Bile acid-binding resins, such as cholestyramine and colestimide, have been clinically used as cholesterol-lowering agents. These agents bind bile acids in the intestine and reduce enterohepatic circulation of bile acids, leading to accelerated conversion of cholesterol to bile acids. A significant improvement in glycemic control was reported in patients with type 2 diabetes whose hyperlipidemia was treated with bile acid-binding resins. To confirm the effect of such drugs on glucose metabolism and to investigate the underlying mechanisms, an animal model of type 2 diabetes was given a high-fat diet with and without colestimide. Diet-induced obesity and fatty liver were markedly ameliorated by colestimide without decreasing the food intake. Hyperglycemia, insulin resistance, and insulin response to glucose, as well as dyslipidemia, were markedly and significantly ameliorated by the treatment. Gene expression of the liver indicated reduced expression of small heterodimer partner, a pleiotropic regulator of diverse metabolic pathways, as well as genes for both fatty acid synthesis and gluconeogenesis, by treatment with colestimide. This study provides a molecular basis for a link between bile acids and glucose metabolism and suggests the bile acid metabolism pathway as a novel therapeutic target for the treatment of obesity, insulin resistance, and type 2 diabetes. Diabetes 56:239 -247, 2007 T ype 2 diabetes and dyslipidemia are common metabolic disorders, and their worldwide prevalence is facing an acute increase, including a foreseen epidemic in diabetes with the number of diabetic individuals expected to more than double, reaching up to 300 million by 2025 (1). Type 2 diabetes and dyslipidemia are more frequently associated with each other than by chance, pointing to a possible common underlying mechanism(s) in their etiology (2). From the clinical point of view, dyslipidemia in patients with type 2 diabetes has several features: predominance of remnant particles and small dense LDL and elevation of plasma triglycerides, especially in a postprandial state, as well as low HDL cholesterol (3). These are highly atherogenic and, thus, predispose patients with diabetes to atherosclerotic disease, such as coronary artery disease and stroke, which not only accounts for 70% of mortality in patients with diabetes, but also places a social and economical burden in many countries (2-7). Therefore, therapeutic strategies that are beneficial for both conditions are strongly warranted.The liver plays a central role in systemic cholesterol metabolism and glucose homeostasis. Accumulating lines of evidence indicate the possible involvement of cholesterol metabolism in the liver, not only in the systemic lipid profile, but also in glucose homeostasis (8 -12), making hepatocellular cholesterol metabolism a key player in the pathogenesis of both dyslipidemia and hyperglycemia. Bile acids are major cholesterol metabolites that are synthesized in the liver and postprandially released into the small intestine. Most bile acids excret...

These data provide direct evidence that Chr11 and Chr14 harbour major susceptibility genes for type 2 diabetes. These two chromosomes interact to cause more severe hyperglycaemia and obesity, which was not observed with the presence of either single chromosome, indicating different modes of gene-gene interaction depending on the phenotype. Marked changes in the phenotypes retained in the consomic strains will facilitate fine mapping and the identification of the responsible genes and their interaction with each other, other genes and environmental factors.

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The serum level of high-density lipoprotein cholesterol (HDL-c), which protects against the development of atherosclerosis, is under genetic control. However, the genetic components responsible for the serum HDL-c level are yet to be determined. A recent knockout mouse study demonstrated that hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is an essential transcriptional regulator of HDL-c metabolism. In this study, the association of an HNF-1 alpha gene polymorphism, isoleucine (Ile) 27 leucine (Leu), with lipid parameters, in particular with serum HDL-c level, was studied in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the three genotypes, the serum HDL-c level was significantly associated with the genotype (P < 0.01, trend test). Subjects with the Ile/Ile genotype had low serum HDL-c levels, and those with the Leu/Leu genotype had high serum HDL-c levels. These results demonstrate that the HNF-1 alpha gene locus is associated with serum HDL-c level and suggest that the Ile27 allele is a risk marker for atherosclerosis.