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C Bogardus

Publications and source records attributed to C Bogardus.

At least 163 records · Page 9Linked to original sources
PubMed1989

Adenosine 3',5'-monophosphate-dependent protein kinase activity decreases in human muscle after insulin infusion.

We have previously reported that the increase in glycogen synthase activity in human muscle during a euglycemic clamp was not associated with a measured increase in glycogen synthase phosphatase activity after a 200-min insulin administration. To investigate further the mechanism of the regulation of human muscle glycogen synthase by insulin, we measured the activity of cAMP-dependent protein kinase before and after a 200-min hyperinsulinemic euglycemic clamp in Southwest American Indians. Insulin infusion resulted in a decreased cAMP-dependent protein kinase activity assayed at physiological cAMP concentration with increased glycogen synthase activity in all subjects (n = 5; P less than 0.01). No significant change was observed in cAMP-independent protein kinase activity. These results suggest that 200 min of insulin administration during a euglycemic clamp may regulate human muscle glycogen synthase activity by mechanisms other than the stimulation of phosphatase; one probable mechanism is by decreasing the activity of cAMP-dependent protein kinase.

Adult↗
PubMed1989

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 (chi 2 = 14.3 with 4 df P less than .01) or a mixture of two normal distributions (chi 2 = 9.9 with 2 df, P less than .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.

Adult↗
PubMed1988

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.

Adult↗
PubMed1988

Reduced rate of energy expenditure as a risk factor for body-weight gain.

The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.

Adolescent↗
PubMed1988

Obesity and insulin resistance: lessons learned from the Pima Indians.

Diabetes and obesity are epidemic in the Pima Indians of the Southwestern United States, and the prevalence of diabetes is increasing. The most likely link between obesity and diabetes is tissue insulin resistance. If obesity is defined as an excess of body fat, then it can only be accurately assessed by measurements of body composition and not by approximations such as body mass index or percent of ideal weight. To compare the metabolic data of individuals of varying size, an accurate measure of metabolic size is needed. Total body weight is not an appropriate means of comparing individuals since obese subjects have a greater proportion of nonmetabolizing mass (triglyceride). Body surface area shows a sex difference, and this may distort data if both sexes are present. From studies of metabolic rate we have determined that metabolic rate is directly proportional to the fat-free mass plus 18 kg, and we suggest that this weight can be equated with metabolic size. Glucose storage in skeletal muscle appears to be important in the disposal of an intravenous glucose load. Consistent with its role in glycogen storage, glycogen synthase enzyme is activated in proportion to the ability to dispose of glucose during a hyperinsulinemic, euglycemic clamp. The role of glycogen synthase is most notable at supraphysiological plasma insulin concentrations; and since glucose uptake at these insulin concentrations is highly familial independent of the degree of obesity, we suggest that there may be a specific genetic defect expressed in skeletal muscle that reduces insulin responsiveness in some subjects. The lack of correlation between 24 hour respiratory quotient measured in a metabolic chamber (a measure of the proportion of fat derived calories) and degree of obesity indicates that in obese Pima Indians insulin resistance is not due to an inhibition of glucose metabolism by free fatty acids (glucose-fatty acid-ketone cycle). Obesity is associated with an increase in fat-free mass almost kilogram- for kilogram with fat mass when compared to the lean state. A role for this increase in fat-free tissue in producing insulin resistance has been given insufficient attention in the past. With an increase in fat-free mass, muscle cells are hypertrophied and capillaries in muscle are more widely spaced. We propose that these biophysical changes in muscle mediate, at least in part, the effects of obesity to produce a reduction in insulin sensitivity and the abnormal kinetics of insulin action found in the obese.(ABSTRACT TRUNCATED AT 400 WORDS)

Body Surface Area↗
PubMed1988

Glucose-6-phosphate stimulation of human muscle glycogen synthase phosphatase.

The influence of glucose-6-phosphate (glucose-6-P) on skeletal muscle glycogen synthase phosphatase was examined in normal glucose-tolerant Southwest American Indians. Phosphatase was stimulated with physiological concentrations of glucose-6-P and inhibited by ATP (5 mmol/L) and glycogen (0.1%). Phosphatase activity was measured before and after insulin infusion using the euglycemic clamp technique. Although glycogen synthase fractional activity increased in all subjects, this increase was not related to a change in phosphatase activity in the absence or presence of glucose-6-P. These results suggest that glycogen synthase phosphatase from human muscle can be regulated by physiological concentrations of glucose-6-P, ATP, and glycogen, and that insulin does not alter glucose-6-P stimulation of the enzyme in normal subjects.

Adenosine Triphosphate↗
PubMed1988

Insulin response of components of whole-body and muscle carbohydrate metabolism in humans.

