stem cell markers nestin, ABCG2, SCF, Thy-1 as well as the pancreatic endocrine transcription factor Isl-1. The cellsmore » were induced to differentiate into a pancreatic endocrine phenotype by defined culture conditions within 3 days. Using quantitative PCR a down-regulation of ABCG2 and up-regulation of pancreatic developmental transcription factors Isl-1, Ipf-1, and Ngn3 were observed together with induction of the islet hormones insulin, glucagon, and somatostatin.« less

Effects of Buoyancy on Laminar and Turbulent Premixed V-Flame

NASA Technical Reports Server (NTRS)

Cheng, Robert K.; Bedat, Benoit

1997-01-01

Turbulent combustion occurs naturally in almost all combustion systems and involves complex dynamic coupling of chemical and fluid mechanical processes. It is considered as one of the most challenging combustion research problems today. Though buoyancy has little effect on power generating systems operating under high pressures (e.g., IC engines and turbines), flames in atmospheric burners and the operation of small to medium furnaces and boilers are profoundly affected by buoyancy. Changes in burner orientation impacts on their blow-off, flash-back and extinction limits, and their range of operation, burning rate, heat transfer, and emissions. Theoretically, buoyancy is often neglected in turbulent combustion models. Yet the modeling results are routinely compared with experiments of open laboratory flames that are obviously affected by buoyancy. This inconsistency is an obstacle to reconciling experiments and theories. Consequently, a fundamental understanding of the coupling between turbulent flames and buoyancy is significant to both turbulent combustion science and applications. The overall effect of buoyancy relates to the dynamic interaction between the flame and its surrounding, i.e., the so-called elliptical problem. The overall flame shape, its flowfield, stability, and mean and local burning rates are dictated by both upstream and downstream boundary conditions. In steady propagating premixed flames, buoyancy affects the products region downstream of the flame zone. These effects are manifested upstream through the mean and fluctuating pressure fields to influence flame stretch and flame wrinkling. Intuitively, the effects buoyancy should diminish with increasing flow momentum. This is the justification for excluding buoyancy in turbulent combustion models that treats high Reynolds number flows. The objectives of our experimental research program is to elucidate flame-buoyancy coupling processes in laminar and turbulent premixed flames, and to

Treatment of dwarfism with recombinant human insulin-like growth factor-1.

PubMed

Ranke, Michael B; Wölfle, Joachim; Schnabel, Dirk; Bettendorf, Markus

2009-10-01

The growth hormone-IGF (insulin-like growth factor) system plays a central role in hormonal growth regulation. Recombinant human (rh) growth hormone (GH) has been available since the late 1980s for replacement therapy in GH-deficient patients and for the stimulation of growth in patients with short stature of various causes. Growth promotion by GH occurs in part indirectly through the induction of IGF-1 synthesis. In primary disturbances of IGF-1 production, short stature can only be treated with recombinant human IGF-1 (rhIGF-1). rhIGF-1 was recently approved for this indication but can also be used to treat other conditions. Selective review of the literature on IGF-1 therapy, based on a PubMed search. In children with severe primary IGF-1 deficiency (a rare condition whose prevalence is less than 1:10,000), the prognosis for final height is very poor (ca. 130 cm), and IGF-1 therapy is the appropriate form of pathophysiologically based treatment. There is no alternative treatment at present. The subcutaneous administration of IGF-1 twice daily in doses of 80 to 120 microg/kg accelerates growth and increases final height by 12 to 15 cm, according to current data. There is, however, a risk of hypoglycemia, as IGF-1 has an insulin-like effect. As treatment with IGF-1 is complex, this new medication should only be prescribed, for the time being, by experienced pediatric endocrinologists and diabetologists.

The insulin secretagogues glibenclamide and repaglinide do not influence growth hormone secretion in humans but stimulate glucagon secretion during profound insulin deficiency.

PubMed

Østergård, Torben; Degn, Kristine B; Gall, Mari-Anne; Carr, Richard D; Veldhuis, Johannes D; Thomsen, Mads K; Rizza, Robert A; Schmitz, Ole

