Bulangu L. Nyomba

Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians.

Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.

Racial differences in the relation between blood pressure and insulin resistance

BACKGROUND Insulin resistance and the concomitant compensatory hyperinsulinemia have been implicated in the pathogenesis of hypertension. However, reports on the relation between insulin and blood pressure are inconsistent. This study was designed to investigate the possibility of racial differences in this relation. METHODS We studied 116 Pima Indians, 53 whites, and 42 blacks who were normotensive and did not have diabetes; the groups were comparable with respect to mean age (29, 30, and 31 years, respectively) and blood pressure (113/70, 111/68, and 113/68 mm Hg, respectively). Insulin resistance was determined by the euglycemic-hyperinsulinemic clamp technique during low-dose (40 mU per square meter of body-surface area per minute) and high-dose (400 mU per square meter per minute) insulin infusions. RESULTS The Pima Indians had higher fasting plasma insulin concentrations than the whites or blacks (176, 138, and 122 pmol per liter, respectively; P = 0.002) and lower rates of whole-body glucose disposal during both the low-dose (12.7, 17.1, and 19.5 mmol per minute; P less than 0.001) and the high-dose (38.0, 43.1, and 45.7 mmol per minute; P less than 0.001) insulin infusions. After adjustment for age, sex, body weight, and percentage of body fat, mean blood pressure (calculated as 1/3 systolic pressure + 2/3 diastolic pressure) was significantly correlated with the fasting plasma insulin concentration (r = 0.42) and the rate of glucose disposal during the low-dose (r = -0.41) and high-dose (r = -0.49) insulin infusions (P less than 0.01 for each) in whites, but not in Pima Indians (r = -0.06, -0.02, and -0.04, respectively) or blacks (r = -0.10, -0.04, and 0.02, respectively). CONCLUSIONS The relations between insulinemia, insulin resistance, and blood pressure differ among racial groups and may be mediated by mechanisms active in whites, but not in Pima Indians or blacks.

Insulin resistance associated with lower rates of weight gain in Pima Indians.

UNLABELLED Insulin resistance is commonly associated with obesity and noninsulin-dependent diabetes. Whereas it predicts the development of diabetes, its effect on body weight change is unknown. We measured glucose disposal rates at submaximally- and maximally-stimulating insulin concentrations in 192 nondiabetic Pima Indians and followed their weight change over 3.5 +/- 1.8 y (mean +/- SD). RESULTS (a) Insulin-resistant subjects gained less weight than insulin-sensitive subjects (3.1 vs. 7.6 kg, P less than 0.0001). (b) The percent weight change per year correlated with glucose disposal at submaximally-(r = 0.19, P less than 0.01) and maximally-stimulating (r = 0.34, P less than 0.0001) insulin concentrations independent of sex, age, initial weight, and 24-h energy expenditure; the correlations were stronger for glucose oxidation than for glucose storage. (c) Weight gain was associated with an increase in insulin resistance more than four times that predicted from the cross-sectional data. We conclude that insulin resistance is associated with a reduced risk of weight gain in nondiabetic Pima Indians.

Distribution of In Vivo Insulin Action in Pima Indians as Mixture of Three Normal Distributions

If a single gene produced insulin resistance, with environmental effects creating some additional variance, insulin action might be distributed as a mixture of two normal distributions if the gene is dominant or recessive or as a mixture of three normal distributions if the gene is codominant. To estimate maximal insulin-stimulated glucose uptake rates (MaxMs), hyperinsulinemic-euglycemic clamps were performed on 245 nondiabetic Pima Indians (126 men, 119 women). Five models (for 1, 2, 3, 4, or 5 components each, normally distributed with a common variance) were fitted to the frequency distribution of MaxM by iterative maximum-likelihood estimation. The three-component model fit the data significantly better than a single normal distribution (χ2 = 14.3 with 4 df P < .01) or a mixture of two normal distributions (χ2 = 9.9 with 2 df, P < .01). Mixtures of four or five normal distributions did not fit the data significantly better than a mixture of three normal distributions. The first component of the distribution comprised 23%, the second 48%, and the third 29% of the total distribution. Similarly, the frequency distributions of fasting plasma insulin concentrations and a principal component score derived from MaxM and fasting insulin were best fitted by a mixture of three normal distributions. These results are consistent with the hypothesis that among Pimas, insulin resistance is determined by a single gene with a codominant mode of inheritance. Segregation analyses of studies performed in pedigrees are indicated to prove or disprove this genetic hypothesis.

Abnormal Regulation of Protein Tyrosine Phosphatase Activities in Skeletal Muscle of Insulin-Resistant Humans

Insulin resistance in skeletal muscle may be an expression of the genetic basis of a common form of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Impaired insulin action results from an apparent postreceptor defect in insulin signal transduction that limits the influence of the hormone on various protein serine/threonine kinases and phosphatases that are thought to contribute to the mechanism by which insulin affects intracellular events. The fact that numerous responses to insulin are affected suggests that the cause of insulin resistance involves an early step in insulin action. Therefore, we examined the influence of insulin on protein tyrosine phosphatase (PTPase) activities, which may counteract the protein tyrosine kinase activity of the insulin receptor in skeletal muscle of insulin-sensitive and insulin-resistant humans. Insulin infusion in vivo produced a rapid 25% suppression of soluble-PTPase activity in muscle of insulin-sensitive subjects, but this response was severely impaired in subjects who were insulin resistant. Insulin did not affect PTPase activity in the particulate fraction of muscle from either group, but basal particulate activity was 33% higher in resistant subjects than in sensitive subjects. Either or both of these abnormal characteristics of PTPase activities could be central to the causes of insulin resistance and NIDDM.

