- Email: [email protected]
Counterregulation to hypoglycaemia: physiology
SESSION 4
Ann. Endocrinol., 2004 ; 65, 1 : 85-87 © Masson, Paris, 2004
Counterregulation to hypoglycaemia: physiology S.A. Amiel RD Lawrence Professor of Diabetic Medicine, King’s College, London, United Kingdom. e-mail : [email protected]
Maintenance of blood glucose concentrations is critical to normal function, as many tissues, not least the brain, use glucose as their preferred metabolic fuel. Glucose enters the circulation from the liver, which stores glucose as glycogen and can synthesise new glucose from other substrates, and from the diet. Glucose is consumed by tissue activity. The rates of endogenous glucose production and tissue glucose utilisation are tightly controlled in health by neuro-endocrine systems which are centrally coordinated. In health, extremes of hypo- or hyper-glycaemia do not occur. As plasma glucose concentrations start to fall, for example in fasting or during exercise, the counterregulatory systems are activated. Pancreatic insulin secretion is reduced and pancreatic glucagon increased, so endogenous, particularly hepatic, glucose production is stimulated. The αcell responds not just to the glucose concentration but also to the cessation of insulin secretion by neighbouring βcells. The glucagon response is diminished in the presence of sulphonylureas (which can maintain endogenous insulin secretion in the face of hypoglycaemia) [19, 27] and lost from patients with diabetes who have lost all endogenous insulin secretion. [4] Catecholamines and the sympathetic nervous system can work to correct hypoglycaemia if the pancreatic response is not enough and become critical in C-peptide deficient diabetic patients treated with insulin [4, 29]. In addition to increasing the drive on the pancreatic counterregulatory mechanisms, catecholamines increase endogenous glucose production by enhancing glycogenolysis. Their peripheral actions on adipose tissue (lipolysis) provide fuel for gluconeogenesis, supporting endogenous glucose production and slowing peripheral tissue utilisation of glucose, both effects contributing to sustaining the blood glucose supply to the brain. Growth hormone and cortisol, which also cause peripheral insulin resistance and indirectly support gluconeogenesis, are important in the sustaining plasma glucose concentrations. Other counterregulatory responses include the enhancement of gastric emptying [18]. In health, the counterregulatory responses are initiated at slightly higher glucose levels than those associated with significant cognitive decline [24] – any upset of this protective hierarchy can lead to clinical problems such as
hypoglycaemia unawareness and counterregulatory failure sometimes seen in diabetes [1]. It should be noted that recovery of cognitive function after induced hypoglycaemia is delayed beyond the restoration of the blood glucose concentrations or the time taken to lose the symptoms of hypoglycaemia or resolve the hormonal responses [11]. In general, hypoglycaemia severe enough to cause brain dysfunction occurs only in the presence of excess insulin (drug treatment for diabetes; tumours secreting insulin or insulin-like growth factors) and/or the deficiency of some or all of the counterregulatory responses. Although counterregulatory responses decline with age (being high in children [2] and delayed and reduced in the elderly [25]), there is no indication that hypoglycaemia becomes a clinical problem outside the settings of such pathology. The major determinant of the glucose level triggering a counterregulatory response appears to be the level of glucose to which the individual has been exposed in the recent past [16, 33]. Counterregulatory responses to hypoglycaemia are initiated by a fall in the metabolic rate of glucose sensing cells. We know this because infusions of non-glucose metabolic fuels such as lactate [23, 35] or 3-OHbutyrate1 can delay the onset and diminish the magnitude of the hormonal responses to experimentally induced hypoglycaemia – with a similar effect on cortical dysfunction. The favoured site for the main mammalian glucose sensor is in the brain, partly because teleologically it makes sense to place it in the tissue that is most dependent on a sustained supply of glucose in its circulation and partly because of classical observations of disturbed glucose regulation in animals with hypothalamic lesions (Claude Bernard’s “Piqûre diabetes”). More recently, a case report of the glycaemic effects of a sarcoid lesion in the hypothalamus, with resolution of problematic hypoglycaemia after shrinkage of the lesion with steroid therapy, confirmed the importance of the hypothalamus in human glucose regulation [12]. Local infusion of glucoprivic agents into the hypothalamus of experimental animals can induce inappropriate counterregulation in non-hypoglycaemic animals [5] and the infusion of glucose or lactate6 into or around the ventromedial hypothalamus of rats diminishes the counterregulatory response to induced systemic hypoglycaemia.
