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Anderwald C.,Medical University of Vienna | Stadler M.,Hietzing Hospital | Stadler M.,Karl Landsteiner Institute of Metabolic Diseases and Nephrology | Golay A.,University of Geneva | And 3 more authors.

Background: Insulin resistance (IR) is implicated as an independent risk factor for vascular disease. The aim of this study was to assess the impact of family history (FH) of type 2 diabetes (T2DM) and/or cardiovascular disease (CVD) on the associations between IR, low-density-lipoprotein cholesterol (LDL-C) and subclinical atherosclerosis (common and internal carotid artery intima media thickness (IMT)) in healthy European adults. Methods: Participants (n=1048) in the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study were grouped according to family history of: (i) type 2 diabetes (FH-T2DM); (ii) cardiovascular disease (FH-CVD); (iii) both (FH-BOTH); or (iv) neither (CON). Insulin resistance (M-value, hyperinsulinaemic euglycaemic clamp), LDL-C and IMT were examined in relation to FH in all available participants, and then within subcohorts (highest quintiles) with higher LDL-C (>3.5 mmol/l (>135 mg/dl), n=252) or greater IR (M-value<5 mg/min/kg, n=299). Results: Carotid IMTs were comparable across the four FH groups, but insulin sensitivity (M-value) was lower (p<0.01) in FH-T2DM (6.1±2.6 mg/min/kg than in either CON (6.9±2.9 mg/min/kg) or FH-CVD (7.1±2.7 mg/min/kg). Within the highest LDL-C quintile, those with FH-CVD (or FH-BOTH) had higher common and internal carotid IMT (6-12%, p<0.05 vs CON). In contrast, within the most IR quintile, FH-CVD was not associated with IMT. Conclusion: In this cross-sectional analysis, family history of T2DM (but not of CVD) was associated with IR. In the presence of elevated LDL-C, FH-CVD (but not FH-T2DM) was associated with increased carotid IMT. Source

Anderwald C.,Medical University of Vienna | Anderwald C.,National Research Council Italy | Anderwald C.,CNR Institute of Biomedical Engineering | Gastaldelli A.,National Research Council Italy | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism

Background: Several epidemiological studies revealed sex-specific differences during oral glucose tolerance tests (OGTTs), such as higher prevalence of glucose intolerance (i.e. increased glucose at the end of the OGTT) in females, which was not yet explained. Thus, we aimed to analyze sex-related distinctions on OGTT glucose metabolism, including gut absorption, in healthy humans. Methods: Females (n = 48) and males (n = 26) with comparable age (females, 45±1 yr; males, 44±2 yr) and body mass index (both, 25 ± 1 kg/m2) but different height (females, 166 ± 1 cm; males, 180±2 cm; P<0.000001), all normally glucose tolerant, as tested by frequently sampled, 3-h (75-g) OGTTs, underwent hyperinsulinemic [40 mU/(min · m2)] isoglycemic clamp tests with simultaneous measurement of endogenous glucose (D-[6,6-2H2]glucose) production (EGP). EGP and glucose disappearance during OGTT were calculated from logarithmic relationships with clamp test insulin concentrations. After reliable model validation by double-tracer technique (r = 0.732; P < 0.007), we calculated and modeled gut glucose absorption (ABS). Results: Females showed lower (P < 0.05) fasting EGP [1.4 ± 0.1 mg/(kg · min)] than males [1.7 ± 0.1 mg/(kg · min)] but comparable whole-body insulin sensitivity in clamp tests [females, 8.1 ± 0.4 mg/(kg · min); males, 8.3 ± 0.6 mg/(kg · min)]. Plasma glucose OGTT concentrations were higher (P<0.04) from 30-40 min in males but from 120-180 min in females. Glucose absorption rates were 21-46% increased in the initial 40 min in males but in females by 27-40% in the third hour (P < 0.05). Gut glucose half-life was markedly higher in females (79 ± 2 min) than in males (65 ± 3 min, P < 0.0001) and negatively related to body height (r = -0.481; P < 0.0001). Conclusions: This study in healthy, glucose-tolerant humans shows for the first time different ABS rates during OGTT in women and men and a negative relationship between body height and gut glucose half-life. Prolonged ABS in females might therefore contribute to higher plasma glucose concentrations at the end of OGTT. Copyright © 2011 by The Endocrine Society. Source

