GDF15 reflects beta cell function in obese patients independently of the grade of impairment of glucose metabolism.

BACKGROUND AND AIMS: Growth differentiation factor 15 (GDF15) is a strong predictor of cardiovascular morbidity and mortality found to be both marker and target of impaired glucose metabolism. GDF15 increases following glucose administration and is up-regulated in obesity and diabetes. We investigate here the relationship between GDF15 and beta cell function. METHODS AND RESULTS: In this cross-sectional study we evaluated GDF15 concentrations in 160 obese subjects (BMI 35-63 kg/m2, age 39.4 ± 18.6 years, m/f 38/122) who underwent a 75 g oral glucose tolerance test (OGTT). Based on the OGTT results, the cohort was divided into two groups: 1) normal fasting glucose and normal glucose tolerance (n = 80), 2) impaired fasting glucose, impaired glucose tolerance or type 2 diabetes (n = 80). The relationship of GDF15 to fasting and OGTT-based dynamic insulin sensitivity and insulin secretion parameters was evaluated. GDF15 was higher in the prediabetes and diabetes groups and correlated with HbA1c, glucose, insulin as well as baseline and dynamic indices of insulin sensitivity and estimated beta cell function. Multiple regression analysis revealed that age, waist-to-height ratio, glomerular filtration rate and prehepatic beta cell function, but not the grade of impairment of glucose metabolism, were independent predictors of GDF15. Subgroup analysis showed that of all parameters of glucose metabolism only C-peptide, fasting prehepatic beta cell function and insulinogenic index remained significantly related to GDF15 in both groups. CONCLUSION: We conclude that in patients with severe obesity, GDF15 strongly relates to beta cell function and should be further investigated as a potential therapeutic target and biomarker guiding treatment options.

Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin-treated Type 2 diabetes mellitus.

AIM: To determine participant knowledge and reporting of hypoglycaemia in the non-interventional Hypoglycaemia Assessment Tool (HAT) study. METHODS: HAT was conducted in 24 countries over a 6-month retrospective/4-week prospective period in 27 585 adults with Type 1 or insulin-treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both. RESULTS: Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut-off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1-3.6 mmol/l; Type 2 diabetes: 3.5-3.8 mmol/l). CONCLUSIONS: Under-reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. (Clinical Trials Registry No: NCT01696266).

Secreted Frizzled-Related Protein 4 (SFRP4) is Elevated in Patients with Diabetes Mellitus.

Recently, SFRP4 was identified as a molecular link between islet inflammation and defective insulin secretion. Gene co-expression analysis detected a molecule associated with type 2 diabetes mellitus (T2D), elevated HbA1c, and reduced insulin secretion in mice as well as in a pilot sample of humans. To our knowledge SFRP4 has never been investigated in patients with different types of diabetes. We included 179 patients: 46 with type 1 diabetes (T1D), 30 age matched healthy controls for patients with T1D (CO-T1D), 55 with T2D, 37 with latent autoimmune diabetes of the adult (LADA) and 30 healthy controls (CO) for patients with T2D and LADA. Apart from anthropometric data, lipids and renal parameters were assessed. SFRP4 levels were measured by a commercial ELISA. Patients with diabetes had significant higher SFRP4 levels than CO: T2D vs. CO: 37.1±26.7 vs. 8.8±3.0 ng/ml, p<0.001; LADA vs. CO: 15.6±6.2 vs. 8.7±3.0 ng/ml, p<0.001; T1D vs. CO-T1D: 24.6±17.9 vs. 16.9±4.5 ng/ml, p=0.011. SFRP4 levels were correlated with age, BMI, HbA1c, HDL-cholesterol, and triglycerides. A multivariate model revealed HDL-cholesterol, triglycerides and BMI as predictors for SFRP4. This is the first study demonstrating that SFRP4 is significantly increased in patients with different types of diabetes suggesting that this protein is generally involved in islet dysfunction and potentially subclinical inflammation irrespective of type of diabetes.

Differential effects of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide and metformin on pancreatic ß-cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes.

