Obesity: Machicao F

Müssig K, Staiger H, Machicao F, Thamer C, Machann J, Schick F, Claussen CD, Stefan N, Fritsche A, Häring HU. · Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital of Tübingen, 72076 Tübingen, Germany. · Metabolism. · Pubmed #19303973 No free full text.

Abstract: Visceral fat mass is a strong and independent predictor of obesity-related disorders. To date, little is known about the genetic determinants of regional body fat distribution in humans. As candidates of regional fat distribution, we investigated the fat mass- and obesity-associated gene, the peroxisome proliferator-activated receptor-delta gene, and the retinoic acid receptor responder 2 (RARRES2) gene. We studied whether genetic variation within these genes contributes to the development of disproportionate visceral obesity and obesity-related traits, such as insulin resistance and beta-cell dysfunction. We genotyped 337 subjects with an increased risk for type 2 diabetes mellitus for tagging single nucleotide polymorphisms (SNPs) in the 3 genes and performed association analyses with anthropometric data and parameters of insulin sensitivity and beta-cell function. All subjects underwent an oral glucose tolerance test; a subset was additionally characterized by a hyperinsulinemic-euglycemic clamp. Body fat distribution was assessed by nuclear magnetic resonance imaging. The fat mass- and obesity-associated gene SNP rs8050136 was nominally associated with body mass index (P = .0130), but not with body fat distribution, after appropriate adjustment. Magnetic resonance imaging-quantified visceral fat mass was significantly associated with RARRES2 SNP rs17173608 and nominally associated with RARRES2 SNP rs10278590 in nonobese subjects (P = .0002 and P = .0423, respectively), with carriers of the minor alleles displaying lower visceral adipose tissue mass. Besides, the minor allele of SNP rs17173608 was nominally associated with a lower waist-to-hip ratio (P = .0295). In obese subjects, these associations were not detected. No associations were found between the peroxisome proliferator-activated receptor-delta gene and measures of whole-body adiposity and of body fat distribution. All SNPs were associated neither with insulin sensitivity nor with insulin secretion. Common genetic variation within RARRES2 is associated with increased visceral fat mass in nonobese subjects. In generalized obesity, this genetic effect may be masked by the close association between whole-body obesity and visceral fat mass.

Staiger H, Machicao F, Schäfer SA, Kirchhoff K, Kantartzis K, Guthoff M, Silbernagel G, Stefan N, Häring HU, Fritsche A. · Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany. · PLoS One. · Pubmed #19088850 links to  free full text

Abstract: BACKGROUND: Very recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency > 0.05) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638). In a subgroup (N = 513), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301), glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p < 0.0001) and reduced OGTT- and IVGTT-induced insulin release (p < or = 0.0007 and p < or = 0.01, respectively). By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p < or = 0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p < or = 0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion. CONCLUSIONS/SIGNIFICANCE: In conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on beta-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk.

Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, Häring HU, Stefan N, Fritsche A. · Department of Internal Medicine, Division of Diabetology, Endocrinology, Nephrology and Angiology, Clinical Chemistry, University of Tübingen, Tübingen, Germany. · Exp Clin Endocrinol Diabetes. · Pubmed #19053021 No free full text.

Abstract: Polymorphisms in the FTO (fat mass- and obesity-associated) gene are associated with obesity. The mechanisms how genetic variation in this gene influences body weight are unknown. Body weight is determined by energy intake/storage and energy expenditure. In this study, we investigated whether genetic variation in FTO influences energy expenditure or food intake in carefully phenotyped subjects. In 380 German subjects, insulin sensitivity was measured by a hyperinsulinemic euglycemic clamp. Lean body mass and body fat were quantified using the bioimpedance method. Indirect calorimetry was used to estimate the metabolic rate. Food intake was assessed using food diaries (mean 11+/-1 d) in 151 subjects participating in a lifestyle intervention program to prevent diabetes. All subjects were genotyped for the FTO single nucleotide polymorphism (SNP) rs8050136. The risk allele of SNP rs8050136 was associated with higher body fat-related parameters (all p< or =0.04, additive inheritance model). Energy expenditure was not affected by the SNP. However, the risk allele of rs8050136 was significantly associated with higher energy intake (p=0.01, dominant inheritance model) during dietary restriction. Our data suggest that the increased body weight in carriers of the risk allele of FTO SNP rs8050136 is a consequence of increased food intake, but not of impaired energy expenditure.

