Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123I-metaiodobenzylguanidine scintigraphy

Hypoadiponectinemia is associated with insulin resistance. However, there is very limited information about the relationship between plasma adiponectin and cardiac autonomic nervous function. We tested the hypothesis that hypoadiponectinemia is associated with cardiac sympathetic overactivity in patients with type 2 diabetes mellitus. Thirty-three male type 2 diabetic patients not on insulin treatment were classified into a hypoadiponectinemia group (plasma adiponectin concentration, <4.0 microg/mL; age, 58.6 +/- 8.6 years [mean +/- SD]; n = 14) and an age-matched normoadiponectinemia group (serum adiponectin concentration, >/=4.0 microg/mL; age, 58.2 +/- 8.1 years; n = 19). In each patient, baroreflex sensitivity, heart rate variability, plasma norepinephrine concentration, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic findings were assessed. Compared with the normoadiponectinemia group, the hypoadiponectinemia group had a higher body mass index (P < .01), higher plasma concentrations of glucose and insulin (P < .05 and P < .01, respectively), higher homeostasis model assessment of insulin resistance (HOMA-IR) values (P < .005), higher plasma triglyceride levels (P < .05), and lower plasma high-density lipoprotein cholesterol levels (P < .05). In the hypoadiponectinemia group, the autonomic function measurements included a lower baroreflex sensitivity (P< .05) and a lower delayed myocardial uptake of (123)I-MIBG (P < .01) with a higher washout rate (P < .05). Multiple regression analysis revealed that the plasma adiponectin level was independently associated with HOMA-IR (F = 9.916) and the percent washout rate of (123)I-MIBG (F = 5.985). Our results suggest that in middle-aged men with type 2 diabetes mellitus, hypoadiponectinemia is associated with cardiac sympathetic overactivity as determined by (123)I-MIBG scintigraphy.     

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.     

Insulin resistance, adipokines, and oxidative stress in nondiabetic, hypercholesterolemic patients: leptin as an 8-epi-prostaglandin F2alpha determinant

Limited data are available on the association of insulin resistance, adipokines, and in vivo lipid peroxidation. We investigated the relationships between insulin resistance, adipokines (leptin, adiponectin, and resistin), and oxidative stress in nondiabetic, hypercholesterolemic patients. Seventy-six nondiabetic patients with hypercholesterolemia participated in this cross-sectional study. Fasting glucose and insulin concentrations were analyzed. Serum leptin, adiponectin, and resistin concentrations and urinary excretion of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) were determined using enzyme-linked immunosorbent assay. We divided all subjects into 3 groups, classified by the tertiles of homeostasis model assessment of insulin resistance (HOMA-IR) values, and clinical parameter comparisons were made among the 3 groups. The results showed that serum leptin (P < .001) and adiponectin levels (P < .05) were significantly different among the groups, although serum resistin was not different. Furthermore, the group with the highest HOMA-IR had a significantly higher urinary 8-epi-PGF(2alpha) excretion than the group with the lowest HOMA-IR (P = .017). Circulating leptin was positively correlated with urinary 8-epi-PGF(2alpha) (r = 0.323, P < .01) and HOMA-IR (r = 0.524, P < .001). Circulating adiponectin was negatively correlated with body mass index (r = -0.252, P < .05) and HOMA-IR (r = -0.228, P < .05). We could not find a relationship between circulating adiponectin or resistin and urinary 8-epi-PGF(2alpha) excretion. Stepwise multiple linear regression analysis showed that leptin was associated with the urinary 8-epi-PGF(2alpha) excretion after adjusting for age, sex, body mass index, blood lipids, and HOMA-IR (P = .002). In conclusion, our results show that more insulin-resistant state of nondiabetic, hypercholesterolemic patients is associated with decreased adiponectin and increased leptin and urinary 8-epi-PGF(2alpha) levels, although no relationship with resistin was observed. Furthermore, serum leptin independently contributed to urinary 8-epi-PGF(2alpha) excretion.     

Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes.

