Incidence ratio of procedures.
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Data Collection↗
Biomedical subjects
C Bogardus
Publications and source records attributed to C Bogardus.
The basics of treatment management.
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Humans↗
Linkage between stature and a region on chromosome 20 and analysis of a candidate gene, bone morphogenetic protein 2.
Sib-pair linkage analysis of the quantitative trait, structure, in over 500 Pima Indians indicates that a genetic determinant of governing stature is located on chromosome 20. Analysis of 10 short tandem repeat polymorphisms localized this linkage to a 3.2cM region that includes D20S98 and D20S66. Using all possible sib-pair combinations, linkage was detected to both stature (P = 0.0001) and to leg length (P = 0.001), but not to sitting height. Single-strand conformational polymorphism analysis of exon 3 of the bone morphogenetic protein 2 (BMP2) gene, a candidate gene in this region, in genomic DNA of 20 of the tallest and 20 of the shortest individuals did not show any consistent differences associated with leg length or height. Sequence analysis of the region encoding the mature protein revealed a single nucleotide substitution, a T to G transversion, not detected by single-strand conformational polymorphism (SSCP) analysis. This transversion results in a conservative amino acid substitution of glycine for valine at codon 80 of BMP2. The frequency of this allele was 0.23 in the sample. No significant differences in height were noted in persons carrying either allele. This indicates that this structural alteration is the mature BMP2 protein does not contribute to the differences in stature observed in the Pima Indians, nor is this structural change in the mature protein likely to be responsible for the linkage observed with stature on chromosome 20.
Alleles↗
Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene.
BACKGROUND: The beta 3-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis. METHODS: To investigate whether mutations in the gene for the beta 3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM). RESULTS: A missense mutation was identified in the gene for the beta 3-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (+/- SD) age at the onset of NIDDM was significantly lower (36 +/- 10 years) than in Trp64Arg heterozygotes (40 +/- 10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance). CONCLUSIONS: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.
Adult↗
Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender.
Recent reports suggest that the white blood cell (WBC) count is related to plasma insulin concentrations and insulin resistance in healthy individuals. The present study examines whether these relations are independent of obesity and the pattern of body fat distribution and tests whether race and gender affect these relations. WBC counts, insulin responses to a 75 gram oral glucose tolerance test (OGTT) and glucose disposal during a two-step hyperinsulinemic euglycemic clamp were measured in 300 men and women (149 Pima Indians, 100 whites, and 51 blacks) with a wide range of obesity. WBC counts were lower in blacks than Pima Indians or whites and tended to be higher in women than men. The subgroups were comparable in age and body weight, but percent body fat and plasma insulin concentrations were higher and glucose disposal during the glucose clamp was lower in Pima Indians than in blacks or whites. In the group as a whole, the WBC count correlated with obesity (body mass index and percent body fat), the waist to thigh ratio (an index of the pattern of body fat distribution), and plasma insulin concentrations and was negatively related to age and glucose disposal during the clamp. In multiple regression analyses, only age, race and obesity were significantly associated with the WBC count. When the analyses were restricted to Pima men, in whom correlations between the WBC count and the metabolic variables appeared the strongest, the WBC count remained significantly associated with plasma insulin concentrations, but not glucose disposal, after controlling for age and obesity. The results of this study indicate that age, race, and obesity are significantly associated with the WBC count in healthy individuals. Plasma insulin concentrations, but not insulin resistance per se, may also be weakly associated with the WBC count, but this may be population specific.
Adult↗
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.
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.
Alternative Splicing↗
A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM.
To assess the role of fasting plasma non-esterified fatty acids (NEFA) in the development of non-insulin-dependent diabetes mellitus (NIDDM), data were analysed from annual examinations of 190 non-diabetic Pima Indians. Glucose tolerance was measured by a 75-g oral glucose tolerance test, insulin action by a euglycaemic hyperinsulinaemic (40 mU x m-2 x min-1) clamp and in vitro lipolysis using isolated abdominal fat cells. After a mean follow-up period of 4.0 +/- 2.4 years (mean +/- SD), 47 subjects developed NIDDM. Risk factors for NIDDM were estimated by proportional-hazards analysis and risk ratios (RR) with 95% confidence intervals (95% CI) calculated at the 90th and 10th percentile of the predictor variables. A large average fat-cell volume was predictive of NIDDM (RR=2.4; 95% CI=1.2-4.8) independent of age, sex, percent body and body fat distribution. A high fasting plasma NEFA concentration was also a risk factor for NIDDM (RR=2.3; 95% CI=1.1-4.7) independent of sex, percent body fat, waist/thigh ratio, insulin-mediated glucose uptake and fasting triglyceride concentration. We conclude that large fat cells and the resulting increased plasma NEFA concentrations are risk factors for the development of NIDDM.
