Thyrotropin levels and their relationship with cardiovascular risk factors in the island of Gran Canaria, Spain. Implications of lowering the upper reference limit of thyrotropin stimulating hormone.

OBJECTIVE: To characterize the cardiovascular risk profile of subjects with high and normal-high concentrations of serum TSH in a sample of adult Spanish subjects from the island of Gran Canaria. DESIGN: Cross-sectional population-based study. SUBJECTS: After excluding 28 individuals on current treatment with levothyroxine and 9 others with TSH levels below the range of normality (0.3-4.9 mU/l), 704 randomly selected subjects (412 women; age range: 30-82 yr) belonging to the Telde Study were assessed. MEASUREMENTS: Participants underwent physical examination and fasting blood analyses to determinate TSH, serum lipids, homocysteine, fibrinogen, von Willebrand factor, plasminogen activator inhibitor- 1, C-reactive protein, and insulin. RESULTS: Twenty-nine participants had serum TSH concentrations above the normal range of normality. Among all the studied variables, only female sex and diastolic blood pressure were significantly associated with TSH levels > or =5 mU/l in a multivariate logistic regression analysis. If the upper normal limit of TSH was reduced up to 2.4 mU/l, an additional group of 106 subjects would be considered to have elevated TSH levels. A serum TSH > or =2.5 mU/l was positive and independently associated with female sex, body mass index, total cholesterol, and homocysteine, and negatively associated with smoking. CONCLUSIONS: Although the impact of serum TSH levels on cardiovascular risk cannot be established from these findings, TSH values within the upper part of the usually accepted normal range were demonstrated to be associated with well-recognized risk factors for cardiovascular disease.

Differences in traditional and emerging cardiovascular risk factors of subjects discordantly classified by metabolic syndrome definitions of the International Diabetes Federation and the National Cholesterol Education Program.

BACKGROUND AND AIM: Several working definitions of metabolic syndrome have been proposed for clinical use. However, individuals can be discordantly classified as having or not having metabolic syndrome depending on the choice of one or another definition. This study compared the cardiovascular risk profile of subjects concordantly and discordantly diagnosed by the criteria of the National Cholesterol Education Program (NCEP) and the criteria of the International Diabetes Federation (IDF). METHODS AND RESULTS: Nine hundred and twenty-nine non-diabetic adult subjects belonging to a cross-sectional population-based study in Gran Canaria island (Spain) were assessed. Participants completed a questionnaire and underwent physical examination, fasting blood analyses, and a standardized oral glucose tolerance test. Two hundred and four subjects (22%) had metabolic syndrome according to both definitions, 31 (3.3%) only by the IDF criteria, and 5 (0.5%) only by the NCEP criteria. Participants fulfilling both proposals showed more adverse age and sex-adjusted measures of BMI, waist, HDL cholesterol, triglycerides, post-load glucose, HOMA-IR and plasminogen inhibitor activator-1 (PAI-1) than individuals exclusively satisfying the IDF criteria. Moreover, in contrast to subjects meeting both criteria, those that fulfilled only the IDF criteria had levels of BMI, waist, total and HDL cholesterol, post-load glucose, glycated HbA1c, C-reactive protein, PAI-1 and fibrinogen not significantly different from those observed in subjects without metabolic syndrome. CONCLUSION: The IDF definition identifies a surplus of individuals whose cardiovascular risk profile, particularly regarding to some non-traditional cardiovascular risk factors, is less adverse than that observed in subjects also diagnosed by the NCEP definition.

Predictors of insulin sensitivity in Type 2 diabetes mellitus.

