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.

Plasma HDL cholesterol levels are inversely related to risk for atherosclerosis. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation, the assembly of free cholesterol and phospholipids with apoA-I. ABCA1 is expressed in many tissues; however, the physiological functions of ABCA1 in specific tissues and organs are still elusive. The liver is known to be the major source of plasma HDL, but it is likely that there are other important sites of HDL biogenesis. To assess the contribution of intestinal ABCA1 to plasma HDL levels in vivo, we generated mice that specifically lack ABCA1 in the intestine. Our results indicate that approximately 30% of the steady-state plasma HDL pool is contributed by intestinal ABCA1 in mice. In addition, our data suggest that HDL derived from intestinal ABCA1 is secreted directly into the circulation and that HDL in lymph is predominantly derived from the plasma compartment. These data establish a critical role for intestinal ABCA1 in plasma HDL biogenesis in vivo.Introduction HDL particles mediate the transport of cholesterol from peripheral tissues to the liver in a process termed reverse cholesterol transport (1, 2), which is postulated to explain, at least in part, their ability to protect against foam cell formation and atherosclerosis. Despite the widespread interest in HDL as a potential therapeutic target (3), the origins of plasma HDL are still elusive. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation by promoting the efflux of cholesterol and phospholipids to apoA-I (4, 5). Mutations in ABCA1 cause Tangier disease (6-8), characterized by near absence of HDL cholesterol and increased risk for atherosclerosis (9-11). ABCA1 is widely expressed throughout the body (12, 13); however, the contributions of ABCA1 in specific tissues to HDL levels and reverse cholesterol transport are still being unraveled, and only recently the role of hepatic ABCA1 in homeostasis of HDL levels was elucidated.Overexpression of hepatic ABCA1 raises HDL cholesterol levels (14, 15), and liver-specific deletion of ABCA1 results in a substantial (∼80%) decrease in plasma HDL cholesterol in chow-fed mice (16). Similarly, a 50% knockdown of hepatic ABCA1 expression by adenovirus-mediated RNA interference in mice is associated with a 40% decrease in HDL cholesterol (17). These results indicate that the liver is the single most important source of plasma HDL in vivo but also suggest the existence of additional, extrahepatic sites of HDL biogenesis.The intestine, along with the liver, is an important site for the synthesis and secretion of apoA-I, the principal apoprotein of HDL,

Graphical Abstract Highlights d T lymphocytes release exosomes containing specific microRNAs d T lymphocyte exosomes can transfer microRNAs to rodent and human pancreatic b cells d The transferred microRNAs trigger chemokine expression and apoptosis of b cells d Blockade of microRNAs transferred in b cells decreases diabetes incidence in NOD mice In Brief Guay et al. show that T cells release exosomes containing specific microRNAs that trigger chemokine expression and apoptosis in recipient pancreatic b cells in type 1 diabetes. Inactivation of miR-142-3p/-5p and miR-155 in b cells results in higher insulin levels, lower insulitis scores, and reduced inflammation and protects NOD mice from diabetes development.