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Background and Purpose Small molecule glucokinase activators ( GKAs) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of S 50131 and S 51434, two novel GKAs with an original scaffold and an atypical pharmacological profile. Experimental Approach Activity of the compounds was assessed i n vitro by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of Langerhans. Efficacy and safety in vivo were evaluated after oral administration in db/db mice by measuring glycaemia, HbA1c and dyslipidaemia-associated events. Key Results S 50131 and S 51434 activated GK and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease HbA1c after a 4-week treatment in db/db mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids ( FFAs), contrasting with the effect of GKA50 and N00236460, two GKAs with sustained HbA1c lowering activity but neutral regarding plasma FFAs. S 50131, but not S 51434, also induced hepatic steatosis, as did GKA50 and N00236460. However, a shorter, 4-day treatment resulted in increased hepatic triglycerides without changing the plasma FFA levels, demonstrating dynamic alterations in the lipid profile over time. Conclusions and Implications In addition to confirming the occurrence of dyslipidaemia with GKAs, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time. [ABSTRACT FROM AUTHOR]

Abstract: In healthy conditions, insulin-like growth factor–I (IGF-I) acts in a coordinated fashion with insulin to lower glycemia, mainly by increasing insulin sensitivity in peripheral tissues. The aim of this study was to explore the relationship between glucose homeostasis and the endocrine IGF-I axis in Zucker diabetic fatty (ZDF) rats. The plasma levels of glucose, insulin, growth hormone, free IGF-I, total IGF-I (associated to insulin-like growth factor binding proteins plus free), and corticosterone were measured in 13-week-old ZDF rats and in age-matched controls under fasting and postprandial conditions. The plasma IGF-I binding capacity was measured by radioligand binding. In ZDF rats, fasting total and free IGF-I levels were reduced by 22% and 92%, respectively, compared with controls. Postprandial free IGF-I was reduced by 35%, whereas total IGF-I was unaffected. The plasma IGF-I binding capacity in ZDF rats was reduced by 24% after fasting and by 13% under postprandial conditions. A clear correlation between free IGF-I and insulin was observed in postprandial controls but not in ZDF rats. A principal component analysis clearly separated ZDF and control rats into 2 main components under both fasting and postprandial conditions. The first component was determined equally by total IGF-I, bound IGF-I, the free to total IGF-I ratio, and the IGF-I binding capacity. The second component was determined mostly by glucose and insulin. Our results show a marked alteration of the plasma IGF-I levels and of the capacity of plasma to bind IGF-I, and a disturbed relationship between IGF-I and postprandial insulinemia in a rat model of type 2 diabetes mellitus. [Copyright &y& Elsevier]

Background: The mass of pancreatic b-cells varies according to increases in insulin demand. It is hypothesized that functionally heterogeneous β-cell subpopulations take part in this process. Here we characterized two functionally distinct groups of β-cells and investigated their physiological relevance in increased insulin demand conditions in rats. Methods: Two rat b-cell populations were sorted by FACS according to their PSA-NCAM surface expression, i.e. βhigh and βlow-cells. Insulin release, Ca2+ 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, βhigh and βlow-cell distribution and functionality were investigated in animal models with decreased or increased β-cell function: the Zucker Diabetic Fatty rat and the 48 h glucose-infused rat. Results: We show that β-cells are heterogeneous for PSA-NCAM in rat pancreas. Unlike βlow-cells, βhigh-cells express functional β-cell markers and are highly responsive to various insulin secretagogues. Whereas βlow-cells represent the main population in diabetic pancreas, an increase in βhigh-cells is associated with gain of function that follows sustained glucose overload. Conclusion: Our data show that a functional heterogeneity of β-cells, assessed by PSA-NCAM surface expression, exists in vivo. These findings pinpoint new target populations involved in endocrine pancreas plasticity and in β-cell defects in type 2 diabetes. [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]

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]