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.     

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.     

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.     

Skeletal muscle magnesium content in identical twins,discordant for type 2 diabetes

BACKGROUND: Low magnesium (Mg) status has been implied as a factor in the development of type 2 diabetes mellitus (DM) and its complications. We therefore studied Mg-status in identical twins, discordant for type 2 DM and in matched controls. Through correlation analysis, possible associations between Mg-status and glucose uptake were evaluated. METHODS: Plasma Mg concentration was measured in 12 monozygote twin pairs, discordant for type 2 DM and in 12 matched controls. Muscle Mg content was measured in 10 persons from each group. An oral glucose tolerance test and a euglycaemic, hyperinsulinaemic clamp were utilized. RESULTS: Neither muscle Mg content nor plasma Mg concentration differed among groups. Plasma Mg concentration decreased during the euglycaemic, hyperinsulinaemic clamp. In the control group, muscle Mg content correlated positively with insulin stimulated glucose disposal rate (r=0.77, p<0.01) and negatively with two hour plasma glucose concentration during an oral glucose tolerance test (OGTT) (r=- 0.64, p<0.05). In the control group, the two hour plasma glucose concentration during an oral glucose tolerance test correlated with the decrease in plasma Mg concentration (r=- 0.80, p<0.002) and with the change in muscle Mg content (r=0.90, p<0.0005) induced by the clamp. None of these associations were found in the two twin groups. CONCLUSIONS: Normal plasma Mg concentration and muscle Mg content were found in persons with type 2 DM and in persons, who were heavily predisposed to the development of type 2 DM, indicating a normal whole-body Mg content. However, the missing associations between measures of glucose disposal and changes in both plasma Mg concentration and muscle Mg content in the two twin groups indicates, that physiological mechanisms, which partly regulates insulin sensitivity and Mg status in healthy individuals are either exhausted or fully utilized in both type 2 DM and in genetically identical twins without DM.     

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.     

Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance

OBJECTIVE: The potential differential contributions of skeletal muscle and adipose tissue to whole body insulin resistance were evaluated in subjects with polycystic ovary syndrome (PCOS). Research Design and METHODS: Forty-two PCOS subjects and 15 body mass index-matched control subjects were studied. Insulin action was evaluated by the hyperinsulinemic/euglycemic clamp procedure. Isolated adipocytes and cultured muscle cells were analyzed for glucose transport activity; adipocytes, muscle tissue, and myotubes were analyzed for the expression and phosphorylation of insulin-signaling proteins. RESULTS: Fifty-seven per cent of the PCOS subjects had impaired glucose tolerance and the lowest rate of maximal insulin-stimulated whole body glucose disposal compared to controls (P < 0.01). PCOS subjects with normal glucose tolerance had intermediate reduction in glucose disposal rate (P < 0.05 vs. both control and impaired glucose tolerance subjects). However, rates of maximal insulin-stimulated glucose transport (insulin responsiveness) into isolated adipocytes were comparable between all three groups, whereas PCOS subjects displayed impaired insulin sensitivity. In contrast, myotubes from PCOS subjects displayed reduced insulin responsiveness for glucose uptake and normal sensitivity. There were no differences between groups in the expression of glucose transporter 4 or insulin-signaling proteins or maximal insulin stimulation of phosphorylation of Akt in skeletal muscle, myotubes, or adipocytes. CONCLUSIONS: Individuals with PCOS display impaired insulin responsiveness in skeletal muscle and myotubes, whereas isolated adipocytes display impaired insulin sensitivity but normal responsiveness. Skeletal muscle and adipose tissue contribute differently to insulin resistance in PCOS. Insulin resistance in PCOS cannot be accounted for by differences in the expression of selected signaling molecules or maximal phosphorylation of Akt.     

