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

Recent evidence suggests that expression of tumor necrosis factor-alpha (TNF-alpha) by adipocytes is a molecular mediator of insulin resistance in obesity. We have therefore tested the hypothesis that variations within the regulatory region of the TNF-alpha gene, which might cause increased adipocyte or generalized TNF-alpha synthesis, are associated with NIDDM, a state in which insulin resistance is routinely observed. Neither the previously known variants within the TNF-alpha promoter at position -308 and -238, nor two newly identified polymorphisms at position -376 and -163, were found at a significantly higher frequency in Caucasian NIDDM patients compared to non-diabetic controls. No genetic variants were found in Pima Indians. These data make it unlikely that mutations within regulatory elements of the TNF-alpha gene are associated with an increase in the prevalence of NIDDM.
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PMID:Genetic variability in the TNF-alpha promoter is not associated with type II diabetes mellitus (NIDDM). 759 12

Non-insulin-dependent diabetes mellitus (NIDDM) has a high prevalence in Pima Indians. The disorder is familial, but the extent to which genetic factors are involved in its etiology is largely unknown. Segregation analysis was used to determine whether familial aggregation of NIDDM in this population could reflect the action of a single major gene. The analysis included 2,697 subjects from 653 nuclear families in which both parents and at least one offspring had been examined in the course of a longitudinal epidemiological study. The REGTL program of the SAGE package was used to fit models in which age at onset of NIDDM is transmitted from parent to offspring under the unified model for segregation analysis. Likelihood-ratio tests were used to test hypotheses related to genetic transmission. The hypothesis of no major effect was strongly rejected (P < .01), as was that of no transmission of the major effect (P < .01). Mendelian transmission was not rejected (P = .91). Similar results were obtained when covariates for obesity and birth cohort were added to the models and when a power transformation of age at onset was estimated. A strong effect of birth cohort with earlier age at onset in the later born cohorts was observed (P < .01). The findings are consistent with the hypothesis that a major gene influences the risk for NIDDM in Pima Indians by affecting age at onset. The expression of this gene may depend on environmental factors that have become more prevalent in recent-birth cohorts.
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PMID:Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. 761 Dec 84

Because tumor necrosis factor-alpha (TNF-alpha) expression is increased in adipose tissue of both rodent models of obesity and obese humans, it has been considered as a candidate gene for obesity. Pima Indians were scored for genotypes at three polymorphic dinucleotide repeat loci (markers) near the gene TNF-alpha at 6p21.3. In a sib-pair linkage analysis, percent body fat, as measured by hydrostatic weighing, was linked (304 sib-pairs, P = 0.002) to the marker closest (10 kb) to TNF-alpha. The same marker was associated (P = 0.01) by analysis of variance with BMI. To search for possible DNA variants in TNF-alpha that contribute to obesity, single stranded conformational polymorphism analysis was performed from 20 obese and 20 lean subjects. Primer pairs were designed for the entire TNF-alpha protein coding region and part of the promoter. Only a single polymorphism located in the promoter region was detected. No association could be demonstrated between alleles at this polymorphism and percent body fat. We conclude that the linkage of TNF-alpha to obesity might be due to a sequence variant undetected in TNF-alpha or due to a variant in some other closely linked gene.
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PMID:Linkage between obesity and a marker near the tumor necrosis factor-alpha locus in Pima Indians. 761 86

Studies, such as those on Pima Indians, have shown that metabolic factors are involved in the development of obesity and that being overweight is not simply a result of "sloth and gluttony." However, the environment also affects the development of obesity. Among individuals in a given environment, the variability in body size is influenced by genetically determined responses to that environment. People with a low metabolic rate (adjusted for body size and composition) are prone to weight gain, whereas those with a high level of spontaneous physical activity are less likely to become obese. Similarly, individuals with a high 24-hour respiratory quotient (RQ) are more likely to gain weight than those with a low RQ. Insulin sensitivity (not insulin resistance) is another metabolic predictor of obesity. Genetic linkage studies suggest a number of genes are linked to the development of obesity. By sibling-pair linkage analysis, tumor necrosis factor-alpha (TNF-alpha) was found to be linked to the percentage of body fat, and other studies have shown that fat cell production of TNF-alpha is greater in obese individuals.
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PMID:Metabolic differences and the development of obesity. 767 9

