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

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activation and proliferation. However, to date, side-effects resulting from the prolongation
of the action of messengers such as related to inflammation, blood pressure and allergic
reactions from DPP-IV inhibition have not been observed in preclinical animal and clinical
human studies (226).
In preclinical studies with normal and diabetic animals, several orally active DPP-
IV inhibitors have been shown to increase plasma levels of intact, biologically active GLP-
1 and GIP, resulting in stimulation of insulin and inhibition of glucagon secretion in a
glucose-dependent manner as well as promotion of beta-cell proliferation, neogenesis and
inhibition of apoptosis (198)
Several studies examining the efficacy of the two DPP-IV inhibitors Sitagliptin
(Januvia) and Vildagliptin (Galvus) in the treatment of DM2 are now on phase III trials and
will be reviewed below
a- Sitagliptin (MK-0431)
A preclinical study has demonstrated that 8 to 12 weeks of treatment of diabetic
mice with an analog of sitagliptin (des-fluoro-sitagliptin), produced restoration of beta-cell
mass and morphology, increased islet insulin content and improved glucose –stimulated
insulin secretion in isolated islets, similar to that observed in preclinical studies following
administration of GLP-1 or GLP-1R analogs (227).
Single doses of 100mg or higher, with an apparent half-life of 8 – 14 hours ,
resulted in inhibition of plasma DPP-IV activity over 24 hours by at least 80%.Sitagliptin
increased the meal-associated rise in active plasma GLP-1 concentrations by approximately
2-fold without causing hypoglycemia (228). Therefore, sitagliptin possesses
pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing
regimen, stimulating insulin secretion,inhibiting glucagon secretion, and reducing
glycemic excursions following an oral glucose load in mild DM2 (229).
There are recent reports, from the ongoing phase III programme with sitagliptin,
involving 3 large studies. In one study, sitagliptin monotherapy reduced significantly
HbA1c and improved glycemic control in the fasting and postprandial state after 24 weeks