Improvement in glucose tolerance as a result of enhanced insulin sensitivity during electroacupuncture in spontaneously diabetic Goto-Kakizaki rats

We studied whether electroacupuncture (EA) applied on the abdomen improved glucose tolerance in the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes mellitus. Male GK rats and nondiabetic Wistar rats were studied under pentobarbital anesthesia. Blood samples were drawn from the ventral tail artery during the fasting stage and after a glucose load (0.5 g/kg). Electroacupuncture (15 Hz, 10 mA) was performed for 90 minutes during both the fasting and intravenous glucose tolerance test (IVGTT) periods. A hyperinsulinemic euglycemic clamp was also carried out to assess glucose uptake during EA. A significant decrease in fasting blood glucose and an increase in plasma insulin levels were observed during the fasting period in GK rats treated with EA. Blood glucose levels after glucose load were also significantly lower in GK rats treated with EA compared with controls. The homeostasis model assessment index during IVGTT indicated an improvement in insulin sensitivity in GK rats treated with EA, whereas glucose infusion rate during hyperinsulinemic clamp was increased significantly during EA. The present study demonstrated that EA improved hyperglycemia in the fasting stage with a marked increase in plasma insulin levels. Electroacupuncture also restored impaired glucose tolerance during an IVGTT in GK rats by enhancing insulin sensitivity.     

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.     

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.     

Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures

The purpose of this study was to explore possible calculations using oral glucose tolerance test (OGTT) values in order to develop a simple measure of insulin sensitivity. We devised a formula for an insulin sensitivity index, ISI(0,120), that uses the fasting (0 min) and 120 min post-oral glucose (OGTT) insulin and glucose concentrations. It appears to be generalizable across a spectrum of glucose tolerance and obesity. Most importantly, our data show that ISI(0,120) correlates well, when applied prospectively in comparative studies, with the insulin sensitivity index obtained from the euglycemic hyperinsulinemic clamp (r = 0.63, P < 0.001). This correlation was demonstrably superior to other indices of insulin sensitivity such as the HOMA formula presented by Matthews, and performed comparably to the computerized HOMA index. Measurement of insulin sensitivity has traditionally been possible only in research settings because of the invasiveness and expense of the methods used. Clinical investigators have therefore sought more practical methods to obtain an index of insulin sensitivity. Such an index should approximate insulin sensitivity as measured by the euglycemic hyperinsulinemic clamp (M). We present ISI(0,120), a simple yet sensitive measure of insulin sensitivity which is adaptable for use in clinical settings as well as large epidemiologic studies.     

Myocardial insulin-mediated glucose uptake and left ventricular geometry

Whole-body insulin sensitivity has been shown to be impaired in subjects with increased left ventricular relative wall thickness (RWT) and in hypertensive subjects with left ventricular hypertrophy, but the relation between myocardial insulin sensitivity and RWT or left ventricular mass index (LVMI) in normotension is not known. We measured myocardial and skeletal muscle glucose uptake with [¹⁸F]fluorodeoxyglucose and positron emission tomography during hyperinsulinemic euglycemic clamp in nine men with wide ranges of echocardiographic RWT and LVMI. The subjects were male, 72-74 years old, normotensive and free from medication or history of heart disease. RWT correlated inversely with skeletal muscle glucose uptake ( r =-0.69, p = 0.04), borderline significantly directly with myocardial glucose uptake (r = 0.62, p = 0.07), and directly with the ratio between myocardial and skeletal muscle glucose uptake (r = 0.77, p = 0.02) during hyperinsulinemic euglycemic clamp. LVMI was not related to insulin-mediated myocardial or skeletal muscle glucose uptake or the ratio between myocardial and skeletal muscle glucose uptake. In conclusion, RWT was inversely related to insulin sensitivity in skeletal muscle and borderline significantly directly related to insulin sensitivity in the myocardium in healthy normotensive elderly men, whereas LVMI was not related to myocardial or skeletal muscle insulin sensitivity.     

Evaluation of insulin sensitivity and glucose effectiveness during a standardized breakfast test: comparison with the minimal model analysis of an intravenous glucose tolerance test

