Kaori Yamaji

Prevention and Treatment of Obesity, Insulin Resistance, and Diabetes by Bile Acid–Binding Resin

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.

Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes

OBJECTIVE Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the role of the insulin transactivator MafA in the expression of insulin in the thymus and susceptibility to type 1 diabetes. RESEARCH DESIGN AND METHODS The expression profiles of transcriptional factors (Pdx1, NeuroD, Mafa, and Aire) in pancreatic islets and the thymus were examined in nonobese diabetic (NOD) and control mice. Thymic Ins2 expression and serum autoantibodies were examined in Mafa knockout mice. Luciferase reporter assay was performed for newly identified polymorphisms of mouse Mafa and human MAFA. A case-control study was applied for human MAFA polymorphisms. RESULTS Mafa, Ins2, and Aire expression was detected in the thymus. Mafa expression was lower in NOD thymus than in the control and was correlated with Ins2 expression. Targeted disruption of MafA reduced thymic Ins2 expression and induced autoantibodies against pancreatic islets. Functional polymorphisms of MafA were newly identified in NOD mice and humans, and polymorphisms of human MAFA were associated with susceptibility to type 1 diabetes but not to autoimmune thyroid disease. CONCLUSIONS These data indicate that functional polymorphisms of MafA are associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes in the NOD mouse as well as human type 1 diabetes.

Fatty liver and obesity : phenotypically correlated but genetically distinct traits in a mouse model of type 2 diabetes

Aims/hypothesisObesity and fatty liver are commonly associated with type 2 diabetes, but the genetic and functional bases linking fatty liver with obesity and diabetes are largely unknown. Our aim was to investigate the association of fatty liver with obesity and other diabetes-related phenotypes and to define the genetic control of obesity and fatty liver.Materials and methodsWe established 306 F2 mice by crossing Nagoya–Shibata–Yasuda (NSY) mice, an animal model of type 2 diabetes, with control C3H mice, and analysed their phenotypes. Whole-genome screening of F2 mice was performed to identify the loci responsible for fatty liver and obesity.ResultsA strong association of fatty liver with obesity, hyperinsulinaemia and hyperglycaemia was observed in F2 mice. Using whole-genome screening in 306 F2 mice, we mapped a new locus for fatty liver (Fl1n) on chromosome 6 (maximum logarithm of odds score [MLS] 10.0) and one for body weight (Bw1n) on chromosome 7 (MLS 5.1). Fl1n was linked to epididymal fat weight as well as fatty liver, but its effects were opposite in the two tissues in that the NSY allele increased liver fat but decreased epididymal fat, suggesting a role of Fl1n in partitioning of fat mass. The sequence of peroxisome proliferator-activated receptor γ (Pparg), a candidate for Fl1n, showed allelic variation between NSY and C3H mice.Conclusions/interpretationThese data suggest that fatty liver and obesity are phenotypically related but genetically independent. Loci homologous to Fl1n and Bw1n are good candidate genes for susceptibility to fatty liver and obesity in humans.

Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14

Aims/hypothesisDiabetogenic loci for type 2 diabetes have been mapped to mouse chromosome (Chr) 11 and 14 in the Nagoya–Shibata–Yasuda (NSY) mouse, an animal model of type 2 diabetes. We aimed to obtain direct evidence of these genes on each chromosome and to clarify their function and interaction in conferring susceptibility to type 2 diabetes.MethodsWe established three consomic strains homozygous for diabetogenic NSY-Chr11, NSY-Chr14 or both on the control C3H background (C3H-11NSY, C3H-14NSY and C3H-11NSY14NSY, respectively), and monitored diabetes-related phenotypes longitudinally. The glucokinase gene was sequenced as a positional candidate gene on Chr11.ResultsC3H-11NSY mice showed hyperglycaemia associated with impaired insulin secretion and age-dependent insulin resistance without obesity. C3H-14NSY mice exhibited hyperglycaemia mainly due to insulin resistance, with a slight increase in percentage body fat. C3H-11NSY14NSY double consomic mice showed marked hyperglycaemia and obesity, which was not observed in single consomic strains. Sequences of the glucokinase gene were allelically variant between NSY and C3H mice.Conclusions/interpretationThese 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.

Molecular Scanning of the Gene for Programmed Cell Death-1 (PDCD-1) as a Candidate for Type 1 Diabetes Susceptibility

Abstract:  Multiple genes are involved in the susceptibility to autoimmune type 1 diabetes. The immunoreceptor programmed cell death‐1 (PDCD‐1), an inhibitory costimulatory molecule regulating peripheral tolerance, was reported to play a role in the development of type 1 diabetes, making the human PDCD‐1 gene, PDCD1, as a candidate for disease susceptibility. In this article, we sequenced all 5 exons and exon–intron junctions of PDCD1 in Japanese subjects, and found 10 sequence variants. Preliminary data suggested no association of these polymorphisms with type 1 diabetes. These sequence variants are valuable for further studies to clarify contribution of PDCD1 to susceptibility to type 1 diabetes.

MHC-linked susceptibility to type 1 diabetes in the NOD mouse: further localization of Idd16 by subcongenic analysis.

Abstract:  Although major histocompatibility complex (MHC)‐linked susceptibility is the strongest component, recent studies demonstrated that MHC‐linked susceptibility to type 1 diabetes consists of multiple components both in humans and non‐obese diabetic (NOD) mouse. In the NOD mouse, Idd16 has been mapped to the region adjacent to, but distinct from Idd1 in the MHC class II region. Establishment of subcongenic NOD.CTS‐H2 lines that possess the same MHC class II as the NOD mouse but non‐NOD‐derived chromosomal region in its adjacent regions, would facilitate further narrowing down of the localization of Idd16.

Contribution of class III MHC to susceptibility to type 1 diabetes in the NOD mouse

Abstract:  A recombinant major histocompatibility complex (MHC) with the same class III region as the NOD mouse, but different class II region from the NOD mouse was identified in the NON mouse, and NOD mice congenic for this recombinant MHC, NOD.NON‐H2, was established. None of the congenic mice homozygous for the NON MHC developed type 1 diabetes, indicating that the NOD MHC is necessary for the development of type 1 diabetes. A small portion of MHC heterozygotes developed late‐onset type 1 diabetes, suggesting the contribution of class III MHC to type 1 diabetes susceptibility.