Publications (19)116.55 Total impact
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Article: Liver fat and lipid oxidation in humans.
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ABSTRACT: Studies in animals show that changes in hepatic fatty acid oxidation alter liver fat content. Human data regarding whole-body and hepatic lipid oxidation are controversial and based on studies of only a few subjects. We examined whether whole-body and hepatic lipid oxidation are altered in subjects with non-alcoholic fatty liver disease (NAFLD) compared with controls. In vivo measurements of rates of substrate oxidation and insulin sensitivity (using the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry and infusion of [3-(3)H]glucose) were performed in subjects with NAFLD [mean liver fat 14.0% (interquartile range 7.5-20.5%), n=29] and in control subjects [1.6% (1.0-3.0%), n=29]. Liver fat was measured using proton magnetic resonance spectroscopy. Plasma concentrations of 3-hydroxybutyrate (3-OHB) were measured as markers of hepatic lipid oxidation. In the basal state, substrate oxidation rates and serum 3-OHB concentrations were comparable in subjects with and without NAFLD. Plasma 3-OHB concentrations were similarly suppressed by insulin in both the groups. During the insulin infusion, whole-body lipid oxidation was inversely correlated with insulin-stimulated glucose disposal (r=-0.48, P<0.0001), which was lower in subjects with NAFLD [3.7+/-0.2 mg/(kg fat-free mass min)] than in the control subjects [5.0+/-0.3 mg/(kg fat-free mass min), P=0.0008]. Hepatic lipid oxidation is unchanged in NAFLD. Whole-body lipid oxidation is increased because of peripheral insulin resistance. These data imply that alterations in hepatic fatty acid oxidation do not contribute to liver fat content in humans.Liver international: official journal of the International Association for the Study of the Liver 07/2009; 29(9):1439-46. · 3.82 Impact Factor -
Article: Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes.
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ABSTRACT: Liver fat is increased in type 2 diabetes. We determined whether it is associated with impaired insulin clearance and to what extent insulin resistance, impaired insulin clearance, or secretion contribute to fasting hyperinsulinemia. We also examined whether insulin suppression of serum free fatty acid (FFA) correlates with liver fat. We compared 68 type 2 diabetic patients and age-, gender-, and body mass index (BMI)-matched nondiabetic subjects. Liver fat was determined by (1)H-MRS, body composition by magnetic resonance imaging, and insulin clearance and action on hepatic glucose production (HGP), glucose uptake, and serum FFA by the euglycemic insulin clamp technique (insulin 0.3 mU/kg x min) combined with infusion of [3-(3)H]glucose. Liver fat was 54% higher and insulin clearance 24% lower in type 2 diabetic patients than nondiabetic subjects. The percent suppression of both HGP and serum FFA by insulin were comparable, but serum insulin concentrations were significantly higher (34 mU/L [interquartile range, 30-39 mU/L] vs 25 mU/L [interquartile range, 22-30 mU/L]; P < .0001) in the type 2 diabetic than the nondiabetic subjects. When this difference was taken into account, both hepatic and adipose tissue insulin sensitivity were impaired in the type 2 diabetic subjects. Liver fat correlated with insulin clearance (r = -0.41; P = .001), and hepatic (r = 0.46; P = .0001) and adipose tissue (r = 0.55; P < .0001) insulin sensitivity. Hepatic but not peripheral insulin sensitivity was independently associated with liver fat content. Insulin clearance and secretion were independent determinants of fasting serum insulin. We conclude that increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance characterize type 2 diabetic patients.Gastroenterology 08/2008; 135(1):122-30. · 11.68 Impact Factor -
Article: Effect of liver fat on insulin clearance.
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ABSTRACT: A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 +/- 1 yr, body mass index (BMI) 26.3 +/- 0.5 kg/m(2)]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU.kg(-1).min(-1) for 240 min) clamp technique combined with the infusion of [3-(3)H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained approximately 40% higher (P < 0.0001) in the high (15.0 +/- 1.5%) compared with the low (1.8 +/- 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml.kg fat free mass(-1).min(-1)) was inversely related to liver fat content (r = -0.52, P < 0.0001), independent of age, sex, and BMI (r = -0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0-41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance (r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity (r = -0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.AJP Endocrinology and Metabolism 12/2007; 293(6):E1709-15. · 4.75 Impact Factor -
Article: Postprandial lipemia associates with liver fat content.
