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Biomedical subjects

Norbert Stefan

Publications and source records attributed to Norbert Stefan.

At least 19 recordsLinked to original sources
PubMed2006

Effect of genotype on success of lifestyle intervention in subjects at risk for type 2 diabetes.

Lifestyle intervention programs including increased physical activity and healthy nutrition have been proven to delay the onset of type 2 diabetes. This is achieved mainly by reducing body weight and improving insulin sensitivity. However, response to lifestyle or dietary interventions does differ between individuals, and the genetic or environmental factors that may account for these differences are not yet precisely characterized. Identification of these factors would be desirable in order to provide an individually tailored preventive strategy for patients at risk of developing diabetes. This review summarizes the so far known genetic variations, which determine responders and nonresponders to a lifestyle intervention. In addition, general methodological approaches to study gene-lifestyle interactions are described.

Diabetes Mellitus, Type 2↗
PubMed2006

Upstream transcription factor 1 gene polymorphisms are associated with high antilipolytic insulin sensitivity and show gene-gene interactions.

Upstream transcription factor 1 (USF1) regulates the expression of many genes involved in lipid and glucose metabolism, among them genes regulating lipolysis. USF1 specifically regulates the expression of the hormone-sensitive lipase gene (HSL) in adipocytes and the hepatic lipase gene (LIPC) in the liver, which was found to be involved in liver fat accumulation. The usf1s1 C > T and usf1s2 G > A single-nucleotide polymorphisms (SNPs) in USF1 are associated with increased in vitro catecholamine-induced lipolysis in adipocytes. We investigated first whether SNPs in USF1 affect the lipolysis-suppressing action of insulin in vivo, and second, whether they interact with the -60C > G SNP in HSL on lipolysis and the -514C > T SNP in LIPC on liver fat. The usf1s1 C > T and usf1s2 G > A SNPs, together with the SNPs in HSL and LIPC, were determined in 407 Caucasians. Lipolysis was estimated as a change in free fatty acid (FFA) levels from baseline to 2 h of a 75-g oral glucose tolerance test (OGTT). Fifty-four subjects had data from a euglycemic hyperinsulinemic clamp with calculation of antilipolytic insulin sensitivity. Subjects carrying the minor alleles (T of usf1s1 and A of usf1s2) had lower 2 h FFA (p = 0.01) and a larger decrease in FFA concentrations during the OGTT (p = 0.02). Antilipolytic insulin sensitivity was higher in these individuals (p = 0.03). No interaction of the usf1s1 C > T and usf1s2 G > A SNPs with the -60C > G SNP in HSL on antilipolytic insulin sensitivity was detected. Liver fat, measured by (1)H magnetic resonance spectroscopy, was elevated only in subjects who were both homozygous for the major alleles of usf1s1 and usf1s2 and carriers of the T allele of the -514C > T SNP in LIPC (p = 0.01). In conclusion, subjects carrying the T allele of SNP usf1s1 and the A allele of SNP usf1s2 have a higher antilipolytic insulin sensitivity. Moreover, both SNPs may interact with the -514C > T SNP in LIPC to determine liver fat.

Adipocytes↗
PubMed2006

The relationships of plasma adiponectin with a favorable lipid profile, decreased inflammation, and less ectopic fat accumulation depend on adiposity.

