Obesity: Stumvoll M

Blüher M, Tönjes A, Stumvoll M. · No affiliation provided · Hepatology. · Pubmed #18570262 No free full text.

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Stumvoll M, Häring H. · No affiliation provided · Obes Res. · Pubmed #12429885 No free full text.

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Sommer G, Garten A, Petzold S, Beck-Sickinger AG, Blüher M, Stumvoll M, Fasshauer M. · Department of Internal Medicine III, University of Leipzig, 04103 Leipzig, Germany. · Clin Sci (Lond). · Pubmed #19016657 No free full text.

Abstract: Over the last few years, it has become obvious that obesity and insulin resistance are linked by a variety of proteins secreted by adipocytes. Visfatin/PBEF (pre-B-cell colony-enhancing factor) has recently been identified as a novel adipokine with insulin-mimetic effects. Furthermore, an enzymatic function has been reported that reveals visfatin/PBEF as Nampt (nicotinamide phosphoribosyltransferase; EC 2.4.2.12.). Moreover, reports on the structure and hormonal regulation of visfatin/PBEF/Nampt have given further insights into its potential physiological role. The present review summarizes studies on visfatin/PBEF/Nampt as a novel adipokine.

Körner A, Kiess W, Stumvoll M, Kovacs P. · University Hospital for Children and Adolescents, Research Laboratory, University of Leipzig, Leipzig, Germany. · Front Horm Res. · Pubmed #18230892 No free full text.

Abstract: Obesity results from the complex interaction of environmental factors that act on a genetic background that determines the susceptibility to obesity. The identification of such obesity susceptibility genes can provide important insights into the mechanism underlying this condition. While candidate gene approaches have not been tremendously successful in identifying relevant genetic contributors to obesity, except PPAR , the advent of genome-wide strategies has recently revealed novel and unexpected genetic factors with strong associations with obesity and/or diabetes, i.e. FTO, TCF7L2, INSIG2, ENPP1, or FASN (reviewed herein), although some of them are not undebated. Considering the function of the encoded proteins, it will now be of interest to investigate the cellular and molecular mechanisms, how these genetic variations affect body weight, energy metabolism and/or obesity-associated morbidity.

Kralisch S, Bluher M, Paschke R, Stumvoll M, Fasshauer M. · Department of Internal Medicine, University of Leipzig, Leipzig, Germany. · Mini Rev Med Chem. · Pubmed #17266636 No free full text.

Abstract: The role of adipocytes has been recently better understood. Several adipocytokines have been identified, including leptin, a main regulator of appetite and energy expenditure, adiponectin and others, as novel insulin-sensitizers/insulin-mimetics, and some others inducing insulin resistance. Adipocytokines thus represent interesting novel drug targets in the future management of obesity.

Klöting N, Stumvoll M, Blüher M. · Medizinische Klinik und Poliklinik III, Universität Leipzig, 04103 Leipzig, Deutschland. · Internist (Berl). · Pubmed #17216235 No free full text.

Abstract: Visceral obesity is an independent risk factor for the development of cardiovascular diseases and type 2 diabetes. This is likely to be due to biological characteristics of visceral tissue, which are different from those of subcutaneous adipose tissue in terms of decreased insulin sensitivity and increased lipolytic activity. In addition, the anatomical site of visceral fat could be one potential reason for the increased cardio-metabolic risk associated with visceral obesity. Visceral adipose tissue drains into the portal vein and therefore the liver is exposed to the undiluted metabolites and adipokines released from visceral fat. There are profound differences between visceral and subcutaneous adipocytes in the metabolism, expression of specific receptors and secretion of a specific adipokine pattern, which could contribute to the adverse consequences of visceral obesity.

Blüher M, Stumvoll M. · Medizinische Klinik und Poliklinik III, Universität Leipzig, Leipzig, Germany. · Dtsch Med Wochenschr. · Pubmed #17139576 No free full text.

