Hyperglucagonemia of Renal Failure

Bilbrey, Gordon L.; Faloona, Gerald R.; White, Martin; Knöchel, James P.

doi:10.1172/jci107624

Cited by 159 publications

(61 citation statements)

References 28 publications

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“…In accordance with the observations of Bilbrey et al (14), the postabsorptive glucagon concentration was increased fourfold in uremic patients (349±32 pg/ml) as compared to controls (90±8 pg/ml, P < 0.001). Basal glucagon levels in uremics were not significantly different in dialyzed (326±34 pg/ml) or undialyzed patients (384±65 pg/ ml).…”

Section: Resultssupporting

confidence: 92%

“…The mechanism of uremia-induced insulin resistance and the improvement in insulin sensitivity after dialysis has not been established. Recently, Bilbrey et al (14) observed increased levels of circulating glucagon, a known insulin antagonist, in chronic renal failure. The pathophysiological significance of these findings was questioned however, since dialysis resulted in marked imThe Journal of Clinical Investigation Volume 57 March 1976.…”

Section: Introductionmentioning

confidence: 99%

“…The pathophysiological significance of these findings was questioned however, since dialysis resulted in marked imThe Journal of Clinical Investigation Volume 57 March 1976. [722][723][724][725][726][727][728][729][730][731] provement in glucose tolerance despite unchanged levels of plasma glucagon (14). The possible role of altered tissue responsiveness to physiological increments of glucagon in uremia and the effect of dialysis on glucagon sensitivity have not been previously examined.…”

Section: Introductionmentioning

confidence: 99%

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Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon.

Sherwin¹,

Bastl²,

Finkelstein³

et al. 1976

J. Clin. Invest.

196

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A B S T R A C T To evaluate the mechanism and role of hyperglucagonemia in the carbohydrate intolerance of uremia, 19 patients with chronic renal failure (12 of whom had undergone chronic hemodialysis for at least 11 mo) and 35 healthy control subjects were studied. Plasma glucagon, glucose, and insulin were measured in the basal state, after glucose ingestion (100 g), after intravenous alanine (0.15 g/kg), and during a 3-h continuous infusion of glucagon (3 ng/kg per min) which in normal subjects, raised plasma glucagon levels into the upper physiological range.Basal concentrations of plasma glucagon, the increment in glucagon after infusion of alanine, and postglucose glucagon levels were three-to fourfold greater in uremic patients than in controls. The plasma glucagon increments after the infusion of exogenous glucagon were also two-to threefold greater in the uremics. The metabolic clearance rate (MCR) of glucagon in uremics was reduced by 58% as compared to controls. In contrast, the basal systemic delivery rate (BSDR) of glucagon in uremics was not significantly different from controls.Comparison of dialyzed and undialyzed uremics showed no differences with respect to plasma concentrations, MCR, or BSDR of glucagon. However, during the infusion of glucagon, the increments in plasma glucose in undialyzed uremics were three-to fourfold greater than in dialyzed uremics or controls. When the glucagon infusion rate was increased in controls to 6 ng/kg per min to produce increments in plasma glucagon comparable to uremics, the glycemic response remained approximately twofold greater in the undialyzed uremics. The plasma glucose response to glu- cagon in the uremics showed a direct linear correlation with oral glucose tolerance which was also improved with dialysis. The glucagon infusion resulted in a 24% reduction in plasma alanine in uremics but had no effect on alanine levels in controls. It is concluded that (a) hyperglucagonemia in uremia is primarily a result of decreased catabolism rather than hypersecretion of this hormone; (b) sensitivity to the hyperglycemic effect of physiological increments in glucagon is increased in undialyzed uremic patients; and (c) dialysis normalizes the glycemic response to glucagon, possibly accounting thereby for improved glucose tolerance despite persistent hyperglucagonemia. These findings thus provide evidence of decreased hormonal catabolism contributing to a hyperglucagonemic state, and of altered tissue sensitivity contributing to the pathophysiological action of this hormone.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon.

Sherwin¹,

Bastl²,

Finkelstein³

et al. 1976

J. Clin. Invest.

196

View full text Add to dashboard Cite

show abstract

“…In the accompanying study, we found increased alanine and glutamine formation and release from skeletal muscle of experimentally uremic rats.' Although resistance to the action of insulin has been postulated in the chronically uremic state (7)(8)(9)(10)(11)(12), insulin insensitivity appeared not to account for the increased muscle amino acid release.' 8-Adrenergic agonists acting through adenylate cyclase and intercellular levels of cAMP appear to modulate the rate of protein degradation and amino acid release from skele-tal muscle (13).…”

Section: Introductionmentioning

confidence: 98%

The Regulation of Skeletal Muscle Alanine and Glutamine Formation and Release in Experimental Chronic Uremia in the Rat

Garber¹

1978

J. Clin. Invest.

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A B S T R A C T The mechanism of the increased alanine and glutamine formation and release from skeletal muscle in experimental uremia was investigated using epitrochlearis preparations from control and chronically uremic rats. In uremic muscle, insensitivity to epinephrine or serotonin suppression of alanine and glutamine release was observed. With control muscles, 1 nm or greater, epinephrine inhibited alanine and glutamine release, whereas with uremic muscles, epinephrine concentrations <1 ,uM did not alter amino acid release. Decreased alanine and glutamine release with 1 nM serotonin was observed in control muscles, but no inhibition was observed with concentrations <1 ,uM in uremic muscle. Muscle amino acid levels were the same in control and uremic muscles in the presence or absence of epinephrine or serotonin. The reutilization of released alanine by protein synthesis or oxidation to CO2 was not differentially affected by epinephrine in uremic muscles as compared with control muscle. Dibutyryl-cAMP inhibited amino acid release equally in uremic and control muscles. Epinephrine or serotonin increased cAMP levels two-to fourfold or more in control than in uremic muscle. Basaland fluoride-stimulated adenylate cyclase activities were equal in uremic and control muscle homogenates and in membrane fractions, but 10lM epinephrinestimulated adenylate cyclase was reduced 30-60% with uremia. At any concentration of epinephrine (0.001-100 usM), the stimulation of membrane adenylate cyclase activity was one-to twofold greater with control membranes than with uremic muscle Dr. Garber is an investigator ofthe Howard Hughes Medical Institute.

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“…It is likely that as a result of increased absorption greater amounts of glucose would be taken up by the liver. The liver is in turn subject to the increased sensitivity of the glucose-elevating effect of glucagon present in uremia (4,28,30). The increase in glucose absorption was proportionate to the concentration of glucose in the solutions perfused, with comparable differences at 4 and 40 mM between uremic and control animals.…”

Section: Discussionmentioning

confidence: 97%