Model Assessment Beta-cell Function Research Articles

Genetically predicted brain cortical structure mediates the causality between insulin resistance and cognitive impairment.

Insulin resistance is tightly related to cognition; however, the causal association between them remains a matter of debate. Our investigation aims to establish the causal relationship and direction between insulin resistance and cognition, while also quantifying the mediating role of brain cortical structure in this association. The publicly available data sources for insulin resistance (fasting insulin, homeostasis model assessment beta-cell function and homeostasis model assessment insulin resistance, proinsulin), brain cortical structure, and cognitive phenotypes (visual memory, reaction time) were obtained from the MAGIC, ENIGMA, and UK Biobank datasets, respectively. We first conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine the susceptibility of insulin resistance on cognitive phenotypes. Additionally, we applied a two-step MR to assess the mediating role of cortical surficial area and thickness in the pathway from insulin resistance to cognitive impairment. The primary Inverse-variance weighted, accompanied by robust sensitivity analysis, was implemented to explore and verify our findings. The reverse MR analysis was also performed to evaluate the causal effect of cognition on insulin resistance and brain cortical structure. This study identified genetically determined elevated level of proinsulin increased reaction time (beta=0.03, 95% confidence interval [95%CI]=0.01 to 0.05, p=0.005), while decreasing the surface area of rostral middle frontal (beta=-49.28, 95%CI=-86.30 to -12.27, p=0.009). The surface area of the rostral middle frontal mediated 20.97% (95%CI=1.44% to 40.49%) of the total effect of proinsulin on reaction time. No evidence of heterogeneity, pleiotropy, or reverse causality was observed. Briefly, our study noticed that elevated level of insulin resistance adversely affected cognition, with a partial mediation effect through alterations in brain cortical structure.

Age-Related Sex Differences in Glucose Tolerance by 75 g Oral Glucose Tolerance Test in Japanese.

To elucidate the age-related sex difference in glucose tolerance, we conducted 75 g oral glucose tolerance tests in 1156 participants. Participants were divided into four groups, namely, young (22-29) males, young females, middle-aged (>50) males, and middle-aged females. According to the Japanese Clinical Practice Guideline for Diabetes 2019, the prevalence of normal glucose tolerance (NGT) was significantly lower in middle-aged than in young participants. The prevalence of high-normal fasting plasma glucose (FPG) was higher, and NGT was lower in young males (high-normal FPG 15.2%, NGT 82.0%) than young females (high-FPG 3.9%, NGT 94.3%). Combined glucose intolerance (CGI) was higher and NGT was lower in middle-aged males (CGI 10.2%, NGT 25.2%) than in middle-aged females (CGI 3.3%, NGT 39.8%). FPG and body mass index (BMI) were the lowest and Homeostatic model assessment beta cell function (HOMA-β) was the highest in young females, followed by young males, middle-aged females, and middle-aged males. Multiple linear regression analysis revealed that BMI weakly correlated with HOMA-β and Matsuda index in all subjects except young females. The superior glucose tolerance in females was apparent in young, but attenuated in middle-aged females. The differences are due to the higher insulin secretion potential and lower BMI in young females.

Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes

IntroductionPancreatic and duodenal homeobox factor-1 (PDX-1) is an imperative gene for insulin secretion in maturity-onset diabetes of the young 4. PDX-1 gene polymorphism was associated with lower first-phase insulin secretion...

Antidiabetic effect of gemigliptin: a systematic review and meta-analysis of randomized controlled trials with Bayesian inference through a quality management system