We measured total body insulin-mediated glucose uptake, carbohydrate oxidation, storage (nonoxidative disposal), muscle glycogen synthase activity, and muscle glucose 6-phosphate (G-6-P) content in response to five levels of insulinemia (means 16, 52, 152, 573, and 5,550 microU/ml) in 16 male glucose-tolerant volunteers. Insulin dissociation constants (KDs) for disposal, storage, and synthase activity (but not for oxidation) are coincident, suggesting that storage via glycogen synthesis could be a major determinant of glucose disposal. Increases in glucose disposal were associated with decreases in muscle G-6-P concentration. These data suggest that the principal control over carbohydrate disposal is exerted after G-6-P. The coincidence of insulin sensitivities for disposal, storage, and synthase activity suggest that storage via glycogen synthesis could be a major determinant of glucose disposal.

Carbohydrate Metabolism↗
PubMed1988

Short-term energy balance: relationship with protein, carbohydrate, and fat balances.

Energy balance (energy intake-energy expenditure) is known to vary considerably on a day-to-day basis in free-living individuals. The extent to which stores of protein, carbohydrate, and fat are used to store short-term surpluses of energy and the extent to which these stores are used to make up temporary energy deficits are incompletely known. We have measured body energy balance as well as carbohydrate, fat, and protein balances in 27 Caucasian men and 27 Caucasian women over a 24-h period in a respiratory chamber. An estimated weight-maintenance diet was fed to each subject. Because of individual differences in family background, body composition, activity, and the failure of some subjects to eat all of their food, these estimates are not exact, and energy balance is rarely achieved. Energy balance was correlated with fat balance in men (r = 0.79, P less than 0.0001) and women (r = 0.72, P less than 0.0001), and the slope of this relationship was not distinguishable from unity in men (1.16 +/- 0.18) or women (0.80 +/- 0.15). There were no correlations between energy balance and either carbohydrate or protein balances. This study demonstrates that carbohydrate and protein stores are closely regulated by adjusting oxidation to intake. Thus fat, rather than carbohydrate or protein, is almost exclusively used or stored in response to day-to-day fluctuations in energy balance.

Adult↗
PubMed1988

No accumulation of glucose in human skeletal muscle during euglycemic hyperinsulinemia.

It has been recently suggested that high glucose infusion rates during euglycemic hyperinsulinemia result in accumulation of free glucose in human skeletal muscle (J. Clin. Invest. 76: 357, 1985). To examine this possibility, we performed a euglycemic, hyperinsulinemic clamp together with biopsies from the quadriceps femoris muscle on seven healthy men. Insulin was infused at successive rates of 40 and 400 mU. m-2.min-1, resulting in mean plasma insulin concentrations of 69 +/- 3 and 1,285 +/- 115 (SE) microU/ml, respectively. Glucose infusion rates averaged 7.79 +/- 0.86 and 12.01 +/- 0.77 mg.kg body wt-1.min-1. The total glucose content in muscle averaged 1.72 +/- 0.26, 1.37 +/- 0.21, and 1.65 +/- 0.35 mmol/kg dry wt at rest, and after the low- and high-dose insulin infusions, respectively (P greater than 0.05). Assuming that the plasma glucose concentration reflects the glucose concentration in the extracellular space and that there are 0.3 liters of extracellular water per kilogram dry weight, the intracellular glucose contents are calculated to be 0.15 +/- 0.25, -0.35 +/- 0.21, and -0.06 +/- 0.34 mmol/kg dry wt at rest, and after the low- and high-dose infusions, respectively. None of these values is significantly different from zero. Thus euglycemic hyperinsulinemia does not result in appreciable accumulation of glucose in the muscle of insulin-sensitive men.

Adult↗
PubMed1988

Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity.

Insulin-mediated glycogen synthase activity in skeletal muscle correlates with the rate of insulin-mediated glycogen deposition and is reduced in human subjects with insulin resistance. To assess the role of glycogen synthase phosphatase as a possible mediator of reduced glycogen synthase activity, we studied 30 Southwestern American Indians with a broad range of insulin action in vivo. Percutaneous biopsies of the vastus lateralis muscle were performed before and during a 440-min euglycemic clamp at plasma insulin concentrations of 89 +/- 5 and 1,470 +/- 49 microU/ml (mean +/- SEM); simultaneous glucose oxidation was determined by indirect calorimetry. After insulin stimulation, glycogen synthase activity was correlated with the total and nonoxidative glucose disposal at both low (r = 0.73, P less than 0.0001; r = 0.68, P less than 0.0001) and high (r = 0.75, P less than 0.0001; r = 0.74, P less than 0.0001) plasma insulin concentrations. Fasting muscle glycogen synthase phosphatase activity was correlated with both total and nonoxidative glucose disposal rates at the low (r = 0.48, P less than 0.005; r = 0.41, P less than 0.05) and high (r = 0.47, P less than 0.05; r = 0.43, P less than 0.05) plasma insulin concentrations. In addition, fasting glycogen synthase phosphatase activity was correlated with glycogen synthase activity after low- (r = 0.47, P less than 0.05) and high- (r = 0.50, P less than 0.01) dose insulin stimulations. These data suggest that the decreased insulin-stimulated glucose disposal and reduced glycogen synthase activation observed in insulin resistance could be secondary to a low fasting glycogen synthase phosphatase activity.

