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.     

Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance

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

Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots

Chronic hepatitis C (CHC) is associated with lipid‐related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two‐step hyperinsulinaemic–euglycaemic clamp with [6,6‐²H₂] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high‐dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post‐treatment: 56.1 ± 8.5 mm , P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid–binding protein and lipocalin‐2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance.     

Undercarboxylated osteocalcin can predict insulin secretion ability in type 2 diabetes

It has been reported that there is an intimate relationship between diabetes and bone metabolism including undercarboxylated osteocalcin (ucOC). In contrast, data on the relationship between ucOC and glucose metabolism are limited in type 2 diabetes. We recruited 50 Japanese patients with type 2 diabetes, and examined the association with ucOC on the insulin secretion, evaluated by both glucagon loading test and meal tolerance test. UcOC was shown to correlate positively with the change in C‐peptide response in the glucagon loading test and C‐peptide response after eating a meal (P = 0.025, P = 0.047). Therefore, ucOC reflects the reserve capacity of β‐cell function, such as the bolus insulin secretion ability in patients with type 2 diabetes.     

Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes

Aims/hypothesis. Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. Methods. Normal (n = 7), impaired glucose tolerant (n = 8) and Type II (non-insulin-dependent) diabetic subjects (n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio –DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. Results. Reciprocal fasting plasma insulin (FPI^–1), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI^–1, HOMA %S, 2-h CIGMA %S and S_I FSIVGTT intercorrelated more than 90 % of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. Conclusion/interpretation. The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative. [Diabetologia (1999) 42: 678–687] Received: 14 September 1998 and in revised form: 4 February 1999     

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

Objective To examine the association between insulin resistance in skeletal muscle and liver in non‐diabetic subjects. Research design and methods A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp performed with ³[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin‐stimulated rate of total glucose disposal during the insulin clamp divided by steady‐state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP × FPI). Results Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty‐eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty‐three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2‐h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. Conclusion In non‐diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2‐h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.     

Glimepiride treatment in a patient with type A insulin resistance syndrome due to a novel heterozygous missense mutation in the insulin receptor gene

Aims/Introduction

Glimepiride is a sulfonylurea known to have unique insulin mimetic and sensitizing effects. We aimed to study the efficacy of glimepiride in a patient with type A insulin resistance syndrome.

Materials and Methods

A 15‐year‐old girl with type A insulin resistance syndrome was treated with glimpiride for 6 months. Self‐monitoring of blood glucose was recorded, and oral glucose tolerance tests on glucose and insulin were measured during the treatment. Hyperinsulinemic euglycemic clamp was used to evaluate whole‐body insulin sensitivity before and after the treatment.

Results

A novel heterozygous missense mutation at exon 19 (c.3427A>T) in the tyrosine kinase domain of the INSR gene was identified, causing an amino acid replacement of phenylalanine for isoleucine at codon 1143 (Ile1143Phe). Before the treatment, the patient's glycated hemoglobin was 7.0%, plasma glucose during oral glucose tolerance test was 6.7, 12.8 and 17.3 mmol/L, and simultaneous serum insulin was 80.7, 137.5 and >300 μU/mL. There were no significant differences between self‐monitored blood glucose measured at each time‐point among different glimepiride dosages, or during the 14 weeks when glimepiride was used at its maximal dosage (6 mg/day). Oral glucose tolerance test showed little change in plasma glucose and serum insulin. Glycated hemoglobin decreased by 0.8% after the treatment. However, a euglycemic clamp study showed that the M value decreased from 5.25 to 2.90 mg/kg/min, showing increased insulin resistance.

Conclusions

Treatment with glimepiride did not improve insulin sensitivity in a patient with type A insulin resistance syndrome carrying Ile1143Phe heterozygous mutation in the INSR gene. Large‐scale long‐term studies assembled worldwide are required to optimize treatment algorithms for patients with type A insulin resistance syndrome.     

Liraglutide,a once‐daily human GLP‐1 analogue,improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function. Methods Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Results The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. Conclusions Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.     

Derivation of a quantitative measure of insulin sensitivity from the intravenous tolbutamide test using the minimal model of glucose dynamics

