Limitation of the validity of the homeostasis model assessment as an index of insulin resistance in Korea

Homeostasis model assessment of insulin resistance (HOMA-IR) is a less invasive, inexpensive, and less labor-intensive method to measure insulin resistance (IR) as compared with the glucose clamp test. The aim of this study was to evaluate the validity of HOMA-IR by comparing it with the euglycemic clamp test in determining IR. We assessed the validity of HOMA-IR by comparing it with the total glucose disposal rate measured by the 3-hour euglycemic-hyperinsulinemic clamp in subjects with type 2 diabetes (n = 47), impaired glucose tolerance (n = 21), and normal glucose tolerance (n = 22). There was a strong inverse correlation (r = -0.558; P < .001) between the log-transformed HOMA-IR and the total glucose disposal rate. There was moderate agreement between the 2 methods in the categorization according to the IR (weighted kappa = 0.294). The magnitude of the correlation coefficients was smaller in the subjects with a lower body mass index (BMI <25.0 kg/m2 , r = -0.441 vs BMI > or =25.0 kg/m2 , r = -0.615; P = .032), a lower HOMA-beta cell function (HOMA- beta <60.0, r = -0.527 vs HOMA- beta > or =60.0, r = -0.686; P = .016), and higher fasting glucose levels (fasting glucose < or =5.66 mmol/L, r = -0.556 vs fasting glucose >5.66 mmol/L, r = -0.520; P = .039). The limitation of the validity of the HOMA-IR should be carefully considered in subjects with a lower BMI, a lower beta cell function, and high fasting glucose levels such as lean type 2 diabetes mellitus with insulin secretory defects.     

Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes

Vanadyl sulfate (VOSO(4)) is an oxidative form of vanadium that in vitro and in animal models of diabetes has been shown to reduce hyperglycemia and insulin resistance. Small clinical studies of 2- to 4-week duration in type 2 diabetes (T2DM) have led to inconsistent results. To define its efficacy and mechanism of action, 11 type 2 diabetic patients were treated with VOSO(4) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than in previous studies. Before and after treatment we measured insulin secretion during an oral glucose tolerance test, and endogenous glucose production (EGP) and whole body insulin-mediated glucose disposal using the euglycemic insulin clamp technique combined [3-(3)H]glucose infusion. Treatment significantly improved glycemic control: fasting plasma glucose (FPG) decreased from 194 +/- 16 to 155 +/- 15 mg/dL, hemoglobin A(1c) decreased from 8.1 +/- 0.4 to 7.6 +/- 0.4%, and fructosamine decreased from 348 +/- 26 to 293 +/- 12 micromol/L (all P < 0.01) without any change in body weight. Diabetics had an increased rate of EGP compared with nondiabetic controls (4.1 +/- 0.2 vs. 2.7 +/- 0.2 mg/kg lean body mass.min; P< 0.001), which was closely correlated with FPG (r = 0.56; P< 0.006). Vanadyl sulfate reduced EGP by about 20% (P< 0.01), and the decline in EGP was correlated with the reduction in FPG (r = 0.60; P< 0.05). Vanadyl sulfate also caused a modest increase in insulin-mediated glucose disposal (from 4.3 +/- 0.4 to 5.1 +/- 0.6 mg/kg lean body mass x min; P< 0.03), although the improvement in insulin sensitivity did not correlate with the decline in FPG after treatment (r = -0.16; P = NS). Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cholesterol (141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05), whereas 24-h ambulatory blood pressure was unaltered. We conclude that VOSO(4) at maximal tolerated doses for 6 weeks improves hepatic and muscle insulin sensitivity in T2DM. The glucose-lowering effect of VOSO(4) correlated well with the reduction in EGP, but not with insulin-mediated glucose disposal, suggesting that liver, rather than muscle, is the primary target of VOSO(4) action at therapeutic doses in T2DM.     

Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects

CONTEXT: Thyroid disease and the metabolic syndrome are both associated with cardiovascular disease. OBJECTIVE: The aim of this study was to explore the hypothesis that thyroid function, in euthyroid subjects, is associated with components of the metabolic syndrome, including serum lipid concentrations and insulin resistance. METHODS: A total of 2703 adult inhabitants of a middle-sized city in The Netherlands participated in this cross-sectional study. Subjects who were not euthyroid were excluded, as were subjects taking thyroid medication, medication for diabetes, and subjects for whom medication data were not available (n = 1122). Homeostasis model assessment for insulin resistance (HOMA-IR) (mU*mmol/liter2) was calculated as fasting insulin (mU/liter) times fasting glucose (mmol/liter) divided by 22.5. The metabolic syndrome was defined according to National Cholesterol Education Program's Adult Treatment Panel III criteria. RESULTS: After adjustment for age and sex, free T4 (FT4) was significantly associated with total cholesterol [standardized beta (beta) = -0.059; P = 0.014], low-density lipoprotein cholesterol (beta = -0.068; P = 0.004), high-density lipoprotein cholesterol (beta = 0.100; P < 0.001), and triglycerides (beta = -0.102; P < 0.001). Both FT4 and TSH were significantly associated with HOMA-IR (beta = -0.133; P < 0.001 and beta = 0.055; P = 0.024, respectively). Median HOMA-IR increased from 1.42 in the highest tertile of FT4 to 1.66 in the lowest tertile of FT4. FT4 was significantly related to four of five components of the metabolic syndrome (abdominal obesity, triglycerides, high-density lipoprotein cholesterol, and blood pressure), independent of insulin resistance. CONCLUSIONS: We have demonstrated an association between FT4 levels within the normal reference range and lipids, in accordance with the earlier observed association between (sub)clinical hypothyroidism and hyperlipidemia. Moreover, low normal FT4 levels were significantly associated with increased insulin resistance. These findings are consistent with an increased cardiovascular risk in subjects with low normal thyroid function.     

Levels of C3 in patients with severe, morbid and extreme obesity: its relationship to insulin resistance and different cardiovascular risk factors

OBJECTIVE: Increased C3 has been related to body mass index (BMI) and insulin resistance, although there are not sufficient studies in subjects with morbid obesity. The purpose of this study was to evaluate the levels of C3 as a function of the BMI in subjects of both sexes, with severe, morbid and extreme obesity, and their possible relationship to insulin resistance or associated diseases such as diabetes, hypertension and dyslipidemia. SUBJECTS: The study included a total of 316 patients (110 men and 206 women) with severe obesity (17.1%), morbid obesity (54.4%) and extreme obesity (28.4%), with an average BMI of 46.70+/-7.37 kg/m2. MEASUREMENTS: The glucose and insulin levels were determined baseline, and 2 h after a 75 g of oral glucose load. The homeostasis model of assessment for insulin resistance (HOMA-IR) was calculated. A lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein AI and apolipoprotein B100) was obtained and C3 levels determined by nephelometry. RESULTS: When distributing the patients by quartiles of BMI, we found a progressive increase in the levels of C3, and no significant differences in the rest of analytical variables studied were found; the mean values of C3 were 127.78+/-29.7 mg/dl.A significant correlation was found between C3 and the BMI (r=0.263, P<0.001), baseline insulin (r=0.237, P=0.001) and HOMA-IR (r=0.237, P=0.001). High blood pressure was found in 111 patients, type 2 diabetes in 74 patients and dyslipidemia in 139 cases. When distributing the levels of C3 according to the number of associated risk factors (hypertension, diabetes and dyslipidemia), we found significant differences between these patients and those who presented no associated diseases (P<0.01). CONCLUSION: A relationship between C3 and the progressive increase of BMI in subjects with severe, morbid or extreme obesity was established. This increase in C3 was closely related to insulin levels and the values for HOMA-IR. Furthermore, we also found an increase in C3 as more diseases related to insulin resistance, such as diabetes, hypertension and dyslipidemia, were associated with the obesity.     

Association between hypoadiponectinemia and cardiovascular risk factors in nonobese healthy adults