Gemigliptin is one of the latest dipeptidyl peptidase-4 inhibitors developed by LG Life Sciences. Since the early 2000s, several randomized controlled trials (RCTs) of gemigliptin have been conducted. However, no study has directly compared its antidiabetic effects through a systematic review and meta-analysis. Therefore, in this study, we performed a systematic review and meta-analysis on RCTs. In particular, a subsequent meta-analysis was performed using Bayesian inference, and an updated quality management system model was integrated throughout our study. The mean differences and 95% confidence intervals for glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), homeostatic model assessment beta cell function (HOMA-β), and low-density lipoprotein (LDL) were evaluated for the efficacy outcomes of gemigliptin as compared to those of placebo and other oral antidiabetic drugs (OADs). In conclusion, we found that gemigliptin was superior to placebo and comparable to other OADs in terms of the effect on HbA1c, FPG, HOMA-β, and LDL. Further, gemigliptin was more effective than other OADs in HbA1c and HOMA-β in Bayesian inference analysis and statistically significant to other OADs in HbA1c and HOMA-β in sensitivity analysis excluding metformin. However, to confirm the results, more studies need to be analysed and the minimum clinically important difference must be applied.

Factors That Influence Pancreatic Beta Cell Function and Insulin Resistance in Newly Diagnosed Type 2 Diabetes Patients: A Sub-Analysis of the MARCH Trial.

IntroductionThe Metformin and Acarbose in Chinese as the initial Hypoglycemic treatment (MARCH) trial has demonstrated a similar efficacy in HbA1c reduction between acarbose and metformin treatments in newly diagnosed type 2 diabetes mellitus (T2DM) patients. The current sub-analysis of the MARCH trail aims to evaluate the baseline characteristics that may influence the improvement of pancreatic β-cell function and insulin resistance after acarbose therapy in Chinese patients with newly diagnosed T2DM.MethodsOf the 784 patients who entered the MARCH trail, 391 were assigned to the acarbose therapy group; 304 of these completed 48 weeks of follow-up of acarbose therapy. At 48 weeks, on the basis of the tertiles of change in homeostasis model assessment–beta cell function (∆HOMA-β) and homeostasis model assessment–insulin resistance (∆HOMA-IR), the subjects were divided into lowly, mediumly, and highly improved groups.ResultsIn the highly improved HOMA-β group, patients had higher systolic blood pressure (SBP), 2-h postprandial blood glucose (PBG), hemoglobin A1c (HbA1c), and lower high-density lipoprotein cholesterol (HDL-c), fasting serum insulin (FINS) concentration, and HOMA-IR in comparison to the lowly improved group (p < 0.05). A positive correlation was observed between HbA1c, SBP, and highly improved ∆HOMA-β (p < 0.05), while an inverse correlation was evident between HDL-c and highly improved ∆HOMA-β (p < 0.05). The highly improved HOMA-IR group had a significantly higher body mass index (BMI), fasting blood glucose (FBG), FINS concentration, and HOMA-β in comparison to the lowly improved group (p < 0.05). A positive correlation was observed between FBG, waist circumference, and highly improved HOMA-IR (p < 0.05).ConclusionNewly diagnosed T2DM Chinese patients with lower baseline HDL-c and higher HbA1c and SBP values are more likely to achieve improvement in beta cell function whereas baseline fasting blood glucose and waist circumference were the significant factors associated with improvement in insulin resistance with acarbose therapy.Trial RegistrationThe clinical trial registry number was ChiCTR-TRC-08000231.

GTF-231, a Mixture of Gymnemic Acid, Trigonelline and Ferulic Acid Significantly Ameliorates Oxidative Stress in Experimental Type 2 Diabetes in Rats.

According to a report by the United States National Health and Nutrition Examination Survey, nearly 60% of patients with diabetes have more than one complication caused by chronic diabetes. Type 2 diabetes is a multifactorial metabolic disorder that accounts for more than 95% of people with diabetes and usually requires multitargeted therapeutic interventions. It arises due to insufficient insulin secretion or its action or both. Recently, we reported that the oral administration of gymnemic acid, trigonelline and ferulic acid in the ratio of 2:3:1 (GTF-231), a mixture of 3 phytoingredients at a concentration of 300 mg/kg body weight significantly improved the glucose homeostasis in rats with low-dose streptozotocin-induced type 2 diabetes that were fed with high-fat diet. In the present study, an effort was made to evaluate the antioxidant potential of GTF-231 in rats with type 2 diabetes. Type 2 diabetes was induced in experimental rats by administration of low-dose streptozotocin (35 mg/kg body weight) and high-fat diet. The biochemical parameters analyzed included levels of fasting blood glucose, glycated hemoglobin, plasma insulin, homeostatic model assessment-insulin resistance, homeostatic model assessment beta-cell function, advanced glycation end products, advanced oxidation protein products, hydroperoxides, malondialdehyde and enzymatic as well as nonenzymatic antioxidants and proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin 1 beta, interleukin-6, nuclear factor-κB and nitric oxide. Histologic observations were made on the pancreatic tissues. The data obtained showed the significant antioxidant properties of GTF-231, which were further evidenced by the histologic observations made on the pancreatic tissue. The observed antioxidant potential of GTF-231 may account for its significant antidiabetic properties.

