Control of hepatic glycogen metabolism in the rhesus monkey: effect of glucose, insulin, and glucagon administration

Rt, Curnow; Rayfield, EJ; George, DT; Zenser, TV; Rubertis, F De

doi:10.1152/ajplegacy.1975.228.1.80

Cited by 54 publications

(12 citation statements)

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“…In man, Liljenquist and co-workers (1) observed that the sustained infusion of exogenous glucagon at a constant rate is accompanied by a peak-decline pattern in net splanchnic cAMP production. Our own previous studies (2) and those of others (3,4) have noted a similar tendency for the hepatic cAMP content of experimental animals to decline from early peak levels during glucagon infusions. Further, in rats with persistent endogenous hyperglucagonemia induced by infection, the hepatic cAMP response to exogenous glucagon is blunted (5).…”

supporting

confidence: 82%

Reduced sensitivity of the hepatic adenylate cyclase-cyclic AMP system to glucagon during sustained hormonal stimulation.

DeRubertis¹,

Craven²

1976

J. Clin. Invest.

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A B S T R A C T Hormone-induced desensitization of hormonal regulation of cyclic AMP (cAMP) content has been described in a number of tissues. In the present study, we examined responses of rat liver to glucagon after periods of sustained exposure to the hormone in vivo and in vitro. In intact anesthetized rats infused with glucagon (50 ng/min) for 1 h or more and in liver slices incubated with the hormone (10 /AM) for this period, hepatic cAMP responsiveness to glucagon was significantly blunted compared with that of tissue exposed to the hormone for shorter periods. The reduction in hepatic cAMP responsiveness to glucagon appeared to be fully expressed by 2 h. With the doses of hormone employed, the sequential alterations in hepatic responsiveness seemed to be limited to the cAMP system, since other parameters of glucagon action did not wane with time.Diminished hepatic cAMP responsiveness during sustained hormonal exposure could not be attributed to decreased glucagon availability, accelerated extracellular release of cAMP, hepatic ATP depletion, or enhanced phosphodiesterase activity. Studies in vitro suggested that modulation of the cAMP response occurred at the level of adenylate cyclase (AC). During sustained exposure of hepatic slices to glucagon, reductions in glucagon-responsive AC correlated temporally with those in cAMP and both changes were reversible. Alterations in glucagon-responsive AC were demonstrated over a wide range of ATP (10 uM-0.1 mM) and glucagon (10 nM-5 mM) concentrations in the cyclase reaction mixture, and appeared to be a noncompetitive phenomenon relative to glucagon. Maximal NaF-responsive AC Dr. DeRubertis is a Clinical Investigator of the Veterans Administration Hospital and American College of Physicians Teaching and Research Scholar.

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supporting

confidence: 82%

Reduced sensitivity of the hepatic adenylate cyclase-cyclic AMP system to glucagon during sustained hormonal stimulation.

DeRubertis¹,

Craven²

1976

J. Clin. Invest.

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“…The present findings in primate fetal liver are analogous to those previously observed with isolated fetal rat liver explants in culture (9). We therefore speculate that direct (glucose concentration-dependent) regulation of glycogen synthetase activity and glycogen synthesis, present in adult mammalian liver (5,7,16,(18)(19)(20), is not developed during early neonatal life. This may contribute to the low plasma glucose removal rates after bolus glucose injection observed at this time (2,4,15,20,30).…”

Section: Discussionsupporting

confidence: 89%

Glucose Regulation by Isolated Near Term Fetal Monkey Liver

et al. 1975

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ExtractNear term fetal monkey livers were perfused with a closed recirculating system and a defined perfusion medium. Livers from normal fetal animals were able to release glucose rapidly into the perfusate when they were exposed to glucagon, cyclic AMP, or an aglycemic perfusate, but they did not remove glucose rapidly from the perfusate, synthesize glycogen, or activate liver glycogen synthetase in response to hyperglycemia (Figs. 1,2, and 3; Table I ). Insulin decreased glucose mobilization in response to aglycemia, but did not stimulate glucose uptake during hyperglycemia; insulin activated glycogen synthetase (Table 1; Figs. 1 and 3). Livers from fetuses of streptozotocin-treated mothers and livers from 2-week-old neonates released more glucose into the perfusate in response to aglycemia then did livers from normal fetal monkeys (Fig. 4). These observations support the possibility that neonatal monkey liver is capable of rapidly mobilizing glucose during periods of hypoglycemia but is unable to take up glucose and store glycogen rapidly during periods of hyperglycernia. SpeculationIncomplete development of glycogen synthetic mechanisms in early postnatal life may contribute to decreased liver glycogen reserves. These decreased reserves may then be inadequate for maintaining normoglycemia during periods of increased glucose uptake or utilization by peripheral tissue. (9,10,27,29) support the possibility that at birth hormonal regulation of glycogen metabolism is competent, but direct glucose regulation of glycogen synthesis has not developed.In humans, development of rapid glucose and glycogen mobilizing responses precedes birth (1, 13, 26), and liver glycogen levels, high at birth, decline rapidly during the first few hours of life (3,28). Idiopathic neonatal hypoglycemia does not appear to be associated with impaired glycogenolytic mechanisms since it usually occurs when liver glycogen stores are depleted (3, 28). Consequently, we considered that incomplete development of glycogen synthetic mechanisms in early postnatal life might contribute to decreased liver glycogen reserves and that these inadequate reserves are incapable of maintaining normoglycemia.We now provide additional support for this possibility based on studies with isolated perfused rhesus monkey livers from near term fetuses of normal mothers and mothers with streptozotocin-induced glucose intolerance, and from normal monkey neonates. In all three groups, hepatic glucose removal rates were low in the presence of high glucose concentrations in the perfusion solution. Changes in circulating glucose concentration did not modify glycogen synthetase activity, but in all instances liver glucose was released in response to hypoglycemia. Direct effects of exogenous glucagon and insulin on hepatic glucose output and glycogen cycle enzyme activity were demonstrated in the near term fetus group. METHODS ANIMALSOne of the primary functions for liver is to maintain blood glucose levels. This is achieved by changes in gluconeogenic Pregnant Macaca mulatt...

