AJP - Gastrointestinal and Liver Physiology

Tranberg, KG

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The hepatic uptake of unlabeled insulin (5--50 mU/kg) was determined in 45 nondiabetic patients without hepatic disease. Thirty patients were studied at normoglycemia and 15 at moderate steady hyperglycemia, induced by intraportal infusion of 80 or 200 mg glucose per h and per kg. The first pass fractional hepatic uptake of insulin (FH) was estimated by comparing the results after a portal and a peripheral infusion of unlabeled insulin in each patient. It varied negatively with the amount of insulin given, decreasing about 50% after a tenfold increase in dose. FH was markedly smaller during steady hyperglycemia than at normoglycemia, regardless of insulin dose. For low doses (5--10 mU/kg), giving insulin concentrations within the physiological range, FH was 0.43 (5 mU/kg) and 0.40 (10 mU/kg) at normoglycemia and 0.16 (10 mU/kg) at hyperglycemia. FH did not vary with the fasting or the glucose-stimulated, endogenous insulin levels recorded before insulin infusion. It is suggested that glucose is more important than insulin in modulating the fractional hepatic uptake of insulin.

Douglas, Janice G.

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Short-term administration of a high potassium diet to rats resulted in reciprocal changes in affinity and number of angiotensin II receptors of adrenal and smooth muscle target tissues as determined by a radioreceptor assay system. The changes consisted of an increase in mean equilibrium association constant ( K a ) of smooth muscle receptor of 39%, from 0.23 ± 0.02 in controls to 0.32 ± 0.03 nM –1 with high K + diet. A decrease in adrenal receptor affinity of 28% occurred as a result of a decrease in mean K a , from 0.9 ± 0.04 in controls to 0.65 ± 0.1 nM –1 with K + loading. The number of smooth muscle receptors for angiotensin II decreased by 42%, and the adrenal receptors increased by 122%. Potassium loading also affected the pressor and steroidogenic responses to angiotensin II. There was an enhanced pressor response to angiotensin II infused into nephrectomized anesthetized rats. The pattern of aldosterone response was more complex and consisted of a less sensitive aldosterone response to angiotensin II but a greater increment above control at high concentrations in isolated adrenal glomerulosa cells. It is possible that the increment in smooth muscle receptor affinity might have mediated the enhanced pressor responsiveness to angiotensin II, while the decrement in adrenal receptor affkity might have contributed to the less sensitive aldosterone response to angiotensin II. These studies emphasize the complexity of receptor alterations that are associated with altered hormonal responses in angiotensin target tissues and document that changes in potassium balance are important modulators. blood pressure; aldosterone; radioreceptor assay Submitted on November 20, 1978 Accepted on June 22, 1979

Sacca, L; Eigler, N; Cryer, PE; Sherwin, RS

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The effect of glucagon and/or epinephrine on the response to physiologic insulin infusion was evaluated in dogs. Insulin alone produced a transient fall (50%) in glucose output, a threefold rise in glucose clearance, and a decline in plasma glucose, which then stabilized (40--45 mg/dl) afer 1 h. Glucagon infusion prevented the fall in glucose output, but had no effect on insulin-induced elevations in glucose clearance. The fall in plasma glucose was delayed (20 min), but late hypoglycemia was unaltered. Epinephrine infusion blocked the fall in glucose output as well as the insulin-induced rise in glucose clearance and uptake. Thus, while epinephrine and glucagon were equally effective in preventing the fall in glucose output induced by insulin, epinephrine was more effective in preventing insulin-induced hypoglycemia by virtue of its direct inhibitory action on insulin-stimulated glucose utilization. Simultaneous addition of glucagon and epinephrine increased glucose output twofold, suppressed glucose clearance, and caused a 15--30 mg/dl increase in plasma glucose despite ongoing hyperinsulinemia. Our data thus indicate that synergistic hormone interactions may play a role in the counterregulation of insulin hypoglycemia.

Fahrenkrug, J; Schaffalitzky de Muckadell, OB; Holst, JJ; Jensen, SL

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The role of nerves that liberate vasoactive intestinal polypeptide (VIP) in the porcine pancrease as mediators of the atropine-resistant action of the vagus on flow and bicarbonate (HCO3) secretion was examined. Efferent electrical stimulation of the vagus in atropinized pigs produced a profuse flow of pancreatic juice with high HCO3 content concomitantly with a significant increase in pancreatic VIP output from 13 to 113 fmol/min. Intravenous administration of somatostatin (SRIF) during continuous electrical vagal stimulation caused a parallel suppression of the VIP release and the pancreatic fluid and HCO3 secretion to prestimulatory values. The SRIF-induced reduction in fluid and HCO3 secretion seemed to be mediated via an inhibition of the VIP release rather than through a direct effect on the exocrine cells, inasmuch as SRIF did not influence the VIP-provoked exocrine response from the in vitro isolated perfused porcine pancreas. The results support the view that VIP is transmitter in the vagally induced atropine-resistant water and HCO3 secretion from the porcine pancreas.

