ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes in North Indians

Genetic susceptibility may be responsible for high prevalence of type 2 diabetes worldwide. A common missense single nucleotide polymorphism, K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene, has recently been associated with type 2 diabetes in Italian, South Indian, and American populations. The objective of this study was to investigate the possible role of K121Q polymorphism in ENPP1 gene with type 2 diabetes in North Indians. The genotype of the ENPP1/PC-1 K121Q polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism analysis for 328 T2DM patients and 326 non-diabetic participants. Anthropometric and clinical characteristics (Body mass index (BMI), glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), Creatinine, HbA1c, and insulin levels) were measured using standard protocols. Their Chi-square analyses were used to test the significance differences in genotypic and allelic frequencies. Association studies were undertaken using the t test and logistic regression analyses. Our results revealed there was no significant difference in the genotypic distribution between T2DM patients and control subjects. The KK and KQ genotype frequencies were similar in T2DM cases and controls (60.7 and 39.3% in T2DM and 59.8 and 40.2% in controls). No subjects with the QQ genotype were found. Binary logistic regression analysis of data did not show any association of K121Q polymorphism with type 2 diabetes (OR; 0.97, 95% CI; 0.7–1.32, P = 0.82). No significant correlation among the BMI, WHR, BP, TG, TC, HDL-C, LDL-C, Glucose, HbA1c, Creatinine, and insulin indices (HOMA-IR) was observed in the individuals carrying KK and KQ genotypes. In conclusion, our results showed that ENPP1/PC-1 K121Q polymorphism is not associated with type 2 diabetes and related quantitative metabolic traits in North Indian Punjabi population.     

Analysis of Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Gene K121Q Polymorphism Association with Some Risk Factors of Atherosclerosis in Patients with Acute Coronary Syndrome

The present study was performed to investigate whether common single-nucleotide polymorphism K121Q (rs1044498) of the ENPP1 gene is associated with the known risk factors of atherosclerosis (overweight, dyslipoproteinemia, hypertension, diabetes, smoking, and hypercoagulability) in persons with acute coronary syndrome. Venous blood of 118 patients was genotyped for the polymorphism by PCR and restriction fragment length polymorphism method. In patients divided into two subgroups according to their genotype (KK and KQ + QQ), the statistically significant differences were revealed only for plasma LDL-cholesterol level and fibrinolytic activity. The carriers of minor allele (KQ + QQ) had lower LDL-cholesterol concentration and the time of fibrinolysis than the major allele homozygotes (KK). The division of patients into subgroups according to presence or absence of some risk factors for atherosclerosis showed no statistically significant differences between K121Q genotype distributions for any of the comparison.     

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes and related metabolic traits in an Iranian population

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been variably associated with insulin resistance and type 2 diabetes (T2D) in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that the K121Q variant might be associated with T2D and related metabolic traits in this population. The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 normoglycemic controls and 155 T2D patients. T2D patients had significantly higher values for systolic and diastolic blood pressure, BMI, glucose, cholesterol, triglyceride, LDL, apoB, insulin, and HOMA-IR, and lower levels of HDL than the normoglycemic subjects. The frequency of the Q allele did not differ between T2D and normoglycemic subjects (OR 0.96, 95% CI 0.90-2.00, P?=?0.70). The Q allele frequency was 16.5% in T2D and 15.2% in normoglycemic subjects. The ENPP1 genotype (KQ?+?QQ) was not associated with the systolic and diastolic blood pressure, glucose, triglyceride, cholesterol, LDL-C and HDL-C, apo B, BMI, HOMA-IR, and insulin levels in both normoglycemic and T2D groups. Our results suggest that the ENPP1 121Q allele might not be associated with T2D and related metabolic traits among Iranian subjects.     

The K121Q polymorphism of the plasma cell glycoprotein-1 gene is not associated with diabetes mellitus type 2 in German Caucasians.