Adiponectin levels are significantly lower in obese adult patients with type 2 diabetes mellitus, essential hypertension, dyslipidemia, and cardiovascular disease. However, the role of hypoadiponectinemia in nonobese healthy adults has not been fully elucidated. In this study, we examined the association between hypoadiponectinemia and cardiovascular risk factors and estimated plasma adiponectin values in nonobese, apparently healthy adults. A total of 204 male and 214 female healthy individuals aged 20 to 80 years, with a body mass index (BMI) of less than 25 kg/m2, were included in this study. We measured patients' plasma adiponectin levels, serum lipid profiles, high-sensitivity C-reactive protein (hs-CRP) levels, fasting glucose levels, and fasting insulin levels. Mean values of plasma adiponectin were 5.45 +/- 3.3 microg/mL in male and 8.16 +/- 4.6 microg/mL in female subjects. The hypoadiponectinemia group (< 4.0 microg/mL) had significantly higher levels (P < .01) of BMI, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglycerides, but lower levels of high-density lipoprotein cholesterol (HDL-C). In males, plasma adiponectin levels were inversely correlated with BMI (r = -0.32, P < .01), HOMA-IR (r = -0.14, P < .05), triglyceride levels (r = -0.17, P < .05), and hs-CRP levels (r = -0.15, P < .05), and positively correlated with HDL-C (r = 0.24, P < .01). In females, plasma adiponectin levels were negatively correlated with BMI (r = -0.31, P < .01), fasting glucose (r = -0.18, P < .01), fasting insulin (r = -0.23, P < .01), HOMA-IR (r = -0.24, P < .01), and triglyceride (r = -0.18, P < .01) levels, and positively correlated with HDL-C (r = 0.37, P < .01). Sex, age, BMI, and HDL-C (P < .01 for each) were found to be independent factors associated with plasma adiponectin levels in multivariate analysis. Hypoadiponectinemia is significantly associated with cardiovascular risk factors such as insulin resistance and atherogenic lipid profiles in nonobese, apparently healthy subjects.     

Thiazolidinediones enhance insulin-mediated suppression of fatty acid flux in type 2 diabetes mellitus

Type 2 diabetes mellitus is characterized by insulin-resistant glucose and lipid metabolism. Thiazolidinediones (TZDs) enhance insulin-mediated glucose disposal, but their effects on lipid kinetics are unknown. We evaluated the effect of the TZD troglitazone on insulin-mediated suppression of fatty acid and glycerol kinetics. Eight obese men and women (body mass index [BMI], 34.1 +/- 2.3 kg/m(2)) with insulin-requiring type 2 diabetes were studied before and after 12 weeks of troglitazone therapy (400 mg/d). Whole-body and abdominal fat masses were determined by dual-energy x-ray absorptiometry and magnetic resonance imaging, respectively. Palmitate and glycerol rates of appearance (R(a)) into plasma were evaluated during a 3-stage hyperinsulinemic euglycemic clamp, which spanned the physiologic range of plasma insulin concentrations that regulate lipolysis. Troglitazone therapy did not alter body composition. Palmitate and glycerol R(a) decreased progressively during each stage of hyperinsulinemia (P <.001). Suppression of palmitate R(a) by insulin was greater after than before troglitazone therapy (P <.001), whereas glycerol R(a) was unchanged. These results demonstrate that TZDs increase insulin-mediated suppression of fatty acid release into plasma in obese subjects with type 2 diabetes mellitus, which may contribute to their metabolic benefits. However, TZD therapy did not affect whole-body glycerol R(a), possibly because of upregulation of lipoprotein lipase action on plasma triglycerides.     

Insulin resistance as a major determinant of increased coronary heart disease risk in postmenopausal women with Type 2 diabetes mellitus.

AIM: To investigate the risk factors associated with clinically defined coronary heart disease (CHD) in women with Type 2 diabetes mellitus (DM). METHODS: CHD status was assessed via standard history and resting electrocardiogram in 41 postmenopausal diabetic and 41 age- and body mass index-matched normoglycaemic women recruited from a community-based cohort. The following parameters were assessed: body composition by dual energy X-ray absorptiometry, blood pressure, metabolic and lipoprotein profile and haemostatic factors. RESULTS: Diabetic women with CHD (n = 14) had greater insulin resistance, calculated by homeostasis model assessment (10.2 (7.0-14.8) vs. 6.5 (5.5-7.7), P = 0.010), and higher plasminogen activator inhibitor-1 (PAI-1) levels (45 (29-69) vs. 24 (19-32) ng/ml, P = 0.013), than those without CHD. They also had higher triglycerides (2.9 (2.2-3.8) vs. 2.1 (1.8-2.4) mmol/l, P = 0.016) and a trend towards reduced low-density lipoprotein particle size (25.5 +/- 0.6 vs. 25.8 +/- 0.5 nm, P = 0.097). In a logistic regression model, insulin resistance was a significant independent predictor of CHD status (odds ratio = 1.33, 95% confidence interval = 1.06-1.68, P = 0.015). In contrast, in normoglycaemic women the major risk factors for CHD were elevated cholesterol, apolipoprotein(a), apolipoprotein B and systolic blood pressure (P = 0.018, P = 0.016, P = 0.006 and P = 0.049, respectively). CONCLUSIONS: Increased insulin resistance in association with elevated PAI-1 and dyslipidaemia appears to underpin the increased risk of CHD in women with Type 2 DM. Therapeutic approaches that increase insulin sensitivity may serve to reduce CHD risk in this vulnerable group. Diabet. Med. 18, 476-482 (2001)     

Effects of pioglitazone and metformin on plasma adiponectin in newly detected type 2 diabetes mellitus

OBJECTIVE: This prospective study evaluates the effect of insulin sensitizers, pioglitazone (PGZ) and metformin (MET) on plasma adiponectin and leptin levels in subjects newly diagnosed with type 2 diabetes mellitus (T2DM). DESIGN: Double blind, randomized, active control, dose escalation study of 12 weeks treatment duration. PATIENTS: Thirty apparently healthy, treatment-naive T2DM patients diagnosed within the past 6 months. MEASUREMENTS: Plasma adiponectin and leptin levels were estimated by enzyme-linked immunosorbent assay (ELISA), and insulin resistance by the homeostasis model of assessment (HOMA-IR). RESULTS: Baseline plasma levels of adiponectin were lower in diabetic (n = 30) subjects than matched controls (n = 10, 6.6 +/- 1.1 vs 10.4 +/- 4.2 microg/ml, P = 0.021). The 12-week treatment with PGZ significantly increased adiponectin concentrations (6.6 +/- 1.1-17.9 +/- 7.4 microg/ml, P < 0.001) with no alteration in the MET treated group (6.8 +/- 1.5-6.7 +/- 2.8 microg/ml, P = 0.9). A significant decrease in plasma leptin levels was observed in the MET treated group (32.0 +/- 28.9-21.4 +/- 23.3 ng/ml, P = 0.024) but not in the PGZ treated group (23.9 +/- 24.1-22.4 +/- 25.4 ng/ml, P = 0.69). The alterations in plasma adiponectin and leptin levels were not associated with any change in body mass index (BMI). PGZ therapy improved insulin sensitivity to a greater degree (P = 0.007 and P = 0.001 for fasting plasma insulin (FPI) and HOMA-IR, respectively) than MET (P = 0.75 and P = 0.02 for FPI and HOMA-IR, respectively) but this improvement was not significantly different from that of MET at the end of 12 weeks (P = 0.146 and P = 0.09 for FPI and HOMA-IR, respectively). However, improvement in insulin sensitivity with PGZ was not commensurate with the increase in adiponectin. Better control of postbreakfast plasma glucose (PBPG) as well as decrease in serum triglycerides (TGs) were also seen with PGZ (PBPG, P < 0.001; TGs, P = 0.013). The rest of the parameters were comparable. Adverse reactions reported were minor and did not result in treatment discontinuation. CONCLUSIONS: Pioglitazone therapy appears to be better in achieving glycaemic control and increasing plasma adiponectin and insulin sensitivity in newly detected type 2 diabetics.     

Insulin sensitivity and intramyocellular lipid concentrations in young Maori men.

AIMS: In muscle, resistance to insulin-mediated glucose uptake is thought to underlie the pre-Type 2 diabetic condition. In European Caucasian men, insulin sensitivity is negatively associated with intramyocellular lipid (IMCL) content, and this may provide an early marker of diabetes risk. This study was designed to examine the relationship between vastus lateralis IMCL content, aerobic fitness, adiposity and markers of insulin sensitivity in healthy, young Maori men. METHODS: The following parameters were measured in 24 Maori men aged 28 +/- 6 years (mean +/- sd): overnight fasting blood concentrations of glucose, insulin and triglycerides; body composition using underwater weighing; maximal oxygen uptake (VO2max) using an incremental treadmill exercise test; and vastus lateralis IMCL concentration using proton nuclear magnetic resonance spectroscopy (1H MRS). RESULTS: All participants had normal fasting blood glucose. Simultaneous multiple regression analysis with homeostasis model assessment-insulin resistance (HOMA-IR) as the dependent variable showed that: (i) increased body fatness and decreased aerobic capacity (per kg lean body mass) are significant predictors of insulin sensitivity as estimated by HOMA-IR; and (ii) although vastus lateralis IMCL concentrations are elevated, they do not contribute to the prediction of insulin sensitivity. CONCLUSIONS: IMCL is not a reliable marker of estimated insulin resistance in this cohort of young, healthy Maori men. However, measures of composition and aerobic fitness may be of use as non-invasive, culturally acceptable measures to help identify Maori men with impaired insulin action, but normal fasting glycaemia.     

A double blind study of the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with type 2 diabetes mellitus.

Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.     

The role of the body mass index and triglyceride levels in identifying insulin-sensitive and insulin-resistant variants in Japanese non-insulin-dependent diabetic patients

Using the minimal model approach shown by Bergman, our group had previously shown 2 variants among non-obese mildly diabetic patients, one with normal insulin sensitivity and the other with insulin resistance. The present study examines whether these 2 variants exist in the ordinary Japanese non-insulin-dependent diabetes mellitus (NIDDM) population and compares the clinical profile between the 2 discrete forms of NIDDM. In addition, we investigated the factors responsible for insulin resistance observed in Japanese NIDDM populations. One hundred eleven untreated Japanese NIDDM subjects (fasting glucose < 10 mmol/L) were assessed for insulin action (homeostasis model assessment [HOMA-IR] = fasting serum insulin (microU/mL) x fasting plasma glucose (mmol/L)/22.5) and the fasting lipid profile. Sixty percent of these patients had normal insulin sensitivity (HOMA-IR < 2.5). The insulin-resistant patients had higher serum cholesterol (188.1 +/- 5.2 v 182.2 +/- 3.9 mg/dL, P> .05) and low-density lipoprotein (LDL) cholesterol (501.2 +/- 16.7 v 469.4 +/- 14.8 mg/dL, P > .05) than the insulin-sensitive patients, but the difference was not statistically significant. In contrast, the former group had a significantly higher body mass index ([BMI] 26.6 +/- 0.8 v 21.7 +/- 0.4 kg/m2, P < .0001) and higher serum triglycerides (181.0 +/- 16.4 (range, 79 to 545) v 95.1 +/- 4.1 (range, 36 to 204) mg/dL, P < .0001) and lower high-density lipoprotein (HDL) cholesterol (47.2 +/- 1.7 v 58.2 +/- 2.5 mg/dL, P < .005) than the latter group. HOMA-IR was related to the BMI. Fifteen of 17 (88%) NIDDM patients with a BMI greater than 27.0 were insulin-resistant, whereas 35 of 38 (92%) NIDDM patients with a BMI less than 21.5 were insulin-sensitive. In the midrange BMI (21.5 to 27.0 kg/m2), patients were equally likely to be insulin-resistant or insulin-sensitive. Analysis of the midrange BMI group showed that HOMA-IR was associated with serum triglycerides (P < .0001) but not with the BMI. These data suggest the following conclusions: (1) Japanese NIDDM patients can be classified into 2 populations, one with normal insulin sensitivity and the other with insulin resistance; (2) NIDDM patients with normal insulin action have a low cardiovascular disease risk factor, whereas those with insulin resistance have a markedly increased cardiovascular disease risk factor; and (3) the BMI and serum triglyceride level per se are associated with insulin action in Japanese NIDDM populations.     

A possible association between primary aldosteronism and a lower beta-cell function