This substudy of the AWARD-3 trial evaluated the effects of the once-weekly glucagon-like peptide-1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C-peptide and glucagon levels were measured up to 3 h post-meal. ß-cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose [AUCglucose (0-3 h)] were observed among all groups. ß-cell function [AUCinsulin /AUCglucose (0-3 h)] increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and ß-cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing ß-cell function, while metformin exerts a greater effect on insulin sensitivity.

Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study.

AIMS: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. METHODS: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged ≥18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for >12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. RESULTS: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. CONCLUSIONS: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.

Treatment of Patients with Obese Type 2 Diabetes with Tantalus-DIAMOND® Gastric Electrical Stimulation: Normal Triglycerides Predict Durable Effects for at Least 3 Years.

The objectives of the present work are to evaluate long-term benefit of nonexcitatory gastric electrical stimulation (GES) by the DIAMOND(®) device on glycemic control and body weight in patients with type 2 diabetes inadequately controlled with oral agents and to determine the magnitude of the modulating effects of fasting plasma triglyceride (FTG) levels on these effects of GES. Sixty one patients with type 2 diabetes [HbA1c > 7.0% (53 mmol/mol) to < 10.5% (91 mmol/mol)] were implanted with the DIAMOND(®) GES device and treated with meal-mediated antral electrical stimulation for up to 36 months. The effects of baseline HbA1c and FTG on glycemic control, body weight, and systolic blood pressure were measured. GES reduced mean HbA1c by 0.9% and body weight by 5.7%. The effects were greater in patients with normal fasting plasma triglycerides (NTG) as compared to those with hypertriglyceridemia. The mean decrease in HbA1c in patients with NTG averaged 1.1% and was durable over 3 years of follow-up. ANCOVA indicated that improvement in HbA1c was a function of both baseline FTG group (p = 0.02) and HbA1c (p = 0.001) and their interaction (p = 0.01). Marked weight loss (≥ 10%) was observed in a significant proportion of NTG patients by 12 months of treatment and persisted through the 3 years. GES improves glycemic control and reduces body weight by a triglyceride-dependent mechanism in patients with type 2 diabetes inadequately controlled on oral agents. It is postulated that this is through a gut-brain interaction that modulates effects on the liver and pancreatic islets.

Fasting plasma triglycerides predict the glycaemic response to treatment of type 2 diabetes by gastric electrical stimulation. A novel lipotoxicity paradigm.

BACKGROUND: Non-stimulatory, meal-mediated electrical stimulation of the stomach (TANTALUS-DIAMOND) improves glycaemic control and causes modest weight loss in patients with Type 2 diabetes who are inadequately controlled on oral anti-diabetic medications. The magnitude of the glycaemic response in clinical studies has been variable. A preliminary analysis of data from patients who had completed 6 months of treatment indicated that the glycaemic response to the electrical stimulation was inversely related to the baseline fasting plasma triglyceride level. METHOD: An analysis of 40 patients who had had detailed longitudinal studies for 12 months. RESULTS: Twenty-two patients with fasting plasma triglycerides ≤ 1.7 mmol/l had mean decreases in HbA1c after 3, 6 and 12 months of gastric contraction modulation treatment of -15 ± 2.1 mmol/mol (-1.39 ± 0.20%), -16 ± 2.2 mmol/mol (-1.48 ± 0.20%) and -14 ± 3.0 mmol/mol (-1.31 ± 0.26%), respectively. In contrast, 18 patients with fasting plasma triglyceride > 1.7 mmol/l had mean decreases in HbA1c of -7 ± 1.7 mmol/mol (-0.66 ± 0.16%), -5 ± 1.6 mmol/mol (-0.44 ± 0.18%) and -5 ± 1.7 mmol/mol (-0.42 ± 0.16%), respectively. Pearson's correlation coefficient between fasting plasma triglyceride and decreases in HbA1c at 12 months of treatment was 0.34 (P < 0.05). Homeostasis model assessment of insulin resistance was unchanged during 12 months of treatment in patients with high baseline fasting triglycerides, while it progressively improved in patients with low fasting plasma triglycerides. Patients with low fasting plasma triglycerides had a tendency to lose more weight than those with high fasting plasma triglycerides, but this did not achieve statistical significance. CONCLUSIONS: The data presented suggest the existence of a triglyceride lipotoxic mechanism that interferes with gastric/neural mediated pathways that can regulate glycaemic control in patients with type 2 diabetes. The data suggest the existence of a triglyceride lipotoxic pathway that interferes with gastric/neural mediated pathways that can regulate glycaemic control.

Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity.

OBJECTIVE: Circulating endothelial progenitor cells (EPCs), responsible for neoangiogenesis and vascular repair, negatively correlate with vascular dysfunction and atherosclerotic risk factors. Because obesity may have a crucial role in the development of endothelial dysfunction, this study evaluated the number and proliferative activity of circulating human EPCs in obese (body mass index (BMI)=48+/-9, n=45) compared with lean (23+/-2, n=45) volunteers. METHODS: EPCs were quantified after isolation of peripheral blood mononuclear cells (PBMCs) using fluorescence-activated cell sorting analyses. In addition, plated PBMCs developed colony-forming units (CFUs) from which 'outgrowth' endothelial cells (OECs) sprouted and differentiated into mature endothelial cells. Growth rates were monitored by periodical microscopic evaluation. Cell-cycle protein expression was determined by western blot analyses. RESULTS: BMI negatively correlated (P<0.01) with the number of CD34(+)/CD133(+)/KDR(+) (r=-0.442), CD34(+)/KDR(+) (r=-0.500) and CD133(+)/KDR(+) (r=-0.282) EPCs. Insulin, leptin, HbA(1c), high-sensitivity C-reactive protein and hypertension, as well as diminished high-density lipoprotein and apolipoprotein A1, were not only associated with obesity but also with significantly reduced EPC levels. Applying selective culture conditions, EPC-CFUs differentiated into OECs that proliferated more slowly when derived from obese compared with lean subjects (obese: 19.9+/-2.2% vs lean: 30.9+/-3.2% grown area per week, P<0.01). The reduced proliferation was reflected by decreased (P<0.05, n=24 for each group) expression of cell-cycle-promoting cyclins and E2F-1, by hypophosphorylation of retinoblastoma protein and by increased (P<0.05, n=24 for each group) expression of the cell-cycle inhibitor p21(WAF-1/Cip1). CONCLUSIONS: Reduced numbers of EPCs along with their premature senescence, as shown in this study, could function as early contributors to the development and progression of vascular dysfunction in obesity.

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance.

OBJECTIVE: Insulin resistance in visceral obesity is substantially driven by adipose tissue inflammation, particularly by macrophages accumulating in obese adipose tissue. In contrast, adipose tissue macrophages express the hemoglobin scavenger receptor (CD163) and heme oxygenase-1 (gene: HMOX1) that together protect from oxidative stress. Our aim was to evaluate the expression of CD163 and HMOX1 in intra-abdominal visceral (omental) and subcutaneous adipose tissue as well as circulating soluble CD163 concentrations in human obesity and its association with adipose tissue inflammation, body fat distribution and insulin resistance. METHODS: CD163, HMOX1 and CD68 mRNA expression in visceral and subcutaneous adipose tissue, serum concentration of soluble CD163 in morbidly obese patients (body mass index (BMI) >40 kg m(-2)), who underwent laparoscopic surgery for gastric banding (n=20), matched for age and sex to controls (BMI<30 kg m(-2); n=20) was analyzed. RESULTS: CD163 expression was highly upregulated in human adipose tissue and soluble CD163 serum concentration was elevated in obese vs lean subjects. HMOX1 was upregulated in adipose tissue by obesity as well and expressed predominantly in macrophages. Although CD163 expression strictly correlated with macrophage abundance, HMOX1 was additionally upregulated within macrophages. This upregulation was significantly lower in visceral compared with subcutaneous adipose tissue. Strikingly, relative visceral adipose tissue expression of HMOX1 negatively correlated with waist-to-hip ratio and the homeostasis model assessment of insulin resistance (both P=0.024). CONCLUSIONS: Visceral obesity is associated with defective upregulation of heme oxygenase-1 in visceral adipose tissue. A lack of this antioxidative and anti-inflammatory enzyme in visceral adipose tissue could contribute to the development of insulin resistance.