The K121Q polymorphism of the human plasma cell membrane glycoprotein 1 (PC-1) gene is known to be associated with diabetes mellitus type 2 in some populations studied, with contradictory results. The purpose of the present study was to examine a possible association between the presence of diabetes and the PC-1 K121Q polymorphism in a German Caucasian population. Associations between the polymorphism and various metabolic and anthropometric parameters were also examined. The presence of the K121Q variant was investigated using polymerase chain reaction restriction fragment-length polymorphism in 402 subjects with diabetes (231 men, 171 women, age 63+/-11 yrs, body mass index 28.7+/-5.1 kg/m2) and in 432 age- and sex-matched controls (247 men, 185 women, age 64+/-7 yrs, BMI 26.5+/-3.7 kg/m2). Ninety-seven subjects were carriers of the K121Q polymorphism in the control and 110 in the diabetic group (allelic frequency 11.9% and 14.7%, respectively, P=0.25). The polymorphism had no significant influence on the presence of atherosclerotic disease, body mass index, and blood pressure, both, in diabetics and in non-diabetic controls. Our data suggest that the K121Q polymorphism of the PC-1 gene is not associated with diabetes, obesity, hypertension or atherosclerosis in a German Caucasian population.     

Gender differences in the relationship of ENPP1/PC-1 variants to obesity in a Turkish population

The ectoenzyme ENPP1 (also termed membrane glycoprotein PC-1 or ENPP1/PC-1) is an inhibitor of insulin-induced activation of the insulin receptor. There is evidence from previous studies that coding variants of ENPP1/PC-1 (K121Q) are associated with type 2 diabetes (T2D) and obesity. Studies in the general Turkish population have demonstrated: unique plasma lipid characteristics, a high prevalence of cardiovascular risk factors, and an increased prevalence of obesity and T2D. We investigated, therefore, the association of ENPP1/PC-1 variants with obesity and T2D in Turkish individuals. The TaqMan allelic discrimination assay was used for genotyping the relationship of ENPP1/PC-1 variants to obesity and T2D in a genetic association study of 1,553 genotyped, randomly selected subjects from the Turkish Heart Study. The K121Q (rs1044498) variant and other previously reported variants (rs997509, rs1799774, rs1044548, rs11964389, rs7754561) were analyzed. In this cohort, the minor allele frequency (MAF) of the K121Q variant was associated with obesity in male, but not in female subjects (male, odds ratio 1.64, 95% confidence interval 1.004-2.698, P = 0.048; female, odds ratio 1.003, 95% confidence interval 0.684-1.471, P = ns). In addition, the previously reported ENPP1/PC-1 "risk haplotype" (Q (rs1044498), delT (rs1799774), and G (rs7754561) alleles) was found to be associated with obesity in male, but not in female, subjects (P = 0.035). In contrast, there was no association of either the K121Q variant or the ENPP1/PC-1 haplotype with T2D. We find evidence that variants of ENPP1/PC-1 are associated with obesity in the male Turkish population; thus, these variants may contribute to the development of the obesity in these individuals.     

The Q121 variant of ENPP1 may protect from childhood overweight/obesity in the Italian population

Ectonucleotide Pyrophosphatase Phosphodiesterase 1 (ENPP1) downregulates insulin signaling by inhibiting the insulin receptor's tyrosine-kinase. K121Q and other ENPP1 single-nucleotide polymorphisms (SNPs), IVS20delT-11 and A/G+1044TGA, have been previously associated with obesity in French children, and the risk haplotype QdelTG has also been associated with this condition in both French and German children. Our aim was to perform a case-control replication study in order to assess the possible association of childhood obesity and overweight with the above-mentioned ENPP1 SNPs, and with the QdelTG haplotype, in the Italian population. A total of 865 healthy Italian children were studied: 453 normal-weight, 243 overweight and 169 obese subjects. Genotyping was performed by Taq-Man or Light-Cycler Technology. The Q variant of K121Q showed a negative association with overweight-obesity under both additive (odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.57-0.97, P = 0.030) and recessive (OR = 0.32, 95% CI = 0.10-0.97, P = 0.035) modes of inheritance. The Z-score of BMI showed a significant decreasing trend from children K/K homozygous to K/Q heterozygous, and to Q/Q homozygous (0.45 vs. 0.28 vs. -0.19; P = 0.009), according to the additive model. The two other SNPs and the QdelTG haplotype did not exhibit any association with overweight/obesity. This is the first child-based study showing a protective role of the 121Q variant of ENPP1 against overweight/obesity.     

