Elevated plasma total homocysteine levels in hyperinsulinemic obese subjects

Homocysteine has been associated with the oxidative stress in the pathogenesis of atherosclerosis. Oxidative stress caused by triglycerides and free fatty acids is known to cause insulin resistance and hyperinsulinemia. On the other hand, insulin resistance may increase homocysteine levels. Since obesity is associated with insulin resistance and hyperinsulinemia, we aimed to study the possible association of homocysteine with hyperinsulinemia in obese subjects. 20 obese male subjects (body mass index >29), aged 33--55 (mean 45 years old) were studied. A fasting blood sample was obtained for the study and the subjects undertook an oral glucose tolerance test with samples taken at 1 and 2 h after glucose. Subjects were divided in two groups according to the fasting insulin levels, < 9 &mgr;U/ml or normoinsulinemic (group 1) and >9 &mgr;U/ml or hyperinsulinemic (group 2). Glucose, insulin, homocysteine, folate, B(12,) total cholesterol, HDL-cholesterol and triglycerides levels were determined in fasting blood samples. In oral glucose tolerance test, glucose, insulin and homocysteine levels were measured. Hyperinsulinemic obese subjects (group 2) had higher levels of insulin and glucose at 1 h and 2 h postglucose, compared with group 1. Fasting total homocysteine and triglyceride levels were also increased in this group, whereas folate and B(12) levels were similar in both groups. Fasting homocysteine significantly correlated with fasting insulin (r = 0.6, p <0.01). Homocysteine levels slightly but significantly decreased after glucose loading in normoinsulinemic but not in hyperinsulinemic obese subjects. These results show that higher homocysteine levels are observed in the hyperinsulinemic obese subjects and suggest that homocysteine could play a role in the higher risk of cardiovascular disease in obesity.     

Serum calcium levels are associated with novel cardiometabolic risk factors in the population-based CoLaus study

Background

Associations of serum calcium levels with the metabolic syndrome and other novel cardio-metabolic risk factors not classically included in the metabolic syndrome, such as those involved in oxidative stress, are largely unexplored. We analyzed the association of albumin-corrected serum calcium levels with conventional and non-conventional cardio-metabolic risk factors in a general adult population.

Methodology/Principal Findings

The CoLaus study is a population-based study including Caucasians from Lausanne, Switzerland. The metabolic syndrome was defined using the Adult Treatment Panel III criteria. Non-conventional cardio-metabolic risk factors considered included: fat mass, leptin, LDL particle size, apolipoprotein B, fasting insulin, adiponectin, ultrasensitive CRP, serum uric acid, homocysteine, and gamma-glutamyltransferase. We used adjusted standardized multivariable regression to compare the association of each cardio-metabolic risk factor with albumin-corrected serum calcium. We assessed associations of albumin-corrected serum calcium with the cumulative number of non-conventional cardio-metabolic risk factors.We analyzed 4,231 subjects aged 35 to 75 years. Corrected serum calcium increased with both the number of the metabolic syndrome components and the number of non-conventional cardio-metabolic risk factors, independently of the metabolic syndrome and BMI. Among conventional and non-conventional cardio-metabolic risk factors, the strongest positive associations were found for factors related to oxidative stress (uric acid, homocysteine and gamma-glutamyltransferase). Adiponectin had the strongest negative association with corrected serum calcium.

Conclusions/Significance

Serum calcium was associated with the metabolic syndrome and with non-conventional cardio-metabolic risk factors independently of the metabolic syndrome. Associations with uric acid, homocysteine and gamma-glutamyltransferase were the strongest. These novel findings suggest that serum calcium levels may be associated with cardiovascular risk via oxidative stress.     

Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

Metabolic syndrome is a proatherosclerotic condition clustering cardiovascular risk factors, including glucose and lipid profile alterations. The pathophysiological mechanisms favoring atherosclerotic inflammation in the metabolic syndrome remain elusive. Here, we investigated the potential role of the antilipolytic drug acipimox on neutrophil- and monocyte-mediated inflammation in the metabolic syndrome. Acipimox (500 mg) was orally administered to metabolic syndrome patients (n = 11) or healthy controls (n = 8). Serum and plasma was collected before acipimox administration (time 0) as well as 2-5 h afterward to assess metabolic and hematologic parameters. In vitro, the effects of the incubation with metabolic syndrome serum were assessed on human neutrophil and monocyte migration toward the proatherosclerotic chemokine CCL3. Two to five hours after acipimox administration, a significant reduction in circulating levels of insulin and nonesterified fatty acid (NEFA) was shown in metabolic syndrome patients. At time 0 and 2 h after acipimox administration, metabolic syndrome serum increased neutrophil migration to CCL3 compared with healthy controls. No effect was shown in human monocytes. At these time points, serum-induced neutrophil migration positively correlated with serum levels of insulin and NEFA. Metabolic syndrome serum or recombinant insulin did not upregulate CCR5 expression on neutrophil surface membrane, but it increased intracellular JNK1/2 phosphorylation. Insulin immunodepletion blocked serum-induced neutrophil migration and associated JNK1/2 phosphorylation. Although mRNA expression of acipimox receptor (GPR109) was shown in human neutrophils, 5-500 μM acipimox did not affect insulin-induced neutrophil migration. In conclusion, results suggest that acipimox inhibited neutrophil proatherosclerotic functions in the metabolic syndrome through the reduction in circulating levels of insulin.     

Elevated serum GGT concentrations predict reduced insulin sensitivity and increased intrahepatic lipids.

Elevated serum gamma-glutamyltransferase (GGT) concentrations have been related to features of the metabolic syndrome as well as increased risk of cardiovascular and liver disease. More recently, elevated GGT levels were shown to predict development of type 2 diabetes in a longitudinal study from Korea. The aim of the present study was to test the hypothesis that serum GGT is associated with glucose tolerance, insulin sensitivity and beta-cell function in a healthy, non-diabetic Caucasian population from the Tübingen family study. Insulin sensitivity was estimated by oGTT (n = 850) or measured by hyperinsulinemic euglycemic clamp (n = 245), respectively. A subgroup (n = 70) underwent additional determination of intrahepatic lipid content using 1H magnetic resonance spectroscopy. Serum GGT was positively correlated with two-hour glucose during oGTT (r = 0.15, p < 0.0001) and negatively correlated with insulin sensitivity from oGTT (r = -0.31, p < 0.0001) and clamp (r = -0.27, p < 0.0001). The relationship between GGT and insulin sensitivity remained significant after adjusting for sex, age, BMI, and AST using multivariate regression analysis. Inclusion of serum triglyceride levels as a parameter of lipid metabolism kept the relationship significant in the oGTT group (p < 0.0001), but not in the smaller clamp group (p = 0.11). Additionally, serum GGT was positively correlated with hepatic lipid content (r = 0.49, p < 0.001) independent of sex, age, BMI, AST or serum triglycerides. There was no significant correlation between GGT and the index for beta-cell function after adjusting for age, sex, BMI and insulin sensitivity (p = 0.74). In conclusion, elevated serum GGT levels predict glucose intolerance probably via insulin resistance rather than beta-cell dysfunction. This may be primarily related to hepatic insulin resistance and increased intrahepatic lipids. The association observed between elevated hepatic lipids and reduced insulin sensitivity might explain the increased diabetes risk observed in subjects with elevated serum GGT concentrations. In the absence of overt liver disease, elevated serum GGT concentrations may point the clinician to incipient disturbances in the glucose metabolism.     

