Butyrate is a short-chain fatty acid produced by the intestinal microbiota through the fermentation of non-absorbable carbohydrates and proteins (e.g. fibers). Sodium butyrate incorporated into the diet displayed a protective action on metabolic, hepatic, pancreatic and intestinal alterations induced by high-fat diet in mice, resulting in significant inhibition of the development of a prediabetic state. Thus, our data suggest that butyrate may have a potential therapeutic use in the treatment of type 2 diabetes and related disorders. AbstractIn this study, we investigated the effect of diet supplementation with sodium butyrate (5% w/w), a short-chain fatty acid produced by the intestinal microbiota, on metabolic parameters, body adiposity, hepatic and pancreatic lipid accumulation, beta cell function/mass as well as on the structure and function of the tight junction-mediated intestinal epithelial barrier in both normal and obese/prediabetic C57 mice fed a regular (control) or high-fat diet for 60 days, respectively. Butyrate treatment significantly inhibited all the high-fat-induced metabolic dysfunctions evaluated, i.e. significantly reduced the weight gain and body adiposity as well as the insulin resistant state, hyperglycemia and hyperinsulinemia, without changing food intake. In addition, high-fat-fed mice treated with this short-chain fatty acid displayed no compensatory hyperplasia of pancreatic beta cells nor marked hepatic steatosis as seen in prediabetic mice after high-fat diet only. Isolated pancreatic islets from high-fat-fed mice treated with butyrate showed improvement of the insulin secretion, which was associated with a significant decrease in lipid accumulation within the pancreas. Butyrate enhanced the intestinal epithelial barrier, as revealed by the FITC-Dextran permeability assay, which was accompanied by a significant increase in the junctional content of the tight junction-associated claudin-1 in intestinal epithelia of jejunum, ileum, and colon of both control and high-fat mice. In conclusion, our results showed that diet supplementation with butyrate inhibits the deleterious effects of high-fat diet intake on metabolic parameters and structure/function of several tissues/ organs associated with type 2 diabetes mellitus in a mouse model, suggesting a potential use of this short-chain fatty acid in the treatment of this endocrine-metabolic disorder.

Gap junctional intercellular communication between ␤-cells is crucial for proper insulin biosynthesis and secretion. The aim of this work was to investigate the expression of connexin (Cx)36 at the protein level as well as the function and structure of gap junctions (GJ) made by this protein in the endocrine pancreas of prediabetic mice. C57BL/6 mice were fed a high-fat (HF) or regular chow diet for 60 days. HF-fed mice became obese and prediabetic, as shown by peripheral insulin resistance, moderate hyperglycemia, hyperinsulinemia, and compensatory increase in endocrine pancreas mass. Compared with control mice, prediabetic animals showed a significant decrease in insulin-secretory response to glucose and displayed a significant reduction in islet Cx36 protein.Ultrastructural analysis further showed that prediabetic mice had GJ plaques about one-half the size of those of the control group. Microinjection of isolated pancreatic islets with ethidium bromide revealed that prediabetic mice featured a ␤-cell-␤-cell coupling 30% lower than that of control animals. We conclude that ␤-cell-␤-cell coupling mediated by Cx36 made-channels is impaired in prediabetic mice, suggesting a role of Cx36-dependent cell-to-cell communication in the pathogenesis of the early ␤-cell dysfunctions that lead to type 2-diabetes.high-fat-fed mice; type 2 diabetes mellitus; connexin 36; connexins; cell-cell communication; insulin secretion; insulin resistance; ␤-cell dysfunction GAP JUNCTION (GJ) CHANNELS provide a pathway for direct exchanges of ions, metabolites, and signaling molecules between adjacent cells. Intercellular communication mediated by these channels, also referred to as cell coupling, plays a crucial role in several cellular and physiological processes, in both developing and adult tissues (7). Thus, GJ coupling has been implicated in the control of cell growth, differentiation and secretion, embryonic development, the propagation and synchronization of neural and cardiac electrical impulses, and many other functions (9,17,24,32). The central role of GJs is further strengthened by increasing evidence linking the etiology of several genetic diseases to mutations or single nucleotide polymorphisms of connexin-coding genes and/or to the dysfunction of connexin-made channels (16,22).Cell-to-cell contacts mediated by GJs are also crucial for proper and fully mature secretory response of the pancreatic ␤-cells (7,10,11,23). Recent data further indicate that GJs may also play a role in controlling the mass of these cells by modulating their growth and their resistance to proapoptotic conditions (20, 21). However, whether GJs participate in the ␤-cell dysfunction, which plays a central role in the pathogenesis of diabetes, is presently supported by only indirect data (7). Thus, the ␤-cells of connexin 36 (Cx36)-null mice are uncoupled and show impaired intercellular synchronization of [Ca 2ϩ ] i transients, increased basal release of insulin, lack of glucose-stimulated insulin release in a normal pulsatile fashion, and a mar...

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