The short insulin tolerance test lacks validity in adolescents with Type 1 diabetes.

AIMS: The short insulin tolerance test (SITT) has been found to be a simple and valid method for determining insulin sensitivity in healthy adults and patients with Type 2 diabetes. In this study we evaluated the reproducibility and validity of SITT in 16 adolescents with Type 1 diabetes. METHODS: Thirteen patients underwent two SITT and eight patients were examined with both SITT and a euglycaemic hyperinsulinaemic clamp. At the SITT insulin sensitivity was measured from the slope of arterialized blood glucose concentrations determined for 16 min after an intravenous bolus injection of short-acting insulin, 0.1 U/kg body weight, and expressed as glucose disappearance rate (KITT). RESULTS: There was a significant correlation between the insulin sensitivity estimations made at the two SITT (r = 0.73, P = 0.003). The reproducibility was low, however, with a coefficient of variation of 38.7%. KITT showed a strong inverse correlation to the fasting blood glucose concentration (r = -0.74, P < 0.0001). We found no correlation between insulin sensitivity measured by SITT and that measured by the euglycaemic clamp. CONCLUSIONS: We conclude that the short insulin tolerance test cannot be used in adolescent patients with Type 1 diabetes for a simple estimation of insulin sensitivity.     

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.     

Study of the rate of early glucose disappearance following insulin injection: insulin sensitivity index

The euglycaemic hyperinsulinaemic glucose clamp is usually considered as the reference technique to evaluate insulin sensitivity. As it is an-expensive and time-consuming tool, we therefore tried to validate a simple insulin tolerance test (ITT) (IV bolus of 0.1 IU/kg of regular insulin, with glucose sampling at −5, 0, 3, 5, 7, 10 and 15 min) and to demonstrate its usefulness. Insulin sensitivity was measured by DG/G0 ratio (G0 = initial glycaemia, DG is the variation between G0 and the glycaemia obtained at 15 min by the calculation of the regression plot). We confirmed the existence of a correlation between the glucose uptake (mg/kg per min) evaluated by glucose clamp and the DG/G0 index (r = 0.9, P < 0.01). There was no stimulation of hormonal counter regulation during the test. The ITT was significantly correlated both with fasting insulin (r = −0.43, P < 0.01), and post-glucose load insulin concentration (r = −0.67, P < 0.01); each measurement expressing insulin sensitivity. Four groups of patients with different insulin sensitivity; controls, NIDDM, gynoid and android obese subjects, were clearly separated by ITT. We showed that fasting glycaemia and DG/G0 were correlated (y = 2.63/x − 0.093; r = 0.82, P < 0.01). These results suggest that ITT could be an easy, quick and low cost method to evaluate insulin resistance in clinical practice and epidemiological studies.     

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

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

The variability in the action of unmodified insulin is more dependent on changes in tissue insulin sensitivity than on insulin absorption

Eight normal subjects were studied twice for 360 min after the subcutaneous injection of unmodified insulin (0.15 U kg-1) during euglycaemic clamps. Insulin absorption was assessed by both the area under the insulin-time curve above baseline (AUC) and time course of absorption (time to 25% and 50% of total AUC). Insulin action was measured as the amount of glucose infused. The maximal serum insulin concentration was 0.27 +/- 0.02 (+/- SE) nmol l-1 at 112 +/- 10 min. Fifty percent of total glucose infused occurred at 218 +/- 7 min. The maximal glucose infusion rate was 5.11 +/- 0.70 mg kg-1 min-1 and occurred at 256 +/- 12 min. Intrasubject coefficients of variation (CV) for total insulin AUC (11.2%), time to 25% of maximum AUC (12.1%) and time to 50% of maximum AUC (10.2%) were considerably lower than that for total insulin action (22.6%). Total insulin AUC did not correlate with total glucose utilization (r = 0.06, NS). We conclude that when glucose concentrations are maintained by euglycaemic clamps the peak of unmodified insulin action is later and the duration longer than traditionally recognized, insulin AUC does not predict insulin action, and the higher variability of insulin action compared with the indices of absorption suggests that day-to-day changes in tissue insulin sensitivity contribute more to the variability in insulin action than changes in absorption.     