Abstract: In the last years type 2 diabetes has reached almost epidemic proportions. More than 170 million individuals are affected worldwide, about 6 million in Germany. In the pathogenesis of type 2 diabetes, insulin resistance in liver, fat and muscle as well as the inability of the pancreatic beta-cell to fully compensate for this insulin resistance are the central pathophysiological events. Both genetic and environmental factors, such as lack of physical exercise and hypercaloric nutrition play a major role in this process, although the precise mechanisms for type 2 diabetes development remain largely unknown. In the characterization of the role of liver, adipose tissue and skeletal muscle in the pathogenesis of type 2 diabetes, tissue specific knockout mouse models have challenged our concepts of glucose homeostasis.

Pliquett RU, Führer D, Falk S, Zysset S, von Cramon DY, Stumvoll M. · University of Leipzig, Faculty of Medicine, III. Medical Department, Leipzig, Germany. · Horm Metab Res. · Pubmed #16933179 No free full text.

Abstract: Appetite and satiety are subject to complex regulation, with neuroendocrine mechanisms playing an important role. The central nervous system is attracting increasing attention as a target tissue for many hormones such as leptin, PYY3-36, ghrelin, glucagon-like-peptide 1 and many others. Among its many well-known functions, insulin is also a potent anorexigenic hormone, and insulin receptors are widely distributed throughout the central nervous system. One way to advance our understanding of central nervous regulation of hunger and satiety in humans is to develop suitable neuroimaging techniques for use in various clinical and experimental conditions. Several studies have been performed using functional magnetic resonance imaging and positron emission tomography to identify areas of the brain that are differentially activated by alteration of the feeding state. These preliminary data are taking shape as a complex neuronal network involving the hypothalamus, thalamus, limbic and paralimbic areas including the insular cortex and the anterior cingulate gyrus and the orbitofrontal cortex. Continuous efforts to understand hormonal effects on these pathways may advance our understanding of human obesity.

Kovacs P, Stumvoll M. · 3rd Medical Department, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103, Germany. · Best Pract Res Clin Endocrinol Metab. · Pubmed #16311221 No free full text.

Abstract: 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.

Kralisch S, Klein J, Bluher M, Paschke R, Stumvoll M, Fasshauer M. · Department of Internal Medicine III, University of Leipzig, Ph.-Rosenthal-Str.27, 04103 Leipzig, Germany. · Expert Opin Pharmacother. · Pubmed #15952917 No free full text.

Abstract: 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.

Stumvoll M, Goldstein BJ, van Haeften TW. · Third Medical Department, University of Leipzig, Leipzig, Germany. · Lancet. · Pubmed #15823385 No free full text.

Abstract: Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas beta-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy.

Fasshauer M, Paschke R, Stumvoll M. · Department of Internal Medicine III, University of Leipzig, Rosenthal-Street 27, 04103 Leipzig, Germany. · Biochimie. · Pubmed #15589686 No free full text.

Abstract: 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.

Machann J, Häring H, Schick F, Stumvoll M. · Department of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Tübingen, Germany. · Diabetes Obes Metab. · Pubmed #15171747 No free full text.

Abstract: 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.

Stumvoll M. · 3rd Medical Department, University of Leipzig, Philipp-Rosenthal-Str. 27, 04301 Leipzig, Germany. · Diabetologia. · Pubmed #15114471 No free full text.

Abstract: Regulation of glycaemia represents a fundamental biological principle, and its failure underlies Type 2 diabetes. The complex aetiology of Type 2 diabetes, which probably involves a medley of molecular mechanisms, requires dissection out of diabetes-associated subphenotypes, such as the non-obese with increased liver fat or the obese with low plasma adiponectin. The concepts of the hyperbolic relationship of insulin secretion and insulin sensitivity with glucose allostasis help us to establish the pathophysiological framework within which such mechanisms must operate. The translation of burgeoning new basic science findings into a physiological and clinical context calls for novel and imaginative clinical experimental tools. For the purpose of this review, four molecules (adiponectin [APM1], stearoyl CoA desaturase-1 [SCD1], insulin receptor substrate-1 [IRS1], peroxisome proliferator-activated receptor-gamma [PPARG]), each with a plausible role in the disease process, have been selected to illustrate the use of such techniques in humans. These include procedures as diverse as isotope dilution for turnover studies (e.g. glycerol turnover as a proxy for lipolysis), conventional and modified clamp procedures, association studies of functionally relevant single nucleotide polymorphisms in candidate genes (e.g. IRS-1 and PPAR gamma), multivariate correlational analyses (as with plasma adiponectin), magnetic resonance spectroscopy to quantify intra-tissue lipid deposition and regional fat distribution, and gas chromatography to determine fatty acid patterns in selected lipid fractions as proxy for intrahepatic enzyme activity. A concerted effort by scientists from many disciplines (genetics and cell biology, physiology and epidemiology) will be required to bridge the growing gap between basic scientific concepts of biological modifiers of glycaemia and concepts that are truly relevant for human Type 2 diabetes.