There is a need for reliable measurements of insulin sensitivity (SI) simpler than the euglycemic hyperinsulinemic clamp or the intravenous glucose tolerance test (IVGTT), which could be used when the simpler surrogates based on fasting insulin (Ib) and glucose (Gb) lose their validity. Several evaluations of SI derived from oral glucose tolerance test (OGTT) or its physiologic form, the standardized breakfast test (SBT), have been proposed. We aimed at determining which SBT-derived measurements of SI give the best prediction of the values obtained with the minimal model analysis of an IVGTT. Twenty-eight subjects (23 females and 5 males; age, 44.3+/-0.6 years) with a wide range of glucose tolerance randomly underwent a hyperglucidic SBT and an IVGTT with minimal model analysis. Correlations of 35 indices (converted if appropriated into similar units) with IVGTT-derived SI were calculated, and the accuracy of the empiric formulas obtained with the 11 best predictions were evaluated with Bland-Altman plots. Subjects covered all the spectrum of SI between 0.19 and 21.3 min-1/(microU.mL-1)x10(-4). Eight procedures yielded satisfactory predictions of minimal model SI: (1) SI (from Matsuda's composite index)=-1.24+65/(IbGbImGm)-0.5; (2) SI=1.89+2690/(IbGbImGm); (3) SI (from Bennett's index)=-2.93+5.16/(log Ibxlog Gb); (4) SI (from Sluiter's index)=0.2+2400/(IpGp); (5) SI=-8.54+38.4/(Belfiore's ISI index); (6) SI (from Cederholm's formula)=76/(Gm log Im); (7) SI=0.248+0.947/GbIm; (8) SI (from Mari's "oral glucose insulin sensitivity" index)=oral glucose insulin sensitivity/Ip; (9) Caumo's model. Glucose effectiveness Sg can also be accurately predicted by the following formula: Sg=2.921e-0.185(G60- Gb) (Ip=insulin peak; Gp=glucose peak; Ia=insulin area; Ga=glucose area; G60=glycemia at 60 minutes). The hyperglucidic SBT can provide accurate evaluations of SI and Sg, either by elaborated models or by simple empiric formulas.     

Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose

Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (∆ISR[AUC]) to incremental area under the glucose curve (∆G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60–120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.     

Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion

OBJECTIVE: To evaluate the impact on glucose and insulin metabolism of transdermal estrogen patches before and after the addition of cyclic dydrogesterone in postmenopausal women. DESIGN: We studied 21 postmenopausal women seeking treatment for symptomatic menopause. All patients received transdermal 50 micrograms/day estradiol for 24 weeks. After 12 weeks of treatment, 10 mg/day dydrogesterone were added. METHODS: During both regimens, insulin and C-peptide plasma concentrations were evaluated after an oral glucose tolerance test (OGTT); insulin sensitivity was evaluated by a hyperinsulinemic euglycemic clamp technique. Insulin and C-peptide response to OGTT were expressed as area under the curve (AUC) and as incremental AUC; insulin sensitivity was expressed as mg/kg body weight. Fractional hepatic insulin extraction (FHIE) was estimated by the difference between the incremental AUC of the C-peptide and insulin divided by the incremental AUC of the C-peptide. Plasma hormone and lipid concentrations were assessed at baseline and at 12 and 24 weeks of treatment. RESULTS: Nine patients proved to be hyperinsulinemic and 12 were normoinsulinemic. Transdermal estrogen treatment significantly decreased the insulin AUC (P < 0.05) and the insulin incremental AUC in hyperinsulinemic patients; addition of dydrogesterone further decreased both the AUC and incremental AUC of insulin. Estrogen alone and combined with dydrogesterone evoked a significant increase in C-peptide AUC in hyperinsulinemic (79.2%) and normoinsulinemic (113%) patients. The treatment increased the values for FHIE and insulin sensitivity in all patients (P < 0.04) and in the hyperinsulinemic group (P < 0.01), whereas it did not affect such parameters in normoinsulinemic patients. CONCLUSIONS: Transdermal estrogen substitution alone and combined with cyclical dydrogesterone may ameliorate hyperinsulinemia in a selected population of postmenopausal women.     

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.     

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.     

Relationship between the hyperinsulinemic-euglycaemic clamp and a new simple index assessing insulin sensitivity in overweight and obese postmenopausal women