BACKGROUND: The metabolic effects of adiponectin, including insulin sensitivity, seem to become stronger with increasing adiposity. Adiposity may also affect the relationship of adiponectin concentrations with serum lipid profile; markers of inflammation, atherosclerosis, and endothelial function; and ectopic fat accumulation. METHODS: We measured plasma adiponectin concentrations, serum lipids, and serum markers of inflammation, atherosclerosis, and endothelial function in 242 Caucasians without type 2 diabetes. We also measured visceral adipose tissue with magnetic resonance tomography and liver and intramyocellular fat with (1)H magnetic resonance spectroscopy. RESULTS: We divided the study participants into 2 groups: lean [mean (SE) total body fat, 26% (0.6%); n = 119] and obese [36% (0.6%); n = 123]. In the obese group, plasma adiponectin concentrations showed a strong positive association with concentrations of HDL cholesterol (P <0.0001) and negative associations with LDL cholesterol, triglycerides, high-sensitivity C-reactive protein, interleukin 6, apolipoprotein B(100), soluble E-selectin, soluble vascular cellular adhesion molecule 1, plasminogen activator inhibitor 1, leukocyte count, and liver and intramyocellular fat (all P <0.03). In the lean group, adiponectin showed a less strong association with HDL cholesterol (P = 0.005) and liver fat (P = 0.03) and no significant associations with the other variables (all P >0.10). High visceral adipose tissue was a strong predictor of low adiponectin concentrations, particularly in the obese group, and attenuated many of the significant relationships. CONCLUSIONS: High adiponectin plasma concentrations are associated with favorable lipid profiles, decreased subclinical inflammation, decreased markers of atherosclerosis and endothelial function, and low ectopic fat accumulation, particularly in obese persons. Adiponectin may also have a concentration-related effect on the relationship between visceral adipose tissue and these metabolic characteristics, especially in obese persons.

Adiponectin↗
PubMed2006

Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1.

Insulin resistance in skeletal muscle is found in obesity and type 2 diabetes. A mechanism for impaired insulin signaling in peripheral tissues is the inhibition of insulin action through serine phosphorylation of insulin receptor substrate (Irs) proteins that abolish the coupling of Irs proteins to the activated insulin receptor. Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. In analogy, in lymphocytes of obese hyperleptinemic human subjects basal Ser-318 phosphorylation levels were increased compared to lean individuals. During a hyperinsulinemic euglycemic clamp, the increment in Ser-318 phosphorylation observed in lean individuals was absent in obese. In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects.

Adult↗
PubMed2006

New imaging techniques of fat, muscle and liver within the context of determining insulin sensitivity.

Body fat distribution and ectopic fat deposition are important determinants of insulin sensitivity. Fat deposition in muscle and the liver, in particular, has been found to impair insulin signalling in these insulin-sensitive tissues. Thus, exact quantification of fat content may help to distinguish between different sites of insulin resistance. Increased fat deposition in the visceral compartment compared with the subcutaneous depot also represents an important factor leading to insulin resistance. Recent data clearly showed that visceral fat is a strong determinant of liver fat content. Exact quantification of fat distribution by magnetic resonance imaging and magnetic resonance spectroscopy may help to define distinct 'fat-distribution phenotypes'. This may allow a search for new candidate genes for type 2 diabetes mellitus and identify, at an early stage, individuals at risk for decline in insulin sensitivity.

Body Fat Distribution↗
PubMed2006

Hepatic lipid accumulation in healthy subjects: a comparative study using spectral fat-selective MRI and volume-localized 1H-MR spectroscopy.

Fat-selective MRI was applied to assess the amount and spatial distribution of hepatic lipids (HL) in healthy subjects. The results were compared with those obtained by localized 1H-MR spectroscopy (MRS). Ninety subjects (23-63 years old) underwent single-slice fat-selective MRI with spatial-spectral excitation and volume-localized spectroscopy at 1.5 T. HLs were analyzed in ventral and dorsal regions of interest (ROIs) of the liver in fat-selective images. Spectra were evaluated using the integral signal of methylene and methyl signals. The fat-selective images showed smooth and homogeneous distribution of HL over the entire cross section of the liver. There was, however, a marked interindividual variability in the amount of HL. MRS revealed a lipid signal fraction between 0.5% and 39.3%. The fat content in the ROIs in images correlated well with the spectroscopic results (r >or= 0.95). Both techniques provide sufficient sensitivity for a reliable and quantitative assessment of liver steatosis in subjects without liver disease. 1H-MRS has a higher sensitivity compared to MRI, especially for small amounts of HL, which may be of interest for metabolic interventions. Fat-selective images provide more spatial information about fat distribution, which makes this technique suitable for clinical imaging of patients with liver disease.

Adult↗
PubMed2006

Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans.

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.

