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02-07-2018 | Hypoglycemia | Review | Article

Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab

Journal: Diabetologia

Authors: Alison D. McNeilly, Rory J. McCrimmon

Publisher: Springer Berlin Heidelberg


Hypoglycaemia remains the most common metabolic adverse effect of insulin and sulfonylurea therapy in diabetes. Repeated exposure to hypoglycaemia leads to a change in the symptom complex that characterises hypoglycaemia, culminating in a clinical phenomenon referred to as impaired awareness of hypoglycaemia (IAH). IAH effects approximately 20–25% of people with type 1 diabetes and increases the risk of severe hypoglycaemia. This review focuses on the mechanisms that are responsible for the much higher frequency of hypoglycaemia in people with diabetes compared with those without, and subsequently how repeated exposure to hypoglycaemia leads to the development of IAH. The mechanisms that result in IAH development are incompletely understood and likely to reflect changes in multiple aspects of the counterregulatory response to hypoglycaemia, from adaptations within glucose and non-glucose-sensing cells to changes in the integrative networks that govern glucose homeostasis. Finally, we propose that the general process that incorporates many of these changes and results in IAH following recurrent hypoglycaemia is a form of adaptive memory called ‘habituation’.
McAulay V, Deary IJ, Frier BM (2001) Symptoms of hypoglycaemia in people with diabetes. Diabet Med 18:690–705 CrossRefPubMed
Frier BM (2014) Impaired awareness of hypoglycaemia. In: Frier BM, Heller SR, McCrimmon RJ (eds) Hypoglycaemia in clinical diabetes. Wiley, India, pp 114–144 CrossRef
Geddes J, Schopman JE, Zammitt NN, Frier BM (2008) Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med 25:501–504 CrossRefPubMed
White NH, Skor DA, Cryer PE, Levandoski LA, Bier DM, Santiago JV (1983) Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive insulin therapy. N Engl J Med 308:485–491 CrossRefPubMed
McCrimmon RJ, Oz G (2012) Cerebral adaptation to recurrent hypoglycemia. In: Seaquist E (ed) Translational endocrinology and metabolism: hypoglycemia in diabetes update. The Endocrine Society, Chevy Chase, MD, pp 89–114
Lawton J, Rankin D, Elliott J et al (2014) Experiences, views, and support needs of family members of people with hypoglycemia unawareness: interview study. Diabetes Care 37:109–115 CrossRefPubMed
Schopman JE, Geddes J, Frier BM (2010) Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes. Diabetes Res Clin Pract 87:64–68 CrossRefPubMed
Iqbal A, Heller SR (2017) The role of structured education in the management of hypoglycaemia. Diabetologia https://​doi.​org/​10.​1007/​s00125-017-4334-z
Choudhary P, Amiel SA (2017) Hypoglycaemia in type 1 diabetes: technological treatments, their limitations and the place of psychology. Diabetologia https://​doi.​org/​10.​1007/​s00125-018-4566-6
Winnick JJ, Kraft G, Gregory JM et al (2016) Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis. J Clin Invest 126:2236–2248 CrossRefPubMedPubMedCentral
Watts AG, Donovan CM (2010) Sweet talk in the brain: glucosensing, neural networks, and hypoglycemic counterregulation. Front Neuroendocrinol 31: 32–43
Fanelli C, Pampanelli S, Epifano L et al (1994) Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia 37:797–807 CrossRefPubMed
Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH (1973) Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science 182:171–173 CrossRefPubMed
Segel SA, Paramore DS, Cryer PE (2002) Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes 51:724–733 CrossRefPubMed
Mokan M, Mitrakou A, Veneman T et al (1994) Hypoglycemia unawareness in IDDM. Diabetes Care 17:1397–1403 CrossRefPubMed
Muller WA, Faloona GR, Aguilar-Parada E, Unger RH (1970) Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 283:109–115 CrossRefPubMed
Quesada I, Tuduri E, Ripoll C, Nadal A (2008) Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol 199:5–19 CrossRefPubMed
Hauge-Evans AC, King AJ, Carmignac D et al (2009) Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58:403–411 CrossRefPubMedPubMedCentral
Briant L, Salehi A, Vergari E, Zhang Q, Rorsman P (2016) Glucagon secretion from pancreatic alpha-cells. Ups J Med Sci 121:113–119 CrossRefPubMedPubMedCentral
McCrimmon RJ, Fan X, Cheng H et al (2006) Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 55:1755–1760 CrossRefPubMed
Tong Q, Ye C, McCrimmon RJ et al (2007) Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 5:383–393 CrossRefPubMedPubMedCentral
Beall C, Ashford ML, McCrimmon RJ (2012) The physiology and pathophysiology of the neural control of the counterregulatory response. Am J Phys Regul Integr Comp Phys 302:R215–R223
Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV (1988) Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 37:901–907 CrossRefPubMed
Davis MR, Mellman M, Shamoon H (1992) Further defects in counterregulatory responses induced by recurrent hypoglycemia in IDDM. Diabetes 41:1335–1340 CrossRefPubMed