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ABSTRACT: Postprandial lipemia and low adiponectin represent novel risk factors for vascular disease. This study aimed to determine whether liver fat content and adiponectin are predictors of postprandial triglyceride (TG)-rich lipoproteins (TRL). Twenty-nine men were allocated into subgroups with either low (< or =5%) or high (>5%) liver fat measured with magnetic resonance proton spectroscopy. Subjects underwent an oral fat tolerance test with measurements of postprandial TG, cholesterol, apolipoprotein B-48 (apoB-48), and apoB-100 in TRL fractions, a euglycemic hyperinsulinemic clamp, and determination of abdominal fat volumes by magnetic resonance imaging. Subjects with high liver fat displayed increased response of postprandial lipids in plasma, chylomicron, and very-low-density lipoprotein 1 (VLDL1) (Svedberg flotation rate 60-400) fractions. Liver fat correlated positively with postprandial responses (area under the curve) of TG (r = 0.597; P = 0.001), cholesterol (r = 0.546; P = 0.002), apoB-48 (r = 0.556; P = 0.002), and apoB-100 (r = 0.42; P = 0.023) in the VLDL1 fraction. Respective incremental areas under the curve correlated significantly with liver fat. Fasting adiponectin levels were inversely correlated with both postprandial lipids and liver fat content. Liver fat remained the only independent correlate in a multiple linear regression analysis for chylomicron and VLDL1 responses. Liver fat content is a close correlate of postprandial lipids predicting the responses of TRL in chylomicrons and VLDL1 better than measures of glucose metabolism or body adiposity. Low adiponectin concentration is closely linked to high liver fat content and impaired TRL metabolism. High liver fat content associated with postprandial lipemia represents potential risk factors for cardiovascular disease.Journal of Clinical Endocrinology & Metabolism 08/2007; 92(8):3052-9. · 6.50 Impact Factor -
Article: Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins.
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ABSTRACT: We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.AJP Endocrinology and Metabolism 05/2005; 288(4):E768-74. · 4.75 Impact Factor -
Article: 3.5 years of insulin therapy with insulin glargine improves in vivo endothelial function in type 2 diabetes.
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ABSTRACT: To determine long-term effects of insulin glargine on vascular function in patients with type 2 diabetes. A total of 49 in vivo endothelial function tests, intrabrachial artery infusions of endothelium-dependent (acetylcholine [ACh]) and endothelium-independent (sodium nitroprusside [SNP]) vasoactive agents, were performed in 11 patients with type 2 diabetes (age: 59+/-2 years; BMI: 29.7+/-0.9 kg/m2; fasting plasma glucose: 226+/-14 mg/dL) and 16 matched normal subjects. The tests in the type 2 diabetic patients were performed before and after 6 months and 3.5 years of combination therapy with insulin glargine and metformin. A control group of type 2 diabetic patients not treated with insulin was studied twice at 6-month intervals. Before treatment, blood flow during infusions of low and high doses of ACh were significantly lower in the type 2 diabetic patients than in the normal subjects (P=0.021 for ANOVA). In the patients with type 2 diabetes, blood flow during infusion of the low dose of ACh averaged 7.1+/-0.8 mL/dL per minute at baseline, 8.8+/-1.0 mL/dL per minute at 6 months (NS), and then increased compared with baseline by 87+/-29% to 11.6+/-1.4 mL/dL per minute at 3.5 years (P<0.02 versus baseline). Blood flow during infusion of the high dose of ACh increased from 8.8+/-0.9 at baseline to 13.0+/-1.9 mL/dL per minute at 6 months (P<0.05) and by 86+/-25% to 14.7+/-1.6 mL/dL per minute at 3.5 years (P<0.01 versus baseline), which was not different from normal subjects. Blood flow during infusion of low (blood flow at 0 months: 7.7+/-0.5; at 6 months: 9.9+/-0.6; P<0.01 for 6 versus 0 months; and 3.5 years: 11.6+/-1.1 mL/dL per minute; P<0.02 for 3.5 years versus 0 months) and high (blood flow at 0 months: 10.7+/-0.9; 6 months: 13.4+/-1.0; P<0.05 for 6 versus 0 months; and 3.5 years: 16.6+/-1.5 mL/dL per minute; P<0.05 for 3.5 years versus 0 months) doses of SNP also increased significantly during insulin therapy. We conclude that insulin glargine therapy improves endothelium-dependent and endothelium-independent vasodilatation. These data support the idea that long-term insulin therapy has beneficial rather than harmful effects on vascular function in type 2 diabetes.Arteriosclerosis Thrombosis and Vascular Biology 02/2004; 24(2):325-30. · 6.37 Impact Factor -
Article: Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver.
