Habitual dietary intake versus glucose tolerance, insulin sensitivity and insulin secretion in postmenopausal women.

OBJECTIVE: The major aim was to study the relation between habitual dietary intake and glucose tolerance, insulin sensitivity and insulin secretion in postmenopausal women. Dietary intake was also compared between women with normal (NGT) or impaired glucose tolerance (IGT). DESIGN: Habitual dietary intake was studied using a modified diet history method, from which the energy, carbohydrate, fat and protein intake was calculated. Glucose tolerance was determined as the 2 h glucose value after a 75 g oral glucose tolerance test. Insulin sensitivity was studied with a euglycemic, hyperinsulinaemic clamp, whilst insulin secretion was measured as the acute (2-5 min) response to iv arginine (5 g) at fasting, 14 and >25 mmol L(-1) glucose. SETTING: Clinical research unit at the University Hospital in Malmo, Sweden. Subjects. A total of 74 women (mean+/-SD age 58.7+/-0.4 years). RESULTS: In the entire group, the 2 h glucose level correlated with polyunsaturated fat intake (PUFA, r = 0.41, P < 0.001), and negatively with carbohydrate intake (r = -0.23, P = 0.05). The relation between 2 h glucose and PUFA was independent of body fat content and insulin sensitivity in a multivariate model. Insulin sensitivity correlated with energy intake (r = 0.31, P = 0.007) and PUFA (r = -0.27. P = 0.022). However, these correlations were not significant after adjustment for body fat content in a multivariate model. There were no correlations between insulin secretory variables and habitual dietary intake. Of the 74 women, 60 had NGT and 14 had IGT. The NGT and IGT groups did not differ in intakes of total energy, carbohydrate or protein. The IGT women had higher intake of PUFA (P = 0.003), whilst the total, saturated and monounsaturated fat intake did not differ between the groups. CONCLUSION: Dietary parameters are not independently associated with insulin sensitivity or insulin secretion in postmenopausal women. Furthermore, dietary habits are largely similar in women with NGT and IGT, although subtle differences cannot be excluded due to the small study size. Therefore, habitual intake of total carbohydrate or total fat seems not to be the major determinant of glucose tolerance in nondiabetic Caucasian postmenopausal women.     

Insulin sensitivity, insulin secretion, and glucose tolerance versus intima-media thickness in nondiabetic postmenopausal women

To study the association between insulin sensitivity and secretion vs. early manifestations of atherosclerosis, we performed a 5-yr prospective study in 84 nondiabetic, postmenopausal women, aged 58.7 +/- 0.4 yr (mean +/- SD). Insulin sensitivity was measured with the euglycemic, hyperinsulinemic clamp, and insulin secretion was measured as the acute response to iv arginine (5 g). Early atherosclerosis was studied by ultrasonography of the right carotid artery. Mean intima-media thickness (IMT), determined 1 cm proximal to the bifurcation, was 0.81 +/- 0.14 mm at baseline and increased by 0.012 +/- 0.014 mm/yr over the 5 yr (P < 0.001). The maximal IMT, determined in the carotid bifurcation, was 1.42 +/- 0.42 mm at baseline and increased by 0.035 +/- 0.049 mm/yr (P < 0.001). Neither basal IMT nor the increase in mean or maximal IMT correlated to insulin sensitivity or secretion. In contrast, both baseline IMT and the progression in IMT over the 5-yr follow-up (both mean common carotid artery IMT and maximal bifurcation IMT) correlated with systolic blood pressure and low-density lipoprotein cholesterol. We conclude that carotid intima-media thickness is not related to insulin sensitivity or secretion in nondiabetic, postmenopausal women. Instead, the strongest association is seen with systolic blood pressure and low-density lipoprotein cholesterol levels.     

