Biomedical subjects

C Bogardus

Publications and source records attributed to C Bogardus.

At least 55 records · Page 3Linked to original sources

PubMed2000

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

Fasting hyperinsulinemia is a widely used surrogate measure of insulin resistance and predicts type 2 diabetes in various populations. Whether fasting hyperinsulinemia predicts diabetes independent of insulin resistance is unknown. In 319 Pima Indians with normal glucose tolerance, fasting plasma insulin concentration and insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp) were inversely related, but at any given M, there was substantial variation, with some subjects being hyperinsulinemic and others being hypoinsulinemic relative to their degree of insulin sensitivity. In 262 of the 319 subjects followed prospectively over 6.4 +/- 3.9 years, a high fasting plasma insulin concentration was a significant independent predictor of diabetes, in addition to low M and low acute insulin response (AIR) (intravenous glucose challenge). In 161 of the 319 subjects with follow-up measurements of M and AIR (5.1 +/- 3.9 years), a high relative fasting plasma insulin concentration predicted a decline in AIR but not in M before the onset of diabetes. The adjusted fasting plasma insulin concentration was a familial trait (heritability of 0.52) and in a genome-wide scan, there was suggestive evidence of linkage (logarithm of odds score 1.77) to a region on chromosome 3q, which harbors the gene encoding GLUT2. These results provide the first prospective evidence in humans that fasting hyperinsulinemia itself has a primary role in the pathogenesis of diabetes, independent of insulin resistance. Whether amelioration of basal insulin hypersecretion will prevent diabetes remains to be elucidated.

Adult↗

PubMed2000

Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, -4alpha, -1beta, and -3beta; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of type 2 diabetes characterized by an early age at onset and autosomal dominant inheritance. MODY can result from heterozygous mutations in at least five genes. The purpose of this study was to determine whether alterations in known MODY genes and two MODY candidate genes contribute to the development of early-onset type 2 diabetes in Pima Indians. RESEARCH DESIGN AND METHODS: The coding regions of the known MODY genes hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, HNF-1beta, and insulin promoter factor 1 and the coding regions of two MODY candidate genes, HNF-3beta and the dimerization cofactor of HNF-1, were sequenced in genomic DNA from Pima Indians. The primary "affected" study population consisted of 46 Pima Indians whose age at onset of type 2 diabetes was < or =20 years. DNA sequence variants identified in the affected group were then analyzed in a group of 80 "unaffected" Pima Indians who were at least 40 years old and had normal glucose tolerance. RESULTS: A total of 11 polymorphisms were detected in these genes. However, none of the polymorphisms differed in frequency among Pima Indians with an early age at onset of diabetes compared with older Pima Indians with normal glucose tolerance. CONCLUSIONS: Mutations in these known MODY or MODY candidate genes are not a common cause of early-onset diabetes in Pima Indians.

Adolescent↗

PubMed2000

Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans.

A polymorphism in FABP2 that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. In vitro, the threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala54). We tested whether this polymorphism affected metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indians, half homozygous for the Thr54 form of IFABP and half homozygous for the Ala54 form, were studied. The groups were matched for sex, age, and body mass index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, and insulin responses were measured after a mixed meal (35% of daily energy requirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were approximately 15% higher after the mixed meal and peaked earlier and were approximately 20% higher at 7 h in response to the high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygotes, but glucose and triglyceride responses were not different.The results of this study suggest that the Thr54 form of IFABP is associated with higher and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentrations may contribute to insulin resistance and hyperinsulinemia in individuals with this allele.

Adipose Tissue↗

PubMed1999

Protein targeting to glycogen/PPP1R5: screening of coding and flanking genomic regions for polymorphisms and association analysis with insulin action in Pima Indians.