2004-01-01

In vitro data have recently suggested that sulfonylureas (SUs) enhance GH secretion by modulating the effects of GHRH and somatostatin in pituitary cells. The present study was undertaken to explore in more detail a possible influence of a single dose of SU (glibenclamide) and a non-SU (repaglinide) insulin secretagogue on circulating GH dynamics. Ten C-peptide-negative type 1 diabetic individuals were examined on three occasions in random order. Either glibenclamide (10.5 mg), repaglinide (8 mg), or placebo was administered after overnight normalization of plasma glucose by iv insulin infusion. Subsequently, GH concentrations were measured regularly after stimulation with GHRH (bolus 0.1 micro g/kg) alone and during concomitant infusion with somatostatin (7 ng.kg(-1).min(-1)). Insulin was replaced at baseline levels (0.25 mU.kg(-1).min(-1)) and plasma glucose clamped at 5-6 mmol/liter. Overall, there were no significant statistical differences in GH responses determined as either GH peak concentrations, integrated levels of GH, or secretory burst mass of GH during the experimental protocol. In contrast, plasma glucagon concentrations were significantly increased during glibenclamide and repaglinide exposure. The present experimental design does not support the hypothesis that acute administration of pharmacological doses of the oral antihyperglycemic agents glibenclamide and repaglinide per se enhance GH release in humans. Additionally, this study shows that these potassium channel inhibitors seem to stimulate glucagon secretion in people who have severe intraislet insulin deficiency (e.g. type 1 diabetes). However, extrapolation of our findings to type 2 diabetic individuals should be done with some caution.

Premixed direct injection disk

DOEpatents

York, William David; Ziminsky, Willy Steve; Johnson, Thomas Edward; Lacy, Benjamin; Zuo, Baifang; Uhm, Jong Ho

2013-04-23

A fuel/air mixing disk for use in a fuel/air mixing combustor assembly is provided. The disk includes a first face, a second face, and at least one fuel plenum disposed therebetween. A plurality of fuel/air mixing tubes extend through the pre-mixing disk, each mixing tube including an outer tube wall extending axially along a tube axis and in fluid communication with the at least one fuel plenum. At least a portion of the plurality of fuel/air mixing tubes further includes at least one fuel injection hole have a fuel injection hole diameter extending through said outer tube wall, the fuel injection hole having an injection angle relative to the tube axis. The invention provides good fuel air mixing with low combustion generated NOx and low flow pressure loss translating to a high gas turbine efficiency, that is durable, and resistant to flame holding and flash back.

A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

PubMed Central

Newgard, Christopher B; An, Jie; Bain, James R; Muehlbauer, Michael J; Stevens, Robert D; Lien, Lillian F; Haqq, Andrea M; Shah, Svati H.; Arlotto, Michelle; Slentz, Cris A; Rochon, James; Gallup, Dianne; Ilkayeva, Olga; Wenner, Brett R; Yancy, William E; Eisenson, Howard; Musante, Gerald; Surwit, Richard; Millington, David S; Butler, Mark D; Svetkey, Laura P

2009-01-01

Summary Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA) or standard chow (SC) diets. Despite having reduced food intake and weight gain equivalent to the SC group, HF/BCAA rats were equally insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1(ser307), accumulation of multiple acylcarnitines in muscle, and was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a poor dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance. PMID:19356713

Coupling between premixed flame propagation and swirl flow during boundary layer flashback

NASA Astrophysics Data System (ADS)

Ebi, Dominik; Ranjan, Rakesh; Clemens, Noel T.

2018-07-01

Flashback of premixed methane-air flames in the turbulent boundary layer of swirling flows is investigated experimentally. The premix section of the atmospheric model swirl combustor features an axial swirler with an attached center-body. Our previous work with this same configuration investigated the flame propagation during flashback using particle image velocimetry (PIV) with liquid droplets as seed particles that precluded making measurements in the burnt gases. The present study investigates the transient velocity field in the unburnt and burnt gas region by means of solid-particle seeding and high-speed stereoscopic PIV. The global axial and circumferential lab-frame flame propagation speed is obtained simultaneously based on high-speed chemiluminescence movies. By combining the PIV data with the global flame propagation speed, the quasi-instantaneous swirling motion of the velocity field is constructed on annular shells, which provides a more intuitive view on the complex three-dimensional flow-flame interaction. Previous works showed that flashback is led by flame tongues. We find that the important flow-flame interaction occurs on the far side of these flame tongues relative to the approach flow, which we henceforth refer to as the leading side. The leading side is found to propagate as a classical premixed flame front relative to the strongly modified approach flow field. The blockage imposed by flame tongues is not limited to the immediate vicinity of the flame base, but occurs along the entire leading side.

Field Effects of Buoyancy on Lean Premixed Turbulent Flames

NASA Technical Reports Server (NTRS)

Cheng, R. K.; Johnson, M. R.; Greenberg, P. S.; Wernet, M. P.