Weyrich P, Albet S, Lammers R, Machicao F, Fritsche A, Stefan N, Häring HU. · Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany. · Exp Clin Endocrinol Diabetes. · Pubmed #18726866 No free full text.

Abstract: AIMS: Procolipase (CLPS) is secreted from the exocrine pancreas into the gastrointestinal tract and becomes proteolytically cleaved into colipase and the pentapeptide enterostatin. While colipase is an indispensable cofactor for pancreatic lipase, enterostatin acts as a hormone that inhibits insulin secretion and confers satiety signals to the brain, thereby restricting further food intake in animal models. As both high fat diet and obesity contribute to insulin resistance, we investigated whether genetic variability of CLPS associates with metabolic traits in non-diabetic humans at diabetes risk. METHODS: Tagging single nucleotide polymorphisms (SNPs) in the human CLPS locus on chr6p21.1 were selected using HapMap data. 498 humans, phenotyped for different glucose and lipid metabolic traits, were genotyped by bidirectional sequencing and multivariate linear regression analyses were undertaken. RESULTS: 2 tagging SNPs (rs3748050 in the Kozak sequence: A/G and rs3748051 in intron 1: A/G), covering 100% of CLPS variability including 8 kb of its promoter, were genotyped for association analyses. The minor alleles of both tagging SNPs associated significantly with a reduced insulin secretion (-20.2%, both SNPs) in various estimation models derived from the oral glucose tolerance test (OGTT; rs3748050/51: 30 min C-peptide levels: p=0.001/0.01, insulinogenic index: p=0.02/0.02, AUC C-peptide/AUC glucose: p=0.01/0.01) after adjustment for relevant covariates. No significant associations with fasting total cholesterol (c), HDL-c, LDL-c, triglycerides and free fatty acids were found (all p > 0.11). CONCLUSIONS: CLPS genetic variability associates with insulin secretory function in non-diabetic humans and may represent a novel candidate gene for development of type 2 diabetes.

Staiger H, Machicao F, Kantartzis K, Schäfer SA, Kirchhoff K, Guthoff M, Silbernagel G, Stefan N, Fritsche A, Häring HU. · Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany. · PLoS One. · Pubmed #18714373 links to  free full text

Abstract: BACKGROUND: Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic beta-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: One thousand five hundred and seventy-eight metabolically characterized non-diabetic German subjects were genotyped for the reported candidate single nucleotide polymorphisms (SNPs) JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8/LGR5 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs10923931, DCD rs1153188, VEGFA rs9472138, and BCL11A rs10490072. Insulin sensitivity was derived from fasting glucose and insulin concentrations, oral glucose tolerance test (OGTT), and hyperinsulinemic-euglycemic clamp. Insulin secretion was estimated from OGTT data. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons (corrected alpha-level: p = 0.0014), none of the SNPs was reliably associated with adiposity, insulin sensitivity, or insulin secretion (all p > or = 0.0117, dominant inheritance model). The risk alleles of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 tended to associate with more than one measure of insulin sensitivity and insulin secretion, respectively, but did not reach formal statistical significance. The study was sufficiently powered (1-beta = 0.8) to detect effect sizes of 0.19 < or = d < or = 0.25 (alpha = 0.0014) and 0.13 < or = d < or = 0.16 (alpha = 0.05). CONCLUSIONS/SIGNIFICANCE: In contrast to the first series of GWA-derived type 2 diabetes candidate SNPs, we could not detect reliable associations of the novel risk loci with prediabetic phenotypes. Possible weak effects of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 on insulin sensitivity and insulin secretion, respectively, await further confirmation by larger studies.

Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Häring HU. · Department of Internal Medicine IV, University of Tübingen, D-72076 Tübingen, Germany. · Arch Intern Med. · Pubmed #18695074 No free full text.

Abstract: BACKGROUND: Obesity represents a risk factor for insulin resistance, type 2 diabetes mellitus, and atherosclerosis. In addition, for any given amount of total body fat, an excess of visceral fat or fat accumulation in the liver and skeletal muscle augments the risk. Conversely, even in obesity, a metabolically benign fat distribution phenotype may exist. METHODS: In 314 subjects, we measured total body, visceral, and subcutaneous fat with magnetic resonance (MR) tomography and fat in the liver and skeletal muscle with proton MR spectroscopy. Insulin sensitivity was estimated from oral glucose tolerance test results. Subjects were divided into 4 groups: normal weight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], < 25.0), overweight (BMI, 25.0-29.9), obese-insulin sensitive (IS) (BMI, > or = 30.0 and placement in the upper quartile of insulin sensitivity), and obese-insulin resistant (IR) (BMI, > or = 30.0 and placement in the lower 3 quartiles of insulin sensitivity). RESULTS: Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (P < .05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (P < .001) and particularly the liver (4.3% +/- 0.6% vs 9.5% +/- 0.8%) and the intima-media thickness of the common carotid artery (0.54 +/- 0.02 vs 0.59 +/- 0.01 mm) were lower and insulin sensitivity was higher (17.4 +/- 0.9 vs 7.3 +/- 0.3 arbitrary units) in the obese-IS vs the obese-IR group (P < .05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2 +/- 0.9 AU and 0.51 +/- 0.02 mm, respectively). CONCLUSIONS: A metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans. Furthermore, ectopic fat in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity.

Haupt A, Thamer C, Machann J, Kirchhoff K, Stefan N, Tschritter O, Machicao F, Schick F, Häring HU, Fritsche A. · Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard-Karls-University of Tübingen, Tübingen, Germany. · Obesity (Silver Spring). · Pubmed #18535549 No free full text.

Abstract: Polymorphisms in the fat mass- and obesity-associated (FTO) gene have been identified to be associated with obesity and diabetes in large genome-wide association studies. We hypothesized that variation in the FTO gene has an impact on whole body fat distribution and insulin sensitivity, and influences weight change during lifestyle intervention. To test this hypothesis, we genotyped 1,466 German subjects, with increased risk for type 2 diabetes, for single-nucleotide polymorphism rs8050136 in the FTO gene and estimated glucose tolerance and insulin sensitivity from an oral glucose tolerance test (OGTT). Distribution of fat depots was quantified using whole body magnetic resonance (MR) imaging and spectroscopy in 298 subjects. Two-hundred and four subjects participated in a lifestyle intervention program and were examined after a follow-up of 9 months. In the cross-sectional analysis, the A allele of rs8050136 in FTO was associated with a higher BMI, body fat, and lean body mass (all P < 0.001). There was a significant effect of variation in the FTO gene on subcutaneous fat (P < or = 0.05) and a trend for liver fat content, nonvisceral adipose tissue, and visceral fat (all P < or = 0.1). However, the single-nucleotide polymorphism was not associated with insulin sensitivity or secretion independent of BMI (all P > 0.05). During lifestyle intervention, there was also no influence of the FTO polymorphism on changes in body weight or fat distribution. In conclusion, despite an association with BMI and whole body fat distribution, variation in the FTO locus has no effect on the success of a lifestyle intervention program.

Tschritter O, Preissl H, Yokoyama Y, Machicao F, Häring HU, Fritsche A. · No affiliation provided · Diabetologia. · Pubmed #17917711 No free full text.