Anderwald C.-H.,CNR Institute of Biomedical Engineering | Anderwald C.-H.,Medical University of Vienna | Anderwald C.-H.,Community Pharmacy | Tura A.,CNR Institute of Biomedical Engineering | And 11 more authors.
Diabetes Care

OBJECTIVE - Obesity leads to severe long-term complications and reduced life expectancy. Roux-en-Y gastric bypass (RYGB) surgery induces excessive and continuous weight loss in (morbid) obesity, although it causes several abnormal anatomical and physiological conditions. RESEARCH DESIGN AND METHODS - To distinctively unveil effects of RYGB surgery on b-cell function and glucose turnover in skeletal muscle, liver, and gut, nondiabetic, morbidly obese patients were studied before (pre-OP, five female/one male, BMI: 49 ± 3 kg/m2, 43 ± 2 years of age) and 7 ± 1 months after (post-OP, BMI: 37 ± 3 kg/m2) RYGB surgery, compared with matching obese (CONob, five female/one male, BMI: 34 ± 1 kg/m2, 48 ± 3 years of age) and lean controls (CON lean, five female/one male, BMI: 22 ± 0 kg/m2, 42 ± 2 years of age). Oral glucose tolerance tests (OGTTs), hyperinsulinemic-isoglycemic clamp tests, and mechanistic mathematical modeling allowed determination of whole-body insulin sensitivity (M/I), OGTT and clamp test β-cell function, and gastrointestinal glucose absorption. RESULTS - Post-OP lost (P < 0.0001) 35 ± 3 kg body weight. M/I increased after RYGB, becoming comparable to CONob, but remaining markedly lower than CONlean (P < 0.05). M/I tightly correlated (τ = 20.611, P < 0.0001) with fat mass. During OGTT, post-OP showed ≥15%reduced plasma glucose from120 to 180 min (≤4.5mmol/L), and 29-fold elevated active glucagon-like peptide-1 (GLP-1) dynamic areas under the curve, which tightly correlated (r = 0.837, P < 0.001) with 84% increased β-cell secretion. Insulinogenic index (0-30 min) in post-OP was ≥29% greater (P < 0.04). At fasting, post-OP showed approximately halved insulin secretion (P < 0.05 vs. pre-OP). Insulin-stimulated insulin secretion in post-OP was 52%higher than before surgery, but 1-2 pmol/min2 lower than in CON ob/CONlean (P < 0.05). Gastrointestinal glucose absorption was comparable in pre-OP and post-OP, but 9-26%lower from 40 to 90 min in post-OP than in CONob/CONlean (P < 0.04). CONCLUSIONS - RYGB surgery leads to decreased plasma glucose concentrations in the third OGTT hour and exaggerated β-cell function, for which increased GLP-1 release seems responsible, whereas gastrointestinal glucose absorption remains unchanged but lower than in matching controls. © 2012 by the American Diabetes Association. Source

Stadler M.,Hietzing Hospital Vienna | Stadler M.,Kings College London | Peric S.,Karl Landsteiner Institute of Metabolic Diseases and Nephrology | Strohner-Kaestenbauer H.,Karl Landsteiner Institute of Metabolic Diseases and Nephrology | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism

Context and Objective: We investigated long term mortality, requirement for renal replacement therapy (RRT), and incidence of other late diabetic complications in an observational cohort study of 641 people with type 1 diabetes (T1DM). Design: Prospective observational cohort study. Setting: The study was conducted at a Tertiary Diabetes Centre in Vienna, Austria. Patients: Acohort with all people with T1DM (n = 641,47%females, 30 ± 11 years) attending their annual diabetes review was created in 1983-1984. Biomedical data were collected. Main Outcome Measures: In 2013 we investigated mortality rates and incidence rates of RRT by record linkage with national registries and incidence of other major diabetes complications by questionnaire. Results: 156 (24%) patients died [mortality rate: 922 (95%CI: 778-1066) per 100 000 person years]. Fifty-five (8.6%) received RRT [incidence rate: 335 (95%CI: 246-423) per 100 000 person years]. The 380 questionnaires (78% return rate) recorded cardiac events, strokes, limb amputations, and/or blindness, affecting 21.8% of survivors. Mortality and incidence of RRT increased in each quartile of baseline HbA1c, with the lowest rates in the quartile with HbA1c≤6.5% (48 mmol/mol) (P < .05). Conclusions: In people with established type 1 diabetes who were observed for almost three decades, the overall mortality was 24% and the incidence of renal replacement therapy was 8.6%, with a 21.8% combined incidence rate of the other hard endpoints in the surviving people. A clear linear relationship between early glycemic control and the later development of end stage renal disease and mortality has been found. Copyright © 2014 by the Endocrine Society. Source

Stadler M.,Hietzing Hospital | Stadler M.,Karl Landsteiner Institute of Metabolic Diseases and Nephrology | Anderwald C.,Medical University of Vienna | Pacini G.,National Research Council Italy | And 10 more authors.

OBJECTIVE - So far it is unclear whether chronic peripheral hyperinsulinemia per se might contribute to ectopic lipid accumulation and consequently insulin resistance. We investigated the effects of systemic instead of portal insulin release in type 1 diabetic patients after successful pancreas-kidney transplantation (PKT) with systemic venous drainage on the intracellular lipid content in liver and soleus muscle, endogenous glucose production (EGP), and insulin sensitivity. RESEARCH DESIGN AND METHODS - In nine PKT patients and nine matching nondiabetic control subjects, intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) were measured using 1H nuclear magnetic resonance spectroscopy. Fasting EGP was measured using D-[6,6-2H2]glucose tracer dilution. A 3-h 75-g oral glucose tolerance test (OGTT) allowed us to assess kinetics of glucose, free fatty acids, insulin, and C-peptide concentrations in plasma and to calculate the clamp-like index (CLIX) for insulin sensitivity and the hepatic insulin resistance (HIR) index. RESULTS - The PKT patients displayed approximately twofold increased fasting insulin (20 ± 6 vs. 9 ± 3 μU/ml; P < 0.0002) compared with that in nondiabetic control subjects and ∼10% increased fasting glucose (P < 0.02) concentrations, but during the OGTT areas under the concentration curves of C-peptide and insulin were similar. IHCL (PKT, 2.9 ± 2.5%; nondiabetic control subjects, 4.4 ± 6.6%), IMCL (PKT, 1.0 ± 0.4%; nondiabetic control subjects, 1.0 ± 0.5%), CLIX (PKT, 8 ± 2; nondiabetic control subjects, 7 ± 3), HIR (PKT, 25.6 ± 13.2; nondiabetic control subjects, 35.6 ± 20 [mg · min-1 · kg-1] x [μU/ml]), and EGP (PKT, 1.6 ± 0.2; nondiabetic control subjects, 1.7 ± 0.2 mg · min-1 · kg-1) were comparable between PKT patients and nondiabetic control subjects. IHCL was negatively correlated with CLIX in all participants (r = -0.55; P < 0.04). CONCLUSIONS - Despite fasting peripheral hyperinsulinemia because of systemic venous drainage, type 1 diabetic patients after PKT show similar IHCL, IMCL, insulin sensitivity, and fasting EGP in comparison with nondiabetic control subjects. These results suggest that systemic hyperinsulinemia per se does not cause ectopic lipid accumulation in liver and skeletal muscle. © 2010 by the American Diabetes Association. Source

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