Studies have shown that obese patients have a lower tissue response to insulin than lean individuals, suggesting that obesity promotes the development of insulin resistance. The mechanisms linking obesity and insulin resistance are not known. Obese patients have decreased glucose oxidation and increased lipid oxidation compared with lean individuals, and are hyperinsulinemic, which may result in downregulation of insulin receptors. Studies in healthy subjects have shown that increased plasma levels of nonesterified free fatty acids resulted in a decrease in peripheral insulin-induced glucose uptake. Obese patients have increased plasma levels of nonesterified free fatty acids, which may be involved in the development of insulin resistance. Patients with central obesity have a greater degree of peripheral insulin resistance and higher plasma insulin levels than patients with lower body obesity. Patients with non-insulin-dependent diabetes mellitus (NIDDM) who become obese have a further reduction in insulin sensitivity. Studies in Pima Indians have shown that adiposity is the most important predictor for NIDDM in children with at least one parent who have diabetes. Insulin sensitivity improves with weight loss in obese patients.
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PMID:Obesity, insulin resistance, and its link to non-insulin-dependent diabetes mellitus. 767 11

Obesity and family history of diabetes are both risk factors for non-insulin-dependent diabetes mellitus (NIDDM), but it has been proposed that lean individuals with NIDDM have a greater load of diabetes susceptibility genes. If this is the case, one might expect a high prevalence of NIDDM in relatives of diabetic individuals with a low body mass index (BMI). Among Pima Indians participating in an epidemiological study, prevalence of NIDDM was evaluated in relation to BMI of a diabetic parent or to the average parental BMI when both parents had diabetes in 1,535 offspring from 547 families. Prevalence of NIDDM was also evaluated in relation to BMI of a randomly selected index diabetic sibling in 1,722 siblings from 721 families. NIDDM was diagnosed by an oral glucose tolerance test. Compared with offspring of diabetic parent(s) at the 25th percentile of BMI, the odds ratio (OR) for diabetes in offspring of diabetic parents at the 75th percentile was 0.6 (95% confidence interval [CI] 0.5-0.7), adjusted for age, sex, BMI in offspring, number of diabetic parents, and age at onset of diabetes and sex of the diabetic parent(s). In the analysis according to BMI in a diabetic sibling, the corresponding OR was 0.8 (95% CI 0.6-0.9). Risk ratios were only modestly higher when the analysis was restricted to relatives of subjects whose BMI had been determined before the onset of diabetes. NIDDM in the presence of a low BMI is more strongly familial than that at a higher BMI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Familial relationships between obesity and NIDDM. 769 10

A low body temperature is associated with a low metabolic rate for a given body size and body composition. These two traits might have been assets in the history of a population subjected to cycles of feast and famine, but became part of an obesity-prone syndrome in our westernized society characterized by plenty of food and a sedentary lifestyle. We tested whether Pima Indians have lower body temperatures than Caucasians, a trait which might partly explain the high prevalence of obesity in this population. Twenty-five Pima Indian (28 +/- 6 yrs, 87.8 +/- 22.8 kg, 29 +/- 9% body fat) and 25 Caucasian (30 +/- 5 yrs, 80.7 +/- 18.4 kg, 22 +/- 11% body fat) men had body core temperatures measured by telemetry for 24 h while in a respiratory chamber. Mean daily body core temperature was 36.93 +/- 0.12 and 36.90 +/- 0.22 degrees C in Pima Indians and Caucasians, respectively. Since body core temperature during sleep (SLBCT) correlated with percentage body fat, a subset of 10 Pima Indians and 10 Caucasians were pair-matched for body weight and percentage body fat. In this group, SLBCT was lower in Pima Indians than in Caucasians (36.45 +/- 0.10 vs 36.65 +/- 0.27 degrees C; P < 0.01) and, ethnic group accounted for 20% of the variance in SLBCT (P < 0.01). Surprisingly, the lower SLBCT was not associated with a low metabolic rate and therefore does not seem to play a role in the etiology of obesity in Pima Indians.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Racial difference in body core temperature between Pima Indian and Caucasian men. 771 84

