Skeletal muscle magnesium content is correlated with plasma glucose concentration in patients with essential hypertension treated with lisinopril or bendrofluazide

The association between change in glucose metabolism and change in skeletal muscle magnesium (Mg) concentration induced by antihypertensive treatment was evaluated in 37 patients with essential hypertension randomly treated with either lisinopril or bendrofluazide. Before and after 6 months of treatment, skeletal muscle biopsies were performed, glucose tolerance was determined by oral (OGTT) and intravenous glucose tolerance tests (IVGTT), and insulin sensitivity was assessed by the hyperinsulinemic euglycemic clamp technique. An inverse relationship was found between the treatment-induced change in fasting plasma glucose concentration and change in skeletal muscle Mg concentration (r = -0.39, P < .05). However, there was no significant correlation between skeletal muscle Mg content and either insulin sensitivity measured by the hyperinsulinemic euglycemic clamp test or glucose tolerance evaluated by IVGTT and OGTT. In conclusion, an increased circulating glucose concentration was correlated with a decreased Mg concentration in skeletal muscle during antihypertensive treatment. However, the Mg concentration in skeletal muscle did not significantly predict the insulin sensitivity or glucose tolerance.     

The Leu7Pro polymorphism of the neuropeptide Y gene regulates free fatty acid metabolism

The Leu7Pro polymorphism in the signal peptide of the preproneuropeptide Y (NPY) has been associated with dyslipidemias and free fatty acid (FFA) levels during exercise. The association of this polymorphism with insulin sensitivity has not been studied. In this study, the Leu7Pro polymorphism was determined in 2 groups of nondiabetic middle-aged subjects (n [equals] 266 and n [equals] 295). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp (n [equals] 266) or with an intravenous glucose tolerance test (IVGTT, n [equals] 295). First-phase insulin secretion was determined as insulin area under the curve (AUC) during the first 10 minutes of the IVGTT. FFAs were measured both in the fasting state and during the hyperinsulinemic clamp. The Leu7Pro polymorphism of the NPY gene was not associated with the rates of whole body glucose uptake, insulin sensitivity index, insulin secretion during the IVGTT, or insulin AUC during the oral glucose tolerance test. However, the Pro7 allele was associated with low FFA levels both in the fasting state (P [equals] .043) and during the hyperinsulinemic clamp (P [equals] .003). In conclusion, the Leu7Pro polymorphism of the NPY gene associates with alterations in FFA metabolism but does not have an impact on insulin sensitivity, insulin secretion, or glucose metabolism. [copy ] 2003 Elsevier Inc. All rights reserved.     

Correlation of oral glucose tolerance test-derived estimates of insulin sensitivity with insulin clamp measurements in an African-American cohort

The purpose of this study was to determine which measures obtained from an oral glucose tolerance test (OGTT) are the best estimates of insulin sensitivity measured directly using the euglycemic hyperinsulinemic clamp procedure. Data were examined from a study conducted on 307 young adult African-American men and women. An OGTT with insulin measurements was conducted after a 12-hour overnight fast. The euglycemic hyperinsulinemic clamp was used to measure insulin-stimulated glucose uptake (M) directly. Pearson's correlation analyses were performed to examine the relationship of OGTT-derived parameters with insulin sensitivity measured using the clamp. There were consistent statistically significant correlations between calculated estimates of insulin sensitivity (fasting insulin/fasting glucose, summed insulin/summed glucose, homeostasis model assessment [HOMA], Quantitative Insulin Sensitivity Check Index [QUICKI]) with insulin sensitivity measured by the insulin clamp (P <.001). The calculated estimates that correlated most strongly with clamp measured insulin sensitivity were QUICKI and the logarithm of summed insulin during the OGTT. These data indicate that fasting and OGTT-derived plasma insulin and glucose concentrations can be used to estimate insulin sensitivity in young adult African-Americans when it is not feasible to conduct the insulin clamp procedure. Calculated indices that include log transformation of plasma insulin concentration improve the estimation of insulin sensitivity.     