中国汉族人群ENPP1基因K121Q多态与2型糖尿病的关联及Meta分析

多个欧洲白人的Meta分析表明核苷酸焦磷酸酶1(Ectonucleotide pyrophosphatase/phosphodiesterase 1, ENPP1)基因K121Q多态与2型糖尿病相关联, 但在日本人、韩国人和中国台湾人的研究中没有发现相关性, 而在中国大陆人群中二者的关联研究结果不尽一致。文章调查了湖北地区539例2型糖尿病患者和404名正常人ENPP1基因K121Q多态性。基因型及等位基因频率在病例组和对照组间没有显著差异(P＞0.05), 但经性别、年龄和体重指数调整后的Logistic回归分析揭示XQ基因型与2型糖尿病显著相关(OR=1.5, 95%CI: 1.39~1.62, P<0.001)。对性别进行的亚组分析显示, 女性病例组Q等位基因和XQ基因型的频率显著高于对照组(Q: 12.4% vs. 6.1%, P=0.001; XQ: 23.7% vs. 11.7%, P=0.001)。结果表明ENPP1基因K121Q多态与湖北汉族人2型糖尿病的关联存在性别差异, 在女性中更明显。文章是对中国大陆人群进行的第一个Meta分析, 结果显示Q等位基因增加2型糖尿病的发病风险(OR=1.42, P=0.042)。     

Association between the ENPP1 K121Q Polymorphism and Risk of Diabetic Kidney Disease: A Systematic Review and Meta-Analysis

The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I^² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.     

ENPP1 affects insulin action and secretion: evidences from in vitro studies

The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities.     

Further evidence for the role of ENPP1 in obesity: association with morbid obesity in Finns

The aim of this study was to investigate a series of single-nucleotide polymorphisms (SNPs) in the genes MC2R, MC3R, MC4R, MC5R, POMC, and ENPP1 for association with obesity. Twenty-five SNPs (2-7 SNPs/gene) were genotyped in 246 Finns with extreme obesity (BMI > or = 40 kg/m2) and in 481 lean subjects (BMI 20-25 kg/m2). Of the obese subjects, 23% had concomitant type 2 diabetes. SNPs and SNP haplotypes were tested for association with obesity and type 2 diabetes. Allele frequencies differed between obese and lean subjects for two SNPs in the ENPP1 gene, rs1800949 (P = 0.006) and rs943003 (P = 0.0009). These SNPs are part of a haplotype (rs1800949 C-rs943003 A), which was observed more frequently in lean subjects compared to obese subjects (P = 0.0007). Weaker associations were detected between the SNPs rs1541276 in the MC5R, rs1926065 in the MC3R genes and obesity (P = 0.04 and P = 0.03, respectively), and between SNPs rs2236700 in the MC5R, rs2118404 in the POMC, rs943003 in the ENPP1 genes and type 2 diabetes (P = 0.03, P = 0.02 and P = 0.02, respectively); these associations did not, however, remain significant after correction for multiple testing. In conclusion, a previously unexplored ENPP1 haplotype composed of SNPs rs1800949 and rs943003 showed suggestive evidence for association with adult-onset morbid obesity in Finns. In this study, we did not find association between the frequently studied ENPP1 K121Q variant, nor SNPs in the MCR or POMC genes and obesity or type 2 diabetes.     

K121Q PC‐1 Gene Polymorphism Is Not Associated with Insulin Resistance in a Spanish Population

