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The insulin receptor (IR) recruits adaptor proteins, so-called insulin receptor substrates (IRS), to connect with downstream signalling pathways. A family of IRS proteins was defined based on three major common structural elements: Amino-terminal PH and PTB domains that mediate protein-lipid or protein-protein interactions, mostly carboxy-terminal multiple tyrosine residues that serve as binding sites for proteins that contain one or more SH2 domains and serine/threonine-rich regions which may be recognized by negative regulators of insulin action. The current model for the role of IRS proteins therefore combines an adaptor function with the integration of mostly negative input from other signal transduction cascades allowing for modulation of signalling amplitude. In this review we propose an extended version of the adaptor model that can explain how signalling specificity could be implemented at the level of IRS proteins. [ABSTRACT FROM AUTHOR]

Many factors influence the outcome of islet transplantation. As islets in the early posttransplant setting are supplied with oxygen by diffusion only and are in a hypoxic state in the portal system, we tested whether small human islets are superior to large islets both in vitro and in vivo. We assessed insulin secretion of large and small islets and quantified cell death during hypoxic conditions simulating the intraportal transplant environment. In the clinical setting, we analyzed the influence of transplanted islet size on insulin production in patients with type 1 diabetes. Our results provide evidence that small islets are superior to large islets with regard to in vitro insulin secretion and show a higher survival rate during both normoxic and hypoxic culture. Islet volume after 48 h of hypoxic culture decreased to 25% compared with normoxic culture at 24 h due to a preferential loss of large islets. In human islet transplantation, the isolation index (islet volume as expressed in islet equivalents/islet number), or more simply the islet number, proved to be more reliable to predict stimulated C-peptide response compared with islet volume. Thus, islet size seems to be a key factor determining human islet transplantation outcome. Diabetes 56:594-603, 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To compare the effect of acute psychosocial stress on glucose concentrations in the fasting state and following food intake in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS -- In study 1, 20 patients were exposed to moderate psychosocial stress by means of the Trier Social Stress Test (TSST) in the fasting state. In study 2, the TSST was applied to 20 additional patients 75 min after intake of a standard meal. Glucose concentrations (by continuous glucose monitoring system), blood pressure, and heart rate were monitored on the control day and on the stress testing day. RESULTS -- In both studies, blood pressure increased in response to TSST from 122/77 ± 14/9 mmHg at baseline to a maximum of 152/93 ± 21/13 mmHg (P < 0.001), and heart rate increased from 80 ± 11 to 99 ± 19 bpm (P < 0.001). In the fasting state (study 1), glucose concentrations remained unchanged during the control day as well as during the stress testing day. In study 2, glucose concentrations were similar on both days before and up to 75 min after the intake of the standard meal. However, a significant delay (of 45 min) in the decrease of glucose concentrations was induced by psychological stress. A two-factor repeated-measures ANOVA revealed a significant difference of glucose concentrations over time (F = 646.65/P < 0.001). CONCLUSIONS -- In the postprandial period, acute psychological stress induced a significantly delayed decrease of glucose concentrations, whereas in the fasting state, no effect on poststress glucose concentrations was observed. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that a progressive decrease in the functional β-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, β-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1β and/or high-glucose-induced β-cell production of IL-1β. Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for the β-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1β-induced apoptosis and impaired function in human β-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1β, or 10 and 100 µmol/l of the sulfonylurea tolbutamide induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1β were blocked by 200 µmol/l diazoxide as well as by 3 and 30 µmol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate the extracellular signal-regulated kinase (ERK) ½, an effect that was abrogated by 3 µmol/l NN414. Similarly, 1 µmol/l of the mitogen-activated protein kinase/ERK kinase ½ inhibitor PD098059 or 1 µmol/l of the L-type Ca[sup2+] channel blocker nimodipine prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca[sup2+] influx and ERK dependent and can be prevented by the β-cell selective potassium channel opener NN414. Diabetes 53:1706-1713, 2004 [ABSTRACT FROM AUTHOR]

