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1. Earlier studies with liver slices showed that inhibition by NH+4 of the oxidation of palmitate to CO2 was greater than total oxidation, whereas salicylate exerted a stronger inhibitory effect on the latter. We have now investigated the effects of NH4Cl and salicylate on ADP-induced O2 consumption by mitochondria (State 3 rate) respiring on pyruvate, and oxidation of [1-14C]- and [2-14C]-pyruvate to14CO2. 2. The rate of State 3 respiration was inhibited and plateaued at 45% with 10 mmol/l NH4Cl. 3. Oxidation of [1-14C]pyruvate was not significantly affected by either NH4Cl or salicylate. Oxidation of [2-14C]pyruvate was strongly inhibited and plateaued at 70% with 1 mmol/1 NH4Cl (IC50 = 0.125 mmol/1). ADP (1 mmol/l) increased the rate of decarboxylation of [2-14C] pyruvate but the extent of NH4Cl inhibition was not affected. Salicylate had a slight activating effect in the absence or presence of NH4Cl. 4. These results indicate that NH4Cl inhibits the oxidative metabolism of acetyl-CoA in the tricarboxylic acid cycle. Therefore, inhibition of fatty acid oxidation to acetyl-CoA as well as its further oxidative metabolism occurring under hyperammonaemia (>0.1 mmol-1.49 mmol/l in Reye's syndrome patients) may be one of the causes of fatty acidaemia. 5. The cumulative inhibitory effects of NH+4 and fatty acyl derivatives on mitochondrial oxidative metabolism and production of ATP, as well as the uncoupling effects of salicylate, may contribute to some of the pathophysiology observed in patients with Reye's syndrome, and enzyme defects of the urea cycle.

Phosphate and a number of other compounds induce membrane permeability transition (MBT) in Ca(2+)-loaded mitochondria. 1-Anilino-8-naphthalene sulfonate (ANS) was used as a fluorescent probe to investigate perturbations on the inner membrane during MBT. Induction of MBT caused ANS fluorescence enhancement with a biphasic rate that reached a plateau. The enhancement is analogous to that reported for de-energization of mitochondria. The fluorescence level was independent of whether ANS was added before or at different times after phosphate. In the absence of ANS, fluorescence was low and remained unchanged. The initial time course of MBT, as followed by large-amplitude swelling, was similar to that of fluorescence enhancement. Ruthenium red, EGTA, ADP, and cyclosporin A inhibited the enhancement. Only EGTA + ADP (or ATP) reversed the enhancement when added after phosphate. Efflux of matrix Ca2+ by sodium acetate or A23187 did not alter ANS fluorescence. The binding parameters (Kd and number of binding sites) were not significantly different, but the fluorescence maximum was more than doubled after MBT. Although the fluorescence of bound ANS showed a nonlinear relationship, it was always higher (73.0 +/- 19.0%) after reaching the plateau. Since ANS binding to membranes is nonspecific, the exact mechanism of the enhanced fluorescence is not apparent. The dependence of the initial rate of fluorescence enhancement on Ca2+ concentration was nonlinear, with 45 microM at half-maximal rate. The dependence on phosphate was hyperbolic with 0.7 mM at half-maximal rate, which is close to the Km value of phosphate carrier. The kinetics is compatible with Ca2+ binding to some membrane component(s) during MBT and cause ANS fluorescence enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)

The temporal relationship of changes in state 3 respiration, lipid peroxidation, and glutathione (GSH) content was investigated in liver mitochondria of hypophysectomized rats after an injection of 3,3',5-triiodo-L-thyronine (T3). Lipid peroxidation induced by ADP/Fe3+/NADPH was determined by the amount of malondialdehyde formed. Hypophysectomy decreased respiration and lipid peroxidation (from 19.88 +/- 3.04 to 14.19 +/- 1.14 nmol malondialdehyde.mg protein-1.10 min-1) but increased GSH content (from 7.06 +/- 2.08 to 12.46 +/- 3.58 nmol/mg protein). Daily injections of a low dose (5 micrograms/100 g) of T3 for 7 days restored the parameters. Time course (up to 96 h) of these changes was followed after one injection of a moderate (100 micrograms/100 g) and high (1000 micrograms/100 g) dose of the hormone. Respiration showed a significant increase at 24 h and declined slightly at 96 h. There was a slow loss of respiratory control ratio after 24 h. Lipid peroxidation remained unchanged at 24 h and showed a gradual increase, becoming significantly higher at 72-96 h depending on the hormone dosage. Changes in GSH content followed a time course similar to that of lipid peroxidation except that it showed a decrease instead of an increase. There was a high degree of inverse linear correlation between lipid peroxidation and GSH (correlation coefficient = 0.95). Because GSH is required for detoxification of hydroperoxides generated by the respiratory chain, it is suggested that lipid peroxidation may play a major role in the modulation of intramitochondrial GSH.

