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It is now clearly demonstrated that fatty acids (FAs) may modulate neural control of energy homeostasis and specifically affect both insulin secretion and action. Indeed, pancreatic β-cells receive rich neural innervation and FAs induce important changes in autonomic nervous activity. We previously reported that chronic infusion of lipids decreased sympathetic nervous system activity and led to exaggerated glucose-induced insulin secretion (GIIS), as would be expected from the known inhibitory effect of sympathetic splanchnic nerve activity on insulin secretion. Intracarotid infusion of lipids that do not change plasma FA concentrations also lead to increased GIIS. This effect of FAs on GIIS was prevented by inhibition of β-oxidation. It is noteworthy that a single intracarotid injection of oleic acid also induced a transient increase in plasma insulin without any change in plasma glucose, suggesting that FAs per se can regulate neural control of insulin secretion. Finally, using whole cell current clamp recordings in hypothalamic slices and calcium imaging in dissociated hypothalamic neurons, we identified a hypothalamic subpopulation of neurons either excited (13%) or inhibited (6%) by FAs. Thus, FAs per se or their metabolites modulate neuronal activity, as a means of directly monitoring ongoing fuel availability by central nervous system nutrient-sensing neurons involved in the regulation of insulin secretion. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by insulin resistance and progressive beta-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate beta-cell function and/or reduced beta-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of beta-cell dysfunction versus decreased beta-cell mass to the "beta-cell failure" of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and beta-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in beta-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans. [ABSTRACT FROM AUTHOR]

Recent studies ascribe a major role to pancreatic β-cell loss in type 2 diabetes. We investigated the dynamics of β-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, β-cell degranulation, and markedly reduced pancreatic insulin content. Reducing calories for 7 days induced normoglycemia in 90% of the animals, restoring β-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, β-cell mass decreased initially but recovered spontaneously to control levels, despite persistent hyperglycemia. Strikingly, however, β-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 β-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. Diabetes 54:138-145, 2005 [ABSTRACT FROM AUTHOR]

Endocrine pancreas plasticity may be defined as the ability of the organ to adapt the beta-cell mass to the variations in insulin demand. For example, during late pregnancy and obesity, the increase of the beta-cell mass, in association with beta-cell hyperactivity, contributes to insulin oversecretion in response to insulin resistance. There is increasing evidence that the ability of the beta-cell mass to expand in adult mammals is much higher than previously thought. During pregnancy, placental hormones, especially placental lactogens, are mainly responsible for the changes in beta-cell mass. The factors involved in beta-cell growth in obesity are far from clear, although increased free fatty acids seem to be the main candidate. Many data suggest that the impairment of insulin secretion in type 2 diabetes is partly related to reduction of beta-cell mass, at least relative to prevailing insulin demand. This defect may originate from genetic predisposition, but the situation is likely worsened by environmental factors such as hyperglycemia (glucotoxicity) and hyperlipidemia (lipotoxicity). Better understanding of beta-cell growth and regeneration mechanisms may allow new strategies in the treatment of type 2 diabetes based on early limitation of beta-cell damage and/or restoration of a functional beta-cell mass. [ABSTRACT FROM AUTHOR]

Recent evidence suggest that GLP-1 analogues (exendin-4) could enhance the β-cell mass. The objective of the present study was to investigate the effect of dipeptidyl-peptidase IV (DPP-IV) inhibitors on β-cell mass after chronic oral treatment in a model of type 2 diabetes. To this aim S 40010, a novel potent selective DPP-IV inhibitor (IC[sub 50] = 2 nM), LAF 237 (Vildagliptin) and exendin-4 were administered for 34 days in 6 week-old db/db mice. S 40010 and LAF 237 where given orally at 20 mg/kg, bid, while exendin-4 was administered ip, at 4 µg/kg/day. Vehicle-treated mice received hydroxyethylcellulose [C]. Both S 40010 and LAF-237 elicited a significant inhibition of plasma DPP-IV activity (30% and 52%, respectively, p<0.01 vs C), associated with an increase of plasma GLP-1 levels (5.3±1.14 and 5.67±1.6 pM, respectively vs C: 1.3±0.4 pM, p<0.05 vs C). Hyperglycemia in db/db mice, measured 2f after food deprivation, was gradually decreased by daily treatment with both DPP-IV inhibitors (-35% on D[sub 34], p<0.05 vs C). This was associated with a diminution of HbA1c of 1.4 % (p<0.05 vs C). S 40010 decreased fasting blood glucose by 55 % (p<0.05 vs C) whereas LAF 237 did not reach statistical significance. S 40010 and LAF 237 reduced hyperglycemia induced by an oral glucose load compared to C mice. Mice treated with S 40010 displayed a significant increase in β-cell mass (2.9-fold, p<0.01 vs C) comparable to that observed with exendin-4, associated to a stimulation of β-cell neogenesis (l.8-fold, p<0.01 vs C). By contrast, the effect of LAF 237 on β-cell mass did not reach significance level. In conclusion, the present results show that in a model of type 2 diabetes, chronic oral treatment with DPP-IV inhibitors, improves the glucose homeostasis attested by HbA1c and both basal and post-prandial glycemia reduction. The enhancement of the β-cell mass due, at least in part, to a stimulation of β-cell neogenesis, suggests a potential for disease modifying activity of DPP-IV inhibitors such as S 40010. [ABSTRACT FROM AUTHOR]