The effect of rosiglitazone on insulin sensitivity, beta cell function, bone mineral density, and body composition in hiv-positive patients on highly-active antiretroviral therapy (HAART).

Highly active antiretroviral therapy (HAART) leads to lipodystrophy and is associated with detrimental changes in glucose and lipid metabolism. This study investigated the impact of rosiglitazone on insulin sensitivity, beta cell function, bone mineral density, and body composition in HIV+ nondiabetic subjects under HAART. In this randomized, double blind, placebo controlled parallel group study, 40 HIV+ subjects were treated with rosiglitazone 4 mg/day (R, n=23) or placebo (P, n=17) for 6 months. Glucose, insulin and C peptide concentrations were analyzed for assessing insulin sensitivity and secretion. Adiponectin and leptin were evaluated. Body fluid compartments were measured with bioelectrical impedance spectroscopy, and bone mineral density and body composition with Dual X Ray absorptiometry. Rosiglitazone improved peripheral insulin sensitivity (+36.7+/-15.7 ml/min/m (2), p=0.03, means+/-SEM), while no change was observed in P (+4.5+/-19.5 ml/min/m (2), p=0.55). Liver insulin resistance, beta cell activity, and hepatic insulin clearance did not change. Plasma adiponectin increased (R: +2.47+/-0.86 microg/ml, p=0.01 vs. P: +0.45+/-0.60, p=0.28). Rosiglitazone had no influence on body composition, fat distribution and bone mineral density but expanded extra-cellular fluid volume in HIV infected persons (R: +0.50+/-0.21 l, p=0.02 vs. P: 0.10+/-0.25 l, p=0.32). Lipid metabolism in P remained unchanged, in R total cholesterol and LDL cholesterol levels increased significantly (p<0.05). Rosiglitazone treatment resulted in improved peripheral insulin sensitivity with increased circulating adiponectin in HIV patients under HAART. No effect was seen on body fat distribution, bone mineral density, and weight. These side effects and their potential for cardiac risk must be weighed against the beneficial effects on glucose metabolism.

Improvement in glycemic control by gastric electrical stimulation (TANTALUS) in overweight subjects with type 2 diabetes.

BACKGROUND: The TANTALUS system (MetaCure Ltd.) is a minimally invasive implantable gastric stimulation modality that does not exhibit malabsorptive or restrictive characteristics. The device applies gastric contractility modulation (GCM) signals to the stomach antrum. The signals are delivered in synchronization to the native electrical activity of the stomach during meals. Retrospective analysis of previous studies indicated that type 2 diabetes mellitus (T2DM) subjects on oral medication with hemoglobin A1c (HbA1c) between 7.5% and 9.5% are the population with most potential benefit from the treatment. The current study includes subjects enrolled prospectively within that range of HbA1c. AIM: To prospectively investigate the potential effect of the TANTALUS system on glycemic control and weight in overweight subjects with T2DM. METHODS: In this European multicenter, open-label study, 13 T2DM obese (6 male, 7 female, BMI 37.2 +/- 1.0 kg/m(2), range 30.4-44.0 kg/m(2)) subjects treated with oral antidiabetic medications but with poor glycemic control (HbA1c > or = 7%, range 7.3-9.5%) were implanted laparoscopically with the TANTALUS system. RESULTS: Thirteen subjects that had completed 3 months of treatment showed a significant reduction in HbA1c from 8.0 +/- 0.2% to 6.9 +/- 0.1% (p < 0.05), whereas fasting blood glucose decreased from 175 +/- 6 mg/dL to 127 +/- 8 mg/dL (p < 0.05). The glycemic improvement was accompanied by reduction in weight from 104.4 +/- 4.4 kg to 99.7 +/- 4.8 kg, and in waist circumference from 122.3 +/- 3.2 cm to 117.0 +/- 3.0 cm. CONCLUSIONS: Interim results with the TANTALUS system suggest that this stimulation regime can potentially improve glucose levels and induce moderate weight loss in obese T2DM subjects on oral antidiabetic therapy with poor glycemic control. Further evaluation is required to determine whether this effect is due to induced weight loss and/or due to direct signal-dependent mechanisms.