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“…an appropriate reduction of endogenous glucose production and Six blood Sam les were obtained during the turnover period for B will achieve a new steady state concentration of plasma glucose glucose 3~ and ' C specific activity. Deproteinized plasma samples by insulin which inhibits gluconeogenesis and glycogenolysis and were passed through Dowex-1 (Cl-) and Dowex-50 (H') resin stimulates glycogenesis (4,6,17). In adults, after hepatic glycogen columns to separate glucose from lactate and charged glucose stores are depleted, gluconeogenesis is the most important regu-metabolites (5).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin inhibits glycogenolysis and gluconeogenesis and enhances glycogenesis resulting in the net suppression of endogenous glucose production (4,6,17). Our data show that a moderate elevation of plasma insulin level effectively reduced gluconeogenesis (groups 2 and 4), but did not influence endogenous glucose production.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Gluconeogenesis and Endogenous Glucose Production by Exogenous Insulin Administration in the Newborn Lamb

Susa

Cowett

et al. 1979

Pediatr Res

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Summaryduction in gluconeogenesis would result in a reduction in endogenous glucose production. Persistent endogenous hepatic glucose production is characterWe have recently shown that the newborn lamb requires a far istic of the newborn lamb in resP"se to exogen""s glucose greater increase in plasma insulin concentration to significantly infusion ' The that decreased for reduce endogenous glucose production (lO-fold increase in plasma insulin may be a major mechanism accounting for the imprecision insulin vs. 3-fold increase required in adult) (5). The reason for in glucose homeostasis was tested in 28 unanesthetized, mixed this developmental difference in glucose control is not clear, breed, term lambs. Either 0, 5.7, 6.2, or 12.5 mg glucose/kg/min although we postulated hepatic insensitivity to insulin in the was infused for a period of 2 hr after which simultaneous infusion newborn may account for it. In those studies, we produced hyperof 0, 1.25, or 6.25 mU porcine insulin/kg/min was administered insulinemia with hyperglycemia by exogenous glucose infusion; for hr produce a eugl~cemic, state. we were unable to differentiate the effect of hyperglycemia from Gluconeogenesis from lactate was measured by determining the hyperinsulinemia. Furthermore, we did not study gluconeogenesis ratio of 14C to 3H in plasma glucose during the simultaneous which is an important regulatory mechanism for glucose homeoinfusion of l4C~lactate and 3H~-glucose. Endogenous hepatic stasis. glucose production was determined by the prime-constant infusionTo dissociate the effects of plasma glucose from plasma insulin technique using 3H6 glucose during a the control of glucose production and gluconeogenesis, varying min turnover period after the infusions. All animals maintained a concentrations of glucose and insulin were infused into newborn constant plasma glucose concentration and glucose specific activ-lambs for sufficient time to produce steady state equilibrium ity during the turnover period. Gluconeogenesis was significantly concentrations of plasma glucose and insulin. Plasma glucose, suppressed when insulin levels were in the 49-61 P U /~ range insulin, glucagon, and glucose specific activity were determined although endogenous glucose production was not affected. When and gluconeogenesis and endogenous glucose production were plasma insulin concentrations were above 200 p U / d , both glu-derived. coneogenesis and endogenous glucose production were significantly suppressed. These changes were observed irrespective of the steady state blood glucose concentration. Plasma glucagon MATERIALS AND METHODS concentrations were the same in all experimental groups and were Twenty-eight mixed breed newborn lambs (3.5 & 0.3 days old; not affected by glucose and insulin infusion nor were they respon-weight 4.6 + 0.2 kg) (M & SE) were the subjects of this study. The sive to differences in plasma glucose or insulin concentrations. newborn lambs were allowed to deliver spontaneously and were Our data indicates that insulin may be the ma...

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Control of hepatic glycogen metabolism in the rhesus monkey: effect of glucose, insulin, and glucagon administration

Cited by 54 publications

References 0 publications

Reduced sensitivity of the hepatic adenylate cyclase-cyclic AMP system to glucagon during sustained hormonal stimulation.

Reduced sensitivity of the hepatic adenylate cyclase-cyclic AMP system to glucagon during sustained hormonal stimulation.

Glucose Regulation by Isolated Near Term Fetal Monkey Liver

Suppression of Gluconeogenesis and Endogenous Glucose Production by Exogenous Insulin Administration in the Newborn Lamb

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