Adult↗
PubMed1988

Increased rate of Cori cycle in obese subjects with NIDDM and effect of weight reduction.

To determine the contribution of the rate of glucose recycling via the Cori cycle (glucose----3-carbon compounds----glucose) to the higher rate of endogenous glucose production (EGPR) in subjects with non-insulin-dependent diabetes mellitus (NIDDM), we studied eight obese, weight-stabilized diabetic Pima Indians before [93.1 +/- 5.4 kg, 38 +/- 2% body fat, fasting plasma glucose (FPG) 254 +/- 11 mg/dl] and after (87.7 +/- 4.7 kg, 36 +/- 2% body fat, FPG 153 +/- 17 mg/dl) a 5-wk weight-loss diet and eight obese Indians (95.0 +/- 4.2 kg, 36 +/- 2% body fat, FPG 97 +/- 1 mg/dl) with normal glucose tolerance. EGPR and glucose recycling rate were measured during a 4-h primed continuous tracer infusion of [1-13C]glucose, and the rate of reincorporation of 1-13C of glucose into C2-6 positions in glucose was quantified by gas chromatography mass spectrometry. Substrate utilization rates were measured by simultaneous indirect calorimetry. EGPR (corrected for measured rate of recycling) decreased in the diabetic subjects from 3.80 to 2.74 mg.min-1.kg-1 fat-free mass (FFM) (P less than .01) after weight loss, approaching the rate observed in nondiabetic subjects (2.09 mg.min-1.kg-1 FFM).(ABSTRACT TRUNCATED AT 250 WORDS)

Body Composition↗
PubMed1988

Muscle glycogen synthesis and disposition of infused glucose in humans with reduced rates of insulin-mediated carbohydrate storage.

Six men with a low rate of insulin-stimulated, non-oxidative carbohydrate disposal (storage) and six with a high storage rate were recruited for study of the fate of insulin-stimulated glucose uptake. [3-3H]glucose was infused before and during a 4-h hyperinsulinemic euglycemic clamp procedure in a dosage regimen designed to maintain a constant specific activity. From the disposition of label, the rate of insulin-mediated glucose incorporation into glycogen in the low-storage subjects was one-fourth that of the high-storage subjects (P less than .02). The insulin-mediated increase in muscle glycogen synthase activity in the low-storage subjects was one-fourth that of the high-storage subjects (P less than .05), suggesting the possibility of a causal relationship. In the high-storage but not the low-storage subjects, the rate of glycolysis inferred from the appearance of metabolized tritium in body water exceeded the carbohydrate oxidation rate (P less than .002). This suggests that in these subjects there is a significant fraction of glycolysis that is not oxidized and that this component of carbohydrate metabolism therefore contributes to storage.

Adult↗
PubMed1988

Insulin resistance in Pima Indians. A combined effect of genetic predisposition and obesity-related skeletal muscle cell hypertrophy.

Obesity and diabetes are epidemic in the Pima Indians of Southwest United States. Recent evidence suggests that a reduced metabolic rate may predispose the obesity and, since metabolic rate appears to be familial, this may predispose to the familial dependence of obesity. Obesity is associated with an increased risk of diabetes. Insulin resistance is associated with obesity, but is also familial, independent of obesity. In this population insulin resistance is a risk factor for the development of diabetes. Diabetes occurs when insulin secretory failure is superimposed on insulin resistance. Reduced glucose storage in muscle, regulated by glycogen synthase, is important in determining insulin resistance especially at high plasma insulin concentrations and it is possible that a specific genetic defect may be the cause of this. Obesity has its major effect on insulin action at lower plasma insulin concentrations and we propose that this may in part be due to abnormalities of insulin action induced by an increased fat-free mass with a consequent enlargement of muscle cells, a reduced capillary supply, and reduced penetration of insulin into muscle in obese subjects. We propose therefore that insulin resistance may be due to a combination of a genetic defect and obesity-induced changes in the biophysical properties of skeletal muscle. These defects, by slightly increasing the plasma glucose concentration and inducing pancreatic glucose insensitivity, may in turn lead to the development of non-insulin-dependent diabetes mellitus.

Biomechanical Phenomena↗
PubMed1987

Hyperglycemia stimulates carbohydrate oxidation in humans.