Inadequate weight loss vs secondary weight regain: laparoscopic conversion from gastric banding to Roux-en-Y gastric bypass.

BACKGROUND: Beside complications like band migration, pouch-enlargement, esophageal dilation, or port-site infections, laparoscopic adjustable gastric banding (LAGB) has shown poor long-term outcome in a growing number of patients, due to primary inadequate weight loss or secondary weight regain. The aim of this study was to assess the safety and efficacy of laparoscopic conversion to Roux-en-Y gastric bypass (RYGBP) in these two indications. METHODS: A total of 25 patients, who underwent laparoscopic conversion to RYGBP due to inadequate weight loss (n = 10) or uncontrollable weight regain (n = 15) following LAGB, were included to this prospective study analyzing weight loss and postoperative complications. RESULTS: All procedures were completed laparoscopically within a mean duration of 219 +/- 52 (135-375) min. Mean body weight was reduced from 131 +/- 22 kg (range 95-194) at time of the RYGBP to 113 +/- 25, 107 +/- 22, and 100 +/- 21 kg at 3, 6, and 12 months, respectively, which results in excess weight losses (EWL) of 28.3 +/- 9.9%, 40.5 +/- 12.3%, and 50.8 +/- 15.2%. No statistically significant differences were found comparing weight loss within these two groups. CONCLUSION: RYGBP was able to achieve EWLs of 37.6 +/- 16.1%, 48.5 +/- 15.1%, and 56.9 +/- 15.0% at 3, 6, and 12 months following conversion, respectively, based on the body weight at LAGB.

Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects.

AIM: The extract of the white-skinned sweet potato Ipomoea batatas (Caiapo) has been shown to ameliorate glucose control by improving insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). The present study was designed to further evaluate its mode of action on insulin sensitivity over an extended period of time as well as the effects on fibrinogen and other markers of low-grade inflammation. METHODS: In this randomized trial, 27 patients with T2DM on diet only received 4 g of Caiapo daily for 5 months; 34 patients placebo. Before and after therapy, insulin sensitivity [oral glucose insulin sensitivity (OGIS), as glucose clearance from oral glucose tolerance test], parameters of diabetes control, lipids, plasma adiponectin, high-sensitivity C-reactive protein (hs-CRP) and fibrinogen were measured. RESULTS: Following Caiapo, we observed an increase in OGIS (293 +/- 15 vs. 321 +/- 12 ml/m(2)/min, p = 0.0072) and adiponectin (5.97 +/- 0.65 to 6.63 +/- 0.70 microg/ml, p = 0.013), while fibrinogen decreased from 3.83 +/- 0.16 to 3.64 +/- 0.18 mg/ml (p = 0.02). This was associated with an improvement in glycated haemoglobin (HbA1c: 6.46 +/- 0.12 vs. 6.25 +/- 0.11%, p = 0.008), fasting glucose (138 +/- 4 vs. 128 +/- 5 mg/dl, p = 0.039) and triglycerides (2.36 +/- 0.22 vs. 2.07 +/- 0.25 mmol/l, p = 0.032). Body weight, lipid levels and hs-CRP were not altered. No changes were observed in the placebo group except for HbA1c, which significantly increased from 6.25 +/- 0.10 to 6.50 +/- 0.12% (p = 0.0001). CONCLUSIONS: This study confirms the beneficial effects of Caiapo on glucose and HbA1c control in patients with T2DM after 5 months follow-up. Improvement of insulin sensitivity was accompanied by increased levels of adiponectin and a decrease in fibrinogen. Thus, Caiapo can be considered as natural insulin sensitizer with potential antiatherogenic properties.

Effect of rosiglitazone on visfatin and retinol-binding protein-4 plasma concentrations in HIV-positive patients.

