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).

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.

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.

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.

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.

Feasibility and efficacy of an isocaloric high-protein vs. standard diet on insulin requirement, body weight and metabolic parameters in patients with type 2 diabetes on insulin therapy.

AIMS: To determine the feasibility and efficacy of a high-protein diet compared with a standard diet aiming for weight maintenance in insulin treated type-2 diabetic patients on insulin requirement, body weight and metabolic parameters over 12 weeks. METHODS: In a randomized controlled trial we assigned 44 type-2 diabetic patients on insulin therapy either to high-protein or standard diet over 12 weeks. Parameters were evaluated at baseline and monthly. RESULTS: After 12 weeks, the high protein diet significantly decreased insulin requirement (9.4 ± 16.3 vs. +0.8 ± 4.8 IU, mean ± SD; p=0.007), fasting plasma glucose (41.7 ± 62.5 vs. 2.1 ± 39.0 mg dl(-1); p=0.02), body mass index (1.1 ± 0.8 vs. 0.3 ± 0.7 kg m(-2); p=0.003), fat-free (0.8 ± 0.5 vs. 0.2 ± 0.5 kg; p=0.001), fat mass (2.6 ± 1.7 vs. 0.8 ± 1.6 kg; p=0.001) and increased serum folate (4.2 ± 8.3 vs. − 0.8 ± 5.5 nmol l(-1); p=0.04) compared to the standard diet. These beneficial metabolic effects are most likely related to the achieved weight loss. No significant differences between groups in renal function were observed. CONCLUSIONS: In this study we demonstrate that a high protein diet with emphasis on plant source protein vs. a standard diet is feasible in insulin-treated type-2 diabetic patients and reduces insulin requirement and body weight and improves metabolic parameters up to 12 weeks. A high protein diet can thus be considered as an appropriate diet choice for type-2 diabetic patients.

Weight loss and weight regain-5-year follow-up for circular- vs. linear-stapled gastrojejunostomy in laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Weight regain (WR) occurs in some patients after laparoscopic Roux-en-Y gastric bypass (LRYGBP). Loss of restriction due to dilation of the gastrojejunostomy (GJS) or the gastric pouch might be the main cause for WR. With different techniques available for the establishment of the GJS, the surgical technique might influence long-term success. METHODS: We present a 5-year follow-up for weight loss and WR of a matched-pair study comparing circular stapled (CSA) to linear stapled (LSA) GJS in a series of 150 patients who underwent primary antecolic antegastric LRYGBP. Complete 5-year follow-up was obtained for 79 % of the patients. RESULTS: Excess BMI loss (EBL) at 3 months was better with the CSA (p = 0.02) and comparable thereafter. The 5-year %EBL was 67.3 ± 23.2 vs. 73.3 ± 24.3 % (CSA vs. LSA, p = 0.19) WR of > 10 kg from nadir was found in 24 patients (16 %) with higher incidence in CSA than in LSA patients (20 % vs. 12 %). The %WR was comparable for both groups, 16 ± 13 vs. 15 ± 19 % (CSA vs. LSA, p = 0.345). Eleven patients underwent surgical re-intervention for WR by placement of a non-adjustable band (n = 2), adjustable band (n = 7) and conversion to distal gastric bypass (n = 2). CONCLUSIONS: CSA and LSA lead to comparable weight loss in this 5-year follow-up. More patients in the CSA group had WR. Weight regain of more than 10 kg was found in one out of seven patients within 5 years postoperatively.

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.

Gastric stimulation in the digestive period modifies length and contractility of the inter-digestive period in obese non-diabetic and diabetic subjects.

