Daily production and metabolic clearance of growth hormone in juvenile diabetes mellitus

Sperling, Mark A.; Wollesen, Flemming; DeLamater, Paul V.

doi:10.1007/bf01239431

Cited by 43 publications

(13 citation statements)

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“…1 h before stopping the insulin infusion, a constant infusion of glucagon (1 ng/kgmin; from Eli Lilly Co.) was begun and continued for a total of 7 h. This dose was chosen because a previous report (9) indicated that it would produce circulating glucagon levels (150-250 pg/ml) similar to those observed after acute withdrawal of insulin (33,34 (35,36). Somatostatin was infused as described above for 8 h via a separate syringe upon stopping the insulin infusion.…”

Section: Experimental Protocolmentioning

confidence: 99%

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

Gerich¹,

Lorenzi²,

Bier³

et al. 1976

J. Clin. Invest.

194

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A B S T R A C T To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal.Infusion of glucagon (1 ng/kg min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94±8 to 126±+12 mg/100 ml over 1 h (P <0.01); growth hormone, P-hydroxybutyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, fi-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P < 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma P-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P < 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin. INTRODUCTIONThe physiologic importance of glucagon and growth hormone in human carbohydrate and lipid homeostasis is poorly understood. Administration of pharmacologic amounts of glucagon can augment lipolysis (1-4), ketogenesis (1-4), and glucose production (1-5) in man, but these effects are difficult to interpret because such quantities of glucagon may promote growth hormone (6) and catecholamine (7) release. Moreover, similar results have not been consistently observed in studies using physiologic concentrations of glucagon (3,8,9). Evidence for the participation of growth hormone in human lipid and carbohydrate metabolism is based largely on results obtained after administration of pharmacologic quantities of growth hormone and on observations in hypophysectomized individuals. Growth hormone, when administered in pharmacologic doses, reportedly diminishes glucose utilization (10-15) and promotes lipolysis (10, 16) and ketosis (10, 15, 16) in man, but similar

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Section: Experimental Protocolmentioning

confidence: 99%

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

Gerich¹,

Lorenzi²,

Bier³

et al. 1976

J. Clin. Invest.

194

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“…Insulin and glucagon were measured by radioimmunoassay using methods previously described (36,37). The glucagon antibody used, GI-5, is highly discriminating for pancreatic glucagon and cross-reacts minimally with gut extracts (36,37).…”

Section: Analytic Techniquementioning

confidence: 99%

“…The glucagon antibody used, GI-5, is highly discriminating for pancreatic glucagon and cross-reacts minimally with gut extracts (36,37). Rabbit antiporcine antibody was used.…”

Section: Analytic Techniquementioning

confidence: 99%

Adrenergic Modulation of Pancreatic Hormone Secretion in Utero: Studies in Fetal Sheep

et al. 1980

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SummaryT o assess the functional maturity of adrenergic modulation of plasma concentration of glucose, a s well a s immunoreactive glucagon (IRC) and immunoreactive insulin (IRI) secretion in utero, adrenergic agonists with or without / 3 (propranolol) or a (phentolamine) antagonists were infused to the chronically catheterized sheep fetus (n = 35) late in the third trimester. Mean f S.E. days at study was 129.5 f 1.5; term is 150 days. In 9 separate studies at gestational age 129 f 1 days, the infusion of saline for 3 hr was not associated with significant changes in the basal levels of glucose, IRC, or IRI.With epinephrine, 6 pg/min (n = 6) glucose rose from 16.7 f 3.6 to 41.9 f 9.7 mg/dl, IRC rose from 75 f 8 to 219 f 45 pg/ml, and IRI fell from 22.6 + 1.7 t o 12.7 + 3.5 microunits/ml ( P < 0.05 for each). Propranolol alone (n = 4) did not alter basal glucose or IRC but significantly suppressed IRI. Propranolol did, however, markedly attentuate the rise in glucose and IRC while exaggerating the fall in IRI during epinephrine infusion. Qualitatively similar but smaller responses were obtained with epinephrine. 0.4 pg/min (n = 10). Similarly, elevation of glucose and suppression of IRI was obtained with norepinephrine, 2 gg/min (n = 5), but IRC levels did not rise significantly. a-Adrenergic blockade alone augmented IRI from 18 + 3 to 38 + 5 microunits/ml without affecting glucose or IRC concentrations; during a blockade, norepinephrine infusion failed to induce the rise in glucose, IRG remained unchanged, and IRI remained elevated (n = 5). 2-Deoxy-D-glucose, 200 mg IV over 30 min, did not affect glucose, IRG, or IRI (n = 5). Thus, appropriate adrenergic modulation of plasma concentrations of glucose, and of IRG and IR1 secretion is established in the third trimester.following placental separation and abrupt cessation of the transfer of nutrients from mother to fetus, thereby suggesting that hypoglycemia acts as the stimulus for the observed changes (15,-17). We have recently reported that in newborn lambs there is a similar 5-fold surge of IRG within minutes of delivery, whereas plasma IRI remains low and unchanged (17). In newborn lambs, however, there was no fall in plasma glucose concentration following delivery, so that unless curtailment of a different major nutrient for the lamb acts as the trigger for IRG secretion, hypoglycemia is not the stimulus for the observed surge in IRG. An abrupt increase in catecholamine secretion at birth could adequately explain the . .observed changes because catecholamines are-known to stimulate glucagon secretion, inhibit insulin secretion, and mobilize free fatty acids (9,12,19,23,26,29,32,38). A rise in circulating free fatty acid levels does occur shortly after delivery (1, 17). Moreover, catecholamines increase markedly and abruptly in the arterial plasma of newborns at delivery (10. 24), and urinary excretion of epinephrine increases in the initial hours of life (27). If this hypothesis regarding the role of catecholamines as the trigger for the observed neonatal cha...

