Increased β-Cell Apoptosis Prevents Adaptive Increase in β-Cell Mass in Mouse Model of Type 2 Diabetes

Abstract

Nondiabetic obese humans adapt to insulin resistance by increasing ␤-cell mass. In contrast, obese humans with type 2 diabetes have an ϳ60% deficit in ␤-cell mass. Recent studies in rodents reveal that ␤-cell mass is regulated, increasing in response to insulin resistance through increased ␤-cell supply (islet neogenesis and ␤-cell replication) and/or decreased ␤-cell loss (␤-cell apoptosis). Prospective studies of islet turnover are not possible in humans. In an attempt to establish the mechanism for the deficit in ␤-cell mass in type 2 diabetes, we used an obese versus lean murine transgenic model for human islet amyloid polypeptide (IAPP) that develops islet pathology comparable to that in humans with type 2 diabetes. By 40 weeks of age, obese nontransgenic mice did not develop diabetes and adapted to insulin resistance by a 9-fold increase (P < 0.001) in ␤-cell mass accomplished by a 1.7-fold increase in islet neogenesis (P < 0.05) and a 5-fold increase in ␤-cell replication per islet (P < 0.001). Obese transgenic mice developed midlife diabetes with islet amyloid and an 80% (P < 0.001) deficit in ␤-cell mass that was due to failure to adaptively increase ␤-cell mass. The mechanism subserving this failed expansion was a 10-fold increase in ␤-cell apoptosis (P < 0.001). There was no relationship between the extent of islet amyloid or the blood glucose concentration and the frequency of ␤-cell apoptosis. However, the frequency of ␤-cell apoptosis was related to the rate of increase of islet amyloid. These prospective studies suggest that the formation of islet amyloid rather than the islet amyloid per se is related to increased ␤-cell apoptosis in this murine model of type 2 diabetes. This finding is consistent with the hypothesis that soluble IAPP oligomers but not islet amyloid are responsible for increased ␤-cell apoptosis. The current studies also support the concept that replicating ␤-cells are more vulnerable to apoptosis, possibly accounting for the failure of ␤-cell mass to expand appropriately in response to obesity in type 2 diabetes. Diabetes 52:2304 -2314, 2003

Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice

“…Actually, we observed markedly increased cellular apoptosis after a long-term, high-fat diet. However, in our study (for 4 months) and another [14] longitudinal study in rodents, proliferation of beta cells was found even after a long-term prediabetic stage, suggesting that compensatory beta cell proliferation is maintained until the loss of the remaining beta cell divisions.…”

“…In addition to necrosis, markedly increased beta cell apoptosis is regarded as one of the major factors in the pathogenesis of diabetes. The cellular mechanisms of increased beta cell apoptosis, which include hyperglycaemia-induced oxidative stress [8,12], are being intensively studied [13][14][15][16][17][18].…”

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

“…On the other hand, most mechanisms that have been suggested to underlie a putative progressive beta cell damage in T2D may not be relevant for the clinical situation or have been difficult to show in vivo, e.g. glucotoxicity due to uncontrolled diabetes and cytotoxicity by islet amyloid polypeptide (IAPP) [21,22] [23]. Mechanistically, it has also been discussed whether chronic hyperglycemia and different genetic variants of the insulin receptor may affect the clinical course of diabetes [24][25][26].…”

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

“…Beta cell number is determined by their replication, neogenesis and apoptosis [5]. Animal studies in rodents revealed that the increased replication of beta cells is the major mechanism for the increased beta cell number seen in non-diabetic obesity [40,41]. Also, in humans, increased body weight is paralleled by an increase in beta cell mass [1,2].…”