Zinc and Homocysteine Levels in Polycystic Ovarian Syndrome Patients with Insulin Resistance

In this study, our objective was to evaluating the value of serum zinc levels as an etiologic and prognostic marker in patients with polycystic ovarian syndrome. We conducted a prospective study, including 53 women with polycystic ovarian syndrome and 33 healthy controls. We compared serum zinc levels, as well as clinical and metabolic features, of the cases. We also compared serum zinc levels between patients with polycystic ovarian syndrome with insulin resistance. Mean zinc levels were found to be significantly lower in patients with polycystic ovarian syndrome than healthy controls. Multiple logistic regression analysis of significant metabolic variables between polycystic ovarian syndrome and control groups (serum zinc level, body mass index, the ratio of triglyceride/high-density lipoprotein cholesterol, and homocysteine) revealed that zinc level was the most significant variable to predict polycystic ovarian syndrome. Mean serum zinc levels tended to be lower in patients with polycystic ovarian syndrome with impaired glucose tolerance than patients with normal glucose tolerance, but the difference was not statistically significant. In conclusion, zinc deficiency may play a role in the pathogenesis of polycystic ovarian syndrome and may be related with its long-term metabolic complications.     

Glycated Hemoglobin,Fasting Insulin and the Metabolic Syndrome in Males. Cross-Sectional Analyses of the Aragon Workers’ Health Study Baseline

Background and Aims

Glycated hemoglobin (HbA1c) is currently used to diagnose diabetes mellitus, while insulin has been relegated to research. Both, however, may help understanding the metabolic syndrome and profiling patients. We examined the association of HbA1c and fasting insulin with clustering of metabolic syndrome criteria and insulin resistance as two essential characteristics of the metabolic syndrome.

Methods

We used baseline data from 3200 non-diabetic male participants in the Aragon Workers'' Health Study. We conducted analysis to estimate age-adjusted odds ratios (ORs) across tertiles of HbA1c and insulin. Fasting glucose and Homeostatic model assessment - Insulin Resistance were used as reference. Here we report the uppermost-to-lowest tertile ORs (95%CI).

Results

Mean age (SD) was 48.5 (8.8) years and 23% of participants had metabolic syndrome. The ORs for metabolic syndrome criteria tended to be higher across HbA1c than across glucose, except for high blood pressure. Insulin was associated with the criteria more strongly than HbA1c and similarly to Homeostatic model assessment - Insulin Resistance (HOMA-IR). For metabolic syndrome, the OR of HbA1c was 2.68, of insulin, 11.36, of glucose, 7.03, and of HOMA-IR, 14.40. For the clustering of 2 or more non-glycemic criteria, the OR of HbA1c was 2.10, of insulin, 8.94, of glucose, 1.73, and of HOMA-IR, 7.83. All ORs were statistically significant. The areas under the receiver operating characteristics curves for metabolic syndrome were 0.670 (across HbA1c values) and 0.770 (across insulin values), and, for insulin resistance, 0.647 (HbA1c) and 0.995 (insulin). Among non-metabolic syndrome patients, a small insulin elevation identified risk factor clustering.

Conclusions

HbA1c and specially insulin levels were associated with metabolic syndrome criteria, their clustering, and insulin resistance. Insulin could provide early information in subjects prone to develop metabolic syndrome.     

Long-term cyclosporine treatment in non-transplanted rats and metabolic risk factors of vascular diseases

Cyclosporine (CsA) is an immunosuppressive agent frequently used in the clinic for prevention of allograft rejection and for the treatment of autoimmune diseases. Despite its desired action on the immune system, CsA treatment may present serious adverse effects, which are masked by the concomitant use of other drugs. The search for effective immunosuppression protocols which does not affect the quality of life of patients is driving research to investigate the CsA involvement in vascular diseases, frequent in patients under immunosuppression. Thus, 45 non-transplanted Wistar rats were treated for 8 weeks with vehicle or 5 or 15 mg/kg CsA (n = 15/group) by gavage administration to evaluate the specific influence of cyclosporine on the levels of risk factors (metabolic and inflammatory) of vascular disease and its mechanism of action. Therefore, serum insulin levels, glucose tolerance test, serum lipids profile, total homocysteine and fibrinogen levels were assessed. The biochemical alterations reported here suggest the development of a framework straight to diabetes. Glucose homeostasis was affected as indicated by decreased insulin levels and altered glucose tolerance test in CsA 15 mg/kg group compared to other groups. Serum insulin and total homocysteine levels presented a significant negative correlation (R = ? 0.76, P < 0.0001). Fibrinogen and serum lipids profiles were significantly increased in CsA 15 mg/kg group compared to other groups and correlated positively with total homocysteine levels. Considering the well-established correlation among insulin resistance, lipid and total homocysteine levels, hypercoagulability and atherosclerosis, we can assume that this protocol of long-term CsA treatment in non-transplanted rats alter biochemical parameters related to cardiovascular and cerebrovascular risk, mainly in CsA 15 mg/kg group. Insulin and tHcy serum levels appear to be central in this process.     

