Site of insulin resistance in type 1 diabetes: insulin-mediated glucose disposal in vivo in relation to insulin binding and action in adipocytes in vitro

To evaluate the mechanism of insulin resistance in type 1 diabetes mellitus, we measured insulin sensitivity in vivo and insulin action in adipocytes in vitro. The study groups consisted of 18 insulin-treated type 1 diabetic patients and 14 matched normal subjects. In each subject, insulin-mediated glucose disposal in vivo was measured by the euglycemic clamp technique. An open surgical biopsy was performed in 9 diabetic and 7 healthy subjects to obtain abdominal sc adipose tissue for the measurement of [125I]insulin binding, D-[14C]-glucose transport, oxidation, and lipogenesis. During the euglycemic clamp studies, similar steady state plasma glucose (4.8 mmol/liter) and insulin (80 mU/liter = 700 pM) levels were maintained in both groups. The rate of glucose metabolism (M) was 43% lower in the diabetic patients (4.75 +/- 0.34 mg/kg X min) than in the normal subjects (8.27 +/- 0.43 mg/kg X min; P less than 0.001). [125I]Insulin binding to adipocytes was reduced in the diabetic patients (26% reduction in tracer binding; P less than 0.05) due to a reduction in receptor number. Insulin binding was not related to the M value at any insulin concentration. Basal and insulin-stimulated rates of glucose transport were not significantly different in diabetic and normal subjects. The basal glucose oxidation rate was reduced by 50% (P less than 0.02), and maximal glucose oxidation was reduced by 49% (P less than 0.03) in the diabetic patients (237 +/- 30 vs. 359 +/- 49 pmol/30,000 cells X 90 min, basal vs. maximal glucose oxidation, respectively) compared to those in normal subjects (513 +/- 101 vs. 700 +/- 133 pmol/30,000 cells X 90 min). The percentage responses of glucose oxidation and glucose transport to insulin were similar in both groups. Glucose oxidation rates at basal (r = 0.68; P less than 0.01), half-maximally (ED50; r = 0.70; P less than 0.01), and maximally (r = 0.64; P less than 0.05) effective insulin concentrations were positively related to the M value. Basal and insulin-stimulated rates of lipogenesis were comparable between the diabetic and normal subjects. In conclusion, insulin-mediated glucose disposal in vivo is reduced in conventionally treated type 1 diabetic patients. In vitro, adipocytes from diabetes bound slightly less insulin at tracer insulin concentrations, but the magnitude of this reduction was not related to impairment of glucose metabolism in vivo. Of the pathways of glucose metabolism studied, the rate of glucose oxidation was most affected. A significant relationship was found between the M value and the rate of in vitro glucose oxidation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of experimental hyperthyroidism on insulin action in growing sheep.

The effects of moderate hyperthyroidism on insulin action were studied in five growing sheep (42 kg live weight [LW]) by the euglycemic hyperinsulinemic clamp technique, with insulin infused at rates of 0.33, 1.00, and 6.00 mU/kg LW/min over successive 2-hour periods. Animals were injected with saline (control) or thyroxine (15 micrograms/kg LW/d) for 21 days and measurements performed during the final 7 days of each period. Thyroxine (T4) treatment elevated plasma T4 less than threefold and plasma triiodothyronine (T3) twofold. T4 treatment elevated basal plasma glucose concentration (P less than .01) and insulin metabolic clearance rate at the highest rate of insulin infusion (P less than .05). The maximal insulin-induced increase in glucose metabolic clearance rate (responsiveness) was unaffected by T4 treatment, but the insulin concentration for a half-maximal response (sensitivity) was lowered during T4 treatment (122 v 58 microU/mL, P less than .05). Insulin infusion failed to completely suppress endogenous glucose output; T4 treatment had no effect. Insulin caused dose-dependent reductions in circulating concentrations of alpha-amino N, alanine, D-3-hydroxybutyrate, and glycerol, but not nonesterified fatty acids (NEFA). T4 treatment increased the sensitivity and responsiveness of alpha-amino N and alanine concentrations to insulin, the sensitivity of D-3-hydroxybutyrate (all P less than .05), and the responsiveness of glycerol to insulin (P less than .01). Thus moderate hyperthyroidism in growing sheep modifies the ability of insulin to regulate metabolism.     

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.     

Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies

We compared estimates of in vivo insulin action derived from insulin tolerance tests (ITT) and euglycemic and hyperglycemic glucose clamp studies in 17 normal subjects and 19 patients with various diseases characterized by insulin resistance. Fifteen subjects underwent an ITT and a euglycemic clamp study, 17 subjects underwent an ITT and a hyperglycemic clamp study, and 4 subjects underwent all 3 tests. The ITT consisted of a bolus iv injection of regular insulin (0.1 U/kg BW). The plasma glucose disappearance rate during the 3- to 15-min period following the insulin injection was taken as a measure of insulin action. In both euglycemic and hyperglycemic clamp studies, which were carried out with standard techniques, the ratio between the amount of glucose infused to maintain glycemia at the desired level and the mean plasma insulin concentration from 60-120 min (M) (euglycemic clamp studies) or 20-120 min (I) (hyperglycemic clamp studies) was used as a measure of insulin action. A close correlation was found between plasma glucose disappearance rate and the M/I ratio during either the euglycemic (r = 0.811; P less than 0.001) or the hyperglycemic (r = 0.826; P less than 0.001) clamp studies. These results suggest that the 15-min ITT is suitable as a simple and rapid estimation of in vivo insulin action when glucose clamp studies are not feasible, as in large series of subjects or serial studies.     

Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPARgamma(2)) is associated with reduced risk for type 2 diabetes. Although increased insulin sensitivity of glucose disposal and lipolysis has been reported, the exact mechanism by which the risk reduction is conferred is not clear. Because the conclusion of greater insulin sensitivity hinged upon lower insulin levels in some studies, it is possible that more efficient insulin clearance is involved. We therefore estimated insulin clearance during a euglycemic hyperinsulinemic clamp (insulin infusion rate divided by steady-state insulin concentration, 229 normal glucose tolerant [NGT] subjects), an oral glucose tolerance test (OGTT) (mean C-peptide divided by mean insulin concentrations, 406 NGT, 54 impaired glucose tolerant or mildly diabetic subjects), and a hyperglycemic clamp (120 minutes, 10 mmol/L, C-peptide divided by insulin in the steady-state, 56 NGT subjects). In the carriers of the Ala allele (prevalence approximately 24%), insulin clearance in all 3 protocols was significantly greater ( approximately 10%), than in controls. While the results from the euglycemic clamp reflect both hepatic and peripheral insulin clearance, those from the OGTT and the hyperglycemic clamp reflect mainly hepatic insulin extraction. Free fatty acids (FFA) during the steady state of the euglycemic hyperinsulinemic clamp were significantly lower in carriers of the Ala allele (26 +/- 5 micromol/L) than in controls (46 +/- 3 micromol/L, P =.02). In conclusion, the Pro12Ala polymorphism is associated with increased insulin clearance. This could be the result of reduced FFA delivery, which has been shown to improve hepatic insulin removal and sensitivity. Because PPARgamma(2) is mainly expressed in adipose tissue, one of the main regulatory effects of the polymorphism may well be the more efficient suppression of (possibly intra-abdominal) lipolysis.     

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.     

Insulin resistance in diabetic microangiopathies

To investigate whether insulin resistance is associated with diabetic microangiopathies in type 2 diabetes mellitus, insulin sensitivity was measured in 133 type 2 diabetic subjects with or without diabetic retinopathy and/or nephropathy. Insulin sensitivity was measured by steady-state plasma glucose method or euglycemic glucose clamp method. Regarding retinopathy, in the insulin-resistant group, advanced retinopathy (preproliferative and proliferative retinopathy) was more frequently observed compared with the insulin-sensitive group (significance: p<0.02). Similarly, as for nephropathy, the occurrence of continuous proteinuria in the insulin-resistant group was significantly (p<0.01) more frequent compared with the insulin-sensitive group. Insulin sensitivity expressed as glucose utilization and glucose clearance was significantly (p<0.05) lower in diabetic subjects with retinopathy (without nephropathy) compared with subjects without the microangiopathies after adjustment for age, body mass index (BMI), fasting blood glucose (FBS), and diabetic duration. Similarly, insulin sensitivity in subjects with nephropathy (without retinopathy) was significantly (p<0.05) decreased compared with those without microangiopathies. Furthermore, insulin resistance was significantly (p<0.01) severe in the subjects with both retinopathy and nephropathy than in those without the two microangiopathies. Insulin resistance of type 2 diabetes is closely associated with the progression of microangiopathies, and causal relationship between insulin resistance and microangiopathies has remained to be solved.     