The association between insulin resistance, metabolic syndrome, and ischemic heart disease among Rumoi residents.

BackgroundIt has widely been proven that metabolic syndrome (MetS) increases the risk of ischemic heart disease (IHD). MetS is confirmed based upon insulin resistance (IR). Our aim of this study is to evaluate the role of MetS and IR in the prediction of IHD incidence.MethodsA total of 404 non‐diabetic participants who underwent 75 g oral glucose tolerance test (75 g OGTT) were enrolled from 2001 to 2009. Risk factors for IHD were measured as well. The homeostatic index of IR (HOMA‐IR) and the homeostatic model assessment beta cell function (HOMA‐β) were calculated according to the homeostasis model assessment. Cox proportional‐hazard regression model was used to estimate hazard ratio (HR). All data were analyzed using SPSS 21 software (IBM, Armonk, NY, USA).ResultsIn our study, the average follow‐up period was 6.7 years. Eighteen subjects of IHD incidence were recorded. After adjusting for age and sex, subjects with IR or hyperinsulinemia had a high risk of IHD, the hazard ratio (95% confidence intervals) for IHD were 4.58 (1.59‐13.15), 4.25 (1.64‐11.91), respectively. The highest hazard ratio was 7.56 (2.27‐25.18) which was found among the subjects with both IR and hyperinsulinemia. In addition, the hazard ratio (95% confidence intervals) of subjects with MetS was 2.80(1.10‐7.09).Conclusions IR and hyperinsulinemia are related to the risk of IHD. IR combined with hyperinsulinemia may be superior to MetS for predicting the IHD incidence.

Effects of dipeptidyl peptidase-4 inhibitors on beta-cell function and insulin resistance in type 2 diabetes: meta-analysis of randomized controlled trials

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel family of glucose-lowering agents. Accumulating evidence suggests that DPP-4 inhibitors preserve pancreatic beta-cell function, but results in previous studies have been inconsistent. We assessed the effects of DPP-4 inhibitors on the homoeostasis model assessment beta-cell function (HOMA-B) or insulin resistance (HOMA-IR) index in patients with type 2 diabetes through a systematic review and meta-analysis of randomized controlled trials (RCTs). Relevant articles were identified from PubMed, Embase, and Cochrane Library databases up to December 27, 2016. We calculated weighted mean differences (WMDs) and 95% confidence intervals (CIs) in each included trial and pooled the data using a random-effects model. Fifty-two trials were included in the present analysis. Compared with placebo control, DPP-4 inhibitors as monotherapy significantly improved HOMA-B (WMD 9.15; 95% CI 7.48, 10.81). Similarly, DPP-4 inhibitors as add-on therapy in combination with other drugs showed significant improvement in HOMA-B (WMD 9.04; 95% CI 5.72, 12.37). However, we found no significant improvement in HOMA-IR following treatment with DPP-4 inhibitors as mono-therapy or as add-on therapy. In conclusion, DPP-4 inhibitors as monotherapy or as add-on therapy significantly improved beta-cell function but had no significant effect on insulin resistance in type 2 diabetes.

