The Metabolic Syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study.

AIMS: To evaluate the cardiovascular risk associated with the presence of the Metabolic Syndrome in Type 2 diabetic subjects. METHODS: Subjects with the Metabolic Syndrome, defined by WHO criteria, were identified in a large sample of non-insulin-treated Type 2 diabetic patients examined within the Verona Diabetes Complications Study (n = 946). At baseline and after a mean of 4.5 years follow-up, cardiovascular disease (CVD) was assessed by medical history, physical examination, electrocardiogram (ECG) and echo-duplex of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were scrutinized in order to identify CVD deaths. In statistical analyses, CVD was considered as an aggregate end-point, including fatal and non-fatal coronary, cerebrovascular and peripheral vascular disease as well as ischaemic ECG abnormalities and vascular lesions at the echo-duplex. RESULTS: The proportion of subjects with the Metabolic Syndrome was very high (92.3%). At the baseline, 31.7% of subjects were coded positive for CVD, which was more prevalent in subjects with the Metabolic Syndrome (32.9 vs. 17.8%, P = 0.005). Among subjects free of CVD at the baseline (n = 559), CVD events during the follow-up were significantly increased in patients with the Metabolic Syndrome as compared with those without it (19.9% vs. 3.9%, P < 0.001). Multiple logistic regression analysis showed that, along with sex, age, smoking and HbA1c, the presence of the Metabolic Syndrome independently predicted prevalent (OR 2.01, P = 0.045) and incident CVD (OR 4.89, P = 0.031). CONCLUSIONS: In Type 2 diabetes, the presence of the Metabolic Syndrome is associated with an almost 5-fold increase in CVD risk.

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.

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

ACE inhibitors improve endothelial function in type 1 diabetic patients with normal arterial pressure and microalbuminuria.

OBJECTIVE: The purpose of this study was to test whether a short-course treatment with ACE inhibitors may restore endothelium-dependent and/or -independent vasodilation in the femoral artery of microalbuminuric patients with type 1 diabetes and normal arterial pressure. RESEARCH DESIGN AND METHODS: We studied nine normotensive microalbuminuric type 1 diabetic patients and two groups of control subjects matched for femoral artery diameter to type 1 diabetic patients after placebo (control group A, n = 17) and ACE inhibitor (control group B, n = 18) treatment, respectively. The patients were enrolled in a double-blind cross-over study with a 1-week trial of either placebo, captopril (25 mg t.i.d.), or enalapril (10 mg/day) in randomized order to ascertain whether short-term ACE inhibition obtained with (captopril) or without (enalapril) a sulfhydryl donor molecule ameliorates vessel wall function. Endothelium-mediated flow-dependent vasodilation and endothelium-independent vasodilation were evaluated in the right common femoral artery by echo Doppler. RESULTS: Both captopril and enalapril normalized (control group B 22.9+/-3.2% per 8 min) endothelium-dependent response (19.6+/-7.5 and 18.0+/-5.3 vs. -10.4+/-4.1% per 8 min, P < 0.01, for both captopril and enalapril versus placebo, respectively) in the type 1 diabetic patients. Captopril (28.4+/-3.5 vs. 17.1+/-3.5% per 5 min during placebo, P < 0.05) but not enalapril (20.1+/-3.0 vs. 31.7+/-2.8% per 5 min, P < 0.05 for enalapril versus control group B, and NS for captopril vs. control group B) ameliorated endothelium-independent vasodilation in type 1 diabetic patients. CONCLUSIONS: ACE inhibition improves endothelium-dependent vasodilation in the femoral artery of normotensive microalbuminuric type 1 diabetic patients. Captopril also ameliorates endothelium-independent vasodilation, possibly through its sulfhydryl donor properties. These results may be of pathophysiological relevance to prevent cardiovascular complications in these patients.

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.

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.

Relationship between fasting insulin and cardiovascular risk factors is already present in young men: the Verona Young Men Atherosclerosis Risk Factors Study.

The associations between fasting plasma insulin concentration and risk factors for cardiovascular disease were examined in 979 18-year-old men participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. Body mass index (BMI), waist-to-hip ratio (WHR), plasma triglycerides and uric acid concentrations, and blood pressure values significantly increased, and the high-density lipoprotein (HDL)-total cholesterol ratio decreased, across quartiles of fasting insulin. Total and low-density lipoprotein cholesterol, concentrations did not change significantly with the increase in fasting insulin levels. After adjustment for BMI, WHR, smoking, alcohol intake and physical activity, only plasma triglycerides significantly increased across insulin quartiles (F = 7.1; P < 0.001). However, systolic blood pressure and uric acid were close to statistical significance (P = 0.06-0.07). Multiple linear regression analysis confirmed that plasma insulin was independently correlated with plasma triglycerides and, to a lesser extent, with blood pressure and uric acid concentration. This analysis pointed out that BMI was a stronger independent predictor of all cardiovascular disease risk factors than fasting insulin. When subjects were categorized according to the number of metabolic and haemodynamic disorders occurring within the same individual, subjects with multiple disorders (i.e, three or four) had higher plasma insulin levels than those with none or few disorders, even after adjusting for BMI, WHR and behavioural variables (F = 4.0; P < 0.01). These results indicate that hyperinsulinaemia is already associated with a cluster of cardiovascular disease risk factors in young adulthood, the strongest independent association being with plasma triglycerides.