应用高葡萄糖钳夹技术评价糖耐量异常的Graves病患者胰岛β细胞功能及胰岛素抵抗

目的应用高葡萄糖钳夹技术评价糖耐量异常（IGT）的Graves病（GD）患者胰岛B细胞功能及胰岛素抵抗。方法筛选合并IGT的GD患者6例（均为初诊未治）,应用高葡萄糖钳夹技术检测胰岛素分泌及胰岛素敏感性,并与正常对照组10例进行比较,所有研究对象均检测谷氨酸脱羧酶（GAD）抗体。结果合并IGT的GD组与正常对照组比较,第一时相胰岛素分泌[（636．31±105．54）mIU／L比（233．56±21．33）mIU／L]、第二时相胰岛素分泌[（146．68±25．0）mIU／L比（67．06±6．23）mIU／L]、最大胰岛素分泌量[（195．05±32．94）mIU／L比（87．64±9．78）mIU／L],胰岛素敏感性指数（11．52±1．90比21．72±3．25）,差异均有统计学意义（P值均〈0．05）。所有研究对象GAD抗体检测均为阴性。结论GAD抗体阴性的GD合并IGT患者胰岛素分泌呈亢进状态,胰岛素敏感性显著低于正常对照组。     

Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp

A group of 22 newly diagnosed noninsulin-dependent diabetic subjects and seven nondiabetic subjects underwent a glucose clamp at plasma glucose 100 mg/dL with insulin infusion rates of 1.0 and 10 mU/kg/min. During both insulin infusion rates, there was a sustained rise in plasma growth hormone (GH) above basal in 18 of the 22 diabetic subjects. Basal GH values were 2.37 +/- 0.67 ng/mL, rising above basal during the lower insulin infusion (6.1 +/- 3.3 ng/mL, P = 0.05) with a further rise at the higher insulin level (8.58 +/- 2.0 ng/mL, P less than 0.001). There was no rise in GH in any of the nondiabetic subjects. In neither group was there any rise above basal in cortisol, prolactin, glucagon, or somatostatin (SRIH). In a group of three nondiabetic subjects, a rise in GH similar to that seen in the diabetic group was induced by elevating the plasma glucose to 200 mg/dL for 60 minutes prior to the euglycemic clamp procedure. However, it is unlikely that changes in plasma glucose account totally for the changes in plasma GH described in the diabetic subjects since a rise in plasma GH was also seen in four diabetic subjects clamped at their fasting plasma glucose. We conclude that in newly diagnosed noninsulin-dependent diabetic subjects there is a rise in plasma GH during the euglycemic clamp procedure, which may be due to both the prior lowering of plasma glucose and the high plasma insulin levels.     

Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically

BACKGROUND: The HIV protease inhibitor (PI) atazanavir does not impair insulin sensitivity acutely but ritonavir and lopinavir induce insulin resistance at therapeutic concentrations. OBJECTIVE: To test the hypothesis that atazanavir combined with a lower dose of ritonavir would have significantly less effect on glucose metabolism than lopinavir/ritonavir in vitro and clinically. METHODS: Glucose uptake was measured following insulin stimulation in differentiated human adipocytes in the presence of ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l). These data were examined clinically using the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing (OGTT) in 26 healthy HIV-negative men treated with atazanavir/ritonavir (300/100 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) for 10 days in a randomized cross-over study. RESULTS: Atazanavir inhibited glucose uptake in vitro significantly less than lopinavir and ritonavir at all concentrations. Ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l) did not further inhibit glucose uptake. During euglycemic clamp, there was no significant change from baseline insulin sensitivity with atazanavir/ritonavir (P = 0.132), while insulin sensitivity significantly decreased with lopinavir/ritonavir from the baseline (-25%; P < 0.001) and from that seen with atazanavir/ritonavir (-18%; P = 0.023). During OGTT, the HOMA insulin resistance index significantly increased from baseline at 120 min with atazanavir/ritonavir and at 150 min with lopinavir/ritonavir. The area under the curve of glucose increased significantly with lopinavir/ritonavir but not with atazanavir/ritonavir. CONCLUSIONS: Both glucose uptake in vitro and clinical insulin sensitivity in healthy volunteers demonstrate differential effects on glucose metabolism by the combination PI atazanavir/ritonavir and lopinavir/ritonavir.     