2003-01-01

The study of field effects of buoyancy on premixed turbulent flames is directed towards the advancement of turbulent combustion theory and the development of cleaner combustion technologies. Turbulent combustion is considered the most important unsolved problem in combustion science and laboratory studies of turbulence flame processes are vital to theoretical development. Although buoyancy is dominant in laboratory flames, most combustion models are not yet capable to consider buoyancy effects. This inconsistency has impeded the validation of theories and numerical simulations with experiments. Conversely, the understanding of buoyancy effects is far too limited to help develop buoyant flame models. Our research is also relevant to combustion technology because lean premixed combustion is a proven method to reduce the formation of oxides of nitrogen (NOx). In industrial lean premixed combustion systems, their operating conditions make them susceptible to buoyancy thus affecting heat distribution, emissions, stability, flashback and blowoff. But little knowledge is available to guide combustion engineers as to how to avoid or overcome these problems. Our hypothesis is that through its influence on the mean pressure field, buoyancy has direct and indirect effects on local flame/turbulence interactions. Although buoyancy acts on the hot products in the farfield the effect is also felt in the nearfield region upstream of the flame. These changes also influence the generation and dissipation of turbulent kinetic energy inside the flame brush and throughout the flowfield. Moreover, the plume of an open flame is unstable and the periodic fluctuations make additional contributions to flame front dynamics in the farfield. Therefore, processes such as flame wrinkling, flow acceleration due to heat release and flame- generated vorticity are all affected. Other global flame properties (e.g. flame stabilization limits and flame speed) may all be coupled to buoyancy. This

Differential insulin and steroidogenic signaling in insulin resistant and non-insulin resistant human luteinized granulosa cells-A study in PCOS patients.

PubMed

Belani, Muskaan; Deo, Abhilash; Shah, Preeti; Banker, Manish; Singal, Pawan; Gupta, Sarita

2018-04-01

Insulin resistance (IR) is one of the significant aberrations in polycystic ovarian syndrome (PCOS), however is only observed in 70%-80% of obese PCOS and 20%-25% of lean PCOS. Hyperinsulinemia accompanies PCOS-IR along with hyperandrogenemia against normal insulin and androgen levels in PCOS-non insulin resistance (NIR). This could possibly be due to defects in the downstream signaling pathways. The study thus aims to unravel insulin and steroidogenic signaling pathways in luteinized granulosa cells isolated from PCOS-IR and NIR vs matched controls. Luteinized granulosa cells from 30 controls and 39 PCOS were classified for IR based on a novel method of down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. We evaluated expression of molecules involved in insulin, steroidogenic signaling and lipid metabolism in luteinized granulosa cells followed by analysis of estradiol, progesterone and testosterone in follicular fluid. Protein expression of INSR- β, pIRS (ser 307), PI(3)K, PKC-ζ, pAkt, ERK1/2, pP38MAPK and gene expression of IGF showed differential expression in the two groups. Increased protein expression of PPAR-γ was accompanied by up regulation in SREBP1c, FAS, CPT-1 and ACC-1 genes in PCOS-IR group. Expression of StAR, CYP19A1, 17 β- HSD and 3 β- HSD demonstrated significant decrease along with increase in CYP11A1, FSH-R and LH-R in both the groups. Follicular fluid testosterone increased and progesterone decreased in PCOS-IR group. This study shows how candidate molecules that were differentially expressed, aid in designing targeted therapy against the two phenotypes of PCOS. Copyright © 2018 Elsevier Ltd. All rights reserved.

PREMIXED FLAME PROPAGATION AND MORPHOLOGY IN A CONSTANT VOLUME COMBUSTION CHAMBER

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hariharan, A; Wichman, IS

2014-06-04

This work presents an experimental and numerical investigation of premixed flame propagation in a constant volume rectangular channel with an aspect ratio of six (6) that serves as a combustion chamber. Ignition is followed by an accelerating cusped finger-shaped flame-front. A deceleration of the flame is followed by the formation of a "tulip"-shaped flame-front. Eventually, the flame is extinguished when it collides with the cold wall on the opposite channel end. Numerical computations are performed to understand the influence of pressure waves, instabilities, and flow field effects causing changes to the flame structure and morphology. The transient 2D numerical simulationmore » results are compared with transient 3D experimental results. Issues discussed are the appearance of oscillatory motions along the flame front and the influences of gravity on flame structure. An explanation is provided for the formation of the "tulip" shape of the premixed flame front.« less

Dual effect of insulin resistance and cadmium on human granulosa cells - In vitro study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belani, Muskaan, E-mail: muskaanbelani@gmail.com

