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A R Shuldiner

Publications and source records attributed to A R Shuldiner.

At least 37 records · Page 2Linked to original sources
PubMed2000

The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes.

OBJECTIVE: Peroxisome-proliferator-activated receptors gamma (PPAR gamma), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR gamma gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPAR gamma2 isoform of the receptor and to be associated with obesity or diabetes-related phenotypes in different populations. SUBJECTS: We studied the occurrence and possible associations of the Pro115Gln and Pro12Ala in the PPAR gamma2 gene with several clinical and metabolic phenotypes in three independent large populations of non-obese non-diabetic, type 2 diabetic, and morbidly obese French Caucasians. RESULTS: The Pro115Gln mutation was not found in any of the 1069 subjects screened including 626 obese patients. The frequency of the Pro12Ala mutation was similar in all groups (0.08, 0.11, 0.09) and was not associated with BMI or any of the clinical parameters tested. CONCLUSIONS: We conclude that the Pro115Gln mutation is not a frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is not associated with clinically significant changes in these populations.

Adult↗
PubMed2000

The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with measures of obesity in Mexican Americans.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-gamma2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P= 0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-gamma, is responsible for this association with measures of obesity in Mexican Americans.

Adult↗
PubMed2000

Analysis of the peroxisome proliferator activated receptor gamma (PPARgamma) gene in HAIRAN syndrome with obesity.

OBJECTIVES: To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor gamma (PPARgamma), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARgamma and the degree of insulin resistance. DESIGN: A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype. PATIENTS: Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non-diabetic non-obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non-diabetic non-obese individuals. MEASUREMENTS: Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARgamma isoforms (PPARgamma1 and PPARgamma2) for single-stranded conformational polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique. RESULTS: A synonymous substitution in codon 477 (CACHis --> CATHis) was found in one patient. A missense mutation in codon 12 of PPARgamma2 (CCAPro --> GCAAla) was found in another patient, but not in any of 25 non-diabetic, non-obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied. CONCLUSIONS: Mutations in the PPARgamma gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.

Acanthosis Nigricans↗
PubMed2000

Insulin response to glucose is lower in individuals homozygous for the Arg 64 variant of the beta-3-adrenergic receptor.

Type 2 diabetes mellitus (type 2 DM) is a polygenic disorder with a variable phenotype that includes both insulin resistance and insulin secretory dysfunction. The Arg 64 beta-3-adrenergic receptor variant allele is associated with an earlier age of onset of type 2 DM. The purpose of this study was to examine the in vivo pathophysiology of this variant allele to determine its contribution to the components of glucose metabolism. We used the frequently sampled iv glucose tolerance tests, minimal model analysis, and analysis of covariance to examine age- and fat-mass-adjusted differences among genotypes. The results demonstrate that individuals homozygous for the Arg 64 allele secrete significantly less insulin in response to a glucose infusion (562+/-116 vs. 962+/-94 pmol/microL), have the highest fasting glucose levels (100.4+/-1.9 vs. 92.48+/-1.60 mg/dL), and have lower glucose effectiveness (0.014+/-0.003 vs. 0.019+/-0.002 min(-1)), compared with those homozygous for the Trp 64 allele. This first report of decreased acute insulin release and lower glucose effectiveness in the Arg 64 genotype may help explain the earlier onset of type 2 DM observed in several populations of individuals with the Arg64 beta-3-adrenergic receptor variant allele.

Adult↗
PubMed2000

Impaired capacity to lose visceral adipose tissue during weight reduction in obese postmenopausal women with the Trp64Arg beta3-adrenoceptor gene variant.

Controversy exists regarding the association between the Trp64Arg variant of the beta3-adrenoceptor gene and visceral obesity. The cross-sectional nature of most studies, the modest effect of the variant, and sex or ethnic differences between groups have contributed to discrepancies among investigations. To overcome these confounding factors, we examined the effect of the Trp64Arg variant on total and visceral adipose tissue loss, insulin sensitivity, and cardiovascular disease risk factors in response to weight reduction in obese older women. A total of 24 women (age 57 +/- 4 years), including 1 Trp64Arg homozygote, 10 Trp64Arg heterozygotes, and 13 normal homozygotes, were admitted to a weight reduction program of 13 +/- 3 months, with weight and nutritional intake stabilization established before testing. Total and regional adiposity were measured with dual-energy X-ray absorptiometry and computed tomography, insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique, and a blood lipid profile was obtained. No baseline differences were noted in adiposity measurements, glucose disposal, and lipid profiles among carriers and noncarriers of the variant allele. In response to weight loss, carriers and noncarriers of the Trp64Arg allele had similar reductions in body weight (-16.4 +/- 5.0 vs. -14.1 +/- 6.2 kg, NS) and body fat (-10.0 +/- 5.2 vs. -11.5 +/- 3.9 kg, NS). However, loss of visceral adipose tissue was 43% lower in carriers of the Trp64Arg allele compared with noncarriers (-46 +/- 27 vs. -81 +/- 51 cm2, P = 0.05). Furthermore, there was less improvement in the total cholesterol-to-HDL cholesterol ratio (-0.18 +/- 0.54 vs. -0.72 +/- 0.56, P = 0.04) in carriers compared with noncarriers of the allele. Although glucose disposal improved in both groups, there was no difference in the magnitude of improvement between carriers and noncarriers of the variant allele. In conclusion, older obese women carrying the Trp64Arg beta3-adrenoceptor gene variant have an impaired capacity to lose visceral adipose tissue in response to prolonged caloric restriction. Despite these genetic differences in loss of intraabdominal adipose tissue, improvement in glucose disposal was similar between groups.