Adipocytes↗
An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.
The intestinal fatty acid binding protein locus (FABP2) was investigated as a possible genetic factor in determining insulin action in the Pima Indian population. A polymorphism at codon 54 of FABP2 was identified that results in an alanine-encoding allele (frequency 0.71) and a threonine-encoding allele (frequency 0.29). Pimas who were homozygous or heterozygous for the threonine-encoding allele were found to have a higher mean fasting plasma insulin concentration, a lower mean insulin-stimulated glucose uptake rate, a higher mean insulin response to oral glucose and a mixed meal, and a higher mean fat oxidation rate compared with Pimas who were homozygous for the alanine-encoding allele. Since the FABP2 threonine-encoding allele was found to be associated with insulin resistance and increased fat oxidation in vivo, we further analyzed the FABP2 gene products for potential functional differences. Titration microcalorimetry studies with purified recombinant protein showed that the threonine-containing protein had a twofold greater affinity for long-chain fatty acids than the alanine-containing protein. We conclude that the threonine-containing protein may increase absorption and/or processing of dietary fatty acids by the intestine and thereby increase fat oxidation, which has been shown to reduce insulin action.
Adult↗
Linkage between obesity and a marker near the tumor necrosis factor-alpha locus in Pima Indians.
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.
Adolescent↗
Skeletal muscle membrane lipid composition is related to adiposity and insulin action.
The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= -0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."
Adipose Tissue↗
Reduced insulin secretion: an independent predictor of body weight gain.
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.
Adipose Tissue↗
Lack of IRS-1 codon 513 and 972 polymorphism in Pima Indians.
Insulin receptor substrate-1 (IRS-1), an endogenous substrate for the insulin receptor tyrosine kinase, mediates many or all of the metabolic actions of insulin. Recently, polymorphism at codons 513 and 972 of the IRS-1 gene resulting in 2 amino acid substitutions that were associated with type II diabetes were found in a Caucasian population. Using allele specific oligonucleotide (ASO) hybridization, we screened 242 diabetic and 190 nondiabetic Pima Indians, a population with a very high prevalence of type II diabetes. Neither of the two mutations was present in either diabetic or nondiabetic subjects. We conclude that polymorphism at codons 513 and 972 of the IRS-1 gene observed in certain Caucasian populations is very rare or absent in Pima Indians.
Adult↗
Evidence for linkage between a region on chromosome 1p and the acute insulin response in Pima Indians.
A low acute insulin response (AIR) is a predictor of non-insulin-dependent diabetes mellitus (NIDDM) in insulin-resistant Pima Indians. We have initiated a search for regions of the genome linked with the AIR using sib-pair linkage analysis as a first step in identifying genes that are determinants of this phenotype. Eighteen short tandem-repeat polymorphisms from chromosome 1 were genotyped in over 900 Pima Indians and tested for linkage with NIDDM and in a subset of Pima Indians for linkage with AIR. The anonymous DNA marker D1S198 on chromosome 1p was linked with AIR (P = 0.000056) in 175 sib pairs from 60 families, all with normal glucose tolerance, but no linkage was observed between D1S198 and NIDDM (P = 0.44, 996 sib pairs). Additional markers genotyped on chromosome 1 did not show linkage with AIR or NIDDM. This study indicates that a locus on chromosome 1p may be a determinant of the phenotypic variation seen in the AIR.
Chromosomes, Human, Pair 1↗
Racial difference in body core temperature between Pima Indian and Caucasian men.
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)
Adipose Tissue↗
Agonist: the case for insulin resistance as a necessary and sufficient cause of type II diabetes mellitus.
The results of many cross-sectional studies have indicated that insulin resistance is a consistent, abnormal metabolic characteristic of people with NIDDM. Recently many investigators studying different populations have reported that insulin resistance is a prediabetic abnormality and is a major risk factor for the disease. Although deficient insulin secretion is also characteristic of people with NIDDM, there are no data to indicate that it precedes the onset of the disease, except in rare instances of families with glucokinase mutations. Therefore, in most cases, it appears that deficient insulin secretion occurs secondarily to insulin resistance, and there is experimental evidence indicating the mechanism of this effect. The clearest examples of this pathophysiologic mechanism are persons with insulin receptor mutations and severe insulin resistance in whom NIDDM develops despite normal insulin secretion. In addition, prospective studies have indicated that NIDDM rarely develops in the most insulin-sensitive subjects, and the relatively lower insulin concentrations in patients with a known beta-cell defect--that is a glucokinase mutation--are compatible with normal glucose tolerance if ideal whole body insulin sensitivity is maintained. These data indicate beyond a reasonable doubt that insulin resistance is a sufficient cause of NIDDM and in most instances is necessary for its development.