A causal role in the pathogenesis of obesity has been proposed for hyperinsulinemia and insulin resistance in populations with a high prevalence of a "thrifty genotype." An alternative hypothesis is that obesity-induced hyperinsulinemia is an adaptation which, by increasing central nervous system insulin signaling (which suppresses food intake), confers resistance to weight gain. To characterize the relationship between the level of insulin secretion and the risk of weight gain, we examined whether any of three different measures of the level of insulin secretion (the area under the plasma insulin curve during both a meal tolerance test and an oral glucose tolerance test, and the acute insulin secretory response to iv glucose) was predictive of weight gain in a prospective study of 97 Pima Indians (64 males and 33 females) with normal glucose tolerance. During a mean (+/- SD) follow-up period of more than 3 yr (males, 3.58 +/- 1.46 yr; females, 3.02 +/- 1.73 yr), average weight increased 2.1 +/- 3.0%/yr in males and 3.5 +/- 3.6%/yr in females, reflecting a mean annual increase in body fat content of 6.9%/yr in both sexes. Insulin secretion was negatively associated with the rate of weight gain, whether assessed by the insulin response during the meal tolerance test (r = -0.35; P < 0.001), the oral glucose tolerance test (r = -0.30; P = 0.004), or the acute insulin secretory response to iv glucose (r = -0.28; P = 0.002). Moreover, the significance of the relationship between each measure of insulin secretion and weight gain persisted after controlling for differences in age, sex, initial body weight, and insulin sensitivity. Relatively reduced insulin secretion, therefore, is a significant and independent predictor of the tendency to gain weight and adiposity in Pima Indians. The presence of relative insulin resistance also conferred an independent reduction in the risk of weight gain in some regression analyses. We conclude that insulin resistance and hyperinsulinemia are unlikely to play a causal role in the development of obesity, and that relatively reduced insulin secretion is a marker of an increased risk of weight gain in this population. These conclusions support the hypothesis that the level of insulin secretion plays an important role in long term body weight regulation.
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PMID:Reduced insulin secretion: an independent predictor of body weight gain. 774 2

Obesity is considered to be one of the major risk factors for developing non-insulin dependent diabetes mellitus (NIDDM). Our cohort study for NIDDM in Aito, Shiga 1980-1990 confirmed that aging, higher body mass index (obesity) and high blood pressure were independent risk factors for developing NIDDM in Japan. In Pima Indians, decreased glucose disposal rate (GDR) is significantly related to percentage of body fat (%fat). Insulin signaling for glycogen synthesis in the skeletal muscles is impaired in the early stages of obesity. Although the molecular mechanism for insulin resistance in obesity is still unknown, hyperinsulinemia induces insulin receptor loss by means of the down regulation mechanism, and prolonged hyperglycemia may induce the impairment of insulin receptor kinase in the skeletal muscles in obese subjects. These dysfunctions in insulin signaling may cause the deterioration of insulin sensitivity, resulting in worsening glycemic control. Thus dysfunction of insulin receptor signaling in skeletal muscles may be a target for preventing diabetes in obese subjects.
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PMID:[Obesity as a risk factor for developing non-insulin dependent diabetes mellitus--obesity and insulin resistance]. 775 Jun 30

Insulin resistance is believed to be a prediabetic condition that results from reduced rates of insulin-mediated glycogen synthesis in skeletal muscle. A decrease in activities of skeletal muscle glycogen synthase and of its regulatory enzyme type-1 protein phosphatase (PP 1) have been previously identified in insulin-resistant Pima Indians. Because the PP1 catalytic beta-subunit is presumed to be the major isoform in the glycogen-bound PP1 complex, we have selected the structural gene for this subunit (PPP1CB) as a candidate for a detailed genetic analysis. We have determined the exon-intron structure of PPP1CB, and have identified a polymorphic (CA)-repeat marker (D2S1237) at this gene. No sequence abnormalities were detected in PPP1CB by Southern blot analysis or by single-stranded conformational polymorphism analysis of all eight coding exons. Using sib-pair linkage analyses, no evidence for linkage was found between the D2S1237 marker at this locus and fasting insulin, insulin-stimulated glucose uptake in vivo, obesity, or non-insulin-dependent diabetes mellitus. Similarly, we have found no evidence for association of D2S1237 with any of these phenotypes. Based on our data we conclude that the structural gene for the PP1 catalytic beta-subunit does not appear to be a major genetic determinant responsible for the PP1 abnormalities characteristic of insulin resistance in Pima Indians.
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PMID:Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin resistance in Pima Indians. 779 87


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