1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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In contrast with GLP-1R agonists, which are administered via injection, the DPP-IV
inhibitors, sitagliptin and vildagliptin, accepted for review by the FDA, are administered
orally and are well tolerated. Major adverse effects have not been reported in clinical trials
examining the efficacy of DPP-IV inhibitors for the treatment of DM2.
In healthy subjects a single dose of 100mg or higher of sitagliptin resulted in
inhibition of plasma DDP-IV activity over 24 hours by at least 80%, increasing meal-
associated rise in active plasma GLP-1 levels two fold without hypoglycemia. Phase III
studies with sitagliptin + ongoing metformin and sitagliptin + ongoing pioglitazone, has
indicated an improvement in HbA1c and glycemic control as well post-meal indices of
β-cell function. The effect of sitagliptin on beta-cell function, assessed by frequently
sampled meal tolerance tests in 3 sub-studies from phase III using the C-peptide minimal
model, showed improvement in beta-cell responsiveness to basal and above-basal glucose
concentrations components following the meals. The dynamic component (beta-cell
responsiveness to the rate of increase in above-basal glucose levels following a meal)
showed numerical but not significant improvements with sitagliptin. Disposition indices
were also improved.
Preclinical studies have demonstrated that vildagliptin increased beta-cell mass
by increasing the number of replicating islet cells and reducing the number of apoptotic
islet cells as assessed in neonatal rats, a model for rapid beta-cell turnover and growth.The
head-to-head comparison of vildagliptin with exenatide in a mouse model of
streptozotocin-induced beta-cell injury showed that both had a protective effect against
beta-cell injury, promoted early differentiation of pancreatic progenitor cells and increased
formation of ductal beta-cells, improving glucose tolerance with the effect being
maintained after the treatment washout.
Although vildagliptin reduced postprandial glucose in DM2 it did not increase post-
meal insulin levels during 4-12 week treatment. In diet-treated DM2 oral glucoseload (75g)
provided an intense glucose stimulus for insulin secretion when compared to a standard
breakfast meal test. In drug naïve patients, 4-week treatment with vildagliptin (100mg bid)
improved β-cell function by increasing insulin secretion at any glucose level while the
slope of β-cell dose response and the potentiation factor were not affected using a