Serum uric acid and related factors in 500 hospitalized subjects.

The study purpose was to determine the following in a large sample of hospitalized patients: (1) the prevalence of hyperuricemia, (2) the association of hyperuricemia with other metabolic disorders, and (3) the factors independently predicting hyperuricemia. Five hundred adult patients (250 men and 250 women) were randomly selected from those admitted as inpatients over a period of 5 months. In all patients, body mass index (BMI), blood pressure, and serum glucose, lipid, creatinine, urea nitrogen, and urate concentrations were measured. The presence of diseases or use of medications known to affect serum urate levels were recorded. The mean level of serum urate was 5.6 mg/dL in the whole sample, 6.0 mg/dL in men and 5.3 mg/dL in women (P = .003, men v women). The prevalence of hyperuricemia was 27.6% (28.8% and 26.4% in men v women, P = nonsignificant). A definite or probable secondary hyperuricemia was found in 87.7% of the subjects. Hyperuricemia was rarely isolated (21%), whereas it was frequently associated with hypertension (60.1%), hyperlipidemia (31.2%), diabetes (28.3%), and obesity (21.7%). In 26.8% of the subjects, hyperuricemia was associated with two metabolic disorders, in 13.8% with three, and in 2.9% with four. Multiple metabolic disorders (three to four) were found in 16.7% of subjects with hyperuricemia. Serum urate levels progressively increased across a range of subjects from those without diabetes, hyperlipidemia, hypertension, or obesity to those with one, two, or a greater number of associated metabolic abnormalities. Multiple stepwise regression analysis showed that 43% of serum urate variability was explained by urea nitrogen levels, triglyceride levels, diuretic therapy, the inverse of creatinine (as an index linearly related to creatinine clearance), and BMI. These results indicate that in hospitalized subjects, hyperuricemia is (1) frequent, (2) a secondary phenomenon in most cases, and (3) frequently associated with other metabolic disorders. The major predictors of high serum urate levels are BMI, triglycerides, parameters of renal function, and use of diuretics. These variables explain a large proportion of serum urate variability.

Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study.

OBJECTIVE: To examine the relationships of serum uric acid concentration with several risk factors of cardiovascular diseases (CVD). SUBJECTS: 957 men 18 y old participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. MEASUREMENTS: Body mass index (BMI), waist/hip ratio (WHR), serum uric acid, serum lipids, blood pressure, fasting insulin and behavioural variables. RESULTS: Serum uric acid concentration showed positive associations with BMI (r = 0.24; P < 0.0001), WHR (r = 0.19; P < 0.0001) and serum triglyceride levels (r = 0.19; P < 0.0001); it was also significantly correlated to systolic (r = 0.08; P < 0.01) and diastolic (r = 0.11; P < 0.001) blood pressure, fasting insulin (r = 0.11; P < 0.001), total (r = 0.12; P < 0.001) and LDL cholesterol (r = 0.10; P < 0.01) plasma concentrations. Life-style characteristics, such as smoking and physical activity did not show any significant association, while daily alcohol intake was positively associated with uric acid concentration (r = 0.09; P < 0.01). While the adjustment for fasting insulin did not substantially change these results, the magnitude of the correlations between uric acid and CVD risk factors markedly decreased when allowance was made for BMI and WHR. Only triglycerides maintained an independent correlation with uric acid levels (r = 0.17; P < 0.0001). In multivariate regression analysis, serum triglycerides, BMI and WHR (at borderline significance) were independent positive predictors of uric acid (R2 of the model 0.122, P < 0.001), while fasting insulin concentration did not give any independent contribution to explain the variability uric acid levels. CONCLUSIONS: These data indicate that, already in young, essentially health subjects, hyperuricaemia associates with several components of the so-called insulin resistance syndrome, thus suggesting that increased levels of uric acid might be another member of this syndrome. In addition, these data suggest that obesity and central body fat distribution, rather than hyperinsulinaemia/insulin resistance, play a major role in linking hyperuricaemia with CVD risk factors clustering in the insulin resistance syndrome. Nevertheless, hypertrigliceridemia is related to hyperuricemia independently of obesity and central body fat distribution.

