Search

In humans, a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of β-cells, with healthy volunteers (HVs). C-peptide-negative (i.e., insulin-deficient) T1D subjects (n = 10) and HVs (n = 9) underwent dynamic positron emission tomography with the radiolabeled serotonin precursor [11C]5-hydroxy-tryptophan ([11C]5-HTP). A significant accumulation of [11C]5-HTP was obtained in the pancreas of the HVs, with large interindividual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [11C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where β-cells normally are the major constituent of the islets. [11C]5-HTP retention in the pancreas was reduced in T1D compared with nondiabetic subjects. Accumulation of [11C]5-HTP in the pancreas of both HVs and subjects with T1D was in agreement with previously reported morphological observations on the β-cell volume, implying that [11C]5-HTP retention is a useful noninvasive surrogate marker for the human endocrine pancreas. [ABSTRACT FROM AUTHOR]

This randomized, 24-week, flexible-dose study (D1441C00125) compared changes in glucose metabolism and insulin sensitivity for non-diabetic patients taking the atypical antipsychotics, quetiapine, olanzapine and risperidone. Primary endpoint: change (baseline to Week 24) in AUC 0-2h plasma glucose following OGTT; primary analysis compared quetiapine and olanzapine. Secondary analyses: changes in AUC 0-2h plasma insulin; ISI; fasting glucose; HbA[sub 1c]; fasting lipids; lipid ratios (post-hoc analyses). Overall, 395 patients completed the study: quetiapine n=115 (mean dose 607 mg/day), olanzapine n=146 (15.2 mg/day), risperidone n=134 (5.2 mg/day). AUC 0-2h plasma glucose, the primary endpoint, was significantly lower for quetiapine vs olanzapine (-12.8 mg/dL x h, p=0.048), with significant increases during treatment with olanzapine (+21.9, 95% CI 11.5, 32.4) and risperidone (+18.8, CI 8.1, 29.4), but not quetiapine (+9.1, CI -2.3, 20.5). AUC 0-2h plasma insulin increased significantly with olanzapine (+24.45%; CI, 11.46, 38.96), but not quetiapine (+13.15%; CI, -0.14, 28.22) or risperidone (+10.74%; CI, -1.2, 24.13). Reductions in ISI were significant with olanzapine (-19.1%, CI -27.9, -9.33) and risperidone (-15.8%, CI -25.1, -5.41) but not quetiapine (-10.8%, CI -21.9, 1.85). Fasting glucose and HbA[sub 1c] increased significantly with quetiapine and risperidone, but remained within the normal range in all groups. Total cholesterol and LDL increased significantly with quetiapine and olanzapine, but not risperidone. Triglycerides, cholesterol/HDL and triglycerides/HDL ratios also increased significantly with olanzapine, but not quetiapine or risperidone. In conclusion, significant reductions in glucose tolerance and insulin sensitivity were seen with olanzapine but not quetiapine. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance is a well-known feature in patients with severely reduced GFR and end-stage renal disease. However, recent studies have shown reduced insulin sensitivity also early in renal disease. In this study we evaluated the impact of change in GFR over time on insulin sensitivity in patients with type 1 diabetes, with or without diabetic nephropathy Patients and methods: In a prospective study GFR ([sup 51]Cr-EDTA clearance) and insulin sensitivity (M-value) was measured in 21 patients with type 1 diabetes 5.1±-0.4 years (range 4.4-6.1) apart. At baseline 8/21 patients had no sign of renal impairment (C), 9/2 had micro- or macroalbuminuria but normal GFR (A) and 4/21 had a reduced GFR (56.2:±:10.8 ml/min/1.73 m²; range 43-65) (G). Blood sampling was performed to assess insulin antagonistic hormones and cytokines. Results: At baseline, a significant difference in M-value was found between patients with normal GFR (C+A; n=17) and reduced GFR (G; n=4) (8.6±3.1 vs. 4.7±2.5 mg/kg LBM/min, p=0.03). At follow up ΔGFR was -13A±20.4 ml /min/1.73 m² (group C; -15.5±21.4, A; -14.9±23.1 and G; - 5.8±13.3) and µM-value 0.5±3.7 mg/kg LBM/min (C; -0.6±2.9, A; 0.2±4.5 and G; 3.4±1.6) in all patients. Interestingly, all patients with a reduced GFR at baseline improved their M-value significantly (p=0.02). No association between ΔGFR and ΔM-value (r²=0.03, p=0.44) was found in all patients or in any of the subgroups (data not shown). Likewise, no association was found between ΔGFR (-20.6±19.8) and ΔM-value (0.5±4.0) in patients (15/21) that had a decline in GFR over time (r²=0.17, p=0.13). During follow up significant reductions in systolic (13.4±20.5 mmHg, p=0.007), diastolic blood pressure (-12.1±11.2 mmHg, p<0.001), total- (-0.7±1.3 mmol/L, p=0.16) and LDL-cholesterol (-0.7±1.0 mmHg, p=0.003) were seen. During the same period intensified blood pressure-, lipid-, and glucose lowering treatments were given (data not shown). No significant changes were seen in BMI, HbA1c, HDL-cholesterol and triglycerides. An increase in PTH (3.4±4.9 pmol/L, p=0.005) and leptin (4.6±9.2 ng/mL, p=0.037) and a decrease in adiponectin (-4.2±6.3, p=0.16) levels over time were found. No significant change was seen for s-cortisol, TNF-α, IGF-1 and hs-CRP. Conclusions: In this study a modest decline in GFR over time in patients with type 1 diabetes does not seem to diminish insulin sensitivity. Effects of intensive treatment with anti-hypertensives and insulin analogues may explain this surprising finding. [ABSTRACT FROM AUTHOR]

