Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r = -0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.

Aims/hypothesis Islet amyloid in type 2 diabetes contributes to loss of beta cell mass and function. Since islets are susceptible to oxidative stress-induced toxicity, we sought to determine whether islet amyloid formation is associated with induction of oxidative stress. Methods Human islet amyloid polypeptide transgenic and non-transgenic mouse islets were cultured for 48 or 144 h with or without the antioxidant N-acetyl-L-cysteine (NAC) or the amyloid inhibitor Congo Red. Amyloid deposition, reactive oxygen species (ROS) production, beta cell apoptosis, and insulin secretion, content and mRNA were measured.Results After 48 h, amyloid deposition was associated with increased ROS levels and increased beta cell apoptosis, but no change in insulin secretion, content or mRNA levels. Antioxidant treatment prevented the rise in ROS, but did not prevent amyloid formation or beta cell apoptosis. In contrast, inhibition of amyloid formation prevented the induction of oxidative stress and beta cell apoptosis. After 144 h, amyloid deposition was further increased and was associated with increased ROS levels, increased beta cell apoptosis and decreased insulin content. At this time-point, antioxidant treatment and inhibition of amyloid formation were effective in reducing ROS levels, amyloid formation and beta cell apoptosis. Inhibition of amyloid formation also increased insulin content. Conclusions/interpretation Islet amyloid formation induces oxidative stress, which in the short term does not mediate beta cell apoptosis, but in the longer term may feed back to further exacerbate amyloid formation and contribute to beta cell apoptosis.

OBJECTIVE -To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and ␤-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 Ϯ SD age 59.6 Ϯ 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 ϫ S I ) as a measure of ␤-cell function.RESULTS -Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean Ϯ SEM AIR g increased from 224 Ϯ 44 to 286 Ϯ 52 pmol/l (P Ͻ 0.05), and S I improved from 2.8 Ϯ 0.5 to 3.5 Ϯ 0.5 ϫ 10 Ϫ5 ⅐ min Ϫ1 ⅐ pmol Ϫ1 ⅐ l (P Ͻ 0.01), resulting in an increase in the disposition index from 688 Ϯ 180 to 1,164 Ϯ 318 ϫ 10 Ϫ5 /min (P Ͻ 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 Ϯ 15 vs. 191 Ϯ 14 mmol ⅐ l Ϫ1 ⅐ min Ϫ1 ; P ϭ 0.002), but this effect was not sustained after washout.CONCLUSIONS -The DPP-4 inhibitor vildagliptin improves insulin sensitivity and ␤-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have ␤-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects.