Summary
Insulin is the cornerstone of therapy for diabetic ketoacidosis because it causes the rate of ketoacid production to fall; this action takes several hours to occur. Insulin also causes H+ to be transported from the intracellular fluid to the extracellular fluid in vitro. The purpose of this study was to determine if insulin led to the acute export of H+ from the intracellular fluid in vivo. If so, we wished to determine if this also occurred during chronic metabolic acidosis, to quantitate the magnitude of the H+ shift, and to evaluate the mechanisms involved. The administration of low- or high-dose insulin to normal dogs and high-dose insulin to dogs with chronic metabolic acidosis caused the concentration of bicarbonate in plasma to decline by close to 3 mmol/l. The PCO2 fell by close to 15 % in all three groups of dogs, so one component of the fall was due to hyperventilation. As the pH of blood did not change, a primary metabolic acidosis also occurred. The fall in bicarbonataemia was not due to net accumulation of organic acids or to a loss of bicarbonate or organic anions in the urine. Taken together, insulin, when given at doses used to treat diabetic ketoacidosis, might induce a significantly greater degree of acidaemia in the extracellular fluid acutely after it is given.
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McGarry JD, Woeltje KF, Kuwajima M, Foster DW (1989) Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diab Metab Rev 5: 271–284
Owen O, Caprio S, Reichard GJ, Mozzoli M, Boden G, Owen R (1983) Ketosis of starvation: a revisit and new perspectives. Clin Endocrinol Metab 12: 359–379
Moore RD (1979) Elevation of intracellular pH by insulin in frog skeletal muscle. Biochem Biophys Res Commun 91: 900–904
Moore RD (1981) Stimulation of Na:H exchange by insulin. Biophys J 33: 203–210
Klip A, Ramlal T, Cragoe EJ Jr (1986) Insulin-induced cytoplasmic alkalinization and glucose transport in muscle cells. Am J Physiol 250: C720-C728
Swan RC, Pitts RF (1955) Neutralization of infused acid by nephrectomized dogs. J Clin Invest 34: 205–212
Halperin ML, Vinay P, Gougoux A, Pichette C, Jungas RL (1985) Regulation of the maximum rate of renal ammoniagenesis in the acidotic dog. Am J Physiol 248: F607-F615
Hastings AB, Sendroy J Jr (1925) The effect of variation in ionic strength on the apparent first and second dissociation constants of carbonic acid. J Biol Chem 65: 445–455
Van Slyke DD, Sendroy J, Hastings AB, Neill JM (1928) Studies of gas and electrolyte equilibria in blood. X. The solubility of carbon dioxide at 38 °C in water, salt solution, serum and blood cells. J Biol Chem 78: 765–799
Moore RD, Gupta RK (1980) Effect of insulin on intracellular pH as observed by 31P NMR spectroscopy. J Quantum Chem 7: 83–92
Halperin ML, Kamel KS, Cheema-Dhadli S (1992) Lactic acidosis, ketoacidosis, and energy turnover: “Figure” you made the correct diagnosis only when you have “counted” on it — Quantitative analysis based on principles of metabolism. Mt Sinai J Med 59: 1–12
Halperin ML, Jungas RL (1983) Metabolic production and renal disposal of hydrogen ions. Kidney Int 24: 709–713
Halperin ML, Vasuvattakul S, Bayoumi A (1991) A modified classification of metabolic acidosis: a pathophysiologic approach. Nephron 60: 129–133
Gillespie G, Elder J, Smith I, Kennedy F, Gillespie I, Kay A, Campbell E (1972) Analysis of basal acid secretion and its relation to insulin response in normal and duodenal ulcer subjects. Gastroenterology 62: 903–911
Bercovici M, Chen C, Goldstein M, Stinebaugh B, Halperin M (1983) Effect of acute changes in the PaCO2 on acid-base parameters in normal dogs and dogs with metabolic acidosis or alkalosis. Can J Physiol Pharmacol 61: 166–173
Fine LG, Badie-Dezfooly B, Lowe AG, Hamzeh A, Wells J, Salehmoghaddam S (1985) Stimulation of Na+/H− antiport is an early event in hypertrophy of renal proximal tubular cells. Proc Natl Acad Sci USA 82: 1736–1740
Mukherjee SP, Mukherjee C (1981) Metabolic activation of adipocytes by insulin accompanied by an early increase in intracellular pH. Ann NY Acad Sci 372: 347–351
Stark R, Read P, O'Doherty J (1980) Insulin does not act by causing a change in membrane potential or intracellular free sodium potassium concentration of adipocytes. Diabetes 29: 1040–1043
Moore RD, Fidelman ML, Seeholzer SH (1979) Correlation between insulin action upon glycolysis and change in intracellular pH. Biochem Biophys Res Commun 91: 905–910
Vander Meulen JA, Klip A, Grinstein S (1987) Possible mechanism for cerebral oedema in diabetic ketoacidosis. Lancet I: 306–308
Stinebaugh BJ, Schloeder FX (1972) Glucose induced alkalosis in fasting subjects: relationship to renal bicarbonate reabsorption during fasting and refeeding. J Clin Invest 51: 1326–1336
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Goguen, J.M., Halperin, M.L. Can insulin administration cause an acute metabolic acidosis in vivo?. Diabetologia 36, 813–816 (1993). https://doi.org/10.1007/BF00400355
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DOI: https://doi.org/10.1007/BF00400355