Raloxifene does not modify insulin sensitivity and glucose metabolism in postmenopausal women

Insulin sensitivity (Si), glucose tolerance, and lipid metabolism were investigated in osteopenic postmenopausal women before and after 6 months of treatment with raloxifene (60 mg/d) or placebo. In a group of women (n = 34), glucose metabolism was evaluated by means of an oral glucose tolerance test (75 g). In another group of women (n = 24), Si and peripheral glucose utilization not dependent on insulin were evaluated by means of a frequently sampled iv glucose tolerance test associated with the minimal model method. No metabolic modification was observed in women receiving placebo. Raloxifene did not significantly modify high density lipoprotein-cholesterol and triglycerides, whereas it significantly decreased low density lipoprotein (LDL) cholesterol (4.84 +/- 0.34 mmol/liter vs. 3.83 +/- 0.49 mmol/liter; P = 0.014) and LDL/high density lipoprotein cholesterol ratio (3.21 +/- 0.31 mmol/liter vs. 2.46 +/- 0.44 mmol/liter; P = 0.012). Fasting levels and responses to the oral glucose tolerance test of glucose, insulin, C-peptide, and C-peptide/insulin were not modified by raloxifene. Similarly, raloxifene did not modify Si (4.22 +/- 4.1 vs. 5.13 +/- 1.75), or insulin (0.025 +/- 0.003 vs. 0.019 +/- 0.002). The present data show that in osteopenic postmenopausal women raloxifene reduces LDL levels but does not modify insulin sensitivity and glucose metabolism.     

Measuring insulin sensitivity in postmenopausal women covering a range of glucose tolerance: comparison of indices derived from the oral glucose tolerance test with the euglycemic-hyperinsulinemic clamp

This study compares indices of insulin sensitivity derived from fasting and oral glucose tolerance test (OGTT) glucose and insulin measurements, with respect to the reference measure (M/I), obtained from the euglycemic-hyperinsulinemic clamp, in postmenopausal women with varying glucose tolerance status. Fasting plasma insulin index, homeostasis model assessment index, and OGTT-derived indices (insulin 120-minute, Matsuda, metabolic clearance rate [MCR] of glucose, insulin sensitivity [ISI], and Cederholm indices) were calculated and compared with the M/I value in 112 postmenopausal women. All indices examined were significantly correlated with M/I (0.28 < or = r(2) < or = 0.56). Association studies revealed that on average, 48% of women were grouped in the same tertile of insulin sensitivity when using M/I and fasting plasma insulin index, and 54% when using M/I and insulin 120-minute index. However, concordance with M/I tertiles were 57%, 58%, 64%, 64%, and 68% for homeostasis model assessment, Matsuda, MCR, ISI, and Cederholm indices, respectively. Finally, correlation coefficients between M/I and insulin sensitivity indices were generally lower in women with normal glucose tolerance compared with women with impaired glucose tolerance or type 2 diabetes mellitus. These results suggest that in postmenopausal women, surrogate indices of insulin sensitivity obtained from OGTT data and incorporating a measurement of body weight or body mass index) (Cederholm, ISI, and MCR indices) appear to be superior to those without OGTT data or body weight-body mass index measurements and, therefore, could offer a better estimate of insulin sensitivity, allowing an improved clinical evaluation of this population at higher risk of cardiovascular disease and type 2 diabetes mellitus.     

Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance

OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.     

Glucose tolerance, insulin secretion, insulin sensitivity and glucose effectiveness in normal and overweight hyperthyroid women

OBJECTIVE Inter-relationships between insulin sensi-tivity and body weight in patients with hyperthyroidism remain incompletely understood. We have examined whether a mild excess of body weight exacerbates the metabolic abnormalities of spontaneous hyperthyroidism. DESIGN AND PATIENTS Insulin-modified intravenous glucose tolerance tests were performed on 14 hyperthy-roid women with body mass indices (BMI) ranging from 21 to 31 kg/m². A control group of 19 healthy women matched for age and BMI was also studied. MEASUREMENTS Intravenous glucose tolerance (KG), first and second-phase integrated insulin responses to glucose, the integrated glucose area under the curve (AUC), and minimal model parameters of insulin sensitivity (SI) and glucose effectiveness (SG) were determined. RESULTS Hyperthyroid women had mean KG, glucose-induced insulin secretion and SG values similar to those in control women. The mean glucose AUC was higher in hyperthyroid patients (P<0.05). Lower insulin sensitivity was observed in hyperthyroid patients than in control women (SI=0.38±0.07 vs 0.59±0.07 l/min pmol 10⁴ (mean±SEM), P<0.05). A steeper decline in insulin sensitivity with increase in body mass index was found in hyperthyroid women when compared with the control group, after adjusting for age. When groups were compared according to their BMI, hyperthyroid women with normal weight (BMI≤25 kg/m², n=8) had mean KG, insulin response to glucose, glucose AUC, SG and SI values similar to those in normal weight control women (n=11). Overweight hyperthyroid patients (BMI>25 kg/m², n=6) had a higher (P<0.05) second-phase insulin response to glucose than normal weight patients, a higher glucose AUC (P<0.05) than normal weight patients and overweight controls (n=8), and a lower SI (P<0.05) than normal weight patients and overweight controls. SG was not influenced by BMI in hyperthyroid patients. CONCLUSIONS These results suggest that overall glucose tolerance was not significantly affected in normal weight hyperthyroid women. However, when a moderate excess of weight is also present, a state of clear insulin resistance occurs.     