Stefan N, Stumvoll M. · Clinical Nutrition and Metabolism Section, NIDDK, NIH, Phoenix, Arizona 85016, USA. · Horm Metab Res. · Pubmed #12384822 No free full text.

Abstract: Adiponectin is a recently identified adipose tissue-derived protein (adipocytokine) with important metabolic effects. It is exclusively expressed in adipose tissue and released into the circulation. Adiponectin expression and/or secretion is increased by insulin like growth factor-1 and ionomycin, and decreased by tumor necrosis factor-alpha, glucocorticoids, beta-adrenergic agonists and cAMP. Data for insulin are somewhat inconclusive. Moreover, adiponectin expression and secretion are increased by activators of peroxisome proliferator-activated receptor (PPAR)-gamma. Besides inhibiting inflammatory pathways, recombinant adiponectin increases insulin sensitivity and improves glucose tolerance in various animal models. This insulin-sensitizing effect appears to be mostly attributable to enhanced suppression of glucose production, but beneficial effects on muscle cannot be excluded. In humans, plasma adiponectin concentrations exceed those of any other hormone by a thousand times; they decrease with obesity and are positively associated with whole-body insulin sensitivity. Therefore, low adiponectin may contribute to the decrease in whole-body insulin sensitivity that accompanies obesity. Furthermore, there is increasing evidence that genetic variants in the adiponectin gene itself and/or in genes encoding adiponectin-regulatory proteins--such as PPAR-gamma--may be associated with hypoadiponectinemia, insulin resistance and type 2 diabetes. This suggests that adiponectin may reflect PPAR-gamma activity in vivo. Finally, reversal or alleviation of hypoadiponectinemia may represent a target for development of drugs improving insulin sensitivity and glucose tolerance.

Stumvoll M, Häring HU. · Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany. · Ann Med. · Pubmed #12173692 No free full text.

Abstract: With the thiazolidinediones rosiglitazone and pioglitazone a novel treatment modality for type 2 diabetes has become available in many countries. As monotherapy, fasting blood glucose and glycosylated hemoglobin (HbA1c), on average, can be improved by approximately 40 mg/dl and almost 1%, respectively. In combination with other agents their efficacy is additive. Thiazolidinediones reduce insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity. The mechanism of action involves binding to the peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also in other tissues. It is likely that thiazolidinediones primarily act in adipose tissue where PPARgamma is predominantly expressed. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g. free fatty acids, adipocytokines such as tumor necrosis factor alpha, resistin, adiponectin) in a way that results in net improvement of insulin sensitivity (i.e. in muscle and liver). Nevertheless, a direct molecular effect in skeletal muscle cannot be excluded. Interference with transcription entails a potential for side-effect risk, that cannot definitively be assessed yet. For example, the in-vitro stimulation of adipogenic differentiation may underlie the clinical observation of weight gain. Theoretically, this may turn out to be counterproductive in the long run. However, there is not sufficient evidence from humans at the moment, especially no long-term data, to allow a conclusive statement. The hepatotoxicity observed with troglitazone, on the other hand, does not seem to be PPARgamma-mediated but secondary to toxic metabolites. Based on differences in drug metabolism this problem is relatively unlikely to occur with rosiglitazone or pioglitazone. Unexplained but not unimportant is the propensity for fluid retention. In summary, with the thiazolidinediones a novel concept for the treatment of insulin resistance is available that in theory could also be used for prevention of type 2 diabetes. Long-term data are indispensable for a final risk-benefit assessment of these substances.

