Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.

Islet amyloid polypeptide (IAPP, amylin) is the major protein component of islet amyloid deposits associated with type 2 diabetes. The polypeptide lacks a well–defined structure in its monomeric state, but readily assembles to form amyloid. Amyloid fibrils formed from IAPP, intermediates generated in the assembly of IAPP amyloid, or both are toxic to β-cells suggesting that islet amyloid formation may contribute to the pathology of type 2 diabetes. There are relatively few reported inhibitors of amyloid formation by IAPP. Here we show that the tea–derived flavanol, (−)-Epigallocatechin 3-Gallate, [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate], (EGCG), is an effective inhibitor of in vitro IAPP amyloid formation and disaggregates preformed amyloid fibrils derived from IAPP. The compound is thus one of a very small set of molecules which have been shown to disaggregate IAPP amyloid fibrils. Fluorescence detected thioflavin-T binding assays and transmission electron microscopy confirm that the compound inhibits unseeded amyloid fibril formation as well as disaggregates IAPP amyloid. Seeding studies show that the complex formed by IAPP and EGCG does not seed amyloid formation by IAPP. In this regard, the behavior of IAPP is similar to the reported interactions of Aβ and α–synuclein with EGCG. Alamar blue assays and light microscopy indicate that the compound protects cultured rat INS-1 cells against IAPP–induced toxicity. Thus, EGCG offers an interesting lead structure for further development of inhibitors of IAPP amyloid formation and compounds that disaggregate IAPP amyloid.

Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin (IL)-1b secretion by bone marrow-derived macrophages. We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and b-cell dysfunction. In cultured islets, macrophages (F4/80+ cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1b, tumor necrosis factor-a, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1b synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with b-cell human IAPP (hIAPP) expression had impaired glucose tolerance, elevated islet Il1b mRNA, and decreased Il10 and Il1rn expression following highfat feeding. Islet macrophages were the major source of these transcripts and expressed increased cell surface Ly6C and CD11c in hIAPP transgenic mice. Clodronate liposome-mediated depletion of islet macrophages improved glucose tolerance and blocked proinflammatory gene expression in hIAPPexpressing mice, despite increasing the amount of islet amyloid. These data provide the first evidence that IAPP aggregates skew resident islet macrophages toward a proinflammatory phenotype and suggest a mechanism by which antiinflammatory therapies may protect b-cells from IAPP-induced islet dysfunction.