On the interplay beween insulin secretion and sensitivity as determinants of glucose tolerance

Both insulin secretion and sensitivity have been claimed to be the main characteristics in the determination of future detoriation in glucose tolerance. In this cross-sectional study insulin secretion and insulin sensiturity were determined in 228 subjects with varying degrees of glucose tolerance. Insulin secretion was measured in an intravenous glucose tolerance test (IVGTT) and insulin sensitivity by the hyperinsulinaemic euglycaemic clamp test. Both the early insulin response in the IVGTT (increment) and the glucose disposal rate in the clamp test (M-value) were found to be related hyperbolically to fasting glucose (r=–0.63 and –0.66, respectively; bothP<0.0001) and in a second-order polynomial manner to the glucose disappearence rate (k-value) in the IVGTT (r=0.53 and 0.48, respectively; bothP<0.0001). Multiple regression analysis showed the insulin increment in the IVGTT and theM-value in the clamp test to be equally important determinants of glucose tolerance, together explaining about 50% of the variation in fasting glucose and thek-value in the IVGTT. In conclusion, in this cross-sectional study insulin secretion and sensitivity studied over a broad range of glucose tolerance were found to be of amost equal importance in the determination of glucose tolerance. However, low levels of insulin increment in the IVGTT were more often associated with glucose intolerance than was a low insulin sensitivity.     

Insulin sensitivity assessment in uncomplicated obese women: comparison of indices from fasting and oral glucose load with euglycemic hyperinsulinemic clamp

BACKGROUND AND AIM: Obesity is associated with a great variability to insulin sensitivity degree. Several formulae developed from measurements in the fasting state and during the oral glucose tolerance test (OGTT) have been proposed to assess insulin sensitivity. AIM: In this work we sought to compare the published insulin sensitivity indices with the metabolized glucose index obtained by hyperinsulinemic euglycemic clamp in uncomplicated obese subjects. Uncomplicated obesity provides a good model in order to study insulin sensitivity per se. METHODS AND RESULTS: In this protocol, 65 obese women affected by uncomplicated obesity (without impaired glucose tolerance, diabetes, hypertension and dyslipidemia) underwent 2 h OGTT and euglycemic hyperinsulinemic clamp. Common formulae obtained in the fasting state and from a 2h OGTT were calculated. Simple linear regression analysis showed that ISI (r=0.592, p=0.01), 2 h OGIS (r=0.576, p=0.02), MCRest (r=0.507, p=0.02), 120 insulin (r=-0.494, p=0.03) and fasting insulin (r=-0.382, p =0.02) are significantly correlated to the M index obtained from the hyperinsulinemic euglycemic clamp. The Bland-Altman plot confirmed the good agreement between indices from OGTT and the clamp. CONCLUSION: OGTT-derived indices provide a good assessment of insulin sensitivity in obesity. OGTT could easily be applied in a large number of obese patients in order to obtain information on both glucose tolerance and insulin sensitivity.     

Pharmacologic Therapies for Acromegaly

Acromegaly is associated with insulin resistance and an increased incidence of cardiovascular disease. However, it remains unclear to what extent the effects of growth hormone (GH) excess on cardiovascular morbidity and mortality are mediated through insulin resistance versus through other direct or indirect effects of GH. Adequate control of GH excess by surgery or pharmacologic interventions is associated with decreased insulin resistance, reflected in decreased plasma insulin levels and fasting glucose levels or improved glucose tolerance. Despite divergent effects of both somatostatin and somatostatin analogs on GH, insulin and glucagon secretion, and glucose absorption, treatment with the somatostatin analogs octreotide and lanreotide has only limited effects on glucose metabolism. However, glucose sensitivity has only been formally examined using a hyperinsulinemic euglycemic clamp in a minority of these studies. Treatment with the GH-receptor antagonist pegvisomant ameliorates insulin sensitivity, reflected in decreased fasting plasma insulin levels and fasting glucose levels. Nonetheless, the effect of pegvisomant on glucose sensitivity has not been formally tested by hyperinsulinemic clamp conditions. In acromegaly, preliminary observations on new octreotide analogs with greater specificity for somatostatin-receptor subtypes indicate that these compounds achieve better control of GH hypersecretion than octreotide, but may also negatively influence insulin release. Assessment of insulin secretion and glucose levels in acromegalic patients during administration of these compounds is thus mandatory.     

