Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians

Aims/hypothesis: We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-γ2 (PPAR- γ 2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) diabetes mellitus among Scandinavian Caucasians. Methods: The Pro12Ala polymorphism was examined using PCR-RFLP. Whole-body insulin sensitivity measured under hyperinsulinaemic-euglycaemic conditions was estimated in a population-based sample of 616 glucose tolerant Swedish Caucasian men at age 70. In addition, insulin sensitivity index was measured using IVGTT and Bergman minimal modelling in a population-based sample of 364 young healthy Danish Caucasians. Finally, we evaluated whether the polymorphism predicted Type II diabetes and IGT in 841 seventy-year-old Swedish men. A case-control study was carried out in 654 unrelated Danish Type II diabetic patients and 742 Danish glucose tolerant subjects matched for age and sex. Results: Whole-body insulin sensitivity was significantly improved in carriers compared with non-carriers of the Ala-allele of the codon 12 polymorphism in Swedish Caucasian men (6.0 ± 2.5 vs 5.6 ± 2.5 mg · kg^–1· min^–1· [mU/l]^–1· 100, p = 0.044). The same tendency, but not significant, was observed in the insulin sensitivity index among the group of young healthy Danish Caucasians. The incidence of Type II diabetes and IGT among the Swedish subjects at the age of 70 was similar in the three genotype-groups of the Pro12Ala variant and the Ala-allele was not related to a lower prevalence of Type II diabetes in Danish Caucasians. Conclusion/interpretation: The Ala-allele of the PPAR-γ2 polymorphism is associated with improved whole body insulin sensitivity among Swedish Caucasians. [Diabetologia (2001) 44: 1170–1176] Received: 27 March 2001 and in revised form: 5 June 2001     

Organisation of the coding exons and mutational screening of the uncoupling protein 3 gene in subjects with juvenile-onset obesity

Summary Uncoupling proteins (UCPs) are mitochondrial transporters that uncouple the cellular respiration releasing stored energy as heat. Recently a third member of the UCP family was identified. Human UCP3 is different from UCP1 and UCP2 by its high and preferential expression in skeletal muscle and consequently the UCP3 gene is an attractive candidate gene for obesity. In this study we have determined the intron/exon organization of the coding region of the UCP3 gene and performed single strand conformation polymorphism (SSCP) analysis and direct sequencing of variants of the gene in 60 Caucasian subjects with juvenile-onset obesity. We detected 4 nucleotide substitutions in the intron regions and 2 silent amino acid variants. During the identification of the intron/exon structure of the gene in a normal healthy male subject with a BMI of 23.5 kg/m², a nucleotide substitution replacing a glycine with a serine was identified at codon 84. This variant was neither found among 156 subjects with juvenile-onset obesity nor among 205 control subjects. In a population based sample of 380 young healthy subjects the Gly/Ser84 variant was found in one female subject with a BMI of 25.5 kg/m² and a fat mass of 23.7 kg. We conclude it is unlikely that variants in the coding region of the UCP3 gene contribute to the pathogenesis of juvenile-onset obesity among Danish Caucasians. [Diabetologia (1998) 41: 241–244] Received: 8 October 1997 and in revised form: 30 October 1997     

Studies of the synergistic effect of the Trp/Arg64 polymorphism of the beta3-adrenergic receptor gene and the -3826 A-->G variant of the uncoupling protein-1 gene on features of obesity and insulin resistance in a population-based sample of 379 young Danish subjects

This study examined whether the simultaneous presence of the previously identified Trp/Arg64 polymorphism of the beta3-adrenergic receptor (BAR) gene and the -3826 A-->G nucleotide variant of the uncoupling protein-1 (UCP1) gene are associated with obesity, insulin resistance, or alterations in size at birth in a Danish study population comprising 379 unrelated young Caucasian subjects. All study participants underwent an iv glucose tolerance test with addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the 2 polymorphisms by applying PCR-restriction fragment length polymorphism. The subjects were divided into 4 groups according to their BAR and UCP1 genotype: wild-type carriers (n = 184), only Trp/Arg64 carriers (n = 29), only A-->G UCP1 carriers (n = 146), and carriers of both genetic variants (n = 20). There were no differences across the genotype groups with respect to body mass index, fat mass, waist to hip ratio, birth weight or length, ponderal index, or weight gain during childhood or adolescence, nor was the combined genotype related to alterations in fasting serum levels of lipids, insulin, or C peptide or the insulin sensitivity index. In conclusion, the present study failed to demonstrate an additive or synergistic effect of the Trp/Arg64 variant of the BAR gene and the -3826 A-->G variant of the UCP1 gene on the development of obesity and insulin resistance among randomly recruited Danish Caucasian subjects.     

Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4α in Caucasians with maturity onset NIDDM

Summary Mutations in the hepatocyte nuclear factor-4α (HNF-4α) gene cause the type 1 form of maturity onset diabetes of the young (MODY1). To address the question of whether genetic variability of HNF-4α is associated with late onset non-insulin-dependent diabetes mellitus (NIDDM) we have sequenced the coding region and intron/exon boundaries of the gene in 36 randomly recruited Danish NIDDM patients. Two nucleotide substitutions that changed the sequence of HNF-4α were identified: Thr/Ile130, which has been reported previously and a novel Val/Met255. The Val/Met 255 mutation was found in 4 of 477 Danish NIDDM patients and in none of 217 glucose tolerant control subjects; thus it cannot be excluded that this mutation may have an impact on NIDDM susceptibility. Among 509 NIDDM patients the allelic frequency of the Thr/Ile130 variant was 4.7 % (95 % confidence interval: 3.4–6.0 %) compared to 1.9 % (0.7–3.1 %) among 239 control subjects (p = 0.008). However, in a population sample of 942 Swedish men with an average age of 70 years the allelic frequency of the variant was similar in 246 men with either impaired glucose tolerance (5.6 % [2.6–8.6 %]) or NIDDM (5.4 % [2.7–8.1 %]) as compared to 666 glucose tolerant men (5.1 % [3.9–6.3 %]). Also in a population sample of 369 young healthy Danes the prevalence of the codon 130 variant (4.7 % [3.2–6.2 %]) was similar to what was found in Swedish Caucasians. Thus, the allelic frequency of the Thr/Ile130 variant among the control subjects in the Danish case-control study deviates from the prevalence in the two other studies which is why we consider the significant association between the codon 130 variant and NIDDM an incidental finding. In glucose tolerant subjects the codon 130 variant in its heterozygous form had no major effect on glucose-induced insulin and C-peptide release although a tendency to a lower insulin secretion during an oral glucose tolerance test was seen in middle-aged subjects. In conclusion, variability in the coding region of the HNF-4α gene is not a common cause of NIDDM among whites of Danish ancestry. However, a Val/Met255 mutation was found exclusively in NIDDM patients (0.8 % of cases) and functional as well as family segregation studies are needed to determine whether this HNF-4α variant is a NIDDM causing mutation. [Diabetologia (1997) 40: 980–983] Received: 17 April 1997 and in revised form: 28 May 1997     

UCP2 A55V variant is associated with obesity and related phenotypes in an aboriginal community in Taiwan

OBJECTIVE: Human uncoupling proteins 2 and 3 (UCP2 and UCP3) are two mitochondrial proteins that are involved in the control of metabolism of fatty acid and possibly protect against oxidative damage. The aim of this study was to analyze genetic associations of four polymorphisms of the UCP2 and UCP3 genes with insulin, leptin concentration and obesity in Taiwan aborigines. RESEARCH METHODS: Four polymorphisms were compared in 324 obese (body mass index (BMI) > or =30 kg/m(2)) and overweight (30>BMI > or =25 kg/m(2)) subjects, and 114 normal weight subjects (BMI <25 kg/m(2)) in an aboriginal community of southern Taiwan. Anthropometric characteristics and fasting levels of insulin, leptin, triglycerides and cholesterol were measured. RESULTS: Before and after adjusting for age distribution, only the Val55 allele in exon 4 of the UCP2 gene increased the risk of overweight and obesity (adjusted odds ratio (OR)=2.02, P=0.004) in comparison with Ala55. UCP2 V55V is also associated with higher fasting insulin levels than A55V (P=0.01) and A55A (P=0.04) in the obese/overweight group. Using the COCAPHASE program of the UNPHASED software, haplotype analysis of three single nucleotide polymorphisms (A55V-G866A-C-55T) revealed that A-G-C (73% in obese subjects and 77% in controls) was the most common haplotype and that the haplotype V-A-T (13% in obese subjects and 5% in controls) was significantly increased in obese and overweight subjects (BMI > or =25 kg/m(2)) (OR=2.62, P<0.001). DISCUSSIONS: UCP2 A55V variant might predispose to obesity and Val55 allele to confer population-attributable risk for 9.5% of obese disorders and increase insulin concentrations. The V-A-T haplotype within UCP2-UCP3 gene cluster is also significantly associated with obesity in Paiwan aborigines.     