OBJECTIVE: Primary aldosteronism (PA) is the most common secondary cause of hypertension and recently has been implicated as a cause of impaired glucose tolerance. We investigated the glucose insulin sensitivity and insulin secretion in patients with idiopathic primary aldosteronism. DESIGN: Thirty PA patients and 60 essential hypertensive (EH) patients as controls were included, matched (1: 2) by their body mass index (BMI) (29.9 +/- 4.3 versus 29.8 +/- 5.8 m/kg), age (53.7 +/- 9.4 versus 59.9 +/- 8.6 years old) and gender (male/female: 8/22 versus 17/43). In all patients, we measured insulin, total cholesterol, triglycerides, C-peptide and fasting glucose levels. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA of pancreatic beta-cell function (HOMA-betaF) indexes were calculated. We also evaluated the response to spironolactone in 19 PA patients. RESULTS: PA patients had higher levels of glucose (5.2 +/- 0.7 versus 4.9 +/- 0.7 mmol/l; P = 0.017). Insulin levels (10.7 +/- 6.5 versus 11.5 +/- 5.8 uUI/ml, P = 0.525) and HOMA-IR (2.51 +/- 1.59 versus 2.45 +/- 1.29 uUI/ml x mmol/l, P = 0.854) were similar in both groups. HOMA-betaF index (138.9 +/- 89.8 versus 179.8 +/- 100.2%, P = 0.049) and C-peptide (0.83 +/- 0.63 versus 1.56 +/- 0.84 ng/dl, P = 0.0001) were lower in PA patients. Potassium was normal in both groups. Negative correlations between serum aldosterone/plasma renin activity (SA/PRA) ratio and HOMA-betaF, and between C-peptide and SA levels were found in all patients. After the spironolactone treatment, we found an increase of C-peptide and insulin levels without changes in HOMA-IR or HOMA-betaF. CONCLUSION: Our results showed differences in glucose metabolism between PA patients and those with hypertension suggesting that these findings could probably be determined by a lower beta-cell function influenced by aldosterone. These findings highlight the importance of aldosterone in glucose metabolism.     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of aortic arch calcification in type 2 diabetic patients

BACKGROUND: The purpose of this study is to evaluate the severity of aortic arch calcification among type 2 diabetic patients in association with diabetes duration, diabetic complications, coronary artery disease and presence of cardiovascular risk factors. PATIENTS AND METHODS: This study included 207 type 2 diabetic patients (101 men) with a mean age of 61.5 +/- 8.1 years and a mean diabetes duration of 13.9 +/- 6.4 years. Aortic arch calcification was assessed by means of posteroanterior chest X-rays. Severity of calcification was graded as follows: grade 0 (no visible calcification), grade 1 (small spots of calcification or single thin calcification of the aortic knob), grade 2 (one or more areas of thick calcification), grade 3 (circular calcification of the aortic knob). RESULTS: Severity of calcification was grade 0 in 84 patients (40.58%), grade 1 in 64 patients (30.92%), grade 2 in 43 patients (20.77%) and grade 3 in 16 patients (7.73%). In simple regression analysis severity of aortic arch calcification was associated with age (p = 0.032), duration of diabetes (p = 0.026), insulin dependence (p = 0.042) and presence of coronary artery disease (p = 0.039), hypertension (p = 0.019), dyslipidaemia (p = 0.029), retinopathy (p = 0.012) and microalbuminuria (p = 0.01). In multiple regression analysis severity of aortic arch calcification was associated with age (p = 0.04), duration of diabetes (p = 0.032) and presence of hypertension (p = 0.024), dyslipidaemia (p = 0.031) and coronary artery disease (p = 0.04), while the association with retinopathy, microalbuminuria and insulin dependence was no longer significant. CONCLUSIONS: Severity of aortic arch calcification is associated with age, diabetes duration, diabetic complications (retinopath), microalbuminuria), coronary artery disease, insulin dependence, and presence of hypertension and dyslipidaemia.     

Increased apolipoprotein C-III levels associated with insulin resistance contribute to dyslipidemia in normoglycemic and diabetic subjects from a triethnic population

Despite the major role of insulin in regulating apolipoprotein C-III (apo C-III) production, little is known about the relationship between apo C-III and insulin resistance. We examined this relationship, and the association of apo C-III with dyslipidemia, in a triethnic sample of 168 subjects with normoglycemia or type 2 diabetes. African-Americans had lower triglycerides (1.21 +/- 0.11 mmol/l) compared with Hispanics (2.01 +/- 0.14 mmol/l) and white non-Hispanics (1.83 +/- 0.15 mmol/l), regardless of gender and type 2 diabetes status (P < 0.01), but this difference was partially accounted for by ethnic difference in apo C-III levels. Metabolic syndrome was associated with high apo C-III (> 14 mg/dl) in Hispanics (OR = 5.6; 95%CI: 1.3-23.4) and white non-Hispanics (OR = 6.9; 95%CI: 1.3-36.4), but not in African-Americans. Apo C-III was the best predictor of triglycerides (R2 = 0.54, P < 0.001), after accounting for demographic and clinical variables. We found an inverse relationship between apo C-III levels and low-density lipoprotein (LDL) particle size in the type 2 diabetes subjects with (r = -0.36, P = 0.02) and without (r = -0.47, P = 0.02) the metabolic syndrome, but in normoglycemic subjects an inverse relationship was evident only in metabolic syndrome subjects (r = -0.52, P < 0.01). These results suggest that higher apo C-III may contribute to the increased cardiovascular risk in subjects with insulin resistance and type 2 diabetes through its effects on triglycerides and LDL particle size.     