Adipose Tissue↗
PubMed2005

A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance.

CONTEXT: The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed in a variety of tissues including liver and skeletal muscle. In animal models, knockout of Kv1.3 has been found to improve insulin sensitivity and glucose tolerance. OBJECTIVE: We examined whether mutations in the Kv1.3 gene exist in humans and whether they are associated with alterations of glucose homeostasis. DESIGN AND SETTING: We conducted a genotype-phenotype association study at a university hospital. PARTICIPANTS AND METHODS: In 50 nondiabetic subjects, we screened approximately 4.5 kb of chromosome 1 comprising the single exon, the promoter/5'-untranslated region, and the 3'-untranslated region of the human Kv1.3 gene for mutations by direct sequencing. Subsequently, all identified single-nucleotide polymorphisms were analyzed in 552 nondiabetic subjects who underwent an oral glucose tolerance test (OGTT). Of these, 304 had undergone an additional hyperinsulinemic euglycemic clamp. MAIN OUTCOME MEASURES: We assessed postprandial blood glucose during OGTT and insulin sensitivity measured by hyperinsulinemic euglycemic clamp. RESULTS: We identified five single-nucleotide polymorphisms in the promoter region (T-548C, G-697T, A-845G, T-1645C, and G-2069A) with allelic frequencies of the minor allele of 26, 23, 9, 41, and 16%, respectively. The -1645C allele was associated with higher plasma glucose concentrations in the 2-h OGTT (P = 0.03) even after adjustment for sex, age, and body mass index (P = 0.002). In addition, it was associated with lower insulin sensitivity (P = 0.01, adjusted for sex, age, and body mass index). Functional in vitro analysis using EMSA showed differential transcription factor binding to the T-1645C polymorphism. CONCLUSIONS: We show that a variant in the promoter of the Kv1.3 gene is associated with impaired glucose tolerance and lower insulin sensitivity. Therefore, the Kv1.3 channel represents a candidate gene for type 2 diabetes.

3' Untranslated Regions↗
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

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↗
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

Palmitate-induced interleukin-6 expression in human coronary artery endothelial cells.

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.

Adult↗
PubMed2004

Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians.

There is evidence from animal models of obesity and type 2 diabetes that increased parasympathetic vagal input to the pancreas contributes to hyperinsulinemia. Compared with Caucasians, Pima Indians have a high risk of type 2 diabetes and exhibit marked hyperinsulinemia and elevated plasma levels of pancreatic polypeptide (PP), an islet hormone considered a surrogate marker of parasympathetic nervous system (PNS) drive to the pancreas. To test if hyperinsulinemia in Pima Indians is due to increased vagal input to the beta-cell, we examined the effect of PNS blockade in 17 Caucasian (aged 35 +/- 8 years, body fat 23 +/- 7% [mean +/- SD]) and 17 Pima Indian males (aged 28 +/- 8 years, body fat 29 +/- 5%) with normal glucose tolerance. Each participant underwent four consecutive standardized liquid meal tests (64% carbohydrate, 22% fat, and 14% protein) during which a primed infusion of atropine was administered for 120 min at the following doses: 0, 2.5, 5, and 10 micro g. kg fat-free mass (FFM)(-1). h(-1). Areas under the curve for early (AUC(0-30 min)) and total (AUC(0-120 min)) postprandial insulin and PP secretory responses were calculated. Early postprandial insulin and PP secretory responses were higher in Pima Indians compared with those of Caucasians (both P = 0.01). Secretion of insulin and PP was inhibited by atropine (both P < 0.001). Increasing doses of atropine attenuated the ethnic difference in PP (P = 0.01) but not in early insulin secretory responses (P = 0.6), an effect that was not due to differences in gastric emptying rate (acetaminophen test) and/or circulating glucose. Similar results were observed for total secretory responses. These results confirm that compared with Caucasians, Pima Indians have an exaggerated PNS drive to pancreatic F-cells that secrete PP. However, the hyperinsulinemia of this population does not appear to be due to increased vagal input to pancreatic beta-cells.

Adult↗