Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry.

Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33-41 mumol/day.m2; 12-15 mg/m2.day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing's syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-2H3]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 +/- 7.5 mumol/day (9.9 +/- 2.7 mg/day) or 15.7 mumol/day.m2; 5.7 mg/m2. day). A previously unreported circadian variation in FPR was observed. Patients with Cushing's syndrome demonstrated unequivocal elevation of FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

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)

Thermic effect of glucose in obese subjects with non-insulin-dependent diabetes mellitus.

A reduced thermic effect of glucose in non-insulin-dependent diabetes mellitus (NIDDM) has been previously reported. To investigate whether this defect is related to 1) a decreased rate of glucose storage, 2) a reduced energy cost of glucose storage, or 3) a defect in the sympathetically mediated component of thermogenesis, we studied the thermic effect of ingested and infused glucose in nine NIDDM obese Pima Indians [90.5 +/- 3.9 kg, 39 +/- 2% fat, fasting plasma glucose (FPG) 130 +/- 10 mg/dl] and in nine nondiabetic obese Pima Indians (99.3 +/- 7.2 kg, 38 +/- 2% fat, FPG 103 +/- 2 mg/dl). Energy expenditure and glucose storage were derived from indirect calorimetry measurements. The thermic effect of 100 g of glucose was found to be similar in both groups (4.0 +/- 0.9 vs. 5.0 +/- 1.3% of energy ingested in diabetic and nondiabetic subjects, respectively) but lower than that previously reported in nonobese subjects. The cost of glucose storage calculated after stimulating storage by constant glucose infusion (0.46 g/min) and variable insulin infusion (19.5 +/- 3.8 vs. 2.9 +/- 0.6 mU.kg-1.min-1 in diabetic and nondiabetic subjects, respectively; P less than .01) was similar in both groups (approximately 0.35 kcal/g glucose stored) and not different from that reported in lean subjects. As opposed to lean and obese Caucasian subjects, energy expenditure failed to markedly decrease during propranolol infusion in both nondiabetic and diabetic Pima Indians. We postulate that the decreased rate of tissue glucose uptake and storage associated with insulin resistance is the major cause of the lower thermic effect of ingested glucose in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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.

Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population.

Relationships have been observed between lipoprotein concentrations and insulin action. These relationships may be important in explaining the association of insulin resistance and abnormalities of lipoprotein metabolism found in obesity, diabetes, and hypertriglyceridemia. We have measured plasma lipoprotein concentrations and indices of insulin action in 85 men and 56 women, all of whom were normolipidemic and had normal glucose tolerance. The subjects were obese Southwestern American Indians (body mass index 34 +/- 1). Insulin action was measured via the hyperinsulinemic clamp with simultaneous indirect calorimetry. Triglyceride concentrations were inversely related to rates of total insulin-mediated glucose disposal (in men and women, respectively, r = -.37, P less than .01; r = -.24, P less than .10), glucose storage (r = -.31, P less than .01; r = -.25, P less than .10), increase in glucose oxidation (r = -.29, P less than .01; r = -.24, P less than .10), and, in men only, suppression of endogenous glucose production (r = -.32, P less than .01). High-density lipoprotein (HDL) cholesterol concentration was positively related to rates of total insulin-mediated glucose disposal (r = .35, P less than .01; r = .33, P less than .05), increase in carbohydrate oxidation (r = .40, P less than .001; r = .39, P less than .001), suppression of endogenous glucose production (r = .24, P less than .05; r = .29, P less than .05), and, in men only, glucose storage (r = .35, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin action in obese non-insulin-dependent diabetics and in their isolated adipocytes before and after weight loss.