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Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Kröber SM, Machicao F, Fritsche A, Häring HU. · Department of Internal Medicine, University of Tübingen, Germany. · Diabetes Care. · Pubmed #16567827 links to  free full text

Abstract: OBJECTIVE: The alpha(2)-Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver. RESEARCH DESIGN AND METHODS: Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by (1)H magnetic resonance spectroscopy. RESULTS: AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P = 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r = -0.22, P = 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r = 0.27, P = 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P = 0.02). CONCLUSIONS: We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance.

Weigert C, Thamer C, Brodbeck K, Guirguis A, Machicao F, Machann J, Schick F, Stumvoll M, Fritsche A, Häring HU, Schleicher ED. · Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, University of Tubingen, Otfried Müller Strasse 10, D-72076 Tubingen, Germany. · J Clin Endocrinol Metab. · Pubmed #15613432 links to  free full text

Abstract: Increases in glutamine:fructose-6-phosphate aminotransferase (GFAT) protein levels directly activate flux through the hexosamine biosynthetic pathway. This pathway has been involved as a fuel sensor in energy metabolism and development of insulin resistance. We screened the 5'-flanking region of the human GFAT gene for polymorphisms and subsequently genotyped 412 nondiabetic, metabolically characterized Caucasians for the two single-nucleotide polymorphisms (SNP) at positions -913 (G/A) and -1412 (C/G) with rare allele frequencies of 42% and 16%, respectively. The -913 G SNP was associated with significantly higher body mass index and percent body fat in men (P = 0.02 and 0.004, respectively), but not in women (P = 0.47 and 0.26, respectively). In the subgroup of individuals (n = 193) who underwent hyperinsulinemic-euglycemic clamp, an association of the -913 G SNP with insulin sensitivity independent of body mass index was not detected. Moreover, the -913 G allele in a group of 71 individuals who had undergone magnetic resonance spectroscopy was associated with higher intramyocellular lipid content (IMCL) in tibialis anterior muscle (4.21 +/- 0.31 vs. 3.36 +/- 0.35; P = 0.04) independent of percent body fat and maximal aerobic power. The -1412 SNP had no effect on percent body fat, insulin sensitivity, or IMCL. In conclusion, we identified two polymorphisms in the 5'-flanking region of GFAT, of which the -913 SNP seems to alter the risk for obesity and IMCL accumulation in male subjects.

Staiger H, Staiger K, Stefan N, Wahl HG, Machicao F, Kellerer M, Häring HU. · Department of Endocrinology, Metabolism and Pathobiochemistry, Medical Clinic, Eberhard-Karls-University, Tübingen, Germany. · Diabetes. · Pubmed #15561952 links to  free full text

Abstract: Obesity-linked insulin resistance is associated with chronic inflammation and cardiovascular complications. Free fatty acids (FFAs) are prominent candidates for the molecular link between these disorders. In this study, we determined whether FFAs contribute to vascular inflammation via induction of interleukin (IL)-6 in coronary artery endothelial cells (CAECs) and coronary artery smooth muscle cells (CASMCs) and whether this is reflected in vivo. In contrast to our findings regarding IL-6 and gp130 (the glycoprotein of 130 kDa) expression, IL-6 receptor mRNA expression was very low in these cells. Palmitate, but not linoleate, induced a significant increase in IL-6 mRNA expression in CAECs (P < 0.001) and, to a less relevant extent, in CASMCs (P < 0.01). gp130 remained unaffected. As to potency, palmitate was comparable with the IL-6-inducer IL-1beta. To substantiate our in vitro data, we examined the plasma FFA pattern in 54 healthy human subjects and studied the relation of individual FFAs with plasma IL-6. IL-6 levels correlated with palmitate, but not with other abundant FFAs, even after adjusting for body fat (r = 0.33, P < 0.05) and total FFAs (r = 0.29, P < 0.05). We show here that the common plasma FFA palmitate induces high levels of IL-6 in CAECs. Furthermore, palmitate correlates with IL-6 in vivo. This points to a potential contribution of palmitate to vascular inflammation.

Stefan N, Stumvoll M, Machicao F, Koch M, Häring HU, Fritsche A. · Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Germany. · Obes Res. · Pubmed #15090636 No free full text.