To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. Insulin-stimulated glucose uptake was decreased both in the diabetic and nondiabetic twin, compared with healthy control subjects (5.2 +/- 0.7 and 8.5 +/- 0.8 vs. 11.4 +/- 0.9 mg/kg x min(-1); P < 0.01 and P < 0.02, respectively). Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 +/- 0.06 to 0.21 +/- 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 +/- 0.10 to 0.16 +/- 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 +/- 0.04 to 0.71 +/- 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. There was an inverse correlation between postclamp Shc mRNA concentration and glucose uptake (r = -0.53, P = 0.01; n = 22) in the controls and nondiabetic twins. However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance.     

Non-invasive evaluation of endothelial dysfunction in uncomplicated obesity: relationship with insulin resistance

Obesity is associated with increased cardiovascular morbidity and amortality. Endothelial dysfunction, involved in the pathogenesis of cardiovascular events, has been demonstrated in obese patients with invasive techniques requiring artery catheterization. The aim of our investigation was to evaluate, with a non-invasive method readily employable on clinical grounds, impaired vasodilatation and its relationship with insulin resistance in uncomplicated obesity. 15 uncomplicated obese subjects (BMI = 36.6 +/- 3.2) and 10 lean controls (BMI = 22.9 +/- 1.25) were enrolled in this study. All subjects underwent measurement of endothelium-dependent (FBFr) vasodilatation by forearm venous occlusion pletysmography after increasing times of ischemia, and measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (M index), by fasting glucose and insulin (HOMA-IR) and by oral glucose tolerance test (ISI index). Endothelium-independent (N-FBFr) vasodilatation was assessed as well. The FBFr was markedly blunted in obese patients versus lean controls (30 s: 2.12 +/- 0.34 vs. 3.63 +/- 0.22, P < 0.01; 60 s: 2.34 +/- 0.42 vs. 3.82 +/- 0.53, P < 0.01; 180 s: 3.20 +/- 0.45 vs. 7.15 +/- 0.35, P < 0.01; 300 s: 4.08 +/- 0.94 vs. 14.1 +/- 0.82, P < 0.001). The N-FBFr was not different in the two groups. High correlation was found between M index and FBFr at all ischemia times. HOMA-IR and ISI were not related with FBFr. The non-invasive evaluation of endothelial dysfunction by a simple and reliable method based on venous occlusive plethysmography shows high correlation between impaired endothelium-dependent vasodilatation and insulin resistance in uncomplicated obesity. This non-invasive test of endothelial function may be routinely performed in the assessment of cardiovascular risk in uncomplicated obesity.     

Metformin improves endothelial function in patients with metabolic syndrome

BACKGROUND: Metabolic Syndrome (MS) is associated with impaired endothelial function and increased cardiovascular risk. Insulin resistance is a key feature of MS and plays an important role in the pathogenesis of endothelial dysfunction. Aim of the present study was to evaluate the effect of metformin on endothelial function and insulin resistance, assessed by the homeostasis model (HOMA-IR, homeostasis model assessment-insulin resistance), in patients with MS. METHODS: Sixty-five subjects (37 men and 28 women, mean age 54 +/- 6 years) with MS were allocated to receive metformin 500 mg twice daily (n = 32) or placebo (n = 33) for 3 months. Before and after treatment we assessed endothelial function, using flow-mediated dilatation of the brachial artery, and HOMA-IR. RESULTS: Patients who received metformin demonstrated statistically significant improvement in endothelium-dependent vasodilation compared with those treated with placebo (from 7.4 +/- 2.1% to 12.4 +/- 1.9% vs. 7.3 +/- 2.5% to 6.9 +/- 2.7%, P = 0.0016, metformin vs. placebo respectively), without significant effect on endothelium-independent response to sublingual glyceryl trinitrate (P =0.32). Metformin improved insulin resistance compared with placebo group (HOMA-IR from 3.39 to 2.5 vs. 3.42 to 3.37; 26% reduction in HOMA-IR, P = 0.01). An association between the improvement in insulin resistance and the improvement in endothelial function (r = -0.58, P = 0.0016) was found. CONCLUSION: Metformin improves both endothelial function and insulin resistance in patients with MS. These findings support the central role of insulin resistance in the development of endothelial dysfunction and the role of metformin for the treatment of patients with MS.     

