Thomas Konrad

Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon‐α

Epidemiological data suggest that chronic hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. Therapy of HCV infection with recombinant interferon‐α (r‐IFN‐α) can also impair of glucose metabolism.

Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women

OBJECTIVE The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. RESEARCH DESIGN AND METHODS We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. RESULTS In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). CONCLUSIONS In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes.

Effect of sedentary behaviour and vigorous physical activity on segment-specific carotid wall thickness and its progression in a healthy population

AIMS This study investigated whether sedentary behaviour and different activity levels have an independent association with carotid intima-media thickness (IMT) and with the 3-year IMT progression in different carotid segments. METHODS AND RESULTS The study population included 614 healthy men and women (mean age = 44 +/- 8 years) without carotid atherosclerosis and without increased coronary heart disease risk, who underwent B-mode carotid ultrasound and objective physical activity assessment by accelerometer (mean monitoring time = 5.7 +/- 1.5 days). Time spent in sedentary (57.6 +/- 9.1%), light (41.0 +/- 9.2%), moderate and vigorous activities was determined. Sedentary behaviour was expressed as the ratio of time spent in sedentary and light activity (sedentary/light ratio) as these two activities occupied the majority of waking time. In 495 subjects, the carotid ultrasound was repeated 3 years after the baseline examination. After adjustment for age and the established risk factors that were independent determinants of carotid wall thickness in our population, sedentary/light ratio was independently associated only with the common carotid artery (CCA) IMT. The 3-year increase in CCA IMT was significantly lower in subjects with periods of vigorous activity (7 +/- 40 microm) when compared with those with light activity only or with periods of moderate activity (22 +/- 51 and 19 +/- 46 microm, respectively, P < 0.05). CONCLUSION The healthy, young-to-middle age population of this study spent more than half of their waking time in sedentary activities. The proportion of time spent in sedentary activities was directly associated with baseline CCA IMT, independently of age and established atherosclerotic risk factors. In the longitudinal analysis, period of vigorous activity influenced the 3-year IMT progression in CCA.

One-Hour Plasma Glucose Identifies Insulin Resistance and β-Cell Dysfunction in Individuals With Normal Glucose Tolerance: Cross-sectional data from the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study

OBJECTIVE Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype. RESEARCH DESIGN AND METHODS A total of 1,205 healthy volunteers (aged 29-61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study. RESULTS One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), beta-cell glucose sensitivity (r = -0.46), and beta-cell rate sensitivity (r = -0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose <or=8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower beta-cell glucose sensitivity (P < 0.001), beta-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, beta-cell glucose sensitivity, beta-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002). CONCLUSIONS Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced beta-cell glucose sensitivity, and reduced beta-cell rate sensitivity.OBJECTIVE Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype. RESEARCH DESIGN AND METHODS A total of 1,205 healthy volunteers (aged 29–61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study. RESULTS One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), β-cell glucose sensitivity (r = −0.46), and β-cell rate sensitivity (r = −0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose ≤8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower β-cell glucose sensitivity (P < 0.001), β-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, β-cell glucose sensitivity, β-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002). CONCLUSIONS Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced β-cell glucose sensitivity, and reduced β-cell rate sensitivity.

Severity of HCV-Induced Liver Damage Alters Glucose Homeostasis in Noncirrhotic Patients with Chronic HCV Infection

Background/Aims: To investigate the link between hepatitis C infection and glucose intolerance, we measured insulin sensitivity, glucose effectiveness and β-cell secretion in noncirrhotic HCV-infected patients with normal glucose tolerance according to WHO criteria as assessed by oral glucose tolerance tests. Methods: Glucose, insulin and C-peptide data from frequently sampled intravenous glucose tolerance tests were analyzed using the minimal modeling technique for glucose and C-peptide to determine insulin sensitivity, glucose effectiveness, first and second phase insulin secretion in noncirrhotic HCV-infected patients (n = 10) and in healthy control subjects (n = 10). Histological activity index (HAI) as well as the extent of fibrosis were evaluated by scoring liver biopsies. Results: Insulin sensitivity (2.72 ± 1.63 vs. 6.84 ± 1.20 10–4 min–1 per µU/ml, p < 0.01) and glucose effectiveness (2.29 ± 0.45 vs. 2.89 ± 0.39 10–2 min–1, p < 0.05) ere significantly lower in patients with HCV-induced liver disease. Insulin sensitivity was negatively related to serum alanine aminotransferase (r = –0.47, p < 0.05) and aspartate aminotransferase concentrations (r = –0.65, p < 0.05). Multiple linear regression analysis revealed a strong relation of insulin sensitivity with fibrosis score and HAI (r = –0.82, p < 0.02 for both). Second phase insulin secretion was significantly enhanced in HCV-infected patients (14.30 ± 2.04 vs. 8.29 ± 1.65 min–1, p < 0.05). Conclusions: HCV-infected patients with normal glucose tolerance are insulin and glucose resistant. The impairment of glucose tolerance appears to be closely related with the severity of HCV-induced liver damage.