Combined exposure of cadmium (Cd) and insulin resistance (IR) might be responsible for subfertility. In the present study, we investigated the effects of Cd in vitro in IR human granulosa cells. Isolated human granulosa cells from control and polycystic ovary syndrome (PCOS) follicular fluid samples were confirmed for IR by decrease in protein expression of insulin receptor-β. Control and IR human granulosa cells were then incubated with or without 32 μM Cd. The combined effect of IR with 32 μM Cd in granulosa cells demonstrated significant decrease in expression of StAR, CYP11A1, CYP19A1, 17β-HSD, 3β-HSD, FSH-R and LH-R. Decrease wasmore » also observed in progesterone and estradiol concentrations as compared to control. Additionally, increase in protein expression of cleaved PARP-F2, active caspase-3 and a positive staining for Annexin V and PI indicated apoptosis as the mode of increased cell death ultimately leading to decreased steroidogenesis, as observed through the combined exposure. Taken together the results suggest decrease in steroidogenesis ultimately leading to abnormal development of the follicle thus compromising fertility at the level of preconception. - Highlights: • Protein expression of INSR-β in granulosa cells to differentiate PCOS-IR and NIR • Cd and IR together decrease steroidogenesis in human granulosa cells in vitro. • Cd and IR increase human granulosa cell death by increase in apoptosis. • Environment and life style are set to hamper pregnancies at preconception level.« less

Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's Disease human lymphoblasts.

PubMed

Naia, Luana; Ferreira, I Luísa; Cunha-Oliveira, Teresa; Duarte, Ana I; Ribeiro, Márcio; Rosenstock, Tatiana R; Laço, Mário N; Ribeiro, Maria J; Oliveira, Catarina R; Saudou, Frédéric; Humbert, Sandrine; Rego, A Cristina

2015-02-01

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

Criteria Development for Gas Turbine Premixer Flameholding Tendencies of Natural Gas and High Hydrogen Content Fuels

NASA Astrophysics Data System (ADS)

Sullivan-Lewis, Elliot Gregory

Due to increasingly stringent air quality requirements, stationary power gas turbines have moved to lean-premixed operation, which reduces pollutant emissions but can result in flashback. Flashback can cause serious damage to the premixer hardware. Curtailing flashback can be difficult with hydrocarbon fuels and becomes even more challenging when the fuel contains hydrogen. The two main approaches for coping with flashback are either to design a combustor that is resistant to flashback, or to design a premixer that will not anchor a flame if flashback occurs. Even with a well-designed combustor, flashback can occur under certain circumstances. Thus it is necessary to determine how to avoid flameholding within the premixer passageways of a gas turbine. To this end, an experiment was designed that would determine the flameholding propensities at elevated pressures and temperatures of three different classes of geometric features commonly found in gas turbine premixers, with both natural gas and hydrogen containing fuel. Experiments to find the equivalence ratio at blow off were conducted within an optically accessible test apparatus with four flameholders: 0.25 and 0.50 inch diameter cylinders, a reverse facing step with a height of 0.25 inches, and a symmetric airfoil with a thickness of 0.25 inches and a chord length of one inch. Tests were carried out at temperatures between 300 K and 750 K, at pressures up to 9 atmospheres. Typical bulk velocities were between 40 and 100 m/s. The effect of the airfoil's angle of rotation was also investigated. Blow off for hydrogen reactions was found to occur at much lower adiabatic flame temperatures than natural gas reactions. Additionally it was observed that at high pressures and high turbulence intensities, reactant velocity does not have a noticeable effect on the point of blow off due in large part to corresponding increases in turbulent flame speed. Finally a semi empirical correlation was developed that predicts flame

Soot Formation in Laminar Premixed Methane/Oxygen Flames at Atmospheric Pressure. Appendix H

NASA Technical Reports Server (NTRS)

Xu, F.; Lin, K.-C.; Faeth, G. M.; Urban, D. L. (Technical Monitor); Yuan, Z.-G. (Technical Monitor)

2001-01-01

Flame structure and soot formation were studied within soot-containing laminar premixed methanefoxygen flames at atmospheric pressure. The following measurements were made: soot volume fractions by laser extinction, soot temperatures by multiline emission, gas temperatures (where soot was absent) by corrected fine-wire thermocouples, soot structure by thermophoretic sampling and transmission electron microscope (TEM), major gas species concentrations by sampling and gas chromatography, and gas velocities by laser velocimetry. Present measurements of gas species concentrations were in reasonably good agreement with earlier measurements due to Ramer et al. as well as predictions based on the detailed mechanisms of Frenklach and co-workers and Leung and Lindstedt; the predictions also suggest that H atom concentrations are in local thermodynamic equilibrium throughout the soot formation region. Using this information, it was found that measured soot surface growth rates could be correlated successfully by predictions based on the hydrogenabstraction/carbon-addition (HACA) mechanisms of both Frenklach and co-workers and Colket and Hall, extending an earlier assessment of these mechanisms for premixed ethylene/air flames to conditions having larger H/C ratios and acetylene concentrations. Measured primary soot particle nucleation rates were somewhat lower than the earlier observations for laminar premixed ethylene/air flames and were significantly lower than corresponding rates in laminar diffusion flames, for reasons that still must be explained.