Insulin resistance, a major predictor of type 2 diabetes mellitus, is genetically inherited in Pima Indians, a population with a high prevalence of the metabolically complex disease. Protein targeting to glycogen/PPP1R5 has recently been identified as a potential regulator of glycogen synthase, the rate-limiting enzyme of the insulin-induced glycogenesis. The gene is located on chromosome 10q23-24, where there is a suggestive linkage to insulin action in this population, establishing it as a functional and positional candidate gene. In this study, we discovered 2 novel polymorphisms upstream of the 5'UTR of the gene, with only one found in Pima Indians, but no polymorphism in the coding sequence. The genotype frequencies of the polymorphism and transcript levels of the gene in skeletal muscle do not correlate with insulin action in the subjects. These results exclude any significant role of protein targeting to glycogen/PPP1R5 in insulin resistance in Pima Indians.

5' Untranslated Regions↗

PubMed1999

Genome-wide scan for CAG/CTG repeat expansions in Pimas with early onset of type 2 diabetes mellitus.

The expansion of polymorphic CAG/CTG repeats in specific genes causes several neurodegenerative disorders and in many instances the length of the disease-causing repeat correlates with the onset age and/or severity of symptoms. Type 2 diabetes mellitus has features in common with diseases resulting from trinucleotide repeat expansion, including a variable age of disease onset and penetrance. We have investigated whether CAG/CTG repeat expansion contributes to the genetic etiology of type 2 diabetes in the Pima Indians, a population with the highest reported prevalence of this disease. Using the Repeat Expansion Detection (RED) method, we determined the size range in nondiabetic Pimas to be between (CAG)20 and (CAG)130 (mean repeat length = 195 bp), which is significantly larger than the mean size reported in Caucasians (150 bp). We compared the distribution of CAG/CTG repeat lengths among 40 Pimas with an early onset of type 2 diabetes (<22 years) and 38 nondiabetic subjects (>55 years). A 240-bp CAG/CTG RED product was found more frequently in early onset diabetics relative to nondiabetic controls (26% vs 11%), whereas a 210-bp band was more prominent in unaffected subjects (29% vs 13%); however, these differences were not statistically significant. In one Pima kindred, we also identified large RED products (>/=360 bp) that displayed intergenerational instability among family members. However, these expansions were not associated with diabetes or any other clinical abnormalities in the carriers. We conclude that this unstable CAG/CTG repeat may represent a novel locus, consisting of large, but apparently nonpathogenic, unstable sequences.

Age of Onset↗

PubMed1999

A type 2 diabetes-associated polymorphic ARE motif affecting expression of PPP1R3 is involved in RNA-protein interactions.

We have previously described a polymorphism in the 3' untranslated region (UTR) of the PPP1R3 gene that encodes the muscle-specific glycogen-targeting regulatory PP1 subunit. This polymorphism alters the distance between two putative mRNA-destabilizing ATTTA (AUUUA) motifs and is distinguished by a 10-nucleotide (allele ARE1) vs a 2-nucleotide interval (allele ARE2). ARE2 is associated with insulin resistance as well as increased prevalence of type 2 diabetes in the Pima Indians, and correlates with reduced expression of this subunit in vivo, causing a 10-fold half-life reduction of reporter mRNA in NIH3T3 cells. Gel shift assays, Northwestern blotting, and RNA-protein UV crosslinking revealed three proteins (43, 80, and 139 kDa) binding to the polymorphic ARE region in these cells. The interactions are sequence specific, and can be suppressed by an unlabeled competitor in a dose-dependent manner. The less stable ARE2 allele shows at least 2-fold higher relative protein binding, indicating that the polymorphic ARE region has a mRNA-destabilizing role. We suggest that the increased protein binding to ARE2 contributes to a faster degradation of PPP1R3 mRNA carrying this allele, and the resulting lower concentration of the protein contributes to insulin resistance, thus increasing the risk for development of type 2 diabetes.

3' Untranslated Regions↗

PubMed1999

Determinants of energy expenditure and fuel utilization in man: effects of body composition, age, sex, ethnicity and glucose tolerance in 916 subjects.

