Fasting Plasma Glucose Concentrations Research Articles

Carbohydrate Nutrition Differs by Diabetes Status and Is Associated with Dyslipidemia in Boston Puerto Rican Adults without Diabetes

Puerto Rican adults have a greater prevalence of type 2 diabetes (T2D) and lower HDL-cholesterol (HDL-C) than the general U.S. population. Carbohydrate nutrition may play a role in this disparity. Cross-sectional analyses included data from 1219 Puerto Ricans aged 45–75 y enrolled in the Boston Puerto Rican Health Study. Using the Pearson chi-square test and ANCOVA, lifestyle characteristics and dietary intake, as assessed by semiquantitative FFQ, were compared by T2D status based on fasting plasma glucose concentration and medication use. Food source rankings for carbohydrate, dietary glycemic load (GL), and fiber were obtained using the SAS procedure PROC RANK. Geometric mean plasma HDL-C and TG concentrations were compared across quintiles of dietary carbohydrate, glycemic index (GI), GL, and fiber by using ANCOVA and tests for linear trend. In multivariable analyses, individuals with T2D (39.5%) had lower dietary carbohydrate, GL, and total sugar intake from lower intake of sugar, fruit drinks, and soda compared with those without T2D. In individuals without T2D, dietary carbohydrate and GL were inversely associated with HDL-C (P < 0.0001). Associations between dietary fiber and HDL-C were confounded by carbohydrate intake, apparently from concurrent consumption of legumes with white rice, a refined carbohydrate food. No associations were observed between carbohydrate, dietary GI, GL, or fiber and TG. In conclusion, individuals with T2D showed evidence of dietary modification. Among those without diabetes, a high intake of refined carbohydrates was associated with decreased HDL-C. Longitudinal research on carbohydrate nutrition in relation to diabetes risk factors and blood lipids in Puerto Ricans is warranted.

Daily physical activity predicts degree of insulin resistance: a cross-sectional observational study using the 2003–2004 National Health and Nutrition Examination Survey

BackgroundThis study examined the independent association of objectively measured physical activity on insulin resistance while controlling for confounding variables including: cardiorespiratory fitness, adiposity, sex, age, and smoking status.MethodsData were obtained from National Health and Nutrition Examination Survey 2003–2004, a cross-sectional observational study conducted by the National Center for Health Statistics of the Centers for Disease Control that uses a stratified, multistage probability design to obtain a nationally representative sample of the U.S. population. The analysis included 402 healthy U.S. adults with valid accelerometer, cardiorespiratory fitness, and fasting plasma glucose and insulin concentrations. After controlling for relevant confounding variables we performed a multiple linear regression to predict homeostatic model of insulin resistance (HOMA-IR) based on average daily minutes of moderate-to-vigorous physical activity (MVPA).ResultsIn our bivariate models, MVPA, cardiorespiratory fitness and body fat percentage were all significantly correlated with log HOMA-IR. In the complete model including MVPA and relevant confounding variables, there were strong and significant associations between MVPA and log HOMA-IR (β= −0.1607, P=0.004). In contrast the association between cardiorespiratory fitness and log HOMA-IR was not significant.ConclusionWhen using an objective measure of physical activity the amount of time engaged in daily physical activity was associated with lower insulin resistance, whereas higher cardiorespiratory fitness was not. These results suggest that the amount of time engaged in physical activity may be an important determinant for improving glucose metabolism.

Leptin therapy in type 2 diabetes

There is a pressing need for new effective therapeutic strategies for addressing the epidemic of type 2 diabetes. Leptin has been shown to reduce hyperglycaemia in rodent models of type 1 diabetes and has recently been shown to normalize fasting plasma glucose concentrations in a rodent model of polygenic obesity and type 2 diabetes. Overall, these findings suggest that leptin may be an effective therapeutic option for both type 1 and type 2 diabetes. However, short-term human clinical studies in overweight and obese patients with recently diagnosed type 2 diabetes have reported minimal efficacy of leptin administration to lower blood glucose levels. Herein, the role of leptin in the maintenance of glucose homeostasis and the potential use of leptin in the treatment of type 2 diabetes are discussed.