Insulin Stimulates Translocation of Human GLUT4 to the Membrane in Fat Bodies of Transgenic Drosophila melanogaster

PubMed Central

Crivat, Georgeta; Lizunov, Vladimir A.; Li, Caroline R.; Stenkula, Karin G.; Zimmerberg, Joshua; Cushman, Samuel W.; Pick, Leslie

2013-01-01

The fruit fly Drosophila melanogaster is an excellent model system for studies of genes controlling development and disease. However, its applicability to physiological systems is less clear because of metabolic differences between insects and mammals. Insulin signaling has been studied in mammals because of relevance to diabetes and other diseases but there are many parallels between mammalian and insect pathways. For example, deletion of Drosophila Insulin-Like Peptides resulted in ‘diabetic’ flies with elevated circulating sugar levels. Whether this situation reflects failure of sugar uptake into peripheral tissues as seen in mammals is unclear and depends upon whether flies harbor the machinery to mount mammalian-like insulin-dependent sugar uptake responses. Here we asked whether Drosophila fat cells are competent to respond to insulin with mammalian-like regulated trafficking of sugar transporters. Transgenic Drosophila expressing human glucose transporter-4 (GLUT4), the sugar transporter expressed primarily in insulin-responsive tissues, were generated. After expression in fat bodies, GLUT4 intracellular trafficking and localization were monitored by confocal and total internal reflection fluorescence microscopy (TIRFM). We found that fat body cells responded to insulin with increased GLUT4 trafficking and translocation to the plasma membrane. While the amplitude of these responses was relatively weak in animals reared on a standard diet, it was greatly enhanced in animals reared on sugar-restricted diets, suggesting that flies fed standard diets are insulin resistant. Our findings demonstrate that flies are competent to mobilize translocation of sugar transporters to the cell surface in response to insulin. They suggest that Drosophila fat cells are primed for a response to insulin and that these pathways are down-regulated when animals are exposed to constant, high levels of sugar. Finally, these studies are the first to use TIRFM to monitor insulin

Generation of insulin-producing cells from human bone marrow-derived mesenchymal stem cells: comparison of three differentiation protocols.

PubMed

Gabr, Mahmoud M; Zakaria, Mahmoud M; Refaie, Ayman F; Khater, Sherry M; Ashamallah, Sylvia A; Ismail, Amani M; El-Badri, Nagwa; Ghoneim, Mohamed A

2014-01-01

Many protocols were utilized for directed differentiation of mesenchymal stem cells (MSCs) to form insulin-producing cells (IPCs). We compared the relative efficiency of three differentiation protocols. Human bone marrow-derived MSCs (HBM-MSCs) were obtained from three insulin-dependent type 2 diabetic patients. Differentiation into IPCs was carried out by three protocols: conophylline-based (one-step protocol), trichostatin-A-based (two-step protocol), and β -mercaptoethanol-based (three-step protocol). At the end of differentiation, cells were evaluated by immunolabeling for insulin production, expression of pancreatic endocrine genes, and release of insulin and c-peptide in response to increasing glucose concentrations. By immunolabeling, the proportion of generated IPCs was modest ( ≃ 3%) in all the three protocols. All relevant pancreatic endocrine genes, insulin, glucagon, and somatostatin, were expressed. There was a stepwise increase in insulin and c-peptide release in response to glucose challenge, but the released amounts were low when compared with those of pancreatic islets. The yield of functional IPCs following directed differentiation of HBM-MSCs was modest and was comparable among the three tested protocols. Protocols for directed differentiation of MSCs need further optimization in order to be clinically meaningful. To this end, addition of an extracellular matrix and/or a suitable template should be attempted.

Insulin-producing Cells from Adult Human Bone Marrow Mesenchymal Stromal Cells Could Control Chemically Induced Diabetes in Dogs: A Preliminary Study.