Stumvoll M, Häring H. · University Hospital, Department of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-Universität, Tübingen, Germany. · Diabetes. · Pubmed #12145143 links to  free full text

Abstract: Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor with a key role in adipocyte differentiation. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-gamma2 is associated with reduced risk for type 2 diabetes. The effect on the individual is weak, but because of a prevalence of >75% of the high-risk Pro allele, the population-attributable risk is enormous. The in vivo effects of the polymorphism are secondary to alterations in adipose tissue, where PPAR-gamma2 is predominantly expressed. Moderate reduction in transcriptional activity of PPAR-gamma as a result of the polymorphism modulates production and release of adipose-derived factors. Both decreased release of insulin-desensitizing free fatty acids, tumor necrosis factor-alpha, and resistin and increased release of the insulin-sensitizing hormone adiponectin result in secondary improvement of insulin sensitivity of glucose uptake and suppression of glucose production. The population effect of this polymorphism may be modulated by environmental or genetic factors such as obesity, ethnicity, ratio of unsaturated to saturated fatty acids, and genetic background. Once diabetes has developed, the protective effect of the Ala allele may be lost, since increased vascular complications and more pronounced beta-cell dysfunction have been reported. These observations, however, are currently unexplained. In conclusion, the Pro12Ala polymorphism in PPAR-gamma2 represents the first genetic variant with a broad impact on the risk of common type 2 diabetes. The precise understanding of its mechanism may lead to novel diagnostic, preventive, and therapeutic approaches for improving the management of type 2 diabetes.

Stumvoll M, Häring H. · Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany. · Horm Res. · Pubmed #11684868 No free full text.

Abstract: Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.

Stumvoll M, Gerich J. · Medical Clinic, Department of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-Universität, Tübingen, Germany. · Clin Lab Med. · Pubmed #11321936 No free full text.

Abstract: Type 2 diabetes mellitus is a heterogeneous disorder characterized by varying degrees of impaired insulin secretion and insulin resistance. The metabolic manifestations of insulin resistance include (1) reduced insulin-stimulated glucose uptake, (2) reduced insulin-suppression of endogenous glucose production, and (3) reduced antilipolysis. All of these mechanisms contribute to the hyperglycemis of T2DM, both post-absorptively and postprandially. In addition, insulin resistance is involved in decreaswed insulin-induced vasodilation, dyslipidemia, and platelet hyperaggregability. The pathogenesis of T2DM involves a combination of genetic and environmental factors. Monogenic causes account for only a minority of insulin resistance and beta cell dysfunction. Among environmental factors the most important are obesity, reduced physical activity, and age. Obesity-associated insulin resistance is thought to be mediated mainly by FFAs whose clearance is reduced in subjects with T2DM. A number of clinical tests have been developed to assess insulin sensitivity and beta cell function in vivo. The euglycemic hyperinsulinemic clamp and the hyperglycemic clamp, respectively, represent the gold standard procedures. Recently, indices calculated parameters of the OGTT have been proposed as surrogates for assessing both insulin sensitivity and beta cell function in clinical situations and epidemiologic studies.

Thamer C, Machann J, Tschritter O, Haap M, Wietek B, Dahl D, Bachmann O, Fritsche A, Jacob S, Stumvoll M, Schick F, Häring HU. · Department of Endocrinology and Metabolism, Eberhard-Karls-University, Tübingen, Germany. · Horm Metab Res. · Pubmed #12660875 No free full text.