Original article High fructose solution induces neuronal loss in the nucleus of the solitary tract of rats

Nucleus tractus solitarius (NTS) is the main region for the cardiovascular regulation including the baroreceptor reflex. Although the physiological and biochemical aspects of a high fructose diet on the brain have been studied, its effects on the quantitative aspects of the NTS have received less attention. The objective of the present study was to quantify the structural changes in the NTS after the consumption of high fructose solution, using stereological methods. Male rats were distributed randomly into two groups. One group received fructose (10%) in tap water for six weeks and the other one received tap water without fructose. The total volume of the NTS and number of the neurons of the nucleus were estimated using stereological methods including Cavalieri and disector methods. The coefficient of error (CE) of the estimators was calculated. Fasting plasma concentrations of glucose, triglyceride, cholesterol and insulin were obtained. Also a glucose tolerance test was done. The results showed no significant changes in glucose, triglyceride, cholesterol and insulin concentrations between the two groups. The glucose tolerance test did not show any differences, either. The mean (coefficient of variation) volume of the NTS and the neuronal number was 0.68 (0.2) mm3 and 68000 (0.13) in the control rats, respectively. But the volume of the NTS and total number of the neurons decreased by 41% in the fructose-treated group (p ≤ 0.01). Consumption of high fructose solution for six weeks led to a decrement in the volume and number of the neurons in the NTS in rats.

Homeostatic model assessment indices in evaluation of insulin resistance and secretion in hemodialysis patients

BackgroundSome previous observations suggest that insulin resistance and glucose metabolism disturbances are frequent complications of chronic kidney disease. However, there are no conclusive studies on other indices of the effectiveness of insulin action in end-stage renal disease (ESRD) patients, including chronically hemodialysed (HD) ones.Material/MethodsThe groups comprised 33 non-diabetic ESRD hemodialysed patients and 33 healthy controls matched for age, sex, and body mass index (BMI). In both groups, HOMA-%B, HOMA-%S, HOMA-IR indices, and DI were calculated using HOMA1 and HOMA2 as measures of insulin resistance. The indices were also assessed in subgroups divided according to BMI.ResultsMean fasting plasma glucose concentrations were lower in ESRD patients than in healthy persons (82.4±10.4 vs. 93.9±11.6, p=0.001). Fasting serum insulin concentrations were similar in both groups (median 6.8 vs. 6.0 mU/l, p=0.698). HOMA1-%B values were higher in ESRD patients than controls (median 137.1 vs. 81.6, p=0.002). HOMA1-%S (median 75.6 vs. 71.5) and HOMA1-IR (median 1.3 vs. 1.4) values were not significantly different (p=0.264 and p=0.189, respectively). DI1 levels were higher for HD patients than for healthy subjects (median 1.16 vs. 0.53, p<0.001). In subgroup analysis, all statistically significant differences were restricted mainly to persons with BMI <25 kg/m2. Similar results as for the HOMA1 model were obtained for HOMA2.Conclusions1. HOMA beta-cell function is strongly correlated with HOMA insulin resistance in HD patients. 2. In non-diabetic ESRD hemodialysed patients, the HOMA indices and DI may be useful and important models in interpretation of glucose metabolism disturbances.

The association of depression and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes.

Background:Diabetes and diabetes-related complications are major causes of morbidity and mortality in the United States. Depressive symptoms and perceived stress have been identified as possible risk factors for beta cell dysfunction and diabetes. The purpose of this study was to assess associations between depression symptoms and perceived stress with beta cell function between African and Haitian Americans with and without type 2 diabetes.Participants and Methods:Informed consent and data were available for 462 participants (231 African Americans and 231 Haitian Americans) for this cross-sectional study. A demographic questionnaire developed by the Primary Investigator was used to collect information regarding age, gender, smoking, and ethnicity. Diabetes status was determined by self-report and confirmed by fasting blood glucose. Anthropometrics (weight, and height and waist circumference) and vital signs (blood pressure) were taken. Blood samples were drawn after 8 – 10 hours over-night fasting to measure lipid panel, fasting plasma glucose and serum insulin concentrations. The homeostatic model assessment, version 2 (HOMA2) computer model was used to calculate beta cell function. Depression was assessed using the Beck Depression Inventory-II (BDI-II) and stress levels were assessed using the Perceived Stress Scale (PSS).Results:Moderate to severe depressive symptoms were more likely for persons with diabetes (p = 0.030). There were no differences in perceived stress between ethnicity and diabetes status (p = 0.283). General linear models for participants with and without type 2 diabetes using beta cell function as the dependent variable showed no association with depressive symptoms and perceived stress; however, Haitian Americans had significantly lower beta cell function than African Americans both with and without diabetes and adjusting for age, gender, waist circumference and smoking. Further research is needed to compare these risk factors in other race/ethnic groups.

