Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although they share approximately 88% of their genome with NOD mice including the H2g7 haplotype, NOR mice remain free of T cell-mediated autoimmune diabetes (IDDM), due to non-MHC genes of C57BLKS/J (BKS) origin. NOR IDDM resistance was previously found to be largely controlled by the Idd13 locus within an approximately 24 cM segment on Chromosome 2 encompassing BKS-derived alleles for H3a, B2m, Il1, and Pcna. NOD stocks carrying subcongenic intervals of NOR Chromosome 2 were utilized to more finely map and determine possible functions of Idd13. NOR- derived H3a-Il1 (approximately 6.0 cM) and Il1-Pcna (approximately 1.2 cM) intervals both contribute components of IDDM resistance. Hence, the Idd13 locus is more complex than originally thought, since it consists of at least two genes. B2m variants within the H3a-Il1 interval may represent one of these. Monoclonal Ab binding demonstrated that dimerizing with the beta 2m(a) (NOD type) vs beta 2m(b) isoform (NOR type) alters the structural conformation, but not total expression levels of H2g7 class I molecules (e.g. Kd, Db). Beta 2m-induced alterations in H2g7 class I conformation may partially explain findings from bone marrow chimera analyses that Idd13 modulates IDDM development at the level of non-hematopoietically derived cell types controlling selection of diabetogenic T cells and/or pancreatic beta cells targeted by these effectors. Since trans-interactions between relatively common and functionally normal allelic variants may contribute to IDDM in NOD mice, the search for Idd genes in humans should not be limited to functionally defective variants.
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PMID:Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for beta 2-microglobulin. 957 May 69

Mice from the inbred strain C57BLKS/J (BKS) exhibit increased susceptibility to both diabetes and atherosclerosis compared to C57BL/6J (B6) mice. To determine whether the differences in diabetes and atherosclerosis are related, we carried out a cross between B6-db/db and BKS. We selected 99 female F2-db/db progeny, tested the progeny for plasma lipids, plasma glucose, and fatty-streak lesions, and used quantitative trait loci (QTL) analysis to identify the chromosomal regions associated with these phenotypes. No major QTL were found for total cholesterol, VLDL-cholesterol, or triglycerides. Two suggestive QTL were found for HDL-cholesterol (LOD scores of 2. 7 and 2.8), and two suggestive loci were found for plasma glucose (LOD scores of 2.3 and 2.0). Lesion size was not correlated with plasma lipid levels or glucose. Lesion size was determined by a locus at D12Mit49 with a LOD score of 2.5 and a significant likelihood ratio statistic. The gene for apolipoprotein apoB lies within the region, but apoB levels were similar in strains B6 and BKS. The QTL on Chr 12 was confirmed by constructing a congenic strain with BKS alleles in the QTL region on a B6 genetic background. We conclude that susceptibilities to diabetes and atherosclerosis are not conferred by the same genes in these strains and that a major gene on Chr 12, which we name Ath6, determines the difference in atherosclerosis susceptibility.
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PMID:Quantitative trait loci analysis for the differences in susceptibility to atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J. 1039 18

Protein restriction is used conventionally in the prevention and treatment of diabetic nephropathy. Recently, the use of soy protein instead of animal protein has been postulated as a new preventive and treatment option. The aim of this study was to determine the qualitative and quantitative effects of dietary protein on biomarkers of diabetic nephropathy in a Type 2 diabetes mellitus mouse model (BKS.cg-m +Lepr(db)/+Lepr(db) mice). Diabetic (+Lepr(db)/+Lepr(db)) and control (m+/m+) mice (n = 24/group) consumed one of four different diets ad libitum [20% casein, 20% soy protein, 12% casein or 12% soy protein (energy-based percentages)] from 35 +/- 4 d of age until termination (184-217 d of age). Blood and urine were collected throughout the study to measure biomarkers of diabetes and diabetic nephropathy. Kidney tissue was collected at the end of the study for weight. In diabetic mice, a 20% casein diet increased urinary albumin excretion to macroalbuminuric levels, whereas a 20% soy protein diet led to no major changes in urinary albumin excretion. Low protein diets (12%), independently of protein type, decreased urinary albumin excretion to low microalbuminuric levels. There were no significant differences in plasma glucose concentrations. These findings show lower urinary albumin excretion when a soy protein diet or a low casein diet is fed, suggesting a delay in the progression of diabetic nephropathy.
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PMID:Altering dietary protein type and quantity reduces urinary albumin excretion without affecting plasma glucose concentrations in BKS.cg-m +Lepr db/+Lepr db (db/db) mice. 1261 36