Body Composition and Common Carotid Artery Remodeling in a Healthy Population

CONTEXT An independent association between obesity and preclinical carotid atherosclerosis has been demonstrated, however, the pathophysiological links were not clearly established. Body composition (BC) influences systemic hemodynamics and may participate in the remodeling of common carotid artery (CCA), independently of risk factors. OBJECTIVE This study evaluated the association between CCA structure and BC in a large population of healthy subjects. DESIGN This was a cross-sectional study. SETTINGS The study was conducted at 19 European centers. SUBJECTS The study included 627 healthy subjects (252 men, age 30-60 yr, body mass index 17-40 kg/m2). MAIN OUTCOME MEASURES CCA luminal diameter and intima-media thickness were measured on digitized ultrasound images. Acoustic properties of CCA wall were evaluated by digital densitometric analysis and described in terms of mean gray level. BC was assessed by electrical bioimpedance. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and plasma adiponectin levels were measured. Associations between CCA structure, age, BC, and metabolic and atherosclerotic risk factors were analyzed by multivariate regression models. RESULTS Independent factors affecting CCA diameter were fat-free mass and waist girth (standardized r = 0.44 and 0.12; P < 0.01 and < 0.0001; R2 = 0.35); independent correlates of intima-media thickness were age, CCA diameter, systolic blood pressure, and low-density lipoprotein-cholesterol (standardized r = 0.39, 0.25, 0.10, and 0.14; P < 0.005-0.0001; R2 = 0.40). The mean gray level of carotid wall was independently associated with age and waist girth (standardized r = 0.23 and 0.12; P < 0.0001 and = 0.001; R2 = 0.30). CONCLUSIONS Findings of this cross-sectional study suggest that BC modulates CCA diameter, and may induce adaptive changes in carotid wall thickness, independently of metabolic and atherosclerotic factors. Central adiposity modifies the acoustic properties of carotid wall.

One-hour plasma glucose identifies insulin resistance and beta-cell dysfunction in individuals with normal glucose tolerance: cross-sectional data from the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study

OBJECTIVE Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype. RESEARCH DESIGN AND METHODS A total of 1,205 healthy volunteers (aged 29-61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study. RESULTS One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), beta-cell glucose sensitivity (r = -0.46), and beta-cell rate sensitivity (r = -0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose <or=8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower beta-cell glucose sensitivity (P < 0.001), beta-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, beta-cell glucose sensitivity, beta-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002). CONCLUSIONS Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced beta-cell glucose sensitivity, and reduced beta-cell rate sensitivity.OBJECTIVE Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype. RESEARCH DESIGN AND METHODS A total of 1,205 healthy volunteers (aged 29–61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study. RESULTS One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), β-cell glucose sensitivity (r = −0.46), and β-cell rate sensitivity (r = −0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose ≤8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower β-cell glucose sensitivity (P < 0.001), β-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, β-cell glucose sensitivity, β-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002). CONCLUSIONS Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced β-cell glucose sensitivity, and reduced β-cell rate sensitivity.

Habitual Physical Activity and Vascular Aging in a Young to Middle-Age Population at Low Cardiovascular Risk

Background and Purpose— Regular endurance exercise has been shown to reduce the age-related increase in arterial stiffness that is thought to contribute to cardiovascular risk. The aim of this study was to evaluate the influence of age and habitual physical activity on carotid artery wall thickness and stiffness in a population of young to middle-age subjects at low cardiovascular risk. Methods— The study population consisted of 432 healthy subjects (166 men; mean±SD age, 43±8 years; range, 30 to 60 years) free of carotid atherosclerosis and with low coronary heart disease risk, as determined by the Framingham prediction score sheet. All subjects underwent B-mode ultrasonography of the extracranial carotid arteries and physical activity assessment by actigraph, an accelerometer capable of monitoring the intensity and duration of body movements. The intima-media thickness of the common carotid artery was measured on ultrasound images, along with systodiastolic changes in luminal diameter, and indices of carotid stiffness were calculated. Results— Intima-media thickness and carotid stiffness increased with age in both men and women (r=0.24 to 0.52, P<0.001). The magnitude of objectively assessed daily physical activity was negatively related to indices of carotid stiffness (r from −0.20 to −0.25, P<0.001) but not to intima-media thickness. In multivariate regression analyses that included several cardiovascular risk factors such as obesity, blood pressure, plasma lipids, and smoking habits, age and physical activity were independently related to carotid stiffness. Conclusions— This study provides cross-sectional evidence that habitual physical activity is inversely related to the age-dependent increase in carotid wall stiffness in a young to middle-age population at low risk.