85
S.A. Amiel
86
Other animal work supports the presence of a further glucose sensor in the portal vein of the liver8,15 and we have shown that oral glucose can diminish slightly the symptomatic and adrenergic responses to systemic hypoglycaemia in man [31]. These data support the concept of a second glucose sensor in the portal vein monitoring the input of glucose from the gastrointestinal tract and influencing the centrally mediated stress response to hypoglycaemia. Studies of neuronal activation using c-fos activation show a network of neurones activated by glucoprivation [28] Neurones whose firing rates are controlled by high or low glucose converge on the ventromedial hypothalamus, which remains a major player in the control of responses to hypoglycaemia [32]. Neuroimaging techniques such as positron emission tomography [34]. and functional magnetic resonance imaging21 are being used to identify regional brain activation in response to glucose ingestion and are potentially useful tools for investigating brain function and metabolism in hypoglycaemia in man [7]. Glucose sensing neurones may well use similar molecular mechanisms for sensing changes in blood glucose concentration as the pancreatic β-cell and appropriate glucose transporters [13], KATP channels [20] and glucokinase have been identified in neurones [22]. At least some aspects of counterregulation occur at higher glucose levels in patients with glucokinase mutations; [14] in vitro, hyperglycaemia and sulphonylureas, which mimic hyperglycaemia by stimulating insulin secretion from the pancreatic β-cell, enhance secretion of the inhibitory neurotransmitter GABA [10]. It has been suggested that glucose sensing neurones respond to hypoglycaemia by de-repressing sympathetic centres, perhaps via diminished secretion of inhibitory neurotransmitters. Our greater understanding of the mechanisms of normal glucose regulation should help us design strategies to help diabetic patients avoid problems with glucose regulation in response to their disease and its treatments.
REFERENCES 1. Amiel SA, Archibald HR, Chusney G, Williams AJK, Gale EAM. Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel. Clin Sci 1991; 81: 189-4. 2. Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 1988; 37: 901-7. 3. Amiel SA, Simonson DC, Sherwin RS, Lauritano AA, Tamborlane WV. Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children. Journal of Pediatrics 1987; 110: 832-7.
Ann. Endocrinol. 4. Bolli G, DeFeo P, Campugnucci P et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon secretion. Diabetes 1983: 32; 134-1. 5. Borg WP, Sherwin RS, During MJ, Borg MA, Shulman GI. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 1995; 44: 180-4. 6. Borg MA, Tamborlane WV, Shulman GI, Sherwin RS. Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 2003; 52: 663-6. 7. Cranston IC, Reed LJ, Marsden PK, Amiel SA. Changes in regional brain 18F-fluorodeoxyglucose uptake at hypoglycemia in Type 1 diabetic men associated with hypoglycemia unawareness and counterregulatory failure. Diabetes 2001; 50: 2329-36. 8. Donovan CM, Hamilton-Wessler M, Halter JB, Bergman RN. Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia. Proc Natl Acad Sci U S A 1994; 91: 2863-7. 9. Dunn-Meynell AA, Routh VH, Kang L, Gaspers L, Levin BE. Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 2002; 51: 2056-65. 10. During MJ, Leone P, Davis KE, Kerr D, Sherwin RS Glucose modulates rat substantia nigra GABA release in vivo via ATPsensitive potassium channels. J Clin Invest 1995; 95: 2403-8. 11. Evans ML, Pernet A, Lomas J, Jones J, Amiel SA. Delay in onset of awareness of acute hypoglycaemia and of restoration of cognitive performance during recovery. Diabetes Care 2000; 23: 893-7. 12. Fery F, Plat L, van de Borne P, Cogan E, Mockel J. Counterregulation of glucose in a patient with hypothalamic sarcoidosis. N Engl J Med. 1999; 340: 852-6. 