Summary Using the decay phase of the glucose response during an intravenous tolbutamide test, a minimal model of glucose dynamics was used to calculate a value for an index of insulin sensitivity. This index describes the efficiency of insulin in accelerating the instantaneous rate of glucose disposal, and provides a measure of insulin resistance. The validity of estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test have been assessed with reference to estimates of this index derived from the intravenous glucose tolerance test for which the model was originally designed. There were three studies: (A) estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test in a group of normal, healthy men and women were compared with results obtained in a comparable group of subjects using the intravenous glucose tolerance test. The two methods gave estimates of the index of insulin sensitivity that were identical; (B) A group of patients taking methandienone, an anabolic steroid previously shown to cause marked insulin resistance, were tested whilst taking the steroid and either before, or at least two months after treatment. Each patient was tested by both intravenous tolbutamide test and intravenous glucose tolerance test on both occasions. Estimates of the index of insulin sensitivity from intravenous glucose tolerance or intravenous tolbutamide procedures both on and off treatment were significantly correlated (off treatment: r _s ,= 0.71, n=9, p<0.05; on treatment: r _s =0.69, n=9, p<0.05); (C) A group of patients undergoing investigations for suspected disturbances in carbohydrate metabolism was studied, each patient having had both an intravenous tolbutamide and intravenous glucose tolerance test. The group studied included patients in whom a degree of insulin resistance would be expected. Estimates of the index of insulin sensitivity from the two methods were closely correlated (r _s =0.95, n=25, p<0.001). This strong, identical correlation obtained between the intravenous glucose tolerance and intravenous tolbutamide tolerance estimates of index of insulin sensitivity in studies B and C over a wide range of values [intravenous tolbutamide tolerance test: 0.11–1.07 min^–1U^–1 1; intravenous glucose tolerance test: 0.12-1.06 min^–1U^–11]. This suggests that the intravenous tolbutamide estimates of index of insulin sensitivity are closely comparable to those derived from intravenous glucose tolerance test over a broad range of insulin sensitivities. We suggest that the use of intravenous tolbutamide to induce a dynamic change in insulin-glucose relationships, and mathematical modelling of those dynamics, can provide a valuable, quantitative measure of insulin sensitivity in a variety of clinical situations.     

Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity

Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic clamp (99 ± 12 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed. Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p < 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity, dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943] Received: 26 January 1999 and in revised form: 1 March 1999     

Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation?

Summary This study investigated early alterations of glucose metabolism in idiopathic haemochromatosis. Circulating concentrations of glucose, insulin, C-peptide, glucagon, and gastric inhibitory polypeptide (GIF) were measured after a 100-g oral glucose load in 10 men with idiopathic haemochromatosis in the non-cirrhotic stage of the disease. All had normal glucose tolerance and normal body weight. Ten matched healthy subjects were studied as controls. Insulin concentrations increased to significantly higher levels in patients with idiopathic haemochromatosis than in the control subjects from 30 to 180min after the glucose load (p<0.01), while fasting insulin concentrations were not significantly different (p> 0.05). Concentrations of glucose, glucagon, C-peptide, and GIF were not significantly different at any time (p> 0.05). Thus, patients with idiopathic haemochromatosis show hyperinsulinaemia and hence insulin resistance without impaired glucose tolerance in the non-cirrhotic stage. Since pancreatic insulin secretion (C-peptide), glucagon secretion, and the entero-insulinar axis (GIP) are not impaired in these non-cirrhotic patients with idiopathic haemochromatosis, iron accumulation in the hepatocytes may be responsible for the impaired insulin effect and may cause impaired hepatic insulin extraction.     

The short insulin tolerance test for determination of insulin sensitivity: a comparison with the euglycaemic clamp.

The glucose clamp technique is currently regarded as the standard test for measuring insulin sensitivity against which other methods are compared but is unsuitable for routine screening of patients outside a hospital base. There is thus a need for a simpler test to measure insulin sensitivity. We have therefore compared the glucose disappearance rate KITT in the first 15 min of the insulin tolerance test (ITT) with the M and M/I values derived from the standard euglycaemic clamp in nine normal subjects and eight subjects with Type 2 (non-insulin dependent) diabetes mellitus and coexisting obesity. All subjects underwent the ITT and euglycaemic clamp in random order. Nine subjects later had a repeat ITT to determine the reproducibility of the test. In the ITT, 0.1 U kg-1 body weight, human Actrapid insulin was given as an IV bolus and simultaneous arterialized and venous blood samples were obtained every minute for 15 min. The first order rate constant for the disappearance of glucose KITT over the period 3-15 min was taken as a measure of insulin sensitivity. The euglycaemic clamp was performed with an insulin infusion of 50 mU kg-1 h-1 for 120 min and a variable rate glucose infusion to maintain blood glucose concentration at 0.5 mmol l-1 below fasting level to minimize the effect of endogenous insulin secretion. The ratio of the mean rate of glucose infused (M, mumol kg-1 min-1) to the plasma insulin over the last 30 min of the clamp was taken as a measure of tissue sensitivity to insulin (M/I) assuming endogenous glucose output was suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

Aim: To study the effect of dipeptidyl peptidase‐4 (DPP‐4) inhibition with saxagliptin on β‐cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel‐group, double‐blind, placebo‐controlled study were drug‐naÏve, aged 43–69 years, with baseline haemoglobin A1c (HbA1c) 5.9–8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0–180 min, fasting state), and intravenous‐oral hyperglycaemic clamp (180–480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C‐peptide deconvolution. Results: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference ?21.8% vs. placebo, p = 0.03). Conclusions: DPP‐4 inhibition with saxagliptin improves pancreatic β‐cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP‐4 inhibition on the β‐cell is warranted.     

Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations

Aims/hypothesis: We aimed to examine whether impaired glucose tolerance is associated with reduced suppression of glucagon concentrations. Methods: Eighty-four non-diabetic women of Caucasian origin and 61 years of age, of whom 48 had normal glucose tolerance (NGT) and 36 had IGT, underwent a 75 g OGTT and a hyperinsulinaemic, euglycaemic clamp with measurement of glucagon, insulin and glucose concentrations. Results: At 2 h after 75 g oral glucose, glucagon concentrations were reduced by 7.1 ± 1.1 ng/l in NGT vs 8.0 ± 1.4 ng/l in IGT, (NS). However, the 2 h reductions in glucagon per mmol/l increase in 2 h glucose or per pmol/l increase in 2 h insulin were both impaired in IGT (p = 0.002 and p = 0.043, respectively) because the 2 h increases in glucose and insulin were higher in IGT than in NGT. Furthermore, suppression of glucagon concentrations during a euglycaemic clamp at hyperinsulinaemic concentrations (NGT: 607 ± 19 pmol/l, IGT: 561 ± 21 pmol/l) was lower in IGT (13.6 ± 1.6 ng/l) than in NGT (23.1 ± 1.2 ng/l; p < 0.001). The suppression of glucagon concentrations during the hyperinsulinaemic, euglycaemic clamp correlated with insulin sensitivity (r = 0.24, p = 0.027) and with the 2 h glucose value during the OGTT (r = –0.52, p < 0.001). Conclusion/interpretation: Impaired glucose tolerance is associated with reduced insulin-induced suppression of glucagon secretion, which could be caused by A-cell insulin resistance. Inappropriately high glucagon secretion could therefore contribute to the metabolic perturbations in IGT. [Diabetologia (2001) 44: 1998–2003] Received: 15 May 2001 and in revised form: 13 July 2001     

Glucose intolerance is predicted by low insulin secretion and high glucagon secretion: outcome of a prospective study in postmenopausal Caucasian women

Aims/hypothesis. To study the pathophysiological importance of changes in insulin sensitivity and islet function over time for alterations in glucose tolerance in a randomly selected large group of non-diabetic women aged 57–59 years over a 3-year period.¶Methods. At baseline and at the 3-year follow-up, glucose tolerance (WHO 75 g oral glucose), insulin sensitivity (euglycaemic, hyperinsulinaemic clamp) and insulin and glucagon secretion (2 to 5-min responses to 5 g i. v. arginine at fasting, 14 and > 25 mmol/l glucose) were measured.¶Results. At baseline, women with impaired glucose tolerance (IGT, n = 28) had lower insulin sensitivity (p = 0.048) than normal women (NGT, n = 58). The arginine-induced insulin responses (AIR) were inversely associated with insulin sensitivity (r≥– 0.55, p < 0.001). When related to the 3-year follow-up, the baseline product of AIR at 14 mmol/l glucose times insulin sensitivity, insulin effect index (IE) (r = – 0.40, p < 0.001) and the arginine-induced glucagon response at 14 mmol/l glucose (AGR, r = 0.28, p = 0.009) both correlated with follow-up 2-h glucose. In a multiple regression model, baseline 2-h glucose, insulin effect index and arginine-induced glucagon response independently predicted 2-h glucose at follow-up (total r = 0.668, p < 0.001). Furthermore, Δinsulin sensitivity (i. e. follow-up minus baseline) correlated with Δinsulin secretion (r = – 0.30, p = 0.006), whereas Δglucagon secretion correlated with Δ2-h glucose (r = 0.30, p = 0.006) over the 3 years. In a multiple regression, alterations in 2-h glucose over the 3 years were independently determined by changes in fasting insulin and glucagon secretion (r = 0.424, p < 0.001).¶Conclusion/interpretation. Low insulin secretion, when judged in relation to insulin sensitivity, and high glucagon secretion, determine glucose tolerance over time in the individual subject. These processes are therefore potential targets for prevention of deterioration in glucose tolerance. [Diabetologia (2000) 43: 194–202]     

Differential effects of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide and metformin on pancreatic β‐cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes

This substudy of the AWARD‐3 trial evaluated the effects of the once‐weekly glucagon‐like peptide‐1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C‐peptide and glucagon levels were measured up to 3 h post‐meal. β‐cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose [AUC_glucose (0–3 h)] were observed among all groups. β‐cell function [AUC_insulin/AUC_glucose (0–3 h)] increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and β‐cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing β‐cell function, while metformin exerts a greater effect on insulin sensitivity.     