UKPDS 19: Heterogeneity in NIDDM: separate contributions of IRS-1 and b3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations

Summary Insulin receptor substrate-1 (IRS-1), β3-adrenergic-receptor (β3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. We studied white Caucasian subjects with NIDDM, 227 being randomly selected, 49 NIDDM within the top two percentiles of insulin resistance; 54 with dyslipidaemia in the top quintile of triglyceride/insulin and the bottom quintile of HDL, and 166 non-diabetic control subjects. We examined the association of the simple tandem repeat DNA polymorphisms (STRPs) near the IRS-1 and GS genes, and the prevalence of mutations at codons of IRS-1 513 and 972, β3-AR 64 and GS 464 using restriction fragment length polymorphism (RFLP). The STRP alleles in IRS-1 were significantly different between NIDDM and control subjects (p = 0.015). The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26 % compared with 11 % in control subjects; p < 0.0005). Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. β3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). The GS 464 mutation was not detected in any of the diabetic or control subjects and the population association study using GS STRP showed no difference in allelic frequencies between NIDDM patients and control subjects. A mutation in lipoprotein lipase at codon 291, associated in the general population with low HDL cholesterol, was not at increased prevalence in the NIDDM patients with dyslipidaemia. In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. β3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. These separate contributions to different features of NIDDM are an example of the polygenic inheritance of this heterogeneous disorder. [Diabetologia (1996) 39: 1505–1511] Received: 9 April 1996 and in revised form: 5 August 1996     

Association between senescence-related uncoupling protein 2 gene polymorphisms and abdominal obesity in Japanese subjects: The Tanno and Sobetsu study

Background:   Uncoupling protein 2 ( UCP2 ) plays an important role in regulating body weight, energy expenditure and insulin secretion. UCP2 is upregulated in white fat in response to fat feeding, and negatively controls insulin secretion. UCP2 also has a function that protects cells from apoptosis and oxidative stress, which shows UCP2 might be a senescence-related gene. Previously, UCP2 -866G/A polymorphism in the promoter region has been reported to alter adipose tissue mRNA expression and is associated with obesity in Caucasians.
Methods:   In this study, we investigated the association between this polymorphism and obesity, insulin secretion and hypertension in the general Japanese population.
Results:   The allele frequency of UCP2 -866G/A polymorphism was significantly higher in Japanese subjects compared to Caucasians. It revealed that subjects only in the obese group with the AA type of UCP2 -866G/A polymorphism had significantly higher levels of body mass index (BMI) and waist circumference. Multiple logistic regression analysis showed that this polymorphism was independently associated with waist circumference. This positive association remained in the analysis of the subgroup younger than 65 years, but not in the older group. This polymorphism did not affect levels of insulin and homeostasis model assessment ratio (HOMA-R).
Conclusions:   These results suggest that the AA type of UCP2 -866G/A polymorphism is related to abdominal obesity, which indicates the possible role of this polymorphism in causing metabolic syndromes.     

A common polymorphism of uncoupling protein 2 gene is associated with hypertension

OBJECTIVES: The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. METHODS: A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P<0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. CONCLUSION: These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.     

A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population

Variability of the uncoupling protein 3 (UCP3) promoter has been associated with increased body mass index (BMI) and altered lipid profiles. Here we tested the hypothesis that variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-yr follow-up among Danish subjects. Mutation screening of approximately 1 kb 5' upstream of the UCP3 gene revealed one previously described -55 C-->T variant. The frequency of the polymorphism was evaluated by restriction fragment length polymorphism analysis in four groups of subjects: 1) a group of 744 obese Danish men who at the draft board examinations had a body mass index (BMI) of at least 31 kg/m(2), 2) a randomly selected control group consisting of 857 draftees, 3) 258 middle-aged subjects, and 4) 409 60-yr-old subjects. The frequency of the T allele was 26.0% (95% confidence interval, 23.8-28.2%) among the obese draftees and 26.9% (24.8-29.0%) in the control group (P = 0.6). The variant was not associated with BMI at a young age or with weight gain after a 26-yr follow-up. The frequency of the T allele was 29.5% (25.6-33.4%) in the middle-aged group and 25.8% (22.8-28.8%) among the 60-yr-old subjects. The polymorphism was not associated with increased BMI or percent body fat in these 2 groups. It is concluded that this variant does not play a major role in the development of common obesity among Danish subjects.     