BACKGROUND: 24-h energy expenditure (24-EE) and 24-h respiratory quotient (24-RQ) are important measurements in obesity research, but their accurate assessment is limited to few specialized laboratories. OBJECTIVES: 1) To provide comprehensive prediction equations for 24-EE, sleeping metabolic rate (SMR) and 24-RQ, based on a large number of Caucasian and Pima Indian subjects, covering a wide range of body weight and composition, body fat distribution, and age and 2) to test whether Pima Indians have lower metabolic rate and/or higher 24-RQ than Caucasians. SUBJECTS AND METHODS: 916 non-diabetic subjects, aged 31.5 +/- 11.9 y, body weight 90.5 +/- 26.1 kg (mean +/- s.d.), (561 males, 355 females; 416 Caucasians, 500 Pima Indians; 720 with normal (NGT) and 196 with impaired (IGT) glucose tolerance) spent 24 h in a respiratory chamber for measurements of 24-EE, SMR and 24-RQ. Fat-free mass (FFM) and fat mass (FM) were assessed by either hydrodensitometry or DEXA. Waist circumference and waist-to-thigh ratio (WTR) were determined as measures of body fat distribution. RESULTS: In a stepwise multiple regression analysis, FFM, FM, sex, age, WTR, and ethnicity were significant independent determinants of 24-EE (2258 +/- 422 kcal/d), explaining 85% of its variability (24-EE (kcal/d)=696 + 18.9 FFM (kg) + 10.O FM (kg) + 180 male -1.9 age (y) + 7.1 WTR (per decimal) + 44 Pima Indian). SMR (1623 +/- 315kcal/d) was determined (78% of variability) by FFM, FM, sex, age, WTR, and glucose tolerance (SMR (kcal/d) = 443 +/- 14.6 FFM (kg) + 6.9 FM (kg) + 79 male - 1.0 age (y) + 5.8 WTR (per decimal) + 38 IGT), but not by ethnicity. Adjustment for the respective variables reduced the variance in 24-EE from 422 to 162 kcal/d and in SMR from 315 to 146kcal/d. 24-RQ (0.854 +/- 0.026) was determined by waist circumference and energy balance (24-RQ = 0.88429-0.00175 waist circumference (cm) + 0.00004 energy balance (%)), but not by sex, ethnicity or glucose tolerance. With this equation only 13% of the variability in 24-RQ could be explained (residual variance 0.024). Compared to Caucasians, Pima Indians had higher 24-EE, but similar SMR and 24-RQ. CONCLUSIONS: This analysis provides comprehensive prediction equations for 24-EE, SMR and 24-RQ from their major known determinants. It confirms the previous findings that, even after adjustment for body composition, age, sex, ethnicity, and glucose tolerance, there is still considerable variability in energy expenditure and substrate oxidation that may, in part, be genetically determined. In adult Pima Indians, we found no evidence for lower metabolic rate or impaired fat oxidation that could explain the propensity towards obesity in this ethnic group.

Adipose Tissue↗

PubMed1999

Energy metabolism in African Americans: potential risk factors for obesity.

BACKGROUND: Recent reports have identified a lower resting metabolic rate in African Americans than in whites, but most studies included only females and used short-term measurements with ventilated-hood systems. OBJECTIVE: Our objective was to compare 24-h measurements of energy metabolism between African American and white women and men using a respiratory chamber. DESIGN: Thirty-eight African American (x +/- SD: 32 +/- 7 y of age, 24 +/- 10% body fat) and 288 white (31 +/- 7 y of age, 26 +/- 12% body fat) subjects spent 24 h in a respiratory chamber for measurement of 24-h energy expenditure (24EE), sleeping metabolic rate (SMR), 24-h respiratory quotient (24RQ), and substrate oxidation rates. RESULTS: After adjustment for sex, age, and body composition (by hydrodensitometry), African Americans had lower SMR (-301 +/- 105 kJ/d; P < 0.01) and higher 24RQ (0.014 +/- 0.004; P < 0.001) than whites, whereas 24EE was similar. A sex-specific analysis, using a subset of 38 whites with an equal sex distribution and similar age and body weight, revealed that African American women had lower SMR (-442 +/- 182 kJ/d; P < 0.05) and lower 24EE (-580 +/- 232 kJ/d; P < 0.05), but similar 24RQ values compared with white women. African American men tended to have lower SMRs than white men (-355 +/- 188 kJ/d; P = 0. 07), but had higher 24RQ values, accounting for a 992 +/- 327-kJ/d lower 24-h fat oxidation rate (P < 0.005). CONCLUSIONS: These data not only confirm the findings of a lower metabolic rate in African American than in white women, but also suggest that fat oxidation is lower in African American men than in white men.