Absorptiometry, Photon↗
PubMed2000

Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). CONCLUSIONS: Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.

Adult↗
PubMed1999

Obesity-related phenotypes and the beta3-adrenoceptor gene variant in postmenopausal women.

We examined the hypothesis that postmenopausal women with the beta3-adrenoceptor gene variant (Trp64Arg) have reduced total daily energy expenditure (TEE), altered free fatty acid kinetics, and increased intra-abdominal fat. A secondary objective was to examine whether the obese state masks the effect of the variant on resting metabolic rate (RMR). There were 23 obese heterozygous women with the genetic variant (age 58 +/- 6 years; BMI 36 +/- 7 kg/m2) who were compared with 19 homozygous obese women with the normal allele (age 56 +/- 4 years; BMI 36 +/- 3 kg/m2). Daily energy expenditure was determined from doubly labeled water and indirect calorimetry, lipolysis from infusion of [1-13C]palmitate, and body fat distribution from computed tomography. No significant differences were found in TEE, RMR, energy expenditure of physical activity, the thermic effect of a meal, fat oxidation as estimated by fasting and postprandial respiratory quotients (RQs), or rate of lipolysis. Similarly, no difference was found in visceral adipose tissue and abdominal subcutaneous fat areas. When RMR was compared between obese (n = 23) and never-obese women with the Trp64Arg variant (n = 16), we found a 317 kcal/day lower RMR in never-obese women after controlling for fat mass, fat-free mass, and age (P < 0.0017). These results do not support the hypothesis that already obese women with the Trp64Arg polymorphism of the beta3-adrenergic receptor gene have lower daily energy expenditure, altered lipolysis, and increased abdominal obesity. On the other hand, the lower RMR in never-obese women suggests that the obese state may mask a moderate effect of the Trp64Arg variant on energy expenditure. Although these results need to be confirmed in other populations, the obese state may have been a confounding factor in previous studies of the beta3-adrenoceptor Trp64Arg variant and energy expenditure.

Arginine↗
PubMed1999

Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study.

We conducted a community-based case-control study of African-American men and women in the Atherosclerosis Risk in Communities Study. The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. In weighted linear regression of all patients and control subjects, the presence of the IRS-1 gene variant was associated with a 0.85 (0.42) kg/m2 higher BMI (P = 0.04). In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI.

Arteriosclerosis↗
PubMed1998

Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor gamma 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men.

To examine the role of the Pro12Ala variant of the human PPARgamma2 gene on adiposity and insulin resistance, we studied the effect of the variant on fat distribution assessed by CT scan, plasma glucose, and insulin levels during a 75g oral glucose load in 215 non-diabetic Japanese men. The allele frequency of the variant was 0. 03 in this population. There were no differences in body mass index (BMI), subcutaneous fat area (S), visceral fat area (V), V/S ratio, fasting plasma insulin levels, or insulin resistance index in homeostatic model assessment between 203 subjects who were homozygous for the wild-type Pro12 allele and 12 subjects with the variant Ala12 allele (11 heterozygotes and one homozygote). These data suggest that the Pro12Ala variant is not a major contributor to adiposity, fat distribution, or insulin resistance in Japanese men.

Adipose Tissue↗
PubMed1998

Genomic characterization of the coding region of the human type II 5'-deiodinase gene.

Type II 5'-Deiodinase (5'DII) is a key element in the maintenance of peripheral thyroid hormone homeostasis through the regulation of local T4 to T3 conversion in pituitary, brain, brown adipose tissue and placenta. The cDNA containing the coding region of the human 5'DII (HDII) has been recently cloned from infant brain. In the present paper we report the genomic structure, chromosomal localization and restriction map of the coding region of HDII. The presence of a single intron located at codon 75 was demonstrated using a PCR-based strategy; the exon-intron junctions were then cloned and partially sequenced. Chromosomal localization was performed by radiation hybrid mapping. This study demonstrated that the entire coding region of the HDII gene is contained in two exons spliced at codon 75 by a 7.4 Kb intron and that the HDII chromosomal location is 14q24.3. These data will allow further studies of the role of HDII in the pathophysiology of thyroid homeostasis.

