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Michael Stumvoll

Publications and source records attributed to Michael Stumvoll.

At least 37 records · Page 2Linked to original sources
PubMed2005

Interleukin-6 is a negative regulator of visfatin gene expression in 3T3-L1 adipocytes.

Visfatin is a novel adipocytokine exerting insulin-mimetic effects in various insulin-sensitive tissues such as liver, muscle, and fat. In contrast, interleukin (IL)-6 is a proinflammatory adipose-secreted factor that induces insulin resistance and plasma concentrations that correlate with the development of type 2 diabetes mellitus. In the present study, the impact of IL-6 on visfatin gene expression in 3T3-L1 adipocytes was determined by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, 30 ng/ml IL-6 time-dependently downregulated visfatin synthesis with a significant 40% suppression seen after 4 h of treatment. Furthermore, the addition of IL-6 for 16 h dose-dependently suppressed visfatin mRNA with significant effects first observed at concentrations as low as 3 ng/ml and a maximal 43% reduction at 30 ng/ml effector. Moreover, inhibitor studies suggested that the negative effect of IL-6 on visfatin expression is, at least in part, mediated by p44/42 mitogen-activated protein kinase. In contrast, troglitazone did not reverse the negative effect of IL-6 on visfatin synthesis under these conditions. Taken together, our study suggests that IL-6 might influence glucose tolerance in part by regulation of the novel insulin-mimetic adipocytokine visfatin.

3T3-L1 Cells↗
PubMed2005

Liver fat and insulin resistance are independently associated with the -514C>T polymorphism of the hepatic lipase gene.

CONTEXT: Liver fat predicts insulin resistance in humans. So far, there is not much information on genetic determinants of liver fat. Hepatic lipase is a liver-specific enzyme that regulates lipid metabolism. OBJECTIVE: First, our object was to investigate whether the functional -514C>T polymorphism of the hepatic lipase gene is associated with liver fat content and with insulin sensitivity. Second, because this polymorphism displays gene-nutrient interactions, we assessed gene-gene interactions with the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma(2) on liver fat content and insulin sensitivity. DESIGN AND METHODS: Cross-sectional data from a total of 1070 nondiabetic subjects were analyzed. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test. A subgroup of 115 subjects underwent measurements of liver fat. RESULTS: The -514C>T polymorphism of the hepatic lipase gene was associated with higher liver fat content (P = 0.005) and lower insulin sensitivity (P = 0.02), both after adjustment for age, gender, and percentage of body fat. This was independent of serum adiponectin concentrations (P = 0.01 and 0.03). However, there was an interaction of the -514C>T polymorphism with the Pro12Ala variant on liver fat (P = 0.09) and insulin sensitivity (P = 0.01). Subjects carrying the -514C>T polymorphism had higher liver fat content and were insulin resistant only before the background of the Pro/Pro genotype of the Pro12Ala polymorphism. CONCLUSIONS: The -514C>T polymorphism of the hepatic lipase gene is associated with higher liver fat content and lower whole-body insulin sensitivity. However, these effects are modulated by the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(2). These findings may be relevant for intervention strategies to prevent increase in liver fat content and insulin resistance.

Adult↗
PubMed2005

Standardized assessment of whole body adipose tissue topography by MRI.

