Increasing evidence indicates that decreased functional beta-cell mass is the hallmark of both Type 1 and Type 2 diabetes. This underlies the absolute or relative insulin insufficiency in both conditions. In this For Debate, we consider the possible mechanisms responsible for beta-cell death and impaired function and their relative contribution to insulin insufficiency in diabetes. Betacell apoptosis and impaired proliferation consequent to hyperglycaemia is one pathway that could be operating in all forms of diabetes. Autoimmunity and other routes to beta-cell death are also considered. Recognition of decreased functional beta-cell mass and its overlapping multifactorial aetiology in diabetic states, leads us to propose a unifying classification of diabetes. [Diabetologia (2004) 47:581-589]

Decreased functional beta-cell mass in type 1 and type 2 diabetes is due to beta-cell apoptosis and impaired secretory function suggested to be mediated, in part, by immune- and/or high-glucose-induced production of IL-1beta acting through the nuclear factor kappaB (NFkappaB)/Fas pathway. The aim of this study was to determine whether two drugs believed to block NFkappaB activation, the thiazolidinedione (glitazone) pioglitazone and the nonsteroidal antiinflammatory drug sodium salicylate, can protect human beta-cells against the toxic effects of IL-1beta and high glucose in vitro. Human islets were maintained in culture 2-4 d at 100 mg/dl (5.5 mm) glucose with or without (control) IL-1beta or at 600 mg/dl (33.3 mm) glucose. IL-1beta and 600 mg/dl glucose increased beta-cell apoptosis and abolished short-term glucose-stimulated insulin secretion. Both drugs protected partially against loss of glucose-stimulated insulin secretion and prevented completely increased apoptosis caused by IL-1beta or 600 mg/dl glucose. IL-1beta secretion from islets was increased by 4-d culture at 600 mg/dl, and this was blocked by pioglitazone. Both drugs prevented activation of beta-cell NFkappaB by high glucose. Pioglitazone and sodium salicylate thus protect human islets against the detrimental effects of IL-1beta and high glucose by blocking NFkappaB activation and may therefore be useful in retarding the manifestation and progression of diabetes.

The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studied the interaction between diet and diabetic predisposition for beta-cell function. A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold increase in serum glucose, insulin, and triglycerides, respectively, in diabetes-prone (DP) but not diabetes-resistant (DR) P. obesus. Hyperglycemia and concurrent 90% depletion of islet immunoreactive insulin stores were partially corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets. The HE diet augmented early and late insulin response in DR islets, whereas in DP islets, secretion progressively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P. obesus by a HE diet, concomitant with a decreased threshold for glucose and a 55% reduction in maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets. There were no differences in islet glucokinase (GK) and hexokinase (HK) Km; however, GK Vmax was 3.7- to 4.6-fold higher in DP islets, and HK Vmax was augmented 3.7-fold by the HE diet in DP islets. We conclude that the insulin-resistant P. obesus has an inherent deficiency in insulin release. In the genetically predisposed P. obesus (DP), augmented islet glucose phosphorylation ability and diet-induced reduction of the glucose threshold for secretion may lead to inadequate insulin secretion and depletion of insulin stores in the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptation to nutritional load seem to determine together the progression to overt diabetes in this species. It is hypothesized that similar events may occur in obese type 2 diabetic patients.

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