PubMed Health⌕ Search

Biomedical subjects

Hans Häring

Publications and source records attributed to Hans Häring.

13 recordsLinked to original sources
PubMed2003

Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPARgamma(2)) is associated with reduced risk for type 2 diabetes. Although increased insulin sensitivity of glucose disposal and lipolysis has been reported, the exact mechanism by which the risk reduction is conferred is not clear. Because the conclusion of greater insulin sensitivity hinged upon lower insulin levels in some studies, it is possible that more efficient insulin clearance is involved. We therefore estimated insulin clearance during a euglycemic hyperinsulinemic clamp (insulin infusion rate divided by steady-state insulin concentration, 229 normal glucose tolerant [NGT] subjects), an oral glucose tolerance test (OGTT) (mean C-peptide divided by mean insulin concentrations, 406 NGT, 54 impaired glucose tolerant or mildly diabetic subjects), and a hyperglycemic clamp (120 minutes, 10 mmol/L, C-peptide divided by insulin in the steady-state, 56 NGT subjects). In the carriers of the Ala allele (prevalence approximately 24%), insulin clearance in all 3 protocols was significantly greater ( approximately 10%), than in controls. While the results from the euglycemic clamp reflect both hepatic and peripheral insulin clearance, those from the OGTT and the hyperglycemic clamp reflect mainly hepatic insulin extraction. Free fatty acids (FFA) during the steady state of the euglycemic hyperinsulinemic clamp were significantly lower in carriers of the Ala allele (26 +/- 5 micromol/L) than in controls (46 +/- 3 micromol/L, P =.02). In conclusion, the Pro12Ala polymorphism is associated with increased insulin clearance. This could be the result of reduced FFA delivery, which has been shown to improve hepatic insulin removal and sensitivity. Because PPARgamma(2) is mainly expressed in adipose tissue, one of the main regulatory effects of the polymorphism may well be the more efficient suppression of (possibly intra-abdominal) lipolysis.

Adult↗
PubMed2003

Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism.

In animals, the adipocyte-derived hormone adiponectin has been shown to improve insulin sensitivity, a key factor in the pathogenesis of type 2 diabetes. In Pima Indians, high plasma adiponectin levels are associated with increased insulin sensitivity and reduced risk of type 2 diabetes. It is unclear whether this is also the case in white individuals and whether an additional beneficial effect on lipid metabolism exists. We therefore analyzed in nondiabetic individuals the associations between plasma adiponectin concentrations and insulin sensitivity measured by a euglycemic-hyperinsulinemic clamp (n = 262) and estimated by an oral glucose tolerance test (OGTT; n = 636) and serum lipid parameters using correlational analysis. Plasma adiponectin concentrations were positively correlated with insulin sensitivity, both measured with the clamp (r = 0.28, P = 0.0015 in women; r = 0.42, P < 0.0001 in men) and estimated from the OGTT (r = 0.37, P < 0.0001 in women; r = 0.41, P < 0.0001 in men) before and after adjusting for sex and percentage of body fat (all P < 0.001). Fasting triglycerides and the free fatty acid (FFA) concentrations during the OGTT (area under the curve) and at 120 min were negatively correlated in both women and men, whereas HDL was positively correlated with plasma adiponectin concentrations (all P < 0.004). Most notable, these relationships remained significant after adjusting for insulin sensitivity of glucose disposal in addition to sex and percentage of body fat (all P < 0.05). In conclusion, high adiponectin predicts increased insulin sensitivity. This relationship is independent of low body fat mass and affects not only insulin-stimulated glucose disposal but also lipoprotein metabolism and insulin-mediated suppression of postprandial FFA release. This suggests pleiotropic insulin sensitizing effects of adiponectin in humans.

Adiponectin↗
PubMed2003

Altered homeostatic adaptation of first- and second-phase beta-cell secretion in the offspring of patients with type 2 diabetes: studies with a minimal model to assess beta-cell function.