Adult↗

PubMed1999

The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.

The pathogenesis of type 2 diabetes involves abnormalities in insulin action, insulin secretion, and endogenous glucose output (EGO). However, the sequence with which these abnormalities develop and their relative contributions to the deterioration in glucose tolerance remain unclear in the absence of a detailed longitudinal study. We measured insulin action, insulin secretion, and EGO longitudinally in 17 Pima Indians, in whom glucose tolerance deteriorated from normal (NGT) to impaired (IGT) to diabetic over 5.1 +/- 1.4 years. Transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response (AIR) to intravenous glucose, but no change in EGO. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and AIR, and an increase in basal EGO. Thirty-one subjects who retained NGT over a similar period also gained weight, but their AIR increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities.

Adult↗

PubMed1999

Skeletal muscle uncoupling protein 3 expression is a determinant of energy expenditure in Pima Indians.

The recent discovery of uncoupling protein (UCP)-2 and UCP-3, and their high expression in skeletal muscle, has renewed interest in a possible role for these proteins in underlying the variability in energy expenditure and therefore metabolic efficiency. Using reverse transcription-polymerase chain reaction, levels of expression of UCP-2 and long and short forms of UCP-3 were measured in skeletal muscle of 19 nondiabetic, male Pima Indians covering a wide range of body weight. Twenty-four-hour energy expenditure was measured in a respiratory chamber in 16 of these individuals. BMI was negatively correlated with the expression levels of the long (r = -0.53, P = 0.025) and short (r = -0.46, P = 0.047) forms of UCP-3. BMI was not correlated with UCP-2 expression. Metabolic rate during sleep, adjusted for fat-free mass and fat mass, was positively correlated with the long form of UCP-3 (r = 0.69, P = 0.006). These results indicate that UCP-3 may be a determinant of energy expenditure and metabolic efficiency in Pima Indians.

Adult↗

PubMed1999

Metabolic characteristics of individuals with impaired fasting glucose and/or impaired glucose tolerance.

With the release of the new 1997 American Diabetes Association diagnostic criteria, a new category was introduced, termed "impaired fasting glucose" (IFG). The metabolic abnormalities of individuals with IFG, compared with those with impaired glucose tolerance (IGT) (World Health Organization criteria), remain to be elucidated. We assessed insulin action (hyperinsulinemic clamp), insulin secretion (25-g intravenous glucose tolerance test), and endogenous glucose output (EGO) (3-(3)H-glucose) in 434 nondiabetic Pima Indians with either normal (NFG; <6.1 mmol/l) or impaired (IFG; 6.1-7.0 mmol/l) fasting glucose and with either normal (NGT; 2-h glucose <7.8 mmol/l) or impaired (IGT; 2-h glucose 7.8-11.1 mmol/l) glucose tolerance: NFG/NGT (n = 307), IFG/NGT (n = 11), NFG/IGT (n = 98), and IFG/IGT (n = 18). Compared with the NFG/NGT group, individuals with IFG/NGT had lower maximal insulin-stimulated glucose disposal (M; -20%, P < 0.01), a lower acute insulin response (AIR) to intravenous glucose (-33%, P < 0.05), and higher EGO (8%, P = 0.055). Individuals with NFG/IGT also had lower M (-21%, P < 0.001) and lower AIR (-8%, P < 0.05), but normal EGO (-1%, NS). Individuals with IFG/IGT showed the most severe abnormalities in M (-27%), AIR (-51%), and EGO (+13%) (all P < 0.001 compared with NFG/NGT). These group differences could be explained by the observation that AIR and EGO, but not M, were more strongly related to the fasting than to the 2-h glucose concentration. Thus, Pima Indians with isolated IFG and isolated IGT show similar impairments in insulin action, but those with isolated IFG have a more pronounced defect in early insulin secretion and, in addition, increased EGO. More severe metabolic abnormalities are present in Pima Indians with combined IFG and IGT.