Diabetes Mellitus, Type 2↗
Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men.
Insulin action and obesity are both correlated with the density of muscle capillary supply in humans. Since the altered muscle anatomy in the obese might affect interstitial insulin concentrations and reduce insulin action, we have cannulated peripheral lymphatic vessels in lean and obese males, and compared peripheral lymph insulin concentrations with whole body glucose uptake during a euglycemic, hyperinsulinemic clamp. Lymph insulin concentrations in the lower limb averaged only 34% of arterial insulin concentrations during 150 min of insulin infusion. Obese subjects had the highest arterial (P < or = 0.0001) and lymph insulin (P < 0.005) concentrations, but the lowest glucose uptake rates (P < 0.002). In contrast to the initial steep rise then plateau of arterial insulins, both lymph insulin and whole body glucose uptake rates rose slowly and did not consistently reach a plateau. In each individual, the glucose uptake closely correlated with peripheral lymphatic insulin concentrations (mean r2 = 0.95). The coupling between glucose uptake and lymph insulin (glucose uptake/pmol insulin) was much steeper in lean subjects than in the obese (P < or = 0.0001). These results indicate that even if insulin diffusion into tissues is rate limiting for insulin action, a tissue defect rather than an insulin diffusion defect causes insulin resistance in obese subjects.
Adult↗
Glycogen synthase: a putative locus for diet-induced hyperglycemia.
Inbred mouse strains fed a diabetogenic diet have different propensities to develop features analogous to type 2 diabetes mellitus. To define chromosomal locations that control these characteristics, recombinant inbred strains from diabetes-prone C57BL/6J (B/6J) and diabetes-resistant A/J strains were studied. Insulin levels and hyperglycemia correlated with two different regions of mouse chromosome 7 (two point LOD scores > 3.0). For insulin levels, 15 of 16 recombinant inbred strains were concordant with a region that contains the tubby mutation that results in hyperinsulinemia. For hyperglycemia, 19 of 23 strains were concordant with the D7Mit25 marker and 20 of 23 strains with the Gpi-1 locus on proximal mouse chromosome 7. Using more stringent criteria for hyperglycemia, 10 of 11 strains characterized as A/J or B/6J like were concordant with D7Mit25. This putative susceptibility locus is consistent with that of the glycogen synthase gene (Gys) recently suggested as a candidate locus by analyses of type 2 diabetes patients. Fractional glycogen synthase activity in isolated muscle was significantly lower in normal B/6J diabetic-prone mice compared with normal diabetic-resistant A/J mice, a finding similar to that reported in relatives of human patients with type 2 diabetes. These data, taken together, raise the possibility that defects in the Gys gene may in part be responsible for the propensity to develop type 2 diabetes.
Animals↗
Muscle sympathetic nerve activity in response to glucose ingestion. Impact of plasma insulin and body fat.
Carbohydrate intake stimulates sympathetic nervous system activity in lean subjects, whereas in obese subjects, the results have been inconsistent. The aim of this study was to directly measure sympathetic neural outflow to skeletal muscle in response to a 75-g oral glucose tolerance test (OGTT) in 15 Pima Indian and 16 Caucasian men, matched for body fat and age, but covering a large range of body weight (57-113 kg) and body fat (4-41%). Fasting muscle sympathetic nerve activity (MSNA) correlated positively with body fat (r = 0.73; P = 0.001) in Caucasians but not in Pima Indians, whereas the increase in MSNA during the OGTT correlated negatively with the percentage of body fat (r = -0.38, P = 0.03) independently of race. In each subject, the increase in MSNA over time correlated positively with the increase in plasma insulin levels, but the slopes of these relationships were inversely related to the percentage of body fat (r = -0.52, P = 0.003) independently of race. In conclusion, obesity is associated with a higher fasting sympathetic neural outflow to muscle but a blunted increase in response to an oral glucose load despite a larger increase in plasma insulin levels. This blunted response may represent another feature of the obesity/insulin resistance syndrome.
Adipose Tissue↗