Background: Other studies have suggested that angiotensin II receptor blockers (ARB) display metabolic benefits, including a lower risk of developing T2DM, compared to antihypertensive therapy with beta blockers and thiazide diuretics. The MEDICA study addressed insulin action and secretion, body fat distribution and liver and muscle fat content following treatments with candesartan (C), hydrochlorothiazide (H) and placebo (P). Design: In a 3-way crossover trial, 26 non-diabetic, abdominally obese (waist >102 cm M, >88 F), hypertensive patients were randomized to 12-wk treatment periods with C (16-32 mg), H (25-50 mg) and P, respectively. 22 subjects (10 M, 12 F) completed the study, mean age 54.8±10.4 (SD) yr, BMI 30.2±3.0 kg/m². At the end of treatment periods, an IVGTT and a euglycaemic hyperinsulinaemic (56 mU/m²/min) clamp were performed. Intrahepatic and intramyocellular (tibialis anterior) lipid content and sc and visceral abdominal adipose tissue (SAT and VAT) were measured using [sup 1]H-MRS and MRI. Results: Blood pressure was reduced (p<0.05) to a similar extent by both C and H compared to P. Insulin sensitivity was lower following H vs C and P (p<0.0l, M-values H 6.07±2.05, C 6.63±2.04 and P 6.90±2.10 mg/kg BW/min). Liver fat content (and liver volume) was significantly higher (p=0.03) following H than both P and C (9.9±9.2, 8.7±9.6 and 7.9±8.9%) and this correlated to the reduction in insulin sensitivity (r²=0.26, p=0.04). The VAT/SAT ratio increased after H vs C and P (p<0.01). FFA (p=0.07), ALT, AST, HbA1c and hsCRP (all p<0.05) levels were higher following H, but not C, vs P. There were no differences between treatments in 1st phase insulin secretion, intramyocellular fat, BMI, HDL and LDL cholesterol, triglycerides, adiponectin, leptin, PAI-1, TNFalpha or interleukins. The metabolic alterations found were independent of potassium levels. Conclusion: In insulin-resistant hypertensive subjects, hydrochlorothiazide caused visceral fat redistribution, liver fat accumulation, impaired insulin sensitivity and low-grade inflammation. No such alterations were seen with an ARB, candesartan, which was similar to placebo. These findings may partly explain the diabetogenic potential of thiazides, and they may have an impact on the choice of antihypertensive treatment in subjects at high risk of developing T2DM. [ABSTRACT FROM AUTHOR]