Oral glucose tolerance test and insulin sensitivity in low insulin responders

Oral and iv glucose tolerance, insulin response to iv and oral glucose load as well as insulin sensitivity were evaluated in 58 'low insulin responders'. They were selected from a group of 226 healthy subjects with normal fasting blood glucose and normal iv glucose tolerance test on the basis of a low insulin response during a standardized glucose infusion test (GIT). The insulin response to GIT was analysed by parameter identification in a mathematical model (parameter KI). Insulin sensitivity was also measured by computer analysis of GIT (parameter KG) and, in a limited group of subjects, by a somatostatin infusion test. Thirty-three low insulin responders had normal OGTT, whereas 5 demonstrated borderline-1, 16 borderline-2, and 4 decreased OGTT. The first group of subjects demonstrated normal or enhanced insulin sensitivity. Borderline and decreased OGTT, in most instances, was accompanied by decreased insulin sensitivity, implying that a subgroup of low insulin responders exhibited signs of both impaired insulin response to glucose and insulin resistance. Since these defects characterize manifest type-2 diabetes, these subjects possibly may run a high risk to develop this type of diabetes. On the other hand, low insulin response in combination with increased insulin sensitivity may reflect adaptation of the secretory capacity of B-cells to the need of insulin.     

Failure to adequately adapt reduced insulin sensitivity with increased insulin secretion in women with impaired glucose tolerance

Summary To study the islet adaptation to reduced insulin sensitivity in normal and glucose intolerant post-menopausal women, we performed a euglycaemic, hyperinsulinaemic clamp in 108 randomly selected women, aged 58–59 years. Of the 20 women with the lowest insulin sensitivity, 11 had impaired glucose tolerance (IGT) whereas 9 had normal glucose tolerance (NGT). These women together with 15 women with medium insulin sensitivity and 16 women with high insulin sensitivity and NGT were further examined with arginine stimulation at three glucose levels (fasting, 14 and >25 mmol/l). In NGT, the acute insulin response (AIR) to 5 g i. v. arginine at all three glucose levels and the slope_AIR, i. e. the glucose potentiation of insulin secretion, were markedly increased in the women with the lowest insulin sensitivity and NGT compared to those with medium or high insulin sensitivity. In contrast, in low insulin sensitivity, AIR was significantly lower in IGT than in NGT (at glucose 14 mmol/l p=0.015, and at >25 mmol/l p=0.048). The potentiation of AIR induced by low insulin sensitivity in women with NGT was reduced by 74% (AIR at 14 mmol/l glucose) and 57% (AIR at >25 mmol/l glucose), respectively, in women with IGT. Also the slope_AIR was lower in IGT than in NGT (p=0.025); the increase in slope_AIR due to low insulin sensitivity was abolished in IGT. In contrast, glucagon secretion was not different between women with IGT as opposed to NGT. We conclude that as long as there is an adequate beta-cell adaptation to low insulin sensitivity with increased insulin secretory capacity and glucose potentiation of insulin secretion, NGT persists.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AIR acute insulin response - AGR acute glucagon response     

