Visceral fat in hypertension: influence on insulin resistance and beta-cell function

Preferential visceral adipose tissue (VAT) deposition has been associated with the presence of insulin resistance in obese and diabetic subjects. The independent association of VAT accumulation with hypertension and its impact on insulin sensitivity and beta-cell function have not been assessed. We measured VAT and subcutaneous fat depots by multiscan MRI in 13 nondiabetic men with newly detected, untreated essential hypertension (blood pressure=151+/-2/94+/-2 mm Hg, age=47+/-2 years, body mass index [BMI]=28.4+/-0.7 kg x m(-2)) and 26 age-matched and BMI-matched normotensive men (blood pressure=123+/-1/69+/-2 mm Hg). Insulin secretion was measured by deconvolution of C-peptide data obtained during an oral glucose tolerance test, and dynamic indices of beta-cell function were calculated by mathematical modeling. For a similar fat mass in the scanned abdominal region (4.8+/-0.3 versus 3.9+/-0.3 kg, hypertensive subjects versus controls, P=0.06), hypertensive subjects had 60% more VAT than controls (1.6+/-0.2 versus 1.0+/-0.1 kg, P=0.003). Intrathoracic fat also was expanded in patients versus controls (45+/-5 versus 28+/-3 cm2, P=0.005). Insulin sensitivity was reduced (10.7+/-0.7 versus 12.9+/-0.4 mL x min(-1) x kg(ffm)(-1), P=0.006), and total insulin output was proportionally increased (64 [21] versus 45 [24] nmol x m(-2). h, median [interquartile range], P=0.01), but dynamic indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) were similar in the 2 groups. Abdominal VAT, insulin resistance, and blood pressure were quantitatively interrelated (rho's of 0.39 to 0.47, P<0.02 or less). In newly found, untreated men with essential hypertension, fat is preferentially accumulated intraabdominally and intrathoracically. Such visceral adiposity is quantitatively related to both height of blood pressure and severity of insulin resistance, but has no impact on the dynamics of beta-cell function.     

Effect of chronic rosiglitazone, metformin and glyburide treatment on beta-cell mass, function and insulin sensitivity in mZDF rats

Here we investigate the effect of rosiglitazone (RSG), metformin (MET) and glyburide (GLIB) on plasma glucose levels, β-cell mass, function and insulin sensitivity in 10-week-old diabetic male Zucker diabetic fatty (mZDF) rats using quantitative morphometry and a mathematical model β-cell mass, insulin and glucose kinetics (βIG). At treatment start, 10-week-old diabetic mZDF rats were severely hyperglycaemic and had very low β-cell function (insulin secretory capacity). RSG treatment significantly lowered plasma glucose levels in 67% of the mZDF rats. MET was effective at lowering plasma glucose levels in 33% of the mZDF rats, while GLIB was completely ineffective at lowering blood glucose levels in 10-week-old mZDF rats. RSG treatment prevented the fall in β-cell mass after 6–8 weeks of treatment accompanied by a significant decrease in β-cell death while MET treatment had no effect on β-cell mass. RSG treatment increased insulin sensitivity 10-fold, increased β-cell function fivefold and modestly increased β-cell mass 1.4-fold. MET treatment increased insulin sensitivity fourfold, with no significant effect on β-cell function or mass. Although RSG treatment was highly successful in lowering plasma glucose levels, the 33% of mZDF rats that did not respond to the treatment had significantly lower β-cell function prior to treatment start compared with the responder group. Thus, the low level of β-cell function at treatment start may explain why none of these agents were completely effective at lowering blood glucose levels in 10-week-old diabetic mZDF rats. Nevertheless, these data suggest that the preservation of β-cell mass and improvement in β-cell function play a role in the overall beneficial effect of RSG in 10-week-old diabetic mZDF rats.     

Relative contribution of insulin sensitivity and beta-cell function to plasma glucose and insulin concentrations during the oral glucose tolerance test.

