Edward J. Peters

Bed-rest-induced insulin resistance occurs primarily in muscle

Treatment of trauma victims and patients with severe illness may contribute to their metabolic derangements by severely restricting physical activity. We sought to quantitate the impact of absolute bed rest alone on insulin regulation of glucose metabolism in six healthy subjects. Six to seven days of strict bed rest resulted in moderate deterioration in oral glucose tolerance and increased both fasting plasma insulin concentration and the insulin response to an oral glucose challenge by more than 40%. Euglycemic insulin clamp studies demonstrated the development of resistance to insulins stimulation of whole-body glucose utilization. This change was characterized by a rightward shift of the insulin dose-response curve (insulin concentration at which 50% of maximal stimulation occurred was 45 +/- 3 (SE) microU/mL in the base line period and 78 +/- 8 microU/mL after seven days of bed rest, P less than .01) with little alteration in the maximal response in the rate of glucose uptake (baseline 15.4 +/- 1.4 mg/kg.min and bed rest 14.0 +/- 1.3 mg/kg.min). In contrast to the shift of sensitivity of whole-body glucose utilization to insulin, suppression of hepatic glucose output by insulin was unchanged by seven days of bed rest. Insulin binding to circulating mononuclear cells was not changed by bed rest. These studies demonstrate that the limited physical activity dictated by bed rest for as little as seven days is associated with substantial resistance to insulins effects on glucose metabolism. Further, the data suggest that these effects occur primarily in skeletal muscle with little change in insulin action on the liver.

Prevalence of Acanthosis Nigricans in an Unselected Population

PURPOSE The intent of this study was to determine, in an unselected population, the prevalence of the hyperinsulinemia-associated skin lesion, acanthosis nigricans. SUBJECTS AND METHODS The posterior neck of every child in the sixth and eighth grades of the public schools of Galveston, Texas, was personally examined by the investigators during a state-mandated school health survey. A total of 1,412 children were examined. RESULTS The data for each child examined included the absence or presence of acanthosis nigricans, height, weight, age, sex, and ethnic background. A subset of the children with the skin lesion also had fasting plasma insulin levels measured. Acanthosis nigricans was present in 7.1% of the 1,412 children examined. The skin lesion was equally distributed between boys and girls and was most common among children with severe obesity. The condition was present in two of 440 white non-Hispanics, 19 of 343 Hispanics, and 80 of 601 blacks examined. The fasting plasma insulin concentrations measured in some of these children and in previously evaluated subjects strongly correlate with the presence and severity of the acanthosis nigricans skin lesion. CONCLUSIONS This skin lesion is much more common than previously believed and has a dramatic ethnic predisposition. We conclude that the high prevalence of this skin lesion further suggests that insulin resistance and hyperinsulinemia, with all of their serious medical implications, are also highly prevalent.

Hormonal control of substrate cycling in humans.

Recent studies have established the existence of substrate cycles in humans, but factors regulating the rate of cycling have not been identified. We have therefore investigated the acute response of glucose/glucose-6P-glucose (glucose) and triglyceride/fatty acid (TG/FA) substrate cycling to the infusion of epinephrine (0.03 microgram/kg.min) and glucagon. The response to a high dose glucagon infusion (2 micrograms/kg.min) was tested, as well as the response to a low dose infusion (5 ng/kg.min), with and without the simultaneous infusion of somatostatin (0.1 microgram/kg.min) and insulin (0.1 mU/kg.min). Additionally, the response to chronic prednisone (50 mg/d) was evaluated, both alone and during glucagon (low dose) and epinephrine infusion. Finally, the response to hyperglycemia, with insulin and glucagon held constant by somatostatin infusion and constant replacement of glucagon and insulin at basal rates, was investigated. Glucose cycling was calculated as the difference between the rate of appearance (Ra) of glucose as determined using 2-d1- and 6,6-d2-glucose as tracers. TG/FA cycling was calculated by first determining the Ra glycerol with d5-glycerol and the Ra FFA with [1-13C]palmitate, then subtracting Ra FFA from three times Ra glycerol. The results indicate that glucagon stimulates glucose cycling, and this stimulatory effect is augmented when the insulin response to glucagon infusion is blocked. Glucagon had minimal effect on TG/FA cycling. In contrast, epinephrine stimulated TG/FA cycling, but affected glucose cycling minimally. Prednisone had no direct effect on either glucose or TG/FA cycling, but blunted the stimulatory effect of glucagon on glucose cycling. Hyperglycemia, per se, had no direct effect on glucose or TG/FA cycling. Calculations revealed that stimulation of TG/FA cycling theoretically amplified the sensitivity of control of fatty acid flux, but no such amplification was evident as a result of the stimulation of glucose cycling by glucagon.