Cardiovascular risk profile in 38-year and 18-year-old men. Contribution of body fat content and regional fat distribution.

OBJECTIVE: To evaluate whether young and middle-age men differ in blood pressure and serum lipid profiles and, if so, to what extent these differences are dependent on total body fat, regional fat distribution, plasma insulin and behavioural variables. SUBJECTS: Random samples of 94 young (18 year-old) and 94 middle-age (38 year-old) healthy men matched for body mass index (BMI). MEASUREMENTS: BMI, total body fat (by bioelectrical impedance), regional fat distribution (by anthropometry), serum lipids, blood pressure, fasting insulin and some behavioural variables. RESULTS: Total body fat was similar in the two groups (mean +/- s.e.: 16.6 +/- 0.5 vs 16.0 +/- 0.6 kg and 20.8 +/- 0.5 vs 20 +/- 0.5%), while waist/hip circumference ratio (WHR) was significantly higher in middle-age as compared to young men (0.96 +/- 0.001 vs 0.92 +/- 0.003, P < 0.0001). The former also had significantly higher serum concentrations of total cholesterol (6.21 +/- 0.13 vs 4.10 +/- 0.10 mmol/l; P < 0.0001). LDL-cholesterol (4.24 +/- 0.11 vs 2.34 +/- 0.10 mmol/l; P < 0.0001), triglycerides 1.40 +/- 0.09 vs 1.02 +/- 0.06 mmol/l; P < 0.01) as well as higher systolic (134.0 +/- 1.6 vs 126.3 +/- 1.4 mmHg; P < 0.0001) and diastolic (86.8 +/- 0.9 vs 82.0 +/- 1.1 mmHg; P < 0.001) blood pressure values. HDL-cholesterol and fasting insulin concentrations were similar in the two groups (1.33 +/- 0.03 vs 1.28 +/- 0.03 mmol/l and 13.7 +/- 0.6 vs 14.7 +/- 0.7 mU/l, respectively). Significant differences in the two groups also were found in daily alcohol consumption (49.6 +/- 5.7 vs 20.0 +/- 3.4 g/day; P < 0.0001), whereas no significant differences were found in smoking and physical activity level. The comparison of subgroups (n = 41) of young and middle-age men matched for both BMI and WHR showed virtually unchanged differences in serum lipids and blood pressure. When age, BMI, WHR, fasting insulin and behavioural variables were included as independent variables in a multiple linear regression analysis in which subjects of the two groups were pooled, age was a significant predictor of total and LDL cholesterol, triglycerides and systolic blood pressure, insulin predicted HDL cholesterol and systolic blood pressure, BMI predicted triglycerides and diastolic blood pressure and WHR was not an independent predictor of any risk factor. CONCLUSIONS: These results indicate that middle-age men have a cardiovascular risk profile less favourable than young men, which is largely independent of differences in total body fat content, regional fat distribution and behavioural variables.

Noninvasive detection of functional alterations of the arterial wall in IDDM patients with and without microalbuminuria.

OBJECTIVE: To test endothelial function in a group of 10 normoalbuminuric and eight microalbuminuric insulin-dependent diabetes mellitus patients (ages 28 +/- 3 [mean +/- SE] and 28 +/- 1 years, respectively), in comparison with 16 control subjects (age 35 +/- 2 years, normal subjects vs. diabetic subjects P = NS), to identify prestructural abnormalities of the arterial wall. An early stage of vascular involvement seems in fact to be characterized by functional alterations of endothelial control on vascular tone and wall interaction with circulating cells. Furthermore, many recent studies suggest the importance of microalbuminuria as an early marker not only of nephropathy but also of retinopathy and macroangiopathy. RESEARCH DESIGN AND METHODS: Endothelium-mediated flow-dependent vasodilation and endothelium-independent vasodilation (induced by glyceryl trinitrate administration) were evaluated in the right common femoral artery by echo-Doppler ultrasound. Arterial wall distensibility was evaluated at the common femoral artery by an echo-tracking system. RESULTS: In spite of a comparable increase in flow velocity, endothelium-mediated vasodilation was significantly reduced in diabetic subjects, particularly in microalbuminuric patients. Endothelium-independent vasodilation was also significantly impaired in diabetic subjects, particularly in microalbuminuric subjects; whereas arterial wall distensibility, an index of the viscoelastic properties of the wall, was similar in the three groups. CONCLUSIONS: These results confirm a reduced vasodilatory capacity in diabetes mellitus, with a more marked alteration in microalbuminuric diabetic subjects. This reliable, noninvasive evaluation of arterial function is particularly useful for early diagnosis of vascular involvement.