Acidotic pH augments glucagon secretion and gluconeogenesis in the isolated perfused rat pancreas and liver

Summary:

To study effects of acidosis on glucagon secretion and gluconeogenetic action of glucagon, rat pancreas and liver were perfused with media of pH 6.4, 6.9, 7.4 and 7.9. Glucagon secretion from the pancreas during glucopenic perfusion (1 mmol/l) was blunted at alkalotic pH, and was augmented at acidotic pH; 0.28 ± 0.18 at pH 7.9 (P < 0.01), 3.57 ± 0.94 at pH 6.9 (P < 0.01) and 1.72 ± 0.36 at pH 6.4 (P < 0.01), vs. 0.66 ± 0.25 pmol for 15 min at pH 7.4. Incorporation rate of ¹⁴C of lactate-U-¹⁴C into glucose carbon one was decreased at pH 7.9 (1.2 ± 0.2% for 15 min, P < 0.05) and was increased at pH 6.9 (2.8 ± 0.5%, P < 0.05) compared to that at pH 7.4 (1.9 ± 0.3%). Percent increasing rate of lactate gluconeogenesis by 1 nmol/l glucagon was not different within a range of pH 6.4-7.9. Thus, glucagon-stimulated gluconeogenesis from lactate was smaller at pH 7.9 (2.2 ± 0.6%) and was significantly greater at pH 6.9 (4.9 ± 0.9%, P < 0.05) than that at pH 7.4 (3.2 ± 0.6%). These results suggest that the pancreatic glucagon secretion and the glucagon-stimulated hepatic gluconeogenesis play more important roles in the maintainance of blood glucose level in the stress states associated with acidosis than without acidosis.

Hydrogen ion concentration - glucagon secretion - glucagon action - gluconeogenesis

References

• 1 Fafournoux P, Demigné C, Rémésy C. Carrier-mediated uptake of lactate in rat hepatocytes.  J Biol Chem. 260 292-299 1985; 
• 2 Gambhir K K, Archer J A, Bradley C J. Characteristics of human erythrocyte insulin receptors.  Diabetes. 27 701-708 1978; 
• 3 Goodman A D, Fuisz R E, Cahill G F. Renal gluconeogenesis in acidosis, alkalosis, and potassium deficiency: Its possible role in regulation of renal ammonia production.  J Clin Invest. 45 612-619 1966; 
• 4 Hale P J, Crase J, Nattrass M. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis.  Br Med J. 289 1035-1038 1984; 
• 5 Havel P J, Akpan J O, Curry D L, Stern J S, Gingerich R L, Ahren B. Autonomic control of pancreatic polypeptide and glucagon secretion during neuroglucopenia and hypoglycemia in mice.  Am J Physiol. 265 R246-R254 1993; 
• 6 Hems D A, Brosnan J T. Effects of metabolic acidosis and starvation on the content of intermediary metabolites in rat kidney.  Biochem J. 123 391-397 1971; 
• 7 Hems R, Ross B D, Berry M N, Krebs H A. Gluconeogenesis in the perfused rat liver.  Biochem J. 101 284-292 1966; 
• 8 Iles R A, Cohen R D, Rist A H, Baron P G. The mechanism of inhibition by acidosis of gluconeogenesis from lactate in rat liver.  Biochem J. 164 185-191 1977; 
• 9 Kashiwagura T, Deutsch C J, Taylor J, Erecinska M, Wilson D F. Dependence of gluconeogenesis, urea synthesis, and energy metabolism of hepatocytes on intracellular pH.  J Biol Chem. 259 237-243 1984; 
• 10 Kitabchi A E, Ayyagari V, Guerra S MO. The efficacy of low-dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis.  Ann Intern Med. 84 633-638 1976; 
• 11 Lloyd M H, Iles R A, Simpson B R, Strunin J M, Layton J M, Cohen R D. The effect of simulated metabolic acidosis on intracellular pH and lactate metabolism in the isolated perfused rat liver.  Clin Sci Mol Med. 45 543-549 1973; 
• 12 Mokuda O, Sakamoto Y. Glucopenia-induced glucagon secretion in perfused rat pancreas is increased by adrenalectomy and decreased by dexamethasone treatment.  Diabetes Nutr Metab. 11 99-103 1998; 
• 13 Mokuda O, Sakamoto Y, Ikeda T, Mashiba H. Effects of anoxia and low free fatty acid on myocardial energy metabolism in streptozotocin-diabetic rats.  Ann Nutr Metab. 34 259-265 1990; 
• 14 Mokuda O, Sakamoto Y, Kawagoe R, Shimizu N. Effect of arterial-portal glucose difference on gluconeogenesis from lactate in the isolated bivascular-perfused rat liver.  Horm Metab Res. 25 285-288 1993; 
• 15 Morand C, Rémésy C, Demigné C. Modulation of glucagon effects by changes in extracellular pH and calcium.  Biochim Biophys Acta. 968 192-202 1988; 
• 16 Müller W A, Faloona G R, Unger R H. Hyperglucagonemia in diabetic ketoacidosis. Its prevalence and significance.  Am J Med. 54 52-57 1973; 
• 17 Pfeiffer E F, Raptis S, Fussgänger R. Secretin, cholecystokinin, pancreozymin and gastrin. In: Jorpes JE, Mutt V (eds.). Handbuch der Experimentellen Pharmakologie, Springer Verlag, Berlin, Heidelberg, New York 34: 289-298 1973
• 18 Sistare F D, Hynes R C. The interaction between the cytosolic pyridine nucleotide redox potential and gluconeogenesis from lactate/pyruvate in isolated rat hepatocytes.  J Biol Chem. 260 12748-12753 1985; 
• 19 Soley M, Chieri R, Llobera M, Herrera E. Glucose infused through the portal vein enhances liver gluconeogenesis and glycogenesis from [3-¹⁴C]pyruvate in the starved rat.  Int J Biochem. 17 685-688 1985; 
• 20 Sumida Y, Shima T, Shirayama K, Misaki M, Miyaji K. Effects of hexoses and their derivatives on glucagon secretion from isolated perfused rat pancreas.  Horm Metab Res. 26 222-225 1994; 
• 21 Tobin R B, Mehlman M A. pH effects on 0₂ consumption and on lactate and pyruvate production by liver slices.  Am J Physiol. 221 1151-1155 1971;