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ABSTRACT: In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the hypothalamic-pituitary-adrenal axis, hence increasing adrenal androgens and 'android' central obesity. This study aimed to examine relationships between these enzymes and detailed measurements of body fat distribution. Twenty-five healthy men (age, 22-57 yr; body mass index, 20.6-35.6 kg/m(2)) were recruited from occupational health services. Body composition was assessed by anthropometric measurements, bioimpedance, and cross-sectional abdominal magnetic resonance imaging scans. Liver fat content was assessed by magnetic resonance imaging spectroscopy. Insulin sensitivity was measured in a euglycemic hyperinsulinemic clamp. Cortisol metabolites were measured in a 24-h urine sample by gas chromatography-mass spectrometry. In vivo hepatic 11HSD1 activity was measured by generation of plasma cortisol after an oral dose of cortisone. In vitro 11HSD1 activity and mRNA were measured in 18 subjects who consented to provide abdominal sc adipose biopsies. Indices of obesity (body mass index, whole-body percentage fat, waist/hip ratio) were associated with higher urinary excretion of 5alpha- and 5beta-reduced cortisol metabolites (for percentage fat, P < 0.05 and P < 0.01, respectively) and increased adipose 11HSD1 activity (P < 0.05). Liver fat accumulation was associated with a selective increase in urinary excretion of 5beta-reduced cortisol and cortisone metabolites (P < 0.01) and a lower ratio of cortisol/cortisone metabolites in urine (P < 0.001) but no difference in in vivo cortisone-to-cortisol conversion or in vitro adipose 11HSD1. Higher excretion of 5beta-reduced cortisol metabolites was independently associated with insulin resistance and hypertriglyceridemia. Lower conversion of cortisone to cortisol was associated with lower fasting plasma cortisol (P < 0.01). However, visceral adipose fat mass was not associated with indices of cortisol metabolism; indeed, after adjusting for the effects of whole-body and liver fat, increased visceral fat was associated with lower cortisol metabolite excretion. We conclude that alterations in 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans. Activation of 5beta-reductase in men with fat accumulation in the liver may confound the interpretation of cortisol metabolite excretion when liver fat content is unknown, and may contribute to altered bile acid and cholesterol metabolism in nonalcoholic steatohepatitis.Journal of Clinical Endocrinology & Metabolism 10/2003; 88(10):4924-31. · 6.50 Impact Factor -
Article: Lowering of LDL cholesterol rather than moderate weight loss improves endothelium-dependent vasodilatation in obese women with previous gestational diabetes.
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ABSTRACT: Effects of weight loss on vascular function are unknown. We compared, in the face of similar weight loss over 3-6 months, effects of orlistat (120 mg t.i.d., n = 23) and placebo (n = 24) on in vivo endothelial function in a high-risk group of obese (BMI 32.1 +/- 0.4 kg/m(2)) premenopausal nondiabetic women with a history of gestational diabetes. Forearm blood flow responses to intra-arterial infusions of acetylcholine (ACh) and sodium nitroprusside (SNP), body composition, and serum lipids were determined before and after weight loss. Weight loss averaged 7.3 +/- 0.2 kg (8.3 +/- 0.1%) and 7.4 +/- 0.2 kg (8.2 +/- 0.1%) of initial body weight in the orlistat and placebo groups, respectively. Forearm and body compositions changed similarly in both groups. Responses to ACh increased by 41% to the low dose (5.9 +/- 0.6 vs. 8.3 +/- 0.3 for flow in the experimental/control arm, P < 0.01) and by 33% to the high dose (7.6 +/- 0.8 vs. 10.1 +/- 0.6, P < 0.001) in the orlistat group, but they remained unchanged in the placebo group. The blood flow responses to SNP did not differ significantly between the groups. LDL cholesterol decreased significantly in the orlistat group from 3.5 +/- 0.2 to 3.0 +/- 0.1 mmol/l (P < 0.01) but remained unchanged in the placebo group. Within the orlistat group, the decrease in LDL cholesterol correlated significantly with the improvement in the blood flow response to ACh (r = -0.44, P < 0.05). Orlistat but not moderate (8%) weight loss per se improves endothelial function in women with previous gestational diabetes. This improvement is associated with a lowering of LDL cholesterol by orlistat.Diabetes Care 06/2003; 26(6):1667-72. · 8.09 Impact Factor -
Article: Rosiglitazone in the treatment of HAART-associated lipodystrophy--a randomized double-blind placebo-controlled study.