To explore the possible association of hyperlipidemia with hyperammonemia and aspirin ingestion, the effects of NH4+, salicylate, and carnitine on the oxidation of [1-14C]palmitic acid to acid-soluble products (ASP) and to CO2 were investigated in rat liver slices. DL-carnitine (5 mM) increased total oxidation (ASP + CO2) more than oxidation to CO2. KCN (1.5 mM) inhibited more than 90% of the oxidation. NH4Cl inhibited the oxidation that reached a maximum at about 40 mM, but the inhibition of oxidation to CO2 (63%) was larger than that of total oxidation (30%). Carnitine did not influence NH4+ inhibition, which is consistent with the results reported for isolated mitochondria. Salicylate effects depended on salicylate concentration as well as on the presence of carnitine. In the absence of carnitine, inhibition of total oxidation reached 90% at 3 mM salicylate but that of oxidation to CO2 reached 50%. Velocity calculated at saturating palmitic acid concentration for total oxidation was slightly increased by 0.75 mM salicylate, but the increase for oxidation to CO2 was larger. At 3 mM salicylate, velocity at saturating palmitic acid concentration for the oxidation was decreased, but the decrease for oxidation to CO2 was smaller than for total oxidation. Carnitine partially relieved the inhibition of total oxidation and further increased the formation of CO2. The combination of 20 mM NH4Cl and 0.75 mM salicylate inhibited total oxidation, which was more than additive of the individual effects, and carnitine partially relieved the inhibition. It is concluded that NH4+ exerted a stronger inhibition of oxidation to CO2 than of oxidation to ASP, whereas salicylate strongly inhibited the oxidation to ASP but increased the oxidation to CO2 by uncoupling mitochondrial oxidative phosphorylation. Therefore, hyperammonemia and aspirin ingestion can inhibit fatty acid oxidation and mitochondrial metabolism that could lead to the pathophysiology seen in some childhood diseases such as Reye's syndrome. Carnitine therapy might offer some benefits.

γ-Glutamyl transpeptidase (GGTP) activity in normal amniotic fluids and corresponding maternal sera obtained at various gestational periods was measured. The ontogenic pattern of enzyme activity in amniotic fluid is very similar to alpha fetoprotein (AFP). However, the levels of these two proteins behaved differently in corresponding maternal sera. Also, in amniotic fluids obtained from pregnancies with neural tube defects (NTD), only AFP concentration was abnormally high whereas GGTP activity was normal.

A newborn infant had an unusual reversible complication caused by light therapy for hyperbilirubinemia. A dark grey-brown color of the skin, urine, and serum developed on the fifth day, after 24 hours of light therapy. Serum bilirubin (direct and total), SGOT, and LDH were elevated. The infant recovered, and bilirubin and enzymes returned to normal after a period of three weeks. A possible pathologic mechanism for this complication is suggested.

A double-blind study comparing the safety and efficacy of 42-548, a new, synthetic tricyclic appetite suppressant, with a placebo was started with 116 obese adolescent patients. All patients received a fixed daily dose of one tablet, one hour before the noon meal, for 12 weeks. A reduced caloric intake was prescribed initially and the patients were instructed to stay on this diet. 42-548 produced an average weight loss of 18.9 lb. at the end of the study, and the placebo a loss of 11.8 lb., a statistically significant difference. The medication was relatively well tolerated.

Potassium chloride concentrations of 100–150 mM were shown to inhibit (20–40%) human and rat liver microsomal glucose-6-phosphatase when the substrate was reduced to physiological concentration. When the enzyme was solubilized by treatment of microsomes with Al2O3 the inhibition could be observed at greater substrate concentrations. Since potassium deprivation is associated with hyperglycemia in both animals and man, these observations may have physiological significance.