Statin diabetogenicity: guidance for clinicians.

Type 2 diabetes (T2D) is a strong, independent risk factor for cardiovascular (CV) and cerebrovascular outcomes. Meta-analysis of five randomised clinical trials (n = 33,040) showed that, although intensive versus standard glycaemic control significantly reduced CV events in people with T2D, the reduction was less than that achieved with lipid-lowering or antihypertensive treatment. Furthermore, fasting plasma glucose (FPG) concentrations were a modest predictor for CV risk in people without T2D. Thus, although effective glycaemic control is important for the prevention/management of T2D, other risk factors must be addressed to effectively reduce CV risk. Reducing low-density lipoprotein-cholesterol levels using statins significantly reduces CV risk in people with and without T2D. Although statins are generally safe and well tolerated, conflicting data exist regarding the diabetogenic effects of some statins. Based on recent clinical trial data, the US Food and Drug Administration have changed the labelling of all statins to include ‘an effect of statins on incident diabetes and increases in haemoglobin A1c and/or FPG’. However, the literature suggests that the beneficial effects of most statins on CV risk continue to outweigh their diabetogenic risks and that statins should remain as first-line therapy for the majority of people with dyslipidaemia and metabolic syndrome or T2D. Mechanisms explaining the potentially higher incidence of T2D with statin therapy have not been confirmed. However, independent predictors for statin-associated T2D appear to include elevated levels of baseline FPG, BMI, blood pressure and fasting triglycerides. Moreover, although some statins (for example, atorvastatin) are associated with increased haemoglobin A1c levels in patients receiving intensive but not moderate therapy, other statins (for example, pitavastatin) have demonstrated neutral or favourable effects on glucose control in patients with and without T2D or metabolic syndrome. The potential diabetogenic effects of statins may therefore differ between drugs. In conclusion, conflicting data exist regarding the diabetogenic effects of statins. Further studies are required to understand whether all statins have the same effect and whether some patient groups are at higher risk than others. Meanwhile, results suggest that the net CV benefit favours the use of statin therapy in patients with dyslipidaemia, irrespective of T2D risk.

A Comparative Study of Thyroid Hormone and Lipid Status of Patient with and without Diabetes in Adults

Introduction: Lipid and thyroid function abnormalities are common in IDDM and NIDDM. Very few studies have addressed this issue in Bangladesh though Bangladeshi population is very much susceptible to patient with diabetes. Aims: To study on lipid profile and thyroid function in IDDM and NIDDM and the effect of glycemic control on it. Patients and Methods: This was a retrospective study carried out in the Dept. of Endocrinology, BIRDEM, Dhaka, Bangladesh during the period of January, 2012 to May, 2012. In this study, population consisted of 120 subjects (Age between 40 - 72 years; and Sex matched) divided into two groups: patient with diabetes 60 subjects (male-30, female-30) and patient without diabetes 60 subjects (male-30, female-30). Plasma glucose, HbA1c and serum lipids were measured by enzymatic method. Thyroid hormones were measured by a Chemiluminescent Micro particle Immunoassay (CMIA).Results: The statistical significance was evaluated by Student’s t-test, Correlation-Coefficient test. All Values are given as mean ± SD. The level of serum TSH in patient with diabetes (3.43 ± 2.71) was significantly (p 0.05) increased compared to patient without diabetes subjects (1.98 ± 1.72). TSH levels were positively correlated with fasting plasma glucose (r = 0.240, p 0.05), serum cholesterol (r = 0.290, p 0.020) and triglyceride concentration (r = 0.246, p 0.05). On the other hand, free T4 levels were inversely correlated with postprandial blood glucose (r =－0.256, p 0.046). Conclusions: It may be concluded that the lipid and thyroid function abnormalities with others socio-demographic and biophysical risk factors were more common in patient with diabetes cases rather than patient without diabetes cases. Therefore, further prospective studies with larger number of patients are required to strengthen the observations of the present study.

