Glucagon and Insulin Binding to Liver Membranes in a Partially Nephrectomized Uremic Rat Model

Soman, Vijay; Felig, Philip

doi:10.1172/jci108759

Cited by 63 publications

(23 citation statements)

References 36 publications

(37 reference statements)

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“…Studies by Sherwin et al (23) have shown that the liver ofchronically uremic subjects displays enhanced sensitivity to the stimulatory effect of glucagon on hepatic glucose production. In subsequent studies Soman and Felig (24) suggested that this higher sensitivity was due to increased glucagon binding to hepatic membranes with a resultant increase in cyclic AMP generation. Thus, it is possible that during conditions in which glucagon is increased, i.e., pure protein feeding or a mixed protein-carbohydrate meal, the suppression of hepatic glucose production by insulin may be incomplete.…”

Section: Discussionmentioning

confidence: 98%

Insulin resistance in uremia.

et al. 1981

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A B S T R A C T Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by -100 ,uU/ ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +0.20 vs. 7.38+0.26 mg/kg-min; P < 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17+0.04 mg/kg-min) and suppressed normally by 94±+2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57+0.03 mg/kg.min) and controls (1.79+0.20 mg/ kg min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42±0.11 mg/kg-min) and controls (0.53+0.12 mg/kg.min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21+1 vs. 52+8 ,umol/min kg of leg wt; P < 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulinmediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.

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Section: Discussionmentioning

confidence: 98%

Insulin resistance in uremia.

et al. 1981

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“…It is likely that as a result of increased absorption greater amounts of glucose would be taken up by the liver. The liver is in turn subject to the increased sensitivity of the glucose-elevating effect of glucagon present in uremia (4,28,30). The increase in glucose absorption was proportionate to the concentration of glucose in the solutions perfused, with comparable differences at 4 and 40 mM between uremic and control animals.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Transport of Glucose and Amino Acids in Experimental Uremia

et al. 1980

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“…Liver membranes (8)(9)(10)(11)(12) Mg protein) were incubated for 10 min at 30°C in a final volume of 50 Ml containing 0.1 mM [a-32P]ATP (1,000-1,500 cpm/pmol), 5 mM MgCI2, 1 mM EDTA, 1 mM[3H]cAMP (-10,000 cpm), 25 mM Tris-HCI, the indicated additives, and an ATP-regenerating system consisting of 0.02 mg/ml myokinase, 0.2 mg/ml creatine phosphokinase, and 20 mM creatine phosphate. The incubations were terminated by the addition of 100 Ml of a stop solution consisting of 40 mM ATP, 10 mM ofcAMP, and 1% sodium dodecyl sulfate.…”

Section: Adenylyl Cyclase Assaysmentioning

confidence: 99%

“…These increased immunoreactive glucagon levels result from increases in a number of molecular weight species, each of which may have glucagon-like immunoreactivity if not biological activity (6)(7)(8). Glucagon-stimulable adenylyl cyclase activity in liver of uremic rats has been found to be increased (9,10). Other more indirect assessments have inferred a decreased activity of this enzyme in chronic uremia (1 1).…”

Section: Introductionmentioning

confidence: 99%

Glucagon-stimulable adenylyl cyclase in rat liver. Effects of chronic uremia and intermittent glucagon administration.

Dighe¹,

Rojas²,

Birnbaumer³

et al. 1984

J. Clin. Invest.

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Astract. The effects of chronic uremia and glucagon administration on glucagon-stimulable adenylyl cyclase in rat liver were assessed by determinations of adenylyl cyclase activities, specific iodoglucagon binding, and the activity of the stimulatory regulatory component of adenylyl cyclase. Glucagon-stimulated adenylyl cyclase was reduced in uremia to 75-80% of control levels (P < 0.05), in the presence or absence of saturating levels of guanosine triphosphate (GTP) and 5'-guanylylimidodiphosphate [GMP-P(NH)P]. Although these changes were accompanied by a concomitant 20% reduction in sodium fluoride-stimulated activity, basal, GTP-, GMP-P(NH)P-, and manganese-dependent adenylyl cyclase activities were unchanged. Using [125I-Tyr'0]monoiodoglucagon as a receptor probe, the number of high affinity glucagon-binding sites was reduced 28% (P < 0.01) in uremic as compared with control liver membranes. However, the affinity ofthese binding sites was unaltered. The S49 cyC-reconstituting activity with respect to both GMP-P(NH)P-and isoproterenol plus GTP-stimulable adenylyl cyclase was unaltered in membranes from uremic as compared with control rats. Intermittent glucagon (80-100 ,g) injections administered at 8-h intervals to normal rats reproduced all ofthe above described effects ofchronic experimental uremia on the adenylyl cyclase system. It is concluded that changes in the hormone-stimulable adAddress all reprint requests to Dr. Garber.Receivedfor publication 22 December 1982 and in revisedform 29 December 1983. enylyl cyclase complex in uremia and with glucagon treatment result primarily from a decrease in the number of hormone-specific receptor sites in hepatic plasma membranes. Since the changes in liver adenylyl cyclase are qualitatively and quantitatively the same in glucagontreated and uremic rats, it is suggested that these may be the result of the hyperglucagonemia of uremia. Further, the data reveal an unexpected dissociation between guanine nucleotide and sodium fluoride stimulation of adenylyl cyclase. Possible causes for this dissociation based on the known subunit composition of cyclase coupling proteins are discussed. IntroductionAbnormal carbohydrate metabolism is a frequent concomitant of chronic renal disease (1-3). As the result, in part, of the diminished renal clearance of glucagon, hyperglucagonemia is frequently observed in renal insufficiency (4, 5). These increased immunoreactive glucagon levels result from increases in a number of molecular weight species, each of which may have glucagon-like immunoreactivity if not biological activity (6-8). Glucagon-stimulable adenylyl cyclase activity in liver of uremic rats has been found to be increased (9, 10). Other more indirect assessments have inferred a decreased activity of this enzyme in chronic uremia (1 1). In light of these discordant data and to determine the impact of the uremic state on the hormone-stimulable adenylyl cyclase complex, we have used a monoiodinated glucagon as a probe of glucagon receptor density and affinity in membrane p...

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Glucagon and Insulin Binding to Liver Membranes in a Partially Nephrectomized Uremic Rat Model

Cited by 63 publications

References 36 publications

Insulin resistance in uremia.

Insulin resistance in uremia.

Intestinal Transport of Glucose and Amino Acids in Experimental Uremia

Glucagon-stimulable adenylyl cyclase in rat liver. Effects of chronic uremia and intermittent glucagon administration.

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