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“…The role of the a adrenergic receptor in mediating growth hormone release is well established (2,17) and hyper responsiveness of growth hormone release to a variety of stimuli has been reported previously in insulin-dependent diabetics (32). T h e exaggerated response is restored toward normal upon instituting careful control of the diabetic state (15).…”

Section: Discussionmentioning

confidence: 90%

“…priately elevated glucagon and growth hormone concentrations in the basal and stimulated state (32,34), it was anticipated that an Speculation effect of a or P adrenergic blockage might be more apparent in this Sympathetic overactivity, documented in poorly controlled juvenile diabetic subjects may, via a receptors, be one of the mechanisms responsible for growth hormone hypersecretion in these subjects. Although the evidence suggesting a role for adrenergic METHODS stimuli in modulating glucagon secretion is compelling, the relative hypersecretion of glucagon in juvenile diabetics in response to SUBJECTS AND PROCEDURES arginine does not seem to be pridominately influenced by-either a or p adrenergic receptors alone.…”

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confidence: 99%

Effect of Adrenergic Blockade on Glucagon and Growth Hormone Secretion in Normal and Diabetic Children

Sperling

Voina

1975

Pediatr Res

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AExtract modulating insulin and growth hormone secretion (2, 17, 22, 26, Studies were conducted in four normal and six diabetic children to 28,29,36). Recent data also implicate a role for adrenergic assess the role of adrenergic blockade on basal and arginine-stim-agonists in stimulating glucagon secretion (18). ~n a t o m i c and ,,lated growth hormone and glucagon secretion. ~~~h subject had, histologic studies demonstrate sympathetic nerve endings directly on three separate occasions, infusion of arginine alone or in on the pancreatic islet (9, 18), and stimulation of the splanchnic conjunction with LY (phentolamine) or P (propranolol) adrenergic sympathetic nerve in dogs (25), cats (8), and calves (4), causes a blockade. ~l i~i~~l l~, there was evidence of adequate blockade rise in glucagon secretion. In man, a variety of stressful situations by each agent. ~~~~l hormone growth levels were not significantly (3, 10, 30) as well as direct inrusion or epinephrine (12) result i n a different in the two groups (1.3 * 0.2 to 2.1 + 1.0 ng/ml in normal rise in plasma glucagon concentration. However, unlike insulin subjects; 3.0 + 1.1 to 6.0 * 3.1 ng/ml in diabetics (mean + and growth hormone, where there is uniform agreement that the SEM)) but the peak growth hormone after arginine was adrenergic effects are mediated via activation of adrenergic cantly greater in the diabetic children than control subjects (34.3 * receptors which are inhibitory or stimulatory, the precise role of 7.2 versus 12.3 A 3.1); in both groups &-blockade suppressed the these receptors in modulating glucagon secretion remains uncergrowth hormone response, whereas P-blockade had no significant tain. Activation of both a or P adrenergic receptors has been effect. ~~~~l glucagon concentrations were similar in both groups reported to either stimulate or inhibit glucagon secretion (7, 1 1, 13, (147 * 31 to 214 * 21 pg/ml in normal subjects; 100 * 20 to 14, 16, 18-20, 23, 36), and contradictory results have been re-124 * 17 pg/ml in diabetics on three different occasioas, despite i;orted within the same species, despite similarities in experithe coexistent hyperglycemia of the diabetics. Neither basal nor mental design ( I 1 , 1 3 7 23). maximally stimulated glucagon secretion was significantly affected T O date few studies have focused on factors affecting glucagon by a or blockade in the juvenile diabetic or control children. The secretion in normal and diabetic children. The present investigaresults suggest that sympathetic overactivity via a receptors may tion in children was therefore undertaken in order to ascertain the contribute to the hypersecretion of growth hormone in juvenile effects of a or P adrenergic blockade on basal and argininediabetes and that the a or adrenergic receptor alone does not stimulated glucagon as well as growth hormone secretion. Because appear to modulate. basal or arginine stimulated glucagon patients with juvenile diabetes have been reported to have inapprosecretion.priately elevated glucagon and growth hormone ...

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Daily production and metabolic clearance of growth hormone in juvenile diabetes mellitus

Cited by 43 publications

References 13 publications

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

Adrenergic Modulation of Pancreatic Hormone Secretion in Utero: Studies in Fetal Sheep

Effect of Adrenergic Blockade on Glucagon and Growth Hormone Secretion in Normal and Diabetic Children

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