Potential utility of combination therapy with nateglinide and telmisartan for metabolic derangements in Zucker Fatty rats.

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular disease. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial hyperglycemia. In this study, we investigated the potential utility of combination therapy with telmisartan, an angiotensin II receptor blocker and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial hyperglycemia and metabolic derangements in Zucker Fatty (ZF) rats. ZF rats fed twice daily were given vehicle, 50 mg/kg of nateglinide, 5 mg/kg of telmisartan, or both for 6 weeks. Combination therapy with nateglinide and telmisartan for 2 weeks ameliorated postprandial hyperglycemia in ZF rats fed twice daily. Furthermore, 6-week treatment with nateglinide and telmisartan not only decreased fasting plasma insulin, triglycerides, and free fatty acid levels, but also improved the responses of blood glucose to insulin and subsequently reduced the decremental glucose areas under the curve in the ZF rats. Combination therapy also restored the decrease of plasma adiponectin levels in the ZF rats. Monotherapy with nateglinide or telmisartan alone didnot significantly improve these metabolic parameters. These observations demonstrate that combination therapy with nateglinide and telmisartan may improve the metabolic derangements by ameliorating early phase of insulin secretion as well as insulin resistance in ZF rats fed twice daily. Our present findings suggest that the combination therapy with nateglinide and telmisartan could be a promising therapeutic strategy for the treatment of the metabolic syndrome.     

Hyperthyroidism is associated with higher plasma endothelin-1 concentrations

The objective of this study was to determine the change of plasma endothelin (ET)-1 concentrations and insulin resistance index after therapy for hyperthyroidism. We studied 20 patients with hyperthyroidism (15 women and 5 men; age, 34.0 +/- 2.8 years), and 31 patients with euthyroid goiters as controls (27 women, 4 men; age, 37.0 +/- 2.4 years). All hyperthyroid patients were treated with antithyroid drugs. The patients received evaluations before and after normalization of thyroid function. The evaluations included body mass index (BMI), body fat, and measurement of circulating concentrations of thyroid hormones, glucose, insulin, and ET-1. Hyperthyroid subjects had higher plasma ET-1 concentrations than the control group (P < 0.001). No significant differences in serum glucose and insulin concentrations or insulin resistance index estimated by the R value of the homeostasis model assessment (HOMA-R) were noted between the groups. Plasma ET-1 concentrations decreased after correction of hyperthyroidism compared with pretreatment (P = 0.006). Serum glucose concentrations decreased after correction of hyperthyroidism (P = 0.005). Moreover, both body weight-adjusted insulin concentrations and the HOMA-R index were also decreased after correction of hyperthyroidism compared with pretreatment (P = 0.026 and P = 0.019, respectively). Pearson's correlation revealed that plasma ET-1 levels positively correlated with serum triiodothyronine (T3) and free thyroxine (FT4) levels. Serum insulin levels and the HOMA-R index positively correlated with BMI and body fat. The HOMA-R index also positively correlated with serum T3 and FT4 levels. Neither insulin levels nor the HOMA-R index correlated with ET-1 levels. Hyperthyroidism is associated with higher plasma ET-1 concentrations. In addition, correction of hyperthyroidism is also associated with a decrease of plasma ET-1 levels as well as the insulin resistance index calculated by HOMA-R.     