Plasma glucose and insulin concentrations have been used in genetic studies as quantitative phenotypic traits and also as surrogates for insulin sensitivity and beta-cell function. However, the significance of these traits in relation to insulin sensitivity and beta-cell function was unknown. We examined how insulin sensitivity and beta-cell function affected plasma glucose and insulin concentrations during the oral glucose tolerance test (OGTT). This is a cross-sectional study enrolling 105 glucose-tolerant subjects (64 females; age, 18 to 40 years; body mass index, 17.58 to 37.57 kg/m(2); waist-to-hip ratio, 0.649 to 1.033 cm/cm). They participated in both OGTTs and hyperglycemic clamps. The relationship between plasma glucose and insulin concentrations and indices of insulin sensitivity and beta-cell function was examined. Univariate analyses showed that insulin sensitivity index (ISI) had some influence on plasma insulin concentrations (r(2) =.2623 to.3814) during the OGTT; however, it had only modest impacts on plasma glucose levels at 60, 90, and 120 minutes (r(2) =.0537 to.1300). Neither first phase (1stIR) nor second phase insulin response (2ndIR) affected plasma glucose concentrations. Multivariate analyses showed an independent impact (all P <.0001) of ISI on plasma glucose concentrations at 60, 90, and 120 minutes and on plasma insulin concentrations at every time point except at 30 minutes. Except for plasma insulin concentration at 30 minutes, of which 24% of the variation can be explained by 1stIR, beta-cell function (either 1stIR or 2ndIR) only had a very modest impact on 30-, 60-, 90- and 120-minute plasma glucose concentrations and on plasma insulin concentration at 60 minutes. In glucose-tolerant subjects, ISI plays an important role in determining postchallenged plasma glucose concentrations at 60, 90, and 120 minutes, as well as plasma insulin concentrations at fasting, 60, 90, and 120 minutes. However, beta-cell function is only reflected in plasma insulin concentration at 30 minutes through 1stIR. Therefore, we conclude that it is essential to measure beta-cell function in vivo if one plans to study the genetic influence of beta-cell dysfunction.     

Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial

AIM: Accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target blood glucose levels. The aim of our study is to evaluate the differential effect on glucose and lipid parameters of the association between glimepiride plus metformin and rosiglitazone plus metformin in patients affected by type 2 diabetes and metabolic syndrome. METHODS: Patients were enroled, evaluated and followed at two Italian centres. We evaluated 99 type 2 diabetic patients with metabolic syndrome (48 males and 47 females; 23 males and 24 females, aged 52 +/- 5 with glimepiride; 25 males and 23 females, aged 54 +/- 4 with cglitazone). All were required to have been diagnosed as being diabetic for at least 6 months and did not have glycaemic control with diet and oral hypoglycaemic agents such as sulphonylureas or metformin, both to the maximum tolerated dose. All patients took a fixed dose of metformin, 1500 mg/day. We administered glimepiride (2 mg/day) or rosiglitazone (4 mg/day) in a randomized, controlled, double-blind clinical study. We evaluated body mass index (BMI), glycaemic control, lipid profile [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol and triglycerides] and lipoprotein parameters [apolipoprotein A-I and apolipoprotein B (Apo B)] during 12 months of this treatment. RESULTS: A total of 95 patients completed the study. Significant BMI decrease was observed at 12 months in glimepiride and rosiglitazone group (p < 0.05 and p < 0.01 respectively) as well as of glycated haemoglobin decrease (p < 0.05 and p < 0.01 respectively), mean fasting plasma glucose and postprandial plasma glucose levels (p < 0.05 and p < 0.01 respectively). A decrease in fasting plasma insulin and postprandial plasma insulin at 12 months (p < 0.05 and p < 0.01 respectively) compared with the baseline value in rosiglitazone group was observed. Furthermore, homeostasis model assessment index improvement was obtained only at 9 and 12 months (p < 0.05 and p < 0.01 respectively) compared with the baseline value in rosiglitazone group. Significant TC, LDL-C and Apo B improvement (p < 0.05 respectively) was present in glimepiride group after 12 months compared with the baseline values, and these variations were significant (p < 0.05) between groups. Of the 95 patients who completed the study, 8.5% of patients in glimepiride group and 12.5% of patients in rosiglitazone group had side-effects (p = not significant). Four patients had transient side-effects in glimepiride group and six patients in rosiglitazone group. Altogether, we did not have statistically significant changes in transaminases. CONCLUSIONS: The rosiglitazone-metformin association significantly improve the long-term control of all insulin-resistance-related parameters in comparison with the glimepiride-metformin-treated group. On the other side, glimepiride treatment is associated to a slight improvement in cholesterolaemia, not observed in the rosiglitazone-treated patients.     