BACKGROUND: The association between phase II of the motor migratory complex (MMC) and hunger remains poorly understood, which may be important in non-diabetic and diabetic obese subjects where gastric inter-digestive motility has been often reported as impaired. We characterize phase II of the MMC and its predictive power on food intake, weight loss, and glycemia in non-diabetic (OB) and diabetic (DM) obese subjects treated with gastric stimulation for 6 months. METHODS: Twelve OB and 12 DM subjects were implanted with bipolar electrodes connected to a gastric stimulator capable of recording antrum electromechanical activity. RESULTS: The phase II mean interval size and duration increased from 156 ± 121 to 230 ± 228 s and from 98 ± 33 to 130 ± 35 min (p < 0.05) in OB and from 158 ± 158 to 180 ± 112 s and from 77 ± 26 to 109 ± 18 min (p < 0.05) in DM after 6 months. There was a significant trend of meals to interrupt the late rather than the early phase II. Nonlinear regression analysis demonstrated that weight loss in OB was significantly associated with the change in interval size of the late phase II and with phase II duration. In the DM group, weight loss and glycemia were also significantly associated with the change in the interval size of the early phase II. CONCLUSIONS: Gastric stimulation delivered in the digestive period can modify the length of the MMC and the contractility in its longest component, phase II. The duration and contractility of the MMC can determine to some extent future intake and, thus, influence energy balance.

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.

Alcohol acutely increases vascular reactivity together with insulin sensitivity in type 2 diabetic men.

Moderate alcohol consumption is associated with increased insulin sensitivity and reduced cardiovascular risk. We hypothesized that this relates to a direct effect of alcohol and therefore investigated whether acute alcohol intake altered insulin sensitivity or endothelial function in patients with type 2 diabetes. In an open-label two period design, the effect of a single oral dose of 40 g of alcohol (168 ml 40% vodka) on an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and on endothelium-dependent (flow mediated, FMD) or endothelium-independent (glyceroltrinitrate (GTN)-induced) vasodilation of the brachial artery measured by ultrasound was studied. Experiments were carried out in twelve male patients with type 2 diabetes mellitus (64+/-6 years, body mass index 28.4+/-5.7 kg/m (2)). Baseline insulin sensitivity index (S (I)) was 1.10+/-0.34 min (-1).microU (-1).ml, baseline FMD was +4.1+/-3.0%, and GTN-induced vasodilation +7.4+/-2.3% from resting brachial artery diameter. Acute alcohol intake increased alcohol plasma levels to 0.33+/-0.04 per thousand, S (I) to 1.86+/-0.45 min (-1).microU (-1).ml (p<0.05), and FMD to +8.2+/-2.8% (p<0.05), while GTN-induced dilation remained unchanged. No relationship was detectable between the observed changes. We conclude that alcohol intake acutely increases endothelium-dependent brachial artery vasodilation in patients with type 2 diabetes together with insulin sensitivity. This acute effect might explain some beneficial effects of low alcohol consumption in epidemiological observations.

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.

Plasma adipocyte and epidermal fatty acid binding protein is reduced after weight loss in obesity.

AIM: Plasma adipocyte fatty acid binding protein (A-FABP) and epidermal fatty acid binding protein (E-FABP) concentrations have been linked to obesity and the metabolic syndrome. In this study, we investigated whether plasma A-FABP and E-FABP concentrations are altered by weight loss in obese patients. METHODS: In a prospective study, fasting plasma A-FABP and E-FABP concentrations were measured before and 6 months after gastric banding in 33 morbidly obese patients, with a body mass index (BMI) of 46 +/- 5 kg/m(2). Eleven healthy subjects with a BMI < 25 kg/m(2) served as controls. RESULTS: A-FABP and E-FABP plasma concentrations were higher in obese subjects (36.7 +/- 6.7 and 3.7 +/- 0.7 ng/ml, respectively) than in controls (18.1 +/- 0.6 and 2.6 +/- 0.5, respectively, p < 0.01). Gastric banding reduced BMI to 40 +/- 5 kg/m(2), A-FABP to 32.6 +/- 5.4 ng/ml and E-FABP to 1.9 +/- 0.7 ng/ml (all p < 0.05) after 6 months. Insulin sensitivity as estimated by the Homeostasis Model Assessment insulin resistance index was unchanged. A-FABP concentrations were significantly associated with BMI before and 6 months after surgery (p < 0.05, r = 0.42 and r = 0.37 respectively). CONCLUSIONS: Elevated plasma A-FABP and E-FABP concentrations in morbidly obese subjects are reduced after gastric banding-induced weight loss. This suggests that FABP may be associated with improvement of metabolic conditions over time.

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.