PubMed

Gabr, Mahmoud M; Zakaria, Mahmoud M; Refaie, Ayman F; Ismail, Amani M; Khater, Sherry M; Ashamallah, Sylvia A; Azzam, Maha M; Ghoneim, Mohamed A

2018-01-01

Ten mongrel dogs were used in this study. Diabetes was chemically induced in 7 dogs, and 3 dogs served as normal controls. For each diabetic dog, 5 million human bone marrow-derived mesenchymal stem cells/kg were differentiated to form insulin-producing cells using a trichostatin-based protocol. Cells were then loaded in 2 TheraCyte capsules which were transplanted under the rectus sheath. One dog died 4 d postoperatively from pneumonia. Six dogs were followed up with for 6 to 18 mo. Euglycemia was achieved in 4 dogs. Their glucose tolerance curves exhibited a normal pattern demonstrating that the encapsulated cells were glucose sensitive and insulin responsive. In the remaining 2 dogs, the fasting blood sugar levels were reduced but did not reach normal values. The sera of all transplanted dogs contained human insulin and C-peptide with a negligible amount of canine insulin. Removal of the transplanted capsules was followed by prompt return of diabetes. Intracytoplasmic insulin granules were seen by immunofluorescence in cells from the harvested capsules. Furthermore, all pancreatic endocrine genes were expressed. This study demonstrated that the TheraCyte capsule or a similar device can provide adequate immunoisolation, an important issue when stem cells are considered for the treatment of type 1 diabetes mellitus.

Synthesis of the human insulin gene. Part II. Further improvements in the modified phosphotriester method and the synthesis of seventeen deoxyribooligonucleotide fragments constituting human insulin chains B and mini-CDNA.

PubMed Central

Sung, W L; Hsiung, H M; Brousseau, R; Michniewicz, J; Wu, R; Narang, S A

1979-01-01

The purification of protected deoxyribooligonucleotides containing phosphotriester internucleotidic linkages has been improved by developing a deactivated silica gel chromatographic technique. The efficiency of this technique as applied in the modified phosphotriester approach has been demonstrated in the rapid synthesis of seventeen pure fragments constituting the sequence of human insulin B and mini-C DNA. The sequence of each oligomer was confirmed by the two-dimensional mobility shift method of fingerprinting. Images PMID:230464

Response mechanisms of attached premixed flames subjected to harmonic forcing

NASA Astrophysics Data System (ADS)

Shreekrishna

The persistent thrust for a cleaner, greener environment has prompted air pollution regulations to be enforced with increased stringency by environmental protection bodies all over the world. This has prompted gas turbine manufacturers to move from nonpremixed combustion to lean, premixed combustion. These lean premixed combustors operate quite fuel-lean compared to the stochiometric, in order to minimize CO and NOx productions, and are very susceptible to oscillations in any of the upstream flow variables. These oscillations cause the heat release rate of the flame to oscillate, which can engage one or more acoustic modes of the combustor or gas turbine components, and under certain conditions, lead to limit cycle oscillations. This phenomenon, called thermoacoustic instabilities, is characterized by very high pressure oscillations and increased heat fluxes at system walls, and can cause significant problems in the routine operability of these combustors, not to mention the occasional hardware damages that could occur, all of which cumulatively cost several millions of dollars. In a bid towards understanding this flow-flame interaction, this research works studies the heat release response of premixed flames to oscillations in reactant equivalence ratio, reactant velocity and pressure, under conditions where the flame preheat zone is convectively compact to these disturbances, using the G-equation. The heat release response is quantified by means of the flame transfer function and together with combustor acoustics, forms a critical component of the analytical models that can predict combustor dynamics. To this end, low excitation amplitude (linear) and high excitation amplitude (nonlinear) responses of the flame are studied in this work. The linear heat release response of lean, premixed flames are seen to be dominated by responses to velocity and equivalence ratio fluctuations at low frequencies, and to pressure fluctuations at high frequencies which are in the

Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.

PubMed

Nelson, O Lynne; Jansen, Heiko T; Galbreath, Elizabeth; Morgenstern, Kurt; Gehring, Jamie Lauren; Rigano, Kimberly Scott; Lee, Jae; Gong, Jianhua; Shaywitz, Adam J; Vella, Chantal A; Robbins, Charles T; Corbit, Kevin C

2014-08-05

The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition. Copyright © 2014 Elsevier Inc. All rights reserved.