Association of adiposity assessed by means of near-infrared interactance with the beta-cell function, insulin resistance and leptin concentrations in non-obese subjects. Exploratory study.

The objective was to identify the association of adiposity with the beta-cell function, insulin resistance and leptin concentrations in non-obese subjects. Twenty-eight healthy, non-obese volunteers were recruited, 14 male and 14 female. Body mass index (BMI) and waist hip ratio (WHR) were calculated. Blood pressure was measured. Adiposity was estimated by means of near-infrared (NIR) interactance method predicting the percentage of body fat (% BF). All subjects were divided into adipose and non-adipose individuals. Serum glucose, insulin and leptin levels were measured. Formulas of the homeostasis model analysis were used to assess the insulin resistance and the beta-cell function. Clinical characteristics and laboratory profile were similar between both groups. There were no significant differences between both groups in beta-cell function, insulin resistance and leptin concentrations. There was a positive significant correlation of % BF with BMI in women (r= .82, P< .001) and in men (r= .85, P< .001). Adiposity was not associated with the beta-cell function, insulin resistance and leptin concentrations in non-obese subjects, and only percent body fat was positive correlated with BMI.     

Association between smoking, insulin resistance and beta-cell function in a North-western First Nation.

AIMS: Aboriginal peoples have a high prevalence of smoking and are at major risk for diabetes. The role of insulin resistance vs. compromised beta-cell function in the link between smoking and glycaemic disease is not clear. This study tested whether relations between insulin resistance and beta-cell function differ between current smokers, former smokers and non-smokers, and if having diabetes modifies smoking-related effects. METHODS: A community-based diabetes screening initiative was mounted for a North-western First Nation (Interior Salishan) in rural British Columbia, Canada. Respondents were on-reserve Aboriginal people (n=156), all adults 18+ years. Glycaemic status was determined by oral glucose tolerance test. Fasting values for glucose and insulin were used to estimate beta-cell function and insulin resistance by homeostasis model assessment (HOMA). Analyses adjusted for age, sex, alcohol intake, education, body mass index and physical activity. RESULTS: For normoglycaemic persons (n=119) current smokers relative to non-smokers had high beta-cell values [difference (95% confidence interval) 19.5 (17.1, 21.9)], while former smokers had low beta-cell values [difference -22.8 (-20.3, -25.3)] (P<0.0001). For diabetic persons (n=37) differences were of equivalent direction but greater magnitude (P<0.0001). Insulin resistance was for normoglycaemic persons highest for current smokers, and for diabetic persons lowest for current smokers (P=0.021). CONCLUSIONS: Former smoking is associated with low beta-cell function, and current smoking with high beta-cell function, independent of diabetes in the North-western First Nation surveyed. Associations between smoking and insulin resistance vary according to glycaemic status. Smoking may have diametric acute and post-cessation effects on beta-cell function and insulin resistance.     