Using atomic absorption spectrophotometry, we have assayed zinc and copper concentrations in the hair of children with typical achondroplasia, familial short stature, or constitutional growth delay, and of unaffected parents of achondroplastic children and healthy adults of similar age and sex as the parents (Table). Specimens consisted of the terminal 2 to 3 inches of hair, obtained from the posterior scalp. Duplicate 60 to 80 mg hair specimens were digested in concentrated nitric:perchloric (3:1) acid mixture. The results are the mean of at least two determinations per specimen. The achondroplastic children were all confirmed as typical examples by physical examination and radiographs of skull, spine, long bones, and pelvis. Several of the parents were noted to have white flecks in their fingernails, which has been reported to be associated with zinc deficiency. The data indicate significantly reduced zinc and increased copper values, and reduced zinc:copper ratio, in the hair of parents and children with achondroplasia.

We have studied the response of blood levels of progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol to acute ACTH stimulation in children with isolated GH deficiency. Patients with isolated GH deficiency had generally higher levels of 11-deoxycortisol and lower levels of cortisol than controls both before and after ACTH stimulation. The steroid levels were almost completely restored to control levels after 3 months of treatment with GH. The pre-ACTH treatment levels of 11-deoxycortisol and cortisol were low in patients with both GH and ACTH deficiencies before and during GH therapy. Therefore, GH alone did not appear to have any effect on the hydroxylation of 11-deoxycortisol to cortisol. Before GH therapy, ACTH increased the concentrations of the two steroids. After GH therapy was started, the increase in 11-deoxycortisol was much smaller, but the increase in cortisol was much larger than before therapy. These results suggest a synergistic effect of GH on ACTH action on the biosynthesis of cortisol in the adrenals. Variations in the levels of 11-deoxycortisol and cortisol during hormonal manipulations lead to the identification of the mitochondrial hydroxylation of 11-deoxycortisol as one of the possible sites of action of GH.

Premature infants have a lower selenium concentration in serum than full-term infants and children. The selenium concentration goes down quickly in infants treated for respiratory distress syndrome without supplementation. One premature infant with bronchopulmonary dysplasia had persistently low concentrations of selenium. Vitamin E supplements did not affect the serum selenium concentration in healthy premature infants. Supplementation with 3 µg/kg of selenium in parenteral fluids prevented the fall in the concentration seen in other infants not supplemented. Premature infants and especially those treated withoxygen may warrant selenium supplementation to the parenteral nutrition solution. Vitamin E supplements alone are apparently not sufficient to prevent selenium deficiency and potential oxygen toxicity.

Zinc levels were measured in hair and serum of boys with constitutional growth delay and familial short status and in several boys before and after oral administration of methyltestosterone. These results show the following: (1) zinc levels in boys beyond stage 3 of genital development are significantly higher than in stage 1 and 2; (2) there is a linear relationship between zinc levels and serum testosterone concentration (up to 250 ng/dL); and (3) methyltestosterone administration raised the zinc concentration in serum and hair, especially in boys with constitutional growth delay. Therefore, increased endogenous production or exogenous supply of testosterone are associated with increased zinc levels. We speculate that the relative testosterone deficiency and hypogonadotropism seen in constitutional growth delay may result in decreased zinc levels, which in turn could cause a further delay in the appearance of secondary sexual characteristics and greater growth retardation.

