Comparative clinical and metabolic studies in diabetes mellitus and sexual ateliotic dwarfism.
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Biomedical subjects
Publications and source records attributed to T J Merimee.
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To clarify the role of insulin and growth hormone (HGH) in regulating substrate production for body fuel during prolonged starvation, 6 normal subjects and 10 HGH-deficient dwarfs were fasted for 6 days. Four of these dwarfs received HGH during the fast. Blood glucose concentration decreased a mean 15 mg/100 ml in both controls and HGH-treated dwarfs, but decreased 50 mg/100 ml in untreated dwarfs. The final level at which the blood glucose stabilized was significantly higher in the former two groups (65 +/-1.0 mg/100 ml and 88 +/-19 mg/100 ml, respectively, versus 39.0 +/-4.0 mg/100 ml in the untreated dwarfs). The decline in plasma insulin concentration showed a comparable pattern, decreasing from a similar basal level to 7.7 +/-0.4 muU/ml in controls, 8.8 +/-1.1 muU/ml in dwarfs treated with HGH, and to a significantly lower level of 3.8 +/-1.1 muU/ml in untreated dwarfs. When glucose concentrations were plotted against paired insulin values, the correlation in both dwarfs and normals was significant. In normals, no correlation existed at any time between plasma HGH levels and plasma concentration of either glucose or free fatty acid. Free fatty acid, beta-hydroxybutyrate, and acetoacetate increased respectively in normals to peak concentrations in plasma of 1.55 +/-0.11, 2.87 +/-0.23, and 0.77 +/-0.09 mmoles/liter. Untreated dwarfs had significantly greater values of all three (mean maximal concentration: FFA = 2.16 +/-0.17 mmoles/liter, beta-hydroxybutyrate = 4.11 +/-0.34 mmoles/liter, and acetoacetate = 1.16 +/-0.10 mmoles/liter). Values returned toward normal in HGH-treated dwarfs. The cahnges in plasma concentrations of beta-hydroxybutyrate and acetoacetate were not due to changes in renal excretion. In starvation, the relation between insulin on the one hand and glucose and free fatty acid on the other hand is maintained in the absence of HGH. However, the setting of blood glucose concentration at which this relation takes place is decreased in the absence of HGH. This results in a lower than normal insulin level and, consequently, in a higher than normal free fatty acid concentration.
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Five subjects were studied by the forearm perfusion technique with proinsulin at a final plasma conceintration of 1.76 x 10(-9) millimole per milliliter. Two of these subjects were studied with single-component insulin at a concentration of 1.96 x 10(-9) millimole per milliliter. Proinsulin is, in general, biologically less potent than single-component insulin. In contrast to insulin, its effects upon adipose tissue are for the most part greater than upon muscle.
The incidence of diabetic retinopathy was determined in 38 diabetics and 31 sexual ateliotic dwarfs deficient only in human growth hormone (HGH). The age and sex distribution were approximately the same in each group. The incidence and pattern of glucose intolerance were similar in diabetics and HGH-deficient dwarfs. The majority of diabetics (21 of 38) and HGH-deficient dwarfs (26 of 31) exhibited insulinopenia after glucose, mixed glucose-beef meals, and the infusion of l-arginine. A smaller number of HGH-deficient dwarfs (5 of 31) and diabetics (8 of 38) had normal or augmented absolute insulin responses to these same provocative stimuli. Hypercholesterolemia and hypertriglyceridemia occurred with greater frequency in both diabetics and HGH-deficient dwarfs than in normal controls. 8 of 21 diabetics and 6 of 21 sexual ateliotics exhibited significant hypertriglyceridemia. Five diabetics and six sexual ateliotics had significantly greater than normal serum cholesterol levels. Nearly half of the diabetics (16 of 38) had significant pathological abnormalities of the retina, but these changes were conspicuously absent in HGH-deficient dwarfs. No retinal lesions were detected in any HGH-deficient dwarf.
A group of 32 sexual ateliotic dwarfs with an isolated deficiency of human growth hormone (HGH) were shown previously to resemble subjects with genetic diabetes mellitus in terms of hyperlipemia, carbohydrate intolerance, and patterns of insulin secretion. 11 of these dwarfs had needle biopsies of the quadriceps femoris carried out and tissue fixed for electron microscopy. Capillary basement membrane thickness was measured and compared with measurements previously obtained in diabetics and normal controls. Measurements were similar in controls and dwarfs (1080 +/-27 A and 1086 +/-90 A, respectively) and significantly less than in diabetics (2403 +/-119 A). Placed in juxtaposition with the absence of retinopathy in dwarfs and the high incidence in the diabetic group (41%), the data support the thesis that these anatomical abnormalities are largely independent of serum lipid and carbohydrate abnormalities. The data are consistent with a supportive, if not causative role of growth hormone in the pathogenesis of these lesions.
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