Pioglitazone-Induced Increase in the Stearoyl-CoA Desaturation Index and Fat Accumulation in Rat Muscles Are Not Related to Lipoprotein Lipase Activity

Muscular insulin resistance is a characteristic of obesity and type 2 diabetes, but little is known about fatty acid (FA) metabolism in insulin-resistant skeletal muscle. In this study, we investigated the effects of the repeated administration of the PPAR-γ agonist pioglitazone on fat accumulation, FA composition, and stearoyl-CoA desaturase (SCD) index in rat tissues. Seventeen 4-week-old male Wistar rats were divided into control (C, n = 9) and pioglitazone treatment (P, n = 8) groups, and all the rats were fed a high-fat and high-sucrose diet for 8 weeks. Vehicle or pioglitazone (3 mg/kg) was orally administered daily to rats in the C group and P group, respectively. In the eighth week of the test period, an oral glucose tolerance test (OGTT) was performed after 12 h fasting. At the end of the test period, serum, liver, perirenal adipose tissue, and skeletal muscles were removed after 12 h fasting. The fasting serum and plasma glucose concentrations and OGTT glucose and insulin levels were significantly lower, while the serum adiponectin concentration was significantly higher in the P group than in the C group. Pioglitazone administration increased fat accumulation in the various muscle types examined, perirenal adipose tissue, and brown adipose tissue (BAT), but decreased fat accumulation in the liver. Pioglitazone administration increased the SCD indices for the muscles, perirenal adipose tissue, and liver, but not those of BAT. The lipoprotein lipase (LPL) activity of the BAT and perirenal adipose tissue, but not the muscles, was higher in the P group than in the C group. These results indicate that pioglitazone administration improved glucose tolerance and increased fat accumulation and SCD indices in the muscles and adipose tissues of rats. The increased fat accumulation was closely correlated with LPL activity in both adipose tissues, but not in the muscles.

Differences in metabolic parameters and cardiovascular risk between American Diabetes Association and World Health Organization definition of impaired fasting glucose in European Caucasian subjects: a cross-sectional study

IntroductionThe American Diabetes Association (ADA) defines impaired fasting glucose (IFG) as fasting plasma glucose concentration of 100–125 mg/dl, whereas the World Health Organization (WHO) and the International Diabetes Federation (IDF) define IFG as fasting plasma glucose levels of 110–125 mg/dl. We identified differences in metabolic parameters and cardiovascular disease (CVD) risk according to the ADA or WHO/IDF definition of IFG.Material and methodsHealthy drug-naive Caucasian (Greek) subjects (n = 396; age 55 ±12 years) participated in this cross-sectional study.ResultsDiastolic blood pressure (DBP) and uric acid levels were higher in the subjects with glucose 100–109 mg/dl compared with those with glucose < 100 mg/dl (87 ±9 mm Hg vs. 84 ±11 mm Hg, p = 0.004 for DBP, 5.6 ±1.5 mg/dl vs. 5.0 ±1.0 mg/dl, p = 0.002 for uric acid), whereas triglyceride levels were lower in subjects with glucose 100–109 mg/dl compared with those with glucose ≥ 110 mg/dl (169 mg/dl (interquartile range (IQR) = 102–186) vs. 186 mg/dl (IQR = 115–242), p = 0.002). Only the ADA definition recognized subjects with significantly increased 10-year CVD risk estimation (SCORE risk calculation) compared with their respective controls (5.4% (IQR = 0.9–7.3) vs. 4.1% (IQR = 0.7–5.8), p = 0.002).ConclusionsThe ADA IFG definition recognized more subjects with significantly increased CVD risk (SCORE model) compared with the WHO/IDF definition.