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ABSTRACT: Highly active antiretroviral therapy (HAART) is associated with metabolic adverse events such as insulin resistance and lipodystrophy, that is, atrophy of subcutaneous fat and accumulation of intra-abdominal fat. Currently, there is no pharmacological treatment for lipoatrophy. Glitazones, a novel class of insulin-sensitizing anti-diabetic agents, increase subcutaneous fat in patients with type 2 diabetes. There are no controlled studies of glitazones in patients with HAART-associated lipodystrophy (HAL). In this randomized, double-blind, placebo-controlled study, 30 patients with HAL received either rosiglitazone (8 mg daily) or placebo for 24 weeks. Baseline characteristics were compared to a group of 30 age-, sex- and weight-matched HIV-negative controls. At baseline, patients with HAL had 1.8-fold (P<0.001) more intra-abdominal and 2.4-fold (P<0.05) more liver fat than HIV-negative controls, who had 1.8-fold (P<0.001) more subcutaneous fat than the patients. After 24 weeks of treatment, rosiglitazone had no effect on body weight, subcutaneous or intra-abdominal fat (magnetic resonance imaging), total body fat (bioimpedance analysis), anthropometric measurements or serum leptin concentrations (a circulating marker of adipose tissue mass). However, rosiglitazone decreased % liver fat (spectroscopy) and serum insulin concentrations, and normalized liver function tests. During the first 12 weeks of rosiglitazone treatment, serum triglycerides increased from 3.5 +/- 0.5 to 6.5 +/- 2.0 mmol/l (from 310 +/- 44 to 575 +/- 177 mg/dl) (P<0.05) and serum cholesterol from 6.0 +/- 0.4 to 7.8 +/- 0.7 mmol/l (from 232 +/- 15 to 301 +/- 27 mg/dl) (P<0.01). Contrary to data in other patient groups, rosiglitazone did not increase subcutaneous fat in patients with HAL after 24 weeks of treatment. Rosiglitazone seemed to ameliorate insulin resistance judged by the decreased serum insulin concentrations and % liver fat. Rosiglitazone unexpectedly caused significant increases in serum triglyceride and cholesterol concentrations, which must be carefully monitored if glitazones are used in these patients.Antiviral therapy 06/2003; 8(3):199-207. · 3.16 Impact Factor -
Article: Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.
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ABSTRACT: Our objective was to determine how 8% weight loss influences subcutaneous, intra-abdominal, and liver fat (LFAT), as well as features of insulin resistance, in obese women with high versus low LFAT. A total of 23 women with previous gestational diabetes were divided into groups of high (9.4 +/- 1.4%) and low (3.3 +/- 0.4%) LFAT based on their median LFAT (5%) measured with proton spectroscopy. Both groups were similar with respect to age, BMI, and intra-abdominal and subcutaneous fat. Before weight loss, women with high LFAT had higher fasting serum insulin and triglyceride concentrations than women with low LFAT. At baseline, LFAT correlated with the percent of fat (r = 0.44, P < 0.05) and saturated fat (r = 0.45, P < 0.05) of total caloric intake but not intra-abdominal or subcutaneous fat or fasting serum free fatty acids. Weight loss was similar between the groups (high LFAT -7.4 +/- 0.2 vs. low LFAT -7.7 +/- 0.3 kg). LFAT decreased from 9.4 +/- 1.4 to 4.8 +/- 0.7% (P < 0.001) in women with high LFAT and from 3.3 +/- 0.4 to 2.0 +/- 0.2% (P < 0.001) in women with low LFAT. The absolute decrease in LFAT was significantly higher in women with high than low LFAT (-4.6 +/- 1.0 vs. -1.3 +/- 0.3%, P < 0.005). The decrease in LFAT was closely correlated with baseline LFAT (r = -0.85, P < 0.001) but not with changes in the volumes of intra-abdominal or subcutaneous fat depots, which decreased similarly in both groups. LFAT appears to be related to the amount of fat in the diet rather than the size of endogenous fat depots in obese women. Women with initially high LFAT lost more LFAT by similar weight loss than those with low LFAT, although both groups lost similar amounts of subcutaneous and intra-abdominal fat. These data suggest that LFAT is regulated by factors other than intra-abdominal and subcutaneous fat. Therefore, LFAT does not appear to simply reflect the size of endogenous fat stores.Diabetes 03/2003; 52(3):701-7. · 8.29 Impact Factor -
Article: Differential effects of oral and transdermal estradiol treatment on circulating estradiol fatty acid ester concentrations in postmenopausal women.
