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BACKGROUND:The mass of pancreatic beta-cells varies according to increases in insulin demand. It is hypothesized that functionally heterogeneous beta-cell subpopulations take part in this process. Here we characterized two functionally distinct groups of beta-cells and investigated their physiological relevance in increased insulin demand conditions in rats. METHODS:Two rat beta-cell populations were sorted by FACS according to their PSA-NCAM surface expression, i.e. beta(high) and beta(low)-cells. Insulin release, Ca(2+) movements, ATP and cAMP contents in response to various secretagogues were analyzed. Gene expression profiles and exocytosis machinery were also investigated. In a second part, beta(high) and beta(low)-cell distribution and functionality were investigated in animal models with decreased or increased beta-cell function: the Zucker Diabetic Fatty rat and the 48 h glucose-infused rat. RESULTS:We show that beta-cells are heterogeneous for PSA-NCAM in rat pancreas. Unlike beta(low)-cells, beta(high)-cells express functional beta-cell markers and are highly responsive to various insulin secretagogues. Whereas beta(low)-cells represent the main population in diabetic pancreas, an increase in beta(high)-cells is associated with gain of function that follows sustained glucose overload. CONCLUSION:Our data show that a functional heterogeneity of beta-cells, assessed by PSA-NCAM surface expression, exists in vivo. These findings pinpoint new target populations involved in endocrine pancreas plasticity and in beta-cell defects in type 2 diabetes.

Type 2 diabetes is an endocrine/metabolic disease characterized by hyperglycemia. It is now well established that insulin resistance and pancreatic beta-cell dysfunction/failure are the two major components of the physiopathology of the disease. Current available therapies do not successfully enable patients with type 2 diabetes to reach glycemic goals. Even with intensive treatment type 2 diabetic patients may face spikes in blood glucose after meals, weight gain, and a loss of effectiveness of their treatments over time. The novel agents recently developed by the Pharmaceutical Industry may either provide an alternative therapeutic strategy or offer useful adjuncts to existing therapies. Glucagon-like peptide 1 (GLP-1), produced in the small intestine and amylin, produced by beta cells in the pancreas, also have glucose lowering effects. Amylin is an hormone secreted after a meal, having a complementary action to insulin. GLP-1, also released in a post-prandial manner, promotes insulin production and secretion, reduces glucagon secretion, delays gastric emptying and induces a feeling of fullness. The most promising effect of GLP-1 is its ability to increase beta-cell mass by stimulating neogenesis and reducing apoptosis in rodents. However the fact that GLP-1 is rapidly degraded by dipeptidylpeptidase IV (DPPIV) in vivo reduces its usefulness. Thus, in order to improve therapeutic efficacy, two approaches have been investigated: the development of GLP-1 analogs resistant to degradation or the development of DPP-IV inhibitors. Synthetic analogs of amylin (pramlintide), GLP-1 (exenatide) and inhibitors of the degradation of GLP-1 (sitagliptin, DPP-IV inhibitor) are now available for clinical use. Promising biological targets being investigated include those leading to insulin sensitization (11beta-HSD-1 inhibitors and antagonists of glucocorticoids receptor), reducing hepatic glucose output (antagonist of glucagon receptor, inhibitors of glycogen phosphorylase and fructose-1,6-biphosphatase) and finally increasing urinary elimination of excess glucose (SGLT inhibitors). A particular role is played by glucokinase activators (GKA) which can both increase insulin secretion and improve hepatic glucose metabolism. In this review, we present a summary of the data available on newly approved treatments (amylin and GLP-1 analogs as well as DPP-IV inhibitors) and give an overview of the targets currently being studied for the treatment of type 2 diabetes with an emphasis on the small molecule drug design.

Recent studies ascribe a major role to pancreatic beta-cell loss in type 2 diabetes. We investigated the dynamics of beta-cell mass during diabetes evolution in Psammomys obesus, a model for nutrition-dependent type 2 diabetes, focusing on the very early and the advanced stages of the disease. P. obesus fed a high-calorie diet for 26 days developed severe hyperglycemia, beta-cell degranulation, and markedly reduced pancreatic insulin content. Reducing calories for 7 days induced normoglycemia in 90% of the animals, restoring beta-cell granulation and insulin content. To dissociate effects of diet from blood glucose reduction, diabetic animals received phlorizin for 2 days, which normalized glycemia and increased the pancreatic insulin reserve to 50% of control, despite a calorie-rich diet. During diabetes progression, beta-cell mass decreased initially but recovered spontaneously to control levels, despite persistent hyperglycemia. Strikingly, however, beta-cell mass did not correlate with degree of hyperglycemia or pancreatic insulin content. We conclude that reduced insulin reserve is the main cause of diabetes progression, whereas irreversible beta-cell mass reduction is a late event in P. obesus. The rapid recovery of the pancreas by phlorizin-induced normoglycemia implies a causal relationship between hyperglycemia and islet dysfunction. Similar mechanisms could be operative during the evolution of type 2 diabetes in humans.