Endogenous sex hormones and glucose tolerance status in postmenopausal women

CONTEXT: In postmenopausal women, endogenous estradiol (E2) and free testosterone (T) have been positively associated with glucose intolerance and type 2 diabetes. Most studies have not examined these associations in a large group of postmenopausal women. OBJECTIVE: The objective was to examine the association between endogenous sex hormones and glucose tolerance in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 1973 postmenopausal women ages 45-84 yr, not taking hormone replacement therapy, in the Multi-Ethnic Study of Atherosclerosis baseline examination. MAIN OUTCOME MEASURES: Impaired fasting glucose (IFG) and diabetes were defined based on fasting blood sugar and/or treatment for diabetes. In women with normal glucose tolerance, insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Increasing quartiles of bioavailable T and E2 and decreasing quartiles of SHBG were associated with significantly increased odds of IFG and diabetes (all P for trend<0.001). Except for the association of bioavailable T with diabetes, the other associations persisted after multivariable adjustment. Although higher dehydroepiandrostenedione (DHEA) was associated with greater odds of IFG (P for trend=0.02), it was not associated with diabetes. Of 1100 women with normal glucose tolerance, E2 and DHEA were positively associated, and SHBG was inversely associated with HOMA-IR (all P<0.001) after multivariable adjustment. Bioavailable T was associated with HOMA-IR (P<0.001), but not fasting glucose. CONCLUSION: Of postmenopausal women, endogenous bioavailable T, E2, and DHEA were positively associated and SHBG was negatively associated with insulin resistance.     

Differential effects of raloxifene and estrogen on insulin sensitivity in postmenopausal women

OBJECTIVES: To test the hypothesis that both raloxifene and estrogen would improve insulin sensitivity in postmenopausal women and that the magnitude of the effect would be similar for both drugs. DESIGN: Placebo-controlled, double-blind, randomized study. SETTING: The General Clinical Research Center of the University of Michigan Medical Center, a university hospital. PARTICIPANTS: Forty-four healthy postmenopausal women 73 +/- 7 years old (mean age +/- standard deviation) who were not receiving hormone replacement therapy. INTERVENTION: Eight weeks of drug therapy with randomization to raloxifene (n = 16), estrogen (n = 14), or placebo (n = 14). MEASUREMENTS: These subjects underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity (SI) and total and regional (central) body composition measurements by dual-energy x-ray absorptiometry at baseline and after 8 weeks of drug therapy. RESULTS: There were no statistically significant differences in age, body mass index, total or central fat mass, or SI between the three groups at baseline. The major outcome variable was SI. After 8 weeks of drug therapy, there was no significant change in SI in the placebo group or in the estrogen group and a significant decrease in SI in the raloxifene group, P =.003. CONCLUSION: In contrast to estrogen's ability to maintain insulin sensitivity, raloxifene decreases insulin sensitivity in healthy nondiabetic postmenopausal women. The clinical significance of this effect of raloxifene to impair insulin sensitivity in postmenopausal women warrants further evaluation in future studies.     

Effect of oral phytoestrogen on androgenicity and insulin sensitivity in postmenopausal women

Aim: The aim of this study was to determine and compare the effect of treatment with transdermal oestrogen and phytoestrogen on insulin sensitivity and sex hormone-binding globulin (SHBG) levels in healthy postmenopausal women. Methods: Forty-three healthy postmenopausal women aged 68 ± 7 (mean ± SD) years who were not receiving hormonal replacement therapy completed a 3 month randomized drug therapy study. The participants were randomized to one of four groups: 0.05 mg or 0.1 mg transdermal oestrogen/day, or 40 or 80 mg oral phytoestrogen (Promensil)/day insulin sensitivity was indirectly measured using the quantitative insulin sensitivity check index (QUICKI). SHBG, total testosterone, oestradiol, and fasting glucose and insulin levels for calculation of insulin sensitivity were obtained at baseline and at monthly intervals during the 3 months of therapy. Results: In healthy nondiabetic postmenopausal women, the rate of change in QUICKI was significantly different between the red clover based phytoestrogen and transdermal oestrogen groups, so that after three months of therapy, QUICKI with red clover based phytoestrogen therapy was lower than that in the transdermal oestrogen group, p = 0.01. Red clover based phytoestrogen therapy was not associated with any changes in SHBG levels whereas transdermal estrogen therapy significantly increased SHBG levels, p = 0.05. Conclusions: In contrast to transdermal oestrogen therapy, oral phytoestrogen therapy does not decrease androgenicity and is associated with a decrease in insulin sensitivity. These effects are similar to those of raloxifene and consistent with phytoestrogen's selective oestrogen receptor modulator properties.     