Validation of the low dose short insulin tolerance test for evaluation of insulin sensitivity

OBJECTIVES The assessment of insulin sensitivity requires an accurate and reproducible technique. The short insulin tolerance test is a simple and rapid method for screening large numbers of subjects when the fasting glucose level is normal. Conventionally, an insulin dose of 0·1 units/kg is used, but this may result in symptomatic hypoglycaemia in healthy thin subjects who are insulin sensitive. In order to overcome this problem we have employed a lower dose of insulin and have studied the reproducibility of this modified technique comparing it with the euglycaemic hyperinsulinaemic clamp. DESIGN Subjects were studied on two separate occasions, once by a short insulin tolerance test and on a second occasion by either a euglycaemic hyperinsulinaemic clamp (insulin infusion of 40 mU/m²/min) or a repeat short insulin tolerance test. PATIENTS Eleven healthy subjects were studied twice with a short insulin tolerance test. A further 10 healthy subjects received a short insulin tolerance test on one day and a euglycaemic hyperinsulinaemic clamp study on another occasion. MEASUREMENTS Insulin sensitivity was measured in the short insulin tolerance test using the slope of arterialized blood glucose concentration from 3 to 15 minutes after an intravenous bolus of short-acting insulin, 0·05 units/kg body weight. In the clamp study, insulin sensitivity was derived from the average amount of glucose infused at steady state (M) and the mean plasma insulin level (l). RESULTS In the short insulin tolerance test no subject developed symptomatic or biochemical hypoglycaemia, defined as a blood glucose < 2·2 mmol/l. The (mean ± SEM) insulin sensitivities for the 11 subjects studied twice were 174±10 and 179±11 μmol/l/min with a coefficient of variation of 6·9±2·6%. There was a close correlation between insulin sensitivity derived from the short insulin tolerance test and that obtained from the euglycaemic clamp studies (so-called M/l ratio) in the same subjects (r= 0·81; P < 0·005). CONCLUSION The short insulin tolerance test employing 0·05 units/kg insulin is a safe, valid and reproducible method for the assessment of insulin sensitivity.     

Independent measures of insulin secretion and insulin sensitivity during the same test: the glucagon-insulin tolerance test

Background. To validate a test for independent assessment of insulin secretion and insulin sensitivity during the same occasion for metabolic studies in clinical practice, i.e. combined glucagon‐stimulated C‐peptide test and insulin tolerance test (GITT). Subjects and methods. We measured C‐peptide response to 0.5 mg of intravenous glucagon followed 30 min later by administration of 0.05 U kg^?1 insulin (insulin tolerance test, ITT). Ten subjects with normal glucose tolerance participated on different days in an ITT, glucagon‐C‐peptide test, ITT followed by glucagon‐C‐peptide test and glucagon‐C‐peptide test followed by ITT to establish whether and how the tests could be combined. The test was then repeated in nine patients with type 2 diabetes to investigate its reproducibility. In 20 subjects with varying degrees of glucose tolerance, the test was compared with the Botnia clamp (an intravenous glucose tolerance test combined with a euglycaemic hyperinsulinemic clamp). Results. When ITT preceded the glucagon test, C‐peptide response was blunted. Therefore, we first administered glucagon and then insulin (GITT). The K_ITT from the GITT was reproducible (CV = 13 %) and correlated strongly with the glucose disposal rate from the Botnia clamp (r = 0.87, r² = 0.75, P < 0.001). The C‐peptide response to glucagon was reproducible (CV = 13 %). The disposition index, providing a measure of beta‐cell function adjusted for insulin sensitivity, calculated from the GITT showed good discrimination between individuals with varying degrees of glucose tolerance. Conclusions. The GITT provides simple, reproducible and independent estimates of insulin sensitivity and secretion on the same occasion for metabolic studies in individuals with normal and abnormal glucose tolerance.     

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B-cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 +/- 0.07 U kg-ideal-body-weight-1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 +/- 0.4 to 9.0 +/- 0.3% at the end of insulin treatment, p less than 0.001), basal C-peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m-2 min-1, respectively) was significantly improved (glucose requirement: to 4.7 +/- 1.0 from 3.0 +/- 0.6 mg kg-1 min-1, p less than 0.05 at first insulin level; to 10.8 +/- 0.5 from 9.3 +/- 0.7 mg kg-1 min-1, p less than 0.01 at second level; to 13.3 +/- 0.6 from 11.8 +/- 0.8 mg kg-1 min-1, p less than 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 +/- 0.4 to 3.3 +/- 0.3 mg kg-1 min-1, p less than 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 +/- 0.4 to 0.3 +/- 0.2 mg kg-1 min-1 after 120 min at 100 mU l-1 plasma insulin, p less than 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 +/- 0.3 to 3.5 +/- 0.3%, NS).     

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man

Summary Two study protocols to examine the effects of chronic (72–96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol·kg^–1·min^–1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20–40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p<0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25–39% (p<0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - CRC Clinical Research Center - Rd rate of glucose disappearance - Ra rate of glucose appearance - HGP hepatic glucose production - NPRQ non-protein respiratory quotient - CV coefficient of variation     

Assessment of insulin sensitivity in glucokinase-deficient subjects

Summary The chronic hyperglycaemia of glucokinase-deficient diabetes results from a glucose-sensing defect in pancreatic beta cells and abnormal hepatic glucose phosphorylation. We have evaluated the contribution of insulin resistance to this form of chronic hyperglycaemia. Insulin sensitivity, assessed by the homeostasis model assessment (HOMA) method in 35 kindreds with glucokinase mutations, was found to be significantly decreased in 125 glucokinase-deficient subjects as compared to 141 unaffected first-degree relatives. Logistic regression analysis showed that in glucokinase-deficient subjects a decrease in insulin sensitivity was associated with deterioration of the glucose tolerance status. A euglycaemic hyperin-sulinaemic clamp was performed in 14 glucokinase-deficient subjects and 12 unrelated control subjects. In six patients and six control subjects the clamp was coupled to dideutero-glucose infusion to measure glucose turnover. Average glucose infusion rates (GIR) at 1 and 5 mU · kg body weight · min^–1 insulin infusion rates were significantly lower in (the glucokinase-deficient) patients than in control subjects. Although heterogeneous results were observed, in 8 out of the 14 patients GIRs throughout the experiment were lower than 1 SD below the mean of the control subjects. Hepatic glucose production at 1 mU · kg body weight^–1 · min^–1 insulin-infusion rate was significantly higher in patients than in control subjects. In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes. Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency. Insulin resistance might also result from interactions between the unbalanced glucose metabolism and susceptibility gene(s) to low insulin sensitivity likely to be present in this population.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - HGP hepatic glucose production - GCK glucokinase - IIR insulin infusion rate - GIR glucose infusion rate - MFH mild fasting hyperglycaemia - NGT normal glucose tolerance - IGT impaired glucose tolerance - HOMA homeostasis model assessment - ANOVA analysis of variance - MODY maturity-onset diabetes of the young     

The action profiles of human NPH insulin preparations

The complete time-action profiles of four subcutaneously injected human NPH insulin preparations (Protaphane HM/Novo; Insulatard Human/Nordisk; Huminsulin Basal/Eli Lilly; Basal H-Insulin/Hoechst) have been investigated by means of the euglycaemic clamp technique (blood glucose 5.0 mmol l-1). Six normal male subjects were connected to a Biostator on five occasions in randomized order including a control study without insulin injection. A stable basal insulin level of about 10 mU l-1 was established by means of a low dose insulin infusion (0.1 mU kg-1 min-1) which subsequently suppressed C-peptide by 35 +/- 19% (mean +/- SD) to levels of around 0.3 nmol l-1. Twelve units of NPH insulin were injected subcutaneously into the abdominal wall and glucose infusion rates were monitored for 19 h. In the control study, the mean glucose infusion rate was 1.11 +/- 0.60 (range 0.32-1.95) mg kg-1 min-1. Maximal glucose infusion rates, reached 5-7 h after injection, were comparable (4.3-4.9 mg kg-1 min-1) for the four different preparations used. Glucose infusion rates returned to basal rates within the 19 h study period. Mean plasma free insulin levels peaked at 17.5-18.6 mU l-1 3-4.5 h after injection and returned to basal levels within 16 h. The time ranges of greater than 90, greater than 75, greater than 50, and greater than 25% of maximal insulin action (as estimated from glucose infusion rates) revealed no significant differences between the four insulin preparations tested. No significant insulin action was observed beyond 17 h after insulin injection of any preparation.     