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

Aims/hypothesis Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor α subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes.Subjects and methods The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.Results No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10–1.25], p=1×10⁻⁶). In case–control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m²; odds ratio 1.63 [95% CI 1.09–2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait.Conclusions/interpretation In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.     

Abnormal glucose transport and GLUT1 cell-surface content in fibroblasts and skeletal muscle from NIDDM and obese subjects

Summary Glucose transport and GLUT1 expression were studied in fibroblasts from 7 lean and 5 obese non-insulin-dependent diabetic (NIDDM) subjects with at least 2 NIDDM first-degree relatives and from 12 lean and 5 obese non-diabetic subjects with no family history of diabetes. The obese individuals also had a strong family history of obesity. Fibroblasts from all of the subjects exhibited no difference in insulin receptor binding, autophosphorylation, and kinase and hexokinase activity. At variance, basal 2-deoxyglucose (2-DG) uptake and ³H-cytochalasin B binding were 50 % increased in cells from individuals with NIDDM (p < 0.001) and/or obesity (p < 0.01) as compared to the lean non-diabetic subjects. Insulin-dependent (maximally stimulated – basal) 2-DG uptake and cytochalasin B binding were decreased three-fold in cells from the diabetic and/or obese subjects (p < 0.01). GLUT1 mRNA and total protein levels were comparable in fibroblasts from all the groups. However, basal GLUT1 cell-surface content was 50 % greater in fibroblasts from the NIDDM and/or obese subjects as compared to the lean non- diabetic individuals while insulin-dependent GLUT1 recruitment at the cell surface was diminished threefold. Increased basal GLUT1 content in the plasma membrane was also observed in skeletal muscle of 4 NIDDM and 3 non-diabetic obese individuals (p < 0.05 vs the lean non diabetic subjects). Basal 2-DG uptake in fibroblasts from diabetic/obese individuals and lean control subjects strongly correlated with the in vivo fasting plasma insulin concentration of the donor. A negative correlation was demonstrated between the magnitude of insulin-dependent glucose uptake by the fibroblasts and plasma insulin levels in vivo. We conclude that a primary abnormality in glucose transport and GLUT1 cell-surface content is present in fibroblasts from NIDDM and obese individuals. The abnormal GLUT1 content is also present in skeletal muscle plasma membranes from NIDDM and obese individuals. [Diabetologia (1997) 40: 421–429] Received: 9 August 1996 and in final revised form: 11 December 1996     

Synergistic effect of polymorphisms in uncoupling protein 1 and β3-adrenergic receptor genes on basal metabolic rate in obese Finns

Summary The polymorphisms in the uncoupling protein 1 (UCP1, A to G) and β ₃-adrenergic receptor (β ₃-AR, Trp64Arg) genes have been suggested to be associated with an increased tendency to gain weight. We investigated the frequency of the A to G polymorphism of the UCP1 gene and its effect on basal metabolic rate (BMR) among obese Finns. We also examined the effects of the simultaneous occurrence of the polymorphisms in the UCP1 and β ₃-AR genes on BMR. Altogether 170 obese subjects (29 men, 141 women, BMI 34.7 ± 3.8 kg/m², age 43 ± 8 years, mean ± SD) participated in the study. The A to G substitution of the UCP1 gene was verified by digestion of the PCR product with Bcl I. The frequency of the A to G polymorphism of the UCP1 gene in obese subjects did not differ significantly from the population-based control subjects (5 vs 1 % for homozygotes (GG) and 35 vs 42 % for heterozygotes (AG), p = 0.077, for trend). BMR adjusted for lean body mass, age and sex (adjBMR) was similar among the three UCP1 gene genotypes of obese subjects (AA n = 90, AG n = 72 or GG n = 8). However, the subjects with the polymorphisms in both UCP1 and β ₃-AR genes (n = 18) had a 79 kcal/day (95 % CI 30–128) lower adjBMR than the subjects without these polymorphisms (n = 76) (1551 ± 77 vs 1629 ± 141 kcal/day, p = 0.002). Furthermore, adjBMR was 63 kcal/day (95 % CI 7–118 kcal/day) lower in the subjects with both polymorphisms (n = 18) compared with the subjects (n = 14) who had only the polymorphism in the β ₃-AR gene (1551 ± 77 vs 1613 ± 76 kcal/day, p = 0.028). The A to G polymorphism of the UCP1 gene did not have an independent effect on BMR, but its simultaneous existence with the Trp64Arg polymorphism of the β ₃-AR gene resulted in more lowered BMR than the Trp64Arg polymorphism of β ₃-AR gene alone. [Diabetologia (1998) 41: 357–361] Received: 12 June 1997 and in final revised form: 7 November 1997     