Alcohol and glucose counterregulation during acute insulin-induced hypoglycemia in type 2 diabetic subjects

To investigate the influence of alcohol on glucose counterregulation and recovery during acute insulin-induced hypoglycemia in type 2 diabetic subjects, 8 diet-treated type 2 diabetic subjects were examined twice after an overnight fast. A graded hyperinsulinemic (1 mU/kg/min, 60 to 195 minutes) euglycemic/hypoglycemic clamp was performed with concomitant infusion of 3-(3)H-glucose to assess glucose turnover. After a euglycemic baseline period (150 to 180 minutes), 200 mL of water was taken either alone or with alcohol (0.4 g/kg body weight). Hypoglycemia (plasma glucose nadir, 2.8 mmol/L) was subsequently induced, and the recovery period followed after discontinuation of insulin and the variable glucose infusion. On both study days, circulating concentrations of insulin and glucose were comparable. Alcohol intake markedly increased plasma lactate (area under the curve [AUC], recovery period) (244 +/- 30 v 12 +/- 4 mmol/L x 240 minutes; P = .00009) and suppressed plasma nonesterified fatty acids (NEFA) (AUC, recovery period) (95 +/- 13 v 161 +/- 18 mmol/L x 240 minutes; P = .0008). No differences were found in the counterregulatory response of catecholamines, cortisol, and growth hormone (GH). However, alcohol intake decreased peak glucagon significantly (155 +/- 12 v 200 +/- 17 pg/mL; P = .038). In diet-treated, mild type 2 diabetic subjects, alcohol does not modify recovery from insulin-induced hypoglycemia.     

Metformin improved insulin resistance in type I, insulin-dependent, diabetic patients

The biguanides have been shown to reduce insulin requirements in type I (insulin-dependent) diabetic patients with an increase in insulin binding to insulin receptors. The aim of this was to measure the effect of metformin (850 mg/twice daily) on insulin sensitivity. Ten type I diabetic patients of normal weight received metformin or placebo in addition to their insulin therapy for seven days. On the last day of metformin or placebo treatment, tissue sensitivity was measured by the euglycemic hyperinsulinaemic clamp procedure using the artificial pancreas. An 18% improvement in glucose uptake was observed after metformin therapy (P less than 0.01). Metformin was therefore effective in improving the insulin action in type I diabetic patients, although its use in such circumstances requires consideration of several other factors.     

Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type 1 diabetes

The influence of continuous sc insulin infusion therapy for 6 weeks on sensitivity to insulin (euglycemic clamp technique) and hepatic glucose production (3-[3H]glucose technique) was measured in 10 type 1 diabetic patients whose mean duration of diabetes was 8 yr. Mean diurnal blood glucose fell from 8.5 +/- 0.8 (SEM) mmol/liter to 6.0 +/- 0.6 mmol/liter (P less than 0.05) and glycosylated hemoglobin from 10.5 +/- 0.4% to 8.7 +/- 0.3%. Insulin requirements declined by 23% from 47 +/- 4 U/day prepump to 36 +/- 2 U/day after 6 weeks of pump therapy (P less than 0.01). During the insulin clamp, plasma insulin was maintained at approximately 90 mU/liter and plasma glucose at approximately 5.0 mmol/liter in all studies. The rate of glucose metabolism in diabetic patients during conventional therapy (4.65 +/- 0.41 mg/kg X min) was 35% lower than in normal subjects (7.20 +/- 0.42 mg/kg X min, n = 14, P less than 0.001). After 6 weeks of pump therapy, total glucose uptake increased by 27% to 5.90 +/- 0.60 mg/kg X min, P less than 0.05 vs. prepump). This was still 18% lower than in the normal subjects (P less than 0.05). Basal hepatic glucose production in the diabetic patients during conventional therapy (3.07 +/- 0.14 mg/kg X min) was 70% higher than in the normal subjects (1.79 +/- 0.07 mg/kg X min, n = 7, P less than 0.001). After 6 weeks of pump therapy, hepatic glucose production fell to 2.48 +/- 0.19 mg/kg X min (P less than 0.05), which was still 40% higher than in the normal subjects (P less than 0.01). Basal hepatic glucose production was directly related to the fasting plasma glucose level (r = 0.67, P less than 0.001) and inversely proportional to fasting insulin concentration (r = -0.48, P less than 0.05) in the diabetic patients. Specific tracer insulin binding to erythrocytes in the diabetic patients (19.4 +/- 1.5%) was comparable to that in the normal subjects (19.6 +/- 1.2%) and remained unchanged during pump therapy. Thus the improved metabolic control resulting from pump therapy is associated with enhancement in sensitivity to insulin, and reduction in basal hepatic glucose production.     