AIMS: To identify the independent predictors of insulin sensitivity in Type 2 diabetes, and to establish whether isolated Type 2 diabetes (i.e. diabetes without overweight, dyslipidaemia and hypertension) is a condition of insulin resistance. METHODS: We examined 45 patients with non-insulin-treated Type 2 diabetes undergoing a 4-h euglycaemic hyperinsulinaemic clamp (20 mU/m2 per min) combined with 3H-3-D-glucose and 14C-U-glucose infusions and indirect calorimetry. We also examined 1366 patients with non-insulin-treated Type 2 diabetes randomly selected among those attending the Diabetes Clinic and in whom insulin resistance was estimated by Homeostasis Model Assessment (HOMA-IR). RESULTS: In the 45 patients undergoing glucose clamp studies, insulin-mediated total glucose disposal (TGD) was independently and negatively associated with systolic blood pressure (standardized beta coefficient = -0.407, P = 0.003), plasma triglycerides (beta= -0.355, P = 0.007), and HbA1c (beta= -0.350, P = 0.008). The overall variability of TGD explained by these variables was 53%. Overweight diabetic subjects with central fat distribution, hypertension, hypertriglyceridaemia and poor glycometabolic control had insulin-mediated TGD values markedly lower than their lean counterparts without hypertension, with normal triglycerides, and with good glycometabolic control (16 +/- 5 vs. 31 +/- 10 micromol/min per kg lean body mass, P < 0.01). Nevertheless, the latter still were markedly insulin-resistant when compared with sex- and age-matched non-diabetic control subjects (31 +/- 10 vs. 54 +/- 13 micromol/min per kg lean body mass, P < 0.01). In the 1366 Type 2 diabetic patients of the epidemiological study, HOMA-IR value was independently associated with HbA1c (beta = 0.283, P < 0.0001), plasma triglycerides (beta = 0.246, P < 0.0001), body mass index (beta = 0.139, P < 0.001), waist girth (beta = 0.124, P < 0.001) and hypertension (beta = 0.066, P = 0.006). CONCLUSION: Overweight, central fat distribution, dyslipidaemia, hypertension and poor glycometabolic control are strong independent predictors of insulin resistance in Type 2 diabetes. However, reduced insulin sensitivity can be found even when Type 2 diabetes is isolated and well controlled.

Relation between soluble adhesion molecules and insulin sensitivity in type 2 diabetic individuals: role of adipose tissue.

OBJECTIVE: The purpose of this study was to explore the relation between insulin resistance and plasma levels of soluble adhesion molecules and to examine the effects of acute hyperinsulinemia on these molecules in type 2 diabetic individuals. RESEARCH DESIGN AND METHODS: Intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E- and P-selectin plasma concentrations were measured in 36 nonobese type 2 diabetic patients without cardiovascular disease and in 7 healthy subjects. Insulin sensitivity was assessed by a 4-h euglycemic ( approximately 5 mmol/l)-hyperinsulinemic ( approximately 300 pmol/l) clamp performed in combination with [(3)H]3-D-glucose infusion. RESULTS: Diabetic subjects were insulin resistant but did not show plasma concentrations of adhesion molecules that were significantly higher than control subjects. In diabetic subjects, plasma ICAM-1 and E-selectin were negatively correlated with total glucose disposal during the insulin clamp (r = -0.432, P < 0.01; and r = -0.375, P < 0.05, respectively), whereas plasma VCAM-1 and P-selectin were not. Plasma ICAM-1 as well as E- and P-selectin were positively correlated with BMI, total body fat (TBF), and waist girth (P < 0.05-0.001). In multiple regression analyses, the relation of plasma ICAM-1 and E-selectin with insulin sensitivity was lost after adjustment for potential confounders, including HbA(1c), blood pressure, and/or LDL cholesterol. In these analyses, BMI was the only independent predictor of plasma ICAM-1 (R(2) = 0.244, P < 0.002), whereas TBF was the only independent predictor of plasma E-selectin (R(2) = 0.202, P = 0.01). The 4-h insulin infusion during the glucose clamp did not significantly change plasma levels of adhesion molecules. CONCLUSIONS: Overall adiposity, rather than insulin resistance, may be a determinant of plasma levels of ICAM-1 and E-selectin in type 2 diabetic individuals. In these patients, acute hyperinsulinemia does not exert any significant effect on plasma adhesion molecules. These findings support the possibility that adipose tissue releases one or more factors that may adversely affect endothelial function on one hand and insulin sensitivity on the other.

Intracellular partition of plasma glucose disposal in hypertensive and normotensive subjects with type 2 diabetes mellitus.