13. Garcia MA, Millan C, Balmaceda-Aguilera C et al. Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem 2003; 86: 709-24. 14. Guenat E, Seematter G, Ohillipe J, Temler E, Jequier E, Tappy L. Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations. Diabetes Metab 2000; 26: 377-384. 15. Hamilton-Wessler M, Bergman RN, Halter JB, Watanabe RM, Donovan CM. The role of liver glucosensors in the integrated sympathetic response induced by deep hypoglycemia in dogs. Diabetes 1994; 43: 1052-60. 16. Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycaemia in non-diabetic humans. Diabetes 1991; 40: 223-6. 17. Hevener AL, Bergman RN, Donovan CM. Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 1997; 46: 1521-5. 18. Horowitz M, O’Donovan D, Jones KL, Feinle C, Rayne CK, Samsom M. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med. 2002; 19: 177-94. 19. Landstedt-Hallin L, Adamson U, Lins PE. Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes. J Clin Endocrinol Metab 1999; 84: 3140-5. 20. Lee K, Dixon AK, Richardson PJ, Pinnock RD. Glucose receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir 6.1 and SUR1 subunits. Journal of Physiology 1999; 515.2: 439-52. 21. Liu Y, Gao JH, Liu H-L, Fox PT. The temporal response of the brain after eating revealed by functional magnetic resonance imaging. Nature 2000; 405: 1058-1062.
Vol. 65, n° 1, 2004 22. Lynch RM, Tompkins LS, Brooks HL, Dunn-Meynell AA, Levin BE. Localization of glucokinase gene expression in the rat brain Diabetes. 2000; 49: 693-700. 23. Maran A, Cranston I, Lomas J, Macdonald IA, Amiel SA. Protection by lactate of cerebral function during hypoglycaemia. Lancet 1994; 343: 16-20. 24. Maran A, Lomas J, Macdonald IA, Amiel SA. Lack of preservation of higher brain function during hypoglycaemia in patients with intensively treated IDDM. Diabetologia 1995; 38: 1412-8. 25. Matyka K, Evans M, Lomas J, Korzon-Burakowska A, Cranston I, Macdonald I, Amiel SA. Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care 1997; 20: 135-41. 26. Mitrakou A, Ryan C, Veneman T et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms and cerebral dysfunction. Am J Physiol 1991; 260: E67-E74. 27. Peacey SR, Rostami-Hodjegan A, George E, Tucker GT, Heller SR. The use of tolbutamide-induced hypoglycemia to examine the intraislet role of insulin in mediating glucagon release in normal humans. Clin Endocrinol Metab 1997; 82: 1458-61. 28. Ritter S, Dinh TT, Llwellyn Smith I. Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-Dglucose induced metabolic challenge. Brain Res 1998; 805: 41-45. 29. Rizza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation: effects of somatostatin and combined alpha- and beta-
Counterregulation to hypoglycaemia: physiology
30.
31.
32.
33.
34.
35.
blockade on plasma glucose recovery and glucose flux rates following insulin induced hypoglycaemia. J Clin Invest 1979; 64: 62-71. Saunders NM, Ritter S. Repeated 2DG induced glucoprivation attenuates fos expression and glucoregulatory responses during subsequent glucoprivation. Diabetes 2000; 49: 18651874. Smith D, Pernet A, Reid H et al. The role of hepatic portal glucose sensing in modulating responses to hypoglycemia. Diabetologia 2002; 45: 1416-24. Song Z, Levin BE, McArdle JJ, Bakhos N, Routh VH. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 2001; 50: 2673-81. Spyer G, Hattersely AT, Macdonald IA, Amiel SA, MacLeod KM. Hypoglycaemic conunterregulation at “normal” blood glucose concentrations in patients with well-controlled Type 2 diabetes. Lancet 2000; 356; 1970-4. Tataranni PA, Gautier JF, Chen K et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci U S A 1999; 96: 4569-74. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction and counterregulatory hormone responses during hypoglcyemia in normal humans. Diabetes 1994; 43: 1311-7.