Shepherd, AP

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It has been postulated that local circulatory control mechanisms regulate the O2 flux to parenchymal cells by two vascular mechanisms: changes in blood flow that minimize capillary PO2 variations and changes in the density of the perfused capillary bed through which O2 extraction is regulated. To test this prediction, isolated loops of canine jejenum and ileum were perfused at either constant blood flow or constant pressure, and intraluminal glucose was used to increase metabolic rate. In the constant-flow series, glucose increased O2 extraction, O2 uptake, and rubidium extraction. Resistance fell when the metabolic rate was elevated. In the constant-pressure series, glucose increased blood flow, O2 extraction, O2 uptake, and capillary filtration coefficients. These results show that vascular resistance falls and that capillary density increases following an increase in oxygen demand. Thus, the glucose-stimulated gut loop seems to be a valid model of metabolic hyperemia, and its behavior would be difficult to reconcile with a purely myogenic theory of intestinal blood flow autoregulation.

Miller, DS; Kinter, WB

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By using blocking concentrations of competitors, i.e., concentrations of other neutral amino acids that cause maximal inhibition, cycloleucine transport into slices or everted sacs of killifish (fundulus heteroclitus) small intestine could be partitioned into three pathways. One is apparently not mediated, a second is inhibited by all neutral amino acids tested (component 1), and a third, is inhibited by alpha-aminocarboxylic acids (component 2), but not by beta-alanine or taurine. Both mediated pathways were Na dependent, and each yielded a linear double reciprocal plot of initial slice uptake vs. cycloleucine concentration. Apparent Kt and Vmax values for component 1 were 0.03 mM and 33 pmol/mg tissue per 3 min, respectively; corresponding values for component 2 were 0.12 mM and 28 pmol/mg tissue per 3 min. Additional experiments with an intestinal brush border membrane vesicle preparation indicate that these mediated components reflect true differences in carrier specificity rather than the differential effects of inhibitors on metabolism or on the Na gradient that drives cycloleucine transport.

Feldman, D; Mondon, CE; Horner, JA; Weiser, JN

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We have recently demonstrated that rat liver can synthesize and secrete corticosteroid-binding globulin (CBG). The present study extends these observations and examines the hormonal regulation of hepatic CBG production. Male rats were pretreated by adrenalectomy and/or glucocorticoid or estrogen administration and the rate of CBG production was measured in vitro. The production rates were assessed by the generation of specific corticosterone binding sites in both a liver-slice preparation and in an isolated perfused liver. The two techniques showed qualitatively similar results. Adrenalectomy enhanced and glucorticoid administration inhibited the rate of CBG production and secretion. Pretreatment of male rats with estradiol stimulated the rate of CBG production. The production rates were 20- to 40-fold higher in the perfused liver demonstrating its superiority over the liver-slice system. The livers from intact rats secreted CBG binding sites at a rate of approximately 18 pmol/g liver per hours, generating an estimated 20% of the total CBG content of a rat each day. The possible clinical implications of the therapeutic use of glucocorticoids that bind to CBG, yet inhibit CBG production, are discussed.

Scalabrino, G.; Ferioli, M. E.; Basagni, M.; Nebuloni, R.; Fraschini, F.

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Page E6 : G. Scalabrino, M. E. Ferioli, M. Basagni, R. Nebuloni, and F. Fraschini. "Endocrine regulation of thymic biosynthetic polyamine decarboxylases in adult rat." Page E8: substitute corrected Table 3. (See PDF)

Shepherd, RE; Moreno, FJ; Cashore, WJ; Fain, JN

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Bilirubin (0.45 mM) inhibited lipolysis and stimulated 1-14Cglucose oxidation by rat fat cells in the presence of an equimolar concentration of bovine serum albumin. Bilirubin was an insulinlike agent with respect to inhibition of lipolysis and stimulation of glucose oxidation. There was a marked inhibition of adenylate cyclase activity of fat cell ghosts by 0.001--0.1 mM bilirubin in the absence of albumin, which was largely reversed by the addition of albumin. Although both bilirubin and free fatty acids bind to albumin, the primary binding sites appear to be separate. The effects of bilirubin at a molar ratio to albumin of 2 or less were not influenced by free fatty acid-to-albumin ratios up to 3. Triglyceride lipase activity of partially purified rat fat cell homogenates was inhibited by bilirubin in the presence of an equimolar concentration of bovine albumin. These data indicate that the antilipolytic action of bilirubin is probably due to direct inhibition of triglyceride lipase through a mechanism that does not involve competition with free fatty acids for binding to albumin.

Schusdziarra, V; Rouiller, D; Pietri, A; Harris, V; Zyznar, E; Conlon, JM; Unger, RH

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The present study was designed to examine pancreatic and gastric D-cell function during the intestinal phase of a liver meal. The intraduodenal instillation of a 20% liver meal (5 ml/min) elicited a significant rise in the plasma levels of somatostatinlike immunoreactivity (SLI) in the pancreatic vein and inferior vena cava, together with the rise in glucagon and insulin levels. The rise in pancreatic vein SLI was not reduced after truncal vagotomy or during atropine infusion. In the stomach, the intestinal liver meal elicited a significant rise in antral but not fundic vein SLI levels. The rise in antral vein SLI was augmented after truncal vagotomy and abolished during atropine infusion, as was the rise in inferior vena caval SLI. In contrast to the protein meal, intravenous infusion of an amino acid mixture elicited a rise in pancreatic vein SLI but not antral or fundic vein SLI. It is concluded that during the intestinal phase of a protein meal, pancreatic and antral but not fundic SLI release is stimulated. The effects of truncal vagotomy and atropine infusion on these responses suggest a close interaction between the vagus and muscarinic cholinergic mechanisms and the D cells of the stomach and pancreas.