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ABSTRACT: Estradiol fatty acid esters are potent lipophilic estrogens with antioxidant properties, transported by lipoproteins in blood. We investigated effects of oral and transdermal estradiol replacement therapy on concentrations of estradiol fatty acid esters in serum in postmenopausal women in a double-blind, randomized fashion. The first group (n = 9) received oral (2 mg/d); the second (n = 10), transdermal estradiol (patch delivering 50 microg/d); and the third group (n = 7), placebo treatment for 12 wk. After extraction of serum and separation of esterified estradiol from nonesterified estradiol, the concentration of saponified estradiol esters was measured by time-resolved fluoroimmunoassay. In the oral estradiol group, the median serum estradiol fatty acid ester concentration rose by 27%, from 77 to 98 pM (P = 0.028) but remained unchanged in the transdermal estradiol and placebo groups. The median concentrations of serum nonprotein-bound estradiol increased similarly in the oral and transdermal estradiol groups. The change in serum estradiol ester concentrations during treatment, but not that of nonesterified estradiol, correlated positively with enhanced forearm blood flow responses in vivo. These data raise the possibility that an increase in serum estradiol fatty acid esters may contribute to beneficial effects of oral estradiol treatment, compared with an equipotent dose of transdermal estradiol.Journal of Clinical Endocrinology & Metabolism 03/2003; 88(2):588-93. · 6.50 Impact Factor -
Article: Insulin-induced decreases in aortic wave reflection and central systolic pressure are impaired in type 2 diabetes.
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ABSTRACT: To determine whether large arteries are resistant to insulin. Insulin normally acutely decreases central systolic pressure by decreasing wave reflection in vivo. This effect occurs before any changes in peripheral vascular resistance or heart rate under normoglycemic conditions. We determined whether the ability of insulin to decrease central aortic pressure is altered in uncomplicated type 2 diabetes. The study subjects consisted of 16 type 2 diabetic patients (age 54 +/- 2 years, BMI 29 +/- 1 kg/m(2)) and 19 matched nondiabetic individuals (51 +/- 2 years, 29 +/- 1 kg/m(2)) studied under normoglycemic-hyperinsulinemic conditions. Central aortic pressure waveforms were synthesized from those recorded in the periphery using applanation tonometry and a validated reverse transfer function to construct the central aortic pressure waveform every 30 min. This method allowed determination of aortic augmentation (the pressure difference between the first and second central systolic pressure waves) and the augmentation index (augmentation divided by pulse pressure). Whole-body insulin sensitivity was 31% lower (P < 0.05) in the type 2 diabetic patients than in the normal subjects. Basally, before the insulin infusion, augmentation averaged 8.9 +/- 1.3 and 11.1 +/- 1.2 mmHg (NS) and the augmentation index averaged 23.1 +/- 2.1 and 27.5 +/- 2.1% (NS) in the normal subjects and diabetic patients, respectively. After 30 min of hyperinsulinemia, augmentation decreased significantly to 6.1 +/- 1.1 mmHg (P < 0.001) in the normal subjects but remained unchanged at 9.1 +/- 1.1 mmHg (NS) in type 2 diabetic patients. At 30 min, the augmentation index had decreased significantly (30 +/- 7% decrease) to 17.9 +/- 2.6% in the normal subjects but remained at 24.4 +/- 2.4% in the diabetic patients (13 +/- 4% decrease, P < 0.05 for change vs. normal subjects). Central systolic pressure decreased significantly by 30 min in the normal subjects but only after 120 min in the type 2 diabetic patients. There were no significant changes in heart rate, pulse pressure, or forearm blood flow during the first 120 min of the insulin infusion. Insulin resistance in type 2 diabetes involves a delay in the ability of insulin to decrease central aortic pressure. This defect could predispose these patients to develop systolic hypertension.Diabetes Care 01/2003; 25(12):2314-9. · 8.09 Impact Factor -
Article: Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy.
