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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse agouti coat color gene encodes a novel paracrine signaling molecule whose pulsatile expression produces a characteristic pattern of banded pigment in individual hairs. Several spontaneous agouti alleles produce adult-onset obesity and diabetes, and have provided important single-gene animal models for alterations in energy metabolism. Utilizing linkage groups conserved between mice and humans, we have cloned the human homolog of the mouse agouti gene from a human chromosome 20 yeast artificial chromosome known to contain S-adenosyl homocysteine hydrolase (AHCY). The human agouti gene, named Agouti Signaling Protein (ASP), encodes a 132 amino acid protein, the mRNA for which is expressed in testis, ovary, and heart, and at lower levels in liver, kidney, and foreskin. As predicted by the interactions of mouse agouti with the extension gene (which encodes the melanocyte receptor for alpha-melanocyte stimulating hormone [alpha-MSH]), expression of ASP in transgenic mice produces a yellow coat, and expression of ASP in cell culture blocks the alpha-MSH-stimulated accumulation of cAMP in mouse melanoma cells. The localization of ASP relative to other loci on chromosome 20 excludes it as a candidate for the MODY1 locus, a gene responsible for one form of early-onset non-insulin-dependent diabetes mellitus or maturity-onset diabetes of the young. The expression of ASP in human tissues suggests a function for agouti homologs in species that do not exhibit the characteristic phenotype of banded hairs.
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PMID:Structure and function of ASP, the human homolog of the mouse agouti gene. 775 71

Pancreatic insulin secretion rates can be accurately derived by mathematical deconvolution of peripheral C-peptide concentrations either by using individual C-peptide kinetic parameters obtained by analysis of the decay curve of biosynthetic human C-peptide or by using published group parameters with appropriate adjustments for age and degree of obesity. Since the cross-reactivity of proinsulin and related peptides is low (< 10%) in many C-peptide assays, this experimental approach avoids the spurious increase in insulin immunoreactivity resulting from cross-reactivity with proinsulin and related peptides in the insulin assay. Application of this technique has demonstrated that the phenotypic expression of beta-cell dysfunction differs in subjects with different genetic mechanisms of non-insulin-dependent diabetes mellitus (NIDDM). Subjects who have maturity-onset diabetes of the young (MODY) due to mutations in the glucokinase gene demonstrate different patterns of altered insulin secretion when compared with subjects who have mutations in the MODY1 gene on chromosome 20. Glucokinase mutations affect the ability of the beta-cell to detect and respond to small increases in glucose above the basal level. However, compensatory mechanisms operative in vivo, which include a priming effect of glucose on insulin secretion, limit the severity of the observed insulin secretory defect, resulting in a generally mild clinical course in these subjects. In contrast, mutations in the MODY1 gene are associated with an inability to increase insulin secretion as the plasma glucose concentration increases above 7-8 mmol/l and the normal priming effect of glucose on insulin secretion is lost. These characteristics of the dose-response relationships between glucose and insulin secretion result in a more severe degree of hyperglycemia than observed in subjects with glucokinase mutations, and these subjects more frequently need insulin treatment. These alterations are evident in prediabetic subjects with normal glucose levels who carry the MODY1 mutation, suggesting that defective beta-cell function is the primary pathogenetic defect in the diabetic syndrome in these subjects. Studies performed in the classic form of NIDDM demonstrate that subjects with mild glucose intolerance and normal fasting glucose concentrations and glycosylated hemoglobin levels consistently demonstrate defective beta-cell function. These results are consistent with studies in the Zucker diabetic fatty rat, an animal model of NIDDM in which prediabetic animals demonstrate extensive alterations in expression of multiple genes involved in the regulation of insulin secretion. It thus appears that abnormal beta-cell function is present at a relatively early stage in the evolution of NIDDM, even before the onset of overt hyperglycemia.
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PMID:Lilly Lecture 1994. The beta-cell in diabetes: from molecular genetics to clinical research. 778 37

Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.
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PMID:Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. 1113 33

The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a. Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The A allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects (n = 348), their parents (n = 272), or young nondiabetic adults (n = 925). However, the rare (<1%) AA homozygotes had a raised BMI in each cohort; this was significant when all cohorts were combined (Z score = 0.67 AA vs. -0.05 G/x, P = 0.02). There was no association with corrected birth weight in 382 normal babies, but the only AA baby was 4,069 g. Our study suggests that genetic variation in SHP is unlikely to be common in the predisposition to diabetes, obesity, or increased birth weight in U.K. Caucasians.
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PMID:Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects. 1271 64