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OBJECTIVE: To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIR(g)) and insulin sensitivity index (S(I)) were determined and used to compute the disposition index (AIR(g) x S(I)) as a measure of beta-cell function. RESULTS: Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean +/- SEM AIR(g) increased from 224 +/- 44 to 286 +/- 52 pmol/l (P < 0.05), and S(I) improved from 2.8 +/- 0.5 to 3.5 +/- 0.5 x 10(-5) x min(-1) x pmol(-1) x l (P < 0.01), resulting in an increase in the disposition index from 688 +/- 180 to 1,164 +/- 318 x 10(-5)/min (P < 0.05). These effects were not sustained after washout. During the MTT, the incremental area under the glucose curve was significantly decreased after treatment (240 +/- 15 vs. 191 +/- 14 mmol x l(-1) x min(-1); P = 0.002), but this effect was not sustained after washout. CONCLUSIONS: The DPP-4 inhibitor vildagliptin improves insulin sensitivity and beta-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have beta-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects. [ABSTRACT FROM AUTHOR]

Islet amyloid contributes to loss of beta-cell mass and function in type 2 diabetes. It is poorly understood how the building block of amyloid, islet amyloid polypeptide (IAPP), misfolds and accumulates within the islet to contribute to cellular dysfunction. We sought to determine whether neprilysin, an amyloid-degrading enzyme, is present in islets and plays a role in the accumulation of amyloid fibrils. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid in which primarily male mice develop amyloid by 12 months of age, were studied at 10 weeks and 6 months of age, enabling investigation of islet changes before and during early amyloidogenesis. Neprilysin was present in islets, including beta-cells, and islet neprilysin mRNA and activity were found to decline with age in nontransgenic mice as well as in hIAPP transgenic female mice. In contrast, neprilysin mRNA and activity did not decrease in amyloid-prone hIAPP transgenic male mice at 6 months compared with nontransgenic mice and female hIAPP transgenic mice. Islet amyloid was detected in 43% of the 6-month-old hIAPP transgenic male mice only, suggesting the sustained elevation of islet neprilysin in these mice was a compensatory mechanism aimed at preventing amyloid accumulation. In keeping with amyloid formation, the proportion of insulin-positive area to islet area was significantly reduced in 6-month-old hIAPP transgenic male mice, which also displayed mild fasting hyperglycemia compared with age-matched transgenic female and nontransgenic mice. Together, these findings demonstrate that neprilysin is a factor associated with islet amyloid accumulation and subsequent deterioration of beta-cell function in hIAPP transgenic male mice.

Impaired fasting glucose (IFG) is more prevalent in men and impaired glucose tolerance (IGT) more prevalent in women. To explore whether this sex difference is related to female sex hormones, we performed a cross-sectional analysis of data from 2,164 (1,329 women and 835 men) first-degree relatives of individuals with type 2 diabetes. Subjects were categorized based on a 75-g oral glucose tolerance test. Sex and hormone replacement therapy (HRT) effects on the distribution of glucose tolerance were assessed using multinomial logistic regression corrected for familial clustering. Compared with men, women were more likely to have isolated IGT (relative risk 1.8 [95% CI 1.3-2.5]) and less likely to have isolated IFG (0.5 [0.3-0.7]) adjusted for ethnicity, age, waist, fasting insulin, and early insulin release (DeltaI(0-30)/DeltaG(0-30)). To evaluate HRT effects, postmenopausal women using (n = 238) or not using (n = 378) HRT were compared. HRT users were more likely to have isolated IGT (2.2 [1.2-4.0]) after adjustment, but the prevalence of isolated IFG did not differ by HRT status. Based on the influence of sex and HRT on the prevalence of isolated IFG and isolated IGT, we conclude that female sex hormones may play an important role in the pathogenesis of IFG and IGT.