Objective : To investigate the effect of the K121Q plasma cell membrane glycoprotein (PC‐1) polymorphism on the components of the insulin resistance syndrome in a population‐based nationwide multicenter study in Spain. Research Methods and Procedures : The subjects of the study were 293 nonrelated adults (44.7% men and 55.3% women) ages 35 to 64 years randomly chosen from a nationwide population‐based survey on obesity and related conditions, including insulin resistance and cardiovascular risk factors. Obesity‐related anthropometric measurements included blood pressure, oral glucose tolerance test, lipid profile (total cholesterol, high‐density lipoprotein‐ and low‐density lipoprotein‐cholesterol, and triglycerides), plasma leptin, insulin levels by radioimmunoassay, and insulin resistance (homeostasis model assessment). K121Q PC‐1 genotypes were determined by restriction fragment‐length polymorphism‐polymerase chain reaction. Results : Overall Q allele frequency was 0.14, with no differences between obese and nonobese individuals (0.15 vs. 0.13). After adjustment for sex, age, BMI, and degree of glucose tolerance, the Q allele was associated with high plasma leptin and triglyceride levels, but not with insulin resistance. Discussion : The results showed that the K121Q PC‐1 polymorphism in the Spanish population has no significant impact on insulin sensitivity.     

Amerindians show no association of PC-1 gene Gln121 allele and obesity: a thrifty gene population genetics

PC-1 Gln121 gene is a risk factor for type 2 diabetes, obesity and insulin resistance in European/American Caucasoids and Orientals. We have aimed to correlate for the first time this gene in Amerindians with obesity and their corresponding individuals genotypes with obesity in order to establish preventive medicine programs for this population and also studying the evolution of gene frequencies in world populations. Central obesity was diagnosed by waist circumference perimeter and food intake independent HDL-cholesterol plasma levels were measured. HLA genes were determined in order to more objectively ascertain participants Amerindians origin. 321 Amerindian blood donors who were healthy according to the blood doning parameters were studied. No association was found between PC-1 Gln121 variant and obesity. Significant HDL-cholesterol lower values were found in the PC-1 Lys121 bearing gene individuals versus PC-1 Gln121 bearing gene ones (45.1 ± 12.7 vs. 48.7 ± 15.2 mg/dl, p < 0.05). Population analyses showed a world geographical gradient in the PC-1 Gln121 allele frequency: around 9% in Orientals, 15% in European Caucasoids and 76% in Negroids. The conclusions are: (1) No association of PC-1 Gln121 gene is found with obesity in Amerindians when association is well established in Europeans. (2) PC-1 Gln121 gene is associated to higher levels of HDL-cholesterol than the alternative PC-1 Lys121 allele. This may be specific for Amerindians. (3) Amerindians have an intermediate frequency of this possible PC-1 Gln121 thrifty gene when compared with Negroid African Americans (78.5%) or Han Chinese (7.5%, p < 0.0001). Historical details of African and other groups may support the hypothesis that PC-1 Gln121 is indeed a thrifty gene.     

Effect of a conjugated linoleic acid and omega-3 fatty acid mixture on body composition and adiponectin

This study aimed to determine the effect of supplementation with conjugated linoleic acids (CLAs) plus n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) on body composition, adiposity, and hormone levels in young and older, lean and obese men. Young (31.4+/-3.9 years) lean (BMI, 23.6+/-1.5 kg/m2; n=13) and obese (BMI, 32.4+/-1.9 kg/m2; n=12) and older (56.5+/-4.6 years) lean (BMI, 23.6+/-1.5 kg/m2; n=20) and obese (BMI, 32.0+/-1.6 kg/m2; n=14) men participated in a double-blind placebo-controlled, randomized crossover study. Subjects received either 6 g/day control fat or 3 g/day CLA (50:50 cis-9, trans-11:trans-10, cis-12) and 3 g/day n-3 LC-PUFA for 12 weeks with a 12-week wash-out period between crossovers. Body composition was assessed by dual-energy X-ray absorptiometry. Fasting adiponectin, leptin, glucose, and insulin concentrations were measured and insulin resistance estimated by homeostasis model assessment for insulin resistance (HOMA-IR). In the younger obese subjects, CLA plus n-3 LC-PUFA supplementation compared with control fat did not result in increased abdominal fat and raised both fat-free mass (2.4%) and adiponectin levels (12%). CLA plus n-3 LC-PUFA showed no significant effects on HOMA-IR in any group but did increase fasting glucose in older obese subjects. In summary, supplementation with CLA plus n-3 LC-PUFA prevents increased abdominal fat mass and raises fat-free mass and adiponectin levels in younger obese individuals without deleteriously affecting insulin sensitivity, whereas these parameters in young and older lean and older obese individuals were unaffected, apart from increased fasting glucose in older obese men.     