Insulin-mediated and glucose-mediated glucose uptake following hemipancreatectomy in healthy human donors

Summary Healthy humans undergoing hemipancreatectomy for the purpose of donation to a family member with IDDM have previously been demonstrated to maintain serum glucose values equal to matched control subjects during short-term glucose infusion despite significant decrements in glucose- and arginine-induced insulin secretion. In order to determine whether humans compensate for hemipancreatectomy by increasing insulin- or glucose-mediated glucose uptake, we measured glucose turnover and insulin sensitivity by three protocols. Insulin-mediated glucose uptake was measured during sequential infusions of insulin at rates of 0.25, 1.0, and 10.0 mU·kg^–1·min^–1 in 12 donor subjects and 12 matched control subjects maintained at euglycaemia. Both groups displayed similar increases in rates of glucose disappearance and similar decreases in rates of hepatic glucose production. Glucose-mediated uptake was calculated as the difference between the rates of glucose disappearance measured during a hyperglycaemic clamp and a euglycaemic clamp performed at identical rates of insulin infusion and was also found to be similar in both donor subjects and control subjects. Both groups also had indistinguishable measures of insulin sensitivity and glucose effectiveness as determined by the minimal model technique. Therefore, donor subjects appear to compensate for diminished insulin secretion following hemipancreatectomy by an unidentified mechanism since neither insulin- nor glucose-mediated glucose uptake are increased.Abbreviations R_d Rate of glucose disappearance - HGP hepatic glucose production rate - IDDM insulin-dependent diabetes mellitus - S_I insulin sensitivity index - S_G glucose effectiveness     

Suppression of insulin secretion by falling plasma glucose levels is impaired in type 2 diabetes

The ability of Type 2 diabetic patients to suppress islet B-cell secretion in response to falling plasma glucose levels has been studied with two different protocols. (1) Five diet-treated diabetic patients and 6 normal subjects were studied after the termination of a hyperglycaemic clamp at 15 mmol l-1 for 150 min, with the plasma glucose levels then being allowed to fall and the glucose clamp re-established at 10 mmol l-1. The plasma insulin levels fell in normal subjects from 178 +/- 141 (+/- SD) mU l-1 at the end of the 15 mmol l-1 clamp to 147 +/- 97 mU l-1 (p less than 0.02) 20 min later, whereas in diabetic patients there was no significant change from 61 +/- 41 to 56 +/- 35 mU l-1, respectively (NS). (2) The second study was performed to assess the turn-off of islet B-cell secretion with diabetic patients and normal subjects starting at comparable plasma insulin levels. Twelve diet-treated diabetic patients and 11 normal subjects were given a continuous low-dose glucose infusion for 60 min at a rate of 5 mg kg-1 ideal body weight min-1, after which the infusion was turned off and the plasma glucose level allowed to fall.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characteristics of insulin resistance in Turner syndrome