Exenatide 对高脂诱导胰岛素抵抗大鼠胰岛素敏感性及糖脂代谢的影响

目的 探讨Exenatide对高脂诱导胰岛素抵抗大鼠胰岛β细胞功能、胰岛素敏感性及糖脂代谢的影响. 方法 高脂诱导胰岛素抵抗大鼠给予Exenatide 6周后,采用静脉葡萄糖耐量(IVGTT)和胰岛素耐量(ITT)试验以及扩展胰岛素钳夹技术测定胰岛素敏感性和糖脂代谢,并观察血浆脂联素水平的变化.结果 高脂大鼠(HF)经Exenatide处理后,Lee′s指数、空腹血浆游离脂肪酸(FFA)、甘油三酯、胆固醇明显降低(均P＜0.01);IVGTT和ITT明显改善,胰岛素分泌水平增高,高剂量组(HFH)较低剂量组(HFL)上述指标改善更为明显.同时,HFH组血浆脂联素水平也明显升高(P＜0.01).在钳夹稳态时,HF组与对照组(NC)相比,血浆FFA、胰岛素水平均明显升高(均P＜0.01),葡萄糖输注率(GIR)、葡萄糖清除率(GRd)明显降低(均P＜0.01),且胰岛素对肝糖输出(HGP)的抑制作用明显障碍(仅抑制26%).经Exenatide(2 μg/kg)处理以后,血浆FFA、胰岛素水平则明显降低(均P＜0.01),GRd、GIR明显升高(均P＜0.01),胰岛素对HGP的抑制作用明显增强(抑制72%).结论 对高脂喂养大鼠用Exenatide预处理可能通过促进β细胞胰岛素分泌和上调血浆脂联素水平,改善糖脂代谢而使机体胰岛素敏感性增加.     

Fasting hyperglycemia impairs glucose- but not insulin-mediated suppression of glucagon secretion

AIM: Our aim was to assess the effect of chronic hyperglycemia on glucose- and insulin-mediated suppression of glucagon secretion by the alpha-cell. METHODS: Thirty subjects with normal glucose tolerance, 27 with impaired fasting glucose and/or impaired glucose tolerance, and 32 type 2 diabetic subjects were studied with oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp. Fasting plasma glucagon concentration and plasma glucagon concentration during the OGTT and insulin clamp were measured. RESULTS: During the OGTT, the decrement in the plasma glucagon concentration (area under the curve) was correlated inversely with the fasting plasma glucose concentration (r = -0.35; P < 0.001). As the fasting glucose level increased, the suppression of plasma glucagon progressively diminished. In contrast, during the euglycemic insulin clamp, the suppression of plasma glucagon was not correlated with the fasting plasma glucose concentration and was similar in subjects with normal glucose tolerance, subjects with impaired fasting glucose/impaired glucose tolerance, and diabetic subjects: 18, 23, and 18%, respectively. CONCLUSION: Insulin-mediated suppression of glucagon secretion is unrelated to the fasting plasma glucose concentration and is not impaired by chronic hyperglycemia. Thus, the defect in plasma glucagon suppression during the OGTT most likely results from impaired glucose-mediated glucagon suppression. The close correlation between fasting plasma glucose concentration and reduced glucagon suppression suggests a glucotoxic effect on alpha-cell function.     

