Frequently-sampled Intravenous Glucose Tolerance Research Articles

Circulating soluble CD36 is associated with glucose metabolism and interleukin-6 in glucose-intolerant men

Recently, soluble CD36 (sCD36) levels were reported to be elevated in type 2 diabetes, and to be tightly correlated with insulin resistance. Our aim was to obtain further insight into the relationship between insulin sensitivity, low-grade inflammation and sCD36. We studied glucose-tolerant (n=90) and glucose-intolerant (n=57) moderately obese men. Insulin sensitivity was measured by the frequent sample intravenous glucose tolerance test, and sCD36 by an in-house ELISA assay. In glucose-intolerant subjects, sCD36 was negatively associated with insulin sensitivity and positively with interleukin-6 (IL-6), fasting glucose, fasting triglycerides, fat-free mass and platelet count. On multiple linear regression analyses, insulin sensitivity contributed 22% of sCD36 variance, independent of age, body mass index (BMI) and IL-6, in glucose-intolerant subjects. The level of sCD36 in subjects with glycosylated haemoglobin (HbA1C) above the mean was higher than in those with HbA1C values below the mean. Insulin sensitivity is a predictor of sCD36 in men with impaired glucose tolerance. IL-6 is related to sCD36 but does not predict sCD36 independent of insulin sensitivity and BMI.

Insulin resistance and compensation in laminitis-predisposed ponies characterized by the Minimal Model

4Summary Glucose metabolism in Welsh and Dartmoor ponies and ponies disposed to pasture laminitis was characterized using the Minimal Model of glucose and insulin dynamics. Laminitis-disposed ponies were selected based on farm records of previous disease incidence and nonparallel hoof-lines. All ponies were maintained on pasture and in early March each underwent a frequent sampling intravenous (iv) glucose tolerance test which involved a bolus of 300 mg/kg glucose followed 20 min later by an iv bolus of 20 mIU/kg insulin. Sampling began just prior to the glucose dose and continued for 4 h. Glucose and insulin curves were modeled to determine insulin sensitivity, glucose effectiveness, acute insulin response to glucose and disposition index. Ponies with previous incidents of laminitis were less insulin sensitive and demonstrated compensatory insulin hypersecretion compared to ponies not at risk. Management of at-risk ponies to avoid insulin resistance and triggers for insulin secretion could reduce the likelihood of developing clinical laminitis.

Hyperglycaemia after glucose loading is a major predictor of preclinical atherosclerosis in nondiabetic subjects

Carotid intima-media thickness (IMT) has proved to be an independent marker of preclinical atherosclerosis. The aim of this study was to determine whether carotid IMT is associated with the plasma glucose concentration in the fasting state, after loading with oral glucose, or with the insulin sensitivity index (ISI) in nondiabetic subjects with different levels of glucose intolerance and insulin resistance. Cross-sectional study. A total of 160 nondiabetic subjects (147 from our obesity-overweight clinic and 13 healthy normal subjects) were included in the present study, among them 33 had normal glucose tolerance (NGT), 13 had impaired fasting glucose (IFG), 80 had impaired glucose tolerance (IGT) and 34 had both IFG and IGT. Carotid IMT was assessed in the common carotid artery by a high-resolution B-mode ultrasound system. Plasma glucose was measured after fasting and at 30 min, 1, 2 and 3 h after a standard 75-g load of glucose. The ISI was calculated from the frequent sampling intravenous glucose tolerance test (FSIGT). Results The IMT values in the NGT group were lower than those in the IFG, IGT and IFG + IGT groups (P < 0.03). No statistical difference in IMT values was found among the latter three groups. Univariate correlation analyses showed that the IMT was positively associated with age, plasma glucose concentrations 1 and 2 h after glucose loading, and serum concentration of low density lipoprotein (LDL) cholesterol (r=0.39, 0.22, 0.25 and 0.18, respectively, P<0.05). Multiple regression analysis showed that only age, plasma glucose concentration 2 h after glucose loading, and LDL cholesterol appeared to be significant correlates of the IMT (P<0.0001), whereas the ISI was not. In nondiabetic subjects with various degrees of glucose intolerance, there was a significant increase in IMT in those with IFG and IGT. Significant determinants of IMT, an indicator of preclinical atherosclerosis, include hyperglycaemia 2 h after a glucose load, age and LDL cholesterol, whereas fasting glucose concentration and the ISI were not significantly associated with IMT.