Relationships between Physical Inactivity and Insulin Secretory Capacity in Non-obese Subjects with Type2 Diabetes Mellitus

PURPOSE: In western countries, obesity is a major risk factor for developing insulin resistance and the onset of type 2 diabetes mellitus (DMII). Conversely, Japanese adults with DMII are often not obese, but have a genetically low insulin secretory capacity. Current Japanese guidelines for treatment of DMII are mainly based on evidence from studies done with obese subject with DMII. Although exercise plays an important role in improving insulin resistance and reducing the risk of DMII, the effects of exercise in non-obese patients with DMII have not been well-studied. We investigated the association between insulin secretory capacity and daily physical activity and sedentary time in non-obese Japanese adults with DMII. METHODS: Subjects were non-obese adult men with DMII (DM; n=12, age; 54.5±7.2 yr, BMI; 24.0±1.8 kg/m2) and a control group of non-obese healthy adult men (C: n=10, age; 53.9±6.6 yr, and BMI; 24.0±1.7 kg/m2). Daily physical activity and sedentary time were measured using a triaxial accelerometer (HJA-350IT OMRON Corporation). Insulin and glucose were measured prior to and two hours after standard meal ingestion. Fasting C-peptide concentrations and the homeostatic model assessment beta cell function (HOMA-β)were used as indices of insulin secretory capacity. RESULTS: Daily step counts and time spent sedentary and in low, moderate, and vigorous physical were not different between two groups (P > 0.05). HOMA-β in DM was significantly lower than in C (DM; 21.1±9.3 %, C; 48.4±23.2 %). The correlation between HOMA-β and moderate to vigorous intensity physical activity time was not significant in either C (r=-0.20, P=0.61) or DM (r=0.13, P=0.68). However, in DM, there was a significant inverse correlation between sedentary and HOMA-β (r=-0.62, P < 0.03) and C-peptide (r=-0.81, P<0.01). CONCLUSIONS: In non-obese Japanese men with DMII, time spent in sedentary behaviors, but not time spent in physical activity, is associated with reduced insulin secretion. These results suggest that reducing inactivity time may be an appropriate strategy to increase insulin secretion capacity in non-obese patients with DMII.

The Effect of Pumpkin on GLP-1 and HOMA-β in Hypercholesterolemic Rats

Abstract Background and aim: High fat and fructose diet may impair β cell function through oxidative stress that is induced by subsequent hypercholesterolemia. The β cell function is usually quantified by homeostatic model assessment beta-cell function (HOMA-β). Oxidative stress may be decreased by β-carotene from pumpkin (Cucurbita maxima). This study aimed to evaluate the effects of pumpkin powder on glucagon-like peptide-1 (GLP-1) level and HOMA-β in rats with high fat and fructose diet. Material and method: A total 25 rats were administered a high fat and fructose diet during 25 days. They were divided into five groups 1) normal, 2) hypercholesterolemic rats 3) hypercholesterolemic rats with 0.16 g pumpkin/200g bodyweight (BW); 4) hypercholesterolemic rats with 0.32 g pumpkin/200 g BW, and 5) hypercholesterolemic rats with 0.64 g of pumpkin/200 g BW. The lipid levels were measured before and after administration of pumpkin for 4 weeks, and at the end of the study, GLP-1 level and HOMA-β were analyzed. Results: Administration of pumpkin to the rats on a high fat and fructose diet reduced total cholesterol, triglyceride, and increased HDL levels. Changes were positively correlated with the amount of pumpkin intake. The decrease of cholesterol levels was positively associated with GLP-1 level, and negatively correlated with HOMA-β Conclusions: This study suggested that pumpkin can improve the HOMA-β and decrease GLP-1 levels, possibly by reducing cholesterol levels.

Ethnic differences in insulin sensitivity and beta-cell function among Asian men.

