Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the mechanism for cortisol enhancement of glucagon-stimulated overall hepatic glucose output (OHGO), we employed the glucose-insulin clamp technique with infusions of [6-3H]glucose and [U-14C]lactate and measured OHGO, glucose utilization, and the turnover and incorporation of lactate in plasma glucose in normal volunteers under four experimental conditions: 1) normoglucagonemia (approximately 150 pg/ml)- normocortisolemia (approximately 14 micrograms/dl); 2) isolated hyperglucagonemia (approximately 550 pg/ml); 3) isolated hypercortisolemia (approximately 32 micrograms/dl); and 4) combined hyperglucagonemia-hypercortisolemia. Isolated hyperglucagonemia caused initial increases in OHGO and lactate gluconeogenesis, which were maximal at 1 h (23.9 +/- 1 and 2.7 +/- 0.4 mumol.kg-1.min-1, respectively) but remained significantly above values in control experiments through 5 h (10.3 +/- 0.7 vs. 8.2 +/- 1.1, P less than 0.03; 2.2 +/- 0.4 vs. 1.2 +/- 0.3, mumol.kg-1.min-1, P less than 0.04, respectively). Hypercortisolemia has no effect on OHGO but increased lactate gluconeogenesis after 3 h. Superimposition of hypercortisolemia on hyperglucagonemia did not further increase OHGO (11.1 +/- 0.7 vs. 10.3 +/- 0.7 mumol.kg-1.min-1, P = NS) but augmented lactate gluconeogenesis additively (isolated hyperglucagonemia = 0.96, isolated hypercortisolemia = 0.98; combined = 2.02 mumol.kg-1.min-1). Neither glucagon nor cortisol affected lactate turnover or glucose utilization. We conclude that glucagon has a persistent effect on OHGO largely accounted for by increased gluconeogenesis. Cortisol augments glucagon-stimulated gluconeogenesis in an additive manner best explained by changes in gluconeogenic enzymes rather than in substrate availability. Finally, the fact that cortisol increased gluconeogenesis without affecting glucose utilization suggests that the liver is more sensitive to the diabetogenic effects of cortisol than are peripheral tissues.
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PMID:Glucagon-cortisol interactions on glucose turnover and lactate gluconeogenesis in normal humans. 218 43

Diurnal concentrations of glucose, the major regulatory hormones, and selected biochemistries were measured serially throughout a 25-h period in 38 healthy type I diabetic patients, 25 patients with acute ketoacidosis, and 20 normal subjects. Poor glucose control, meal intolerance, and hypercortisolemia were the dominant abnormalities in the healthy diabetic subjects. Ketonemia due to elevated plasma beta-hydroxybutyrate concentrations without ketonuria (nitroprusside reaction) was a frequent finding in a group of poorly controlled diabetic subjects. In the patients with acute ketoacidosis, the dominant abnormalities were overproduction of epinephrine and cortisol. High glucagon and growth hormone concentrations were documented in about one-half of these patients. We conclude that (1) the hyperglycemia, meal intolerance, and abnormal ketone body metabolism seen in these patients are caused by inadequacies in their insulin regimens; (2) ketone body underutilization contributes to diabetic ketosis; (3) epinephrine and cortisol overproduction are important components of acute ketoacidosis; and (4) the complex hormone-metabolic interactions in type I diabetes can best be explained by a multihormonal hypothesis with the primary defect being loss of beta-cell function.
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PMID:Hormone and metabolic profiles in children and adolescents with type I diabetes mellitus. 682 6

The role of physiological hypercortisolemia in the regulation of fuel metabolism in man was examined during a 5-h primed-continuous infusion of cortisol which raised plasma cortisol levels to 40 microgram/dl. Plasma glucose increased by 15--20 mg/dl (P less than 0.005) in spite of unchanged rates of glucose production. Glucose uptake and clearance, on the other hand, fell by 15% (P less than 0.05) and 30% (P less than 0.005), respectively, thereby accounting for cortisol-induced hyperglycemia. Total blood ketones during cortisol infusion increased 3-fold above saline control values (P less than 0.01) despite comparable FFA levels in the two groups. In addition, there was a selective 40% rise in total branched chain amino acids (P less than 0.005) during cortisol infusion. These effects of cortisol on glucose, ketone, and amino acid metabolism occurred in the absence of significant changes in the plasma insulin or glucagon concentration. Furthermore, cortisol infusion had no effect on [125I]insulin binding to circulating monocytes. Our data thus suggest that acute elevations of plasma cortisol have antiinsulin effects in man which may occur independent of alterations in insulin receptors.
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PMID:The influence of acute physiological increments of cortisol on fuel metabolism and insulin binding to monocytes in normal humans. 610 51