We adapted a minimal model to assess beta-cell function during a hyperglycemic glucose clamp and to uncover peculiar aspects of the relationship among beta-cell function, plasma glucose, and insulin sensitivity (IS) in offspring of Caucasian patients with type 2 diabetes (OfT2D). We pooled two data sets of OfT2D (n = 69) and control subjects (n = 45) with normal glucose regulation. Plasma C-peptide was measured during a hyperglycemic clamp ( approximately 10 mmol/l) to quantify model-based first-phase secretion and glucose sensitivity of second-phase secretion (beta). IS was quantified during the hyperglycemic clamp. In the pooled data, first-phase secretion was linearly and negatively related to fasting plasma glucose, but not IS; OfT2D lay on a distinct line shifted to the left of the control subjects. In contrast, beta was negatively related to IS, and OfT2D lay on a distinct line shifted more and more to the left of the control subjects, as IS was worse. Thus, in OfT2D lower beta-cell adaptive responses exist between ambient glycemia and first-phase insulin secretion and between IS and second-phase secretion. Under conditions leading to decreased insulin sensitivity, these disturbed relationships may lead to progression to diabetes in OfT2D.

Adult↗
PubMed2003

Assessing the shape of the glucose curve during an oral glucose tolerance test.

OBJECTIVE: The oral glucose tolerance test (OGTT) is used to define the status of glucose tolerance based on the plasma glucose level at 120 min. The purpose of the present study was to identify parameters that determine the shape of the plasma glucose course measured at 0, 30, 60, 90, and 120 min during an OGTT. RESEARCH DESIGN AND METHODS: OGTT data from 551 subjects (485 with normal glucose tolerance [NGT] and 66 with impaired glucose tolerance [IGT]) were analyzed. We distinguished between "monophasic," "biphasic," and unclassified glucose shapes. A "shape" index based on the extent and the direction of the plasma glucose change in the second hour allowed us to treat shape as a continuous variable. RESULTS: In the biphasic group, the NGT-to-IGT ratio was slightly higher (173/20 vs. 209/40, P = 0.08) and the male-to-female ratio was lower (60/133 vs. 120/129, P = 0.0003). Subjects with a biphasic shape had significantly lower age, BMI, waist-to-hip ratio (WHR), HbA(1c), plasma glucose, and area under the insulin curve (insulin(AUC)) and a better estimated insulin sensitivity and secretion (using validated indexes) than monophasic subjects (all P < 0.05). By adjusting this shape index for glucose(AUC) (as continuous measure of glucose tolerance), correlations with age, BMI, WHR, HbA(1c), and insulin(AUC) were completely abolished. The adjusted shape index was still higher in female than in male subjects but lower in IGT than in NGT subjects (both P = 0.0003). Finally, we tested common polymorphisms in insulin receptor substrate (IRS)-1, IRS-2, calpain-10, hepatic lipase, and peroxisome proliferator-activated receptor-gamma for association with the shape index. CONCLUSIONS: We conclude that the plasma glucose shape during an OGTT depends on glucose tolerance and sex. In addition, genetic factors seem to play a role. The shape index may be a useful metabolic screening parameter in epidemiological and genetic association studies.

Administration, Oral↗
PubMed2003

Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes.

OBJECTIVE: Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness. RESEARCH DESIGN AND METHODS: In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced VO(2max), measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n = 424) and measured by a euglycemic-hyperinsulinemic clamp (n = 185). Subjects included in the study were young (34 +/- 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n = 183), a second-degree relative with T2DM (n = 94), or no family history of T2DM (control subjects, n = 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). RESULTS: BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P = 0.76). The appropriateness of beta-cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 +/- 4 units) versus control subjects (104 +/- 6 units, P = 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results. CONCLUSIONS: In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced VO(2max) precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature.

Adult↗
PubMed2002

Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes.

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.

Adipocytes↗
PubMed2002

Relationships among age, proinsulin conversion, and beta-cell function in nondiabetic humans.

