Direct Measures Of Insulin Sensitivity Research Articles

Sensitivity to acute insulin-mediated suppression of plasma free fatty acids is not a determinant of fasting VLDL triglyceride secretion in healthy humans.

One important mechanism whereby obesity-associated insulin resistance leads to VLDL overproduction is thought to be by the increased flux of free fatty acids (FFAs) from extrahepatic tissues to liver, which arises as a direct consequence of impaired insulin action in adipose tissue and skeletal muscle. The aim of the present study was to address whether direct measures of peripheral tissue insulin sensitivity with regard to FFAs and glucose in the fasting state are good predictors of postabsorptive VLDL triglyceride secretion rate (VLDL-TG ASR) in humans, independent of obesity. Eighteen healthy control subjects, after an overnight fast, underwent three studies 3 weeks apart, in random order. Study 1: VLDL-TG levels, fractional clearance rate (per h), and VLDL-TG ASR were determined after an intravenous bolus of [1,1,2,3,3-(2)H(5)] glycerol. Study 2: Insulin sensitivity (S(I)), acute insulin response (AIR), and acute C-peptide response to glucose were assessed by frequently sampled intravenous glucose tolerance test using the minimal model approach. Study 3: Insulin-mediated suppression of plasma FFAs (k) and insulin clearance were assessed in response to a low-dose stepwise intravenous insulin infusion. BMI (R(2) = 0.54), AIR, and fasting insulin levels were positively and S(I) negatively correlated with VLDL-TG ASR, but there was no significant association with plasma FFAs or k. Only BMI remained significantly associated with VLDL-TG ASR in multivariate analysis. The best multivariate model for VLDL-TG ASR (R(2) = 0.61, P = 0.0008) included BMI (P = 0.0008) and S(I) (P = 0.12, inversely correlated). VLDL-TG secretion is predicted by BMI, independently of direct measures of insulin sensitivity. The sensitivity to insulin's acute suppressive effect on plasma FFA levels during fasting is not an important determinant of postabsorptive VLDL-TG secretion in humans.

Increased insulin sensitivity in young, growth hormone deficient children.

Although growth hormone (GH) has well documented insulin antagonistic effects, GH deficient adults often demonstrate insulin resistance. In young GH deficient children, increased susceptibility to hypoglycaemia might indicate increased insulin sensitivity; however, this has not been documented. We therefore determined insulin sensitivity in GH deficient and GH sufficient children. Prospective study of children undergoing insulin tolerance tests for clinical investigation of GH or cortisol secretion at a regional Paediatric Endocrine/Growth Clinic between October 1986 and December 1997. Ninety-one tests were performed in children with GH deficiency and 142 tests in children with normal GH response to insulin (peak GH > or = 20 IU/l). The standard insulin tolerance test was modified to permit frequent measurements of glucose (0, 5, 10, 15, 20, 30, 45, 60 and 90 minutes). Rate of log glucose disappearance in the first 15 minutes was calculated as a direct measure of insulin sensitivity. GH deficient children were more insulin sensitive than GH sufficient children (P = 0.004) and had lower glucose nadirs post-insulin (P = 0.005). Subgroup analysis revealed that these differences were greater in younger (< 12 years old) or pre/early pubertal children. In 14 prepubertal children, exogenous sex steroid priming resulted in lower insulin sensitivity (P < 0.05) compared to nonprimed tests. Young GH deficient children were more insulin sensitive than children with normal GH secretion. This difference attenuated with age and puberty, possibly secondary to pubertal sex steroids; however, insulin resistance as reported in GH deficient adults, was not observed in adolescents.

Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds.

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.

Insulin resistance syndrome in preeclampsia.