The glucose response to an oral fat tolerance test in young men with a paternal history of premature myocardial infarction: possible early indication of insulin resistance. The EARS 2 study

Concentrations of cholesterol, triglycerides and glucose are higher in young men with a paternal history of premature myocardial infarction than in age- and sex-matched controls. To test the hypothesis that insulin resistance constitutes the biological expression of increased coronary risk in these subjects. A total of 407 male university students with a paternal history of premature myocardial infarction (cases) and 415 age- and sex-matched controls were investigated for differences in insulin sensitivity. Four methods of assessing insulin sensitivity were used: (i) insulin and glucose responses to an oral glucose tolerance test (OGTT); (ii) insulin and glucose responses to an oral fat tolerance test (OFTT); (iii) minimal modelling of insulin and glucose data from a frequent sample intravenous glucose tolerance test performed on a subset of 55 cases and 50 controls and (iv) homeostasis model assessment (HOMA) of insulin resistance. The OFTT glucose response discriminated between cases and controls, with a smaller fall in glucose in cases compared with controls. The negative area under the glucose curve (AUC) (mean [standard error of the mean (SEM)]) was -1.42 (0.09) mmol min/L in cases and -1.76 (0.09) in controls (P = 0.004). Peak height (mean [SEM]) was -0.65 (0.02) mmol/L in cases and -0.73 (0.02) in controls (P = 0.007). The insulin responses were similar in cases and controls. Insulin AUC (mean [SEM]) was 161 (10) mU min/L in cases and 148 (10) in controls (P = 0.34). This combination of findings suggests that insulin-stimulated glucose uptake was reduced in the cases. These findings were consistent across European regions. None of the other methods revealed any differences between cases and controls. In young men with a paternal history of myocardial infarction, an OFTT detects altered insulin sensitivity that is not identified by an OGTT, minimal modelling or HOMA.

Successful treatment of renovascular hypertension has no effect on insulin sensitivity.

The association of insulin resistance (IR) and essential hypertension is well known, but a causal relationship has not been proven. Patients with secondary hypertension as a result of renal artery stenosis (RAS) usually do not reveal IR, but no study has addressed the effect of blood pressure reduction after successful treatment of RAS on insulin sensitivity and glucose effectiveness. The insulin sensitivity index (SI) and glucose effectiveness (SG) were measured before and after successful intervention of an angiographically proven significant RAS in 18 out of 23 patients (eight males/10 females; mean age 51.5 +/- 13.1 years) in which improvement/cure of arterial hypertension was achieved. After a mean of 10.7 months, patients were reevaluated for 24-h blood-pressure measurement, kidney function, adrenaline, noradrenaline, plasma-renin-activity (PRA), aldosterone, atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP), and glucose metabolism parameters such as basal insulin, glucose disappearance constant (K-value), SI and SG. For calculation of SI and SG, insulin and glucose data from the modified frequent sampling intravenous glucose tolerance test (FSIGT) were submitted to the MINMOD program. After intervention, systolic 24-h blood pressure had decreased from 156.1 +/- 16.4 mmHg to 139.9 +/- 15.1 mmHg, and diastolic 24-h blood pressure from 97.1 +/- 14.7 mmHg to 87.3 +/- 13.4 mmHg. No significant change in SI (before 4.3 +/- 2.0, after 4.8 +/- 2.0 min(-1) per microU mL(-1)) or SG (before 1.55 +/- 0.42x10(-2) min(-1), after 1.8 +/- 0.48x10(-2) min(-1)) was observed. Aldosterone decreased from 246.7 +/- 180.7 to 115 +/- 61.4 (P=0.009) as PRA decreased from 12.4 +/- 11.4 to 4.2 +/- 7.6 ng mL h(-1) (P=0.01). Creatinine clearance, and adrenaline and noradrenaline levels as well as ANP and cGMP did not change after treatment for RAS. Subsequent to the definition of IR (SI < or =3.2x10(-4) min(-1) per microU mL(-1)) some differences among these two subgroups (SI < or =3.2, or SI>3.2) could be found. Patients with IR (n=8) were characterized by a higher body mass index (BMI), higher basal insulin values and significantly lower cGMP values. Only the group without IR (n=10) developed significant improvement of systolic blood pressure. We conclude that blood pressure reduction by treatment of RAS does not alter insulin action and that there is no link between the circulating concentrations of renin/aldosterone and glucose metabolism in renovascular hypertension (RVH). The results do not support the hypothesis of a direct link between blood pressure in RVH and the individual state of insulin sensitivity. However, patients with a normal SI are more likely to experience an almost normalization of arterial blood pressure after treatment for RAS.