Identifying women with persistent abnormal glucose metabolism following gestational diabetes mellitus: changing times, changing populations and changing needs

Introduction: An oral glucose tolerance test (OGTT) six weeks after delivery is considered the gold standard test to identify persistently abnormal glucose metabolism in women with gestational diabetes mellitus (GDM) but the National Institute for Health and Clinical Excellence (NICE) recommends fasting plasma glucose (FPG) alone. This however, cannot be used to diagnose those with persisting impaired glucose tolerance and will also fail to identify some women with persisting diabetes mellitus (DM). This study aims to identify the percentage of women with DM and impaired glucose tolerance (IGT) that would be missed using this strategy. Methods: Data from 147 women from two sites were analysed. Fishers’ exact test was used to demonstrate differences between OGTT and FPG and a receiver operating characteristic curve was used to try and identify a FPG concentration that would predict a post-glucose load abnormality. Results: Fifty-two of the 147 women had a persistent abnormality in glucose metabolism. Twenty-three had impaired fasting glycaemia (IFG), 21 had IGT and eight women had DM. Only seven of the eight women with DM had a FPG ≥ 7.0 mmol/L and hence one out of eight women with DM (12.5%) and all 21 women with IGT would have been missed if FPG alone were used (p&lt;0.001). Conclusion: Postnatal FPG alone is inadequate to identify all women with DM and would miss a significant number of women with IGT. An OGTT in all women with diagnosed GDM remains the gold standard test to identify persistent abnormal glucose metabolism in these women.

Glycemic control: a combination of lifestyle management and the use of drugs.

Some 30% of contemporary cardiology patients have coexisting known diabetes, and another 40% have either undiagnosed diabetes or prediabetes. There is still no final conclusive evidence of cardiovascular benefit by good glycemic control in type 2 diabetes, although studies like the United Kingdom Prospective Diabetes Study (UKPDS) and the Prospective Pioglitazone Clinical Trial in Macrovascular Events, and meta-analyses based on these and other randomized controlled trials of blood glucose-lowering therapies have been encouraging. On the other hand, microvascular disease is clearly reduced by good glycemic control. Structured education has remained a mandatory prerequisite of any successful treatment. Not only is appropriate weight management by diet and exercise able to revert new onset diabetes to normal, but it is also the foundation of any successful pharmacotherapy of diabetes. Aiming at normal fasting plasma glucose concentrations of 5.3 mmol/L or 95 mg/dL appears to be safe since publication of the long-term outcome results of the Outcome Reduction with an Initial Glargine INtervention trial. Individualized target glycosylated hemoglobin levels as near to normal as safely possible (i.e., <7% and avoiding hypoglycaemia) are the goal for glycemic control. Hypoglycemia seems to emerge as a real concern in cardiology patients. Based on the findings of UKPDS, including the “legacy” study, metformin is the most widely recommended first-line drug therapy in type 2 diabetes, also in terms of preventing cardiovascular complications. An alternate first-line option in some parts of the world, especially Asian countries, is the class of alpha-glucosidase inhibitors. In most patients, combination therapies with two or three classes of drugs are warranted. Early combination are the golden strategy as type 2 diabetes is a multi-causal disease; the various classes of drugs have distinct and synergistic modes of action, and the blood glucose-lowering efficacy of these drugs is more or less fully maintained in combination. The recent joint American Diabetes Association/European Association for the Study of Diabetes position statement mentions five options as step two of the treatment algorithm for combination with metformin: sulfonylureas, pioglitazone, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and basal insulin.

Effect of short-term GH and testosterone administration on body composition and glucose homoeostasis in men receiving chronic glucocorticoid therapy

Long-term pharmacological glucocorticoid (GC) therapy leads to skeletal muscle atrophy and weakness. The objective of this study was to investigate whether short-term treatment with GH and testosterone (T) can increase lean mass without major impairment of glucose homoeostasis in patients on GC therapy. This was a prospective, open-label, randomised, crossover study. Twelve men (age 74±6 years) on chronic GC treatment participated. The effects of 2 weeks' treatment with GH, testosterone and the combination of both on lean body mass (LBM), appendicular skeletal muscle mass (ASMM), extracellular water (ECW), body cell mass (BCM) and plasma glucose concentrations were investigated. LBM increased significantly after GH (Δ1.7±1.4 kg; P=0.007) and GH+testosterone (Δ2.4±1.1 kg; P=0.003), but not testosterone alone. ASMM increased after all three treatment periods; by 1.0±0.8 kg after GH (P=0.005), 1.7±0.4 kg after GH+testosterone (P=0.002) and 0.8±1.0 kg after testosterone (P=0.018). The increase in ASMM was larger with combined treatment than either GH or testosterone alone (P<0.05). ECW increased significantly after GH+testosterone by 1.5±2.6 l (P=0.038) but not after GH or testosterone alone. BCM increased slightly after single and combined treatments, but the changes were not significant. Fasting glucose increased significantly after GH (Δ0.4±0.4 mmol/l, P=0.006) while both fasting (Δ0.2±0.3 mmol/l, P=0.045) and post glucose-load (Δ1.8±2.3 mmol/l, P=0.023) plasma glucose concentrations increased after GH+testosterone. GH and testosterone induce favourable and additive body compositional changes in men on chronic, low-dose GC treatment. In the doses used, combination therapy increases fasting and postprandial glucose concentration.

Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low

BackgroundAlthough the Fat Mass and Obesity (FTO) and Melanocortin-4 Receptor (MC4R) genes have been consistently associated with obesity risk, the association between the obesity-risk alleles with type 2 diabetes is still controversial. In some recent meta-analyses in which significant results have been reported, the associations disappeared after adjustment for body mass index (BMI). However gene-diet interactions with dietary patterns have not been investigated. Our main aim was to analyze whether these associations are modulated by the level of adherence to the Mediterranean Diet (MedDiet).MethodsCase-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and 3,622 non-diabetic subjects) with no differences in BMI. Diet was assessed by validated questionnaires. FTO-rs9939609 and MC4R-rs17782313 were determined. An aggregate genetic score was calculated to test additive effects. Gene-diet interactions were analyzed.ResultsNeither of the polymorphisms was associated with type 2 diabetes in the whole population. However, we found consistent gene-diet interactions with adherence to the MedDiet both for the FTO-rs9939609 (P-interaction=0.039), the MC4R-rs17782313 (P-interaction=0.009) and for their aggregate score (P-interaction=0.006). When adherence to the MedDiet was low, carriers of the variant alleles had higher type 2 diabetes risk (OR=1.21, 95%CI: 1.03-1.40; P=0.019 for FTO-rs9939609 and OR=1.17, 95%CI:1.01-1.36; P=0.035 for MC4R-rs17782313) than wild-type subjects. However, when adherence to the MedDiet was high, these associations disappeared (OR=0.97, 95%CI: 0.85-1.16; P=0.673 for FTO-rs9939609 and OR=0.89, 95%CI:0.78-1.02; P=0.097 for MC4R-rs17782313). These gene-diet interactions remained significant even after adjustment for BMI. As MedDiet is rich in folate, we also specifically examined folate intake and detected statistically significant interaction effects on fasting plasma glucose concentrations in non-diabetic subjects. However these findings should be interpreted with caution because folate intake may simply reflect a healthy dietary pattern.ConclusionsThese novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition.

Population PK/PD analysis of metformin using the signal transduction model

Metformin, a biguanide glucose lowering agent, is commonly used to manage type 2 diabetes. The molecular mechanisms of metformin have not been fully identified, but turnover of biomarkers such as glucose and signalling pathways or translocation of glucose transporters are closely related to the glucose-lowering effects of metformin. The PK/PD of metformin have been investigated in healthy humans and patients with type 2 diabetes mellitus and modelling has been performed using an indirect response model. The purpose of this investigation was to develop a population PK/PD model for metformin using a signal transduction model in healthy humans and predict the PK/PD profile in patients with type 2 diabetes. The aim was to compare a previous model (a biophase model) with the signal transduction model, and use a more appropriate model to follow the actions of metformin. Additionally, our developed model was appropriate to predict the time course of plasma metformin and fasting plasma glucose (FPG) concentrations in patients with type 2 diabetes. To our knowledge, this is the first published population PK/PD analysis using the signal transduction model for metformin. AIMS To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes. Following the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes. Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h(-1) (4.18%), 113 l (56.6%) and 0.41 h(-1) , respectively. Covariate analyses revealed that creatinine clearance (CL(CR) ) significantly influenced metformin: CL/F= 52.6 × (CL(cr) /106.5)(0.782) . The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 µg ml(-1) (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values. The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.