PURPOSE: To assess standardized whole body adipose tissue topography in a cohort of subjects at an increased risk for type 2 diabetes and to compare fat distribution in subgroups regarding anthropometric (age, body mass index [BMI]) and metabolic parameters (insulin sensitivity). MATERIALS AND METHODS: A total of 80 volunteers (40 females, 40 males) underwent T1-weighted MR imaging of the entire body. Standardized adipose tissue (AT) profiles were calculated considering the different body structure of the participants. The measured data were interpolated to a defined number of sampling points enabling a direct comparison of the profiles independent on body structure. Resulting mean profiles and region-dependent standard deviations of four age groups and three BMI-groups were compared for females and males. Correlations between insulin sensitivity and body fat distribution were analyzed. RESULTS: Reliable adipose tissue profiles could be obtained from all volunteers. In BMI-matched subgroups, females show significant higher AT and subcutaneous abdominal AT (P < 0.05 both), but lower visceral AT (P < 0.01) compared to the males. Furthermore, visceral AT increases with age, as shown in the matched age groups. In both gender groups, insulin-resistant subjects are characterized by higher visceral adipose tissue (VAT) compared to insulin-sensitive subjects. In addition, profiles of insulin-resistant subjects show more AT in the shoulder/neck region but less AT in the upper extremities. CONCLUSION: Standardized assessment of whole body AT profiles based on T1-weighted MRI provides a reliable basis for interindividual comparison of the body fat distribution and allows a fast and reliable quantification of total body adipose tissue and the distribution of different AT components as subcutaneous and visceral fat in different body regions. Differences in standardized profiles might enable an early identification of people at risk of metabolic disorders, as not only the amount but also the distribution of AT is expected to play an essential role in the pathogenesis of metabolic diseases.

Adipose Tissue↗
PubMed2005

Fatty acids and insulin resistance in muscle and liver.

Free fatty acids (FFAs) circulate round the body and represent important nutrients and the key oxidative fuel for the heart and resting skeletal muscle. In addition, FFAs are thought to be potent signalling molecules. Growing evidence indicates that FFAs may be involved in type 2 diabetes mellitus and obesity by mediating insulin resistance. In 1963, it was postulated that accumulated glucose-6-phosphate as a result of increased FFA oxidation leads to decreased glucose uptake. An alternative hypothesis is that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity, which appears to be a consequence of decreased insulin receptor substrate-1-associated phosphatidyl inositol 3 kinase activity. Moreover, FFAs can arise locally, and increased intramyocellular and hepatocellular lipids have been shown to be associated with insulin resistance. This paper reviews the main aspects of FFA metabolism in the development of insulin resistance in skeletal muscle and liver, as well as the role of ectopic lipid deposits as a local source of FFAs. Finally, the role of thiazolidinediones as modulators of FFA-induced insulin resistance will be discussed.

Diabetes Mellitus, Type 2↗
PubMed2005

The association between plasma adiponectin and insulin sensitivity in humans depends on obesity.

OBJECTIVE: In humans, low plasma adiponectin concentrations precede a decrease in insulin sensitivity and predict type 2 diabetes independently of obesity. However, it is possible that the contribution of adiponectin to insulin sensitivity is not equally strong over the whole range of obesity. RESEARCH METHODS AND PROCEDURES: We investigated the cross-sectional association between plasma adiponectin levels and insulin sensitivity in different ranges of body fat content [expressed as percentage of body fat (PFAT)] in a large cohort of normal glucose-tolerant subjects (n = 900). All individuals underwent an oral glucose tolerance test (OGTT), and 299 subjects additionally a euglycemic hyperinsulinemic clamp. In longitudinal analyses, the association of adiponectin at baseline with change in insulin sensitivity was investigated in a subgroup of 108 subjects. RESULTS: In cross-sectional analyses, the association between plasma adiponectin and insulin sensitivity, adjusted for age, gender, and PFAT, depended on whether subjects were lean or obese [p for interaction adiponectin x PFAT = <0.001 (OGTT) and 0.002 (clamp)]. Stratified by quartiles of PFAT, adiponectin did not correlate significantly with insulin sensitivity in subjects in the lowest PFAT quartile (R2 = 0.10, p = 0.13, OGTT; and R2 = 0.10, p = 0.57, clamp), whereas the association in the upper PFAT quartile was rather strong (R2 = 0.36, p < 0.0001, OGTT; and R2 = 0.48, p = 0.003, clamp). In longitudinal analyses, plasma adiponectin at baseline preceded change in insulin sensitivity in obese (n = 54, p = 0.03) but not in lean (n = 54, p = 0.68) individuals. DISCUSSION: These data suggest that adiponectin is especially critical in sustaining insulin sensitivity in obese subjects. Thus, interventions to reduce insulin resistance by increasing adiponectin concentrations may be effective particularly in obese, insulin-resistant individuals.