87
Ann. Endocrinol., 2004 ; 65, 1 : 85-87 © Masson, Paris, 2004
Counterregulation to hypoglycaemia: physiology S.A. Amiel RD Lawrence Professor of Diabetic Medicine, King’s College, London, United Kingdom. e-mail : [email protected]
Maintenance of blood glucose concentrations is critical to normal function, as many tissues, not least the brain, use glucose as their preferred metabolic fuel. Glucose enters the circulation from the liver, which stores glucose as glycogen and can synthesise new glucose from other substrates, and from the diet. Glucose is consumed by tissue activity. The rates of endogenous glucose production and tissue glucose utilisation are tightly controlled in health by neuro-endocrine systems which are centrally coordinated. In health, extremes of hypo- or hyper-glycaemia do not occur. As plasma glucose concentrations start to fall, for example in fasting or during exercise, the counterregulatory systems are activated. Pancreatic insulin secretion is reduced and pancreatic glucagon increased, so endogenous, particularly hepatic, glucose production is stimulated. The αcell responds not just to the glucose concentration but also to the cessation of insulin secretion by neighbouring βcells. The glucagon response is diminished in the presence of sulphonylureas (which can maintain endogenous insulin secretion in the face of hypoglycaemia) [19, 27] and lost from patients with diabetes who have lost all endogenous insulin secretion. [4] Catecholamines and the sympathetic nervous system can work to correct hypoglycaemia if the pancreatic response is not enough and become critical in C-peptide deficient diabetic patients treated with insulin [4, 29]. In addition to increasing the drive on the pancreatic counterregulatory mechanisms, catecholamines increase endogenous glucose production by enhancing glycogenolysis. Their peripheral actions on adipose tissue (lipolysis) provide fuel for gluconeogenesis, supporting endogenous glucose production and slowing peripheral tissue utilisation of glucose, both effects contributing to sustaining the blood glucose supply to the brain. Growth hormone and cortisol, which also cause peripheral insulin resistance and indirectly support gluconeogenesis, are important in the sustaining plasma glucose concentrations. Other counterregulatory responses include the enhancement of gastric emptying [18]. In health, the counterregulatory responses are initiated at slightly higher glucose levels than those associated with significant cognitive decline [24] – any upset of this protective hierarchy can lead to clinical problems such as
hypoglycaemia unawareness and counterregulatory failure sometimes seen in diabetes [1]. It should be noted that recovery of cognitive function after induced hypoglycaemia is delayed beyond the restoration of the blood glucose concentrations or the time taken to lose the symptoms of hypoglycaemia or resolve the hormonal responses [11]. In general, hypoglycaemia severe enough to cause brain dysfunction occurs only in the presence of excess insulin (drug treatment for diabetes; tumours secreting insulin or insulin-like growth factors) and/or the deficiency of some or all of the counterregulatory responses. Although counterregulatory responses decline with age (being high in children [2] and delayed and reduced in the elderly [25]), there is no indication that hypoglycaemia becomes a clinical problem outside the settings of such pathology. The major determinant of the glucose level triggering a counterregulatory response appears to be the level of glucose to which the individual has been exposed in the recent past [16, 33]. Counterregulatory responses to hypoglycaemia are initiated by a fall in the metabolic rate of glucose sensing cells. We know this because infusions of non-glucose metabolic fuels such as lactate [23, 35] or 3-OHbutyrate1 can delay the onset and diminish the magnitude of the hormonal responses to experimentally induced hypoglycaemia – with a similar effect on cortical dysfunction. The favoured site for the main mammalian glucose sensor is in the brain, partly because teleologically it makes sense to place it in the tissue that is most dependent on a sustained supply of glucose in its circulation and partly because of classical observations of disturbed glucose regulation in animals with hypothalamic lesions (Claude Bernard’s “Piqûre diabetes”). More recently, a case report of the glycaemic effects of a sarcoid lesion in the hypothalamus, with resolution of problematic hypoglycaemia after shrinkage of the lesion with steroid therapy, confirmed the importance of the hypothalamus in human glucose regulation [12]. Local infusion of glucoprivic agents into the hypothalamus of experimental animals can induce inappropriate counterregulation in non-hypoglycaemic animals [5] and the infusion of glucose or lactate6 into or around the ventromedial hypothalamus of rats diminishes the counterregulatory response to induced systemic hypoglycaemia.