Beneficial effects of nateglinide on insulin resistance in type 2 diabetes

Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients.     

Changes in insulin sensitivity and clearance in anorexia nervosa

Anorexia nervosa (AN) is a state of self-induced malnutrition characterized by a marked pursuit of thinness and the fear of obesity. Although low fasting blood glucose and insulin have been demonstrated, there is contradictory data on insulin sensitivity and a lack of information about insulin metabolism and its metabolic effects in AN. Insulin sensitivity, kinetics, and metabolic effects were measured using the euglycemic clamp in nine females with AN (age 25.2 +/- 1.9 years and 70.6 +/- 2.2% ideal body weight), and the results compared with seven female normal controls (NC) (age 23.6 +/- 1.0 years and 92.7 +/- 2.5% ideal body weight). Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and C-peptide were significantly lower in AN as compared to NC (84.3 +/- 1.5 v 91.5 +/- 1.7 mg dL-1, 9.3 +/- 1.0 v 13.5 +/- 1.4 microU mL-1, and 0.26 +/- 0.03 v 0.41 +/- 0.02 pmol mL-1) (P less than 0.05). During the glucose clamp, the glucose metabolized (M), the metabolic clearance rate of glucose (MCRg), and the glucose metabolized per unit of insulin (M/I ratio) were all higher in AN as compared to NC (M, 8.7 +/- 1.2 v 6.9 +/- 0.6 mg min-1 kg-1; MCRg, 9.9 +/- 1.5 v 7.4 +/- 0.6 mL min-1 kg-1; M/I ratio, 8.6 +/- 1.6 v 5.0 +/- 0.3 mg min-1 kg-1/microU mL-1 X 100), but only the M/I ratio attained statistical significance (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Validation of simple indices to assess insulin sensitivity based on the oral glucose tolerance test in the Japanese population

The homeostasis model assessment (HOMA) represents a simple index for evaluating insulin sensitivity, but clinical use is limited. Insulin sensitivity indices calculated from plasma glucose and plasma insulin concentrations after an oral glucose tolerant test (OGTT) have been proposed, but have not been validated in the Japanese population. We compared these indices with the euglycemic hyperinsulinemic clamp technique to evaluate the predicting insulin sensitivities in 77 Japanese subjects with varying degrees of glucose tolerance (normal glucose tolerance, n=40; impaired glucose tolerance, n=22; and type 2 diabetes mellitus, n=15). Insulin sensitivity was measured by the euglycemic hyperinsulinemic glucose clamp technique using an artificial pancreas, and expressed as the M-value. Weak inverse correlations existed between the HOMA index and M-values (r=-0.227, P=0.0468). An alternative index calculated by Matsuda's formula correlated with the M-value (r=0.450, P=0.0001). A second index calculated by Stumvoll's formula also correlated with the M-value (r=0.641, P=0.0001). Finally, a third index calculated by Gutt's formula also significantly correlated with the M-value (r=0.526, P=0.0001). All three indices are applicable for clinical use. The second index is the most sensitive measure of insulin sensitivity in the Japanese population.     

Repeatability characteristics of simple indices of insulin resistance: implications for research applications.