The role of plasma fatty acid composition in endogenous glucose production in patients with type 2 diabetes mellitus

Hepatic insulin resistance and increased endogenous glucose production (EGP) are associated with increased plasma free fatty acids (FFA). However, the contribution of FFA composition to the regulation of EGP is not known. Six obese nondiabetic subjects and 6 patients with type 2 diabetes mellitus (DM2) were studied after an overnight and a 3-day fast. Plasma insulin concentrations after an overnight fast were similar in the DM2 and nondiabetic patients (88.8 +/- 26.4 v 57.6 +/- 12.6 pmol/L, not significant [NS]) despite increased plasma glucose (9.9 +/- 1.8 v 5.1 +/- 0.1 mmol/L, P <.01) and EGP (510.3 +/- 77.7 v 298.3 +/- 18.3 micromol x m(-2) x min(-1), P <.05) in the patients with DM2. Absolute rates of gluconeogenesis using the heavy water method were also increased in the patients with DM2 (346.8 +/- 74.9 v 198.8 +/- 16.4 micromol x m(-2). min(-1), P <.05). No differences were observed in plasma polyunsaturated fatty acids (PUFA) between the diabetic and nondiabetic subjects. However, total saturated fatty acid (SFA) concentrations (350 +/- 37.4 v 230.9 +/- 33.3 micromol/L, P <.02) were significantly increased in the diabetic subjects. Rates of EGP were correlated with total plasma FFA concentration (r =.71, P <.01) and the concentration of SFA (r =.71, P <.01), but not monounsaturated fatty acids or PUFA. Rates of gluconeogenesis were also correlated with plasma FFA (r =.64, P <.05) and SFA (r =.67, P <.05). We observed no relationship between EGP and either total FFA or fatty acid composition after a 3-day fast. We conclude that increases in EGP are associated with concentrations of plasma SFA after an overnight fast.     

Lipoprotein alterations in hemodialysis: differences between diabetic and nondiabetic patients

Both renal failure and type 2 diabetes may contribute synergistically to the dyslipemia of diabetic renal failure with the development of atherosclerosis as the possible consequence. It has not yet been conclusively evaluated whether diabetic patients with end-stage renal failure under maintenance hemodialysis (HD) show accentuated alterations in plasma lipids and lipoproteins in comparison to nondiabetics under HD. These abnormalities would involve hepatic lipase activity and the regulation of triglyceride-rich lipoprotein metabolism. The purpose of the present study was to evaluate whether type 2 diabetic patients undergoing HD exhibited a lipid-lipoprotein profile different from that of nondiabetic hemodialyzed patients. We compared plasma lipids, apoprotein (apo) A-I and B, and lipoprotein parameters among 3 groups: 25 type 2 diabetics, 25 nondiabetics, both undergoing HD, and 20 healthy control subjects. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) were isolated by sequential ultracentrifugation. Hepatic lipase activity was measured in postheparin plasma. Both groups of HD patients showed higher triglyceride and IDL cholesterol (P <.001), and lower high-density lipoprotein (HDL) cholesterol (P <.01) and apo A-I (P <.001) levels compared to the control group, even after adjustment for age and body mass index (BMI). However, no differences were found in lipid, lipoprotein, and apoprotein concentrations between diabetic and nondiabetic HD patients, except for high LDL triglyceride content of diabetic HD patients (P <.01). Nondiabetics undergoing HD also presented higher LDL triglyceride levels than controls (P <.05). LDL triglyceride correlated with plasma triglycerides (r = 0.51, P <.001). A lower LDL cholesterol/apo B ratio was found in each group of HD patients in comparison to controls (P <.02). Comparing the diabetic and nondiabetic patients, hepatic lipase activity remained unchanged, but significantly lower than control subjects (P <.001). Hepatic lipase correlated with log-triglyceride (r = -0.31, P <.01), IDL cholesterol (r = -0.41, P <.001), and LDL triglyceride (r = -0.32, P <.01). In conclusion, both diabetic and nondiabetic HD patients shared unfavorable alterations in lipid-lipoprotein profile not different between them but different from a healthy control group. The only difference between the groups of HD patients was a significant LDL triglyceride enrichment, which correlated negatively with hepatic lipase activity. Lipoprotein abnormalities in HD patients would enhance their risk for the development of atherosclerosis.     