Abstract: The recently identified adipocytokine adiponectin has been shown to improve insulin action and decrease triglyceride content in skeletal muscle (by stimulating lipid oxidation) in mice. In the present study, we tested the hypothesis that high serum concentrations of adiponectin are associated with lower intramyocellular (IMCL) fat content by promoting lipid oxidation in humans. IMCL-content in predominantly non-oxidative tibialis anterior muscle and oxidative soleus was determined by proton magnetic resonance spectroscopy in a cross- sectional study involving 63 healthy volunteers. In a second set of experiments, changes in IMCL in both muscles were measured after a three days dietary lipid challenge (n = 18) and after intravenous lipid challenge (n = 12) with suppressed lipid oxidation under hyperinsulinemia. Adiponectin serum concentrations were found to be negatively correlated with IMCL in the oxidative soleus muscle (IMCL [sol]) (r = - 0.46, p < 0.001) independent of measures of obesity, but not with IMCL in the non-oxidative tibialis anterior muscle (IMCL [tib]) (p = 0.40). Adiponectin serum concentrations were negatively correlated with the observed increase in IMCL load after dietary lipid challenge in the tibialis (r = 0.53, p = 0.03) but not in the soleus muscle. During suppression of lipid oxidation by hyperinsulinemia, no effect of adiponectin on IMCL was observed in either soleus or tibialis muscle. Overall, the presented findings are consistent with the hypothesis that adiponectin promotes lipid oxidation in humans resulting in lower intracellular lipid content in human muscle. These results are consistent with animal data, where adiponectin could be shown to enhance lipid oxidation and reduce muscle triglycerides.

Stefan N, Stumvoll M, Bogardus C, Tataranni PA. · Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA. · Am J Physiol Endocrinol Metab. · Pubmed #12582008 links to  free full text

Abstract: High concentrations of nonesterified fatty acids (NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians. To test this hypothesis, fasting plasma NEFA concentrations, body composition, insulin action (M), acute insulin response (AIR, 25-g IVGTT), and glucose tolerance (75-g OGTT) were measured in 151 Pima Indians [107 normal glucose tolerant (NGT), 44 impaired glucose tolerant (IGT)] at the initial visit. These subjects, participants in ongoing studies of the pathogenesis of obesity and type 2 diabetes, had follow-up measurements of body composition, glucose tolerance, M, and AIR. In NGT individuals, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were negatively associated with AIR after adjustment for age, sex, percent body fat, and M (P = 0.03). Longitudinally, high fasting plasma NEFA concentrations at the initial visit were not associated with change in AIR. In individuals with IGT, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were not associated with AIR. Longitudinally, high fasting plasma NEFA concentrations at the initial visit were associated with a decrease in AIR before (P < 0.0001) and after adjustment for sex, age at follow-up, time of follow-up, change in percent body fat and insulin sensitivity, and AIR at the initial visit (P = 0.0006). In conclusion, findings in people with NGT indicate that fasting plasma NEFA concentrations are not a primary etiologic factor for beta-cell failure. However, in subjects who have progressed to a state of IGT, chronically elevated NEFA seem to have a deleterious effect on insulin-secretory capacity.

Fritsche A, Schmülling RM, Häring HU, Stumvoll M. · Department of Endocrinology, Metabolism and Pathobiochemistry, Eberhard-Karls-Universität, Tübingen, Germany. · Acta Diabetol. · Pubmed #10928231 No free full text.

Abstract: Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy.

Hoffmann K, Planitz C, Rüschendorf F, Müller-Myhsok B, Stassen HH, Lucke B, Mattheisen M, Stumvoll M, Bochmann R, Zschornack M, Wienker TF, Nürnberg P, Reis A, Luft FC, Lindner TH. · Institute of Medical Genetics, Charité University Medicine Berlin, Germany. · J Hypertens. · Pubmed #19373111 No free full text.

Abstract: OBJECTIVE: Genome-wide linkage studies and genome-wide association studies have not as yet identified major genes contributing to primary hypertension in the general population. This state-of-affairs suggests considerable heterogeneity with small contributing effects for primary hypertension, or other complex genetic traits, in outbred populations. Isolated populations, as recent data from Iceland and French Canada suggest, could offer a solution to this problem. METHODS: We studied a Slavic isolate in Germany, the Sorbs, and genotyped 1040 polymorphic microsatellite markers in 87 multigeneration families. RESULTS: Our genome-wide linkage scan revealed a locus on chromosome 1p36.13 at D1S3669-D1S2826 (40.95 cM Marshfield coordinates; logarithm of the odds = 3.45, nominal P = 0.00003) that reached genome-wide significance (P = 0.004), indicating the increased power in isolated populations. The chromosome 1 locus maps to a region in which traits such as diabetes, hyperlipidemia, obesity and BMI cluster. CONCLUSION: Our results suggest that this locus contributes to the metabolic syndrome, and that further attention in this and other populations is warranted.