Isosteviol reduces plasma glucose levels in the intravenous glucose tolerance test in Zucker diabetic fatty rats

Aim:  The aim of this study was to test the effect of isosteviol on blood glucose and insulin levels during the intravenous glucose tolerance test (IVGTT) in Wistar and Zucker diabetic fatty (ZDF) rats.
Methods:  ZDF rats were divided into a control and three isosteviol treatment (1, 5 and 10 mg/kg) groups. Wistar rats were divided into a control group and an isosteviol treatment group (10 mg/kg). The rats were fasted for 12 h prior to infusion of isosteviol and glucose (1.0 g/kg). Blood samples were taken at 0, 5, 15, 30, 60, 90 and 120 min after the injection of glucose. Glucose concentrations were determined by the glucose oxidase method, and plasma insulin was analysed by radioimmunoassay. The area under the curve (AUC) of the net change in plasma glucose concentration was used to compare the isosteviol treatment and control groups.
Results:  In ZDF rats, isosteviol at 5 and 10 mg/kg caused a significant (p < 0.05) reduction in the AUC of glucose during the IVGTT. However, isosteviol did not increase plasma insulin concentrations in ZDF rats. In Wistar rats, isosteviol did not significantly affect plasma glucose or insulin levels during the IVGTT.
Conclusion:  Isosteviol exerts an antihyperglycaemic effect during IVGTT in ZDF rats but not in Wistar rats. Isosteviol has no significant effect on plasma insulin concentrations. The glucose-lowering effect of isosteviol may be due to changes in the sensitivity of peripheral tissues to insulin.     

New insulin sensitivity index from the oral glucose tolerance test

A new insulin sensitivity index was devised on the basis of an autoregressive model and its validity was investigated. Using data from the 75-g oral glucose tolerance test (OGTT), 115 subjects were divided into 3 groups: 40 with normal glucose tolerance, 34 with impaired glucose tolerance, and 41 with type 2 diabetes mellitus. The new insulin sensitivity index: oral glucose insulin sensitivity index (GSI) was calculated from five sets of plasma glucose and insulin levels obtained at 0, 30, 60, 90 and 120 min during OGTT using a formula based on an autoregressive model. Forty-three of the 115 subjects were examined for insulin sensitivity index (ISI) by euglycemic hyperinsulinemic clamp. GSI decreased in the order of normal glucose tolerance group>impaired glucose tolerance group>diabetic group. There was a significant correlation between GSI and the ISI derived from euglycemic hyperinsulinemic clamp study data in all 43 subjects who underwent both tests (r=0.72; P<0.0001). The ISI calculated by previous methods poorly correlated with the ISIs obtained by euglycemic hyperinsulinemic clamp study. In conclusion, this new insulin sensitivity index based on the data obtained from OGTT using an autoregressive model is comparable to an insulin sensitivity index by euglycemic hyperinsulinemic clamp technique and may be superior to previous indexes that have been devised to determine insulin sensitivity from OGTT data.     

Peripheral insulin release after pancreatic resection: the effect of decreased beta-cell mass with systemic or portal drainage

Surgical alteration of the pancreas can result in several anatomic alterations which may affect insulin release. We evaluated the effects of resection, systemic drainage, and autotransplantation of the canine pancreas on peripheral insulin levels and glucose disposal as measured by iv glucose tolerance tests (IVGTT) and a steady state hyperglycemic challenge (clamp). Proximal pancreatectomy (PPx) with reduced beta-cell mass and intact portal drainage resulted in a modestly elevated fasting glucose level and increased integrated glucose response to IVGTT. Compared to preoperative normals, basal insulin was unchanged from preoperative controls; however, peak insulin and integrated insulin response to IVGTT were decreased in PPx animals. Splenocaval drainage or autotransplantation of the distal pancreas resulted in normalization of the severely altered insulin response and fasting glucose levels. K values were significantly reduced after all three procedures. Clamp studies confirmed the basal glucose and insulin findings of the IVGTT. During the clamp, PPx animals had peripheral insulin values approximately 50% of normal controls, while autotransplantation and splenocaval drainage animals had insulin values that approximate normal controls. All three postsurgical groups had blunted insulin levels during stable hyperglycemia. Glucose utilization rates were severely decreased in all three groups. Reduction of beta-cell mass with intact portal drainage resulted in reduced insulin response to glucose challenge by either IVGTT or clamp. Systemic drainage of this same reduced beta-cell mass resulted in peripheral insulin levels comparable to normal controls. Denervation (autotransplantation) had little additive effect. All three groups demonstrated severely decreased rates of glucose disappearance as measured by both IVGTT and clamp studies. Therefore, reduction in beta-cell mass, drained systemically or portally, results in altered glucose disposal regardless of the peripheral insulin levels.     