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.     

Effects of pioglitazone and metformin on intracellular lipid content in liver and skeletal muscle of individuals with type 2 diabetes mellitus

Both ectopic fat accumulation and changes of the amount of several adipocyte secreting proteins (adipokines) are thought to contribute to the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now investigated the effects of 2 insulin-sensitizing drugs, pioglitazone and metformin, on body fat composition and serum adipokine concentrations in individuals with type 2 diabetes mellitus. A total of 41 diabetic patients were treated with pioglitazone (n =21) or metformin (n =20) for 6 months. Intramyocellular lipid content (IMCL) and hepatic lipid content as well as the areas of subcutaneous and visceral fat deposits in the abdomen were determined by nuclear magnetic resonance spectroscopy before and after drug treatment. The serum concentrations of adiponectin and retinol binding protein 4 were also determined by enzyme-linked immunosorbent assays. Pioglitazone treatment reduced both hepatic lipid content (12.0 +/- 6.1 vs 8.4 +/- 3.7 arbitrary units [AU], P < .01) and IMCL (8.4 +/- 3.6 vs 6.3 +/- 2.4 AU/creatine, P < .01), whereas metformin reduced only IMCL (7.0 +/- 3.6 vs 5.8 +/- 2.0 AU/creatine, P < .05). Although the areas of visceral and subcutaneous fat were not significantly affected by treatment with either drug, pioglitazone induced a significant reduction in the ratio of visceral to subcutaneous fat area (0.92 +/- 0.41 vs 0.85 +/- 0.41, P < .05). Pioglitazone treatment also resulted in a marked increase in serum adiponectin concentration (5.6 +/- 4.1 vs 16.2 +/- 9.9 microg/mL, P < .0001) and a small but significant decrease in serum retinol binding protein 4 concentration (73.4 +/- 25.1 vs 65.1 +/- 23.7 microg/mL, P < .05). These results suggest that pioglitazone may improve insulin sensitivity both by affecting serum adipokine concentrations and by reducing the intracellular triglyceride content of liver and skeletal muscle in individuals with type 2 diabetes mellitus.     

A relationship between insulin resistance and reduction in oxidative stress in vivo by atorvastatin

OBJECTIVES: To examine the relationship between insulin resistance (IR) and the reduction of oxidative stress in vivo by the statin atorvastatin. METHODS: This study included 40 patients with hypercholesterolemia without a history of diabetes mellitus (21 males, 19 females, mean age 62 +/- 11 years). Homeostasis assessment insulin resistance (HOMA-IR) was used as a marker for insulin resistance. The patients were divided into two groups [IR group (n = 24) and non-IR group (n = 16), using the cut off level of 1.73]. Urinary 8-iso-prostaglandin F2alpha (U-8-iso) excretion was used as an oxidative stress marker. The subjects were treated with atorvastatin (10 mg/day) for 12 weeks. RESULTS: The IR group had significantly higher U-8-iso levels than the non-IR group before atorvastatin administration (211 +/- 112 vs 137 +/- 33 pg/mg Cr, p = 0.01). Low-density lipoprotein cholesterol, triglyceride, and 8-iso levels were significantly reduced in both groups after 12 weeks, U-8-iso levels were significantly higher in the IR group than the non-IR group (178 +/- 61 vs 110 +/- 38 pg/mg Cr, p = 0.003), and HOMA-IR showed no significant change. Multiple regression analysis after 12 weeks showed that HOMA-IR and triglyceride levels were independent variables for U-8-iso levels (standard regression coefficient = 0.60, 0.59, p < 0.0001, p = 0.0002). CONCLUSIONS: Insulin resistance is important in the occurrence of oxidative stress in patients with hypercholesterolemia. Since atorvastatin does not reduce insulin resistance, further therapy to reduce insulin resistance is necessary for early prevention of cardiovascular events during atorvastatin treatment.     