Adult↗

PubMed1999

Metabolic factors contributing to increased resting metabolic rate and decreased insulin-induced thermogenesis during the development of type 2 diabetes.

Previous studies have indicated that individuals with type 2 diabetes have an increased resting metabolic rate (RMR) but decreased insulin-induced thermogenesis (IIT) compared with those with normal glucose tolerance (NGT). When and by which mechanisms these abnormalities occur during the development of diabetes remain unknown. In 560 Pima Indians, sleeping metabolic rate (respiratory chamber) was higher not only in subjects with diabetes (+4.9%, P < 0.001) but also in those with impaired glucose tolerance (IGT) (+2.7%, P < 0.01) compared with subjects with NGT. Longitudinally, RMR (ventilated hood) increased progressively in 17 subjects in whom glucose tolerance deteriorated from NGT to IGT (+4.2%) to diabetes (+2.6%) over 5.1 +/- 1.4 years (P < 0.05 for trend). In parallel, IIT (% increase in metabolic rate during an insulin/glucose infusion) decreased during the transition from NGT (11.7%) to IGT (7.3%) to diabetes (6.5%) (P < 0.05 for trend). In 151 subjects, basal endogenous glucose output (3-3H-glucose), fasting insulin and free fatty acid concentrations, and glucose disposal (hyperinsulinemic clamp) were significant determinants of RMR, independent of body composition, age, and sex. Nonoxidative and oxidative glucose disposal, RMR, and fasting insulin and glucose concentrations were determinants of IIT. Differences in RMR and IIT between glucose tolerance groups decreased after adjusting for these factors. These findings indicate that increases in RMR and decreases in IIT occur early in the development of type 2 diabetes, and that both changes are related to the progressive metabolic abnormalities that occur during the development of the disease.

Adult↗

PubMed1998

Polymorphism in the 3' untranslated region of MTG8 is associated with obesity in Pima Indian males.

Obesity has a genetic component and predisposes for the development of type 2 diabetes mellitus. One approach to identifying new candidate genes for obesity is to explore potential regulatory factors expressed in fat tissue that may play a role in adipocyte development or metabolic control. Because we found relatively abundant mRNA levels of the putative transcription factor MTG8 in human adipose tissue, a polymorphic microsatellite marker in the 3' untranslated region of this gene was genotyped in 281 Pima Indians, a population with one of the highest reported rates of obesity. We detected a male-specific association with age-adjusted percentage body fat (p = 0.0002), body mass index (p = 0.01), waist circumference (p = 0.008), and thigh circumference (p = 0.02). Comparative analysis of all 13 MTG8 exons in 30 Pimas did not reveal any genetic variants which could explain the association with obesity in males.

Alleles↗

PubMed1998

Postabsorptive respiratory quotient and insulin-stimulated glucose storage rate in nondiabetic pima indians are related To glycogen synthase fractional activity in cultured myoblasts.

A decreased ratio of fat to carbohydrate oxidation rate (an elevated respiratory quotient) predicts the development of obesity. Skeletal muscle accounts for a major fraction of total body lipid oxidation and is the principle site for reduced glucose storage in insulin-resistant subjects. The potentially important role that muscle has in promoting obesity or insulin resistance may be based on metabolic control intrinsic to skeletal muscle. Cultured skeletal muscle provides a system to examine the importance of inherent metabolic traits in muscle biopsies from obese and insulin-resistant subjects. Glycogen synthase fractional activity (GSFA) was measured in cultured myoblasts from 21 Pima Indians characterized in vivo using indirect calorimetry and a euglycemic hyperinsulinemic clamp. Basal GSFA in cultured muscle cells is inversely correlated with postabsorptive respiratory quotient of the muscle donors (r = -0.66, P = 0.001) and with in vivo high dose insulin-stimulated glucose storage rates (r = 0.47, P = 0.04). These results indicate that the postabsorptive respiratory quotients and insulin-mediated glucose storage rates in vivo share a common regulatory mechanism with GSFA in cultured myoblasts. Abnormal regulation of glycogen synthase phosphorylation state may be an intrinsic defect in skeletal muscle associated with obesity and insulin resistance.