The aim of this study was to ascertain whether the presence of hypertension conveys a more severe degree of insulin resistance in type 2 diabetes mellitus and, if so, which biochemical pathways are involved. We quantitated the rates of total glucose disposal, glycogen synthesis (GS), glycolysis, glucose oxidation, endogenous glucose production, and LOX in the basal state and during a 4-h euglycemic ( approximately 5 mM) hyperinsulinemic ( approximately 300 pM) clamp carried out in combination with a dual-tracer infusion ([(3)H]-3- and [(14)C]-U-D-glucose) and indirect calorimetry in 42 nonobese noninsulin-treated type 2 diabetic subjects (22 hypertensive and 20 normotensive) and 23 nonobese nondiabetic subjects (9 without and 14 with essential hypertension). Compared with normotensive controls, both groups of diabetic subjects were markedly insulin resistant. In the basal state, all glucose fluxes were similar in diabetic subjects with or without hypertension. During insulin infusion, total glucose disposal was significantly reduced in hypertensive diabetic subjects, compared with their normotensive counterparts (18.7 +/- 1.0 vs. 28.6 +/- 3.0 micromol/min.kg lean body mass; P < 0.01). This difference was almost entirely explained by a marked reduction in GS (4.5 +/- 2.0 vs. 12.5 +/- 3.3 micromol/min.kg lean body mass; P < 0.01). Endogenous glucose production was not different in the two diabetic groups during insulin infusion and was significantly higher than in normotensive controls. Lipid oxidation was less suppressed by hyperinsulinemia in hypertensive than in normotensive diabetic subjects (1.46 +/- 0.1 vs. 0.91 +/- 0.1 micromol/min.kg lean body mass; P < 0.01). Glucose fluxes were not significantly different in nondiabetic subjects with essential hypertension and in normotensive diabetic individuals. These results indicate that hypertension markedly aggravates insulin resistance featuring type 2 diabetes mellitus. The molecular defects underlying this phenomenon involve primarily GS.

Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.

OBJECTIVE: To evaluate whether the homeostasis model assessment (HOMA) is a reliable surrogate measure of in vivo insulin sensitivity in humans. RESEARCH DESIGN AND METHODS: In the present study, we compared insulin sensitivity as assessed by a 4-h euglycemic (approximately 5 mmol/l) hyperinsulinemic (approximately 300 pmol/l) clamp with HOMA in 115 subjects with various degrees of glucose tolerance and insulin sensitivity. RESULTS: We found a strong correlation between clamp-measured total glucose disposal and HOMA-estimated insulin sensitivity (r = -0.820, P<0.0001), with no substantial differences between men (r = -0.800) and women (r = -0.796), younger (aged <50 years, r = -0.832) and older (r = -0.800) subjects, nonobese (BMI <27 kg/m2, r = -0.800) and obese (r = -0.765) subjects, nondiabetic (r = -0.754) and diabetic (r = -0.695) subjects, and normotensive ( r = -0.786) and hypertensive (r = -0.762) subjects. Also, we found good agreement between the two methods in the categorization of subjects according to insulin sensitivity (weighted k = 0.63). CONCLUSIONS: We conclude that the HOMA can be reliably used in large-scale or epidemiological studies in which only a fasting blood sample is available to assess insulin sensitivity

Effect of chronic treatment with lacidipine or lisinopril on intracellular partitioning of glucose metabolism in type 2 diabetes mellitus.

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity.

Prevalence of insulin resistance in metabolic disorders: the Bruneck Study.

The prevalence of insulin resistance in the most common metabolic disorders is still an undefined issue. We assessed the prevalence rates of insulin resistance in subjects with impaired glucose tolerance (IGT), NIDDM, dyslipidemia, hyperuricemia, and hypertension as identified within the frame of the Bruneck Study. The study comprised an age- and sex-stratified random sample of the general population (n = 888; aged 40-79 years). Insulin resistance was estimated by homeostasis model assessment (HOMA(IR)), preliminarily validated against a euglycemic-hyperinsulinemic clamp in 85 subjects. The lower limit of the top quintile of HOMA(IR) distribution (i.e., 2.77) in nonobese subjects with no metabolic disorders (n = 225) was chosen as the threshold for insulin resistance. The prevalence of insulin resistance was 65.9% in IGT subjects, 83.9% in NIDDM subjects, 53.5% in hypercholesterolemia subjects, 84.2% in hypertriglyceridemia subjects, 88.1% in subjects with low HDL cholesterol, 62.8% in hyperuricemia subjects, and 58.0% in hypertension subjects. The prevalence of insulin resistance in subjects with the combination of glucose intolerance (IGT or NIDDM), dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia and/or low HDL cholesterol), hyperuricemia, and hypertension (n = 21) was 95.2%. In isolated hypercholesterolemia, hypertension, or hyperuricemia, prevalence rates of insulin resistance were not higher than that in nonobese normal subjects. An appreciable number of subjects (n = 85, 9.6% of the whole population) was insulin resistant but free of IGT, NIDDM, dyslipidemia, hyperuricemia, and hypertension. These results from a population-based study documented that 1) in hypertriglyceridemia and a low HDL cholesterol state, insulin resistance is as common as in NIDDM, whereas it is less frequent in hypercholesterolemia, hyperuricemia, and hypertension; 2) the vast majority of subjects with multiple metabolic disorders are insulin resistant; 3) in isolated hypercholesterolemia, hyperuricemia, or hypertension, insulin resistance is not more frequent than can be expected by chance alone; and 4) in the general population, insulin resistance can be found even in the absence of any major metabolic disorders.

Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus.

To evaluate the effects of chronic cigarette smoking on insulin sensitivity in patients with noninsulin-dependent diabetes mellitus (NIDDM), we examined 28 smokers and 12 nonsmokers with NIDDM, of similar sex, age, body mass index, waist/hip ratio, alcohol consumption, physical activity level, glycometabolic control, diabetes duration, and treatment. Insulin and C-peptide responses to oral glucose load were significantly higher in smokers than nonsmokers, whereas glucose levels were not substantially different. During insulin clamp (20 mU/min.m2), carried out in combination with tritiated glucose infusion and indirect calorimetry, total glucose disposal was markedly reduced in smokers vs. nonsmokers [19 +/- 1.2 vs. 33 +/- 5 mumol/min.kg fat-free mass (FFM); P < 0.001], in a dose-dependent fashion (F = 6.8, P < 0.001 by ANOVA when subjects were categorized for number of cigarettes smoked per day). Oxidative (9 +/- 1 vs. 14 +/- 2 mumol/min.kg FFM; P < 0.01) and nonoxidative (10 +/- 1 vs. 19 +/- 4 mumol/min.kg FFM; P < 0.01) pathways of insulin-mediated intracellular glucose metabolism were similarly reduced in smokers vs. nonsmokers. Plasma free fatty acid levels (240 +/- 33 vs. 130 +/- 23 microEq/L; P < 0.05) and lipid oxidation rate (1.39 +/- 0.1 vs. 0.95 +/- 0.2 mumol/ min.kg FFM; P < 0.05) were less suppressed by hyperinsulinemia in smokers than nonsmokers. In conclusion, chronic cigarette smoking seems to markedly aggravate insulin resistance in patients with NIDDM.

Obesity worsens cardiovascular risk profiles independently of hyperinsulinaemia.

OBJECTIVE: To investigate whether human obesity is characterized by a worse cardiovascular risk profile (than no obesity) even in the absence of hyperinsulinaemia. SUBJECTS AND DESIGN: A total of 367 healthy subjects (247 nonobese and 120 obese) with normal glucose tolerance and without family history of diabetes mellitus. INTERVENTIONS: A 75-g oral glucose tolerance test was performed in all participants. MAIN OUTCOME MEASURES: Anthropometry, blood pressure, fasting plasma lipids and urate, plasma glucose and insulin concentrations at fasting, 1 h and 2 h after oral glucose load. RESULTS: In a multivariate linear regression analysis, body mass index was strongly related to all cardiovascular risk factors, independently of sex, age and plasma insulin. When risk factors were compared in 37 normoinsulinaemic obese subjects (plasma insulin within one standard deviation of the mean values observed in the 247 nonobese subjects), and in 37 sex- and age-matched normoinsulinaemic nonobese subjects, we found that plasma glucose levels were similar in the two groups, whereas plasma triglyceride (1.50 +/- 0.13 vs. 1.13 +/- 0.08 mmol L-1; mean +/- SE), low-density lipoprotein cholesterol (3.42 +/- 0.25 vs. 2.77 +/- 0.18 mmol L-1) and urate (290 +/- 12 vs. 255 +/- 12 mumol L-1) levels were significantly higher, and plasma high-density lipoprotein cholesterol concentrations were lower (1.27 +/- 0.04 vs. 1.46 +/- 0.06 mmol L-1) in obese than in nonobese subjects with normal plasma insulin levels (P < 0.01). Also systolic (132 +/- 2 vs. 124 +/- 2 mmHg) and diastolic (86 +/- 1 vs. 81 +/- 1 mmHg) blood pressure values were significantly higher in normoinsulinaemic obese subjects than in normoinsulinaemic nonobese individuals (P < 0.001). CONCLUSIONS: These results suggest that in human obesity a worse cardiovascular risk profile is found (than in the nonobese) independently of the presence of hyperinsulinaemia.