Rosiglitazone improves insulin sensitivity in nonobese subjects with impaired glucose tolerance: the role of adiponectin and C-reactive protein

To evaluate the effects of rosiglitazone (ROS) on serum adiponectin and C-reactive protein (CRP) in nonobese subjects with impaired glucose tolerance (IGT), we enrolled 21 patients with body mass index < or =24 kg/m(2) to receive ROS 4 mg daily for 12 weeks. Fifteen age-, sex-, and body mass index-matched healthy subjects were recruited as controls. A 75-g oral glucose tolerance test (OGTT), hemoglobin A(1c), fasting glucose, insulin, C-peptide, lipid profiles, adiponectin, and CRP levels were determined before initiation and at the end of the 12-week ROS treatment. Insulin resistance and beta-cell function were calculated using the homeostasis model assessment method (HOMA-IR and HOMA-beta, respectively). Compared with healthy controls, the ROS-treated subjects had significantly higher glycemic indices, HOMA-IR, CRP, and glucose and insulin concentrations in response to OGTT, and lower HOMA-beta level. After 12 weeks of ROS therapy, the results showed statistically significant changes from baseline in 2-hour plasma glucose during OGTT (9.4 +/- 0.3 vs 8.3 +/- 0.4 mmol/L, P < .05), HOMA-IR (2.6 +/- 0.2 vs 1.9 +/- 0.3, P < .05), HOMA-beta (63.4 +/- 12.5 vs 90.1 +/- 13.0, P < .05), and glucose and insulin concentrations during OGTT in nonobese subjects with IGT. In addition, elevation of serum adiponectin and decrease in CRP levels were significantly found after ROS treatment. Of 21 patients treated with ROS, 5 subjects were converted to normal (converter), 1 progressed to diabetes, and 15 remained in IGT status (nonconverter). There was a significant amelioration in HOMA-IR (-2.10 +/- 1.03 vs -0.07 +/- 0.33, P < .05) without significant changes in adiponectin and CRP levels in converter compared with nonconverter. We conclude that ROS effectively enhanced insulin sensitivity and beta-cell function to improve adiponectin and CRP levels in nonobese patients with IGT. The amelioration of insulin resistance may be a major determinant to predict the conversion of IGT independent of the changes in adiponectin and CRP.     

Exercise training increases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects

Exercise training improves insulin sensitivity in subjects with and without type 2 diabetes. However, the mechanism by which this occurs is unclear. The present study was undertaken to determine how improved insulin signaling, GLUT4 expression, and glycogen synthase activity contribute to this improvement. Euglycemic clamps with indirect calorimetry and muscle biopsies were performed before and after 8 weeks of exercise training in 16 insulin-resistant nondiabetic subjects and 6 type 2 diabetic patients. Training increased peak aerobic capacity (Vo(2peak)) in both nondiabetic (from 34 +/- 2 to 39 +/- 2 mL O(2)/kg fat-free mass [FFM]/min, 14% +/- 2%, P <.001) and diabetic (from 26 +/- 3 to 34 +/- 3 mL O(2)/kg FFM/min, 32% +/- 4%) subjects. Training also increased insulin-stimulated glucose disposal in nondiabetic (from 6.2 +/- 0.5 to 7.1 +/- 0.7 mg/kg FFM/min) and diabetic subjects (from 4.3 +/- 0.6 to 5.5 +/- 0.6 mg/kg FFM/min). Total glycogen synthase activity was increased by 46% +/- 17% and 45% +/- 12% in nondiabetic and diabetic subjects, respectively, in response to training (P <.01 v before training). Moreover, after training, glycogen synthase fractional velocity was correlated with insulin-stimulated glucose storage (r = 0.53, P <.05) and the training-induced improvement in glucose disposal was accounted for primarily by increased insulin-stimulated glucose storage. Training also increased GLUT4 protein by 38% +/- 8% and 22% +/- 10% in nondiabetic and diabetic subjects, respectively (P <.05 v. before training). Akt protein expression, which was decreased by 29% +/- 3% (P <.05) in the diabetic subjects before training (compared to the nondiabetics), increased significantly in both groups (P <.001). In contrast, exercise training did not enhance the ability of insulin to stimulate insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3 (PI 3)-kinase activity. The present data are consistent with a working model whereby 8 weeks of exercise training increases insulin-stimulated glucose disposal primarily by increasing GLUT4 protein expression without enhancing insulin-stimulated PI 3-kinase signaling, and that once the glucose enters the myocyte, increased glycogen synthase activity preferentially shunts it into glycogen synthesis.     