Adiponectin↗
PubMed2005

Novel thyrotropin receptor germline mutation (Ile568Val) in a Saxonian family with hereditary nonautoimmune hyperthyroidism.

OBJECTIVE: Hereditary nonautoimmune hyperthyroidism is caused by activating thyrotropin receptor (TSHR) germline mutations. We describe a family from Saxony, Germany, with this condition. Recurrent thyrotoxicosis and goiter were prevalent in three generations, affecting in addition to the 16-year-old index patient, her father and late paternal grandmother. Hyperthyroidism in the girl was remarkable for its poor response to methimazole (40-60 mg/d) treatment. METHODS AND RESULTS: Molecular analysis of genomic DNA extracted from peripheral blood leucocytes showed a TSHR germline mutation in the girl and her father. This mutation results in a new amino acid exchange of valine for isoleucine in TSHR codon 568 (Ile568Val). Only the wild-type TSHR sequence was found in the girl's mother. On functional characterization in COS-7 cells, the novel Ile568Val TSHR mutation conferred constitutive activation of the cAMP pathway (2- to 3-fold increase of basal cyclic adenosine monophosphate [cAMP]), but not of the inositol phosphate cascade. As a consequence of the molecular findings, total thyroidectomy has been performed in the girl. She is now euthyroid on levothyroxine replacement therapy. CONCLUSION: This is the second Saxonian family with autosomal-dominant nonautoimmune hyperthyroidism, adding to a total of 13 families and 11 individuals with activating TSHR germline mutations worldwide. We suggest that the condition may indeed be more frequent than previously thought and that consequent assessment of a family history in children as well as adults with thyroid autonomy will contribute to ensure correct diagnosis and adequate treatment of patients with activating TSHR germline mutations.

Adolescent↗
PubMed2005

Therapeutic perspectives of adipocytokines.

Various adipocyte-secreted factors have been described which profoundly affect insulin sensitivity and might potentially link obesity, insulin resistance and cardiovascular disease. Among those, adiponectin, visfatin and omentin appear as insulin-sensitising adipocytokines, whereas TNF-alpha, IL-6 and resistin induce insulin resistance. Moreover, leptin is a fat-derived key regulator of appetite and energy expenditure. Due to their profound effect on whole-body glucose and energy metabolism, adipocytokines have attracted interest as potential new therapeutics for diabetes mellitus and obesity. The current knowledge on function, regulation and therapeutic potential of various adipocytokines, as well as their clinical implications, are discussed in this review.

Adipocytes↗
PubMed2005

Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes.

Recently, visfatin was characterized as a novel adipo-cytokine that is upregulated in obesity and exerts insulin-mimetic effects in various tissues. To clarify expression and regulation of this adipocytokine, visfatin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction in 3T3-L1 adipocytes during adipogenesis and after treatment with various hormones known to alter insulin sensitivity. Visfatin expression was about 6-fold higher in 3T3-L1 adipocytes in vitro as compared with epididymal fat in vivo and increased during adipogenic conversion more than 3-fold. Interestingly, 100 nM dexamethasone significantly increased visfatin mRNA by almost 1.5-fold. In contrast, 500 ng/ml growth hormone (GH), 10 ng/ml tumor necrosis factor (TNF) alpha, and 10 microM isoproterenol downregulated visfatin expression by 45%, 36%, and 43% respectively. Insulin did not influence synthesis of this adipocytokine. The effects of dexamethasone, GH, TNFalpha and isoproterenol were time- and dose-dependent. Furthermore, activation of G(s)-protein-coupled pathways by forskolin and cholera toxin was sufficient to significantly downregulate visfatin mRNA. Taken together, our results show a differential regulation of visfatin mRNA by insulin resistance-inducing hormones, supporting the view that this adipo-cytokine might be an interesting novel candidate linking core components of the metabolic syndrome such as obesity and insulin resistance.