Background: This paper analyses the direct medical costs of type 2 diabetes and its complications in Switzerland. Methods: Individual healthcare resource consumption related to type 2 diabetes and its complications was determined retrospectively in 1479 non-incident and non-dying patients over 12 months (1998-1999). Literature-derived attributable risks were used to correct for non-diabetes related macrovascular disease. Results: A total of 111 primary care physicians from 19 cantons throughout Switzerland participated. Their diabetic patients on average had 10.3 consultations per year related to this disease (95% CI: 10.0-10.7). Patients spent on average 2.7 days (95% CI: 2.2-3.3) per year in hospital due to diabetes and diabetes-related complications. Mean annual type 2 diabetes-related direct medical costs per patient amounted to CHF 3,508 / € 2,323 (95% Cl: CHF 3,140-3,876 / € 2,080-2,567). They were particularly high in patients with insulin treatment or with complications. After application of attributable risks and a correction for the use of adjuvant materials, costs were CHF 3,324 / € 2,201. Assuming 250,000 patients with type 2 diabetes in Switzerland leads to an estimate of CHF 0.88 billion spent for this disease and its complications in 1998. This represents a share of about 2.2% of the country's total healthcare expenditures. Conclusion: These findings demonstrate the high economic importance of type 2 diabetes and its complications in Switzerland. [ABSTRACT FROM AUTHOR]

Background: Magnesium deficiency has been associated with type 2 diabetes and may reduce insulin sensitivity and impair glucose tolerance. The etiology of magnesium depletion in diabetes is unclear. Animal studies suggest that diabetes may impair magnesium absorption; however, there are no published data on magnesium absorption in humans with diabetes. Objective: Magnesium absorption from a test meal and the excretion and retention of magnesium were compared between patients with type 2 diabetes and healthy control subjects. Design: A meal labeled with 10 mg 26Mg isotopic label was administered, and stool and urine samples were collected for 10 and 6 d, respectively. Apparent absorption was calculated as the difference between the oral dose of 26Mg isotopic label and the total amount of the isotopic label excreted in the feces. Magnesium retention was calculated from the apparent absorption and urinary excretion of 26Mg isotopic label in the 6 d after administration. Results: Mean (± SD) values for fractional magnesium absorption in the diabetic patients and the control subjects were 59.3 ± 7.0% and 57.6 ± 8.5%, respectively (NS). Mean (± SD) urinary magnesium excretion values in the diabetic patients and the control subjects were 11.2 ± 2.6% and 11.7 ± 3.8%, respectively (NS); retention values were 54.2 ± 7.1% and 51.4 ± 6.1%, respectively (NS). Conclusion: Dietary magnesium absorption and retention are not impaired in patients with reasonably well-controlled type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The recent JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) trial is another study providing evidence about the effectiveness of statin therapy in reducing cardiovascular risk. Yet, in this study significantly higher glycated hemoglobin levels and incidence rates of diabetes were observed in persons treated with rosuvastatin than the placebo group. It should be noted that adverse effects on glucose metabolism have already been reported, albeit rarely, in previous trials with statins. Although the exact mechanisms involved are unknown, it seems that statins may deteriorate glycemic control by decreasing different metabolites, including isoprenoid and ubiquinone, normally produced during the process of cholesterol synthesis. We therefore suggest that, if statins are prescribed, patients should be monitored closely for blood glucose control even though the higher incidence of diabetes by statin therapy may represent a rare finding. [ABSTRACT FROM AUTHOR]

Background: In the Diabetes Prevention Program (DPP), interventions with metformin (plus standard lifestyle advice) or intensive lifestyle changes (ILC) reduced the risk of developing type 2 diabetes mellitus (DM) by 31% and 58%, respectively, versus control (standard lifestyle advice only) in patients with impaired glucose tolerance (IGT).Objective: The goal of this study was to establish whether implementing the active treatments used in the DPP would be cost-effective in Australia, France, Germany, Switzerland, and the United Kingdom.Methods: A Markov model simulated 3 states—IGT, type 2 DM, and deceased—using probabilities from the DPP and published data. Country-specific direct costs were used throughout.Results: Assuming only within-trial effects and costs of interventions, both metformin and ILC improved life expectancy versus control. Mean improvements in nondiscounted life expectancy were 0.11 and 0.22 years for metformin and ILC, respectively. Both interventions were associated with cost savings versus control in all countries except the United Kingdom, where a small increase in costs was observed in both intervention arms. When a lifetime effect of interventions was assumed, incremental improvements in life expectancy were 0.35 and 0.90 years for metformin and ILC, respectively. Results were sensitive to probabilities of developing type 2 DM, the projected long-term duration of effect of interventions after the 3-year trial period, the relative risk of mortality for type 2 DM compared with IGT, and the costs of implementing the interventions.Conclusions: Based on probabilities from the DPP and published data, in this model analysis, incorporation of the DPP interventions into clinical practice in 5 developed countries was projected to lead to an increase in DM-free years of life, improvements in life expectancy, and either cost savings or minor increases in costs compared with standard lifestyle advice in a population with IGT. Thus, financial constraints should not prevent the implementation of DM prevention programs. [Copyright &y& Elsevier]