The inbred mouse strain C57BLKS/J (BKS) carrying a mutation of the leptin receptor lepr(-/-) (BKS-db) is a classic mouse model of type 2 diabetes. While BKS was originally presumed to be a substrain of C57BL/6J (B6), it has become apparent that its genome contains introgressed regions from a DBA/2 (DBA)-like strain and perhaps other unidentified sources. It has been hypothesized that the strikingly enhanced diabetes susceptibility of BKS-db compared with B6-db is conferred by this introgressed DNA. Using high-density single nucleotide polymorphisms, we have mapped the DBA and other contaminating DNA regions present in BKS. Thus, approximately 70% of its genome appears to derive from B6, with approximately 20% from DBA and another 9% from an unidentified donor. Comparison with 56 diverse inbred strains suggests that this donor may be a less common inbred strain or an outbred or wild strain. Using expression data from a B6 x DBA cross, we identified differentially regulated genes between these two strains. Those cis-regulated genes located on DBA-like blocks in BKS constitute primary candidates for genes contributing to diabetes susceptibility in the BKS-db strain. To further prioritize these candidates, we identified those cis-acting expression quantitative trait loci whose expression significantly correlates with diabetes-related phenotypes.
Diabetes 2005 Apr
PMID:Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility. 1579 61

To identify new genetic determinants relevant to type 2 diabetes (T2D), diabetic F2 progeny were generated by intercrossing F1 mice obtained from a cross of BKS.Cg-Lepr(db)+/+m and DBA/2, and T2D-related phenotypes were measured. In the F2 population, increased susceptibility to diabetes and obesity was observed. We also detected the major quantitative trait loci (QTL) modifying the severity of diabetes on chromosome 9, where peaks of logarithm of odds (LOD) overlapped for three traits. To identify candidate genes in the QTL intervals, we combined "expression QTL" (eQTL), taking mRNA levels as quantitative traits, and "interstrain sequence variations, including cSNPs." As a result, four genes were identified from cosegregation of clinical QTL with eQTL and 13 genes were found from interstrain cSNPs as candidates in the T2D modifier QTL. Our combined approach shows the acceleration of the discovery of candidate genes in the QTL of interest, spanning several megabases.
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PMID:Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL. 1582 Mar 11

Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used to dissect the genetic complexity influencing the observed phenotypes. The underlying defect in the fat mutant is a Ser202Pro change in carboxypeptidase E (CPE), an enzyme responsible for the final proteolytic processing step of prohormone intermediates. On the HRS/J (HRS) inbred strain background, mice homozygous for the fat mutation exhibit early onset hyperinsulinemia followed by postpubertal moderate obesity without hyperglycemia. In contrast, on the C57BLKS/J (BKS) genetic background, fat/fat mice become severely obese, hyperinsulinemic, and hyperglycemic. Therefore, in the Cpe(fat) genetic model, the fat mutation is necessary but not sufficient for the development of obesity, Type II diabetes, and related metabolic disorders. To dissect the susceptibility loci responsible for modifying obesity- and diabetes-associated traits, we characterized, both genetically and phenotypically, fat/fat male progeny from a large intercross between BKS. HRS-fat/fat and HRS-+/+ mice. Four major loci were mapped, including a locus for body weight (body weight 1) on chromosome 14; a locus for hyperglycemia (fat-induced diabetes 1) on chromosome 19; a locus for hyperglycemia, hyperinsulinemia, and hypercholesterolemia (fat-induced diabetes 2) on chromosome 5; and a locus for adiposity and body weight (fat-induced adiposity 1) on chromosome 11. The identification of these interacting genetic determinants for obesity and Type II diabetes may allow better definition of the obesity/diabetes-related hormone signaling pathways and ultimately may provide new insights into the pathogenesis of these complex diseases.
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PMID:Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia. 1587 Mar 93

Human diabetics frequently suffer delayed wound healing, increased susceptibility to localized and systemic infections, and limb amputations as a consequence of the disease. Lower-limb infections in diabetic patients are most often polymicrobial, involving mixtures of aerobic, facultative anaerobic, and anaerobic bacteria. The purpose of this study is to determine if these organisms contribute to synergy in polymicrobial infections by using diabetic mice as an in vivo model. The model was the obese diabetic mouse strain BKS.Cg-m +/+ Lepr(db)/J, a model of human type 2 diabetes. Young (5- to 6-week-old) prediabetic mice and aged (23- to 24-week-old) diabetic mice were compared. The mice were injected subcutaneously with mixed cultures containing Escherichia coli, Bacteroides fragilis, and Clostridium perfringens. Progression of the infection (usually abscess formation) was monitored by examining mice for bacterial populations and numbers of white blood cells at 1, 8, and 22 days postinfection. Synergy in the mixed infections was defined as a statistically significant increase in the number of bacteria at the site of injection when coinfected with a second bacterium, compared to when the bacterium was inoculated alone. E. coli provided strong synergy to B. fragilis but not to C. perfringens. C. perfringens and B. fragilis provided moderate synergy to each other but only in young mice. B. fragilis was anergistic (antagonistic) to E. coli in coinfections in young mice at 22 days postinfection. When age-matched nondiabetic mice (C57BLKS/J) were used as controls, the diabetic mice exhibited 5 to 35 times the number of CFU as did the nondiabetic mice, indicating that diabetes was a significant factor in the severity of the polymicrobial infections.
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PMID:Synergy in polymicrobial infections in a mouse model of type 2 diabetes. 1611 26

