Acute suppression of
dipeptidyl peptidase IV (DPP-IV) activity improves
glucose tolerance in the Zucker fatty rat, a rodent model of
impaired glucose tolerance, through stabilization of
glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent
DPP-IV inhibitor,
FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single
oral administration. In the Zucker fatty rat,
FE 999011 dose-dependently attenuated
glucose excursion during an oral
glucose tolerance test and increased
GLP-1 (7-36) release in response to intraduodenal
glucose. Chronic treatment with
FE 999011 (10 mg/kg, twice a day for 7 days) improved
glucose tolerance, as suggested by a decrease in the
insulin-to-
glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of
type 2 diabetes, chronic treatment with
FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of
hyperglycemia by 21 days. In addition, treatment with
FE 999011 stabilized food and water intake to prediabetic levels and reduced
hypertriglyceridemia while preventing the rise in circulating
free fatty acids. At the end of treatment, basal plasma
GLP-1 levels were increased, and pancreatic gene expression for
GLP-1 receptor was significantly upregulated. This study demonstrates that
DPP-IV inhibitors such as
FE 999011 could be of clinical value to delay the progression from
impaired glucose tolerance to
type 2 diabetes.