85
S.A. Amiel
86
Other animal work supports the presence of a further glucose sensor in the portal vein of the liver8,15 and we have shown that oral glucose can diminish slightly the symptomatic and adrenergic responses to systemic hypoglycaemia in man [31]. These data support the concept of a second glucose sensor in the portal vein monitoring the input of glucose from the gastrointestinal tract and influencing the centrally mediated stress response to hypoglycaemia. Studies of neuronal activation using c-fos activation show a network of neurones activated by glucoprivation [28] Neurones whose firing rates are controlled by high or low glucose converge on the ventromedial hypothalamus, which remains a major player in the control of responses to hypoglycaemia [32]. Neuroimaging techniques such as positron emission tomography [34]. and functional magnetic resonance imaging21 are being used to identify regional brain activation in response to glucose ingestion and are potentially useful tools for investigating brain function and metabolism in hypoglycaemia in man [7]. Glucose sensing neurones may well use similar molecular mechanisms for sensing changes in blood glucose concentration as the pancreatic β-cell and appropriate glucose transporters [13], KATP channels [20] and glucokinase have been identified in neurones [22]. At least some aspects of counterregulation occur at higher glucose levels in patients with glucokinase mutations; [14] in vitro, hyperglycaemia and sulphonylureas, which mimic hyperglycaemia by stimulating insulin secretion from the pancreatic β-cell, enhance secretion of the inhibitory neurotransmitter GABA [10]. It has been suggested that glucose sensing neurones respond to hypoglycaemia by de-repressing sympathetic centres, perhaps via diminished secretion of inhibitory neurotransmitters. Our greater understanding of the mechanisms of normal glucose regulation should help us design strategies to help diabetic patients avoid problems with glucose regulation in response to their disease and its treatments.
REFERENCES 1. Amiel SA, Archibald HR, Chusney G, Williams AJK, Gale EAM. Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel. Clin Sci 1991; 81: 189-4. 2. Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 1988; 37: 901-7. 3. Amiel SA, Simonson DC, Sherwin RS, Lauritano AA, Tamborlane WV. Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children. Journal of Pediatrics 1987; 110: 832-7.
Ann. Endocrinol. 4. Bolli G, DeFeo P, Campugnucci P et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon secretion. Diabetes 1983: 32; 134-1. 5. Borg WP, Sherwin RS, During MJ, Borg MA, Shulman GI. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 1995; 44: 180-4. 6. Borg MA, Tamborlane WV, Shulman GI, Sherwin RS. Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 2003; 52: 663-6. 7. Cranston IC, Reed LJ, Marsden PK, Amiel SA. Changes in regional brain 18F-fluorodeoxyglucose uptake at hypoglycemia in Type 1 diabetic men associated with hypoglycemia unawareness and counterregulatory failure. Diabetes 2001; 50: 2329-36. 8. Donovan CM, Hamilton-Wessler M, Halter JB, Bergman RN. Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia. Proc Natl Acad Sci U S A 1994; 91: 2863-7. 9. Dunn-Meynell AA, Routh VH, Kang L, Gaspers L, Levin BE. Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 2002; 51: 2056-65. 10. During MJ, Leone P, Davis KE, Kerr D, Sherwin RS Glucose modulates rat substantia nigra GABA release in vivo via ATPsensitive potassium channels. J Clin Invest 1995; 95: 2403-8. 11. Evans ML, Pernet A, Lomas J, Jones J, Amiel SA. Delay in onset of awareness of acute hypoglycaemia and of restoration of cognitive performance during recovery. Diabetes Care 2000; 23: 893-7. 12. Fery F, Plat L, van de Borne P, Cogan E, Mockel J. Counterregulation of glucose in a patient with hypothalamic sarcoidosis. N Engl J Med. 1999; 340: 852-6. 