Increases in weight and body size increase the odds for hypertension during 7 years of follow-up

Changes in BMI and body size were compared to incident hypertension in 24,550 men and 10,111 women followed prospectively as part of the National Runners' Health Study to test whether long-term weight change affects hypertension risk. Incident hypertensions were reported by 2,143 men and 430 women during (mean +/- s.d.) 7.8 +/- 1.8 and 7.5 +/- 2.0 years of follow-up, respectively. Despite being active, men's and women's BMI increased 1.15 +/- 1.70 and 0.95 +/- 1.89 kg/m(2), respectively, and their waist circumferences increased 2.97 +/- 5.02 and 3.29 +/- 6.67 cm, respectively. Compared to those whose BMI declined, those who gained >or=2.4 kg/m(2) had an odds ratio (95% confidence interval) of 1.68 (1.45, 1.94) for becoming hypertensive if male and 1.42 (1.05, 1.92) if female. Men whose waist circumference increased >or=6 cm had an odds ratio of 1.22 (1.01, 1.47) for becoming hypertensive compared to those whose waists decreased. In both sexes, the odds for hypertension were significantly related to BMI at follow-up when adjusted for baseline BMI, but generally not to baseline BMI when adjusted for follow-up BMI. In the subset whose weights remained relatively unchanged during follow-up (+/-0.4 kg/m(2)), each kg/m(2) increment in BMI was associated with an odds ratio for becoming hypertensive of 1.19 (1.14, 1.24) in men and 1.11 (1.02, 1.20) in women. Thus, even among lean, physically active individuals: (i) weight gain increases hypertension risk; (ii) higher body weight increases the hypertension risk in a dose-dependent manner in the absence of any weight change; and (iii) there is no advantage carried forward to having been previously lean.     

A +2138InsCAGACC polymorphism of the melanocortin receptor 3 gene is associated in human with fat level and partitioning in interaction with body corpulence

BACKGROUND: The melanocortin system includes five receptors (MC1R to MC5R), and mouse and human MC4R has been shown to be involved in the regulation of feeding, and mouse MC3R in body composition. To verify a possible similar effect of MC3R in humans, we analyzed one insertion and one single nucleotide polymorphism by restriction fragment length polymorphisms (RFLP), and a microsatellite (D20S32e) in relation to body composition and glucose metabolism. METHODS: Eight hundred twelve subjects of the Québec Family Study (QFS) cohort were analyzed for body composition, food intake, and energy metabolism phenotypes. Southern Blot with the complete MC3R cDNA was used to detect a new +2138InsCAGACC variant by Pst1 restriction. PCR-RFLP with BsaJ1 was used to type amino acid polymorphism V81I arising from a G241A nucleotide change. PCR and automatic DNA sequencers were used for the analysis of the TG dinucleotide repeat D20S32e located between -1933/-1892 of MC3R. In a covariance analysis among genotypes, phenotypes were adjusted for age and sex as covariates. Food intake and energy metabolism phenotypes were also adjusted for body mass index (BMI), and leptin and abdominal fat, as assessed by a computed tomography scan, for fatness using six skinfold thicknesses. RESULTS: An association between the +2138InsCAGACC MC3R polymorphism was observed with fat mass (FM), percent body fat (%FAT), and total abdominal fat (ATF). Homozygote subjects for the +2138 insertion variant allele in normal weight (BMI < 25 kg/m(2)) and overweight (25 < or = BMI < 30 kg/m(2)) subjects showed a similar level of fatness despite the overall difference in BMI. In normal weight, homozygotes for the insertion allele showed higher mean values than heterozygotes and homozygotes for wild-type allele without insertion (%FAT: 24.0 +/- 1.1 versus 19.3 +/- 0.9 and 20.5 +/- 0.8, p = 0.0005; FM: 15.7 +/- 0.9 kg versus 11.7 +/- 0.7 kg and 12.6 +/- 0.6 kg, p = 0.0003). In contrast, overweight subjects homozygote for the variant allele showed lower mean values (%FAT: 27.0 +/- 1.2 versus 31.4 +/- 0.8 and 30.9 +/- 0.7, p = 0.002; FM: 18.3 +/- 1.0 kg versus 22.8 +/- 0.8 kg and 22.0 +/- 0.6 kg, p = 0.0001). This resulted in a similar level of body fat between both BMI groups for subjects homozygote for the insertion allele versus wild-type allele carriers (%FAT: +/-2-3% versus +/-10-12%; FM: +/-2 kg versus +/-9-11 kg). In obese subjects (BMI > or = 30 kg/m(2) ), a lower level of ATF was seen (-15%, p = 0.002). Other polymorphisms and phenotypes tested showed no association. CONCLUSION: A new 12138InsCAGACC MC3R polymorphism is associated with the level of adiposity and with body fat partitioning in interaction with corpulence in humans.     