Abstract: OBJECTIVE: The common C825T polymorphism of the gene that encodes the G protein beta3 subunit has been shown to influence lipolysis in human adipocytes and to be associated with hypertension, body fat distribution, and obesity. In addition, it has been shown to be associated with insulin resistance in a small group of hypertensive subjects. We investigated whether this polymorphism contributed to the variability in obesity in our population from southern Germany and whether it was associated with insulin sensitivity of lipolysis and/or glucose disposal. RESEARCH METHODS AND PROCEDURES: We determined percentage body fat, body fat distribution, glucose tolerance [oral glucose-tolerance test (OGTT)], insulin sensitivity, and serum free fatty acids using data from OGTTs (N = 774) and clamp (euglycemic hyperinsulinemic clamp, N = 216) in normal and impaired glucose tolerant subjects who were genotyped for this polymorphism. RESULTS: Compared with noncarriers of the C825T mutation, subjects with the C825T variant (prevalence approximately 32%) had higher percentage body fat (p = 0.02) and higher BMI (p = 0.03). No conclusive effect was seen on serum free fatty acids measured either during fasting or at the end of a 2-hour OGTT. Insulin sensitivity determined during the OGTT and during the clamp, both adjusted for age, gender, and percentage body fat, was not different between the genotypes (p = 0.33 and p = 0.48, respectively). DISCUSSION: We have concluded that the C825T polymorphism in the G protein beta3 subunit played an important role in the determination of obesity in this German population. However, it probably had no direct effects on insulin sensitivity of lipolysis and glucose disposal.

't Hart LM, Fritsche A, Rietveld I, Dekker JM, Nijpels G, Machicao F, Stumvoll M, van Duijn CM, Häring HU, Heine RJ, Maassen JA, van Haeften TW. · Deparment of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. · Diabetes. · Pubmed #14749262 links to  free full text

Abstract: IGFs are important regulators of pancreatic beta-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI.

Staiger H, Kausch C, Guirguis A, Weisser M, Maerker E, Stumvoll M, Lammers R, Machicao F, Häring HU. · Department of Endocrinology, Metabolism, and Pathobiochemistry, Medical Clinic Tübingen, Eberhard-Karls-University, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. · Diabetologia. · Pubmed #12827245 No free full text.

Abstract: AIMS/HYPOTHESIS: Adiponectin, an adipocytokine known to be down-regulated in obesity-linked disorders, is considered to be a potential key mediator of insulin sensitivity. In this study, we asked whether adiponectin is able to regulate ten selected genes possibly associated with insulin sensitivity in human skeletal muscle cells. METHODS: To this end, we treated in vitro differentiated human myotubes with the culture supernatant of HEK293 cells stably transfected with human recombinant adiponectin and assessed gene expression by RT-PCR. Intracellular adiponectin protein was quantified by radioimmunoassay and visualized by Western blotting. RESULTS: In contrast to the control supernatant, the adiponectin-containing supernatant consistently induced expression of adiponectin mRNA in human myotubes from eight different donors (mean increase: 90-fold over control; n=8, p<0.001). This increase in mRNA was paralleled by a rise in intracellular adiponectin protein (mean increase: 8.3-fold over control; n=4, p<0.05). Expression of the other nine candidate genes was not altered. In human skin fibroblasts and HepG2 cells, the adiponectin-enriched supernatant did not induce relevant amounts of adiponectin mRNA. CONCLUSIONS/INTERPRETATION: In conclusion, we show here that adiponectin gene expression is specifically inducible in skeletal muscle cells.

Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Häring H. · Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany. · Diabetes. · Pubmed #11756320 links to  free full text

Abstract: The adipocyte-derived hormone adiponectin seems to protect from insulin resistance, a key factor in the pathogenesis of type 2 diabetes. Genome-wide scans have mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. A common silent T-G exchange in nucleotide 94 (exon 2) of the adiponectin gene has been associated with increased circulating adiponectin levels. Metabolic abnormalities associated with the G allele have not been reported. We therefore assessed whether this polymorphism alters insulin sensitivity and/or measures of obesity using the Tübingen Family Study database (prevalence of the G allele, 28%). In 371 nondiabetic individuals, we found a significantly greater BMI in GG + GT (25.5 +/- 0.7 kg/m(2)) compared with TT (24.1 +/- 0.3 kg/m(2); P = 0.02). Insulin sensitivity (determined by euglycemic clamp, n = 209) was significantly lower in GG + GT (0.089 +/- 0.007 units) compared with TT (0.112 +/- 0.005 units; P = 0.02). This difference disappeared completely on adjustment for BMI. Because our population contains a relatively high proportion of first-degree relatives of patients with type 2 diabetes, we stratified by family history (FHD). Much to our surprise, the genotype differences in BMI and insulin sensitivity in the whole population were attributable entirely to differences in the subgroup without FHD, whereas in the subgroup with FHD, the G allele had absolutely no effect. Moreover, individuals without FHD had a significantly lower BMI than individuals with FHD (25.2 +/- 0.4 vs. 26.2 +/- 0.5 kg/m(2); P = 0.01), which was not the case for the GG + GT subgroup without FHD (27.0 +/- 0.9 kg/m(2); NS). This suggests that in individuals without familial predisposition for type 2 diabetes, the adiponectin polymorphism may mildly increase the obesity risk (and secondarily insulin resistance). In contrast, in individuals who are already burdened by other genetic factors, this small effect may be very hard to detect.

Tschritter O, Hennige AM, Preissl H, Grichisch Y, Kirchhoff K, Kantartzis K, Machicao F, Fritsche A, Häring HU. · No affiliation provided · Diabetologia. · Pubmed #19018512 No free full text.

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Kantartzis K, Fritsche A, Machicao F, Häring HU, Stefan N. · No affiliation provided · Diabetes Care. · Pubmed #16443913 links to  free full text

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Stefan N, Fritsche A, Machicao F, Tschritter O, Häring HU, Stumvoll M, Stumvogel M. · No affiliation provided · Diabetologia. · Pubmed #15298357 No free full text.

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Stumvoll M, Wahl HG, Jacob S, Rettig A, Machicao F, Häring H. · Department of Endocrinology and Metabolism, Eberhard-Karls-Universität, D-72076 Tübingen, Germany. · J Lipid Res. · Pubmed #11714847 links to  free full text

Abstract: Free fatty acids released during triglyceride lipolysis play an important role in obesity-associated insulin resistance of glucose disposal. Individual sensitivity of lipolysis to the suppressive effect of insulin varies greatly among healthy subjects. It is possible that genetic factors contribute to this variation. Among the many proteins involved in the regulation of lipolysis, hormone-sensitive lipase (HSL) represents a prime candidate for genetic variants contributing to the biological variation of insulin sensitivity of lipolysis. We determined the insulin sensitivity of lipolysis (suppression of isotopically [primed-continuous infusion of d5 glycerol] measured glycerol rate of appearance) and of glucose disposal, using a three-step (n = 20) or standard (n = 53) hyperinsulinemic euglycemic clamp in 73 healthy, unrelated subjects. To assess the possible role of genetic polymorphisms, we directly sequenced the coding region of the HSL gene and the noncoding exon B from these subjects. We identified two silent mutations and three amino acid polymorphisms: Arg262Met (prevalence, 5%), Glu620Asp (prevalence, 31%) and Ser681Ile (prevalence, 22%). The latter two are located in the regulatory domain of HSL but neither had a significant impact on insulin sensitivity of lipolysis or glucose disposal (with and without adjustment for obesity and age as covariates; all P values > 0.20). We conclude that a number of genetic polymorphisms in HSL exist, some of which are highly prevalent. Neither of the polymorphisms we identified in the coding region, however, contributed measurably to the biological variation of insulin sensitivity in our lean, healthy population.