Regulation of Lipolysis in Severely Burned Children

In this study, the rates of lipid mobilization and of lipolysis have been quantified in severely burned children. In all 12 patients studied, the basal rates were determined. In seven patients, the lipolytic responsiveness to an infusion of epinephrine (0.015 μg/kg/min) was tested, and in the other five patients, the response to beta-adrenergic blockade (propranolol, 1 mg/kg) was tested. The rate of appearance (Ra) of free fatty acids (FFA) was quantified by means of the infusion of 1-13C-palmitate to determine the rate of lipid mobilization, and Ra glycerol was determined using d5-glycerol to assess the rate of lipolysis more directly. In five patients, body composition was determined after recovery by means of H218O dilution. The basal rate of lipolysis was higher than normal in the burned children. In four of the seven patients infused with epinephrine, there was a pronounced increase in Ra glycerol. In all patients given beta-blockade, Ra glycerol decreased greatly. Changes in Ra FFA corresponded with the changes in Ra glycerol in each case. Total body fat was very low (approximately 2% body weight), reflecting the surgical removal of fat in the process of burn wound excision. From these data it is concluded that lipolytic responsiveness to catecholamines in severely burned children is variable, but not absent, despite chronically elevated levels of catecholamines. The total extent of lipolysis may be limited by the available fat mass in children treated with fascial excision. In such patients, the limitation in the ability to mobilize an adequate amount of FFA to fully meet energy requirements provides an important rationale for the clinical practice of providing nutritional support in hourly boluses, as opposed to infrequent meals, since any period of even a few hours in which nutrients are not being absorbed will result in an energy substrate deficiency and consequent increase in amino acid oxidation.

Effect of elevated free fatty acids on glucose oxidation in normal humans

In vitro studies indicating an inverse relationship between free fatty acid (FFA) availability and glucose oxidation led to proposal of the glucose-fatty acid cycle. In vivo studies have yielded conflicting results regarding the effect of FFA on glucose oxidation. In the present study the effect of FFA on glucose oxidation was determined in six normal volunteer subjects. The rate of glucose uptake was fixed by using a constant glucose infusion to suppress endogenous glucose production. Glucose was infused continuously overnight and during the four hour study at 8 mg/kg X min to ensure use of glucose as an energy substrate by virtually all tissues. Following a two-hour baseline glucose infusion, infusion of 20% IV fat emulsion at 1.0 mL/min plus heparin was added to the constant glucose infusion for two additional hours. Total carbohydrate oxidation was determined by indirect calorimetry, and the direct oxidation of the infused (plasma) glucose was measured by the use of U-13C-glucose. Glycogen oxidation was calculated as the difference between total carbohydrate oxidation and the oxidation of plasma glucose. Glucose uptake was calculated from the infusion rate, corrected for any changes in plasma and/or urine glucose concentration. Glucose uptake closely approximated the rate of IV glucose infusion and was unchanged by fat infusion. The percent of CO2 production from U-13C-glucose oxidation (74.5 +/- 12.3, mean +/- SD) was not affected by FFA, nor was the percent of glucose uptake oxidized (37.5 +/- 4.0).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance with acanthosis nigricans: The roles of obesity and androgen excess☆

The roles of hyperandrogenemia and obesity in the syndrome of severe insulin resistance with acanthosis nigricans were evaluated in studies of 11 females with this condition. Our results in these subjects were compared to evaluations of control subjects matched for degree of androgen excess or obesity. Fasting insulin levels were 3-, 5-, and 15-fold higher in the obese (OB), hyperandrogenemic (HO), and acanthosis nigricans (AN) groups, respectively, when compared to normal females. Responsiveness to a standard bolus of exogenous insulin was 78% of normal in the OB group, 40% of normal in the HO group, and 30% of normal in the AN group. Insulin binding to monocytes from both the OB group, and the HO group was modestly diminished primarily due to decreased receptor number. As a group, AN subjects when compared to either normal or weight-matched controls, demonstrated a significant decrease in monocyte insulin binding predominantly due to a decrease in receptor number. However, two patients in the AN group had normal insulin binding suggesting a postreceptor mechanism for the insulin resistance in at least some of these subjects. In vivo glucose utilization insulin dose response curves were determined in 3 acanthotic subjects using the euglycemic clamp technique. All 3 of these subjects had a right shift of the curve and diminished maximal utilization, consistent with combined receptor and postreceptor defects in insulin action. In evaluating the relationship between hyperandrogenemia, insulin resistance, and acanthosis nigricans, significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Obesity, acanthosis nigricans, insulin resistance, and hyperandrogenemia: Pediatric perspective and natural history