Blüher M, Bashan N, Shai I, Harman-Boehm I, Tarnovscki T, Avinaoch E, Stumvoll M, Dietrich A, Klöting N, Rudich A. · Department of Medicine, University of Leipzig, 04107 Leipzig, Germany. · J Clin Endocrinol Metab. · Pubmed #19351724 No free full text.

Abstract: CONTEXT: Adipose tissue in obesity is thought to be exposed to various stresses, predominantly in intraabdominal depots. We recently reported that p38MAPK and Jun N-terminal kinase (JNK), but not ERK and inhibitory-kappaB kinase beta, are more highly expressed and activated in human omental (OM) adipose tissue in obesity. OBJECTIVE: The aim was to investigate upstream components of the pathways that culminate in activation of p38MAPK and JNK. SETTING AND PATIENTS: Phosphorylation and expression of kinases were studied in paired samples of OM and sc adipose tissue from lean and obese subjects of two different cohorts (n = 36 and n = 196) by Western and real-time PCR analyses. The association with fat distribution, macrophage infiltration, insulin sensitivity, and glucose metabolism was assessed by correlation analyses. Results: The amount of phosphorylated forms of the kinases provided evidence for an activated stress-sensing pathway consisting of the MAP3K Ask1 (but not MLK3 or Tak1), and the MAP2Ks MKK4, 3/6, (but not MKK7), specifically in OM. OM Ask1-mRNA was more highly expressed in predominantly intraabdominally obese persons and most strongly correlated with estimated visceral fat. Diabetes was associated with higher OM Ask1-mRNA only in the lean group. In OM, macrophage infiltration strongly correlated with Ask1-mRNA, but the obesity-associated increase in Ask1-mRNA could largely be attributed to the adipocyte cell fraction. Finally, multivariate regression analyses revealed OM-Ask1 as an independent predictor of whole-body glucose uptake in euglycemic-hyperinsulinemic clamps. CONCLUSIONS: An Ask1-MKK4-p38MAPK/JNK pathway reflects adipocyte stress associated with adipose tissue inflammation, linking visceral adiposity to whole-body insulin resistance in obesity.

Ebert T, Bachmann A, Lössner U, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M. · Department of Internal Medicine III, University of Leipzig, 04103 Leipzig, Germany. · Metabolism. · Pubmed #19303977 No free full text.

Abstract: Angiopoietin-related growth factor (AGF) was recently introduced as a novel liver-derived protein that antagonizes obesity and insulin resistance. In the current study, we investigated circulating AGF levels in relation to renal function and type 2 diabetes mellitus (T2DM). Angiopoietin-related growth factor was determined by enzyme-linked immunosorbent assay in subjects with a glomerular filtration rate greater than 50 mL/min (n = 60, 30 diabetic and 30 nondiabetic) and in patients on chronic hemodialysis (CD; n = 60, 32 diabetic and 28 nondiabetic). Furthermore, AGF was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation. Median serum AGF levels were significantly lower in CD patients (125.9 +/- 96.3 microg/L) as compared with subjects with a glomerular filtration rate greater than 50 mL/min (164.0 +/- 95.4 microg/L) (P < .05). Furthermore, AGF serum levels were significantly increased in diabetic patients (161.7 +/- 114.2 microg/L) as compared with nondiabetic subjects (123.0 +/- 88.2 microg/L) (P < .01). Moreover, CD negatively and T2DM positively predicted AGF concentrations in multiple regression analysis. In addition, fasting serum glucose was independently and positively correlated with circulating AGF in all patients and controls. Our results suggest that renal dysfunction is negatively and T2DM is positively associated with AGF serum levels. Further studies are needed to better elucidate the physiologic significance of circulating AGF in human disease.