Autophagy is an evolutionarily conserved machinery for bulk degradation of cytoplasmic components. Here, we report upregulation of autophagosome formation in pancreatic beta cells in diabetic db/db and in nondiabetic high-fat-fed C57BL/6 mice. Free fatty acids (FFAs), which can cause peripheral insulin resistance associated with diabetes, induced autophagy in beta cells. Genetic ablation of atg7 in beta cells resulted in degeneration of islets and impaired glucose tolerance with reduced insulin secretion. While high-fat diet stimulated beta cell autophagy in control mice, it induced profound deterioration of glucose tolerance in autophagy-deficient mutants, partly because of the lack of compensatory increase in beta cell mass. These findings suggest that basal autophagy is important for maintenance of normal islet architecture and function. The results also identified a unique role for inductive autophagy as an adaptive response of beta cells in the presence of insulin resistance induced by high-fat diet.

OBJECTIVEExogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis.RESEARCH DESIGN AND METHODSAfter continuous infusion of low (300 pmol · kg−1 · day−1) or high (24 nmol · kg−1 · day−1) dose of exendin-4 in C57BL/6 or apolipoprotein E–deficient mice (apoE−/−), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes.RESULTSTreatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE−/− mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-κB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI14-22, a protein kinase A–specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b.CONCLUSIONSOur data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.

Insulin resistance is associated with the circulating free fatty acid (FFA) level and intracellular lipid content in muscle and liver. We investigated the effect of 2-wk diet and exercise therapy on total adiposity, circulating FFA, intracellular lipid content in muscle and liver, and peripheral insulin sensitivity. Type 2 diabetic patients were divided into a diet group (n = 7) and a diet plus exercise group (n = 7). We performed a hyperinsulinemic-euglycemic clamp study before and after treatment. Intramyocellular lipid (IMCL) in the tibialis anterior muscle and intrahepatic lipid (IHL) were evaluated by (1)H-magnetic resonance spectroscopy. Fasting FFA were not altered, and total body fat showed a slight, but significant, decrease in both groups after treatment. IMCL was decreased by 19%, and the glucose infusion rate was increased by 57% in the diet plus exercise group, whereas neither IMCL nor glucose infusion rate was significantly altered in the diet group. However, IHL showed a significant decrease in both groups. In summary, we found that 2 wk of diet and exercise decreased IMCL and increased muscle insulin-mediated glucose uptake, whereas diet with or without exercise decreased IHL. These effects were evident despite a small decrease in body fat and were observed independently of fasting FFA levels.

OBJECTIVEMounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and "live gut bacteria" in the systemic circulation of Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODSUsing a sensitive reverse transcription-quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers. We also analyzed the presence of gut bacteria in blood samples. RESULTSThe counts of the Clostridium coccoides group, Atopobium cluster, and Prevotella (obligate anaerobes) were significantly lower (P < 0.05), while the counts of total Lactobacillus (facultative anaerobes) were significantly higher (P < 0.05) in fecal samples of diabetic patients than in those of control subjects. Especially, the counts of Lactobacillus reuteri and Lactobacillus plantarum subgroups were significantly higher (P < 0.05). Gut bacteria were detected in blood at a significantly higher rate in diabetic patients than in control subjects (28% vs. 4%, P < 0.01), and most of these bacteria were Gram-positive.

A gene for somatostatin, a mammalian peptide (14 amino acid residues) hormone, was synthesized by chemical methods. This gene was fused to the Escherichia coli beta-galactosidase gene on the plasmid pBR322. Transformation of E. coli with the chimeric plasmid DNA led to the synthesis of a polypeptide including the sequence of amino acids corresponding to somatostatin. In vitro, active somatostatin was specifically cleaved from the large chimeric protein by treatment with cyanogen bromide. This represents the first synthesis of a functional polypeptide product from a gene of chemically synthesized origin.