Summary
It is controversial as to whether ketone bodies are utilized by the human brain as a fuel alternative to glucose during hypoglycaemia. To clarify the issue, we studied 10 normal volunteers during an experimental hypoglycaemia closely mimicking the clinical hypoglycaemia of patients with Type 1 (insulin-dependent) diabetes mellitus or insulinoma. Hypoglycaemia was induced by a continuous infusion of insulin (0.40 mU·kg−1·min−1 for 8 h, plasma insulin ≈180 pmol/l) which decreased the plasma glucose concentration to approximately 3.1 mmol/l during the last 3 h of the studies. Subjects were studied on two occasions, i. e. spontaneous, counterregulatory-induced post-hypoglycaemic increase in 3-β-hydroxybutyrate (from ≈ 0.2 to ≈ 1.1 mmol/l at 8 h), or prevention of post-hypoglycaemic hyperketonaemia (plasma β-hydroxybutyrate ≈ 0.1 mmol/l throughout the study) after administration of acipimox, a potent inhibitor of lipolysis. In the latter study, glucose was infused to match the hypoglycaemia observed in the former study. The glycaemic thresholds and overall responses of counterregulatory hormones, symptoms (both autonomic and neuroglycopenic), and deterioration of cognitive function (psychomotor tests) were superimposable in the control study in which ketones increased spontaneously after onset of hypoglycaemic counterregulation, as compared to the study in which ketones were suppressed (p=NS). The fact that responses of counterregulatory hormones, symptoms and deterioration in cognitive function were not exaggerated when posthypoglycaemic hyperketonaemia was prevented, indicate that during hypoglycaemia, the counterregulatory-induced endogenous hyperketonaemia does not provide the human brain with an alternative substrate to glucose. Thus, it is concluded that during hypoglycaemia, endogenous hyperketonaemia does not contribute to brain metabolism and function.
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References
Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260: E67-E74
Pardridge WM (1983) Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev 63: 1481–1535
Cryer P, Gerich J (1985) Glucose counterregulation, hypoglycemia and intensive insulin therapy of diabetes mellitus. N Engl J Med 313: 232–241
De Feo P, Perriello G, De Cosmo S et al. (1986) Comparison of glucose counterregulation during short-term and prolonged hypoglycemia in normal humans. Diabetes 35: 563–569
Owen OE, Morgan AP, Kemp HG et al. (1967) Brain metabolism during fasting. J Clin Invest 46: 1590–1595
Flatt JP, Blackburn GL, Randers G, Stanbury JB (1974) Effects of ketone body infusion on hypoglycemic reaction in postabsorptive state in dogs. Metab Clin Exp 23: 151–158
Stricker HM, Rowland N, Saller CF, Friedman MI (1977) Homeostasis during hypoglycemia: central control of adrenal secretion and peripheral control of feeding. Science 196: 79–81
Frolund J, Kerult H, Christiansen NJ, Alberti KGMM (1980) Effect of ketone body infusion on plasma catecholamine and substrate concentrations during acute hypoglycemia in man. J Clin Endocrinol Metab 50: 557–561
Amiel AS, Archibald HR, Chusney G, Williams AJK, Gale EAM (1991) Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel. Clin Sci 81: 189–194
Fanelli C, Calderone S, Epifano L et al. (1993) Demonstration of a critical role for FFA in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in man. J Clin Invest (in press)
McGuire E, Helderman J, Tobin R, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573
Bolli GB, Dimitriadis GD, Pehling GB et al. (1984) Abnormal glucose counterregulation after subcutaneous insulin in insulindependent diabetes mellitus. N Engl J Med 310: 1706–1711
Bolli GB, Gottesman IS, Campbell PJ, Haymond MW, Cryer PE, Gerich JE (1984) Glucose counterregulation and waning of insulin in the Somogyi phenomenon (posthypoglycemic hyperglycemia). N Engl J Med 311: 1214–1219
Bendtson I, Kverneland A, Pramming S, Binder C (1988) Incidence of nocturnal hypoglycemia in insulin-dependent diabetic patients on intensive therapy. Acta Med Scand 223: 543–548
Bending JJ, Pickup JC, Collins ACG, Keen H (1985) Rarity of a marked “dawn phenomenon” in diabetic subjects treated by continuous subcutaneous insulin infusion. Diabetes Care 8: 28–33
Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777–781
De Feo P, Gallai V, Mazzotta G et al. (1988) Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man. J Clin Invest 82: 436–444
Boyle P, Schwartz N, Shah S et al. (1988) Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 318: 1487–1492
Fanelli C, De Feo P, Porcellati F et al. (1992) Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis. J Clin Invest 89: 2005–2013
Lowry O, Passonneau J (1972) Typical fluorimetric procedures for metabolite assays. In: Lowry O, Passonneau J (eds) A flexible system for enzymatic analysis. Academic Press, New York, pp 89–92
Zar J (1984) Biostatistical analysis. Prentice Hall, Inc., Englewood Cliffs, pp 168–260
Veneman T, Mitrakou A, Mokan M (1993) Mechanism for reduced awareness and counterregulatory hormone responses to hypoglycemia after fasting. Diabetes 42 [Suppl 1]: 45 A
Drenick EJ, Alvarez LC, Tamasi GC, Brinckman AS (1972) Resistance to symptomatic insulin reactions after fasting. J Clin Invest 51: 2757–2762
Adamson U, Lins P-E, Grill V (1989) Fasting for 72 h decreases the responses of counterregulatory hormones to insulin-induced hypoglycaemia in normal man. Scand J Clin Lab Invest 49: 751–756
Bonadonna R, Zych K, Boni C, Ferrannini E, De Fronzo RA (1989) Time dependence of the interaction between lipid and glucose in humans. Am J Physiol 257: E49-E56
Page MA, Williamson DH (1971) Enzymes of ketone body utilization in human brain. Lancet II: 66–69
Robinson AM, Williamson DH (1980) Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 60: 143–187
Urion D, Vremen HJ, Weiner MW (1979) Effect of acetate on hypoglycemic seizures in mice. Diabetes 28: 1022–1026
Rizza R, Haymond M, Verdonk C et al. (1981) Pathogenesis of hypoglycemia in insulinoma patients: suppression of hepatic glucose production by insulin. Diabetes 30: 377–381
Miles J, Haymond MW, Nissen SL, Gerich JE (1983) Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Invest 71: 1554–1561
Gerich JE, Mokan M, Veneman T, Korytkowski M, Mitrakou A (1991) Hypoglycemia unawareness. Endocr Rev 12: 356–371
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Fanelli, C., Di Vincenzo, A., Modarelli, F. et al. Post-hypoglycaemic hyperketonaemia does not contribute to brain metabolism during insulin-induced hypoglycaemia in humans. Diabetologia 36, 1191–1197 (1993). https://doi.org/10.1007/BF00401065
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DOI: https://doi.org/10.1007/BF00401065