DNS of turbulent premixed slot flames with mixture inhomogeneity: a study of NOx formation

NASA Astrophysics Data System (ADS)

Luca, Stefano; Attili, Antonio; Bisetti, Fabrizio

2016-11-01

A set of Direct Numerical Simulations of three-dimensional methane/air lean flames in a spatially developing turbulent slot burner are performed. The flames are in the thin-reaction zone regimes and the jet Reynolds number is 5600. This configuration is of interest since it displays turbulent production by mean shear as in real devices. The gas phase hydrodynamics are modeled with the reactive, unsteady Navier-Stokes equations in the low Mach number limit. Combustion is treated with finite-rate chemistry. The jet is characterized by a non-uniform equivalence ratio at the inlet and varying levels of incomplete premixing for the methane/air mixture are considered. The global equivalence ratio is 0.7 and temperature is 800 K. All simulations are performed at 4 atm. The instantaneous profiles of the mass fractions of methane and air at the inlet are sampled from a set of turbulent channel simulations that provide realistic, fully turbulent fields. The data are analyzed to study the influence of partial premixing on the flame structure. Particular focus is devoted to the assessment of heat release rate fluctuations and NOx formation. In particular, the effects of partial premixing on the production rates for the various pathways to NOx formation are investigated.

Insulin resistance and the metabolism of branched-chain amino acids in humans.

PubMed

Adeva, María M; Calviño, Jesús; Souto, Gema; Donapetry, Cristóbal

2012-07-01

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.

Lability landscape and protease resistance of human insulin amyloid: a new insight into its molecular properties.

PubMed

Malisauskas, Mantas; Weise, Christoph; Yanamandra, Kiran; Wolf-Watz, Magnus; Morozova-Roche, Ludmilla

2010-02-12

Amyloid formation is a universal behavior of proteins central to many important human pathologies and industrial processes. The extreme stability of amyloids towards chemical and proteolytic degradation is an acquired property compared to the precursor proteins and is a major prerequisite for their accumulation. Here, we report a study on the lability of human insulin amyloid as a function of pH and amyloid ageing. Using a range of methods such as atomic force microscopy, thioflavin T fluorescence, circular dichroism, and gas-phase electrophoretic mobility macromolecule analysis, we probed the propensity of human insulin amyloid to propagate or dissociate in a wide span of pH values and ageing in a low concentration regime. We generated a three-dimensional amyloid lability landscape in coordinates of pH and amyloid ageing, which displays three distinctive features: (i) a maximum propensity to grow near pH 3.8 and an age corresponding to the inflection point of the growth phase, (ii) an abrupt cutoff between growth and disaggregation at pH 8-10, and (iii) isoclines shifted towards older age during the amyloid growth phase at pH 4-9, reflecting the greater stability of aged amyloid. Thus, lability of amyloid strongly depends on the ionization state of insulin and on the structure and maturity of amyloid fibrils. The stability of insulin amyloid towards protease K was assessed by using real-time atomic force microscopy and thioflavin T fluorescence. We estimated that amyloid fibrils can be digested both from the free ends and within the length of the fibril with a rate of ca 4 nm/min. Our results highlight that amyloid structures, depending on solution conditions, can be less stable than commonly perceived. These results have wide implications for understanding the propagation of amyloids via a seeding mechanism as well as for understanding their natural clearance and dissociation under solution conditions unfavorable for amyloid formation in biological systems and

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

PubMed

Højlund, Kurt

2014-07-01

Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

Changes in glucose tolerance and insulin sensitivity following 2 weeks of daily cinnamon ingestion in healthy humans.

PubMed

Solomon, Thomas P J; Blannin, Andrew K

2009-04-01

Cinnamon can improve fasting glucose in humans yet data on insulin sensitivity are limited and controversial. Eight male volunteers (aged 25 +/- 1 years, body mass 76.5 +/- 3.0 kg, BMI 24.0 +/- 0.7 kg m(-2); mean +/- SEM) underwent two 14-day interventions involving cinnamon or placebo supplementation (3 g day(-1)). Placebo supplementation was continued for 5 days following this 14 day period. Oral glucose tolerance tests (OGTT) were performed on days 0, 1, 14, 16, 18, and 20. Cinnamon ingestion reduced the glucose response to OGTT on day 1 (-13.1 +/- 6.3% vs. day 0; P < 0.05) and day 14 (-5.5 +/- 8.1% vs. day 0; P = 0.09). Cinnamon ingestion also reduced insulin responses to OGTT on day 14 (-27.1 +/- 6.2% vs. day 0; P < 0.05), as well as improving insulin sensitivity on day 14 (vs. day 0; P < 0.05). These effects were lost following cessation of cinnamon feeding. Cinnamon may improve glycaemic control and insulin sensitivity, but the effects are quickly reversed.

Zinc Up-Regulates Insulin Secretion from β Cell-Like Cells Derived from Stem Cells from Human Exfoliated Deciduous Tooth (SHED).