Thiazolidinediones (TZD) may improve insulin resistance in patients with diabetes and HIV. The novel adipocytokines visfatin and retinol-binding protein-4 (RBP-4) have been proposed to influence the development of impaired glucose tolerance. The impact of TZD on these cytokines is yet unknown. In this randomized, double-blind, placebo-controlled parallel group study, 37 lean HIV-positive subjects aged 19-50 years were treated with 8 mg/day rosiglitazone (n=20) or placebo (n=17) for 6 months. Insulin sensitivity was estimated from the homeostasis model assessment (HOMA) index. Fasting visfatin, RBP-4, leptin, and adiponectin plasma concentrations were analyzed by immunoassays. Rosiglitazone had no effect on impaired insulin sensitivity, but increased median plasma visfatin from 6.2 ng/ml (95% CI: 5.9; 6.5) to 13.7 ng/ml (12.6; 19.1) (P<0.001) and adiponectin from 3.2 ng/ml (2.2; 4.0) to 4.0 ng/ml (3.3; 8.5; P<0.001). RBP-4 was lowered from 21.0 ng/ml (19.6; 23.1) to 16.3 ng/ml (15.2; 17.0; P<0.001), and leptin concentrations were unchanged. Adipocytokine concentrations were stable in subjects receiving placebo, where a deterioration in insulin sensitivity was detectable (P<0.05). Changes in visfatin and RBP-4 were correlated in subjects receiving rosiglitazone (r=-0.64, P<0.01) but not placebo (r=0.12, P=0.15). TZD treatment affects circulating adipocytokine concentrations in subjects with HIV. Reductions in RBP-4 and increases in visfatin may contribute to the pharmacodynamic action of TZD on glucose homeostasis. Quantification of adipocytokines might be useful to assess TZD treatment effectiveness in insulin-resistant subjects with HIV.

Increased levels of circulating islet amyloid polypeptide in patients with chronic renal failure have no effect on insulin secretion.

To elucidate the metabolism of islet amyloid polypeptide (IAPP) with respect to a possible renal elimination we investigated IAPP levels in 20 lean, nondiabetic patients with renal failure maintained on chronic hemodialysis (HD) and in 20 healthy controls. The basal levels of IAPP were significantly higher in uremic patients than in controls (15.1 +/- 3.2 vs. 3.2 +/- 0.2 pM, P < 0.001) suggesting renal excretion of IAPP. To investigate the impact of chronically elevated levels of endogenous IAPP on insulin secretion and insulin sensitivity, a frequently sampled intravenous glucose tolerance test (FSIGT) was performed in a subset of patients on hemodialysis and in age-matched healthy controls (C) and obese patients with normal (NGT) and with impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was 8.7 +/- 1.5 in C (P < 0.05 vs. NGT, P < 0.01 vs. IGT), 5.4 +/- 0.9 in HD (P < 0.05 vs. IGT), 3.1 +/- 1.0 in NGT, and 2.0 +/- 0.5 in IGT. First phase insulin secretion was increased in patients on HD compared with those of several control groups. The results of this study therefore indicate a renal route of metabolism of IAPP. Increased endogenous circulating IAPP levels over a long period of time do not lead to a decrease in insulin release in patients on HD and do not cause the insulin resistance commonly seen in obesity and diabetes. Increased levels of circulating IAPP therefore are not likely to be a pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM).

A noninvasive method to measure splanchnic glucose uptake after oral glucose administration.