Insulin sensitivity, glucose effectiveness, and insulin secretion in nondiabetic offspring of patients with non—insulin-dependent diabetes mellitus: A cross-sectional study

To evaluate the factors that determine the worsening of intravenous glucose tolerance in subjects at high risk for developing non—insulin-dependent diabetes mellitus (NIDDM), 15 glucose-tolerant offspring of NIDDM patients and 21 control subjects were studied. Each subject underwent a frequently sampled intravenous glucose tolerance (FSIGT) test. The intravenous glucose tolerance index (K G index) was calculated between minutes 10 and 40 of a FSIGT test. Insulin sensitivity (S 1), glucose effectiveness at zero insulin (GEZI), and first- and second-phase insulin responsiveness (Φ 1 and Φ 2) were estimated using glucose and insulin kinetic minimal models. The acute insulin response to glucose (AIRg) was calculated as the area under the insulin curve above the basal level between 0 and 10 minutes, and the suprabasal insulin effect was determined by the product of S 1 times AIRg. Offspring had a lower S 1 than control subjects (14.1 ± 7.5 v 9.25 ± 4.20 × 10 −5 · min −1(pmol · L −1) −1, P < .01), and their AIRg was similar (3,284 ± 2,280 v 3,105 ± 1,499 pmol · L −1, NS). Sample division according to the median K G value showed that control subjects with low tolerance had a lower AIRg (4,417 ± 2,531 v 2,043 ± 1,068 pmol · L −1, P < .05) and a lower suprabasal insulin effect (0.057 ± 0.03 v 0.023 ± 0.009 min −1, P < .05) than control subjects with high tolerance. Offspring with low tolerance had a lower AIRg (2,574 ± 1,197 v 3,707 ± 1,656 pmol · L −1, P < .05) and a lower GEZI (0.101 ± 0.05 v 0.212 ± 0.08 · 10 −1 · min −1, P < .05) than offspring with high tolerance. Offspring with high and low tolerance showed lower Φ 1 (375 ± 155 v 272 ± 181 v 698 ± 336 (pmol · L −1)min(mmol · L −1), NS) than control subjects with high tolerance. In conclusion, our data suggest that decreases in GEZI and AIRg are the main factors responsible for the worsening of intravenous glucose tolerance in the offspring of NIDDM patients.

Relationships between insulin resistance and lipoproteins in nondiabetic African Americans, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study.

The study purpose was to explore the association between dyslipidemia and insulin resistance in three ethnic groups. The Insulin Resistance Atherosclerosis Study (IRAS) is a multicenter epidemiologic study conducted at four clinical centers in California, Texas, and Colorado. The study population for this analysis consisted of 931 non-Hispanic white, African American, and Hispanic men and women (aged 45 to 64 years) without diabetes. The IRAS clinical examinations included lipoprotein measures, a 75-g glucose tolerance test, and the frequently sampled intravenous glucose tolerance (FSIGT) test. The results show a consistent relationship between insulin-mediated glucose disposal and dyslipidemia in African American, Hispanic, and non-Hispanic white men and women. Further, LDL size was inversely associated with insulin resistance in all three ethnic groups. These findings indicate that dyslipidemia is a fundamental part of the insulin resistance syndrome in all of the ethnic groups studied.

Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease

In uremic patients resistance to the action of insulin has been documented, but it is not known at what stage of renal disease it appears. We therefore examined 29 patients with IgA glomerulonephritis (IgAGN) and 21 patients with adult polycystic kidney disease (ADPKD) in different stages of renal failure, and in addition, healthy age-matched subjects. Insulin sensitivity and other variables of glucose metabolism were assessed using a frequent sampling intravenous glucose tolerance test (minimal-model technique). Glomerular filtration rate (GFR) was assessed in renal patients using the inulin-clearance technique. Mean insulin sensitivity index (SI), that is, insulin sensitivity, was significantly lower (P < 0.001) in all patients combined than in matched healthy subjects (N = 16; 14 males, mean age 42 +/- 3 years; mean SI 8.6 +/- 0.8 min-1 uU/ml). The mean SI was not significantly different in patients with renal disease of immune (IgAGN) or non-immune (ADPKD) origin, and it was not correlated with GFR (r = 0.01, P < 0.52), intact PTH (r = -0.23, P < 0.11) or calcitriol concentration (r = -0.03, P < 0.82). Consequently, the mean SI was similar in renal patients with GFR within the normal range (N = 19; 17 males, mean age 41 +/- 2 years; mean GFR 119 +/- 5 ml/min/1.73 m2; 5.1 +/- 0.7 min-1 uU/ml), in patients with mild to moderate renal failure (N = 16; 15 males, 46 +/- 3 years; 67 +/- 4 ml/min/1.73 m2; 5.1 +/- 0.7 min-1 microU/ml) and in patients with advanced renal failure (N = 15; 13 males, 46 +/- 3 years; 25 +/- 2 ml/min/1.73 m2; 4.7 +/- 0.6 min-1 uU/ml). Mean fasted plasma insulin concentration, the area under the curve for plasma insulin concentration (AUC) and total insulin delivery (TID) during the glucose tolerance test were significantly higher in patients than in healthy subjects, reflecting hyperinsulinemia in renal patients. Further, fasted plasma insulin concentration (r = -0.32, P < 0.009), AUC (r = -0.62, P < 0.0001) and TID (r = -0.34, P < 0.004) in patients were significantly correlated with insulin sensitivity (SI). The present data document that insulin resistance and concomitant hyperinsulinemia are present early in the course of renal disease, that is, even in patients with GFR within the normal range, irrespective of the type of renal disease. This observation may have potential implications with respect to the high cardiovascular morbidity and mortality in patients with renal disease.

Insulin sensitivity, glucose effectiveness, and β-cell function in obese males with essential hypertension: Investigation of the effects of treatment with a calcium channel blocker (diltiazem) or an angiotensin-converting enzyme inhibitor (quinapril)

It has been suggested that hyperinsulinemia secondary to insulin resistance may be a pathogenetic factor common to obesity, non-insulin-dependent diabetes mellitus (NIDDM), and hypertension. Furthermore, β-blockers and thiazide diuretics have been shown to be capable of increasing insulin resistance and thus of inducing NIDDM in predisposed individuals. We used the minimal model approach (MMA) to glucose metabolism and insulin kinetics to compare peripheral insulin sensitivity and β-cell function in hypertensive and normotensive obese men. The hypertensive group consisted of 37 obese men with mild to moderate hypertension; following a drug-free period of 4 weeks, 20 of these subjects received diltiazem and 17 quinapril over the 12-week study period. The normotensive (control) group contained 17 obese men without microalbuminuria, dyslipidemia, or a family history of essential hypertension or NIDDM. Before and at the end of the 12-week study period, subjects underwent frequently sampled intravenous glucose tolerance (FSIGT) tests. The results were used to estimate an insulin sensitivity index (S 1), a glucose effectiveness index (S G), and β-cell sensitivity to glucose indices during first- and second-phase insulin secretion (Φ 1 and Φ 2) using the minimal models of glucose metabolism and insulin kinetics. No significant differences in S l or S G were detected between the hypertensive and control groups. Twelve weeks' treatment with diltiazem led to a slight but significant increase in Φ 1; however, neither diltiazem nor quinapril had significant effects on S l or S G. We conclude that men with obesity and hypertension have no greater insulin resistance than those with obesity alone, suggesting that hypertension is not generally associated with any significant increase in insulin resistance. Treatment with diltiazem or quinapril does not have undesirable effects on glucose metabolism. However, treatment with diltiazem led to a significant increase in β-cell sensitivity to glucose; this is of particular interest, given the importance of Φ 1 for peripheral glucose uptake.