Screening for variants of the uncoupling protein 2 gene in Japanese patients with non-insulin-dependent diabetes mellitus.

We examined genetic mutations in the coding regions of the uncoupling protein 2 (UCP2) gene in 100 patients with non-insulin-dependent diabetes mellitus (NIDDM). The sequences of each exon-intron boundary were detected by polymerase chain reaction (PCR) using specific primer pairs designed in the cDNA sequence of UCP2 and a cycle-sequence method. Using the specific primer pairs in the intron 5'- or 3'-untranslated region, each exon with its exon-intron boundaries was amplified with the PCR method, and the PCR products were analyzed using a single-strand conformation polymorphism (SSCP) method. One nucleotide substitution in exon 4 was found, which exchanged Ala (gcc) at position 55 of the amino acid sequence for Val (gtc), previously reported in Denmark by Urhammer et al in 1997. The polymorphism was reanalyzed in all patients and 120 normal subjects using a PCR-restriction fragment length polymorphism method. There was no difference in the genotype distribution between patients and normal subjects, and our genotype distribution was similar to the Danish study. Furthermore, there were no clinical differences between genotype groups among the patients. No other mutation including the exon-intron boundary was found in these patients. Genetic mutations of UCP2 may not be commonly associated with obesity or diabetes in Japanese subjects.     

Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contributes to human obesity. SUBJECTS: Ninety-one obese children (BMI>4 standard deviations from age related mean) and 419 Caucasian adults from the Isle of Ely Study. DESIGN: Single strand conformation polymorphism (SSCP) analysis was used to scan the coding region of the UCP3 gene in 91 severely obese children. A common polymorphism identified in this gene (c-55t) has been shown to associate with lower UCP3 mRNA expression. Polymerase chain reaction-based forced restriction digestion was used to detect this allele in Caucasian adults. Multiple regression analysis was used to determine associations between the c-55t genotype and anthropometric, energetic and biochemical indices relevant to obesity. MEASUREMENTS: For the obese children, SSCP analysis and sequencing of variants were carried out. For the Isle of Ely Study, c-55t genotype and anthropometric (body mass index, waist-hip ratio, percentage body fat), energetic (dietary fat intake, physical activity index, adjusted metabolic rate, maximum oxygen consumption) and biochemical indices (pre- and post-glucose challenge plasma triglycerides, non-esterified fatty acids, insulin and glucose) were determined. RESULTS: A previously reported missense mutation (V102I) was detected in a single obese Afro-Carribean child. Twenty-one percent of the genes examined in the Isle of Ely study carried the c-55t promoter variant. Age-adjusted body mass index (BMI) was significantly (P=0.0037) lower in carriers of this variant. CONCLUSION: Mutations in the coding sequence of UCP3 are unlikely to be a common monogenic cause of severe human obesity. In a Caucasian population the UCP3 c-55t polymorphism is negatively associated with BMI.     