Plasma neuropeptide Y in impaired glucose tolerance

Neuropeptide Y (NPY) has been shown to be associated with insulin resistance, since central administration of the peptide induces muscular insulin resistance. NPY also occurs in pancreatic nerves and inhibits insulin secretion. In this study, we examined the plasma NPY levels in 10 women, aged 57–59 years, with impaired glucose tolerance (IGT), which is often accompanied by a combination of reduced insulin sensitivity and impaired insulin secretion. They were 145±4.1 pmol/l compared with 143±4.3 pmol/l in 10 age-matched women with normal glucose tolerance (NGT) (NS). Furthermore, the plasma NPY did not correlate with fasting glucose or insulin levels, the 2-h glucose value after a 75 g oral glucose challenge or insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp technique. This suggests that plasma NPY is not altered in IGT.     

A simple method for quantitation of insulin sensitivity and insulin release from an intravenous glucose tolerance test.

Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pioglitazone on beta-cell function in metabolic syndrome patients with impaired glucose tolerance

OBJECTIVE: To determine the potential effects of pioglitazone on beta-cell function in metabolic syndrome patients with impaired glucose tolerance and probe into the possible mechanisms. RESEARCH DESIGN AND METHODS: Twenty-two subjects were treated with pioglitazone 30 mg/day for 4 months. At baseline and after treatment, each subject underwent an IVGTT. The acute insulin response (AIRg), the glucose disappearance rates (coefficients K) and the ratio of Deltainsulin/Deltaglucose (DeltaI/DeltaG) were calculated according to IVGTT results. Hyperglycemic clamp study was conducted to determine the second-phase insulin response, insulin sensitivity index (ISI) and glucose infusion rate (GIR). Euglycemic-hyperinsulinemic clamp study was made to measure the glucose disposal rate (GDR). Plasma glucose, free fatty acids (FFAs), serum insulin and proinsulin levels were measured. RESULTS: AIRg unchanged (P = 0.25) after treatment, whereas the values of coefficients K (P < 0.01) and DeltaI/DeltaG increased (P < 0.05). The second-phase insulin response and GIR were both demonstrated marked increments (P < 0.01 and P < 0.01, respectively). Pioglitazone therapy also resulted in improvement of ISI value (P < 0.05). And the increment of GDR during the euglycemic-hyperinsulinemic clamp was also significant (P < 0.01). Furthermore, a decrease in fasting proinsulin level was observed (P < 0.001). And plasma glucose, FFAs and serum insulin levels all declined. The increase of DeltaI1/DeltaG1 was positively correlated with the improvement of GDR (r = 0.536, P = 0.089). And a positive relationship was observed between the change in the second-phase insulin response and change in K value (r = 0.682, P = 0.021). CONCLUSIONS: Short-term pioglitazone therapy improved beta-cell dysfunction, the mechanism might involve the attenuation of insulin resistance.     