The characteristics of insulin resistance, in Turner syndrome are still unclear. For this purpose in 4 patients with Turner syndrome and in 8 control females we performed an euglycaemic hyperinsulinemic glucose clamp at the following insulin infusion rates (50 and 100 mU/Kg x h), each period lasting 120 min. A simultaneous infusion of D-3-H-glucose allowed us to determine in basal conditions and during the clamp hepatic glucose output and glucose disappearance rate (Rd). In basal conditions plasma glucose (4.8 +/- 0.1 vs 4.6 +/- 0.2 mmol/1 p = NS) and plasma glucagon (102 +/- 7.5 vs 112 +/- 11.3 ng/l p = NS) were similar in both groups despite higher plasma insulin (19 +/- 1.8 vs 7 +/- 2.2 mU/l p less than 0.05) and C-peptide (1.0 less than 0.1 vs 0.8 +/- 0.06 pmol/l p less than 0.05) levels in patients with Turner syndrome. In the last 60 min of the lower insulin infusion rate glucose infusion rate (4.1 +/- 0.3 vs 2.9 +/- 0.4 mg/Kg x min p less than 0.05) and glucose disappearance rate (3.89 +/- 0.12 vs 2.63 +/- 0.11 mg/Kg x min p less than 0.01) were significantly reduced in patients with Turner. On the contrary hepatic glucose output was similarly suppressed in both groups of subjects. Doubling the insulin infusion rate, we obtained similar results in patients and controls respectively. So we conclude that in Turner syndrome the insulin resistance state is mainly due to a muscular receptor defect.     

Measurement of insulin sensitivity: influence of potassium supply during euglycaemic glucose clamps in healthy volunteers.

Insulin sensitivity can be quantitatively measured by the hyperinsulinaemic euglycaemic glucose clamp technique. Infusion of insulin during the clamp procedure leads to a decline of kalaemia unless potassium is supplied. We investigated whether supplementation of potassium during euglycaemic glucose clamps influences insulin sensitivity. In a randomised study the insulin sensitivity index (S(I)) was determined with two-step hyperinsulinaemic (insulin infusion rates 0.25 (step 1) and 1.0 mU kg(-1) min(-1) (step 2)) euglycaemic (5.0 mmol L(-1)) glucose clamps in 20 healthy male volunteers on two different study days. On one day blood potassium was kept constant by means of a variable i.v. potassium chloride infusion ("eukalaemic potassium clamp"), whereas on the other day the decline in blood potassium was monitored only. Without potassium supply kalaemia decreased from basal levels of 4.35 +/- 0.18 mval L(-1) to 4.25 +/- 0.17 (step 1) and further to 3.88 +/-0.14 mval L(-1) (step 2 (mean +/- SD)). Without and with potassium supply the insulin sensitivity index measured was comparable (S1 10.6 +/- 3.6 vs. 9.5 +/- 3.5 ml min(-1) m2 per microU ml(-1), n.s.; glucose infusion rates 3.6+/-1.6/12.6 +/- 2.6 (step 1/step 2) vs. 3.7 +/- 1.5/12.2 +/- 2.7 mg kg(-1) min(-1), n.s.). In conclusion, this study shows that potassium supply during hyperinsulinaemic euglycaemic glucose clamps in healthy subjects does not influence the insulin sensitivity index.     

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.     

Nicotine infusion acutely impairs insulin sensitivity in type 2 diabetic patients but not in healthy subjects

OBJECTIVES: The aim of this study was to examine if an acute nicotine infusion alters insulin sensitivity to a similar degree in type 2 diabetic patients as in healthy control subjects. DESIGN: . Double-blind, cross-over, placebo-controlled, randomized experimental study. Nicotine 0.3 microg kg-1 min(-1) or NaCl was infused (2 h) during a euglycaemic hyperinsulinaemic clamp (4 h) to assess insulin sensitivity. SETTING: University research laboratory. SUBJECTS: Six male and female type 2 diabetic patients [DM2; age 54 +/- 10 (mean +/- SD) years; body mass index (BMI) 25.6 +/- 2.9 kg m(-2)] treated with diet or one oral hypoglycaemic agent and six age- and BMI-matched control subjects (Ctr). MAIN OUTCOME MEASURE: Insulin sensitivity (rate of glucose infusion per kg fat free body mass and minute), nicotine and free fatty acid (FFA) levels, pulse rate and blood pressure. RESULTS: The infusions produced similar nicotine levels in both groups. In the absence of nicotine, DM2 were more insulin resistant than Ctr (6.7 +/- 0.4 vs. 10.9 +/- 0.3 mg kg-1 LBM min(-1), respectively; P < 0.0001). This insulin resistance was further aggravated by the nicotine infusion in DM2 but not in Ctr (4.6 +/- 0.3 vs. 10.9 +/- 0.3 mg kg(-1) LBM min(-1); P < 0.0001). Only minor differences were seen in FFA levels, pulse rates and blood pressure. CONCLUSIONS: At this low infusion rate, nicotine aggravated the insulin resistance in DM2 but not in Ctr. This finding may be because of the (dysmetabolic) diabetic state per se or to an increased sensitivity to environmental factors associated with a genetic predisposition for type 2 diabetes. These results show that diabetic subjects are particularly susceptible to the detrimental effects of nicotine.     