Because changes in lipids, lipoprotein, and other metabolic processes, such as hyperinsulinemia and hyperuricemia, found in preeclampsia resemble the main features of the insulin resistance syndrome, it has been proposed that insulin resistance may be the common denominator for such metabolic changes. Several groups, using euglycemic-hyperinsulinemic clamping or intravenous glucose tolerance tests (Bergman's minimal model technique), have demonstrated insulin resistance during late pregnancy. Women with preeclampsia had higher fasting insulin levels, but also exaggerated hyperinsulinemia, in response to an oral glucose tolerance test, which is consistent with increased insulin resistance in preeclampsia. No direct measurement of insulin sensitivity (clamp or minimal model) has as yet been performed during preeclampsia. Increased insulin resistance can activate the sympathetic nervous system and lead to an increase in expression of receptors for endothelin, both of which events lead to increased blood pressure. Hyperinsulinemia can also induce hypertriglyceridemia, leading to endothelial dysfunction and reduction of prostacyclin production. This hyperinsulinemia can persist for as long as 17 years after preeclamptic pregnancy and may contribute to a woman's increased risk of cardiovascular disease. Insulin resistance may not be the cause of preeclampsia, but is one of the pathogenic factors, especially in genetically predisposed women.

Ovarian morphology and insulin sensitivity in women with bulimia nervosa

Hyperinsulinaemia has a role in the development of hyperandrogenism and polycystic ovary syndrome in women of normal weight. Polycystic ovaries are common in women with bulimia nervosa and this study aimed to determine whether women with bulimia nervosa are insulin resistant and to examine the relation between insulin sensitivity and ovarian morphology. A short intravenous insulin tolerance test was used as a direct measure of insulin sensitivity in a group of women with bulimia nervosa and a control group. A series of 12 women with bulimia nervosa and normal weight was compared with a control group of 9 healthy women who had no clinical signs of eating disorder or hyperandrogenism and did not have polycystic ovaries. Bulimic behaviour was assessed using the BITE (Bulimia Investigation Test, Edinburgh) questionnaire and clinical interviews. Ovarian morphology was assessed using transabdominal ultrasonography. Insulin sensitivity and serum insulin, fasting glucose, LH, FSH, prolactin, testosterone, androstenedione and sex hormone binding globulin (SHBG) were measured and compared between the two groups. Ten of the 12 women with bulimia nervosa underwent ovarian ultrasound examination and they all had polycystic ovaries. There was no difference in serum LH, FSH, testosterone, androstenedione of SHBG concentrations between the women with bulimia nervosa and the non-bulimic control group. Fasting blood glucose concentrations were normal in all the women studied and did not differ between the women with bulimia nervosa and the control women. There was also no difference in fasting serum insulin or insulin sensitivity between the women with bulimia nervosa and the nonbulimic women. Bulimia nervosa is not associated with insulin resistance and chronic hyperinsulinaemia.

A BREIF ORIGINAL CONTRIBUTION

Both abnormal insulin levels and low insulin sensitivity have been implicated as risk factors for Type II diabetes mellitus and cardiovascular disease. While insulin level is relatively simple to assess, direct measurement of insulin sensitivity is much more invasive, costly, and time-consuming. The authors considered eight previously described measures or indices of insulin sensitivity derived from the frequently sampled intravenous glucose tolerance test (FSIGT). Each one was evaluated by strength and consistency of association with insulin sensitivity computed from glucose clamp (S1(clamp)), across three glucose tolerance groups, including participants with normal glucose tolerance (n = 11), impaired glucose tolerance (n = 20), and non-insulin-dependent diabetes mellitus (n = 24). Minimal model analysis (MINMOD S1(22)), based on the 22-sample FSIGT, performed best based on statistical criteria of strong and consistent association with S1(clamp). An insulin sensitivity measure similar to that of Galvin et al. (Diabetic Medicine 1990;9:921–8), defined as glucose disappearance (10–50 minutes) divided by insulin area under the curve above baseline from 0–50 minutes, performed best based on statistical criteria and time-savings. Galvin insulin sensitivity is simple to calculate, requires only a 50–minute FSIGT, and is significantly (p ≤ 0.001) and not inconsistently (p = 0.12 for inconsistent association) associated with S1(clamp) over a wide range of glucose tolerance. Am J Epidemiol 1995;142:724–32.

Physiological and metabolic consequences of obesity

Fasting plasma insulin levels provide an indirect indication of insulin resistance. Glucose utilization rate, measured by the euglycemic clamp technique, is a direct measure of insulin sensitivity. Insulin sensitivity decreases with increasing body mass index (BMI) in the range of 27 to 35 kg/m 2. A higher waist-to-hip ratio is associated with lower insulin sensitivity, after adjusting for BMI. Obese patients have higher plasma free fatty acid levels and less suppression of lipolysis by insulin than lean individuals. The increased supply of fatty substrates and their competition with glucose for oxidation constitute a component of insulin resistance in obesity. Both systolic and diastolic blood pressure are increased with BMI. The hemodynamic effects may be due to an increase in cardiac output and enhanced activity of the adrenergic nervous system.