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ABSTRACT: To determine liver fat content in patients with highly active antiretroviral therapy (HAART)-associated lipodystrophy. Lipodystrophy in several animal models is associated with fat accumulation in insulin-sensitive tissues, such as the liver. This causes hyperinsulinaemia, dyslipidaemia and other features of insulin resistance. A cross-sectional study. Three age- and weight-matched groups were compared: 25 HIV-positive men with HAART-associated lipodystrophy (HAART+LD+), nine HIV-positive men receiving HAART, but without lipodystrophy (HAART+LD-), and 35 HIV-negative healthy men (HIV-). Liver fat content was measured using proton spectroscopy. Intra-abdominal and subcutaneous fat were determined using magnetic resonance imaging. Liver fat content was significantly higher in the HAART+LD+ (8 +/- 10%) than the HIV- (5 +/- 7%; P < 0.05) or the HAART+LD- (3 +/- 5%; P < 0.01) group. Liver fat content correlated with serum fasting insulin in the HAART+LD+ (r = 0.47; P < 0.05) and HIV- groups (r = 0.65; < 0.001), but not with the amount of intra-abdominal fat. Within the HAART+LD+ group, serum insulin did not correlate with the amount of intra-abdominal fat. The HAART+LD+ group had a lower serum leptin concentration when compared to the two other groups. Features of insulin resistance, including hepatic fat accumulation, were not found in HAART+LD-group. The severity of the insulin resistance syndrome in patients with HAART-associated lipodystrophy is related to the extent of fat accumulation in the liver rather than in the intra-abdominal region. Fat accumulation in the liver may therefore play a causative role in the development of insulin resistance in these patients.AIDS 11/2002; 16(16):2183-93. · 6.24 Impact Factor -
Article: Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis.
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ABSTRACT: Cardiovascular disease is the major cause of excessive mortality in patients with rheumatoid arthritis (RA). We determined whether endothelial dysfunction characterizes patients with newly diagnosed RA (n=10) compared with normal subjects (control group, n=33) and whether it is reversible with 6 months of anti-inflammatory therapy. Endothelial function was determined by measuring vasodilatory responses to intrabrachial artery infusions of acetylcholine (ACh at 7.5 and 15 microg/min, low and high dose, respectively), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP, 3 and 10 micro g/min), an endothelium-independent vasodilator. Before treatment, blood flow responses (fold increase in flow) to low-dose SNP were 30% lower in the RA versus the control group (4.1+/-0.4-fold versus 5.9+/-0.5-fold, respectively), and responses to high-dose SNP were 34% lower in the RA group versus the control group (5.1+/-0.6-fold versus 7.7+/-0.7-fold, respectively; P<0.001). The responses to low-dose ACh were 50% lower in the RA group versus the control group (3.0+/-0.5-fold versus 6.6+/-0.7-fold, respectively), and responses to high-dose ACh were 37% lower in the RA group versus the control group (5.0+/-0.4-fold versus 7.9+/-0.8-fold, respectively; P<0.001). After therapy, clinical and laboratory markers of inflammation had significantly decreased. Blood flow responses to ACh increased significantly (P=0.02). We conclude that newly diagnosed patients with RA have vascular dysfunction, which is reversible with successful therapy. Therefore, early suppression of inflammatory activity may reduce long-term vascular damage.Arteriosclerosis Thrombosis and Vascular Biology 10/2002; 22(10):1637-41. · 6.37 Impact Factor -
Article: Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes.
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ABSTRACT: We determined whether fat accumulation in the liver is associated with features of insulin resistance independent of obesity. We recruited 27 obese nondiabetic women in whom liver fat (LFAT) content was determined by proton spectroscopy, intra-abdominal and subcutaneous fat by magnetic resonance imaging, and insulin sensitivity by the euglycemic insulin clamp technique. The women were divided based on their median LFAT content (5%) to groups with low (3.2 +/- 0.3%) and high (9.8 +/- 1.5%) liver fat. The groups were almost identical with respect to age (36 +/- 1 vs. 38 +/- 1 years in low vs. high-LFAT), body mass index (32.2 +/- 0.6 vs. 32.8 +/- 0.5 kg/m(2)), waist-to-hip ratio, intra-abdominal, subcutaneous, and total fat content. Women with high LFAT had features of insulin resistance including higher fasting serum triglyceride (1.93 +/- 0.21 vs. 1.11 +/- 0.09 mM, p < 0.01) and insulin (14 +/- 3 vs. 10 +/- 1 mU/L, p < 0.05) concentrations than women with low LFAT. The group with high LFAT also had higher 24-hour blood pressures, and lower whole-body insulin sensitivity compared with the low-LFAT group. In obese women with previous gestational diabetes, LFAT, rather than any measure of body composition, is associated with features of insulin resistance.Obesity research 09/2002; 10(9):859-67. · 4.95 Impact Factor -
Article: Liver-Fat Accumulation and Insulin Resistance in Obese Women with Previous Gestational Diabetes
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ABSTRACT: Objective: We determined whether fat accumulation in the liver is associated with features of insulin resistance independent of obesity.Research Methods and Procedures: We recruited 27 obese nondiabetic women in whom liver fat (LFAT) content was determined by proton spectroscopy, intra-abdominal and subcutaneous fat by magnetic resonance imaging, and insulin sensitivity by the euglycemic insulin clamp technique. The women were divided based on their median LFAT content (5%) to groups with low (3.2 0.3%) and high (9.8 1.5%) liver fat. The groups were almost identical with respect to age (36 1 vs. 38 1 years in low vs. high-LFAT), body mass index (32.2 0.6 vs. 32.8 0.5 kg/m2), waist-to-hip ratio, intra-abdominal, subcutaneous, and total fat content.Results: Women with high LFAT had features of insulin resistance including higher fasting serum triglyceride (1.93 0.21 vs. 1.11 0.09 mM, p < 0.01) and insulin (14 3 vs. 10 1 mU/L, p < 0.05) concentrations than women with low LFAT. The group with high LFAT also had higher 24-hour blood pressures, and lower whole-body insulin sensitivity compared with the low-LFAT group.Discussion: In obese women with previous gestational diabetes, LFAT, rather than any measure of body composition, is associated with features of insulin resistance.Keywords: proton spectroscopy, magnetic resonance imaging, hypertension, triglyceridesObesity 08/2002; 10(9):859-867. · 4.28 Impact Factor -
Article: Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men.