Plasma obestatin is lower at fasting and not suppressed by insulin in insulin-resistant humans

Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n = 18, 13 females and 5 males, age 47 +/- 2 yr, BMI = 25.5 +/- 0.9 kg/m(2)) and low (IR; n = 18, 12 females and 6 males, age 45 +/- 2 yr, P = 0.49, BMI = 27.5 +/- 1.1 kg/m(2), P = 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU.min(-1).m(-2)) isoglycemic clamp tests. M(100-120 min) was higher in IS (10.7 +/- 0.7) than in IR (4.4 +/- 0.2 mg.min(-1).kg(-1), P < 10(-9)), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 +/- 6% vs. IS: 82 +/- 5%, P < 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24-28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 +/- 26 pg/ml vs. IS: 469 +/- 23 pg/ml, P < 0.02). Clamp insulin infusion reduced plasma obestatin to approximately 81% of basal values in IS (P < 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M (r = 0.34, P = 0.04), HDL cholesterol (r = 0.45, P = 0.01), and plasma ghrelin concentrations (r = 0.80, P < 0.000001) and negatively with measures of adiposity, plasma FFA during clamp (r = -0.42, P < 0.01), and systolic blood pressure (r = -0.33, P < 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulin-resistant persons.     

Skeletal muscle lipid metabolism with obesity

The objectives of this study were to 1). examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2). determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [n = 8; body mass index (BMI) 23.8 +/- 0.58 kg/m(2)], overweight/obese (n = 8; BMI 30.2 +/- 0.81 kg/m(2)), and extremely obese (n = 8; BMI 53.8 +/- 3.5 kg/m(2)) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 +/- 5.2 nmol x g(-1) x h(-1)) patients compared with normal-weight (71.0 +/- 5.0 nmol x g(-1) x h(-1)) and overweight/obese (82.2 +/- 8.7 nmol x g(-1) x h(-1)) patients, respectively. Palmitate oxidation was negatively (R = -0.44, P = 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation.     

Determining the waist circumference in african americans which best predicts insulin resistance

Total body size and central fat distribution are important determinants of insulin resistance. The BMI and waist circumference (WC) thresholds in African Americans that best predict insulin resistance are unknown. Our goal was to determine the BMI and WC values in African Americans, which optimally predict insulin resistance. The subjects were African Americans (68 men, 63 women), aged 35 +/- 8 years (mean +/- s.d.), with a BMI of 30.9 +/- 7.5, in the range of 18.5-54.7 kg/m(2), and with a WC of 98 +/- 18, in the range of 69-173 cm. Insulin resistance was defined by the lowest tertile of the insulin sensitivity index (S(I)). The Youden index was calculated to determine the WC and BMI thresholds that predict insulin resistance with an optimal combination of sensitivity and specificity. In men the thresholds that optimally predicted insulin resistance were a BMI > or =30 kg/m(2) or a WC > or =102 cm. For women, insulin resistance was best predicted by a BMI > or =32 kg/m(2) or a WC > or =98 cm. In African Americans, insulin resistance (in men) was best predicted by a WC > or =102 cm, and in women by a WC > or =98 cm, or by a BMI value that fell in the obese category (men: > or =30 kg/m(2), women: > or =32 kg/m(2)).