Hepatic glucose production pathways after three days of a high-fat diet

ObjectiveA three-day high-fat diet induces hepatic steatosis and hepatic insulin resistance in rats without altering fasting plasma glucose concentration or the rate of glucose production. However, as the nutrient profile available to the liver is substantially altered by a high-fat diet, we hypothesized that the relative fluxes supporting hepatic glucose production would be altered. Materials/MethodsTo test this hypothesis, we used multiple tracers ([3,4-13C2]glucose, 2H2O, and [U-13C3]propionate) followed by NMR analysis of blood glucose to quantify net glucose production and the contributions of glycogen and key gluconeogenesis precursors in 4–5-h fasted rats. ResultsNMR analysis demonstrated that the majority of blood glucose was derived from glycogen and the citric acid cycle, while a smaller fraction of glucose was derived from glycerol in both controls and high-fat-fed animals. High-fat feeding was associated with a two-fold increase in plasma glycerol concentration and an increase in the contribution (both fractional and absolute) of glycerol-gluconeogenesis. The increase in gluconeogenesis from glycerol tended to be balanced by a decrease in glycogenolysis. The absolute fluxes associated with the citric acid cycle including gluconeogenesis from the cycle intermediates, pyruvate cycling and the citric acid cycle flux itself, were not altered by this short high-fat diet. ConclusionsA short term high-fat diet altered the specific pathways for hepatic glucose production without influencing the overall rate of glucose production or flux in the citric acid cycle.

Relationship of amyloid-β with vascular endothelial cell damage induced by diabetic serum

To explore the relationship of the impairment of human umbilical vein endothelial cell (HUVEC) with amyloid-β. HUVECs were cultured in the serum of patients with type 2 diabetes mellitus (DM) or serum of healthy control (HC), while fetal bovine serum (FBS) was used as a negative control. The proliferative activity of HUVEC were assessed by thiazolyl blue tetrazolium bromide (MTT) after 72 h. The supernatant concentrations of superoxide dismutase (SOD), maleic dialdehyde (MDA), nitric oxide (NO), amyloid-β40 (Aβ40) and Aβ42 were measured after 0.5, 3 and 72 h respectively. Glycosylated hemoglobin values, fasting plasma glucose and fasting plasma Aβ40 concentrations of diabetic patients were higher than those of healthy counterparts (P < 0.01). Proliferative activity of HUVECs in group DM were significantly lower than that of group HC. Both group and the time of intervention had crossover effects on the levels of MDA, SOD, NO and Aβ40 ((163 ± 64), (207 ± 69), (286 ± 75) ng/L in group DM; (146 ± 76), (154 ± 75), (161 ± 72) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05) and Aβ42 ((48 ± 46), (54 ± 43), (79 ± 44) ng/L in group DM; (41 ± 12), (44 ± 16), (48 ± 12) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05). With the elongating time of intervention, the levels of SOD and NO decreased significantly in group DM and reached the lowest after 72 h while increased significantly in groups HC and FBS and peaked after 72 h. The concentrations of MDA, Aβ40 and Aβ42 increased significantly in all three groups while the fastest and marked increments were found in group DM (P < 0.01). Pearson correlation analysis showed that SOD was negatively correlated with Aβ40 (r = -0.482, P = 0.02) and Aβ42 (r = -0.422, P = 0.02) while MDA positively with Aβ40 (r = 0.418, P < 0.05) and Aβ42 (r = 0.833, P < 0.05) after 72 h. Oxidative stress of vascular endothelial cells may be correlated with Aβ40 and Aβ42 in diabetes.

Low Lung Function and Risk of Type 2 Diabetes in Japanese Men: The Toranomon Hospital Health Management Center Study 9 (TOPICS 9)

ObjectiveTo evaluate the effect of elevated fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) concentrations on lung dysfunction and to prospectively investigate whether reduced lung function would be independently predictive of diabetes. Participants and MethodsFrom January 6, 1997, through December 22, 2008, we observed 5346 men with no history of diabetes or lung dysfunction. Hazard ratios (HRs) for incident diabetes (FPG ≥126 mg/dL, HbA1c ≥6.5%, or self-reported clinician-diagnosed diabetes) were estimated for spirometry indices as continuous and categorical variables. ResultsElevated HbA1c concentrations within the normal range were significantly and more strongly associated with reduced forced vital capacity and forced expiratory volume in the first second after expiration (FEV1) than were FPG concentrations. During a 4.0-year follow-up, diabetes developed in 214 individuals. A 10-point decrease in percentage of FEV1 predicted value was associated with an increased HR of 1.21 (95% confidence interval [CI], 1.09-1.34; P=.001) for diabetes after adjustment for demographic factors and body mass index. This association remained significant even after adjustment for metabolic factors, smoking status, and FPG or HbA1c concentrations but was attenuated substantially after adjustment for baseline HbA1c values (HR, 1.13; 95% CI, 1.01-1.26; P=.03). Lower quartile (Q) categories of percentage of FEV1 predicted value were associated with increased risk of diabetes independently of known predictors including HbA1c (HR, 1.73; 95% CI, 1.14-2.62 for Q1; and HR, 1.76; 95% CI, 1.15-2.69 for Q2). ConclusionReduced lung function was significantly related to chronic glycemic exposure within a normal range. Relatively low pulmonary function was an independent risk factor for diabetes in apparently healthy Japanese men.