Effects of short-term very low-calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects

The study aimed to analyze the effects of a short-term very low-calorie diet (VLCD) on intramyocellular lipid (IMCL), total body fat, and insulin sensitivity in a group of obese nondiabetic and type 2 diabetic subjects. Seven untreated type 2 diabetic and 5 obese nondiabetic individuals were studied before and after a 6-day VLCD using proton magnetic resonance spectroscopy to quantify IMCL, dual-energy x-ray absorptiometry to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity. In both groups, decrements in total body fat mass and body mass index were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared with baseline values in nondiabetic subjects (56% decrease) and type 2 diabetic subjects (40% decrease) (P < .05), and this was accompanied by an overall 9.3% increase in maximally stimulated glucose disposal rate (P < .01). Intramyocellular lipid was significantly correlated with insulin sensitivity (r = -0.69, P < .01) and waist circumference (r = 0.72 and 0.83, baseline and postdiet, respectively; both P < .01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as body mass index, percentage of body fat, or total body fat (P = not significant). In conclusion, short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in nondiabetic and type 2 diabetic subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL both in nondiabetic and type 2 diabetic subjects in the absence of substantial changes in total body fat. These observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than to body fat per se.     

Microalbuminuria, cardiovascular autonomic dysfunction, and insulin resistance in patients with type 2 diabetes mellitus

Urinary albumin excretion/microalbuminuria and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. We tested the hypothesis that the presence of microalbuminuria would correlate with cardiovascular autonomic dysfunction and insulin resistance in type 2 diabetic patients. The study group consisted of 15 Japanese patients with type 2 diabetes and microalbuminuria (age: 56 +/- 10 years, mean +/- SD). The control group consisted of 19 age-matched patients with normalbuminuria (56 +/- 7 years). Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability, plasma norepinephrine concentration, and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy. BRS was lower in the microalbuminuria group than in the normalbuminuria group (P < .05). Early and delayed 123I-MIBG myocardial uptake values were lower (P < .05 and P < .005, respectively) and the percent washout rate of 123I-MIBG was higher (P < .0005) in the microalbuminuria group than in the normalbuminuria group. Fasting plasma glucose (P < .05) and insulin concentrations (P < .05), and the homeostasis model assessment (HOMA) index (P < .01) were higher in the microalbuminuria group than in the normalbuminuria group. Multiple regression analysis showed that urinary albumin excretion was independently predicted by the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin concentration, and the HOMA index. Our results indicate that the presence of microalbuminuria in our Japanese patients with type 2 diabetes is characterized by depressed cardiovascular autonomic function and insulin resistance, and that the myocardial uptake of 123I-MIBG at delayed phase, fasting plasma insulin, and HOMA index are independent predictors of urinary albumin excretion.     

Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3

BACKGROUND/AIMS: Obesity is associated with impaired treatment responses in chronic hepatitis C. The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection. METHODS: Eighty-two patients were studied; 59 received interferon/ribavirin while 23 received peg-interferon/ribavirin. RESULTS: The overall SVR was (77%). Patients with a SVR had lower mean serum insulin (10.7+/-0.8 microU/ml vs. 22.2+/-4.9; P = 0.03), fibrosis stage (1.9+/-0.1 vs. 2.7+/-0.3; P = 0.007) and insulin resistance measured by the homeostasis model (HOMA-IR) (2.5+/-0.2 vs. 6.1+/-1.5; P = 0.03). Age, gender, ethnicity, alcohol consumption, treatment regimen, viral load, portal activity and steatosis did not influence the SVR. By linear regression, body mass index (P < 0.001) and fibrosis stage (P < 0.001) were independently associated with HOMA-IR. After adjusting for fibrosis stage, patients with HOMA-IR of < 2 were 6.5 times more likely to achieve SVR than those with HOMA-IR > or = 2. CONCLUSIONS: Even in treatment-responsive genotypes 2 and 3, high HOMA-IR is associated with a reduced response. Improving insulin sensitivity may be a useful adjunct to anti-viral therapy in these individuals.     

Longitudinal hair chromium profiles of elderly subjects with normal glucose tolerance and type 2 diabetes mellitus

Longitudinal hair chromium (H-Cr) profiles in a group of patients with type 2 diabetes mellitus (n = 59; age, 62 +/- 9 years) and healthy elderly (control) subjects (n = 49; age, 59 +/- 10 years) matched by age and sex were measured by solid sampling electrothermal atomic absorption spectrometry, providing data on the magnitude of variation of Cr content along the hair length. H-Cr average (H-Cr(av)) and H-Cr proximal (H-Cr(pr))(.), relating to the average Cr content of the whole hair and the proximal 3-mm hair length, respectively, were also obtained. No significant difference between the healthy and diabetic group was found in mean H-Cr(av) or H-Cr(pr) contents (248 +/- 108 vs 247 +/- 143 and 233 +/- 98 vs 278 +/- 195 ng/g, respectively. However, women in the control group had significantly lower H-Cr values (P < .01) compared with men, but this difference was absent in the diabetic population. The distribution of log H-Cr(pr) values in the control population displayed a Gaussian shape, in contrast to the substantially wider distribution, skewed toward lower H-Cr(pr) values, observed in the diabetic group. The magnitude of variation in H-Cr content in the patient group over an interval of approximately 2 to 3 months (time of growth of the hair sampled) was found to be a factor of more than 2 larger than that in the control population (+/- 58% vs +/- 26%). A strong relationship (R = 0.656; P < .01) between log H-Cr(pr) and log fasting plasma Cr was observed in the diabetic group (n = 20). The mean fasting plasma Cr value of this group was 0.41 +/- 0.10 microg Cr per liter. No correlation between H-Cr(av.) and duration of diabetes was observed. A strong positive association was observed in the control population between H-Cr(pr) and fasting plasma insulin (n = 22; R = 0.6157; P < .01), and H-Cr(pr) and fasting plasma glucose (n = 24; R = 0.4118; P < .05), which is indicative of the interrelation of these parameters. In the control population, H-Cr(av) showed a slight decrease with age (n = 54; R = 0.2691; P < .05), which is assumed to be the result of increased insulin resistance caused by various age-associated factors including Cr deficiency. None of the above relationships was significant in the diabetic group. Evidence is presented that justifies the assumption that the longitudinal H-Cr profile resembles the variation in Cr metabolic rate over the time span of growing hair, which is not appreciably affected by external contamination. This suggests that glucose intolerance (type 2 diabetes mellitus) is an important factor that disturbs Cr metabolism.     