In Montreal, Quebec, a randomized, double blind study was conducted in eight healthy men at Hotel-Dieu Hospital during administration of cortisol (2 mcg/kg per minute for 5 h) with RU-486 (600 mg), during cortisol administration with a placebo, during 0.9% saline administration with RU-486, and during normal saline administration with a placebo. Clinicians administered a primed continuous infusion of D-[6,6-2H]glucose and [1-13C-]leucine during each test to determine hepatic glucose production and plasma leucine appearance rate. Continuous infusion of labeled bicarbonate in four men was also conducted to calculate the recovery factor of carbon dioxide in their breath. Researchers wanted to examine glucose and protein metabolism during hypercortisolemia with or without RU-486 and the effects of RU-486 on the metabolic effects of acute cortisol deficiency. Among men receiving the placebo, plasma glucose levels were higher during cortisol infusion than saline infusion (5.5 vs. 4.7 mmol/l; p 0.01). The leucine appearance rate was also higher during cortisol infusion than saline infusion (2.24 vs. 2 mcmol/kg per min; p 0.05) as well as leucine oxidation (0.51 vs. 0.31 mcmol/kg; p 0.01). Hepatic glucose production did not change in either placebo group. Cortisol did not induce the same metabolic changes when it was administered after RU-486. Normal saline infusion after RU-486 induced a short-term lower plasma glucose level and hepatic glucose production. Insulin, C-peptide, or glucagon did not change. Cortisol induced increased growth hormone (GH) levels (e.g., at 240 min, 5.9 vs. 1.7 mcg/l; p 0.01) while GH levels did not change when cortisol was administered after RU-486. These findings show that RU-486 suppresses the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in males. Long-term studies could reveal the potential of RU-486 to prevent the adverse effects of chronic glucocorticoid administration. RU-486 allows researchers to study the metabolic effects of cortisol in males.
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PMID:RU 486 prevents the acute effects of cortisol on glucose and leucine metabolism. 788 13

Hydrocortisone was infused overnight into nine normal healthy adults on three occasions at 0, 80, and 200 micrograms.kg-1.h-1, producing plasma cortisol concentrations of 10.6 +/- 1.2, 34.0 +/- 2.0, and 64.9 +/- 4.3 micrograms/dl, respectively. L-[1-13C]leucine, L-[phenyl-2H5]phenylalanine, and L-[2-15N]glutamine were infused during the last 7 h of hypercortisolemia to measure amino acid kinetics. During the last 3.5 h, somatostatin, glucagon, and insulin were infused to reduce the cortisol-induced elevation in plasma insulin to basal. Hypercortisolemia increased plasma glucose, free fatty acid (FFA), and insulin concentrations. Institution of the somatostatin clamp returned insulin to basal but increased glucose and FFA. Acute hypercortisolemia increased protein breakdown 5-20%, as measured by increases in leucine and phenylalanine appearance rates. Normalizing insulin during hypercortisolemia did not alter phenylalanine flux but enhanced leucine appearance rate, the latter result indicating that insulin was affecting leucine metabolism during hypercortisolemia. The fraction of the leucine flux that was oxidized was not significantly increased with hypercortisolemia, but disposal by the nonoxidative route of leucine uptake for protein synthesis was increased. Hypercortisolemia increased cycling of amino acids by increasing protein breakdown and synthesis, but the increase in this process could have increased resting energy expenditure (REE) only 1-2%. Hypercortisolemia increased glutamine flux in a dose-dependent fashion through an increase in de novo synthesis, which presumably reflects increased release from skeletal muscle. Hypercortisolemia increased REE 9-15% at the 80 and 200 micrograms.kg-1.h-1 infusion rates. Respiratory quotient did not rise with cortisol infusion but tended to decrease, suggesting that the increase in REE was fueled by increased oxidation of fat. These data demonstrate that hypercortisolemia increases metabolic rate and may be in part responsible for the hypermetabolic state in injury.
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PMID:Effect of cortisol on energy expenditure and amino acid metabolism in humans. 790 Jul 96

The present study was undertaken to determine whether an acute physiologic rise in plasma cortisol during selective insulin deficiency would have significant effects on glycerol and beta-hydroxybutyrate metabolism in conscious overnight-fasted dogs. Each experiment consisted of a two hour dye equilibration period, a 40 minute basal period, and a 3 hour experimental period. A continuous infusion of indocyanine green dye for blood flow estimation was initiated at the start of the equilibration period and continued throughout the experiment. In both of two protocols selective insulin deficiency was created during the experimental period by infusing somatostatin peripherally (0.8 microgram/kg-min) with basal replacement of glucagon intraportally (0.65 ng/kg-min). In the test protocol (CORTISOL, n = 5), 3.0 micrograms/kg-min of hydrocortisone was infused during the experimental period. In the control protocol (SALINE, n = 5), saline was infused. Net hepatic balances were determined using the (A-V) difference technique. During selective insulin deficiency alone (SALINE), the arterial blood glycerol level increased from 81 +/- 19 to 140 +/- 11 microM (p < 0.01) and net hepatic glycerol uptake (NHGlyU) tended to increase from 2.3 +/- 0.3 to 3.3 +/- 0.6 mumol/kg-min (0.05 < 0.1). The arterial plasma free fatty acid (FFA) level remained unchanged at 1041 +/- 35 microM. The arterial beta-hydroxybutyrate (BHOB) level increased slightly from 21 +/- 4 to 29 +/- 5 microM while net hepatic beta-hydroxybutyrate production (NHBP) remained unchanged (1.0 +/- 0.2 mumol/kg-min). During acute hypercortisolemia with selective insulin deficiency (CORTISOL), similar changes occurred in the arterial blood glycerol level and net hepatic glycerol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of acute hypercortisolemia on beta-hydroxybutyrate and glycerol metabolism during insulin deficiency. 790 56