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ABSTRACT: We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R(a)) and suppression of serum FFA [euglycemic insulin clamp combined with [3-(3)H]glucose (0-300 min); insulin infusion rate, 0.3 mU/kg.min, 120-300 min] were measured. The men were divided into groups of low (mean +/- SD, 1.7 +/- 0.2%) and high (10.5 +/- 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 +/- 2 vs. 42 +/- 2 yr), body mass index (25 +/- 1 vs. 26 +/- 1 kg/m(2) ), waist to hip ratio (0.953 +/- 0.013 vs. 0.953 +/- 0.013), maximal oxygen uptake (35.6 +/- 1.5 vs. 33.5 +/- 1.5 ml/kg.min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 +/- 0.6 vs. 5.3 +/- 0.6 mU/liter; P < 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 +/- 0.2 vs. 0.9 +/- 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 +/- 0.1 vs. 1.6 +/- 0.1 mmol/liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 +/- 3 vs. 122 +/- 3 mm Hg; P < 0.05). Basal glucose R(a) and serum FFA were comparable between the groups, whereas insulin suppression of glucose R(a) [51 +/- 8 vs. 20 +/- 12 mg/m(2).min during 240-300 min (P < 0.05) or -55 +/- 7 vs. -85 +/- 12% below basal (P < 0.05, high vs. low LFAT)] and of serum FFA (299 +/- 33 vs. 212 +/- 13 micromol/liter; 240-300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 +/- 12 mg/m(2).min) and those with low LFAT (156 +/- 14 mg/m(2).min; P = NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects.Journal of Clinical Endocrinology & Metabolism 07/2002; 87(7):3023-8. · 6.50 Impact Factor -
Article: Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity.
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ABSTRACT: Insulin resistance is associated with an increased risk of atherothrombotic vascular disease, but the mechanisms are poorly understood. We determined how insulin in vivo regulates platelet activation in nonobese and obese subjects by using methods mimicking thrombus formation. Twelve nonobese (aged 42+/-2 years, body mass index 24.0+/-0.4 kg/m(2)) and 14 obese (aged 43+/-1 years, body mass index 37.2+/-1.5 kg/m(2)) subjects were studied under euglycemic hyperinsulinemic (3-hour insulin infusion of 1 mU. kg(-1). min(-1)) conditions. Before and at the end of hyperinsulinemia, the following were determined: (1) platelet-related early hemostasis (shear rate of approximately 4000 s(-1)) by platelet function analysis; (2) platelet deposition to collagen during whole-blood perfusion (shear rate of 1600 s(-1)); (3) aggregation responses to collagen, thrombin receptor-activating peptide, ADP, and epinephrine; and (4) platelet cGMP concentrations. Insulin action on glucose metabolism was 69% lower in the obese subjects (1.6+/-0.2 mg. kg(-1). min(-1)) than in the nonobese subjects (5.4+/-0.4 mg. kg(-1). min(-1), P<0.0001). The in vivo insulin infusion inhibited platelet deposition to collagen from 4.3+/-0.6x10(6) to 3.5+/-0.4x10(6) per square centimeter in the nonobese subjects (P<0.05) but failed to do so in the obese subjects (5.2+/-0.8x10(6) versus 5.5+/-0.7x10(6) per square centimeter, P=NS; P<0.01 versus nonobese subjects). Epinephrine- and ADP-primed closure times by platelet function analysis were prolonged by insulin in the nonobese but not the obese subjects (P<0.05 for between-group difference). In the nonobese subjects, insulin decreased aggregation to all agonists and significantly increased platelet cGMP concentrations (2.5+/-0.3 versus 3.2+/-0.5 pmol/10(9) for before versus after insulin, respectively; P<0.01). In the obese subjects, insulin did not alter collagen-induced aggregation or cGMP concentrations (1.9+/-0.2 versus 1.8+/-0.1 pmol/10(9) for before versus the end of in vivo hyperinsulinemia, respectively; P=NS). These data demonstrate that normal in vivo insulin action inhibits platelet interaction with collagen under conditions mimicking thrombus formation and reduces aggregation to several agonists. These platelet-inhibitory actions of insulin are blunted or absent in obese subjects and could provide 1 mechanism linking insulin resistance to atherothrombotic disease.Arteriosclerosis Thrombosis and Vascular Biology 01/2002; 22(1):167-72. · 6.37 Impact Factor -
Article: Elevated fasting insulin concentrations associate with impaired insulin signaling in skeletal muscle of healthy subjects independent of obesity.