The effects of hypophysectomy and subsequent administration of growth hormone, thyroxine, insulin, and testosterone were examined in rat liver for the relationship between the thermotropic effects on State 3 respiration (ADP induced) and fatty acid composition of the phospholipid fraction of intact mitochondria as well as of inner membrane vesicles. The Arrhenius profile for energy-linked (succinate) State 3 respiration of mitochondria from hypophysectomized rats lacked the discontinuity at 23.5 °C seen with mitochondria from normal rats. After injections of the hormones the discontinuity representing the transition temperature from gel to liquid crystalline state of lipids occurred at different temperatures: 18.5 °C for growth hormone, 26.0 °C for thyroxine, 19.5 °C for growth hormone + thyroxine, 27.6 °C for insulin, and 25.3 °C for testosterone. The energy of activation between 37.5 and 23.5 °C was 1.9 times greater for hypophysectomy than for controls. Growth hormone was the most effective in restoring the energy of activation to normal, above as well as below transition temperature. The effect of thyroxine appears to be due to a larger stimulation of the State 4 respiration than that of growth hormone, insulin, or testosterone, especially at higher temperatures. Phospholipids extracted from intact mitochondria or inner membrane vesicles of hypophysectomized rats contained less arachidonic acid (20:4) and more linoleic acid (18:2) than those of normal rats. In addition, the contents of some of the minor fatty acids were also changed. Calculated unsaturation index showed an 18.8 and 14.9% depletion in unsaturation in whole mitochondria and inner membranes, respectively. Among the different hormones used to treat the hypophysectomized rats, growth hormone was the most effective in restoring the transition temperature and fatty acid composition to normal levels and increasing the gain in body weight. Although the other hormones increased total unsaturation index to some extent, some of the individual fatty acids were affected differently. Good correlation exists between the unsaturation index of mitochondrial fatty acids and transition temperature of State 3 respiration. These results strongly suggest a role for the hormones, particularly growth hormone, in the control of mitochondrial membrane fluidity of hypophysectomized rat liver, through fatty acid composition of phospholipids.

Skinfold thickness was found to decrease during the first 6–10 wk and then remain constant when human growth hormone therapy was begun in 34 growth hormone-deficient children. Linear growth increased at a constant rate during the first 6 mo. Two children, who routinely received their injection in the same arm at the same site, developed a localized area of markedly diminished subcutaneous fat at the injection site, Height, weight, total-body potassium, and triceps skinfold thickness were measured at 2-mo intervals in nine children receiving human growth hormone. Total-body potassium was measured with the 54-Nal detector whole-body counter of the Brookhaven National Laboratory. The study extended over a period of 20 consecutive mo. Triceps skinfold thickness rapidly decreased during the initiation of therapy with growth hormone, and returned to pretreatment values during a 5-mo control period when therapy was temporarily discontinued. Rate of weight gain was most rapid during this 5-mo control period and was reduced during two periods when growth hormone was being administered. Total body potassium and height increased very little during the control period when weight gain was greatest, and both increased rapidly during the two periods of growth hormone treatment. The data show clearly the initial changes in body fat and lean tissue that occur when human growth hormone is administered to children with growth deficiency.

To understand the early molecular events that lead to some of the effets of growth hormone on liver, a dose of 3H-HGH (18 × 106 cpm, 60 μg) was give i.v. to hypophysectomized rats. After the injection, livers were homogenized and fractionated by centrifugation. Specific activity (cpm/mg protein) and total radioactivity expressed as percent of that in the homogenate were estimated (table). 3H-HGH in the homogenate was estimated by precipitation with TCA, and with Na2SO4 as 3H-HGH antibody complex with and without unlabeled hormone. Up tp 10 min most homogenate was antigenically and 3H-HGH in the homogenate was antigenically similar to the injected dose. In contrast, when 3H-HGH was added in vitro before homogenization most radioactivity (77%) appeared in the cytoplasm and the rest distributed almost eqully among the other fractions. These results indicate (1) the early rapid uptake by the particulate fractions may be of functional significance and the important initial binding sites may be mitochondria and microsomes; (2) the movement of 3H-GH in liver cell may be from the microsomal and mitochondrial fractions into cytoplasm; (3) after 10 min 3H-HGH is degraded or deacetylated.

17 children between 5 and 15 years of age received mazindol for one year (2 mg daily). Their height was carefully evaluated by 2 physicians at 6 month intervals, and they were observed for the following year without any therapy. In each case, the growth rate slowed during mazindol administration (0.6 in/yr) compared to the previous year (1.5 in/yr). Assays of growth hormone during mazindol administration demonstrated reduced responses to insulin hypoglycemia and arginine (2 patients) and exercise (3 patients). It seems likely that mazindol reduces growth by increasing nor-epinephrine in the ventromedial nucleus of the hypothalamus, and it is interesting that increasing dopamine in that nucleus stimulates growth hormone release.

