Effects of the dipeptidyl peptidase-IV inhibitor ASP8497 on glucose tolerance in animal models of secondary failure

ArticleinEuropean journal of pharmacology 622(1-3):71-7 · September 2009with13 Reads
DOI: 10.1016/j.ejphar.2009.09.024 · Source: PubMed
Abstract
Unlabelled: Sulfonylureas promote insulin secretion and potently lower blood glucose levels, however, they induce hypoglycemia and undergo a reduction in efficacy when administered long-term (secondary failure). The dipeptidyl peptidase (DPP)-IV inhibitor ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, inhibits the degradation of glucagon-like peptide-1 (GLP-1), an incretin hormone, and promotes insulin secretion in a glucose-dependent manner. ASP8497 is therefore less likely to induce hypoglycemia and less likely to show reduced efficacy even after repeated administration. Here, to determine whether or not ASP8497 improves glucose tolerance in Zucker fatty rats, we examined the effects of ASP8497 and gliclazide, a sulfonylurea, on glucose tolerance after repeated administration. We also developed an animal model of secondary failure using streptozotocin-nicotinamide-induced diabetic mice. Results: ASP8497 (3mg/kg) improved glucose intolerance in Zucker fatty rat without any attenuation (blood glucose AUC: P=0.034 vs. vehicle) while gliclazide (10mg/kg) did not (P=0.916 vs. vehicle). Furthermore, ASP8497 (3, 10mg/kg) was found to effect glucose tolerance dose-dependently (3mg/kg: P=0.230, 10mg/kg: P=0.003 vs. glibenclamide (10mg/kg)) by enhancing insulin secretion in mice inadequately controlled with glibenclamide. Our results suggest that ASP8497 may be effective even in patients with secondary failure who are unable to maintain satisfactory glycemic control using sulfonylureas.
    • "The primary goal of this study was to investigate the durability, and not absolute efficacy, of different antidiabetic treatments on glucose homeostasis and how well glycemic changes correlated to pancreatic b-cell mass. Individual compound doses were carefully selected according to standard dose ranges used in diabetic rat models, as reported previously for empagliflozin (Luippold et al., 2012; Thomas et al., 2012), liraglutide (Sturis et al., 2003; Brand et al., 2009; Schwasinger-Schmidt et al., 2013), and glibenclamide (Margolis 1987; Mine et al., 2002; Someya et al., 2009). Because rodents and humans display different pharmacokinetics, it should be noted that the dose ranges applied in preclinical diabetes studies are generally lower than that used in diabetic patients, that is, dosing regimens cannot directly be translated to clinical settings. "
    [Show abstract] [Hide abstract] ABSTRACT: Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and anti-diabetic efficacy. Through an insulin and β-cell independent mechanism, empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-cell mass with empagliflozin or liraglutide at week 4, while only empagliflozin showed β-cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and anti-diabetic efficacy.
    Article · Jul 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Glucokinase activators increase insulin release from pancreatic beta-cells and hepatic glucose utilization by modifying the activity of glucokinase, a key enzyme in glucose-sensing and glycemic regulation. Sulfonylureas are antihyperglycemic agents that stimulate insulin secretion via a glucose-independent mechanism that is vulnerable to secondary failure through beta-cell desensitization. The present study determined whether glucokinase activator treatment retains its glucose-lowering efficacy in male, adult, non-diabetic Sprague-Dawley rats desensitized to sulfonylurea treatment and whether glucose-lowering during chronic glucokinase activator treatment is subject to secondary failure. Animals were given food containing either glimepiride (a sulfonylurea), Compound B (3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide, an experimental glucokinase activator), or no drug for up to 5 weeks. Food containing 0.04% of either drug produced acute (within 4-8 h) and significant (P<0.05) reductions in blood glucose to approximately 50% of control levels. Chronic treatment with either 0.01% or 0.04% glimepiride resulted in complete failure of glucose-lowering efficacy within 3 days whereas the efficacy of Compound B was sustained throughout the entire study. Glipizide, also a sulfonylurea, had no glucose-lowering effect when given by gavage (3mg/kg) to glimepiride-desensitized animals whereas Compound B retained full glucose-lowering efficacy in glimepiride-desensitized animals. Oral glucose tolerance was significantly impaired, compared with controls, in animals treated with glimepiride for two weeks but was enhanced to a small extent in animals treated with Compound B. Compound B also significantly increased pancreatic insulin content, compared with controls. These findings suggest that Compound B has sustained glucose-lowering effects in a rat model of sulfonylurea failure.
    Article · May 2010
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