Estimated glucose disposal rate in assessment of renal function in patients with type 1 diabetes

Insulin resistance has been documented in type 1 diabetes and may contribute to the high risk for cardiovascular disease in this population and progression of nephropathy. We investigated associations of renal parameters, including urinary albumin excretion rate (UAE), serum creatinine and creatinine clearance, with surrogate measure of insulin sensitivity calculated using a formula derived from euglycemic-hyperinsulinemic clamp studies (estimated glucose disposal rate, eGDR). Study included 353 patients with type 1 diabetes, none showed signs of adrenal, thyroid, renal, or cardiovascular diseases. Insulin sensitivity was measured with eGDR calculated with the equation: 24.31-(12.22xWHR)-(3.29xHT)-(0.57xHbA1c). The units were mgkg(-1)min(-1); WHR=waist to hip ratio; HT=hypertension. Correlations and logistic regression analysis were performed to identify relationships between renal parameters and eGDR, individual components of insulin resistance and risk of insulin resistance. UAE and serum creatinine significantly correlated with insulin resistance measured by eGDR (r=-0.13, and -0.17, all p<0.05), and its components disorders, WHR and HbA1c. After stratifying patients in quartiles of eGDR, those in the upper quartile of the eGDR had significantly reduced levels of UAE and serum creatinine, compared to subjects in lowest quartile. In a logistic regression analysis risk for development of insulin resistance in our subjects were independently predicted only by UAE (odds ratio = 1.01, p<0.01). Our results provide evidence of associations between insulin resistance and its components disorders with renal parameters, such as UAE and serum creatinine. Insulin resistance, measured with eGDR, predicts the increment in UAE in subjects with type 1 diabetes. Since progression to microalbuminuria is likely to occur in majority of diabetic patients, there is a need to further explore the role of risk factors such as insulin resistance.     

Independent influence of insulin, catecholamines, and thyroid hormones on metabolic syndrome

The objective of this study was to examine whether metabolic syndrome, defined according to adult treatment panel III criteria, is associated with insulin, catecholamines, and thyroid hormones, independently of age and gender. A cohort of 651 euthyroid overweight and obese patients, 440 women and 211 men, aged 18-68 years, were examined. Central fat accumulation (indirectly measured by waist circumference), fasting thyroid-stimulating hormone (TSH), FT(3), FT(4), insulin, glucose, and lipid (cholesterol, HDL-cholesterol, and triglyceride) serum concentrations, 24-h urinary catecholamines, and the level of insulin resistance (estimated by homeostasis model assessment for insulin resistance (HOMA(IR))) were measured. Patients with metabolic syndrome showed higher insulin (P < 0.001) and FT(3) (P < 0.001) serum levels and higher 24-h urinary noradrenaline (P < 0.001) than subjects without this syndrome. The number of metabolic syndrome parameters was directly associated with insulin (P < 0.001) and FT(3) (P < 0.05) serum levels, and with 24-h urinary noradrenaline (P < 0.001) in the whole population. When a multiple regression analysis was performed with the metabolic syndrome as the dependent variable, and age, gender, and insulin, and TSH, FT(3), FT(4) serum levels, and 24-h urinary noradrenaline and adrenaline as independent variables, the metabolic syndrome maintained an independent positive association with age (P < 0.001), male sex (P < 0.001), insulin (P < 0.001), and 24-h urinary noradrenaline (P < 0.001). In conclusion, this study suggests that insulin and noradrenaline cooperate independently to the development of the metabolic syndrome.     

Insulin secretion in metabolically obese, but normal weight, and in metabolically healthy but obese individuals