The aim of the present study was to examine the relationships among beta-cell function, proinsulin conversion to insulin, and age. We studied insulin and proinsulin secretion in nondiabetic subjects during an oral glucose tolerance test (OGTT) using published indexes of beta-cell function (n = 379, age 16--68 years) and a modified hyperglycemic clamp (10 mmol/l, additional glucagon-like peptide [GLP-1] infusion, final arginine bolus; n = 50, age 19--68 years). Proinsulin conversion to insulin was assessed using proinsulin/insulin (PI/I) ratios immediately after an acute stimulus (OGTT, 30 min; hyperglycemic clamp, 2.5-5.0 min after glucose and arginine). There was a negative correlation between age and beta-cell function (adjusted for insulin sensitivity, BMI, and fasting glucose) in the OGTT (r = -0.21, P < 0.001) and first phase of the hyperglycemic clamp (r = -0.30, P = 0.03), but not second phase (r = -0.08, P = 0.6) or arginine-induced insulin secretion (r = 0.06, P = 0.7). There was a positive correlation between age and the PI/I ratio in the OGTT (r = 0.24, P < 0.001). Analogously, there was also a positive correlation between age and the PI/I ratio during first phase (r = 0.37, P = 0.009) and arginine stimulation (r = 0.33, P = 0.01) of the hyperglycemic clamp. First-phase insulin secretion of the hyperglycemic clamp was inversely correlated with the PI/I ratio (r = -0.60, P < 0.001). Interestingly, adjusting first-phase secretion rate for the PI/I ratio abolished the linear relationship with age (r = -0.06, P = 0.7). In conclusion, aging is associated with deteriorating beta-cell function and deteriorating proinsulin conversion to insulin. The age effect on insulin secretion appears to be attributable at least in part to an impairment of proinsulin conversion to insulin.

Adult↗
PubMed2002

The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism.

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.

Adipocytes↗
PubMed2002

The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia.

Genetic factors play an important role in the pathogenesis of type 2 diabetes. The relevance to type 2 diabetes of the common polymorphism Glu23Lys in the potassium inward rectifier 6.2 (KIR6.2) gene is still controversial. The aim of this study was to assess whether this polymorphism influences beta-cell function, alpha-cell function, or insulin action. We therefore studied 298 nondiabetic subjects using an oral glucose tolerance test (OGTT) and 75 nondiabetic subjects using a hyperglycemic clamp (10 mmol/l) with additional glucagon-like peptide (GLP)-1 and arginine stimulation. The prevalence of the Lys allele was approximately 37%, and the Lys allele was associated with higher incremental plasma glucose during the OGTT (P = 0.03, ANOVA). Neither first- nor second-phase glucose-stimulated C-peptide secretion was affected by the presence of the polymorphism; nor were maximal glucose-, GLP-1-, or arginine-induced C-peptide secretion rates; nor was insulin sensitivity (all P > 0.7). However, the relative decrease in plasma glucagon concentrations during the 10 min after the glucose challenge was reduced in carriers of the Lys allele (10 +/- 3% decrease from baseline in Lys/Lys, 18 +/- 2% in Glu/Lys, and 20 +/- 2% in Glu/Glu; P = 0.01, ANOVA). In conclusion, our findings suggest that the common Glu23Lys polymorphism in KIR6.2 is not necessarily associated with beta-cell dysfunction or insulin resistance but with diminished suppression of glucagon secretion in response to hyperglycemia. Our findings thus confirm its functional relevance for glucose metabolism in humans.

Adult↗
PubMed2002

Retraction.

Explore the source record for details and available documents.

Retraction Notice↗
PubMed2001

Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity.

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene is associated with a reduced risk of type 2 diabetes. A beneficial effect on insulin sensitivity is reported in some but not all populations. It is possible that this genetic variant produces a characteristic phenotype only against a certain genetic background. We therefore tested the hypothesis that carriers of the Ala allele of PPARgamma2 exhibit a different phenotype against the background of the Gly972Arg polymorphism in the insulin receptor substrate (IRS) 1. We determined insulin sensitivity in the four combinations defined by the absence or presence of the polymorphic allele (healthy, glucose tolerant subjects), by the oral glucose tolerance test (OGTT; using a validated index, n=318) and hyperinsulinemic clamp ( n=201). Insulin sensitivity was not or was only marginally different between Pro/Pro and X/Ala in the overall population. Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARgamma2) + X/Arg (IRS-1) than in Pro/Pro (PPARgamma2) + X/Arg (IRS-1). On the other hand, insulin sensitivity was similar in the X/Ala (PPARgamma2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARgamma2) + Gly/Gly (IRS-1). The results were practically identical using insulin sensitivity from the clamp. In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARgamma) which was not present in the whole population or against the Gly972 (IRS-1) background. This suggests that the Ala allele of PPARgamma2 becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism. Allowing for gene-gene interaction effects may reveal novel information regarding metabolic effects of genetic variants.

Amino Acid Substitution↗