13. Garcia MA, Millan C, Balmaceda-Aguilera C et al. Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem 2003; 86: 709-24. 14. Guenat E, Seematter G, Ohillipe J, Temler E, Jequier E, Tappy L. Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations. Diabetes Metab 2000; 26: 377-384. 15. Hamilton-Wessler M, Bergman RN, Halter JB, Watanabe RM, Donovan CM. The role of liver glucosensors in the integrated sympathetic response induced by deep hypoglycemia in dogs. Diabetes 1994; 43: 1052-60. 16. Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycaemia in non-diabetic humans. Diabetes 1991; 40: 223-6. 17. Hevener AL, Bergman RN, Donovan CM. Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 1997; 46: 1521-5. 18. Horowitz M, O’Donovan D, Jones KL, Feinle C, Rayne CK, Samsom M. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med. 2002; 19: 177-94. 19. Landstedt-Hallin L, Adamson U, Lins PE. Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes. J Clin Endocrinol Metab 1999; 84: 3140-5. 20. Lee K, Dixon AK, Richardson PJ, Pinnock RD. Glucose receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir 6.1 and SUR1 subunits. Journal of Physiology 1999; 515.2: 439-52. 21. Liu Y, Gao JH, Liu H-L, Fox PT. The temporal response of the brain after eating revealed by functional magnetic resonance imaging. Nature 2000; 405: 1058-1062.
Vol. 65, n° 1, 2004 22. Lynch RM, Tompkins LS, Brooks HL, Dunn-Meynell AA, Levin BE. Localization of glucokinase gene expression in the rat brain Diabetes. 2000; 49: 693-700. 23. Maran A, Cranston I, Lomas J, Macdonald IA, Amiel SA. Protection by lactate of cerebral function during hypoglycaemia. Lancet 1994; 343: 16-20. 24. Maran A, Lomas J, Macdonald IA, Amiel SA. Lack of preservation of higher brain function during hypoglycaemia in patients with intensively treated IDDM. Diabetologia 1995; 38: 1412-8. 25. Matyka K, Evans M, Lomas J, Korzon-Burakowska A, Cranston I, Macdonald I, Amiel SA. Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care 1997; 20: 135-41. 26. Mitrakou A, Ryan C, Veneman T et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms and cerebral dysfunction. Am J Physiol 1991; 260: E67-E74. 27. Peacey SR, Rostami-Hodjegan A, George E, Tucker GT, Heller SR. The use of tolbutamide-induced hypoglycemia to examine the intraislet role of insulin in mediating glucagon release in normal humans. Clin Endocrinol Metab 1997; 82: 1458-61. 28. Ritter S, Dinh TT, Llwellyn Smith I. Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-Dglucose induced metabolic challenge. Brain Res 1998; 805: 41-45. 29. Rizza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation: effects of somatostatin and combined alpha- and beta-
Counterregulation to hypoglycaemia: physiology
30.
31.
32.
33.
34.
35.
blockade on plasma glucose recovery and glucose flux rates following insulin induced hypoglycaemia. J Clin Invest 1979; 64: 62-71. Saunders NM, Ritter S. Repeated 2DG induced glucoprivation attenuates fos expression and glucoregulatory responses during subsequent glucoprivation. Diabetes 2000; 49: 18651874. Smith D, Pernet A, Reid H et al. The role of hepatic portal glucose sensing in modulating responses to hypoglycemia. Diabetologia 2002; 45: 1416-24. Song Z, Levin BE, McArdle JJ, Bakhos N, Routh VH. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 2001; 50: 2673-81. Spyer G, Hattersely AT, Macdonald IA, Amiel SA, MacLeod KM. Hypoglycaemic conunterregulation at “normal” blood glucose concentrations in patients with well-controlled Type 2 diabetes. Lancet 2000; 356; 1970-4. Tataranni PA, Gautier JF, Chen K et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci U S A 1999; 96: 4569-74. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction and counterregulatory hormone responses during hypoglcyemia in normal humans. Diabetes 1994; 43: 1311-7.
87