Serum was collected from hypophysectomized rat (HyR) 30 min. after an I.V. injection of hGH. The serum was used to prepare an antiserum (AS) in a rabbit. AS was adsorbed with lyophilized HyR serum (5 mg/ml) and centrifuged to obtain adsorbed antiserum (AAS). Immunoelectrophoresis (pH 9.5) using AS produced a number of lines with normal, HyR serum and Hy + hormone-treated serum but no line with hGH or insulin. AAS did not react with HyR serum but produced a single identical line (at beta globulin) with normal or Hy + GH treated serum. This precipitin line which was also present when whole AS was used may correspond to somatomedin produced in response to hGH. A similar and identical precipitin line was obtained with HyR + bGH treated serum but not with normal human serum. These results suggest that (1) hGH and bGH produce immunologically similar somatomedin(s) in the rat, (2) human somatomedin is immunologically different from rat somatomedin. This laboratory has already shown differences in the kinetics of bGH and hGH uptake by human liver slices.

Growth hormone deficiency has been reported in 10-20% of Russell-Silver dwarfs. Two siblings with all the classical features of Russell-Silver Syndrome were low in growth hormone (insulinarginine stimulation test), and blood and hair zinc (Zn). They received 50 mg elemental Zn orally each day for 2 months and 50 mg weekly for 4 more months. Growth hormone and Zn determinations were repeated at 6 months: It appears there is a direct relationship between the growth hormone response and Zn nutritional status. We have data indicating that growth hormone therapy increases hair Zn and decreases urinary Zn in children with growth hormone deficiency. These two children provide new data indicating that there are patients whose growth hormone production is affected by their Zn nutritional status.

Concentration of zinc in hair and serum of children with short stature (familial or constitutional) was measured by atomic absorption spectrophotometry. Some of them were treated with methyltestosterone (MT), 10 mg. daily. Our Zn values were similar to those reported for normal children. Nevertheless, children receiving MT had higher Zn levels than the children without medication. Since Zn deficiency is associated with growth retardation, these results raise the question of whether increased Zn retention may be one of the mechanisms by which androgens accelerate growth. We were unable to find any significant difference between the Zn levels from children with familial short stature and those from children with constitutional growth delay.

Concentration of zinc (Zn) in hair, urine and serum were measured by atomic absorption spectrophotometry in one 14-month old girl with typical features of Fetal Alcohol Syndrome (FAS) (peculiar facies, congenital malformations, pre and post natal growth deficiency). She was born to an alcoholic woman who continued drinking heavily throughout her pregnancy. Zinc level was low in hair (66 μg/g) and urine (266.8 μg/g of creatinine) but normal in serum(95 μg%), reflecting probable chronic depletion of Zn. (Normal values are: hair 193 ± 18 μg/g, serum 75-160 μg%, urine 400-600 μg/g.) It has been shown that the offspring of Zn-deficient rats have marked growth retardation and high incidence of congenital malformation, some of which are similar to those seen in FAS. Alcoholic patients have been found to lose increased amounts of zinc in urine. Therefore, it is tempting to speculate that congenital Zn deficiency plays an important role in the pathogenesis of this syndrome.

We have shown in laboratory animals that GH stimulates several mitochondrial processes like protein synthesis, bulk-protein turnover, levels of eytochromes and enzymes, and respiratory activity. We have presently studied respiratory activity (RA) in white cells (WC) and thymidine uptake in LY of children before and after GH therapy. RA (ngm of O2/mg protein or/μg DNA) was measured in WC. prepared by layering whole blood on metrizoate-dextran medium, with a Clark-Oxygen electrode in Krebs-Ringer solution containing glucose. There is significant correlation (r =0.8) between percent increase in respiration due to GH therapy for 1 month and height Rain after 4-8 months of therapy in 16 children. This correlation may have significance in the early prediction of growth-promoting effect during therapy. LY, isolated by layering whole blood over Lymphoprep, showed an increase in WBC, LY count and rosette forming LY in 11-12 children but showed a decrease in 5-6 children. There is a significant decrease in thymidine uptake by unstimulated LY in all 12 children. Therefore, stimulation index (uptake with stimulation by phytohemagglutinim/uptake without stimulation) increased. These results suggest that GH therapy may reduce basal rate of DNA synthesis in LY.