The effect of raloxifene on glyco-insulinemic homeostasis in healthy postmenopausal women: a randomized placebo-controlled study

The effect of raloxifene, a selective estrogen receptor modulator recently approved as a therapeutic agent for menopause, on glyco-insulinemic metabolism was investigated in 40 healthy postmenopausal women. At the baseline and after 12 wk of raloxifene (60 mg/d) or placebo administration, all aspects of glucose metabolism were evaluated in each subject using both an oral glucose tolerance test (OGTT; 75 g) and a hyperinsulinemic euglycemic clamp to assess peripheral insulin sensitivity. Glucose, insulin, and C-peptide, measured in fasting conditions, as well as glucose and insulin responses to OGTT [expressed as area under curve (AUC)] were not modified by raloxifene, whereas C-peptide-AUC increased significantly (P < 0.05). Furthermore, a trend toward an improvement of peripheral insulin sensitivity and hepatic clearance of the hormone (fractional hepatic insulin extraction) was observed in the raloxifene-treated women with respect to the control patients. When the subjects were studied in relation to their insulin secretion in response to the glucose load, the patients, classified as hyperinsulinemic, showed the most significant response to the raloxifene treatment. In these women, the selective estrogen receptor modulator was able to induce a significant reduction of insulin circulating plasma values (P < 0.01) through both an increase of fractional hepatic insulin extraction (P < 0.01) and an improvement of the peripheral insulin sensitivity (P < 0.05). On the contrary, no net change of insulin dynamics was observed in normoinsulinemic and placebo-treated women. The present data indicate that raloxifene does not negatively influence glyco-insulinemic metabolism in unselected postmenopausal women and may indeed improve the excessive insulin responsiveness to OGTT in a selected population of hyperinsulinemic postmenopausal women.     

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.     

Effects of Heparin-induced Non-esterified Free Fatty Acid on Minimal Model-derived Insulin Sensitivity in Individuals with Varying Degrees of Glucose Intolerance

The effects of heparin-induced non-esterified free fatty acid (NEFA) release on insulin sensitivity index were studied in individuals with varying degrees of glucose intolerance and beta cell dysfunction during the frequently sampled intravenous glucose tolerance test (IVGTT). The groups comprised: Group 1 (n = 5): newly diagnosed Type 2 diabetic patients, Group 2 (n = 11): impaired glucose tolerance patients (IGT), and Group 3 (n = 16): healthy normal glucose tolerance subjects. The serum insulin and c-peptide levels were severely blunted in the diabetic patients when compared to both non-diabetic groups. Mean fasting and post-heparin plasma NEFA levels were approximately 1.8 fold greater (p < 0.05) in the diabetic patients when compared to the other two groups. The mean insulin sensitivity index was lowest in the diabetic patients, intermediate in the IGT patients, and highest in the healthy controls. A significant negative relationship was found between the insulin sensitivity index and stimulated NEFA (r = ?0.537, p < 0.008) but not with the fasting NEFA levels in our subjects. In summary, the frequently sampled IVGTT protocol that employs heparin flushes results in marked elevations in NEFA in Type 2 diabetic patients with poor beta cell dysfunction but not in subjects with intermediate or normal glucose tolerance. The higher plasma NEFA levels during heparin injections could worsen the model-derived, insulin sensitivity index and could impair the ability to achieve an acceptable modelling in Type 2 diabetic patients. We therefore suggest heparin should be avoided in such patients when using this protocol.     

Gender-related differences in the metabolic response to fasting

CONTEXT: Free fatty acids (FFA) may induce insulin resistance via synthesis of intramyocellular ceramide. During fasting, women have lower plasma glucose levels than men despite higher plasma FFA, suggesting protection from FFA-induced insulin resistance. OBJECTIVE: We studied whether the relative protection from FFA-induced insulin resistance during fasting in women is associated with lower muscle ceramide concentrations compared with men. MAIN OUTCOME MEASURES AND DESIGN: After a 38-h fast, measurements of glucose and lipid fluxes and muscle ceramide and fatty acid translocase/CD36 were performed before and after a hyperinsulinemic euglycemic clamp. RESULTS: Plasma glucose levels were significantly lower in women than men with a trend for a lower endogenous glucose production in women, whereas FFA and lipolysis were significantly higher. Insulin-mediated peripheral glucose uptake was not different between sexes. There was no gender difference in muscle ceramide in the basal state, and ceramide did not correlate with peripheral glucose uptake. Muscle fatty acid translocase/CD36 was not different between sexes in the basal state and during the clamp. CONCLUSION: After 38 h of fasting, plasma FFA were higher and plasma glucose was lower in women compared with men. The higher plasma FFA did not result in differences in peripheral insulin sensitivity, possibly because of similar muscle ceramide and fatty acid translocase/CD36 levels in men and women. We suggest that during fasting, women are relatively protected from FFA-induced insulin resistance by preventing myocellular accumulation of ceramide.     