The objectives of this study were to evaluate test characteristics, such as normality of distribution, variation, and repeatability, of simple fasting measures of insulin sensitivity and to use the results to choose among these measures. Duplicate fasting samples of insulin and glucose were collected before 4 h of euglycemic hyperinsulinemic clamping using insulin infusion rates ranging from 40-600 mU/m2 x min. Currently recommended estimates of insulin sensitivity, including the fasting insulin, 40/insulin, the homeostasis model assessment, the logarithmic transformation of the homeostasis model assessment, and the Quantitative Insulin Sensitivity Check Index, were evaluated. The normality of distribution and the variability of the tests (coefficient of variation and discriminant ratio) were compared between the measures and against the "gold standard" hyperinsulinemic clamp. Data from 253 clamp studies in 152 subjects were examined, including 79 repeated studies for repeatability analysis. In subjects ranging from lean to diabetic, the log transformed fasting measures combining insulin and glucose had normal distributions and test characteristics superior to the other simple indices (logarithmic transformation of the homeostasis model assessment coefficient of variation, 0.55; discriminant ratio, 13; Quantitative Insulin Sensitivity Check Index coefficient of variation, 0.05; discriminant ratio, 10) and statistically comparable to euglycemic hyperinsulinemic clamps (coefficient of variation, 0.10; discriminant ratio, 6.4). These favorable characteristics helped explain the superior correlations of these measures with the hyperinsulinemic clamps among insulin-resistant subjects. Furthermore, therapeutic changes in insulin sensitivity were as readily demonstrated with these simple measures as with the hyperinsulinemic clamp. The test characteristics of the logarithmic transformation of the homeostasis model assessment and the Quantitative Insulin Sensitivity Check Index are superior to other simple indices of insulin sensitivity. This helps explain their excellent correlations with formal measures both at baseline and with changes in insulin sensitivity and supports their broader application in clinical research.     

Insulin action during acute starvation: evidence for selective insulin resistance in normal man

The effects of insulin on glucose utilization, lipolysis, and potassium and phosphate metabolism were studied during short-term fasting in six lean subjects using a sequential euglycemic glucose clamp technique (two additional subjects were used in 70 mU/m2/min clamp studies). The subjects were infused with insulin for four hours at four rates ranging from 6 to 442 mU/m2/min before and after a 48-hour fast. Insulin was infused for one hour at each rate in all experiments. Fasting markedly reduced glucose utilization at all insulin infusion rates. On the other hand, the decline in levels of free fatty acids that occurred at insulin concentrations of 30 microU/ml was virtually identical before and after fasting. After insulin was infused for four hours, serum phosphate had decreased in all subjects (P less than 0.001) and strongly correlated with glucose disposal rates (r = 0.76, P less than 0.005). The plasma potassium level also declined in all subjects but did not relate to fasting or glucose disposal. These studies demonstrate that starvation produces selective insulin resistance. The biologic effect of insulin on glucose utilization and plasma phosphate shifts is clearly diminished. Free fatty acid and potassium metabolism are unaffected by starvation.     

Surrogate estimates of insulin sensitivity in Chinese diabetic patients and their offspring.

AIMS: To evaluate the relationship between surrogate measures of insulin sensitivity and results from euglycaemic insulin clamp in Chinese diabetic patients and their offspring. METHODS: The study included 59 volunteers from 20 diabetic families. Each participant completed a 75-g oral glucose tolerance test (OGTT) and a euglycaemic insulin clamp. We tested the correlation of surrogate measures of insulin sensitivity with M-values and M/I ratios (the amount of glucose infused during 90-120 min of the clamp was defined as M, and the mean values of plasma insulin during 90-120 min as I) from the euglycaemic insulin clamp. These measures included fasting insulin (FPI), insulin at 120 min of OGTT, insulin area under the curve of OGTT, fasting glucose-to-insulin ratio, homeostasis model assessment for insulin sensitivity (HOMA-IR and HOMA %S) and the Matsuda-DeFronzo index from OGTT. RESULTS: The Matsuda-DeFronzo index closely correlated to M-value and M/I in 21 diabetic, 38 non-diabetic individuals and the 59 participants overall (with M-value, r = 0.68, 0.84 and 0.84; with M/I, r = 0.71, 0.72 and 0.75, respectively, all P < 0.001). Without OGTT, HOMA %S was a good surrogate index for diabetic (correlated to M-value and M/I, r = 0.71 and 0.68, P = 0.001) and for non-diabetic subjects (to M-value, r = 0.73; to M/I, r = 0.55, both P < 0.001). FPI was as good as HOMA %S and Matsuda-DeFronzo index. CONCLUSIONS: The Matsuda-DeFronzo index, HOMA %S and FPI are good surrogate estimates of insulin sensitivity in Chinese diabetic subjects and their offspring.