Heller SR, Cryer PE (1991) Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes 40:223–226 CrossRefPubMed
McCrimmon RJ, Evans ML, Fan X et al (2005) Activation of ATP-sensitive potassium channels in the ventromedial hypothalamus amplifies counterregulatory responses to acute hypoglycemia in normal and recurrently hypoglycemic rats. Diabetes 54:3169–3174 CrossRefPubMed
Jacobson L, Ansari T, McGuinness OP (2006) Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice. Am J Physiol Endocrinol Metab 290:E678–E684 CrossRefPubMedPubMedCentral
Rooijackers HM, Wiegers EC, Tack CJ, van der Graaf M, de Galan BE (2016) Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from functional and metabolic neuroimaging studies. Cell Mol Life Sci 73:705–722 CrossRefPubMed
Boyle PJ, Kempers SF, O'Connor AM, Nagy RJ (1995) Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus. N Engl J Med 333:1726–1731 CrossRefPubMed
Henry PG, Criego AB, Kumar A, Seaquist ER (2010) Measurement of cerebral oxidative glucose consumption in patients with type 1 diabetes mellitus and hypoglycemia unawareness using 13C nuclear magnetic resonance spectroscopy. Metabolism 59:100–106 CrossRefPubMed
Öz G, DiNuzzo M, Kumar A et al (2017) Cerebral glycogen in humans following acute and recurrent hypoglycemia: implications on a role in hypoglycemia unawareness. J Cereb Blood Flow Metab 37:2883–2893 CrossRefPubMed
Jiang L, Herzog RI, Mason GF et al (2009) Recurrent antecedent hypoglycemia alters neuronal oxidative metabolism in vivo. Diabetes 58:1266–1274 CrossRefPubMedPubMedCentral
Osundiji MA, Hurst P, Moore SP et al (2011) Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats. Metabolism 60:550–556 CrossRefPubMed
McCrimmon RJ, Shaw M, Fan X et al (2008) Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57:444–450 CrossRefPubMed
George PS, Tavendale R, Palmer CN, McCrimmon RJ (2015) Diazoxide improves hormonal counterregulatory responses to acute hypoglycemia in long-standing type 1 diabetes. Diabetes 64:2234–2241 CrossRefPubMed
Chan O, Cheng H, Herzog R et al (2008) Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory responses after antecedent hypoglycemia. Diabetes 57:1363–1370 CrossRefPubMedPubMedCentral
Hedrington MS, Farmerie S, Ertl AC, Wang Z, Tate DB, Davis SN (2010) Effects of antecedent GABAA activation with alprazolam on counterregulatory responses to hypoglycemia in healthy humans. Diabetes 59:1074–1081 CrossRefPubMedPubMedCentral
Davis SN, Shavers C, Costa F, Mosqueda-Garcia R (1996) Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. J Clin Investig 98:680–691 CrossRefPubMedPubMedCentral
Mikeladze M, Hedrington MS, Joy N et al (2016) Acute effects of oral dehydroepiandrosterone on counterregulatory responses during repeated hypoglycemia in healthy humans. Diabetes 65:3161–3170 CrossRefPubMedPubMedCentral
Moheet A, Mangia S, Kumar A et al (2015) Naltrexone for treatment of impaired awareness of hypoglycemia in type 1 diabetes: a randomized clinical trial. J Diabetes Complicat 29:1277–1282 CrossRefPubMedPubMedCentral
Vele S, Milman S, Shamoon H, Gabriely I (2011) Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus. J Clin Endocrinol Metab 96:3424–3431 CrossRefPubMedPubMedCentral
Belfort-DeAguiar RD, Naik S, Hwang J, Szepietowska B, Sherwin RS (2015) Inhaled formoterol diminishes insulin-induced hypoglycemia in type 1 diabetes. Diabetes Care 38:1736–1741 CrossRefPubMedPubMedCentral
McNeilly AD, Gallagher JR, Dinkova-Kostova AT et al (2016) Nrf2-mediated neuroprotection against recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes. Diabetes 65:3151–3160 CrossRefPubMed
Puente EC, Silverstein J, Bree AJ et al (2010) Recurrent moderate hypoglycemia ameliorates brain damage and cognitive dysfunction induced by severe hypoglycemia. Diabetes 59:1055–1062 CrossRefPubMedPubMedCentral
Thompson RF, Spencer WA (1966) Habituation: a model phenomenon for the study of neuronal substrates of behavior. Psychol Rev 73:16–43 CrossRefPubMed
Rankin CH, Abrams T, Barry RJ et al (2009) Habituation revisited: an updated and revised description of the behavioral characteristics of habituation. Neurobiol Learn Mem 92:135–138 CrossRefPubMed
Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA (1994) Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 344:283–287 CrossRefPubMed
McCrimmon RJ (2017) RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia. Diabet Med 34:148–155 CrossRefPubMed
McNeilly AD, Gallagher JR, Huang JT, Ashford MLJ, McCrimmon RJ (2017) High-intensity exercise as a dishabituating stimulus restores counterregulatory responses in recurrently hypoglycemic rodents. Diabetes 66:1696–1702 CrossRefPubMed

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Jean-Pierre Riveline uses data from real-life continuous glucose monitoring studies to illustrate how these can uncover critical information about clinical outcomes that are hard to assess in randomized controlled trials.

This video has been developed through unrestricted educational funding from Abbott Diabetes Care.

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