Human islet amyloid polypeptide-induced ß-cell cytotoxicity is linked to formation of α-sheet structure.

Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet ß-cells. Several factors contribute to ß-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated ß-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated ß-cell loss.

Prevention versus intervention of type 1 diabetes.

Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials.

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

OBJECTIVE: In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity. RESEARCH DESIGN AND METHODS: For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. RESULTS: In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. CONCLUSIONS: In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients.

Insulin resistance is a primary component in the pathophysiology of type 2 diabetes. In latent autoimmune diabetes in adults (LADA), insulin resistance has been reported to be significantly lower than in autoantibody-negative type 2 diabetes (T2DM), but whether this might be related to differences in body mass index (BMI) has not been excluded. Furthermore, previous studies have used limiting inclusive criteria for LADA, requiring only the presence of GADA or IA-2A. To apply more inclusive criteria for LADA, consistent with recent recommendations, we defined LADA by clinical manifestations characteristic of T2DM, but with the presence of any combination of GADA, IA-2A, ICA, or IAA. We recruited 43 LADA patients, 70 T2DM patients, and 150 non-diabetic controls. Insulin resistance was assessed by both the homeostasis model assessment and the quantitative insulin sensitivity check index, and BMI was calculated. We found that insulin resistance in LADA is equivalent to that of T2DM. When insulin resistance is assessed as a function of BMI, both diabetic populations demonstrated an insulin resistance equally greater than normal controls. The interaction between insulin resistance and BMI in the two diabetic groups was significantly different from that demonstrated in non-diabetic controls. In summary, LADA demonstrates insulin resistance of similar magnitude to T2DM, but with the concurrent component of an immune attack against the pancreatic beta-cells. LADA patients may be at significant risk for metabolic consequences of insulin resistance other than glucose metabolism, such as those described in the metabolic syndrome. As complications and treatment regimens specific to LADA are realized, improved means of identification of LADA will become increasingly important.