3T3-L1 Cells↗
PubMed2005

Plasma visfatin concentrations and fat depot-specific mRNA expression in humans.

Visceral and subcutaneous adipose tissue display important metabolic differences that underlie the association of visceral obesity with obesity-related cardiovascular and metabolic alterations. Recently, visfatin was identified as an adipokine, which is predominantly secreted from visceral adipose tissue both in humans and mice. In this study, we examined whether visfatin plasma concentrations (using enzyme immunosorbent assay) and mRNA expression (using RT-PCR) in visceral and subcutaneous fat correlates with anthropometric and metabolic parameters in 189 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. Visfatin plasma concentration correlates positively with the visceral visfatin mRNA expression (r(2) = 0.17, P < 0.0001), BMI (r(2) = 0.062, P = 0.004), percent body fat (r(2) = 0.048, P = 0.01), and negatively with subcutaneous visfatin mRNA expression (r(2) = 0.18, P < 0.0001). However, in a subgroup of 73 individuals, in which visceral fat mass was calculated from computed tomography scans, there was no correlation between plasma visfatin concentrations and visceral fat mass. We found no significant correlation between visfatin plasma concentrations and parameters of insulin sensitivity, including fasting insulin, fasting plasma glucose concentrations, and the glucose infusion rate during the steady state of an euglycemic-hyperinsulinemic clamp independent of percent body fat. Visfatin gene expression was not different between visceral and subcutaneous adipose tissue in the entire study group nor in selected subgroups. We found a significant correlation between visceral visfatin gene expression and BMI (r(2) = 0.06, P = 0.001) and percent body fat (measured using dual-energy X-ray absorptiometry) (r(2) = 0.044, P = 0.004), whereas no significant association between BMI or percent body fat and subcutaneous visfatin mRNA expression existed (both P >0.5). In conclusion, visfatin plasma concentrations and visceral visfatin mRNA expression correlated with measures of obesity but not with visceral fat mass or waist-to-hip ratio. In addition, we did not find differences in visfatin mRNA expression between visceral and subcutaneous adipose tissue in humans.

Absorptiometry, Photon↗
PubMed2004

The -913 G/A glutamine:fructose-6-phosphate aminotransferase gene polymorphism is associated with measures of obesity and intramyocellular lipid content in nondiabetic subjects.

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.

Adult↗
PubMed2004

Adiponectin, obesity, and cardiovascular disease.

Several adipocyte-secreted factors have been demonstrated to potentially link obesity, insulin resistance, and cardiovascular disease. Among those, adiponectin is an insulin-sensitizing and anti-inflammatory adipokine, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. Recently, two adiponectin receptors (AdipoR) have been isolated and adenosine monophosphate kinase (AMPK), as well as acetyl coenzyme A carboxylase (ACC), appear to be critical downstream mediators for various effects of this adipokine. In addition to beneficial metabolic effects, adiponectin seems to be vasoprotective by interfering with various atherogenic processes. Of clinical interest, thiazolidinediones (TZDs) which are used in the treatment of type 2 diabetes stimulate adiponectin expression and secretion whereas several hormones dysregulated in insulin resistance and obesity downregulate this adipokine. The current knowledge on regulation and function of adiponectin in obesity, insulin resistance, and cardiovascular disease is summarized in this review and its clinical implications are discussed.

Acetyl-CoA Carboxylase↗
PubMed2004

Endogenous glucose production, insulin sensitivity, and insulin secretion in normal glucose-tolerant Pima Indians with low birth weight.