Impaired insulin-mediated amino acid plasma disappearance in non-alcoholic fatty liver disease: a feature of insulin resistance

BACKGROUND AND AIM: Insulin resistance is a main feature, and possibly a pathogenic factor, of non-alcoholic fatty liver disease. It is usually measured on glucose metabolism; the effects on amino acid regulation have never been assessed. In particular, no data are available on insulin-dependent branched-chain amino acid metabolism, which is under insulin control. MATERIALS AND METHODS: We measured amino acid disappearance from plasma during an euglycemic glucose clamp in 39 biopsy-proven non-alcoholic fatty liver disease patients and in ten control subjects. A primed-constant infusion of insulin (constant rate, 40 mU/m2 per min for 2 h) was used to raise plasma insulin to approximately 100 mU/l. Euglycemia was maintained by a variable glucose infusion, a measure of tissue insulin sensitivity. Plasma amino acids were assayed during the clamp after ninhidrin derivatization. RESULTS: Fasting plasma amino acids were similar in the two groups. Steady-state insulin levels were significantly higher in non-alcoholic fatty liver disease patients, whereas tissue sensitivity to insulin was reduced by 50%. The plasma disappearance of branched-chain amino acids, as well as the disappearance of the sum of glutamine and glutamate and that of serine were significantly reduced in non-alcoholic fatty liver disease. Differences were maintained after adjustment for steady-state insulin, and correlated with reduced tissue sensitivity to glucose. CONCLUSION: Insulin resistance in non-alcoholic fatty liver disease patients also affects amino acid metabolism, especially for amino acids involved in peripheral muscle nitrogen exchange. The metabolic effects of altered protein/amino acid metabolism must be considered.     

TNF—α诱导的胰岛素抵抗小鼠胰岛素敏感性及糖脂代谢的变化

目的探讨TNF-α诱导的胰岛素抵抗（IR）小鼠胰岛素敏感性及糖脂代谢的变化。方法23只健康雄性C57BL／6J小鼠随机分为4组：高剂量（H）组、中剂量（M）组、低剂量（L）组分别给予腹腔注射6、3、1μg·kg^-1·d^-1的TNF-α，正常对照（NC）组注射等体积的生理盐水，共7天。采用静脉葡萄糖耐量试验（IVGTT）和3-[^3H]葡萄糖为示踪剂的扩展胰岛素钳夹技术，评价小鼠胰岛素敏感性和糖脂代谢的变化。结果TNF-α处理后，小鼠FBG、血浆胰岛素（Ins）和FFA水平均增高，且H组明显高于NC、M和L组。IVGTT结果显示H组糖耐量减低，Ins释放水平明显高于其他组。在胰岛素钳夹术中，H组基础葡萄糖清除率（GDR）和肝糖输出率（HGP）明显高于NC组（P＜50.01）。在钳夹稳态时，H组血浆Ins水平明显高于NC组（P＜0.01），Ins对FFA的抑制作用较NC组明显降低（P＜0.01），H组葡萄糖输注率（GIR）明显低于NC组（P＜0.01）；钳夹稳态时小鼠GDR明显增加，但H组GDR的增加仍明显低于NC组（P＜0.01）；钳夹结束时，NC组HGP被完全抑制，而H组仅被抑制59％。结论高剂量TNF-α（6μg·kg^-1·d^-1）处理可导致小鼠糖脂代谢紊乱以及肝和外周组织的球。     

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

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