This study was undertaken to further investigate the effect of acute selective insulin deficiency on glycogenolysis and gluconeogenesis occurring during chronic physiological hypercortisolemia in conscious overnight fasted dogs. After an 80-min tracer and dye equilibration period and a 40-min basal period, selective insulin deficiency was created during the 180-min experimental period by infusing somatostatin peripherally (0.8 micrograms.kg-1.min-1) with basal replacement of glucagon intraportally (0.65 ng.kg-1.min-1). In the cortisol group (n = 5), a continuous infusion of hydrocortisone (3.5 micrograms.kg-1.min-1) was begun 5 days before the experiment. In the saline group (n = 5), there was no infusion of cortisol. [3-3H]glucose, [U-14C]alanine, and indocyanine green dye were used to assess glucose production and gluconeogenesis using tracer and arteriovenous difference techniques. During selective insulin deficiency in the saline group, the arterial plasma glucose level (Glc) increased from 109 +/- 2 to 285 +/- 19 mg/dl; glucose production increased from 2.7 +/- 0.2 to 4.5 +/- 0.3 mg.kg-1.min-1. Gluconeogenic efficiency and conversion of alanine to glucose (Conv) increased by 300 +/- 55 and 356 +/- 67%. During selective insulin deficiency in the cortisol group, Glc increased from 117 +/- 3 to 373 +/- 50 mg/dl; glucose production increased from 3.3 +/- 0.5 to 6.9 +/- 0.7 mg.kg-1.min-1. Gluconeogenic efficiency and Conv increased by 268 +/- 41 and 393 +/- 75%, respectively. The maximal glycogenolytic rate increased significantly more in the cortisol group than in the saline group, accounting for the difference in glucose production. These results suggest that, even during chronic hypercortisolemia, acute insulin deficiency has more pronounced effects on glycogenolysis than gluconeogenesis.
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PMID:Effects of chronic hypercortisolemia on carbohydrate metabolism during insulin deficiency. 817 83

Cortisol's effects on lipid metabolism are controversial and may involve stimulation of both lipolysis and lipogenesis. This study was undertaken to define the role of physiological hypercortisolemia on systemic and regional lipolysis in humans. We investigated seven healthy young male volunteers after an overnight fast on two occasions by means of microdialysis and palmitate turnover in a placebo-controlled manner with a pancreatic pituitary clamp involving inhibition with somatostatin and substitution of growth hormone, glucagon, and insulin at basal levels. Hydrocortisone infusion increased circulating concentrations of cortisol (888 +/- 12 vs. 245 +/- 7 nmol/l). Interstitial glycerol concentrations rose in parallel in abdominal (327 +/- 35 vs. 156 +/- 30 micromol/l; P = 0.05) and femoral (178 +/- 28 vs. 91 +/- 22 micromol/l; P = 0.02) adipose tissue. Systemic [(3)H]palmitate turnover increased (165 +/- 17 vs. 92 +/- 24 micromol/min; P = 0.01). Levels of insulin, glucagon, and growth hormone were comparable. In conclusion, the present study unmistakably shows that cortisol in physiological concentrations is a potent stimulus of lipolysis and that this effect prevails equally in both femoral and abdominal adipose tissue.
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PMID:Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans. 1206 58

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing's disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4-17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269-900 nM during the immediate postoperative period (2-20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4-17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200-600 mg/d) (n = 4) and metyrapone (750 mg-3 g/d) +/- aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25-2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150-300 nM) occurred at mean 1.16 yr (0.40-2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6-2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0-17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4-12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.
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PMID:Clinical and endocrine responses to pituitary radiotherapy in pediatric Cushing's disease: an effective second-line treatment. 1251 24

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 +/- 53 vs. 337 +/- 57 pg/ml, P = 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 +/- 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 +/- 28 vs. 192 +/- 28 pg/ml, P = NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemia-induced hypercortisolemia is not primarily responsible for the generation of HAAF.
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PMID:Antecedent hypercortisolemia is not primarily responsible for generating hypoglycemia-associated autonomic failure. 1656 37


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