Antagonism Between the Effects of Insulin and Glucagon on the Isolated Liver

Mackrell, Dennis J.; Sokal, Joseph E.

doi:10.2337/diab.18.11.724

Cited by 115 publications

(42 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation is consistent with studies in perfused rat liver in which insulin, even when used in extremely high concentration, failed to suppress hepatic glucose release induced by supraphysiologic levels of glucagon (57). Similar observations have been made by Mackrell and Sokal who demonstrated differences in sensitivity of various hepatic processes to control by insulin and glucagon (58). It is also consistent with the observation that net glucose uptake by the canine liver does not begin until the glucagon: insulin ratio is less than 1/10 (59).…”

supporting

confidence: 80%

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

Liljenquist¹,

Bomboy²,

Lewis³

et al. 1974

J. Clin. Invest.

138

View full text Add to dashboard Cite

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.

show abstract

supporting

confidence: 80%

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

Liljenquist¹,

Bomboy²,

Lewis³

et al. 1974

J. Clin. Invest.

138

View full text Add to dashboard Cite

show abstract

“…Studies in the isolated perfused rat liver have demonstrated antagonism between the actions of glucagon and insulin in the regulation of several metabolic processes including glycogenolysis. Several laboratories have observed that the glycogenolytic effect of physiologic levels of glucagon (3 X 10-1, 1 X 10-, 4 X 10', and 4 X 10's M) could be inhibited by insulin (5,(29)(30)(31). These same groups also noted that the glycogenolytic activity of higher doses of glucagon (6 X 10', 1 X 10 , 1 X 104, and 2 X 10' M) could not be inhibited by insulin even when extremely high insulin levels (2.5 X 10V M; 3,600 AU/ml) were employed.…”

Section: Results and Commentsmentioning

confidence: 99%

Effect of Glucagon on Net Splanchnic Cyclic AMP Production in Normal and Diabetic Men

Liljenquist¹,

Bomboy²,

Lewis³

et al. 1974

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T Glucagon activates hepatic adenylate cyclase, thereby increasing acutely the liver content of cyclic AMP (cAMP) as well as the release of cAMP into the hepatic vein. Insulin, on the other hand, antagonizes this glucagon-mediated cAMP production, thus providing a hypothetical mechanism through which insulin might correct some of the metabolic abnormalities of diabetes.To study this hormonal interaction in man, net splanchnic cAMP production (NScAMPP) was investigated in normal and insulin-dependent diabetic men under basal conditions and in response to intravenous glucagon, 50 ng/kg/nmin for 2 h.In normals (n = 19), basal hepatic vein cAMP concentration was 23.6±1.1 nM and NScAMPP was 1.7±0.6 nmol/min. Glucagon stimulated NScAMPP in four normal subjects to a peak of 99.6±43 nmol/min at 25 min with a subsequent fall to 12.4±5.1 nmol/min by 90 min despite continuing glucagon infusion. Endogenous insulin secretion was stimulated as indicated by rising levels of immunoreactive insulin and C-peptide (connecting peptide) immunoreactivity, raising the possibility that endogenous insulin might be responsible for the fall in NScAMPP that followed the initial spike.In the diabetics (n = 8), basal hepatic vein cAMP concentration was 24.7±1.2 nM and NScAMPP was undetectable. Glucagon stimulated NScAMPP in five diabetics to a peak of 169.9±42.6 with a subsequent fall to 17.4±3.9 nmol/min by 90 min even though endogenous

show abstract

“…Furthermore, the age-associated changes in the G/I ratio determined for portal blood were almost the same as those determined for peripheral blood. While glucagon is known to increase G-6-Pase and F-1,6-DPase activities and accelerate the rate of gluconeogenesis and glucose out put in the liver, insulin suppresses the effects of glucagon (10,11,(24)(25)(26). In addition, it has been well established that the G/I ratio but not the absolute concentration of either hormone determines hepatic carbohydrate metabolism in vitro and in vivo (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

The Possible Role of Age-Related Increase in the Plasma Glucagon/Insulin Ratio in the Enhanced Hepatic Gluconeogenesis and Hyperglycemia in Genetically Diabetic (C57BL/KsJ-db/db) Mice

Kodama¹,

Fujita²,

Yamazaki³

et al. 1994

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

ABSTRACT-Genetically diabetic db/db mice and their normoglycemic littermates (+/+ mice) were studied to determine plasma levels of glucose, glucagon and insulin and hepatic gluconeogenic enzyme ac tivities. Plasma glucose levels did not differ significantly between the 5-week-old db/db and + / + mice, but increased with age in the former until the animals were 16-week-old. Similar age-associated changes were observed in the activities of the gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-l,6 diphosphatase (F-1,6-DPase). While the plasma levels of insulin and glucagon that peaked at 7 weeks of age did not parallel the hyperglycemia, the plasma glucagon/insulin (G/I) ratio roughly paralleled the hyperglycemia. Analysis of individual values for the db/db mice revealed statistically significant (P<0.001) correlations between plasma glucose levels and hepatic G-6-Pace (r=0.78) or F-1, 6-DPase (r=0.74) activ ity. There were also significant correlations between the G/I ratio and plasma glucose levels (P<0.001, r=0.66), hepatic G-6-Pase (P<0.01, r=0.48) or F-1,6-DPase (P<0.01, r=0.57) activity. It is thus conclud ed that the relative predominance of glucagon over insulin action plays an important role in the age associated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.Keywords: Diabetic (db/db) mouse, Glucagon/insulin ratio, Gluconeogenesis, Hyperglycemia Genetically diabetic (db/db) mouse was first described by Hummel et al. (1) as an animal model of NIDDM (non-insulin-dependent diabetes mellitus). Detailed stud ies from the same laboratory have later showed that hyperinsulinemia was the first detectable abnormality in the mice (2-4). Interestingly, the blood insulin levels which decrease with age appear to be inversely correlated with the blood glucose levels. On the other hand, we have recently demonstrated that insulin resistance occurred in db/db mice before the manifestation of hyperglycemia and remained constant during the course of developing hyperglycemia (5). We thus speculate that insulin resistance causes compensatory insulin release that causes age-associated insulin depletion and leads to development of hyperglycemia. Decreased glucose utilization due to in sufficient insulin release was considered to be an explana tion for the hyperglycemia in db/db mice.It has also been postulated that accelerated glucose production contributes to the hyperglycemia of db/db mice (6). The speculation was extended by Chan et al. (7), who showed that hepatic glycogenolytic and gluconeo genic enzyme activities increased in db/db mice. While glucagon enhances hepatic glucose production by stimulating gluconeogenesis and glycogenolysis, db/db mice are hyperglucagonemic (4, 8) presumably due to en hanced pancreatic glucagon release (9). These results sug gest that hyperglucagonemia which enhances hepatic glu cose production plays an important role in the develop ment of hyperglycemia in db/db mice.As described ...

show abstract

Antagonism Between the Effects of Insulin and Glucagon on the Isolated Liver

Cited by 115 publications

References 11 publications

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

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

Effect of Glucagon on Net Splanchnic Cyclic AMP Production in Normal and Diabetic Men

The Possible Role of Age-Related Increase in the Plasma Glucagon/Insulin Ratio in the Enhanced Hepatic Gluconeogenesis and Hyperglycemia in Genetically Diabetic (C57BL/KsJ-db/db) Mice

Contact Info

Product

Resources

About