Defective insulin response of phosphorylase phosphatase in insulin-resistant humans.

Insulin-stimulated glycogen synthase activity in human muscle is reduced in insulin-resistant subjects. Insulin regulation of human muscle glycogen synthase may require activation of a type-1 protein phosphatase (PP-1). We investigated the change of phosphorylase phosphatase and glycogen synthase activities in muscle biopsies obtained during a 2-h hyperinsulinemic euglycemic clamp in 12 insulin-sensitive (group S) and 8 insulin-resistant (group R) subjects. Fasting phosphorylase phosphatase activity was lower in group R than in group S, and did not increase significantly with insulin infusion in group R until 20 min. In group S, phosphorylase phosphatase was significantly stimulated by 10 min, remaining significantly higher than in group R at all time points. The insulin-mediated changes in phosphatase activities were not decreased by 3 nM okadaic acid but were completely inhibited by 1 microM okadaic acid, thereby verifying that insulin-stimulated phosphorylase phosphatase is accounted for by a PP-1. Subcellular fractionation demonstrated reduced fasting PP-1 activities in both the glycogen and cytosolic fractions of muscle obtained from subjects in group R compared to those in group S. These results suggest that insulin activation of PP-1 could contribute to the stimulation of glycogen synthase by this hormone in human muscle. Lower fasting PP-1 activity in cytosol and glycogen fractions plus lower insulin-stimulated PP-1 activity could explain, in part, reduced insulin-stimulated glycogen synthase in skeletal muscle of insulin-resistant subjects.

Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin-resistant humans.

Insulin-stimulated glycogen synthase activity in human muscle correlates with insulin-mediated glucose disposal and is reduced in insulin-resistant subjects. Inhibition of the cyclic AMP-dependent protein kinase (A-kinase) is considered as a possible mechanism of insulin action for glycogen synthase activation. In this study, we investigated the time course of insulin action on human muscle A-kinase activity during a 2-h insulin infusion in 13 insulin-sensitive (group S) and 7 insulin-resistant subjects (group R). Muscle biopsies were obtained from quadriceps femoris muscle at times 0, 10, 20, 40, and 120 min. Insulin infusion resulted in significant inhibition of A-kinase activity at 20 and/or 40 min using 0.2, 0.6, and 1.0 microM cyclic AMP in group S. A-kinase activities both before and after insulin administration were lower in group S than in group R using 0.6 microM cyclic AMP. The decrease in apparent affinity for cyclic AMP during insulin infusion was larger for group S compared with group R. Glycogen synthase activity increased significantly after insulin infusion in both groups and was higher in group S compared with group R. The data suggest that a defective response of A-kinase to insulin in insulin-resistant subjects could contribute to their reduced insulin stimulation of skeletal muscle glycogen synthase.

Skeletal muscle glycogen synthase activity in subjects with non-insulin-dependent diabetes mellitus after glyburide therapy☆

Sulfonylureas are used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) largely because of their ability to enhance insulin secretion and possibly to potentiate insulin action. In this study, we investigated the effects of chronic glyburide treatment on glycogen synthase activity determined in skeletal muscle biopsies taken during euglycemic hyperinsulinemic clamps in nine Pima Indians with NIDDM. Insulin was infused at the rate of 40 mU/m2/min (low dose) followed by 400 mU/m2/min (high dose). Compared with the fasting value, the mean glycogen synthase activity assayed at low glucose-6-phosphate (G6P) concentration (active glycogen synthase) showed no significant changes during insulin infusion before glyburide treatment. After glyburide treatment, the mean active glycogen synthase increased by 39% (P less than .05) above the fasting value during the high-dose insulin infusion. Total glycogen synthase activity assayed at high G6P concentration did not change after glyburide treatment. Changes of insulin-stimulated active glycogen synthase associated with glyburide treatment correlated with changes in total body glucose disposal rates (r = .70, P less than .05) during euglycemic clamps. We conclude that glyburide treatment of subjects with NIDDM is associated with an increase in insulin action in vivo and concomitantly with improved insulin action on skeletal muscle glycogen synthase.

Euglycemic hyperinsulinemia increases glucose 1,6-bisphosphate in human skeletal muscle

1. The effects of physiologic concentrations of insulin on the contents of glucose 1,6-bisphosphate (glucose 1,6-P2) and regulators of glucose 1,6-P2 synthase in intact human skeletal muscle have been investigated. 2. Insulin increased glucose 1,6-P2 from a basal value of 70 +/- 6 to 135 +/- 12 mumol/kg dry wt (P less than 0.001). 3. Activation of synthase could not be associated with changes in its inhibitors (fructose 1,6-P2, Pi, citrate) or its substrate glucose 6-P.