Evidence of higher insulin resistance in NIDDM patients with ischaemic heart disease.

Prospective studies have shown a relationship between hyperinsulinaemia, an indirect index of insulin resistance, and IHD in men with normal glucose tolerance. In NIDDM this association is less clear possibly due to the poor significance of insulin and C-peptide concentrations as an index of insulin resistance. Therefore, only a direct measurement of insulin sensitivity could clarify the possible relationship between insulin resistance and IHD in NIDDM. We have evaluated insulin sensitivity, by means of an ITT, and some risk factors for IHD in 72 men with NIDDM, 36 with and 36 without IHD, attending our out-patient Diabetic Clinic. The two groups were of similar age, duration of diabetes, glycaemic control and body composition. Subjects with IHD were more insulin resistant (K(ITT) index 2.45 +/- 0.18 vs 3.12 +/- 0.13% per min, in patients with and without IHD, respectively, p < 0.004), had higher total (p = 0.011) and LDL serum cholesterol levels (p = 0.010) and greater prevalence of hypertension (p = 0.001) compared to subjects without IHD. Using step-wise logistic regression analysis, insulin resistance (odds ratio 2.57, 95% CI 1.87-3.28, p = 0.008), hypertension (odds ratio 8.17, 95% CI 6.86-9.48, p = 0.002), total serum cholesterol levels (odds ratio 1.02, 95% CI 1.005-1.035, p = 0.015) and BMI (0.79, 95% CI 0.67-0.97, p = 0.049) were independently associated with IHD. After adjustment for age and duration of diabetes, only insulin sensitivity was directly related to the age of onset of IHD, independently from other clinical and metabolic parameters (p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

A minimal-model-based glucose clamp yielding insulin sensitivity independent of glycemia.

A new technique is introduced for automatic control of the blood sugar ("glucose clamp") at basal (euglycemic) or elevated (hyperglycemic) levels during variable insulin infusion. A minimal mathematical model of glucose kinetics is implemented on a laboratory minicomputer during clamp experiments. From the measured time course of plasma glucose concentration, the computer estimates the fractional disappearance rate of glucose (X) and calculates the rate of exogenous infusion required to match the desired concentration (M). Eight clamp experiments were performed on three conscious dogs. Euglycemic (N = 4): insulin was infused at 8, 40, and 150 microU/min for sequential 2.5-h periods )I, II, and III); hyperglycemic (N = 4): following the establishment of 140 mg/dl hyperglycemia (period I), insulin was infused at 30 and 120 mU/min for 2.5 h each (periods II and III). Plasma insulin levels [range: 21 +/- 9 (basal) to 1729 +/- 209 microunits/ml] were matched in comparable periods in the two types of experiments [P greater than 0.8 (I); P greater than 0.5 (II), P greater than 0.2 (III)]. Glucose was successfully clamped for all periods at euglycemia (99.6 +/- 0.7% of desired value) and hyperglycemia (100.0 +/- 1.1% desired 140-mg/dl value). Glucose infusion rates necessary to achieve stable glycemia were greater at elevated than basal glucose (P less than 0.001) despite comparable insulinemia during the three insulin infusion periods. Thus, the glucose infusion rate versus insulin level (M/I) was glycemia-dependent, and therefore not a direct measure of insulin sensitivity. In contrast, the insulin-induced increases in fractional glucose disappearance (delta X), also provided by our clamp technique during experiments, were highly correlated within insulin (r = 0.08 to r = 0.99, P less than 0.01) and independent of glycemia (P greater than 0.7). The ratio delta X/delta I (increase in glucose fractional disappearance rate/incremental insulin level) was a measure of insulin sensitivity independent of glycemia, and could successfully differentiate insulin-resistant from normal animals (P less than 0.001; delta X/delta I in three animals: 6.9 X 10(-4), 5.5 X 10(-4), and 1.4 X 10(-4) min-1 microunits/ml). Thus, this model-dependent glucose clamp technique provides a direct measurement of insulin sensitivity independent of glycemia.