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...

SummaryProgrammed cell death-1 (PD-1) is a co-stimulatory molecule that inhibits T cell proliferation. We aimed to clarify PD-1 expression in CD41 T cells and the association between PD-1 expression and the 7785C/T polymorphism of PDCD1, with a focus on the two subtypes of type 1 diabetes, type 1A diabetes (T1AD) and fulminant type 1 diabetes (FT1D), in the Japanese population. We examined 22 patients with T1AD, 15 with FT1D, 19 with type 2 diabetes (T2D) and 29 healthy control (HC) subjects. Fluorescence-activated cell sorting (FACS) and real-time PCR were utilized to analyse PD-1 expression quantitatively.Genotyping of 7785C/T in PDCD1 was performed using the TaqMan method in a total of 63 subjects (21 with T1AD, 15 with FT1D and 27 HC). FACS revealed a significant reduction in PD-1 expression in CD4 1T cells in patients with T1AD (mean: 4Á2 vs. 6Á0% in FT1D, P 5 0Á0450; vs. 5Á8% in T2D, P = 0Á0098; vs. 6Á0% in HC, P 5 0Á0018). PD-1 mRNA expression in CD4 1 T cells was also significantly lower in patients with T1AD than in the HC subjects. Of the 63 subjects, PD-1 expression was significantly lower in individuals with the 7785C/C genotype than in those with the C/T and T/T genotypes (mean: 4Á1 vs. 5Á9%, P 5 0Á0016). Our results indicate that lower PD-1 expression in CD4 1 T-cells might contribute to the development of T1AD through T cell activation.

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Association studies are a potentially powerful approach to identifying susceptibility variants for common multifactorial diseases such as type 1 diabetes, but the results are not always consistently reproducible. The IDDM5 locus has recently been narrowed to an ϳ200-kb interval on chromosome 6q25 by two independent groups. These studies demonstrated that alleles at markers in the mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2)/ SUMO4 region were associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association of the SUMO4 gene with type 1 diabetes. To clarify the contribution of the M55V polymorphism of the SUMO4 gene to type 1 diabetes susceptibility, 541 type 1 diabetic patients and 768 control subjects were studied in Asian populations. T ype 1 diabetes is a common multifactorial disease caused by the autoimmune destruction of insulin-producing ␤-cells of the pancreas. Previous studies have suggested that Ͼ20 genetic intervals are associated with susceptibility to type 1 diabetes (1,2). Of these, four loci have been identified and replicated as disease susceptibility genes by genetic association studies: the HLA class II genes (IDDM1) (3), INS gene (IDDM2) (4), CTLA4 gene (IDDM12) (5), and PTPN22 gene (6). Recently, the IDDM5 locus has been narrowed down to an ϳ200-kb interval on chromosome 6q25 by two independent groups (7,8). Several single nucleotide polymorphisms (SNPs) that were in linkage disequilibrium in the SUMO4/mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2) region were found to be associated with susceptibility to type 1 diabetes (7,9). The SUMO4 gene, encoding small ubiquitin-like modifier 4, is a posttranslational modifier, which has recently been identified as a novel member of the SUMO family and is suggested to modify immune response through the putative substrate, inhibitor of nuclear factor-B␣, a suppressor of nuclear factor-B (NF-B) (7). SUMO4 is located entirely within the sixth intron of the MAP3K7IP2 gene (Fig. 1), whose product indirectly regulates the activation of NF-B in response to interleukin-1 stimulation (10,11).Among the disease-associated SNPs in the SUMO4/ MAP3K7IP2 gene, a common nonsynonymous SNP (rs237025) encoding a methionine-to-valine substitution at codon 55 (M55V) of SUMO4 was proposed as the causative variant of IDDM5 by two groups but with alleles with opposite risk (7,9). The original report by Guo et al. (7) with subjects from diverse ethnic groups and the subsequent study by Park et al. (12) in Korean subjects showed that possession of the G allele was significantly associated with increased risk for type 1 diabetes, whereas studies in Caucasian subjects of European descent showed no association (13-15) or even an association of the A allele with the disease (9).Of note is the positive association in studies with subjects from Asian populations (7,12) in contrast to the lack of association in subjects of European descent (13,14) and a tendency for an opposite assoc...

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