We studied the syndrome of acanthosis nigricans, obesity, insulin resistance, and hyperandrogenemia in 22 patients. Although isolated case reports in adolescents have appeared, this syndrome has not received full recognition as a pediatric entity. Our patients (17 girls, five boys) had a mean weight 5.7 SD above the mean for age, although mean height was only 0.5 SD above the mean for age. All patients had acanthosis nigricans. Their insulin resistance was significantly greater than that in a control group with comparable obesity. Fasting insulin concentration was 5.25 microU/ml in lean controls, 19.6 microU/ml in obese controls, and 49.8 microU/ml in study patients (P less than 0.002). Mean glucose disappearance rate during an insulin tolerance test was 6.7%/min in lean controls, 5.19%/min in obese controls, and 2.35%/min in study patients (P less than 0.02). After menarche, mean plasma testosterone concentration was 106 ng/dl, compared with less than 50 ng/dl in all lean and obese control patients. Data derived from our series of patients lead us to conclude that (1) this is a genetic syndrome, although the exact mode of inheritance is unclear; (2) the natural history of the syndrome invariably begins with the onset of obesity, followed by acanthosis nigricans that worsens with progressive weight gain; (3) acanthosis nigricans is thus a marker for hyperinsulinemia, which occurs before hyperandrogenemia; (4) hyperandrogenemia occurs only after menarche. Identification of this syndrome should permit monitoring for the development of hyperandrogenemia during puberty and determination of other affected family members.

Lipolytic response to metabolic stress in critically ill patients.

ObjectiveTo measure whole-body lipolysis and fatty acid re-esterification in critically ill patients. DesignThe rates of appearance of glycerol and palmitic acid in blood plasma were measured by infusing stable isotope tracers [2H5]glycerol and [1-13C]palmitic acid, respectively. Energy expenditure was measured by indirect calorimetry. SettingMedical ICU of The University of Texas Medical Branch Hospital, a universitybased referral center. PatientsFive uninjured critically ill patients. Four patients were hospitalized because of respiratory insufficiency and one because of myocardial infarction. Three patients died during their hospitalization. InterventionsMetabolic studies were performed in each patient after an overnight (12-hr) fast. Measurements and Main ResultsMean ± SE glycerol and fatty acid rates of appearance were 4.5 ±1.0 and 11.5 ± 0.8 umol/kg-min, respectively. The ratio of fatty acid to glycerol rate of appearance was 2.9 ± 0.5. Resting energy expenditure was 132 ± 6% of predicted. ConclusionsAn accelerated rate of lipolysis is part of the metabolic response to severe stress, regardless of its etiology. Because the rate of fatty acid release far exceeded energy requirements, fatty acids that were not oxidized as fuel were re-esterified to triglyceride, presumably in the liver.

Acanthosis nigricans and obesity: Acquired and intrinsic defects in insulin action

Six obese, severely acanthotic females were evaluated for insulin resistance by an oral glucose tolerance test, intravenous insulin tolerance test, and insulin binding to freshly isolated monocytes, as well as studies of cultured skin fibroblasts. After baseline studies were obtained, the acanthotic subjects were maintained for 14 days on a 500 calorie diet, and the evaluations were repeated. Initial evaluation demonstrated normal glucose tolerance, but marked fasting hyperinsulinemia (57 +/- 5 microU/mL) and dramatically blunted response to exogenous insulin (KITT, 2.0%/min) when compared with five nonacanthotic weight-matched controls (insulin, 15 +/- 2 microU/mL; KITT, 5.2%/min). Monocyte insulin binding for the acanthotic group (0.251 +/- 0.050%/10(6) cells) was only 56% of the binding seen in the obese controls (0.447 +/- 0.108%). After the acanthotic females dieted for 14 days, their hyperinsulinemia and monocyte insulin binding improved, but failed to normalize. The response to exogenous insulin was unchanged and remained drastically blunted. In contrast to the normal insulin binding found in the cultured fibroblasts from the nonacanthotic obese controls, insulin binding to fibroblasts from the acanthotic group was decreased by 40%, suggesting that an intrinsic defect in insulin binding was present. Thus, we conclude that this cohort of acanthotic obese females are considerably more insulin-resistant than nonacanthotic weight-matched females. Furthermore, these studies suggest that the severe insulin resistance results from a combination of an acquired defect related to obesity and an inherent cellular defect in insulin action at, or beyond, the receptor.

Autophosphorylation of Cultured Skin Fibroblast Insulin Receptors From Patients With Severe Insulin Resistance and Acanthosis Nigricans

The severe insulin resistance with acanthosis nigricans seen in young women without insulin-receptor autoantibodies is characterized by hyperinsulinemia and decreased in vivo responsiveness to insulin. We evaluated the potential cellular defects in insulin-receptor binding and autophosphorylation in 12 subjects with this syndrome. When evaluated as a group, insulin binding to freshly isolated monocytes was 55% that of controls. Specific binding of insulin to skin fibroblasts in monolayer culture was 49% that of controls. Maximal insulin-stimulated receptor autophosphorylation was only 27% that of controls. Individual data demonstrated that the diminished autophosphorylation activity was out of proportion to the diminished fibroblast insulin binding in cell lines from most subjects and was <50% of the predicted activity in 6 of the 12 studied cell lines. These data are consistent with genetically determined defects leading to diminished numbers of cell surface insulin receptors with intact tyrosine kinase autophosphorylation in many of our cell lines. However, in at least half, there appeared to be an additional defect beyond insulin binding, resulting in a disproportionate decrease in insulin-sensitive phosphorylation of the insulin-receptor β-subunit.