• A mildly obese 15-year-old boy had short stature with rounded facies and short, stubby hands and toes. He had the fully expressed syndrome of pseudohypoparathyroidism but was the only member of his family who had all the somatic characteristics of this disease. The serum parathyroid hormone level was substantially elevated. Urinary excretion of cyclic adenosine monophosphate and phosphate failed to increase following intravenous infusion of parathyroid hormone. However, he did not have hypocalcemia. The present entity is probably a transient form of pseudohypoparathyroidism with partial responsiveness of skeletal adenyl cyclase to parathyroid hormone. ( Am J Dis Child 129:1092-1095, 1975)

Mitochondrial (mito) protein synthesis has been shown to be influenced by hypophysectomy (Hy) and GH treatment (JBC 248 4263:1973). Cytochromes a, a3, b, c, C1 and flavin have now been measured by difference spectrophotometry in purified mito of rats after Hy and subsequent treatment with hGH and bGH. Concentrations were calculated independently of one another by solving simultaneous equations - mean ± SD. Hy significantly decreased (p 0.01) the concentration (nmoles/mg protein) of all cytochromes and subsequent GH treatment increased. hGH did not but bGH did decrease flavin to near normal level. This appears to be the first reported difference in the mechanism of action between the two hormones in Hy rats.

Serum lipid abnormalities have been found to be associated with zinc deficiency (Zn-). We observed that serum triglycerides (TG) responded rapidly to alterations in zinc nutritional status. After 7 days on Zn- diet (Zn 1 ppm), TG were increased by 200%, whereas in rats fed a control (C) diet (100 ppm) no changes in TG levels were recorded. By continuing the Zn- diet the TG increased gradually to 600% of the initial value after day 28, when TG leveled off. Thus, the elevation in TG preceded clinical signs of Zn-, and the elevation in TG is higher in the more severely deficient rats. Zn- rats fed the C diet or a Zn enriched (Zn +) diet (500 ppm) were repleted with Zn rapidly and TG decreased to normal values. Thus, hypertriglyceridemia (HTG) of Zn- is reversible when dietary Zn is increased and body stores of Zn are repleted. The HTG may be related to the decrease in post heparin plasma lipoprotein lipase between Zn- (370 ± 98 DPM glycerol release/mg protein/30 min) and C (510 ± 124). To test the hypothesis that Zn- rats have a higher level of endogenous lipid production, in vitro liver metabolism experiments were undertaken. Liver slices were incubated with (14C) glucose or (14C) palmitate and their utilization for TG synthesis and 14C02 production was measured. The results showed higher incorporation into TG in Zn- rats which may be due to an abnormality in carbohydrate metabolism.

1153 OBESITY IN CHILDREN. RELATIONSHIP BETWEEN ZINC (ZN) TRIGLYCERIDE (TG) AND TESTOSTERONE (T)

GH has been shown to sensitize the adrenal glands to ACTH, probably by increasing the activity of the mitochondrial 11-hydroxylase. In kidney cell culture, stimulation of 1α -hydroxylase, another mitochondrial enzyme, could be induced by GH. We are presenting the long term effect (6 months) of GH replacement (0.1u/k IM three times per week) on 25 (OH) Vit D and 1,25 (OH)2Vit D levels in 12 GH-deficient children (table). The acute responsiveness (3h) of the same metabolites to the PTH administration (250u IV) was also evaluated before and after GH therapy in three children. There was not significant increase of 1,25 (OH)2D3 before GH. However, 6 months after GH therapy the PTH administration induced a 3-fold increase in the 1,25 (OH)2D3 levels, suggesting that GH exerts its effect predominantly in the kidney mitochondria by increasing the sensitivity of the 1α -hydroxylase to PTH.

A case study details the clinical, biochemical, and roentgenographic findings in a diastrophic dwarf. The clinical findings were scoliosis and lordosis of the spine, club feet, cleft palate, dysplastic hips, and flexion contractures of knee joints and short extremities. Biochemical abnormalities observed were high cholesterol level, abnormal glucose tolerance, low growth hormone levels, and abnormal excretion of xanthurenic and kynurenic acids following tryptophan loading.

Oral glucose tolerance tests on 24 children with achondroplasia showed glucose intolerance in 16 of them. They were also found to have significantly elevated levels of plasma free fatty acids after an overnight fast, which rose still higher following human growth hormone administration. Plasma insulin levels were normal, but growth hormone levels were significantly below normal at 8 am, and tended to remain low during the day. These data are consistent with the concept that children with achondroplasia have a defect in peripheral glucose utilization.