OBJECTIVE: The purpose of this study was to compare assessment of insulin sensitivity from hyperinsulinemic euglycaemic (HIEG) clamp with indexes derived from fasting and oral glucose tolerance test (OGTT). SUBJECTS AND METHODS: Cross-sectional study with 107 sedentary non-diabetic overweight and obese postmenopausal (BMI=32.4+/-0.4 kg/m(2)) women undergoing both HIEG clamp and OGTT. Pairs of data were analyzed using Pearson correlation and Bland-Altman graphs analysis. Comparison between correlations was made using the method reported by Zar. RESULTS: All the indexes derived from either the OGTT or surrogate indexes were highly correlated with all the clamp-derived formulas (P<0.0001). However, HOMA and QUICKI were generally less correlated than OGTT-derived indexes. Analogically to QUICKI, we calculated a new formula derived from the OGTT measurements of glucose and insulin named simple index assessing insulin sensitivity (SI(is)OGTT)=1/[log(sum glucose t(0-30-90-120)) (mmol/l)+log(sum insulin t(0-30-90-120)) (microUI/ml)]. By using this formula, we found high significant correlations (r's=0.61-0.65; P<0.0001) with the clamp results. Moreover, the correlations of SI(is)OGTT with the clamp data were higher than for other previously published indexes. CONCLUSION: In that large group of non-diabetic overweight and obese postmenopausal women insulin sensitivity index derived from OGTT provided more accurate information than fasting based formula. We propose a new simple index for the assessment of insulin sensitivity from the OGTT data (SI(is)OGTT). The advantage of this new formula over all previously published OGTT-derived indexes of insulin sensitivity is that it is 1) easy to calculate 2) better correlated than other indexes of insulin sensitivity and 3) not affected by the way clamp results are expressed. Further studies are needed to validate SI(is)OGTT index in other populations.     

Glucose metabolism in children with renal failure: oral or intravenous glucose tolerance.

There is debate about the most suitable test for investigation of glucose tolerance in children with chronic renal failure. We therefore studied the agreement between the two most commonly used glucose tolerance tests in 33 children with chronic renal failure (mean age 10.9+/-5.3 years, median GFR was 24 ml/min/1.73 m2). All children underwent an oral glucose tolerance test (OGTT) with blood sampling up to 180 minutes and after an oral load of 1.75 g/kg and a standard intravenous glucose tolerance test (IVGTT) using 0.5 g/kg i.v. The two tests were performed at an interval of 23+/-5 days, with 9 patients having the OGTT before and 24 after the IVGTT. In order to account for the differing glucose load, a subgroup of 19 patients also received a glucose infusion test (GIT) using a total of 1.75 g/kg i.v. On IVGTT, 27 patients had a normal and 6 had a pathological glucose decay constant (k-value). On OGTT, 12 patients had an impaired glucose tolerance (IGT) and 3 patients were diabetic according to WHO standard, and only 18 patients had a normal glucose tolerance. While there was good correlation between both glucose and insulin concentrations between IVGTT and OGTT, only when reapplying the WHO criteria of a glucose concentration below 6.7 mmol/l to the concentration measured 180 minutes instead of 120 minutes after oral glucose load, the agreement between the two tests improved. The proportion of normal findings on GIT when compared to OGTT was identical. When using the appropriate definitions for normal and abnormal carbohydrate tolerance, interestingly the insulin (IRI) concentrations on OGTT were not discriminative between the normal and the pathological group, whereas IRI first phase secretion on IVGTT and IRI 0-180 AUC on GIT did discriminate. We conclude that the standard WHO OGTT criteria may have to be reconsidered in children with chronic renal failure and that OGTT should be extended to 180 minutes. The IVGTT, particularly when insulin early phase secretion (at 0, 1, 3 and 5 minutes) is also monitored, provides a reliable test for assessing glucose tolerance in children with chronic renal failure.     

Insulin sensitivity,and β-cell function in relation to hemoglobin A1C

Background and aimsThe A1C diagnostic criterion for identifying individuals at increased risk for diabetes, introduced by the American Diabetes Association in 2010, was not defined on the basis of the principal pathophysiological abnormalities responsible for the development and progression of type 2 diabetes; we therefore wished to gain a deeper insight into the metabolic abnormalities characterizing the group of at risk individuals with an A1C value of 5.7–6.4%.Methods and resultsAs many as 338 non-diabetic offspring of type 2 diabetic patients were consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT), and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp. As compared with subjects with A1C <5.7%, individuals with A1C of 5.7–6.4% exhibited lower insulin sensitivity after adjusting for age, gender and body mass index (BMI). Insulin secretion estimated from the OGTT, did not differ between the two groups. By contrast, as compared with subjects with A1C <5.7%, the acute insulin response (AIR) during an IVGTT and both IVGTT-derived and OGTT-derived disposition indexes were reduced in individuals with A1C of 5.7–6.4% after adjusting for age, gender and BMI. As A1C increased to ≥5.7%, a sharp decrease in insulin sensitivity and β-cell function, measured as disposition index, was observed.ConclusionsCaucasian individuals with A1C ≥5.7% exhibit both core pathophysiological defects of type 2 diabetes i.e. insulin resistance and β-cell dysfunction.