Minimal model analyses of insulin sensitivity and glucose-dependent glucose disposal in black and white Americans: a study of persons at risk for type 2 diabetes.

We have examined the impact of race and positive family history of type 2 diabetes on glucose/insulin dynamics and the two components of glucose disposal in healthy, first-degree relatives of black and white American patients with type 2 diabetes mellitus who are at a greater risk from the disease and their healthy control subjects. Seventeen black and 15 white relatives were studied. Twenty-two black people and 24 white people, without family history of type 2 diabetes, served as healthy control subjects. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified frequent sampling intravenous glucose tolerance (FSIGT) tests were performed in each subject. Insulin sensitivity index (SI) and glucose effectiveness (SG) were calculated using the MINIMOD method described by Bergman et al. Mean fasting and post-stimulation serum glucose levels were not significantly different in the black and white relatives. However, mean serum insulin responses to oral and/or intravenous stimulation were significantly greater in the blacks than whites, irrespective of positive family history of diabetes. The mean SI was significantly (P < 0.02) lower (52%) in the black (3.67 +/- 0.56) than the white [7.50 +/- 1.93 x 10(-4) min-1 (mU1)-1] relatives. Comparing the healthy controls, the mean SI was significantly (P < 0.02) lower (51%) in black than white controls (4.84 +/- 0.78 vs. 9.71 +/- 1.27 x 10 min-1(mU1)-1]. Mean SG and KG were greater (P < 0.05) in the blacks than whites, irrespective of family history of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity and body fat distribution in normotensive offspring of hypertensive parents

Lean, healthy normotensive sons of essential hypertensive parents (OHyp) have lower insulin sensitivity (SI) than sons of normotensive parents (ONorm). We have tried to find out whether this disturbance in insulin metabolism is related to altered body fat distribution, fuel metabolism, or both.21 OHyp and 21 ONorm of similar age and body-mass index were investigated after fasting overnight. Body composition was assessed by dual-energy X-ray absorptiometry and fuel metabolism by indirect calorimetry and urinary nitrogen excretion. Plasma insulin and glucose concentrations were measured during the frequent sampling intravenous glucose tolerance test, and SI was calculated by the minimum model method. Systolic blood pressure and heart rate were slightly but not significantly higher in OHyp than ONorm but the groups did not differ in fasting plasma insulin or glucose concentrations, carbohydrate or lipid oxidation, lean and fat mass, bone mineral content, or distribution of body fat. By contrast, SI was significantly lower in OHyp than ONorm (8·2 [0·7] vs 13·4 [1·5] 10-4 L mU-1 min-1, p<0·01). Within the whole study population upper-body fat mass was positively correlated with fasting plasma insulin (r=0·33, p<0·03) and lipid oxidation was positively correlated with SI (r=0·35, p<0·04) and negatively correlated with subscapular/triceps skinfold thickness (r=-0·43, p<0·01).Thus, impairment of SI precedes both the development of overt hypertension and gain or redistribution of body fat. Therefore, the concept that SI is low as a result of altered fat distribution has to be reconsidered, at least in young male offspring of hypertensive parents.

MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test

Insulin sensitivity and pancreatic responsivity are the two main factors controlling glucose tolerance. We have proposed a method for measuring these two factors, using computer analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). This ‘minimal modelling approach’ fits two mathematical models with FSIGT glucose and insulin data: one of glucose disappearance and one of insulin kinetics. MINMOD is the computer program which identifies the model parameters for each individual. A nonlinear least squares estimation technique is used, employing a gradient-type of estimation algorithm, and the first derivatives (not known analitically) are computed according to the ‘sensitivity approach’. The program yields the parameter estimates and the precision of their estimation. From the model parameters, it is possible to extract four indices: (1) S G , the ability of glucose per se to enhance its own disappearance at basal insulin, (2) S 1, the tissue insulin sensitivity index, (3) φ 1, first phase pancreatic responsitivity, and (4) φ 2, second phase pancreatic responsitivity. These four characteristic parameters have been shown to represent an integrated metabolic portrait of a single individual.