PubMed

Kim, Gyuyoup; Shin, Ki-Hyuk; Pae, Eung-Kwon

2016-12-13

Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting β cell-like stem cells (i.e., SHED-β cells). We observed that ZIP8 expression increased as SHED differentiated into SHED-β cells, and that zinc supplementation at day 10 increased the levels of most pancreatic β cell markers-particularly Insulin and glucose transporter 2 (GLUT2). We confirmed that SHED-β cells produce insulin successfully. In addition, we note that zinc supplementation significantly increases insulin secretion with a significant elevation of ZIP8 transporters in SHED-β cells. We conclude that SHED can be converted into insulin-secreting β cell-like cells as zinc concentration in the cytosol is elevated. Insulin production by SHED-β cells can be regulated via modulation of zinc concentration in the media as ZIP8 expression in the SHED-β cells increases.

Culture of impure human islet fractions in the presence of alpha-1 antitrypsin prevents insulin cleavage and improves islet recovery.

PubMed

Loganathan, G; Dawra, R K; Pugazhenthi, S; Wiseman, A C; Sanders, M A; Saluja, A K; Sutherland, D E R; Hering, B J; Balamurugan, A N

2010-01-01

supplementation improved postculture recovery of islets in impure preparations compared with nontreated controls (72% +/- 9% vs 47% +/- 15%). Islet viability as measured using membrane integrity assays was similar in both the control (98% +/- 2%) and the A1AT-treated groups (99% +/- 1%). EM results revealed a reduction or absence of secretory granules after exposure to proteases (TCE). Culture of impure human islet fractions in the presence of A1AT prevented insulin cleavage and improved islet recovery. A1AT supplementation of islet culture media, therefore, may increase the proportion of human islet products that meet release criteria for transplantation. Copyright 2010 Elsevier Inc. All rights reserved.

21 CFR 170.60 - Nitrites and/or nitrates in curing premixes.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Nitrites and/or nitrates in curing premixes. 170... guanylate, hydrolysates of animal or plant origin (such as hydrolyzed vegetable protein), oleoresins of... of an authorizing food additive regulation. A food additive petition submitted pursuant to §§ 171.1...

Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

PubMed Central

Sloop, Kyle W.; Willard, Francis S.; Brenner, Martin B.; Ficorilli, James; Valasek, Kathleen; Showalter, Aaron D.; Farb, Thomas B.; Cao, Julia X.C.; Cox, Amy L.; Michael, M. Dodson; Gutierrez Sanfeliciano, Sonia Maria; Tebbe, Mark J.; Coghlan, Michael J.

2010-01-01

OBJECTIVE The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. RESEARCH DESIGN AND METHODS Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. RESULTS Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. CONCLUSIONS These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization. PMID:20823098

Insulin Resistance in Alzheimer's Disease

PubMed Central

Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

2014-01-01

Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

Label-Free Detection of Insulin and Glucagon within Human Islets of Langerhans Using Raman Spectroscopy

PubMed Central

Hilderink, Janneke; Otto, Cees; Slump, Cees; Lenferink, Aufried; Engelse, Marten; van Blitterswijk, Clemens; de Koning, Eelco; Karperien, Marcel; van Apeldoorn, Aart

2013-01-01

Intrahepatic transplantation of donor islets of Langerhans is a promising therapy for patients with type 1 diabetes. It is of critical importance to accurately monitor islet quality before transplantation, which is currently done by standard histological methods that are performed off-line and require extensive sample preparation. As an alternative, we propose Raman spectroscopy which is a non-destructive and label-free technique that allows continuous real-time monitoring of the tissue to study biological changes as they occur. By performing Raman spectroscopic measurements on purified insulin and glucagon, we showed that the 520 cm-1 band assigned to disulfide bridges in insulin, and the 1552 cm-1 band assigned to tryptophan in glucagon are mutually exclusive and could therefore be used as indirect markers for the label-free distinction between both hormones. High-resolution hyperspectral Raman imaging for these bands showed the distribution of disulfide bridges and tryptophan at sub-micrometer scale, which correlated with the location of insulin and glucagon as revealed by conventional immunohistochemistry. As a measure for this correlation, quantitative analysis was performed comparing the Raman images with the fluorescence images, resulting in Dice coefficients (ranging between 0 and 1) of 0.36 for insulin and 0.19 for glucagon. Although the use of separate microscope systems with different spatial resolution and the use of indirect Raman markers cause some image mismatch, our findings indicate that Raman bands for disulfide bridges and tryptophan can be used as distinctive markers for the label-free detection of insulin and glucagon in human islets of Langerhans. PMID:24167603