Metabolically obese but normal-weight (MONW) individuals present metabolic disturbances typical of obese individuals. Additionally, metabolically healthy but obese (MHO) individuals have been identified who are relatively insulin sensitive and have a favorable cardiovascular risk profile. We compared insulin secretion patterns of MONW and MHO with those of two age-matched groups comprising nonobese individuals or obese insulin-resistant subjects, respectively. To this end, 110 nonobese subjects and 87 obese subjects were stratified into quartile based on their insulin-stimulated glucose disposal (M(FFM)). Insulin secretion was estimated by acute insulin response (AIR) during an intravenous glucose-tolerance test (IVGTT), and the disposition index was calculated as AIR x M(FFM). We found that, as defined, M(FFM) was lower in MONW, who exhibited higher triglycerides, free-fatty acid (FFA), and 2-h postchallenge glucose levels compared to normal nonobese group. Insulin secretion was higher in MONW than in normal nonobese subjects, but disposition index was lower in MONW. Disposition index did not differ between MONW and insulin-resistant obese. M(FFM) was higher in MHO who exhibited lower waist circumference, blood pressure (BP), triglycerides, FFA, insulin levels, and higher high-density lipoprotein (HDL) cholesterol compared to insulin-resistant obese. Insulin secretion did not differ between insulin-resistant obese and MHO, but disposition index was lower in the former group. In conclusion, MONW and insulin-resistant obese showed decreased compensatory insulin secretion compared to normal nonobese and MHO subjects, respectively. Because these subjects also exhibited a worse metabolic risk profile, these findings may account for their increased risk for type 2 diabetes.     

Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance

BACKGROUND/AIMS: Insulin resistance is associated with serum C-reactive protein (CRP) levels. We aimed to evaluate the effect of bicalutamide on insulin resistance and serum CRP levels in non-obese polycystic ovarian syndrome (PCOS) patients. METHODS: 40 non-obese patients (BMI < or =25 kg/m2) with PCOS and, 40 age- and BMI-matched healthy women were studied. Patients received bicalutamide orally at the dose of 25 mg/day. Serum CRP levels were measured with immunometric assay. Homeostasis model assessment (HOMA-IR) index was used for insulin resistance. RESULTS: Mean Ferriman-Gallwey score (FGS) (p = 0.001), insulin (p = 0.001), serum glucose (p = 0.001), prolactin (p < 0.003), total (p < 0.04) and free testosterone (p = 0.001) and free androgen index (FAI) levels (p = 0.001) of PCOS subjects were higher than in the control group. Mean HOMA-IR of PCOS patients was higher than in control subjects (2.43 +/- 1.2 and 0.94 +/- 0.37, p = 0.001). CRP levels in subjects with PCOS was also higher than in control subjects (4.27 +/- 1.33 and 0.98 +/- 0.19, p = 0.001). After bicalutamide treatment, FGS, free and total testosterone and FAI decreased (p = 0.001). HOMA-IR, prolactin and CRP levels did not show any statistical difference with bicalutamide treatment. CONCLUSIONS: PCOS patients had insulin resistance and a high CRP level. Bicalutamide treatment did not influence insulin resistance and CRP level in PCOS, and this ineffectiveness of bicalutamide on CRP levels may be the result of insulin resistance and/or high prolactin levels at this time.     

Correlations of insulin resistance and neoplasms

Insulin resistance is a worldwide risk factor for the two most dangerous human disease groups; namely, for cardiovascular lesions and malignancies. The insulin resistance syndrome have five basic criteria: hyperglycemia, visceral obesity, elevated serum triglyceride level, low HDL-cholesterol level (dyslipidemia) and hypertension. Each of these criteria alone are risk factors for cancer, and they mean together a multiple risk. Insulin resistance of the liver, skeletal muscles, and fatty tissue leads to a reactive hyperinsulinemia by the increased secretory activity of the beta-cells. Insulin has diverse metabolic effects, and at the same time is a growth factor. It enhances the production and mitogenic activity of other, insulin-like growth factors, and leads to pathological cell proliferation. In the uncompensated phase of insulin resistance hyperglycemia appears, which promotes tumor genesis by several pathways. The elevated serum glucose level is advantageous for the increased DNA synthesis of the tumor cells. It provokes deliberation of free radicals, which will cause derangement of both the DNA and the enzymes having a role in the repair mechanisms. Hyperglycemia leads to a nonenzymatic glycation of protein structures, and the glycated products enhance the deliberation of free radicals, cytokines and growth factors. Insulin resistance means an enhanced risk for breast, pancreas, liver, colon, bladder, prostate and oral cavity cancers. The moderately increased fasting glucose level is also a risk factor for breast, stomach and colon cancers, even without manifestation of type 2 diabetes. Insulin resistance promotes tumor progression as well. In cancer patients with hyperglycemia or type 2 diabetes, the rate of tumor recurrence, metastatic spread and fatal outcome is higher as compared with the tumor patients without metabolic disease. The correlation between insulin resistance and tumor promotion reveals new possibilities in the prevention and treatment of cancer. The healthy diet, physical activity and weight loss increase insulin sensitivity, and decrease the risk for both cardiovascular diseases and malignancies.     