Adult↗

PubMed1998

An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians.

Type 2 diabetes mellitus is a common chronic disease that is thought to have a substantial genetic basis. Identification of the genes responsible has been hampered by the complex nature of the syndrome. Abnormalities in insulin secretion and insulin action predict the development of type 2 diabetes and are, themselves, highly heritable traits. Since fewer genes may contribute to these precursors of type 2 diabetes than to the overall syndrome, such genes may be easier to identify. We, therefore, undertook an autosomal genomic scan to identify loci linked to prediabetic traits in Pima Indians, a population with a high prevalence of type 2 diabetes. 363 nondiabetic Pima Indians were genotyped at 516 polymorphic microsatellite markers on all 22 autosomes. Linkage analyses were performed using three methods (single-marker, nonparametric multipoint [MAPMAKER/SIBS], and variance components multipoint). These analyses provided evidence for linkage at several chromosomal regions, including 3q21-24 linked to fasting plasma insulin concentration and in vivo insulin action, 4p15-q12 linked to fasting plasma insulin concentration, 9q21 linked to 2-h insulin concentration during oral glucose tolerance testing, and 22q12-13 linked to fasting plasma glucose concentration. These results suggest loci that may harbor genes contributing to type 2 diabetes in Pima Indians. None of the linkages exceeded a LOD score of 3.6 (a 5% probability of occurring in a genome-wide scan). These findings must, therefore, be considered tentative until extended in this population or replicated in others.

Adult↗

PubMed1998

Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects.

Oxidative metabolism of glucose is regulated by pyruvate dehydrogenase (PDH) that can be inhibited by isoforms of PDH kinase (PDK). Recently, increased PDK activity has been implicated in the pathogenesis of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) in obese subjects. Using quantitative RT-PCR, we measured mRNA of PDK2 and PDK4 isoforms in skeletal muscle biopsies from nondiabetic Pima Indians, a population with a high prevalence of NIDDM associated with obesity. PDK2 and PDK4 mRNAs were positively correlated with fasting plasma insulin concentration, 2-h plasma insulin concentration in response to oral glucose, and percentage body fat, whereas both isoforms were negatively correlated with insulin-mediated glucose uptake rates. Measurements of PDK2 and PDK4 mRNA during the hyperinsulinemic-euglycemic clamp and of PDK2 in cell culture indicated that both transcripts decrease in response to insulin. Increased fatty acid (FA) oxidation has been traditionally viewed as the cause for increased PDK activity contributing to insulin resistance in obese subjects. In contrast, our data indicate that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased FA oxidation.

Adult↗

PubMed1998

Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians.

An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.

Chromosome Mapping↗

PubMed1998

Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians.

Electrophoretic variants of the vitamin D-binding protein (DBP) have been associated with type 2 diabetes as well as with metabolic characteristics that predispose to type 2 diabetes in several populations. The Gc gene that encodes DBP maps to chromosome 4q12, a region that has recently been found to be potentially linked to plasma glucose and insulin concentrations in Pima Indians. Therefore, the gene that encodes DBP was analyzed as a candidate gene for our linkage findings in the Pima Indians. Sequence analysis of the coding exons identified two previously described missense polymorphisms at codons 416 and 420, which are the genetic basis for the three common electrophoretic variants of DBP (Gc1f, Gc1s, and Gc2). These variants in DBP were associated with differences in oral glucose tolerance in nondiabetic Pima Indians.

Adult↗