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

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reduction in HbA1c over 24 weeks, maintaining the glycemic control over the study period.
Proinsulin levels and proinsulin/insulin ratio were significantly reduced with sitagliptin
compared with placebo, suggesting improvement in beta-cell function without additional
weight gain (233).
b- Vildagliptin (LAF – 237)
In preclinical studies, the ability of vildagliptin to augment beta-cell mass by
enhancing endogenous incretin action was assessed in neonatal rats, a model for rapid beta-
cell turnover and growth. Neonatal rats were treated once daily with vildagliptin or vehicle
(control) for 21 days. Vildagliptin increased the number of replicating islet cells
significantly and reduced the number of apoptotic islet cells. Additionally, there was a
significant increase in pancreatic insulin content and beta-cell mass even 1 week after
discontinuation of treatment (234). The head-to-head comparison of vildagliptin with
injectable exenatide on in-vivo beta cell regulation in streptozotocin-induced beta cell
injury in mice, demonstrated that both drugs are equally effective in reducing the
streptozotocin–induced proliferative response, a protective effect against beta-cell injury as
well as in promoting early differentiation of pancreatic progenitor cells, in increasing
formation of ductal beta-cell, and improving glucose tolerance to a similar extent in STZ-
diabetic mice. Furthermore, the effect was maintained after the treatment washout (235).
In clinical studies with vildagliptin, postmeal glucose levels were significantly
decreased but postmeal insulin levels were unchanged (220). Although such findings might
be interpreted to suggest that DPP-IV inhibitors do not improve insulin secretion in patients
with DM2, it should be recognized that circulating insulin levels are not a direct measure of
insulin secretion and that insulin secretion must be considered in the context of ambient
glucose levels. Accordingly, beta-cell function can be improved, without appreciable
changes in circulating insulin levels, particularly if glucose values are reduced (236). The
effect of 4-week treatment with vildagliptin (100 mg, twice daily) on meal-related beta-