Relationship between adiponectin and metabolic variables in Caribbean offspring of patients with type 2 diabetes mellitus.

AIM: To examine the relationship between adiponectin and metabolic variables in the offspring of patients with type 2 diabetes mellitus. METHODS: Fasting blood samples and anthropometric indices were taken from 34 subjects, offspring of patients with type 2 diabetes, and 24 healthy control subjects without any immediate family history of diabetes. Plasma glucose and serum adiponectin, insulin, triglycerides, total cholesterol, HDL and LDL cholesterol levels were measured, and insulin resistance (IR) was calculated based on the homeostasis model assessment (HOMA) method. RESULTS: Offspring and control subjects were sex-matched, but the offspring were older and had higher body mass index and waist circumference than the control subjects (p < 0.05). The offspring had significantly higher mean fasting plasma glucose concentrations; however, their mean serum insulin, adiponectin, triglyceride, total cholesterol, HDL and LDL cholesterol and HOMA-derived IR levels did not significantly differ from those of the control subjects (p > 0.05). While the negative correlation between serum adiponectin and HDL cholesterol levels in the offspring remained statistically significant after adjusting for the effect of age, sex and BMI (r = -0.37, p < 0.05), the negative correlation between adiponectin and serum triglyceride, LDL cholesterol or IR levels became non-significant after controlling for the above variables (p > 0.05 in all cases). CONCLUSION: The correlation between adiponectin and some known biochemical risk factors for developing diabetes and cardiovascular disease in the offspring of patients with diabetes warrants further study to evaluate its potential in assessing the risk of developing these disorders.     

Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats

Insulin resistance, impaired glucose tolerance, high circulating levels of free fatty acids (FFA), and postprandial hyperlipidemia are associated with the metabolic syndrome, which has been linked to increased risk of cardiovascular disease. We studied the metabolic responses to an oral glucose/triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three groups of conscious 7-h fasted Zucker rats: lean healthy controls, obese insulin-resistant/dyslipidemic controls, and obese rats treated with the dual peroxisome proliferator-activated receptor alpha/gamma agonist, tesaglitazar, 3 mumol.kg(-1).day(-1) for 4 wk. Untreated obese Zucker rats displayed marked insulin resistance, as well as glucose and lipid intolerance in response to the glucose/TG load. The 2-h postload area under the curve values were greater for glucose (+19%), insulin (+849%), FFA (+53%), and TG (+413%) compared with untreated lean controls. Treatment with tesaglitazar lowered fasting plasma glucose, improved glucose tolerance, substantially reduced fasting and postload insulin levels, and markedly lowered fasting TG and improved lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. Mechanisms of tesaglitazar-induced lowering of plasma TG were studied separately using the Triton WR1339 method. In anesthetized, 5-h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced very low-density lipoprotein (VLDL) apolipoprotein CIII content by 86%, compared with obese controls. In conclusion, the glucose/lipid tolerance test in obese Zucker rats appears to be a useful model of the metabolic syndrome that can be used to evaluate therapeutic effects on impaired postprandial glucose and lipid metabolism. The present work demonstrates that tesaglitazar ameliorates these abnormalities and enhances insulin sensitivity in this animal model.     

Serum Liver Fatty Acid Binding Protein Levels Correlate Positively with Obesity and Insulin Resistance in Chinese Young Adults

Background

Liver fatty acid–binding protein (FABP1) plays an inconclusive role in adiposity. We investigated the association of serum FABP1 levels with obesity and insulin resistance in Chinese young people under 30 years old.