Association of UCP3 gene -55C>T polymorphism and obesity in a Spanish population

BACKGROUND/AIMS: The uncoupling protein 3 (UCP3) gene has been suggested as a possible determinant affecting obesity risk given its function in the regulation of energy metabolism. However, available genetic association studies have been inconsistent, which could be attributable to not considering individual lifestyle patterns, such as physical activity, a factor that affects UCP3 expression. The objective of this study was to assess the association between the UCP3 -55C>T polymorphism and the risk of obesity. METHODS: Case-control study conducted in a sample of Spanish adults. 157 obese subjects (BMI > or = 30) and 150 controls (BMI < 25) participated in the study. UCP3 -55C>T polymorphism was identified by the polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The odds ratio (OR) for obesity (95% confidence interval [CI]) according to the presence of UCP 3 gene -55C>T polymorphism (heterozygotes and homozygotes merged together), adjusting for age, sex, and recreational physical activity, was 0.61 (0.37-1.00), p = 0.05. Interestingly, this association was only manifest among those with higher recreational physical activity (OR: 0.46, 95% CI 0.21-0.99, p = 0.05) and not among those with lower physical activity (OR: 0.84, 95% CI 0.41-1.70, p = 0.84). CONCLUSION: UCP3 -55C>T polymorphism carriers have apparently a lower risk of obesity when taking into consideration recreational energy expenditure. Interestingly, this inverse beneficial association may only occur in people with a high level of physical activity.     

Plasma leptin levels are related to body composition, sex, insulin levels and the A55V polymorphism of the UCP2 gene

OBJECTIVE: Circulating leptin levels show a high degree of individual variability even after the main effect of body fatness is accounted for. We therefore wanted to determine the roles of variation in body composition, age, sex and polymorphisms of the UCP2 gene and promoter region on levels of circulating leptin. SUBJECTS: One hundred and fifty Caucasian subjects, which represented a cross-section of the population from NE, Scotland, were recruited. MEASUREMENTS: Body composition was measured using dual X-ray absorptiometry. Fasted circulating leptin, insulin, T3 and T4 levels were measured, and all individuals were genotyped for the UCP2 polymorphisms A55V, -866G>A and exon-8 ins/del. RESULTS: The results indicate that circulating leptin was significantly related to sex and principle component (PC) scores representing overall adipose tissue mass and a second representing the contrast of central to peripheral bone mineral content. Residual leptin was associated with the A55V polymorphism (P< 0.001) explaining 11.3% of the residual variance. There was a marginal effect associated with exon-8 ins/del (P=0.045) explaining 4.4% of the residual variance in leptin. Log(e) transformed circulating fasting insulin was related to PC scores representing general adiposity and sex. Residual Log(e) insulin was associated with the A55V and exon-8 ins/del polymorphisms explaining 5.7% (P=0.015) and 5% (P=0.026) of the residual variation, respectively. The -866G>A polymorphism was not significantly associated with residual leptin or insulin. Leptin and insulin were significantly (P=0.007) correlated. Statistically removing the effect of insulin on leptin still showed association between leptin and A55V (P=0.002). Removing the effect of leptin on insulin, the A55V polymorphism was no longer significant (P=0.120). After accounting for the correlation between insulin and leptin, the exon-8 ins/del was no longer significant for residual leptin (P=0.119) or Log(e) insulin (P=0.252). CONCLUSION: These data suggest that the A55V polymorphism directly affected the levels of leptin but not via an effect on insulin.     

Variants of uncoupling protein-2 gene and obesity: interaction with peroxisome proliferator-activated receptorgamma2

OBJECTIVE: To analyse the association of the UCP2 gene, alone or in combination with the PPARgamma2 gene, with obesity. DESIGN: Cross-sectional, case-control study. STUDY POPULATION: From a working population of 4500 Italian Caucasian employees of the Italian telephone company participating in a firm-sponsored health screening programme, we selected all those with obesity [n = 122; body mass index (BMI) > or = 30 kg/m2]. For each case, three nonobese age- and sex-matched individuals were selected as controls from the same population (n = 374). Included in the study were also 76 severely obese (BMI > or = 40 kg/m2) patients consecutively admitted to the obesity clinic of the department. Diabetic individuals were excluded. MEASUREMENTS: The -866G/A UCP2 and the Pro12Ala PPARgamma2 polymorphisms were determined on genomic DNA of the studied individuals. Several metabolic and anthropometric measures were also obtained, like plasma glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol and BMI. RESULTS: BMI, plasma glucose, insulin, triglycerides, total and HDL cholesterol were not significantly different in carriers and noncarriers of the -866G/A variant. No significant association was observed between the -866G/A UCP2 gene polymorphism and moderate or severe obesity. This was also observed when the UCP2 polymorphism was analysed in combination with the PPARgamma2 polymorphisms. CONCLUSIONS: The -866G/A variants of the UCP2 gene are not associated with either obesity or other features of the metabolic syndrome in the studied groups of the Italian population. This negative finding is not modified after a combined analysis of the UCP2 polymorphism and the Pro12Ala polymorphism of PPARgamma2.     