We have developed a noninvasive method to estimate splanchnic glucose uptake (SGU) in humans (oral glucose clamp technique [OG-CLAMP]), which combines a hyperinsulinemic clamp with an oral glucose load (oral glucose tolerance test). We validated this method in 12 nondiabetic subjects using hepatic vein catheterization (HVC) during an oral glucose tolerance test. During HVC, splanchnic blood flow increased from 1,395 +/- 64 to 1,935 +/- 109 ml/min, returning to basal after 180 min and accounted for 45 +/- 7% of SGU in lean and 19 +/- 5% in obese subjects (P < 0.05). SGU estimated during the OG-CLAMP was 22 +/- 2% of the glucose load, and this was significantly correlated (r = 0.90, P < 0.0001) with SGU (35 +/- 4%) and with first pass SGU (24 +/- 3%; r = 0.83, P < 0.001) measured during HVC. SGU was higher in obese than in lean subjects during OG-CLAMP (27 +/- 1% vs 18 +/- 3%, P < 0.01) and HVC (44 +/- 4% vs 26 +/- 5%, P < 0.05). In conclusion, SGU during the OG-CLAMP is well correlated to SGU measured during HVC. An increase in splanchnic blood flow is a major contributor to SGU in lean subjects. SGU is increased in obese subjects as measured by both methods.

Evidence for decreased splanchnic glucose uptake after oral glucose administration in non-insulin-dependent diabetes mellitus.

The role of splanchnic glucose uptake (SGU) after oral glucose administration as a potential factor contributing to postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) has not been established conclusively. Therefore, we investigated SGU in six patients with NIDDM and six weight-matched control subjects by means of the hepatic vein catheterization (HVC) technique. In a second part, we examined the applicability of the recently developed OG-CLAMP technique in NIDDM by comparing SGU and first-pass SGU during HVC with SGU during the OG-CLAMP experiment. The OG-CLAMP method combines a euglycemic, hyperinsulinemic clamp and an oral glucose tolerance test (75 g) during steady state glucose infusion (GINF). During HVC, SGU equals the splanchnic fractional extraction times the total (oral and arterial) glucose load presented to the liver. For OG-CLAMP, SGU was calculated as first-pass SGU by subtracting the integrated decrease in GINF over 180 min from 75 g. Cumulative splanchnic glucose output after oral glucose correlated significantly between both methods and was increased significantly in NIDDM patients (73.1+/-5.1 g for HVC, 76.5+/-5.5 for OG-CLAMP) compared with nondiabetic patients (46.7+/-4.4 g for HVC, 57.5+/-1.9 for OG-CLAMP). Thus, in NIDDM patients, SGU (7.4+/-2.1 vs. 37.8+/-5.9% in nondiabetic patients, P < 0.001) and first-pass SGU (4.7+/-1.7 vs. 26.5+/-5.1% in nondiabetic patients, P < 0.01) were decreased significantly during HVC, as was SGU during OG-CLAMP (3.9+/-1.7 vs. 23.4+/-2.5% in nondiabetic patients, P < 0.0001). SGU measured during OG-CLAMP correlated significantly with SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.94, P < 0.01 for nondiabetic patients) and first-pass SGU (r = 0.87, P < 0.05 for NIDDM patients; r = 0.84, P < 0.05 for nondiabetic patients) during HVC. In conclusion, (a) SGU after oral glucose administration is decreased in NIDDM as measured by both methods, and (b) SGU during the OG-CLAMP is well-correlated to SGU and first-pass SGU during HVC in NIDDM. The decrease in SGU in NIDDM might contribute to postprandial hyperglycemia in diabetic subjects.

Mechanisms of the kinetic defect in insulin action in obesity and NIDDM.

To evaluate kinetic defects in insulin action, we performed time-course studies during hyperinsulinemic (120 mU x m(-2) x min(-1)) isoglycemic clamps in seven subjects with NIDDM (194 +/- 29 mg/dl) and in seven lean and seven obese nondiabetic subjects. The time course of whole-body glucose disposal rate (GDR), leg glucose uptake (LGU), hepatic glucose output (HGO), and muscle insulin receptor tyrosine kinase (IRTK) activation were measured. The obese and NIDDM subjects had marked delays in activation of GDR (T50 74 +/- 14 and 95 +/- 15 min, respectively, compared with 33 +/- 2 min in lean control subjects), arteriovenous glucose difference (T50 80 +/- 12 and 109 +/- 31 min compared with 30 +/- 3 min) and LGU (T50 89 +/- 25 and 98 +/- 27 min compared with 29 +/- 4 min). All three measurements reached normal levels in the NIDDM group after 4-5 h of insulin infusion. Although only a limited number of data points could be obtained from serial muscle biopsies, no delay in the rate of activation of IRTK was apparent in the obese and NIDDM groups. In conclusion, 1) in obese and NIDDM subjects, insulin-mediated GDR and LGU are delayed to a similar degree; 2) mass action normalizes GDR and LGU in NIDDM, but only after several hours of insulin infusion; and 3) The kinetic defect in NIDDM and obesity most likely involves intracellular loci distal to activation of the insulin receptor kinase.

