Journal Club

1. Journal Club 2009年1月29日（木） 8：20～8：50 B棟8階カンファレンスルーム 薬剤部TTSP 石井 英俊

2. Dipeptidyl Peptidase-4 Inhibition by Vildagliptin and the Effect on Insulin Secretion and Action in Response to Meal Ingestion in Type 2 Diabetes. Diabetes Care, volume 32, number 1, January 2009

3. Glucagon-like peptide-1(GLP-1) • A peptide hormone produced by the enteroendocrine L cells of the intestinal mucosa. • One of the most potent stimulants of insulin release, GLP-1 is responsible for a significant part of the insulin response to oral glucose. • Released in response to caloric intake. • Exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets. • Slow gastric emptying. • Inhibit inappropriate postmeal glucagon release. • Reduce food intake. GLP-1-based therapies for the treatment of type 2 diabetes;UpToDate, アクセス日(2009年1月17日)

4. Dipeptidyl Peptidase-4(DPP-4) • DPP-4 is a widely distributed enzyme that deactivates a variety of other bioactive peptides, including GIP and GLP-1. • Vildagliptin is a one of the DPP-4 inhibitor. • DPP-4 inhibitors increase insulin secretion and suppress glucagon concentrations. GLP-1-based therapies for the treatment of type 2 diabetes;UpToDate, アクセス日(2009年1月17日)

5. Background • GLP-1, GLP-1 receptor agonists, and DPP-4 inhibitors all lower postprandial glucose concentration. Among these agents, only DPP-4 inhibitors differ with regard to their effects on glucose metabolism.

6. Objective • To determine the mechanism by which DPP-4 inhibitors lower postprandial glucose concentrations.

7. Methods • Subjects • 14 subjects with type 2 diabetes. • Subjects characteristics • Mean age : 53.1±2.0 years • BMI : 33.9±1.5 kg/m2 • Lean body mass : 73.8±2.3 kg • A1C : 6.1±0.2 %

8. Methods • Study design Randomized, double-blind, placebo-controlled crossover design. Subjects received either 50 mg vildagliptin or placebo taken before breakfast and the evening meal over a 10-day treatment period with the two treatment intervals being separated by at least a 2-week washout period.

9. Result

10. Meal ingestion Insulin injection （0.02 IU/kg BW） Glucose concentrations in the presence and absence of vildagliptin. Administration of vildagliptin resulted in lower fasting glucose, a lower postmeal peak, and a lower glycemic area above basal over the duration of the study.

11. Meal ingestion Insulin injection （0.02 IU/kg BW） Insulin concentrations in the presence andabsence of vildagliptin. Insulin concentrations did not differ when subjects received vildagliptin or placebo before or after meal ingestion.

12. Meal ingestion Insulin injection （0.02 IU/kg BW） C-Peptide concentrations in the presence and absence of vildagliptin. C-Peptide concentrations did not differ in the fasting state or after meal ingestion.

13. Insulin injection （0.02 IU/kg BW） Meal ingestion Glucagon concentrations in the presence and absence of vildagliptin. Fasting glucagon concentrations did not differ in the presence or absence of vildagliptin. However, over the first 5 hr after meal ingestion, treatment with vildagliptin resulted in lower postprandial glucagon concentrations.

14. Meal ingestion Insulin injection （0.02 IU/kg BW） Insulin action in the presence and absence of vildagliptin. Vildagliptin did not alter net insulin action or the effects of insulin on glucose disposal. The change in glucose concentrations after insulin administration, did not differ in the presence or absence of vildagliptin.

15. Insulin secretion and disposition indexes in the presence and absence of vildagliptin.

16. Conclusions • DPP-4 inhibitors increase insulin secretion and suppress glucagon concentrations. In contrast, they do not alter hepatic insulin clearance, insulin action, or glucose effectiveness. Taken together with the previous report in the same subjects indicating that DPP-4 inhibitors do not alter gastric emptying, these data demonstrate that DPP-4 inhibitors lower postprandial glucose concentrations solely by altering α- and β-cell function.

17. Conclusions • The present data indicate that short-term (9 days) inhibition of DPP-4 does not alter insulin action in individuals with type 2 diabetes. Vildagliptin was only administrated for 9 days before the experiment, raising the possibility that an effect on insulin action might have been observed with longer periods of administration.

18. summary • Vildagliptin lowers glucose concentrations through its effects on insulin and glucagon secretion. • Vildagliptin has no direct effect on insulin action to increase glucose utilization or decrease glucose production. • A novel observation is that vildagliptin alter α-cell responsiveness to insulin administration.

19. Exenatide(GLP-1 analogue) • Resistant to DPP-4 degradation and therefore exhibits a prolonged half-life(2.4hr). • Exenatide has been shown to promote beta cell regeneration and differentiation in prediabetic and diabetic rats. • Insulinotropic effects are suppressed as the plasma glucose approaches 72mg/dL. • Slows gastric emptying, suppresses inappropriately elevated glucagon levels, and lead to weight loss. • Not recommended for patients with end-stage renal disease or severe renal impairment. • Route of administration:s.c. • Dose:5 or 10mg twice daily

20. Sitagliptin(DPP-4 inhibitors) • A reduction in the dose of sitagliptin is recommended in patients with moderate to severe renal insufficiency or end-stage renal disease. • The rate of gastric emptying is unchanged. • Weight neutral or cause slight weight gain. • Usual dose:100mg once daily • Route of administration:p.o.