Remnant-like lipoprotein particle level and insulin resistance are associated with in-stent restenosis in patients with stable angina

BACKGROUND: The aim of this study was to evaluate the independent effect of serum remnant-like lipoprotein particle level and insulin resistance on in-stent restenosis in nondiabetic patients with stable angina. METHODS: The study included 64 nondiabetic patients with stable angina who underwent successful coronary stenting. At the time of stenting, we evaluated the patients' lipid profiles including remnant-like lipoprotein particles cholesterol, plasma glucose and insulin levels, and insulin resistance by the homeostasis model assessment. RESULTS: There was no significant difference in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels between two patient groups with (n=15) and without (n=49) in-stent restenosis. Plasma remnant-like lipoprotein particles cholesterol level was significantly higher in patients with restenosis than in patients without restenosis (8.2+/-7.0 mg/dl vs. 4.5+/-2.6 mg/dl, P=0.006). Although plasma glucose level was similar between the two groups, insulin level and homeostasis model assessment were significantly higher in patients with restenosis, compared with those without restenosis (11.2+/-12.4 vs. 7.1+/-2.8, P=0.039; and 2.6+/-2.9 vs. 1.7+/-0.7, P=0.040, respectively). In multivariate logistic regression analysis, plasma remnant-like lipoprotein particles cholesterol level (>4.8 mg/dl; the 75th percentile of the distribution of remnant-like lipoprotein particles cholesterol level) was the independent predictor of in-stent restenosis (odds ratio: 8.15; confidence interval: 1.02-65.16; P=0.048). CONCLUSIONS: Our findings suggest that high serum remnant-like lipoprotein particles cholesterol level, and not insulin resistance may be an independent risk factor on in-stent restenosis in nondiabetic patients with stable angina.     

Factors related to exercise capacity in asymptomatic middle-aged type 2 diabetic patients

AIM: We aimed to look at the relationship between exercise capacity and metabolic variables in unselected consecutive asymptomatic middle-aged type 2 diabetic patients as a potential marker for undiagnosed coronary heart disease. METHOD: Ninety patients (49 +/- 6 years) were included in the study. All patients performed a treadmill exercise test using the Bruce protocol. According to achieved EC, patients were separated into three groups; Group I (n, 24) 8 > metabolic equivalents (METs) > or = 5, Group II (n, 54) 11 > METs > or = 8 and Group III (n, 12) METs > or = 11. RESULTS: Patients in group I are more likely to be of female gender and to have a family history of coronary heart disease (CHD) than in group III (P = 0.015, P = 0.009, respectively). When compared to group III, patients in group I had higher fasting insulin and fibrinogen levels (P = 0.049 and P = 0.01, respectively). Homeostasis model assessment for insulin resistance (HOMA-IR) index (P = 0.03) was also higher in group I than in group III. We found a significant negative correlation between achieved exercise capacity and age (r = -0.204, P = 0.048), fasting insulin (r = -0.209, P = 0.048), HOMA-IR (r = -0.204, P = 0.048) as well as fibrinogen (r = -0.301, P = 0.007). CONCLUSION: Reduced exercise capacity was associated with increased insulin resistance as assessed by HOMA-IR index in asymptomatic middle-aged type 2 diabetic patients.     

Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus

Resistin is an adipocyte-derived peptide that might play a role in obesity and insulin resistance. However, its role in humans is largely unclear. Although many studies have measured the expression of human resistin in tissues, the circulating concentrations of resistin and its relation to metabolic parameters in humans are unknown. We developed an ELISA for human resistin and measured plasma concentrations in aged individuals with or without type 2 diabetes mellitus. To validate the results of plasma resistin concentrations in our subjects, plasma adiponectin concentrations were also determined, which were higher in nondiabetic subjects than in type 2 diabetic patients and correlated with the homeostasis model assessment for insulin resistance (HOMA-IR). Log-transformed plasma resistin concentrations (log-resistin) were higher in diabetic patients compared with normal individuals (0.50 +/- 0.39 vs. 0.28 +/- 0.51 ng/ml; P < 0.001), and this difference was significant after controlling for gender and body mass index. Log-resistin did not show a significant correlation with HOMA-IR, waist circumference, body mass index, blood pressure, or total cholesterol. The plasma glucose concentration was an independent factor associated with log-resistin. In conclusion, plasma resistin concentrations are elevated in patients with type 2 diabetes, but are not associated with insulin resistance or obesity.