To determine the effects of weight loss on insulin action in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in their isolated adipocytes, we studied nine weight-stabilized Pima Indians [7 females and 2 males; age 39 +/- 3 yr; wt 99.9 +/- 8.2 kg; body fat 39 +/- 2% (means +/- SE)] before and after a 6.7 +/- 1.3-kg weight loss and decrease in fasting plasma glucose from 250 +/- 11 to 148 +/- 15 mg/dl. In vivo insulin action was measured during a 3-insulin-step, hyperglycemic (approximately 310 mg/dl) clamp with somatostatin (250 micrograms/h). At a clamp plasma insulin concentration of 10 microU/ml, glucose disposal rates did not change after weight loss; at approximately 100 microU/ml, glucose disposal rates increased by 21% [from 4.3 +/- 0.2 to 5.3 +/- 0.4 mg X min-1 X kg-1 of fat-free mass (FFM), P less than .01] mostly due to increased carbohydrate oxidation rates (2.0 +/- 0.3 to 2.8 +/- 0.3 mg X min-1 X kg-1 FFM, P less than .02); at 2400 microU/ml, glucose disposal rates increased by 37% (11.4 +/- 0.6 to 15.6 +/- 1.4 mg X min-1 X kg-1 FFM, P less than .02) mostly due to increased nonoxidative carbohydrate disposal rates or storage (7.5 +/- 0.6 to 10.9 +/- 1.3 mg X min-1 X kg-1 FFM, P less than .04). Sensitivity of glucose disposal to insulin in the physiologic range (measured as change in glucose disposal rate per unit change in insulin concentration between clamps at approximately 10 and approximately 100 microU/ml) was very low in these diabetic subjects and did not change after weight loss. Adipocyte cell size, basal and maximal insulin-stimulated glucose transport, and half-maximal rate for transport did not change after weight loss. The data suggest that insulin in the physiologic range has no apparent effect on glucose disposal in patients with NIDDM before or after weight loss. However, a moderate weight loss is associated with enhanced capacity to transport and metabolize glucose in vivo. The discrepancy between in vivo and in vitro results suggests that the adipocyte may not always reflect in vivo insulin action. Diabetes 36:227-36, 1987.

Familial dependence of the resting metabolic rate.

Human obesity is known to be a familial disorder. We studied 130 nondiabetic adult southwestern American Indians (74 men and 56 women) from 54 families to determine whether the resting metabolic rate, as measured by indirect calorimetry, is a familial trait that is independent of individual differences in fat-free mass (estimated mass of metabolically active tissue), age, and sex. We found that most of the variance in the resting metabolic rate (83 percent, P less than 0.0001) was accounted for by three covariates--fat-free mass, age, and sex--and that fat-free mass was the most important determinant. Family membership accounted for an additional 11 percent (P less than 0.0001) of the variance in the resting metabolic rate. Thus, resting metabolic rate is a familial trait in this population, and it is independent of differences in fat-free mass, age, and sex. We also found that persons from families with lower resting metabolic rates were no more obese than persons from families with higher metabolic rates. This finding may be partly explained by the close correlation between fat-free mass and percentage of body fat (r = 0.81, P less than 0.0001), which indicates that the resting metabolic rate, as adjusted for fat-free mass, is already partly adjusted for obesity. Only prospective studies will elucidate whether the familial dependence of the resting metabolic rate is a contributing mechanism to the familial predisposition to obesity.

Glucose storage is a major determinant of in vivo "insulin resistance" in subjects with normal glucose tolerance.

In vivo "resistance" to the action of insulin on glucose uptake is commonly found in obesity and is characteristic of noninsulin-dependent diabetes mellitus in obese subjects. To investigate the relationship among glucose uptake, glucose oxidation, and nonoxidative glucose disposal (storage) in subjects with normal glucose tolerance, we studied 25 caucasians and 79 southwestern American Indians, including lean and obese subjects in both groups. The euglycemic clamp technique with simultaneous indirect calorimetry was used to determine rates of glucose uptake and glucose oxidation. These studies were performed at two rates of insulin infusion (40 and 400 mU/m2 X min), with resulting mean plasma insulin concentrations of 113 and 1839 microU/ml, respectively. At the lower insulin infusion rate, there was no glucose storage in subjects with a glucose uptake rate of about 2.2 mg/kg fat free mass X min. In contrast, glucose storage accounted for over 45% of the glucose disposal in subjects with glucose uptake rates over 7.0 mg/kg fat free mass X min studied at similar insulin concentrations. At the high insulin infusion rate, over 70% of the difference in glucose uptake between subjects with a low or high capacity for glucose disposal was due to glucose storage. These studies demonstrated that in normal subjects at both physiological and maximally stimulating plasma insulin concentrations, glucose storage is a major factor in distinguishing between those with low or high rates of insulin-mediated glucose disposal. Since glucose storage may be a specifically activated process, we hypothesize that failure to activate glucose storage is a major defect causing in vivo insulin resistance in subjects with normal glucose tolerance.