A missense mutation of the muscle glycogen synthase gene (M416V) is associated with insulin resistance in the Japanese population

Summary Muscle glycogen synthase (GYS1) is a key enzyme of non-oxidative pathway of glucose metabolism that has been reported to be related to insulin resistance in non-insulin-dependent diabetic (NIDDM) patients. We scanned the GYS1 gene for mutation by single strand conformational polymorphism in 244 non-obese Japanese NIDDM patients and 181 non-diabetic control subjects, and found two missense mutations; Met to Val at position 416 in the exon 10 (M416V) and Pro to Ala at position 442 in the exon 11 (P442A). The P442A mutation was found in only one NIDDM patient treated with sulfonylureas. On the other hand, the M416V mutation was widely found in the Japanese population. The mutant allele frequency in the NIDDM patients (13.7 %) was slightly higher but not statistically significant compared with that in non-diabetic subjects (9.7 %). However, the insulin sensitivity index [SI: × 10^{− 4}× min^{− 1}× (μU/ml)^{− 1}] estimated by Minimal Model analysis in the NIDDM patients carrying the M416V mutation was significantly lower than that in those without the mutation (1.18 ± 0.27, n = 21 vs 2.20 ± 0.20, n = 60, mean ± SEM, p < 0.01). Glucose effectiveness, age, body mass index, and levels of glycated haemoglobin and serum lipids were not significantly different between the two groups. The same trend could be seen in non-diabetic subjects (SI: 3.70 ± 0.46, 9 subjects with the mutation vs 5.94 ± 0.66, 19 subjects without the mutation, p < 0.05). These findings indicate that the M416V mutation of the GYS1 gene is one of the factors contributing to the insulin resistance in the Japanese population and may play some role in the pathogenesis of NIDDM. [Diabetologia (1997) 40: 947–952] Received: 7 February 1997 and in revised form: 10 April 1997     

Incidence of NIDDM and the effects of gender, obesity and hyperinsulinaemia in Taiwan

Summary Our aim is to determine non-insulin-dependent diabetes mellitus (NIDDM) incidence in Taiwan and examine its relation to obesity and hyperinsulinaemia in Chinese men and women. A total of 995 men and 1195 women aged 35–74 years free from diabetes in two townships in Taiwan were followed up with a second examination. At baseline general and metabolic data were recorded, and detailed anthropometric parameters and plasma glucose and insulin were assessed. World Health Organisation (WHO) criteria of fasting glucose 7.8 mmol/l or greater was utilized for defining diabetes. The age-standardized incidence rate based on the United States population in 1970 was 9.3/1000 (CI 5.8–12.8) in men and 9.3/1000 (CI 6.2–12.4) in women and the based on the WHO population in 1976 was 8.9/1000 (CI .5–12.3) in men and 8.9/1000 (CI 5.9–11.9) in women for the Chinese who had a mean BMI slightly greater than 24 (kg/m²). The predictability of the plasma glucose level was greater than that of the insulin level and the obesity indices. NIDDM incidence increased approximately threefold with each 0.67 mmol/l increase in plasma glucose level in men and women. The present study demonstrated the essential relationship of not only BMI but also central obesity indices (such as subscapular and waist circumference) to the incidence of NIDDM among men and women and a stronger relationship between NIDDM incidence and obesity in women than in men. The predictive effects of obesity indices and fasting plasma insulin values on NIDDM risk were independent of each other in men. Obesity and hyperinsulinaemia each without the presence of the other can lead to an increased risk of NIDDM. In women the NIDDM incidence increased more than additively in those with both obesity and hyperinsulinaemia compared to those with single obesity or hyperinsulinaemia. A slightly higher incidence of NIDDM in Taiwan than in western countries was found. The importance of obesity is indicated for predicting NIDDM in the community. Hyperinsulinaemia was found to play a significant role in predicting NIDDM incidence independent of obesity in men and synergistically with obesity in women. [Diabetologia (1997) 40: 1431–1438] Received: 20 January 1997 and in final revised form: 11 June 1997