Methodology and Principal Findings

Cross-sectional analysis including 200 obese and 172 normal-weight subjects matched for age and sex, anthropometric measurements were performed and serum FABP1 and biochemical characteristics were measured. Insulin resistance was determined by homeostasis model assessment of insulin resistance (HOMA-IR) and by the insulin sensitivity index (S_i) derived from Bergman’s minimal model. FABP1 levels in obese subjects were significantly higher than those in normal-weight subjects (p<0.001) and the significance remained after adjustment for age, gender, alanine and aspartate aminotransferases (p<0.001). Serum FABP1 levels were significantly correlated with many metabolic-related parameters, with BMI and triglycerides as the independent determinants. FABP1 levels remained an independent risk factor of insulin resistance assessed by binary S_i (OR = 1.868 per SD unit, 95% CI [1.035–3.373], p = 0.038) after adjustment for age, sex, BMI, waist circumference, systolic blood pressure, serum triacylglycerol, total cholesterol, HDL- and LDL-cholesterol,. FABP1 levels were also elevated with an increasing number of components of the metabolic syndrome (p for trend <0.001). Multiple regression modeling for the MetS and its components demonstrated that hypertriglyceridemia and low HDL-cholesterol were significantly correlated to serum FABP1 levels.

Conclusions and Significance

Serum FABP1 correlates positively with obesity and insulin resistance in Chinese young adults. Our data supports the fact that FABP1 might be an important mediator participating in fatty acid metabolism and energy balance.     

Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion.

Insulin responsiveness was studied with the euglycaemic glucose clamp technique in seven patients with type I diabetes and in six control subjects matched for age and weight. The glucose disposal rate was significantly reduced in the diabetic subjects when they were receiving conventional insulin treatment compared with the control group, showing insulin resistance in the diabetics. The diabetic patients were again studied after eight days of intensified metabolic control achieved with continuous subcutaneous insulin infusion. During the infusion a more physiological insulin regimen was used compared with their regular treatment, less of the total insulin dose being given as continuous infusion and more as bolus doses before meals. The insulin resistance in the diabetics was largely reversed after this improved metabolic control. Dose response studies showed an increased glucose disposal rate at all plasma insulin concentrations, including the maximum insulin concentration, indicating a predominant effect of the continuous infusion regimen at the postreceptor level. The improved insulin effect seen with continuous subcutaneous insulin infusion could be due to the improved metabolic control achieved as well as the more physiological regimen.     

Association between Serum Leptin Concentrations and Insulin Resistance: A Population-Based Study from China

Background

Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported.

Methods

A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance.

Results

In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001).

Conclusions

There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.     

Clinical and biochemical characterization of women with polycystic ovary syndrome in North Rhine-Westphalia.

Polycystic ovary syndrome (PCOS), defined as the combination of oligoanovulation and hyperandrogenism, affects more than 5% of women of reproductive age. Insulin resistance and hyperinsulinemia appear to play an important role in its pathogenesis. Here, we will present a characterization of a PCOS cohort from North Rhine-Westphalia in Germany. Clinical features, family history as well as endocrine and metabolic parameters were prospectively recorded from 200 successive patients. All patients were evaluated for insulin resistance and beta-cell-function by oral glucose tolerance test. Patient data were compared with those of 98 age-matched control women. PCOS patients showed significantly higher BMI, body fat mass and androgen levels as well as impaired glucose and insulin metabolism. A positive family history of PCOS and diabetes was more frequent in PCOS patients. Insulin resistance (71%) was the most common metabolic abnormality in PCOS patients followed by obesity (52%) and dyslipidemia (46.3%), with an incidence of 31.5% for the metabolic syndrome. C-reactive protein and other cardiovascular risk factors were frequently elevated even in young PCOS patients. While the clinical characteristics and endocrine parameters of this German PCOS cohort were heterogeneous, they were comparable to those from other Caucasian populations.