Association of elevated insulin-like growth factor binding protein-1 with insulin resistance in hyperthyroidism

OBJECTIVE: Insulin-like growth factor binding-protein-1 (IGFBP-1) has a role in glucose homeostasis and is present at high concentrations in hyperthyroidism. We have investigated the relationship between IGFBP-1 concentration and glucose homeostasis in hyperthyroidism. DESIGN: Patients and controls had intravenous glucose tolerance tests (IVGTT) and/or oral glucose tolerance tests (OGTT). Patients were tested when hyperthyroid and when euthyroid whilst the controls were tested once. The IVGTT was used to assess insulin sensitivity and the OGTT to establish that the study group had abnormal glucose tolerance. The hyperthyroid patients were treated with methimazole to restore euthyroidism. PATIENTS: Ten patients (9 females) and 13 healthy controls (9 females) consented to the study. Ten patients and nine controls (7 females) had IVGTT. Six patients (5 females) and six controls (4 females) had OGTT. MEASUREMENTS: Glucose, insulin, glucagon, GH and IGFBP-1 were measured during GTT. IGF-I, free thyroid hormones, and TSH concentrations were measured basally. RESULTS: Hyperthyroid subjects were insulin resistant and 67% had impaired glucose tolerance. Fasting IGFBP-1 levels were doubled in hyperthyroid subjects compared to healthy controls and correlated positively with free T4 (r = 0.84, P < 0.0001), with peak glucose during the OGTT (r = 0.68, P < 0.005) with peak insulin during the IVGTT (r = 0.51, P < 0.005) and negatively with glucose disappearance constant (r = - 0.52, P < 0.005). IGFBP-1 was highly phosphorylated in hyperthyroid and control subjects. Fasting insulin and IGFBP-1 levels were unrelated but IGFBP-1 suppressed acutely during GTT in all groups. GH levels fell less in patients with hyperthyroidism than in normals during GTTs. CONCLUSIONS: We conclude that in hyperthyroidism thyroid hormones directly increase fasting IGFBP-1 concentration but acute regulation of IGFBP-1 by insulin is normal and that elevated fasting phosphorylated IGFBP-1 concentration is associated with insulin resistance.     

Rosiglitazone improves muscle insulin sensitivity,irrespective of increased triglyceride content,in ob/ob mice

The present study was performed to examine the effects of rosiglitazone treatment on tissue-specific insulin sensitivity. Therefore, we used obese, insulin-resistant ob/ob mice and measured the effects of rosiglitazone treatment on insulin sensitivity and simultaneously tissue-specific uptake of glucose and free fatty acids (FFA) under hyperinsulinemic euglycemic clamp conditions. Rosiglitazone treatment resulted in significantly higher body weight and decreased plasma levels of glucose, insulin, and triglyceride (TG). Glucose tolerance, as well as insulin sensitivity, was improved upon rosiglitazone treatment, as assessed by glucose tolerance and insulin sensitivity tests. Hyperinsulinemic euglycemic clamps showed increased glucose infusion rates with increased whole body insulin sensitivity. Rosiglitazone treatment resulted in increased glucose uptake by cardiac and skeletal muscle under hyperinsulinemic euglycemic clamp conditions, while no differences were observed in FA uptake. Measurement of TG content showed that rosiglitazone treatment resulted in decreased TG content of cardiac muscle, but increased TG content of skeletal muscle. We conclude that rosiglitazone treatment leads to strong improvement of insulin sensitivity, irrespective of increased muscle TG content, in ob/ob mice.