Analysis of the relationship between body mass index, insulin resistance, and beta-cell function: a cross-sectional study using the minimal model

The objective of our research was to identify the mathematical model that would best define the relationship between obesity, insulin resistance (IR), and beta-cell function. Eighty-seven healthy subjects with a wide range of body mass index (BMI) were studied. Insulin sensitivity (IS) was calculated using Bergman's minimal model. Acute insulin response (AIRg) was calculated as the secretion of insulin during the first 10 minutes following a glucose bolus. IS x AIRg was used as an index of insulin-mediated glucose uptake (IMGU). The relationships among BMI, IS, fasting plasma insulin (FPI), and AIRg were studied in linear relationship terms and in terms of the hyperbolic function. Where the best fit was linear, the Jones and Molitoris method was used to investigate whether the 2-line fit was significantly better. The division of the population into BMI quartiles shows that from the third quartile, IS (12.4 +/- 6.0 v 11.0 +/- 6.4 v 4.8 +/- 1.8 v 3.2 +/- 2.0 E-5 min(-1)[pmol/L](-1), P < .01) diminishes. Nevertheless, a plateau was established between the last 3 quartiles for IS x AIRg. AIRg related to BMI via a breakpoint of 29.3 kg . m(-2). The best fits for both the BMI/IS and BMI/FPI relationships were hyperbolic. Our data indicate that obesity represents a continuum of IR, with severity increasing as BMI increases. Nevertheless, above a value of 29 kg . m(-2) and despite great increases in adiposity, IS tends to descend slowly. Moreover, there seems to be an IMGU threshold at a BMI value of approximately 27 kg . m(-2), above which an increase in adiposity leads to a greater fall in IS x AIRg. Furthermore, this threshold also appears to affect pancreatic response to a glucose stimulus.     

Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of beta-cell function with oral antidiabetic medications: a pilot study with sitagliptin

Aim: Studies evaluating the effects of oral antidiabetic drugs (OADs) on beta‐cell function in type 2 diabetes mellitus (T2DM) are confounded by an inability to establish the actual baseline degree of beta‐cell dysfunction, independent of the deleterious effects of hyperglycaemia (glucotoxicity). Because intensive insulin therapy (IIT) can induce normoglycaemia, we reasoned that short‐term IIT could enable evaluation of the beta‐cell protective capacity of OADs, free from confounding hyperglycaemia. We applied this strategy to assess the effect of sitagliptin on beta‐cell function. Methods: In this pilot study, 37 patients with T2DM of 6.0 + 6.4 years duration and A1c 7.0 + 0.8% on 0–2 OADs were switched to 4–8 weeks of IIT consisting of basal detemir and premeal insulin aspart. Subjects achieving fasting glucose <7.0 mmol/l 1 day after completing IIT (n = 21) were then randomized to metformin with either sitagliptin (n = 10) or placebo (n = 11). Subjects were followed for 48 weeks, with serial assessment of beta‐cell function [ratio of AUC_Cpep to AUC_gluc over Homeostasis Model Assessment of Insulin Resistance (HOMA‐IR) (AUC_Cpep/gluc/HOMA‐IR)] on 4‐h meal tests. Results: During the study, fasting glucagon‐like‐peptide‐1 was higher (p = 0.003) and A1c lower in the sitagliptin arm (p = 0.016). Nevertheless, although beta‐cell function improved during the IIT phase, it declined similarly in both arms over time (p = 0.61). By study end, AUC_Cpep/gluc/HOMA‐IR was not significantly different between the placebo and sitagliptin arms (median 71.2 vs 80.4; p = 0.36). Conclusions: Pretreatment IIT can provide a useful strategy for evaluating the beta‐cell protective capacity of diabetes interventions. In this pilot study, improved A1c with sitagliptin could not be attributed to a significant effect on preservation of beta‐cell function.     

Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased beta-cell function

To identify the pathogenic factors responsible for glucose intolerance of aging, we measured a variety of metabolic parameters, including insulin sensitivity and islet cell function, in 10 young (18-36 yr old) and 10 older (57-82 yr old) men of normal body weight. Subject groups had equivalent fasting plasma glucose and fat cell size values. Frequently sampled iv glucose tolerance tests were performed, and the data were analyzed by computer using the minimal model approach. This technique yields the following measures: SI, the insulin sensitivity index; phi 1 and phi 2, indices of first and second phase beta-cell responsiveness to glucose; n, fractional insulin clearance, and SG, a measure of dynamic glucose disappearance dependent on glucose per se. We also evaluated beta-cell responsiveness independently by measuring the plasma insulin response to arginine injections at three levels of glycemia and calculated potentiation slope from the relationship between the acute insulin response to arginine and the prestimulus glucose level. The older men were glucose intolerant (glucose disappearance rate, 1.32% min-1) compared to the younger men (glucose disappearance rate, 2.21% min-1; P less than 0.01). This intolerance was the result of both a beta-cell defect and insulin resistance. The potentiation slope (r = -0.67; P less than 0.02) and phi 2 (r = -0.47; P less than 0.05) both decreased with age. In addition, SI in the older group was diminished 63% (2.4 vs. 6.5; 10(-4) min-1/microU/ml; P less than 0.001) and was unrelated to differences in body fat. No differences were found in either n or SG. These studies suggest that the diminished glucose tolerance of aging in normal weight men has multifactorial causality. Both beta-cell dysfunction and insulin resistance are important. In contrast, we found little evidence for changes in insulin clearance or insulin-independent glucose disappearance contributing to age-related glucose intolerance.     

罗格列酮联合阿司匹林治疗对糖尿病代谢综合征患者胰岛素抵抗的影响

目的探讨罗格列酮（RGZ）联合阿司匹林（Asp）治疗对糖尿病代谢综合征（MS）患者胰岛素抵抗（IR）的影响。方法126例MS患者按随机区组设计法分为基础治疗组（31例）,Asp组（31例）,RGZ组（32例）,RGZ联合Asp组（32例）,观察各组治疗前后FPG、2hPG、HbA1c、Ins、C-P、C—RP、纤维蛋白原水平及HOMA—IR等的变化。结果RGZ联合Asp组FPG、2hPG、Ins、HOMA—IR、炎症因子水平均较其他三组下降。结论RGZ联合Asp应用可协同改善糖尿病MS患者IR,并具有抗炎作用。     

Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2

OBJECTIVES: Hepatitis C virus (HCV) infection is linked to greater insulin resistance. Although HCV itself is a candidate for the development of insulin resistance, the effects of antiviral treatment on impaired glucose metabolism remain unclear. The aim of this study is to examine the effects of clearance of HCV on insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate (IRS)1/2, central molecules for insulin signaling. METHODS: We analyzed 89 biopsy-proven patients with chronic HCV infection. Patients received interferon-alpha or interferon-alpha plus ribavirin for 6 months and were classified into three groups at 6 months after the conclusion of antiviral therapy according to their response to antiviral therapy: sustained responders (N = 29), relapsers (N = 12), and nonresponders (N = 48). Insulin resistance and beta-cell function were assessed by the homeostasis model assessment method (HOMA-IR and HOMA-%B, respectively). Hepatic expression of IRS1/2 was evaluated by immunoblotting and immunostaining in 14 sustained responders. RESULTS: In nonresponders and relapsers, there were no significant changes in HOMA-IR and HOMA-%B values after antiviral therapy. On the other hand, in sustained responders, HOMA-IR values significantly decreased to 1.7 +/- 0.8 from 3.1 +/- 1.1 (P < 0.05) after antiviral therapy. Similarly, HOMA-%B values significantly decreased to 90.6 +/- 10.0 from 113.7 +/- 15.3 (P < 0.05). Immunoblotting showed a threefold increase in IRS1/2 expression after clearance of HCV. Immunostaining revealed that greater IRS1/2 expression was seen in hepatocytes. CONCLUSIONS: We showed that clearance of HCV improves insulin resistance, beta-cell function, and hepatic IRS1/2 expression.     

Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.     