It is unclear whether the increase in availability of substrates for energy production in diabetes can lead to enhanced systolic function early in the disease, before the onset of structural changes to the myocardium. To examine this issue, BKS.Cg-m +/+ Lepr db (db/db) mice with type 2 diabetes and wild type controls had left ventricular pressure-volume relationships determined in situ. We demonstrated that the db/db mice, when compared to their wild type controls, generated greater left ventricular pressure and an enhancement of left ventricular systolic function based on enhanced power/EDV, positive dP/dt, preload recruitable stroke work, dP/dt--EDV relationship, and curvilinear end-systolic elastance. This enhancement in systolic function occurred despite the db/db mice having greater body weight, but similar preload (end-diastolic volume) and afterload (effective arterial elastance). We postulate that the previously described enhancement in renal glomerular filtration rate seen early in type 2 diabetes may be in part due to enhanced left ventricular systolic function early in this disease.
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PMID:Enhanced left ventricular systolic function early in type 2 diabetic mice: clinical implications. 1630 47

Most quantitative trait loci (QTL) studies have focused on detecting the genetic effects of individual QTLs. This study thoroughly dissected the genetic components of type 2 diabetic mice, including a search for epistatic interactions and multi-locus additive effects that result in variation in diabetes-related phenotypes. F2 population was generated from BKS.Cg-Leprdb+/+m and DBA/2 intercross and separated into six subpopulations by sex and the db-dependent diabetes severity. Single-locus and pairwise genome scans first identified the QTLs in these F2 subpopulations, and next covariate-dependent scans confirmed their sex-, db- and sex-by-db-specific effects in the combined populations. Single-locus genome scans detected four QTLs (QBIS1, QBIS2, QBIS3 and QBIS4) that presented their genetic effects beyond sex, but most QTLs showed their effects specifically in limited conditions. This highly conditional feature of the QTLs was accentuated in the pairwise analysis. The pairwise genome scans uncovered a total of 27 significantly interacting or additively acting pairs of loci, showing a better fit to explain the total phenotypic variation of the traits. These significant pairs affected the traits under constantly varying combinations of loci in a time series or in both sexes. In addition, pairwise analysis indicated the appropriate genetic background in constructing congenic strains to obtain the maximum power in the replication of phenotypes. Our study showed high degree of complexity in the genetics of type 2 diabetes in mice, and it suggested that a comprehensive understanding of the multi-locus effects was essential to disentangle the complex genetics of diabetes and obesity in humans.
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PMID:Multidimensional genome scans identify the combinations of genetic loci linked to diabetes-related phenotypes in mice. 1632 90

The C57BLKS/J (BKS) inbred mouse strain is a widely used animal model of type 2 diabetes. In the presence of the diabetes (db) mutation, obese BKS-db mice develop severe diabetes. Genetic studies of diabetes-susceptibility in this strain are facilitated by the fact that BKS is a genetic composite between the diabetes-resistant C57BL/6J (B6) and susceptible DBA/2J (DBA) strains. On this basis, it has been hypothesized that diabetes-susceptibility in BKS is conferred by DBA-derived alleles. However, recent studies revealed non-B6/non-DBA genetic material in BKS. To identify the origin of this genetic component, we generated a genomic map of BKS using 537 microsatellite markers. Our results demonstrate that, in addition to B6 and DBA, BKS contains alleles from at least three other strains, including 129, C57BL/10 and an unidentified mouse strain. We also analyzed two congenic strains, B6-db and BKS-db, which are widely used for the genetic mapping of diabetes-susceptibility loci. We identified several donor-derived genomic regions introduced during the generation of these congenic strains. In summary, our study reveals novel aspects of the genetic fine-structure of BKS and related strains and facilitates the identification of diabetes-susceptibility loci in this mouse model.
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PMID:Genetic analysis of the diabetes-prone C57BLKS/J mouse strain reveals genetic contribution from multiple strains. 1648 Nov 51


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