Individuals with low birth weight (LBW) are at increased risk of developing type 2 diabetes in later life. Whether impairments in endogenous glucose production (EGP), insulin action, insulin secretion, or a combination thereof account for this association is unclear. We, therefore, examined these parameters in Pima Indians with normal glucose tolerance. Body composition, glucose and insulin responses during a 75-g oral glucose tolerance test (OGTT), EGP, insulin-stimulated glucose disposal during low- and high-dose insulin infusion (M-low and M-high, hyperinsulinemic glucose clamp), and acute insulin response (AIR) to a 25-g intravenous glucose challenge were measured in 230 Pima Indians (147 men and 83 women, aged 25 +/- 0.4 years [mean +/- SE; range, 18 to 44]) with normal glucose tolerance. A subgroup of 63 subjects additionally underwent biopsies of subcutaneous adipose tissue for determination of adipocyte cell size and lipolysis. Subjects in the lowest quartile of birth weight (birth weight: 2,891 +/- 33 g, LBW, n = 58) were compared to those whose birth weight was in the upper 3 quartiles (birth weight: 3,657 +/- 28 g, NBW, n = 172). Age- and sex-adjusted body mass index (BMI), percent body fat, and waist-to-thigh ratio (WTR) were similar in LBW and NBW subjects. Suppression of EGP during the clamp was less in LBW than in NBW subjects before (P = .002) and after adjustment for age, sex, percent body fat, and M-low (P = .02). M-low and M-high were less in LBW than in NBW subjects before (P = .05 and P = .01) and after adjustment for age, sex, percent body fat, and WTR (P = .04 and P = .05). AIR was not different in LBW compared to NBW subjects before adjustments (P = .06), but it was lower in LBW than in NBW subjects after adjustment for age, sex, percent body fat, and M-low (P = .02), suggesting that AIR did not increase appropriately for the decrease in insulin-stimulated glucose disposal (M). In addition, average adipocyte cell size (P = .08) and basal lipolysis (P = .02) were higher in the LBW than in the NBW group. These results show that Pima Indians with LBW manifest a variety of impairments in metabolism in adulthood. Among these, a lesser insulin-stimulated suppression of EGP and a lesser insulin secretory capacity are the predominant ones. We conclude that interaction of multiple defects may contribute to increased susceptibility to type 2 diabetes among individuals with LBW.

Adipocytes↗
PubMed2004

C825T polymorphism of the G protein beta3 subunit is associated with obesity but not with insulin sensitivity.

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.

Adipose Tissue↗
PubMed2004

Intramyocellular lipids and insulin resistance.

Lipids are stored not only in adipocytes but also 'ectopically' in tissues such as muscle, liver, beta cells and others. From a metabolic perspective, intramyocellular lipids (IMCLs) have recently become a focus of interest. This review summarizes history, measurement techniques and interpretation of muscle lipid data. Problems in biopsies with the separation of those metabolically active lipid droplets in the cytoplasm of myocytes from further lipids in adipocytes are discussed as well as considerations important for analysis of correlations between IMCL content and insulin sensitivity under various circumstances. The relatively new approach to non-invasive assessment of the IMCL content by magnetic resonance spectroscopy (MRS) is described in detail and exemplary spectra from different skeletal muscle types in humans are presented. The MRS technique allows human examinations of large cohorts for a detailed assessment of the interactions among metabolic parameters such as age, measures of adiposity, hormonal and ethnic factors and insulin resistance. IMCLs are generally positively correlated with measures of obesity and negatively with insulin sensitivity. Paradoxically, physical fitness (maximal aerobic capacity) increases both IMCL content and insulin sensitivity and therefore has to be taken into account as a confounding factor. Intervention studies with MRS further allowed to elucidate the regulation of IMCL. Molecular mechanisms and potential genetic factors on IMCL regulation are discussed as well as possible mechanisms of current treatment strategies for improving insulin sensitivity.

Animals↗
PubMed2004

Genetic factors and insulin secretion: gene variants in the IGF genes.

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.

Adult↗