Effect of aging and physical inactivity on glucose tolerance and insulin sensitivity

It has been well documented that glucose intolerance is associated with aging, but it is not yet clear whether this phenomenon is due to the aging process itself or is secondary to the appearance of other age-related conditions among which physical inactivity is one of most important variables. To evaluate the effect of aging process and/or physical inactivity on insulin action, this study was undertaken using the euglycemic insulin clamp technique and the oral glucose tolerance test (OGTT). Subjects without diabetes mellitus and other serious diseases consisted of 14 non-obese aged individuals and 10 young controls (YC group), ranging in age from 63 to 85 yrs, and from 19 to 21 yrs, respectively. The aged individuals were further divided into two groups (one was termed as the AS group, in which 7 aged subjects had been confined to bed for at least 3 months and the other was termed as the AC group in which 7 aged controls kept their daily physical activity such as walking). The results of OGTT did not show any remarkable differences between AC and YC groups. In the AS group, however, glucose intolerance and low insulin response during OGTT were observed. In view of the tissue insulin action, MCR, which is thought as a reliable marker for tissue insulin action, evaluated by euglycemic insulin clamp was 5.31 +/- 0.68, 8.57 +/- 1.20, 9.60 +/- 0.35 ml/kg/min in the AS, AC and YC groups, respectively (AS less than AC, p less than 0.05, AS less than YC, p less than 0.01, AC less than YCM, N.S.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women

In the present study, we hypothesized that estradiol, via its ability to vasodilate in an endothelium-dependent manner, might enhance vascular effects of insulin. Basal and insulin-stimulated peripheral blood flow and resistance, arterial stiffness, and glucose metabolism were determined in 27 healthy postmenopausal women before and after 12 weeks of treatment with either transdermal or oral estradiol or corresponding placebo preparations. Whole body insulin sensitivity was determined using the euglycemic insulin clamp technique (rate of continuous insulin infusion 1 mU/kg.min), forearm blood flow with a strain-gauge plethysmography, and arterial stiffness using pulse wave analysis. Estradiol therapy increased basal peripheral blood flow (1.5 +/- 0.1 vs. 1.9 +/- 0.1 mL/dL.min, 0 vs. 12 weeks; P: < 0.01), decreased peripheral vascular resistance (65 +/- 3 vs. 52 +/- 3 mm Hg/mL/dL.min, respectively; P: < 0.01), and diastolic blood pressure (78 +/- 2 vs. 75 +/- 2 mm Hg, respectively; P: < 0.05) but had no effect on large artery stiffness. Infusion of insulin did not acutely alter peripheral blood flow but diminished large artery stiffness significantly both before and after the 12-week period of estradiol therapy. No measure of acute insulin action (glucose metabolism, blood flow, or large artery stiffness) was altered by estradiol or placebo treatment. These data demonstrate that insulin and estradiol have distinct hemodynamic effects. Physiological doses of estradiol increase peripheral blood flow but have no effects on large artery stiffness, whereas physiological concentrations of insulin acutely decrease stiffness without changing peripheral blood flow. Putative vasculoprotection by estradiol is, thus, not mediated via alterations in arterial stiffness or insulin sensitivity.     

Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance

Summary Recent evidence suggests that the post-prandial hyperglycaemia in impaired glucose tolerance is primarily due to impaired suppression of basal hepatic glucose output. This in turn appears to be secondary to decreased first phase insulin secretion, although decreased hepatic insulin sensitivity, which is a feature of non-insulin-dependent diabetes mellitus, might also play a role. Eight mildly overweight subjects with impaired glucose tolerance and eight closely matched control subjects with normal glucose tolerance underwent an intravenous glucose tolerance test to assess first phase insulin secretion. Insulin sensitivity was examined by a 150-min hyperinsulinaemic-euglycaemic clamp. Somatostatin was infused from 150 min to suppress endogenous insulin secretion, and glucagon and insulin were replaced by constant infusion. Glucose with added dideuterated glucose (labelled infusion technique) was infused to maintain euglycaemia. First phase insulin secretion ( 0–10 min insulin area ÷ 0–10 min glucose area) was significantly decreased in the subjects with impaired glucose tolerance (median [range]: 1.2 [0.2–19.4] vs 9.1 [2.6–14.5] mU·mmol^–1; p<0.01). During the clamp, circulating insulin (93±8 [mean±SEM] and 81±10 mU·l^–1) and glucagon (54±4 and 44±6 ng·l^–1) levels were comparable. Total glucose disposal was decreased in subjects with impaired glucose tolerance (2.78±0.27 vs 4.47±0.53 mg·kg^–1·min^–1; p<0.02), and was primarily due to decreased non-oxidative glucose disposal. However, hepatic glucose output rates were comparable during the clamp (0.38±0.10 and 0.30±0.18 mg·kg^–1·min^–1). Therefore, the main defects in subjects with impaired glucose tolerance are decreased first phase insulin secretion and peripheral non-oxidative glucose disposal, but hepatic glucose output shows normal responsiveness to insulin.Abbreviations FPIS First phase insulin secretion - PG plasma glucose - NIDDM non-insulin-dependent diabetes mellitus - IGT impaired glucose tolerance - HGO hepatic glucose output - IVGTT intravenous glucose tolerance test - OGTT oral glucose tolerance test     

