Interactions of Glucagon and Insulin on the Metabolism of Perfused Livers from Fasted Rats

A B S T R A C T The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusing somatostatin (1 ug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+6 and 81±8%, respectively. Intraportal infusion of insulin and glucagon at rates of400 ,uU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques.Isolated glucagon deficiency resulted in a 35+5% (P < 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration ofthe plasma glucagon level. Isolated insulin deficiency resulted in a 52+16% (P < 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon.In conclusion, in the anesthetized dog fasted overThis work was presented in part at

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“…5 Cherrington, A. D., et al Manuscript in preparation. regulating glucose production-by the liver after an ovemight fast.…”

Section: Resultsmentioning

confidence: 99%

“…In conclusion, in the anesthetized dog fasted over-INTRODUCTION The ability of glucagon to increase hepatic glucose production has been well documented both in vivo (1)(2)(3) and in vitro (4,5). Similarly, the inhibitory action of insulin on glucose output has been clearly established (6)(7)(8)(9)(10).…”

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confidence: 95%

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog.

Cherrington¹,

Chiasson²,

Liljenquist³

et al. 1976

J. Clin. Invest.

243

100

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“…It is possible that other abnormalities might also influence the development of hepatic autophagy. A reduced concentration of insulin in the presence of a high glucagon level augments hepatic gluconeogenesis in the perfused rat liver preparation (24)(25)(26)(27)(28). This effect has been demonstrated even when amino acids are omitted from the perfusate (24), suggesting that hepatic amino acids are among the precursors.…”

Section: Resultsmentioning

confidence: 99%

Hepatic Autophagy in Uncontrolled Experimental Diabetes and Its Relationships to Insulin and Glucagon

Amherdt¹,

Harris²,

Renold³

et al. 1974

J. Clin. Invest.

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A B S T R A C T Exogenous glucagon is known to increase hepatic lysosomes, but the relationships between endogenous glucagon and insulin levels and hepatic lysosomes have not been examined. To determine if the hormones of the pancreatic islets influence the development of these organelles glycogenosomes, dense bodies, and autophagosomes were morphometrically quantitated in normal rats, in rats with mild streptozotocin diabetes with normal hormone levels, and in rats with severe streptozotocin diabetes with hyperglucagonemia, hypoinsulinemia, and clinical evidence of uncontrolled diabetes and ketoacidosis. In the latter volume density of lysosomes averaged 222.8 X 10-' (SEM ±19.8 X 10-4), significantly above the control value of 75 X 10-4 (SEM ±7.0 X 10-4) (P < 0.0005); glycogenosomes were absent in the diabetics, the increase being largely the result of increased autophagosomes. Insulin treatment corrected the hyperglucagonemia, hypoinsulinemia, and other manifestations of uncontrolled diabetes and reduced the volume density of lysosomes to 37.4 X 10-4 (SEM ±2.0 X 10-4), significantly below both the untreated diabetic rats and the nondiabetic controls (P < 0.0025). In mild streptozotocin diabetes, in which hyperglucagonemia, hypoinsulinemia, and other evidence of uncontrolled diabetes were absent, lysosomes averaged 77.6 x 10-4 ( SEM + 5.5 X 10-4), not different from the controls. A statistically significant correlation between all measurements of lysosomal volume density and plasma

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“…Hence, the ability of glucagon to stimulate these two processes in man has been questioned (8,9). The assessment of the lipolytic and ketogenic activity of glucagon in man has been complicated by the inherent capability of glucagon to stimulate insulin secretion (14) and the fact that insulin inhibits both lipolysis and ketogenesis (2,(15)(16)(17). Indeed, early studies in vivo in various species, including man, showed a marked decline in circulating free fatty acids (FFA) after glucagon administration (18)(19)(20)(21)(22), attributed to the observed rise in plasma immunoreactive insulin (IRI)1 (23,24).…”

Section: Introductionmentioning

confidence: 99%

Effects of Glucagon on Lipolysis and Ketogenesis in Normal and Diabetic Men

Liljenquist¹,

Bomboy²,

Lewis³

et al. 1974

J. Clin. Invest.

138

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A B S T R A C T The effect of glucagon (50 ng/kg/min) on arterial glycerol concentration and net splanchnic production of total ketones and glucose was studied after an overnight fast in four normal and five insulin-dependent diabetic men. Brachial artery and hepatic vein catheters were inserted and splanchnic blood flow determined using indocyanine green. The glucagon infusion resulted in a mean circulating plasma level of 4,420 pg/mI.In the normal subjects, the glucagon infusion resulted in stimulation of insulin secretion indicated by rising levels of immunoreactive insulin and C-peptide immunoreactivity. Arterial glycerol concentration (an index of lipolysis) declined markedly and net splanchnic total ketone production was virtually abolished. In contrast, the diabetic subjects secreted no insulin (no rise in C-peptide immunoreactivity) in response to glucagon. Arterial glycerol and net splanchnic total ketone production in these subjects rose significantly (P = < 0.05) when compared with the results in four diabetics who received a saline infusion after undergoing the same catheterization procedure.Net splanchnic glucose production rose markedly during glucagon stimulation in the normals and diabetics despite the marked rise in insulin in the normals. Thus, the same level of circulating insulin which markedly suppressed lipolysis and ketogenesis in the normals failed to inhibit the glucagon-mediated increase in net splanchnic glucose production. It is concluded (a) that glucagon at high concentration is capable of stimulating lipolysis and ketogenesis in insulin-deficient diabetic man; (b) that insulin, mole for mole, has more antilipolytic activity in man than glucagon has lipolytic activity; and (c) that glucagon, on a molar basis, has greater stimulatory activity than insulin has inhibitory activity on hepatic glucose release.

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Interactions of Glucagon and Insulin on the Metabolism of Perfused Livers from Fasted Rats

Cited by 81 publications

References 50 publications

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog.

The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog.

Hepatic Autophagy in Uncontrolled Experimental Diabetes and Its Relationships to Insulin and Glucagon

Effects of Glucagon on Lipolysis and Ketogenesis in Normal and Diabetic Men

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