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Variations in the antagonistic effects of insulin and glucagon on glycogen metabolism in cultured foetal hepatocytes.

ABSTRACT: The antagonistic effects of insulin and glucagon on glycogen formation and mobilization were studied in cultured 18-day foetal rat hepatocytes with regard to different modes of exposure. Hormone combinations were achieved with a constant dose of 10 nM-insulin (maximal for the glycogenic effect of this hormone) and increasing doses of glucagon [from 0.03 to 10 nM: concn. causing half-maximal response (ED50) = 0.3 nM)]. When insulin and glucagon were added simultaneously, increasing glucagon concentrations progressively depressed the glycogenic effect of insulin and 0.3 nM-glucagon antagonized the insulin effect completely. The maximal glycogenolytic effect of glucagon was observed at concentrations greater than 1 nM. When the two hormones were introduced successively, with an interval of 4 h between additions, the effect of the second hormone was always fully expressed between 4 and 8 h. at which time the effect of the first hormone had ceased; the dominance of glucagon over insulin was also lost, due to cell desensitization to glucagon. Both continuous or intermittent (10 min on/10 min off periods) exposure to insulin and/or glucagon gave similar antagonistic effects, while in cells exposed to insulin plus glucagon alternating with exposure to insulin or glucagon alone, the glycogenic effect of insulin was less or more antagonized respectively by glucagon. Whatever the situation, the results obtained could not be related to antagonism by a glucagon-induced rise in either cyclic AMP levels (ED50 = 3 nM) or cell-surface hormone binding. Thus, depending on the hormonal state and the mode of hormone administration, regulation of glycogenesis in cultured foetal hepatocytes appears to be different from that predicted by the insulin/glucagon molar ratio, which is strikingly altered in the perinatal period.

SUBMITTER: Menuelle P

PROVIDER: S-EPMC1151198 | biostudies-other | 1991 Jul

REPOSITORIES: biostudies-other

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Project description:The pathways of glycogen synthesis from glucose were studied using double-isotope procedures in 18-day cultured foetal-rat hepatocytes in which glycogenesis is strongly stimulated by insulin. When the medium containing 4 mM-glucose was supplemented with [2-3H,U-14C]glucose or [3-3H,U-14C]glucose, the ratios of 3H/14C in glycogen relative to that in glucose were 0.23 +/- 0.04 (n = 6) and 0.63 +/- 0.09 (n = 8) respectively after 2 h. This indicates that more than 75% of glucose was first metabolized to fructose 6-phosphate, whereas 40% reached the step of the triose phosphates prior to incorporation into glycogen. The stimulatory effect of 10 nM-insulin on glycogenesis (4-fold) was accompanied by a significant increase in the (3H/14C in glycogen)/(3H/14C in glucose) ratio with 3H in the C-2 position (0.29 +/- 0.05, n = 6, P less than 0.001) or in the C-3 position (0.68 +/- 0.09, n = 8, P less than 0.01) of glucose, whereas the effect of a 12 mM-glucose load (3.5-fold) did not alter these ratios. Fructose (4 mM) displaced [U-14C]glucose during labelling of glycogen in the presence and absence of insulin by 50 and 20% respectively, and produced under both conditions a similar increase (45%) in the (3H/14C in glycogen)/(3H/14C in glucose) ratio when 3H was in the C-2 position. 3-Mercaptopicolinate (1 mM), an inhibitor of gluconeogenesis from lactate/pyruvate, further decreased the already poor labelling of glycogen from [U-14C]alanine, whereas it increased both glycogen content and incorporation of label from [U-14C]serine and [U-14C]glucose with no effect on the relative 3H/14C ratios in glycogen and glucose with 3H in the C-3 position of glucose. These results indicate that an alternative pathway in addition to direct glucose incorporation is involved in glycogen synthesis in cultured foetal hepatocytes, but that insulin preferentially favours the classical direct route. The alternative foetal pathway does not require gluconeogenesis from pyruvate-derived metabolites, contrary to the situation in the adult liver.

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Variations in the antagonistic effects of insulin and glucagon on glycogen metabolism in cultured foetal hepatocytes.

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