Effect of Glucagon: Insulin Ratios on Hepatic Metabolism

Parrilla, Roberto L.; Goodman, M N; Toews, C. J.

doi:10.2337/diab.23.9.725

Cited by 161 publications

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“…In agreement with the high concentration of glucagon, cAMP concentrations in the liver are relatively high during the suckling period (34,35). Although a high ambient concentration of glucagon and a high intracellular concentration of cAMP are associated with a stimulation of proteolysis in adult hepatocytes (1,4,56), we have found that a high intracellular level of cAMP cannot yet stimulate autophagic proteolysis in cultured hepatocytes of fetal and suckling rats (13). The portal concentration of insulin increased 4-fold during development.…”

Section: Discussionsupporting

confidence: 64%

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Changes in Hepatic Nitrogen Balance in Plasma Concentrations of Amino Acids and Hormones and in Cell Volume after Overnight Fasting in Perinatal and Adult Rat

et al. 1995

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ARSTRImportant regulatory factors of intrahepatic protein synthesis and proteolysis are amino acids, glucagon, insulin, and cell volume. We have investigated the changes in these factors with development and after an overnight fast and evaluated their contribution to changes in the hepatic nitrogen balance in vivo. In the fed state, glucagon levels were highest in suckling animals and gradually declined in older rats, whereas the concentration of insulin increased during development. The amino acid concentrations in liver and plasma declined during the suckling period to levels that in vitro are highly permissive for induction of autophagic proteolysis. In all age groups investigated, fasting was associated with a drop in hepatic protein content, together with a marked decrease in hepatocellular volume and insulin concentrations. On the other hand, glucagon concentrations and the concentration of many amino acids in plasma and liver responded to fasting with a pronounced decrease in perinatal and suckling animals, but this response had become blunted at weaning and had disappeared in adult animals. These findings suggest that insulin and/or hepatocellular volume are more likely candidates as short-term physiologic regulators of the hepatic nitrogen balance than are glucagon or amino acids. In glucosesupplemented fetuses, high levels of insulin could not compensate for a decreased hepatocellular volume in averting a catabolic state, suggesting that cell volume is the more important factor. Although our study cannot discriminate between the effects of fasting on protein synthesis and degradation, our findings show unequivocally that, for a rapid growth of the liver, suckling animals have to be fed around-the-clock. (Pediatr Res 38: 1018-1025, 1995)The cellular protein content is regulated by modulation of the rates of synthesis and/or degradation. The nutritional and hormonal status have been shown to be of paramount importance as modulators of the rate of synthesis and degradation of proteins in the liver (1-7). In vivo studies in which the effect of refeeding after prolonged periods of starvation (2-5 d) was studied (8-10) and in vitro studies with perfused livers (cf. Ref. I), freshly isolated (6,7,11,12) or cultured hepatocytes (13-15) have identified amino acids and the hormones insulin and glucagon as major determinants of hepatic lysosomal proteolysis and protein synthesis. High ambient concentrations of amino acids and insulin suppress intrahepatic proteolysis (1, 6, 7) and stimulate protein synthesis (16-19), whereas glucagon exerts the opposite effect (1,13,14,20). More recently, it was proposed that lysosomal proteolysis in rat liver is also regulated by changes in the volume of the hepatocyte, an increase in cell volume being inhibitory (21, 22). As indicated, most of these findings were obtained from in vitro studies, involving strong manipulation of the nutritional and hormonal environment of the hepatocytes. In this respect, we had previously observed in cultured hepatocytes that intrahepatic lysoso...

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Section: Discussionsupporting

confidence: 64%

“…The portal concentration of insulin increased 4-fold during development. A well known effect of insulin is its stimulation of protein synthesis and its inhibition of protein breakdown (1,6,10,56). …”

Section: Discussionmentioning

confidence: 99%

Changes in Hepatic Nitrogen Balance in Plasma Concentrations of Amino Acids and Hormones and in Cell Volume after Overnight Fasting in Perinatal and Adult Rat

et al. 1995

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“…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%

“…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). These results together with the above discussion suggest that the rela tive predominance of glucagon over insulin activities may induce an elevation of hepatic gluconeogenic enzymes activity and contribute to the age-dependent development of hyperglycemia in db/db mice.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, there is no doubt that insulin and gluca gon have reciprocal roles in regulating blood glucose levels and that the plasma glucagon/insulin (G/I) ratio is an essential unit in regulating hepatic carbohydrate metabolism in vitro and in vivo (10)(11)(12). We thus deter mined the plasma glucagon and insulin levels simulta neously with hepatic gluconeogenic enzyme activities in db/db mice aged 5 -16 weeks when the hyperglycemia dramatically developed and examined the relationships between these parameters and the G/I ratio.…”

mentioning

confidence: 99%

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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

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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 ...

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Scanning microdensitometry of glycogen zonation in the livers of rats adapted to a controlled feeding schedule and to 30, 60, or 90% casein diets

Richards

Potter

1980

Am. J. Anat.

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The effect of diet composition on diurnal changes in glycogen zonation patterns in rat liver was investigated in individually-caged male Sprague-Dawley rats adapted to the 2 + 22 controlled feeding and lighting schedule and to diets containing 30% casein/55% carbohydrates, 60% casein/25% carbohydrates, or 9.0% casein (30 rats/dietary group). Three rats from each dietary group were killed at the following times relative to the onset of feeding (0 min):--60, --30, 0, 15, 30, 45, 60, 90, 120, and 180 min. Glycogen in cryostat sections from the median and right lateral lobes of the liver was fixed and stained by standard techniques. The optical density of glycogen at points along the path between the central and portal veins of a given lobule was determined, and lobular glycogen gradients of replicate animals were integrated to form a composite lobular glycogen distribution profile. In the period from--60 to 0 min, liver glycogen levels were similar for rats on any of the diets, and the glycogen concentration was similar in periportal (P), midlobular (M), and centrilobular (C) hepatocytes. During the 0- to 45-min period, diet-related glycogen depletion occurred (90 > 60 > 30% casein) by asymmetrical glycogen loss (P > M > C hepatocytes) from the liver lobules. Similar food intake curves occurred for all diets. During the 45- to 180-min period, asymmetrical glycogen accumulation began in lobular parenchymal cells (P > M > C hepatocytes), and rate of accumulation was related to dietary to dietary composition (30 > 60 > 90% casein). The differential responses of parenchymal cells within liver lobules to physiological stimuli resulted in glycogen distribution changes that were rapid and of large magnitude. Our results are consistent with the hypothesis that periportal and midlobular hepatocytes are more metabolically responsive and active than centrilobular hepatocytes

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Effect of Glucagon: Insulin Ratios on Hepatic Metabolism

Cited by 161 publications

References 0 publications

Changes in Hepatic Nitrogen Balance in Plasma Concentrations of Amino Acids and Hormones and in Cell Volume after Overnight Fasting in Perinatal and Adult Rat

Changes in Hepatic Nitrogen Balance in Plasma Concentrations of Amino Acids and Hormones and in Cell Volume after Overnight Fasting in Perinatal and Adult Rat

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

Scanning microdensitometry of glycogen zonation in the livers of rats adapted to a controlled feeding schedule and to 30, 60, or 90% casein diets

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