Novel insulin sensitivity index derived from oral glucose tolerance test

The euglycemic hyperglycemic clamp is generally regarded as a reference method for assessing insulin sensitivity. However, this method is laborious and expensive. The oral glucose tolerance test (OGTT), the most commonly used method for evaluating whole body glucose tolerance, has often been used to assess insulin sensitivity. In the previous studies the correlation between the insulin sensitivity index (ISI) obtained from the OGTT (ISI(OGTT)) and those obtained from the glucose clamp (ISI(Clamp)) may not be satisfactory. This is because the glucose clamp study is designed for measuring peripheral glucose utilization, whereas plasma glucose responses during the OGTT are the results of peripheral glucose utilization and hepatic glucose production. Based on this problem, we developed a new equation, ISI(OGTT), [1.9/6 x body weight (kg) x fasting plasma glucose (mmol/liter) + 520 - 1.9/18 x body weight x area under the glucose curve (mmol/h.liter) - urinary glucose (mmol)/1.8] / [area under the insulin curve (pmol/h.liter) x body weight], which would represent peripheral glucose utilization only. We tested our equation with ISI(Clamp) and also compared with others. Thirty-three healthy volunteers (16 males) with normal glucose tolerance underwent a 75-g, 3-h OGTT on the morning of d 1 and a glucose clamp on the morning of d 2. Their mean (+/-SD) age and body mass index were 30.8 +/- 8.3 yr and 22.0 +/- 3.9 kg/m(2), respectively. The mean (+/-SD) glucose disposal rate and ISI determined by glucose clamp were 27.46 +/- 16.55 micro mol/kg.min and 7.39 +/- 2.72 micro mol/kg.min/pmol.liter, respectively. Pearson's correlation coefficient between our ISI(OGTT) and ISI(Clamp) was 0.869 (P < 0.0001) which was stronger than those corresponding values calculated from HOMA, QUICKI, Belfiore, Cederholm, Gutt, Matsuda, and Stumvoll, the respective values of which were 0.404, 0.434, 0.643, 0.533, 0.584, 0.734, and 0.508. In conclusion, the ISI(OGTT) derived from our equation is more suitable than others in assessing insulin sensitivity in subjects with normal glucose tolerance. Further studies in subjects with impaired glucose tolerance and diabetes mellitus should be performed to confirm the validity of this equation.     

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.     

Diacerhein improves glucose tolerance and insulin sensitivity in mice on a high-fat diet

Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.     

Effects of a long-term treatment with raloxifene on insulin sensitivity in postmenopausal women

Aims/hypothesis Our aim was to investigate the effect of long-term administration of raloxifene, a selective estrogen receptor modulator, on insulin sensitivity, glucose tolerance and plasma lipid concentrations in a group of postmenopausal women.Methods A total of 24 women with postmenopausal osteoporosis were consecutively enrolled and randomly assigned to take raloxifene, 60 mg/day for 12 months or placebo. At baseline and after 6 and 12 months, in each subject insulin sensitivity (M-index) was assessed by means of an euglycaemic hyperinsulinaemic clamp. Plasma concentrations of total cholesterol, triglycerides and HDL-cholesterol were also measured and glucose tolerance was evaluated.Results In the raloxifene-treated group, the M index decreased after 6 and 12 months with respect to the placebo group (–21%, p=0.042 and –23%, p=0.018, respectively). Neither fasting plasma glucose nor glucose tolerance changed in the raloxifene-treated group, compared to the placebo group. Low density lipoprotein cholesterol concentrations decreased at 12 months (–13%, p=0.047).Conclusion/interpretation A long-term treatment with raloxifene in osteoporotic, otherwise healthy post-menopausal women can reduce insulin sensitivity without affecting glucose tolerance.     

Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.