Acute exposure to resveratrol inhibits AMPK activity in human skeletal muscle cells

Recent studies have suggested resveratrol (RSV) as a new natural therapeutic agent to treat type 2 diabetes and lipid-induced insulin resistance. Here, we investigated whether RSV could reverse palmitate-induced insulin resistance in human primary muscle cells. Myotubes obtained from six healthy men (54 ± 3 years (mean ± SE), BMI 25.0 ± 1.7 kg/m(2), fasting plasma glucose concentration (fP-glucose) 5.47 ± 0.09 mmol/l) were treated for 4 h with 100 μmol/l RSV and/or 0.2 mmol/l palmitate, and stimulated with or without 100 nmol/l insulin. Assays of glucose uptake, glycogen synthesis, palmitate oxidation, intracellular signalling and AMP-activated protein kinase (AMPK) activity were performed. RSV did not reverse palmitate-induced impairment of glucose metabolism. Surprisingly, RSV decreased glucose uptake and glycogen synthesis in human skeletal muscle cells. Palmitate oxidation and phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase β (ACCβ) were inhibited by RSV, and RSV completely blocked the activity of AMPK isoform complexes α1/β2/γ1 and α2/β2/γ1 in in-vitro kinase activity assays. Endoplasmic reticulum (ER) stress was increased in response to RSV, as indicated by increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) and increased expression of CCAAT/enhancer binding protein homologous protein (CHOP). Acute exposure to RSV inhibits AMPK activity, fatty-acid oxidation and glucose metabolism in human myotubes.

Prevalence and Associated Factors of Diabetes and Impaired Fasting Glucose in Chinese Hypertensive Adults Aged 45 to 75 Years

ObjectiveThis study examined the prevalence of impaired fasting glucose (IFG) and diabetes and their associated factors in 17,184 Chinese hypertensive adults aged 45–75 years.MethodsA cross-sectional investigation was carried out in a rural area of Lianyungang, China. Previously undiagnosed diabetes [fasting plasma glucose (FPG) ≥7.0mmol/l] and IFG (6.1–6.9mmol/l) were defined based on FPG concentration. Previously diagnosed diabetes was determined on the basis of self-report. Total diabetes included both previously diagnosed diabetes and previously undiagnosed diabetes.ResultsThe prevalence of previously diagnosed diabetes, undiagnosed diabetes, and IFG were 3.4%, 9.8%, and 14.1%, respectively. About 74.2% of the participants with diabetes had not previously been diagnosed. In the multivariable logistic-regression model, older age, men, antihypertensive treatment, obesity (BMI ≥25kg/m2), abdominal obesity (waist circumference ≥90cm for men and ≥80cm for women), non-current smoking, a family history of diabetes, higher heart rate, lower physical activity levels, and inland residence (versus coastal) were significantly associated with both total diabetes and previously undiagnosed diabetes. Furthermore, methylene- tetrahydrofolate reductase (MTHFR) 677 TT genotype was an independent associated factor for total diabetes, and current alcohol drinking was an independent associated factor for previously undiagnosed diabetes. At the same time, older age, men, abdominal obesity, non-current smoking, current alcohol drinking, a family history of diabetes, higher heart rate, and inland residence (versus coastal) were important independent associated factors for IFG.ConclusionIn conclusion, we found a high prevalence of diabetes in Chinese hypertensive adults. Furthermore, about three out of every four diabetic adults were undiagnosed. Our results suggest that population-level measures aimed at the prevention, identification (even if only based on the FPG evaluation), and treatment of diabetes should be urgently taken to overcome the diabetes epidemic in Chinese hypertensive adults.