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ABSTRACT: Insulin signaling is impaired in the skeletal muscle of obese subjects but whether defects in skeletal muscle insulin signaling also characterize insulin resistance of non-obese individuals is unknown. The detection of insulin signaling defects in muscle biopsies is hampered by the variation of the contaminating non-muscle elements such as blood, connective tissue, fat, and blood vessel structures. Freeze-drying and macroscopic purification of the muscle fibers prior to the analysis might offer a possibility to minimize the analytical variation due to these contaminants. In the present study we first determined whether insulin signaling could be reliably assessed in freeze-dried muscle specimens, which are free of non-muscle contaminants, and then applied this method to the study of insulin signaling in weight-matched insulin-sensitive and insulin-resistant non-diabetic men. In rat muscle, increases in tyrosine phosphorylation of insulin receptor (IR) and activity of the insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity by insulin were similar or higher in freeze-dried and purified muscle than wet muscle. Prior to freeze-drying and purification, biopsies of human vastus lateralis muscle contained between 1% and 40% non-muscle contaminants (11+/-3%, mean+/-SEM, n=19). In freeze-dried biopsies of human vastus lateralis muscle taken before and after 30 min of hyperinsulinemia (serum free insulin 61+/-1 mU/l) in 13 non-diabetic men, insulin increased IR tyrosine phosphorylation 1.4-fold (p<0.05) and IRS-1-associated PI 3-kinase activity 1.7-fold (p<0.005). Insulin-stimulated PI 3-kinase activity was significantly inversely correlated with the fasting serum insulin concentration (r=-0.57, p<0.05). When divided according to the median fasting serum insulin concentration, the men with high fasting insulin [HI, n=7, age 44+/-3 years, body mass index (BMI) 25+/-1 kg/m(2)] as compared to the men with low fasting insulin [LI, n=6, age 45+/-3 years (NS), BMI 24+/-1 kg/m(2) (NS)] had lower rates of whole-body glucose uptake (3.4+/-0.4 vs 5.5+/-0.3 mg/kg min, p<0.005), higher fasting plasma glucose concentrations (5.9+/-0.2 vs 5.2+/-0.1 mmol/l, p<0.05), higher fasting serum triglycerides (1.4+/-0.2 vs 0.9+/-0.1 mmol/l, p<0.05) and lower high-density lipoprotein (HDL) cholesterol concentrations (1.3+/-0.1 vs 1.7+/-0.1 mmol/l, p<0.05). Insulin-stimulated IR tyrosine phosphorylation (p<0.05) and IRS-1-associated PI 3-kinase activity (p<0.05) were significantly lower in the HI than the LI group. Taken together these data demonstrate that early insulin signaling events can be reliably assessed in freeze-dried human skeletal muscle, and that in vivo insulin resistance and its accompanying features are associated with defects in early insulin signaling events in human skeletal muscle independent of body weight.Diabetes/Metabolism Research and Reviews 18(3):209-16. · 3.37 Impact Factor
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Institutions
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2002–2009
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University of Helsinki
- • Department of Oral Medicine
- • Department of Dental Public Health
Helsinki, Province of Southern Finland, Finland
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2002–2003
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Helsinki University Central Hospital
- Department of Medicine
Helsinki, Province of Southern Finland, Finland
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