The Effect of Menopause on Carotid Artery Remodeling, Insulin Sensitivity, and Plasma Adiponectin in Healthy Women

BACKGROUND The mechanisms by which menopause may influence the systemic subclinical atherosclerosis are unexplained. The aim of this cross-sectional study was to evaluate the associations between early menopause, established cardiovascular (c-v) risk factors, metabolic parameters (insulin secretion and sensitivity, plasma adiponectin), and carotid intima-media thickness (IMT) in healthy women. METHODS In 74 menopausal women (mean age = 51 +/- 3 years, mean duration of menopause = 2.9 +/- 1.2 years) and in 74 nonmenopausal women comparable for age and body mass index (BMI), common carotid artery (CCA) luminal diameter, and IMT in different carotid segments were measured in digitized ultrasound images. Insulin sensitivity and secretion were assessed using the euglycemic hyperinsulinemic clamp technique and oral glucose tolerance test (OGTT). Insulin secretion was reconstructed by mathematical modeling. RESULTS CCA diameter (5.55 +/- 0.46 vs. 5.21+/- 0.51 mm, P < 0.001), CCA IMT (608 +/- 78 vs. 576 +/- 74 microm, P < 0.01) and systolic blood pressure (BP) (117 +/- 12 vs. 113 +/- 11 mm Hg, P < 0.05) were higher in menopausal women, whereas CCA IMT/diameter ratio and IMT in other carotid segments did not differ between the groups. By multivariate models, independent predictors of CCA diameter were menopause and body weight (cumulative R2 = 0.37) and independent correlates of CCA IMT were luminal diameter, systolic BP and low-density lipoprotein (LDL) cholesterol (cumulative R2 = 0.48). Fasting insulin, insulin secretion, and sensitivity and plasma adiponectin were similar in the two groups and were not related to carotid IMT. CONCLUSIONS Early menopause is associated with CCA remodeling, characterized by a proportional increase in luminal diameter and wall thickness, independent of atherosclerotic risk factors and metabolic variables.

From Metabolic Normality to Cardiometabolic Risk Factors in Subjects With Obesity

The aim of the study was to evaluate the 3 years incidence of cardiometabolic risk factors, such as impaired fasting glucose, reduced high‐density lipoprotein (HDL)‐cholesterol, increased plasma triglycerides or blood pressure as well as impaired glucose tolerance in overweight or obese (ow/ob) and normal body weight (nbw) subjects metabolically normal at baseline. Subjects from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study were analyzed. We analyzed 284 nbw and 152 ow/ob subjects who, at baseline, did not show any of the above‐mentioned cardiometabolic risk factors. At 3 years, these parameters were re‐evaluated. Intima‐media thickness (IMT) of the common carotid artery (CCA) was echographically measured. At follow‐up, the incidence of one or more cardiometabolic risk factors was 57.2% in ow/ob vs. 31.7% in nbw (P < 0.0001). After adjustment for age, sex, menopause status, lifestyle parameters, insulin sensitivity, and fasting insulinemia, BMI remained significantly linked to the development of one or more cardiometabolic risk factors (P = 0.02). An increased BMI at follow‐up was significantly associated with the development of cardiometabolic alterations, in both nbw and ow/ob groups (P = 0.04). Ow/ob subjects who, at 3 years follow‐up, remained metabolically normal, showed a less favourable cardiometabolic profile, when compared to nbw counterparts. In ow/ob metabolically normal males and females, intima‐media of the common carotid at follow‐up was thicker than in nbw (P = 0.03 for males, P = 0.04 for females). In conclusion, metabolically normal obese subjects show a higher incidence of cardiometabolic risk factors, in a short follow‐up period. Weight gain is significantly associated with the development of these factors, in both nbw and ow/ob subjects.