HCV synergizes with body weight in the promotion of insulin resistance

Summary. Hepatitis C virus (HCV) infection appears to contribute to the development of insulin resistance (IR). Among the multiple determinants of IR, body mass index (BMI) is the most important. We investigated the contribution of HCV to BMI‐associated IR using a transgenic mouse model expressing HCV core protein. Eight transgenic and five nontransgenic littermate controls were evaluated. Glucose and insulin tolerance tests (ITT) were performed on two separate occasions. Multivariate linear mixed modelling was used to evaluate and compare the effect of weight on IR between HCV core transgenic and nontransgenic controls. There were no statistically significant differences in glucose or ITT (P = 0.58 and P = 0.59, respectively) between the two groups, and no difference in median weights between transgenic and control mice (P = 0.11). However, there was greater variance in the distributions of Tg when compared to nontransgenic mice for both glucose and insulin tolerance. When evaluating this closely, a differential contribution of weight to IR curves between these groups was noted (P = 0.05). Among nontransgenic mice, IR curves for mice of different weights were comparable, however, for transgenic mice, higher weights resulted in larger levels of IR curves with slower decay. In all animals, steatosis was absent or minimal. We conclude that weight has a greater effect on IR in HCV core expressing transgenic mice than littermate controls. HCV therefore synergizes with weight in the promotion of IR. Steatosis was not a prerequisite for the development of IR, implying that HCV’s effects on IR may be independent of steatosis.     

Effect of dexamethasone on insulin sensitivity,islet amyloid polypeptide and insulin secretion in humans

Summary The response of islet amyloid polypeptide and insulin and their molar ratios were investigated in eight healthy volunteers before and after treatment with dexamethasone by oral and frequently-sampled intravenous glucose tolerance tests. Following dexamethasone treatment the insulin sensitivity index decreased significantly from 6.5±1.3 to 4.1±1.0 (U·ml^–1·min^–1, p<0.05. The area under the curve representing above-basal levels of insulin during oral glucose tolerance test increased significantly following dexamethasone treatment from 48132±9736 to 82230±14846 pmol·l^–1·3 h^–1, p<0.05, the area under the curve of islet amyloid polypeptide increased from 1308±183 to 2448±501 pmol·l^–1·3h^–1, p<0.05. The overall insulin/islet amyloid polypeptide molar ratios calculated from the area under the curve during the 3-h period of the oral glucose tolerance test was not significantly different before and after dexamethasone treatment (42±5 vs 40±4). During the oral glucose tolerance test the insulin/islet amyloid polypeptide ratio increased significantly from baseline to 30 min (p<0.05), then declined towards initial values before and after dexamethasone treatment. In conclusion, dexamethasone induced a significant decrease in insulin sensivity and a significant increase in insulin secretion during the oral glucose tolerance test. However, in contrast to previous animal experiments we did not find a change in the insulin/islet amyloid polypeptide ratio before and after dexamethasone treatment.     

Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64-year-old women

Abstract. Fagerberg B, Kellis D, Bergström G, Behre CJ (Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden). Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64‐year‐old women. J Intern Med 2011; 269 : 636–643. Objectives. To examine how serum adiponectin levels predict the incidence of type 2 diabetes, from different prediabetic states, in relation to insulin sensitivity and β‐cell function during 5.5 years of follow‐up. Methods. In a population‐based cohort of 64‐year‐old Caucasian women, we assessed glucose tolerance, insulin sensitivity as homeostasis model assessment, insulin secretion as acute insulin response, lifestyle factors and serum concentrations of adiponectin and high‐sensitivity C‐reactive protein. After 5.5 years of follow‐up, 167 women with normal glucose tolerance (NGT) and 174 with impaired glucose tolerance (IGT) at baseline were re‐examined and incidence of diabetes was assessed. Results. A total of 69 new cases of diabetes were detected during follow‐up. Diabetes incidence was independently predicted by low levels of serum adiponectin, insulin resistance and insulin secretion, cigarette smoking, impaired fasting glucose (IFG) and IGT at baseline. Serum adiponectin below 11.54 g L^?1 was associated with an odds ratio of 3.6 (95% confidence interval 1.4–8.6) for future type 2 diabetes. At baseline, a high serum adiponectin concentration correlated positively with high levels of insulin sensitivity and insulin secretion. Women with incident diabetes had lower serum adiponectin levels in the NGT, IFG and IGT groups at baseline compared to those who did not develop diabetes during follow‐up. Conclusions. Low adiponectin concentrations were associated with future diabetes independently of insulin secretion and sensitivity, as well as IGT, IFG, smoking and abdominal obesity.