Relationship between insulin resistance and left ventricular diastolic dysfunction in patients with impaired glucose tolerance and type 2 diabetes

AIM: The aim of this study was to explore the relationship between insulin resistance (IR) and the left ventricular diastolic function in patients with type 2 diabetes and subjects with impaired glucose tolerance (IGT). METHODS: The study included 119 subjects who underwent oral glucose tolerance test (OGTT). IR was assessed using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI). Left ventricular diastolic function was assessed using trans-thoracic Doppler echocardiography. RESULTS: Based on the OGTT results, 29 subjects had normal glucose tolerance (NGT), 20 subjects had impaired glucose tolerance (IGT), and 70 patients had type 2 diabetes. There were significant differences among the patients in groups with NGT, IGT and diabetes regarding HOMA-IR (4.20 +/- 1.20 vs. 6.45 +/- 3.83 vs. 8.70 +/- 6.26; P < 0.001) and QUICKI (0.54 +/- 0.11 vs. 0.49 +/- 0.08 vs. 0.47 +/- 0.08; P < 0.001). In subjects with NGT, IGT and patients with diabetes, the pulsed Doppler transmitral variables were: E-wave (0.72 +/- 0.16 cm/s vs. 0.62 +/- 0.13 cm/s vs. 0.58 +/- 0.17 cm/s; P < 0.001), A-wave (0.61 +/- 0.13 cm/s vs. 0.62 +/- 0.11 cm/s vs. 0.71+/- 0.14 cm/s; P = 0.006) and E/A ratio (1.22 +/- 0.33 vs. 1.02 +/- 0.24 vs. 0.85 +/- 0.26; p < 0.001). The proportion of subjects with an E/A ratio <1 was 27.6% in the group with NGT, 55% in the group with IGT and 75.7% in the group with diabetes (P < 0.001). The E/A ratio correlated with HOMA-IR (r = -0.30, p = 0.001) and QUICKI (r = 0.37, p < 0.0001). Multiple linear regression model showed that IR (assessed by QUICKI) was an independent correlate of diastolic dysfunction (P = 0.034). CONCLUSIONS: In subjects with impaired glucose tolerance and patients with type 2 diabetes, insulin resistance is associated with impaired diastolic function of the left ventricle.     

Telomere shortening occurs in Asian Indian Type 2 diabetic patients.

AIM: Telomere shortening has been reported in several diseases including atherosclerosis and Type 1 diabetes. Asian Indians have an increased predilection for Type 2 diabetes and premature coronary artery disease. The aim of this study was to determine whether telomeric shortening occurs in Asian Indian Type 2 diabetic patients. METHODS: Using Southern-blot analysis we determined mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leucocyte DNA. Type 2 diabetic patients without any diabetes-related complications (n = 40) and age- and sex-matched control non-diabetic subjects (n = 40) were selected from the Chennai Urban Rural Epidemiology Study (CURES). Plasma level of malondialdehyde (MDA), a marker of lipid peroxidation, was measured by TBARS (thiobarbituric acid reactive substances) using a fluorescence method. RESULTS: Mean (+/- SE) TRF lengths of the Type 2 diabetic patients (6.01 +/- 0.2 kb) were significantly shorter than those of the control subjects (9.11 +/- 0.6 kb) (P = 0.0001). Among the biochemical parameters, only levels of TBARS showed a negative correlation with shortened telomeres in the diabetic subjects (r = -0.36; P = 0.02). However, telomere lengths were negatively correlated with insulin resistance (HOMA-IR) (r = -0.4; P = 0.01) and age (r = -0.3; P = 0.058) and positively correlated with HDL levels (r = 0.4; P = 0.01) in the control subjects. Multiple linear regression (MLR) analysis revealed diabetes to be significantly (P < 0.0001) associated with shortening of TRF lengths. CONCLUSIONS: Telomere shortening occurs in Asian Indian Type 2 diabetic patients.     

Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase

BACKGROUND: Within the metabolic syndrome, insulin resistance and compensatory hyperinsulinemia are associated with blood pressure (BP) elevation through various potential mechanisms. Thiazolidinediones are antihyperglycemic agents that decrease insulin resistance. OBJECTIVE: To determine the effect of the thiazolidinedione rosiglitazone on BP and insulin resistance in patients with type 2 diabetes and hypertension. METHODS: In 20 subjects (nine men and 11 women) with type 2 diabetes but with a poor glycemic control, and with poorly controlled or newly diagnosed hypertension, rosiglitazone 4 mg daily was added-on therapy for 26 weeks. At baseline and at the end of the treatment period patients underwent ambulatory blood pressure monitoring, a hyperinsulinemic euglycemic clamp, and blood tests for glucose, insulin, HbA1c, lipids, and routine laboratory parameters. RESULTS: Insulin sensitivity estimated with the clamp significantly increased (Mbw/I index changed from 33.9 +/- 2.6 to 41.9 +/- 3.2 micromol/min per kg per nmol/l, P < 0.001) and the HOMA-IR index significantly decreased (6.34 +/- 0.39 versus 4.40 +/- 0.33, P < 0.001) during rosiglitazone treatment. Ambulatory BP presented small but significant reductions for the total 24-h period (135.3 +/- 1.8 versus 129.9 +/- 1.7 mmHg, P < 0.001 for systolic BP and 76.0 +/- 1.6 versus 71.9 +/- 1.6 mmHg, P < 0.001 for diastolic BP), daytime and night-time. The changes in systolic and diastolic BP correlated with the change in insulin sensitivity (r = -0.78, P < 0.01 and r = -0.68, P < 0.01, respectively). There were also significant reductions in fasting plasma glucose (9.39 +/- 0.41 versus 7.55 +/- 0.31 mmol/l, P < 0.001), insulin (94.0 +/- 0.41 versus 79.5 +/- 5.6 pmol/l, P < 0.01) and HbA1c (8.15 +/- 0.24 versus 7.24 +/- 0.19%, P < 0.001). CONCLUSIONS: Treatment of type 2 diabetic hypertensive patients with rosiglitazone significantly increased insulin sensitivity and lowered ambulatory BP. These changes were strongly correlated. Thiazolidinediones may thus possess a BP-lowering effect beyond their antihyperglycemic properties.     

Insulin action and skeletal muscle blood flow in patients with Type 1 diabetes and microalbuminuria

Our objective was to determine whether Type 1 diabetic patients with microalbuminuria are less sensitive to the effects of insulin on glucose metabolism and skeletal muscle blood flow, compared to those with normal albumin excretion, after careful matching for confounding variables. We recruited 10 normotensive Type 1 diabetic patients with microalbuminuria and 11 with normoalbuminuria matched for age, sex, body mass index, duration of diabetes and HbA(1c). Peripheral and hepatic insulin action was assessed using a two-step euglycaemic hyperinsulinaemic clamp (2 h at 0.4 mU x kg(-1) x min(-1), 2 h at 2.0 mU x kg(-1) x min(-1)) combined with isotope dilution methodology. Skeletal muscle blood flow was determined by venous occlusion plethysmography. During the clamps, glucose infusion rates required to maintain euglycaemia were similar in the microalbuminuric subjects and controls (step 1, 8.2+/-1.4 (SE) vs 9.2+/-1.3 micromol x kg(-1) x min(-1): step 2, 30.9+/-2.7 vs 32.0+/-3.8 micromol x kg(-1) x min(-1)), as was hepatic glucose production basally and at steady state in step 1. In step 2, hepatic glucose production was lower in the microalbuminuric group (2.9+/-0.9 vs 6.4+/-0.7 micromol x kg(-1) x min(-1), P=0.005). During step 2, skeletal muscle blood flow increased significantly above baseline in the normoalbuminuric group (4.1+/-0.5 vs 3.2+/-0.4 ml x 100-ml(-1) x min(-1), P=0.01) but not in the microalbuminuric group (2.4+/-0.3 vs 2.3+/-0.4 ml x 100-ml(-1) x min(-1)). In conclusion, microalbuminuria in Type 1 diabetes was found to be associated with impairment of insulin-mediated skeletal muscle blood flow, but not with insulin resistance.