罗格列酮对高脂饮食诱导非酒精性脂肪肝大鼠胰岛素抵抗及脂联素的影响

目的:探讨罗格列酮对高脂饮食所致的非酒精性脂肪肝大鼠模型胰岛素抵抗及脂联素的影响.方法:30只大鼠随机分为3组,即模型组(高脂饮食 蒸馏水ig),空白对照组(正常饲料 蒸馏水ig)和罗格列酮组[高脂饮食 罗格列酮3 mg/(kg·d)ig].观察各组血脂、肝功、胰岛素抵抗指数(HOMA-IR)的变化和各组肝组织HE染色与脂肪特异性的苏丹Ⅲ染色的变化.采用实时荧光定量聚合酶链式反应(PCR)和免疫印迹(western blot)检测各组肝组织的脂联素水平.结果:模型组与空白对照组相比,甘油三酯(TG)(1.51±0.37 mmol/L vs 0.98±0.51 mmol/L,P<0.01),总胆固醇(TC)(2.74±0.65 mmol/L vs 1.71±0.37 mmol/L,P<0.05),ALT(450.20±244.12 U/L vs 264.56±48.44 U/L,P<0.011,AST(460.30±310.13 U/L vs 196.11±52.23 U/L,P<0.01)和HOMA-IR(3.46±1.16 vs 1.07±0.26,P<0.01)均显著升高.罗格列酮治疗可使TG(1.27±0.50 mmol/L),ALT(360.26±244.37 U/L,AST(300.20±233.13 U/L)以及HOMR- IR(1.44±0.37)得到明显改善(均P<0.05).从组织病理学亦可得到证实.肝组织实时荧光定量PCR及免疫印迹显示罗格列酮组的Adiponectin mRNA(552.40±268.13 vs 215.95±135.87,P<0.05)和蛋白表达均较模型组升高.结论:高脂饮食可诱导大鼠NAFLD和IR发生,并使肝功,血脂异常升高.罗格列酮可以改善高脂饮食大鼠的脂肪肝及IR情况,可能与Adiponectin缓解IR和NAFLD改善有关.     

Changes in serum adiponectin concentrations and endothelial function after intensive insulin treatment in people with newly diagnosed type 2 diabetes: a pilot study

Aims

We aimed to assess changes in serum adiponectin and endothelial function after intensive insulin treatment in patients with newly diagnosed type 2 diabetes mellitus (T2DM).

Methods

Patients with newly diagnosed T2DM were randomly assigned to Group A (intensive insulin treatment) or Group B (conventional insulin treatment). Before treatment and 2 weeks after plasma glucose concentrations had been maintained at the specified concentrations, blood samples were obtained to measure serum adiponectin and nitric oxide (NO) concentrations. A total of 21 patients were randomized to each Group.

Results

Adiponectin, NO, endothelium-dependent vasodilation (EDD), and endothelium-independent vasodilation (EID) measures were significantly higher post-treatment than pre-treatment in Group A (all P < 0.05). Only EID was significantly higher in Group B (P < 0.05). Post-treatment adiponectin and NO concentrations, and EDD were significantly higher in Group A compared with Group B (all P < 0.05). Both treatment regimens were well tolerated (all patients completed the study). The most common adverse event was hypoglycemia. Thus, early intensive insulin therapy can increase serum adiponectin and NO concentrations and improve endothelial function in patients with newly diagnosed T2DM.

Conclusions

These effects may underlie the reduced incidence of microvascular and macrovascular in patients who receive early intensive hypoglycemic therapy.     

Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit elevated levels of serum C-reactive protein (CRP) and impaired endothelium dysfunction which are directly correlated with insulin resistance. Because rosiglitazone improves insulin sensitivity, we tested whether rosiglitazone treatment ameliorates high-sensitivity (hs)CRP levels and endothelial dysfunction in these patients. DESIGN: Thirty-one women with PCOS were recruited (mean age, 24.7+/-3.9 (s.e.) years; mean body mass index (BMI), 25.6+/-3.2 kg/m2). All women were treated with 4 mg rosiglitazone daily for 12 months. METHODS: Serum levels of testosterone, LH, FSH, sex hormone-binding globulin (SHBG), insulin and hsCRP were measured. The BMI, hirsutism scores and insulin sensitivity indices were calculated before and after treatment. Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli before and after treatment. RESULTS: After treatment with rosigitazone there were significant decreases in serum testosterone (91.2+/-37.5 vs 56.1+/-21.8 ng/dl; P < 0.01) and fasting insulin concentrations (12.5+/-7.6 vs 8.75+/-4.03 microU/ml; P = 0.015). Insulin resistance indices were significantly improved after rosiglitazone treatment (P < 0.05). There were no significant changes in BMI, waist circumference, serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, FSH and LH levels. Hirsutism score was decreased significantly after treatment (10.8+/-1.8 vs 7.6+/-1.7; P < 0.05). Twenty-four of the women reverted to regular menstrual cycles. Levels of SHBG increased significantly after treatment (28.7+/-8.7 vs 48.4+/-11.2 nmol/l; P < 0.01). Serum hsCRP levels were decreased significantly after rosiglitazone treatment (0.25+/-0.1 vs 0.09+/-0.02 mg/dl; P = 0.006). There was also significant improvement in endothelium-dependent vascular responses after rosiglitazone treatment (9.9+/-3.9 vs 16.4+/-5.1%; P < 0.01). CONCLUSIONS: We conclude that rosiglitazone treatment improves insulin sensitivity in women with PCOS. It also decreases androgen production without significant weight gain. More importantly, it has beneficial effects on endothelial dysfunction and low-grade chronic inflammation in normal weight young women with PCOS.     

Short-term exercise improves beta-cell function and insulin resistance in older people with impaired glucose tolerance

BACKGROUND: There is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Normal aging is associated with insulin resistance and impaired insulin secretion, with greater defects in people with IGT. Short-term exercise has been found to increase insulin sensitivity, but little is known about acute exercise effects on beta-cell function in older people with IGT. METHODS: We assessed the effects of 7 consecutive days of supervised aerobic exercise (1 h/d at 60-70% heart rate reserve) in 12 sedentary older people with IGT. Screening included oral glucose tolerance test, stress/maximal O(2) uptake test, and dual-energy x-ray absorptiometry scan. Participants had a frequently sampled iv glucose tolerance test at baseline and 15-20 h after the seventh exercise session. Insulin sensitivity (S(I)), glucose disappearance constant (Kg, a measure of iv glucose tolerance), acute insulin response to glucose (AIRg), and disposition index (AIRg x S(I)), a measure of beta-cell function in relation to insulin resistance, were calculated. RESULTS: Exercise was well tolerated. Body weight, fasting glucose, fasting insulin, and iv glucose tolerance were unchanged with exercise. S(I) increased by 59%, AIRg decreased by 12%, and disposition index increased by 31%. There was no significant change in fasting lipid, catecholamine, leptin, or adiponectin levels. CONCLUSIONS: Short-term exercise not only improved insulin resistance but also significantly enhanced beta-cell function in older people with IGT. These effects of short-term exercise on beta-cell function cannot be explained by changes in body weight or circulating levels of lipids, leptin, adiponectin, or catecholamines.     

Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone

Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and antiatherosclerotic properties. Because adipose tissue depots differ in the strength of their association with the adverse metabolic consequences of obesity, we studied the secretion of adiponectin in vitro from paired samples of isolated human omental and sc adipocytes and its regulation by insulin and rosiglitazone. Cells were incubated for 12 or 24 h with and without treatment with 100 nM insulin, 8 micro M rosiglitazone, or both combined; adiponectin secreted into the culture medium was measured by a RIA with a human adiponectin standard and normalized for cellular DNA content. Secretion of adiponectin by omental cells was generally higher than sc cells and showed a strong negative correlation with body mass index (r = -0.78;P = 0.013). In contrast, secretion from the sc cells was unrelated to body mass index. Compared with sc-derived adipocytes, adiponectin secretion from omental cells was increased by insulin or rosiglitazone alone and was up to 2.3-fold higher following combined treatment with insulin and rosiglitazone, whereas secretion from sc adipose cells was unaffected by these treatments. These data suggest that reduced secretion from the omental adipose depot may account for the decline in plasma adiponectin observed in obesity. Furthermore, enhanced adiponectin secretion from fat cells derived from the visceral compartment in response to rosiglitazone alone or in combination with insulin may play a role in some of the systemic insulin-sensitizing and antiinflammatory properties of the thiazolidinediones.