Background and objectives:Lean Asian Indians are less insulin sensitive compared with Chinese and Malays, but the pancreatic beta-cell function among these ethnic groups has yet to be studied in depth. We aimed to study beta-cell function in relation to insulin sensitivity among individuals of Chinese, Malay and Asian-Indian ethnicity living in Singapore.Subjects and methods:This is a sub-group analysis of 59 normoglycemic lean (body mass index (BMI) <23 kg m−2) adult males (14 Chinese, 21 Malays and 24 Asian Indians) from the Singapore Adults Metabolism Study. Insulin sensitivity was determined using fasting state indices (homeostatic model assessment—insulin resistance), the euglycemic-hyperinsulinemic clamp (ISI-clamp) and a liquid mixed-meal tolerance test (LMMTT) (Matsuda insulin sensitivity index (ISI-Mat)). Beta-cell function was assessed using fasting state indices (homeostatic model assessment—beta-cell function) and from the LMMTT (insulinogenic index and insulin secretion index). The oral disposition index (DI), a measure of beta-cell function relative to insulin sensitivity during the LMMTT, was calculated as a product of ISI-Mat and insulin secretion index.Results:Asian Indians had higher waist circumference and percent body fat than Chinese and Malays despite similar BMI. Overall, Asian Indians were the least insulin sensitive whereas the Chinese were most insulin sensitive. Asian Indians had higher beta-cell function compared with Chinese or Malays but these were not statistically different. Malays had the highest incremental area under the curve for glucose during LMMTT compared with Asian Indians and Chinese. However, there were no significant ethnic differences in the incremental insulin area under the curve. The oral DI was the lowest in Malays, followed by Asian Indians and Chinese.Conclusion:Among lean Asians, Chinese are the most insulin sensitive whereas Asian Indians are the least insulin sensitive. However, Malays demonstrate higher postprandial glucose excursion with lower beta-cell response compare with Chinese or Asian Indians. The paths leading to type 2 diabetes mellitus might differ between these Asian ethnic groups.

Effects of One Year Treatment of Vildagliptin Added to Pioglitazone or Glimepiride in Poorly Controlled Type 2 Diabetic Patients

The aim of the study was to compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic and insulin resistance related-indices in poorly controlled type 2 diabetic patients (T2DM). 168 patients with T2DM were randomized to take either pioglitazone 30 mg once a day plus vildagliptin 50 mg twice a day or glimepiride 2 mg 3 times a day plus vildagliptin 50 mg twice a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), adiponectin (ADN), resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high sensitivity C-reactive protein (Hs-CRP) at their baseline values, and after 3, 6, 9, and 12 months of treatment. We observed a similar improvement of HbA1c, FPG, PPG, and Hs-CRP compared to baseline in the 2 groups. Fasting plasma insulin, FPPr, Pr/FPI ratio, R, and TNF-alpha were significantly decreased and ADN was significantly increased with pioglitazone plus vildagliptin, but not with glimepiride plus vildagliptin. HOMA-IR, and HOMA-beta values obtained with pioglitazone plus vildagliptin were significantly better than the values obtained with glimepiride plus vildagliptin. Pioglitazone plus vildagliptin were found to be more effective in preserving beta-cell function, and in reducing insulin resistance, and inflammatory state parameters.

Serum visfatin in Asian women with polycystic ovary syndrome

Objective. To determine serum visfatin levels in Asian polycystic ovary syndrome (PCOS) women and its correlations with various parameters.Study design. Case–control study.Setting. University hospital.Subjects. Eighty women were enrolled in this study. Of these, 40 women were PCOS and 40 age-matched subjects with regular menstrual cycles were controls.Intervention. Seventy-five gram oral glucose tolerance tests were performed in all women. Fasting venous blood samples for serum visfatin, insulin and androgen levels were obtained both from the PCOS and the control women.Main outcome measures. Serum concentrations of visfatin, fasting insulin (FI), fasting glucose, 2-h post-load glucose (2hPG), homeostasis model assessment insulin resistance, homeostasis model assessment beta cell function, total testosterone, free testosterone, androstenedione and dehydroepiandrosterone sulfate were measured in both groups.Results. Women with PCOS had significantly higher serum visfatin levels than the healthy controls [100.39 ± 41.90 vs. 45.09 ± 28.24 mg/ml, p < 0.01]. PCOS women also had significantly higher concentrations of all androgens (p < 0.01). Insulin resistance seemed to be greater in the PCOS than the control groups, but did not reach a statistically significant level. In the PCOS group, serum visfatin levels were positively correlated with 2hPG, and systolic blood pressure and diastolic blood pressure. Serum visfatin levels were negatively associated with FI (r = −0.80, p = 0.03) and positively associated with systolic and diastolic blood pressure (r = 0.77, p = 0.04, r = 0.79, p = 0.03, respectively) in the sub-group of PCOS women with abnormal glucose tolerance (AGT).Conclusions. Asian PCOS women had significantly higher serum visfatin levels than age-matched healthy controls. Their levels were significantly correlated with 2hPG and blood pressure in PCOS women, and with FI and blood pressure in PCOS women with AGT.

Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy

To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy. After a 2-week screening period, adult patients 18-80 years of age entered a 4-week run-in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]. The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (-0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels < or =7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction > or =0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of beta-cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, -0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0-2.5% across groups), and serious AEs (2.0-5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively. In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA(1c) > or =7% and < or =10%) on exercise and diet. A total of 521 patients aged 27-76 years with a mean baseline HbA(1c) of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue. After 18 weeks, HbA(1c) was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA(1c) reduction: -0.60% and -0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA(1c) (> or =9%) experienced greater placebo-subtracted HbA(1c) reductions with sitagliptin (-1.20% for 100 mg and -1.04% for 200 mg) than those with HbA(1c) <8% (-0.44% and -0.33%, respectively) or > or =8% to 8.9% (-0.61% and -0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight. Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet.

The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome

To establish whether visceral fat mass is the most significant variable correlating with insulin resistance and other metabolic parameters in women with polycystic ovary syndrome (PCOS). Prospective cross-sectional trial. Reproductive medicine clinic. Forty women with anovulatory PCOS. Measurements were taken at recruitment, and analysis was performed to define correlations between the outcome measures and the explanatory variables. Visceral and subcutaneous fat by computed tomography scan, insulin resistance, anthropometric measures, markers of the metabolic syndrome and androgens. Strong linear correlation of visceral fat to insulin resistance (r = 0.68, P < 0.001) was observed. There were also statistically significant correlations with fasting insulin (r = 0.73, P < 0.001), homeostasis model assessment beta-cell function (r = 0.50, P = 0.007), triglycerides (r = 0.45, P = 0.003), high-density lipoprotein cholesterol (r = -0.42, P = 0.007), urate (r = 0.47, P = 0.002), Sex hormone binding globulin (r = -0.39, P = 0.01) and luteinising hormone (r = -0.32, P = 0.02). There were no significant correlations of testosterone with fat distribution or metabolic parameters. Insulin resistance showed closest correlation to visceral fat mass (r = 0.68, P < 0.001), then to waist circumference (r = 0.62, P < 0.001), with the weakest correlation being waist:hip ratio (r = 0.36, P = 0.01). The best regression model for predicting insulin resistance is with visceral fat mass and triglycerides as the explanatory variables (r = 0.72, P < 0.001). Visceral fat is the most significant variable correlating with metabolic dysfunction in women with PCOS. Our data support the hypothesis that visceral fat either causes insulin resistance or is a very early effect of it. It also implies that reducing visceral fat should reduce insulin resistance which may account for the observations that exercise and weight loss appear to be more effective interventions than pharmacological treatments. The best anthropometric measure of insulin resistance is waist circumference.

Persistence of impaired pancreatic β-cell function in children treated for acute lymphoblastic leukaemia

Treatment for acute lymphoblastic leukaemia can induce alterations of glucose metabolism, but long-term follow-up data on this topic are still absent. We aimed to study glucose metabolism by intravenous and oral glucose tolerance testing in 32 children affected by acute lymphoblastic leukaemia and who were off-therapy for at least 1 year. 22 (69%) children presented with impaired first-phase insulin response, which in nine children was associated with impaired glucose tolerance and in one child with overt diabetes. Fasting insulin (4.65 mU/L, 95% CI 1.1-8.1; p=0.008), insulinogenic index (0.46; 0.02-0.98; p=0.03), and homoeostatic model assessment beta-cell function (80.1, 7.2-153; p=0.02) were reduced in the children with impaired insulin response. Chemotherapy for acute lymphoblastic leukaemia is associated with beta-cell function damage, which persists even after therapy has been stopped.