Decrease of stimulated amylin release precedes impairment of insulin secretion in type II diabetes.

Amylin, a 37-amino acid polypeptide, has been identified as the major protein component of pancreatic amyloid deposits in patients with non-insulin-dependent (type II) diabetes mellitus. Amylin is stored and released together with insulin and has been proposed to play a major role in the pathogenesis of type II diabetes. To compare amylin release and its proportion to insulin secretion under different metabolic conditions, oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in healthy, lean control subjects, obese patients with normal and impaired glucose tolerance (NGT and IGT, respectively), and obese type II diabetic patients. Compared with control subjects, basal and stimulated amylin secretion during OGTT was significantly higher in obese patients with NGT and IGT but not in type II diabetic patients. The integrated amylin response was significantly higher in obese patients with NGT than lean control subjects and type II diabetic patients matched for degree of obesity. The amylin-insulin ratio decreased slightly in obese subjects with NGT and IGT and significantly in type II diabetic patients. Amylin secretion was significantly stimulated during IVGTT in control subjects and obese patients with NGT and IGT but not in type II diabetic patients. These findings suggest that amylin is physiologically released by pancreatic beta-cells in a constant ratio to insulin in nondiabetic subjects. Glucose-stimulated amylin secretion is increased in obese subjects with NGT and IGT. In type II diabetes mellitus, amylin secretion relative to that of insulin is decreased, and amylin is not stimulated by IVGTT.

Effect of obesity on insulin resistance in normal subjects and patients with NIDDM.

Insulin resistance (IR) is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) as well as obesity, and a majority of NIDDM patients are obese. To assess the effect of obesity independent of NIDDM on IR, we studied the relationship between IR and obesity in 65 normal and 58 NIDDM subjects; we used body mass index (BMI) as a measure of obesity and glucose infusion rate (GINF) during a euglycemic hyperinsulinemic (120 mU.m-2.min-1) glucose clamp as a measure of IR. In lean normal subjects, GINF was 57.7 +/- 2.2 mumol.kg-1.min-1 (10.4 +/- 0.4 mg.kg-1.min-1) and the lean NIDDM subjects were markedly insulin-resistant, with a GINF of 34.4 +/- 2.8 mumol.kg-1.min-1 (6.2 +/- 0.5 mg.kg-1.min-1). Obese normal subjects were also insulin-resistant compared with lean normal subjects, with a GINF of 36.1 +/- 2.2 mumol.kg-1.min-1 (6.5 +/- 0.4 mg.kg-1.min-1), and obesity caused an increase in IR in NIDDM, with a GINF of 21.1 +/- 1.4 mumol.kg-1.min-1 (3.8 +/- 0.25 mg.kg-1.min-1) in the obese NIDDM subjects. Therefore, approximately 61% of the IR in obese NIDDM subjects is due to NIDDM, with 39% due to obesity, demonstrating a greater impact of NIDDM than of obesity in causing IR. The correlation between GINF and BMI was much better in normal subjects (r = -0.75) than in NIDDM subjects (r = -0.50) as was the relationship between fasting insulin level and BMI (r = -0.59 in normal subjects, r = -0.48 in NIDDM subjects). As expected, the fasting insulin level was also strongly correlated to GINF in normal subjects (r = -0.61); however, this relationship was weaker in NIDDM subjects ( r = -0.46). In conclusion, 1) obesity has a major impact to cause insulin resistance in nondiabetic subjects, but the effect of obesity on IR in NIDDM is less; 2) NIDDM per se is the major contributor to IR in NIDDM; and 3) the fasting insulin level is a better surrogate marker of IR in nondiabetic subjects than in NIDDM patients.