Base Sequence↗
PubMed1998

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.

Adult↗
PubMed1998

No effect of Trp64Arg beta3-adrenoceptor polymorphism on the plasma leptin concentration in Pima Indians.

In rodents, administration of leptin promotes beta3-adrenergic stimulation of thermogenesis in brown adipose tissue. Conversely, administration of a beta3-adrenoceptor (beta3-AR) agonist decreases leptin mRNA expression and secretion, suggesting that leptin and sympathetic nervous system activity mediated through the beta3-AR comprise a negative-feedback loop. It has recently been proposed that a defect in the beta3-AR in humans may contribute to a resistance to the sympathetically mediated effects of leptin on thermogenesis and lipolysis, thus leading to obesity and type 2 diabetes mellitus. We thus hypothesized that the Trp64Arg variant in the human beta3-AR would be associated with elevated plasma leptin concentrations. We studied 101 healthy nondiabetic Pima Indians: 11 Arg64 homozygotes, 35 Trp64 homozygotes, and 55 heterozygotes. The fasting plasma leptin concentration as an absolute value or after adjustment for percent body fat and sex was not associated with the beta3-AR genotype. Thus, the data do not support an influence of the Trp64Arg variant on the plasma leptin concentration.

Adult↗
PubMed1998

Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians.

The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, and polymorphisms in these genes may contribute to obesity through effects on energy metabolism. DNA sequencing of UCP2 and UCP3 revealed three polymorphisms informative for association studies: an Ala-->Val substitution in exon 4 of UCP2, a 45 bp insertion/deletion in the 3'-untranslated region of exon 8 of UCP2 and a C-->T silent polymorphism in exon 3 of UCP3. Initially, 82 young (mean age = 30 +/- 7 years), unrelated, full-blooded, non-diabetic Pima Indians were typed for these polymorphisms by direct sequencing. The three sites were in linkage disequilibrium ( P < 0.00001). The UCP2 variants were associated with metabolic rate during sleep (exon 4, P = 0.007; exon 8, P = 0.016) and over 24 h (exon 8, P = 0.038). Heterozygotes for UCP2 variants had higher metabolic rates than homozygotes. The UCP3 variant was not significantly associated with metabolic rate or obesity. In a further 790 full-blooded Pima Indians, there was no significant association between the insertion/deletion polymorphism and body mass index (BMI). However, when only individuals >45 years of age were considered, heterozygotes (subjects with the highest sleeping metabolic rate) had the lowest BMI (P = 0.04). The location of the insertion/deletion polymorphism suggested a role in mRNA stability; however, it appeared to have no effect on skeletal muscle UCP2 mRNA levels in a subset of 23 randomly chosen Pima Indians. In conclusion, these results suggest a contribution from UCP2 (or UCP3) to variation in metabolic rate in young Pima Indians which may contribute to overall body fat content later in life.

Adolescent↗
PubMed1998

Trp64Arg variant of the beta3-adrenoceptor and insulin resistance in obese postmenopausal women.

There is controversy regarding the role of the Trp64Arg variant of the beta3-adrenergic receptor (beta3AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 +/- 6 yr old) heterozygous for the beta3AR variant and in 14 women (57 +/- 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in beta3AR heterozygotes (241 +/- 135 mg/min) vs. normal homozygotes (379 +/- 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 +/- 27 mg/min) and normal homozygotes (164 +/- 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 +/- 57 mg/min) and normal homozygotes (56 +/- 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 +/- 111 mg/min) than for normal homozygotes (441 +/- 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp64Arg variant in the beta3AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.

Aged↗
PubMed1997

Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation.

Peroxisome proliferator activated receptor-gamma (PPAR gamma) is a nuclear receptor that regulates adipocyte differentiation, and possibly lipid metabolism and insulin sensitivity. As such, PPAR gamma is a promising candidate gene for several human disorders including obesity and type 2 diabetes mellitus. Screening for mutations in the entire coding region of the PPAR gamma gene (both gamma 1 and gamma 2 isoforms) was performed with DNA of 26 diabetic Caucasians with or without obesity. Two base substitutions were identified: a silent mutation at nucleotide 1431 (CACHis-->CATHis) and a missense mutation (CCGPro-->GCGAla) at codon 12 of PPAR gamma 2. The allele frequency of the Pro12Ala PPAR gamma 2 variant was 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese. We conclude that the Pro12Ala PPAR gamma 2 gene variant is present in diverse populations. Further studies of the Pro12Ala variant will determine its relevance to obesity, insulin resistance, and type 2 diabetes.

Adult↗
PubMed1997

Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene.

We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.

Adipose Tissue↗