beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms.

Abstract

Type 2 diabetes is characterized by a progressive loss of ␤-cell function throughout the course of the disease. The pattern of loss is an initial defect in early or firstphase insulin secretion, followed by a decreasing maximal capacity of glucose to potentiate all nonglucose signals. Last, a defective steady-state and basal insulin secretion develops, leading to complete ␤-cell failure requiring insulin treatment. This functional loss exceeds the expected impact of a 20-50% loss of ␤-cells reported at autopsy, which has been associated with amyloid deposits. This review summarizes the nature of the amyloid deposition process and its association with disproportionate hyperproinsulinemia. It reviews recent studies in IAPP (islet-amyloid polypeptide, or amylin) transgenic mice developing islet amyloid deposits and hyperglycemia to suggest that the process of amyloid fibril formation impairs function early and leads to ␤-cell failure and eventual death. Based on the known association of amyloid deposits and relative hyperproinsulinemia, it is hypothesized that fibril formation begins during impaired glucose tolerance after other factors cause the initial defects in early insulin secretion and insulin action. Thus, the process that leads to ␤-cell loss is implicated in the deposition of amyloid and the late unrelenting progressive hyperglycemia now found in all patients despite current therapies. Diabetes 50 (Suppl.

Protein hydrolysate co-ingestion does not modulate 24 h glycemic control in long-standing type 2 diabetes patients

“…Such a defect is indicative of a progressive insensitivity of the b-cell to glucose (Porte and Kahn, 2001). Even though insulin secretion in response to glucose ingestion is blunted in long-standing type 2 diabetes patients, we have shown that co-ingestion of a protein hydrolysate/leucine mixture can stimulate endogenous insulin secretion resulting in a 2-4-fold greater postprandial insulin response (van Loon et al, 2003;Manders et al, 2005Manders et al, , 2006a.…”

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

“…Individuals with type 2 diabetes mellitus (T2DM) have impaired b-cell function, which leads to reduced or absent first phase and curtailment of the second phase in postprandial blood insulin levels (Porte & Kahn 2001). In addition, the normal rhythmic variations in blood insulin levels are replaced by irregular or lost insulin oscillations (Lang et al 1981).…”

The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: a prospective epidemiological analysis

“…Compared with non-diabetic individuals, those with diabetes are two to three times more likely to have a CV event; moreover, the proportion of people with diabetes who will die from cardiovascular causes is >70% [2]. Epidemiological and mechanistic explanations that have been proposed to account for this strong relationship include: (1) prolonged exposure to hyperglycaemia and its consequences [3]; (2) antecedent and concurrent insulin resistance [4,5]; (3) effective insulin deficiency [6]; (4) associated lipid and blood pressure abnormalities [7]; and (5) an as yet undefined determinant of both diabetes and CV disease. Varying proportions of individuals with diabetes manifest one or Listed by country in References 13 and 15. more of these abnormalities; however, as diabetes is defined on the basis of an elevated glucose level, everyone with diabetes has a history of hyperglycaemia.…”