Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus.

Type 2 diabetes is accompanied by chronic insulin resistance and a progressive decline in b-cell function (1). Obesity is a major risk factor for the development of type 2 diabetes (2, 3) and is thought to confer increased risk for type 2 diabetes through obesity-associated insulin resistance (4). However, most people who are obese do not develop diabetes but compensate their relative insulin resistance by increasing insulin secretion (5). In rodent models of obesity without diabetes there is (as opposed to non-obese littermates) an adaptive increase in b-cell mass to meet metabolic demands (6). Although not many data are available, studies suggest that b-cell mass is also adaptively increased in non-diabetic obese humans (7, 8). b-cell mass is regulated by a balance of b-cell replication and apoptosis, as well as development of new islets from exocrine pancreatic ducts (neogenesis) (9, 10). Disruption of any of the pathways of b-cell formation or increased rates of b-cell death would result in decreased b-cell mass and thus reduced capacity to produce insulin. There is controversy whether b-cell mass is decreased in type 2 diabetes mellitus (8, 11–17). These discrepancies are in part due to the paucity of available data in humans. Furthermore, it is controversial whether b-cell apoptosis is truly increased in type 2 diabetes. A recent (18) very carefully conducted study gives new and convincing data indicating that increased apoptosis rather than decreased neogenesis or replication may be the main mechanism leading to reduced b-cell mass in type 2 diabetics. Autopsy material from obese patients with diabetes or with impaired fasting glucose (IFG) or without diabetes as well as from lean patients was examined. The authors report that obesity in non-diabetic humans is accompanied by a 50% increase in relative b-cell volume as compared with lean non-diabetic humans. However, the non-diabetic obese humans died younger than the non-diabetic lean humans and the difference found on autopsy may be due to difference in age. Obese humans with IFG and type 2 diabetes had a respective 40 and 63% deficit in relative b-cell volume. The decreased b-cell volume in patients with type 2 diabetes was due to a reduced number of b-cells rather than a smaller volume of individual cells and occurred irrespectively of whether they were treated with diet alone or oral medications or insulin. There was no difference in the mean fasting plasma glucose levels among these three treatment groups. Lean subjects with type 2 diabetes had a 41% deficit in relative b-cell volume compared with lean non-diabetic subjects. These findings are consistent with other carefully conducted recent studies in which b-cell mass is decreased in type 2 diabetes (8, 15, 17). Neogenesis, while increased in obesity, was comparable in all groups. Decreased b-cell replication was found with aging (18). Because new islet formation, the predominant input into the b-cell mass, appears intact in type 2 diabetics (18), the mechanism for the decreased b-cell mass would have to be increased b-cell apoptosis. Indeed, a significantly increased frequency of apoptotic events were detected in lean type 2 diabetic vs non-diabetic cases. When normalized to the b-cell volume, the frequency of apoptosis was 3-fold higher in obese cases of type 2 diabetes and 10-fold higher in lean cases of type 2 diabetics as compared with their controls. Thus, relative b-cell volume and therefore b-cell mass is decreased in both obese and lean humans with type 2 diabetes compared with non-diabetic ageand weight-matched controls. The fact that patients with IFG, a risk group for developing diabetes, had a 40% deficit in relative b-cell volume indicates that loss of b-cells is an early process in the pathogenesis of diabetes mellitus (18). Once b-cell mass decreases below a critical level and insulin production no longer meets metabolic demands we have hyperglycemia. Does a 60% decrease in b-cell mass – as found in this study – translate into impaired glucose metabolism? Humans who have undergone 50% pancreatectomy have impaired glucose tolerance and insulin secretion in response to a hyperglycemic clamp (19 –23). On this basis we may assume that a 60% reduction in b-cell mass in the face of insulin resistance may be sufficient to result in hyperglycemia. What are the mechanisms for the increased apoptosis found in the islets of type 2 diabetics? The islet in type 2 diabetes is characterized by deposits of polypeptide (IAPP) (15, 24–29). This peptide causes apoptosis of b-cells (30, 31), particularly when it is in H IG H L IG H T European Journal of Endocrinology (2003) 149 99–102 ISSN 0804-4643