We examined whether hyperglycemia stimulates carbohydrate oxidation independent of insulin. Rates of total glucose disposal and substrate oxidation (indirect calorimetry) were measured at 4 insulin concentrations and at each level of insulin at 4 glucose concentrations in 88 separate studies in 22 normal volunteers. The insulin sensitivity of carbohydrate and lipid oxidation was independent of glycemia, but glucose, independent of insulin, increased the absolute rate of carbohydrate oxidation and decreased lipid oxidation. To compare the ability of glucose and insulin to stimulate carbohydrate oxidation, oxidation rates were examined at similar rates of total glucose disposal induced by hyperinsulinemia or hyperglycemia. At physiological matched rates of glucose disposal, insulin stimulated carbohydrate oxidation 2.4-fold more than glucose. The free fatty acids (FFA) were significantly lower in the presence of hyperinsulinemia than hyperglycemia. When compared at similar (supraphysiological) rates of total glucose disposal, where the FFA were completely suppressed, the rate of carbohydrate oxidation was related to the total rate of glucose disposal rather than the ambient glucose or insulin concentrations. We conclude that both glucose and insulin can increase carbohydrate oxidation in humans. We propose that the rate of carbohydrate oxidation is determined by FFA availability and by glucose availability independent of the FFA level in glucose-consuming tissues. Although FFA availability is almost solely determined by insulin, both glucose and insulin can increase carbohydrate oxidation by increasing glucose availability.

Blood Glucose↗
PubMed1987

Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle.

We examined the insulin dose-response characteristics of human muscle glycogen synthase and phosphorylase activation. We also determined whether increasing the rate of glucose disposal by hyperglycemia at a fixed insulin concentration activates glycogen synthase. Physiological increments in plasma insulin but not glucose increased the fractional activity of glycogen synthase. The ED50: s for insulin stimulation of whole body and forearm glucose disposal were similar and unaffected by glycemia. Glycogen synthase activation was exponentially related to the insulin-mediated component of whole body and forearm glucose disposal at each glucose concentration. Neither insulin nor glucose changed glycogen phosphorylase activity. These results suggest that insulin but not the rate of glucose disposal per se regulates glycogen synthesis by a mechanism that involves dephosphorylation of glycogen synthase but not phosphorylase. This implies that the low glycogen synthase activities found in insulin-resistant states are a consequence of impaired insulin action rather than reduced glucose disposal.

Adult↗
PubMed1987

Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man.

We have compared the capillary density and muscle fiber type of musculus vastus lateralis with in vivo insulin action determined by the euglycemic clamp (M value) in 23 Caucasians and 41 Pima Indian nondiabetic men. M value was significantly correlated with capillary density (r = 0.63; P less than or equal to 0.0001), percent type I fibers (r = 0.29; P less than 0.02), and percent type 2B fibers (r = -0.38; P less than 0.003). Fasting plasma glucose and insulin concentrations were significantly negatively correlated with capillary density (r = -0.46, P less than or equal to 0.0001; r = -0.47, P less than or equal to 0.0001, respectively). Waist circumference/thigh circumference ratio was correlated with percent type 1 fibers (r = -0.39; P less than 0.002). These results suggest that diffusion distance from capillary to muscle cells or some associated biochemical change, and fiber type, could play a role in determining in vivo insulin action. The association of muscle fiber type with body fat distribution may indicate that central obesity is only one aspect of a more generalized metabolic syndrome. The data may provide at least a partial explanation for the insulin resistance associated with obesity and for the altered kinetics of insulin action in the obese.

Adipose Tissue↗
PubMed1987

In vivo insulin action is familial characteristic in nondiabetic Pima Indians.

Non-insulin-dependent diabetes mellitus (NIDDM) is a genetic disorder characterized by two major pathogenic processes: reduced insulin action and a relative or absolute decrease in plasma insulin concentrations. We studied 116 nondiabetic siblings from 45 families to determine if in vivo insulin action showed any aggregation among siblings. Subjects were Pima Indians from the Gila River Indian Community in Arizona who, as a group, have the highest reported incidence and prevalence of NIDDM in the world. In vivo insulin action was determined by the euglycemic-clamp technique at two rates of insulin infusion in each subject with resulting mean plasma insulin concentrations of 119 and 1938 microU/ml. After adjustment for age, sex, and degree of obesity, there was significant aggregation among siblings of in vivo insulin action at the high insulin infusion rate (P less than or equal to .0001). Family membership independently accounted for approximately 34% of the variance in this measure of insulin action. Glucose uptake at the lower insulin infusion rate also showed familial aggregation (P less than .01), with family membership independently accounting for approximately 15% of the variance of this measurement. We conclude that in vivo insulin action is a familial characteristic. The familial component of insulin action occurs in addition to the effects of obesity, age, and sex on insulin action. Therefore it is not sufficient to simply know that an individual is lean or obese to predict his/her in vivo insulin resistance, because it must also be known whether he/she is from an insulin-resistant or insulin-sensitive family.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