Table of Contents Author Guidelines Submit a Manuscript
International Journal of Endocrinology
Volume 2016 (2016), Article ID 9801640, 13 pages
http://dx.doi.org/10.1155/2016/9801640
Review Article

Challenges in Modelling Hypoglycaemia-Associated Autonomic Failure: A Review of Human and Animal Studies

School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA 5000, Australia

Received 27 April 2016; Revised 1 September 2016; Accepted 18 September 2016

Academic Editor: Michael Horowitz

Copyright © 2016 Manjula Senthilkumaran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. P. E. Cryer, L. Axelrod, A. B. Grossman et al., “Evaluation and management of adult hypoglycemic disorders: an endocrine society clinical practice guideline,” The Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 3, pp. 709–728, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. J. E. Sprague and A. M. Arbeláez, “Glucose counterregulatory responses to hypoglycemia,” Pediatric Endocrinology Reviews, vol. 9, no. 1, pp. 463–473, 2011. View at Google Scholar · View at Scopus
  3. A. Iqbal and S. Heller, “Managing hypoglycaemia,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 30, no. 3, pp. 413–430, 2016. View at Publisher · View at Google Scholar
  4. A. J. M. Verberne and M. P. Gilbey, “Highlights in basic autonomic neurosciences: autonomic control of the counter-regulatory response and glucose homeostasis,” Autonomic Neuroscience: Basic & Clinical, vol. 169, no. 1, pp. 1–3, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. P. E. Cryer, “Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes,” Diabetes, vol. 54, no. 12, pp. 3592–3601, 2005. View at Publisher · View at Google Scholar · View at Scopus
  6. B. E. de Galan, B. J. J. W. Schouwenberg, C. J. Tack, and P. Smits, “Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes,” Netherlands Journal of Medicine, vol. 64, no. 8, pp. 269–279, 2006. View at Google Scholar · View at Scopus
  7. A. J. Garber, P. E. Cryer, J. V. Santiago, M. W. Haymond, A. S. Pagliara, and D. M. Kipnis, “The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man,” The Journal of Clinical Investigation, vol. 58, no. 1, pp. 7–15, 1976. View at Publisher · View at Google Scholar · View at Scopus
  8. I. Quesada, E. Tudurí, C. Ripoll, and Á. Nadal, “Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes,” Journal of Endocrinology, vol. 199, no. 1, pp. 5–19, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. S. R. Heller, “Hypoglycaemia: its pathophysiology in insulin treated diabetes and hypoglycaemia unawareness,” The British Journal of Diabetes and Vascular Disease, vol. 11, no. 1, pp. 6–9, 2011. View at Publisher · View at Google Scholar · View at Scopus
  10. P. E. Cryer, “The barrier of hypoglycemia in diabetes,” Diabetes, vol. 57, no. 12, pp. 3169–3176, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. C. C. Connolly, R. E. Ivy, B. A. Adkins-Marshall et al., “Counterregulation by epinephrine and glucagon during insulin-induced hypoglycemia in the conscious dog,” Diabetes Research and Clinical Practice, vol. 31, no. 1–3, pp. 45–56, 1996. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Kalra, J. Mukherjee, A. Ramachandran et al., “Hypoglycemia: the neglected complication,” Indian Journal of Endocrinology and Metabolism, vol. 17, no. 5, pp. 819–834, 2013. View at Publisher · View at Google Scholar
  13. M. A. DeRosa and P. E. Cryer, “Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation,” American Journal of Physiology—Endocrinology and Metabolism, vol. 287, no. 1, pp. E32–E41, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. S. E. Dagogo-Jack, S. Craft, and P. E. Cryer, “Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia,” The Journal of Clinical Investigation, vol. 91, no. 3, pp. 819–828, 1993. View at Publisher · View at Google Scholar · View at Scopus
  15. T. Lingenfelser, W. Renn, U. Sommerwerck et al., “Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients,” Diabetes, vol. 42, no. 4, pp. 610–618, 1993. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Rattarasarn, S. Dagogo-Jack, J. J. Zachwieja, and P. E. Cryer, “Hypoglycemia-induced autonomic failure in IDDM is specific for stimulus of hypoglycemia and is not attributable to prior autonomic activation,” Diabetes, vol. 43, no. 6, pp. 809–818, 1994. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Vele, S. Milman, H. Shamoon, and I. Gabriely, “Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 11, pp. 3424–3431, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. S. A. Segel, D. S. Paramore, and P. E. Cryer, “Hypoglycemia-associated autonomic failure in advanced type 2 diabetes,” Diabetes, vol. 51, no. 3, pp. 724–733, 2002. View at Publisher · View at Google Scholar · View at Scopus
  19. S. R. Heller and P. E. Cryer, “Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans,” Diabetes, vol. 40, no. 2, pp. 223–226, 1991. View at Publisher · View at Google Scholar · View at Scopus
  20. A. M. Arbelaez, W. J. Powers, T. O. Videen, J. L. Price, and P. E. Cryer, “Attenuation of counterregulatory responses to recurrent hypoglycemia by active thalamic inhibition a mechanism for hypoglycemia-associated autonomic failure,” Diabetes, vol. 57, no. 2, pp. 470–475, 2008. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Moheet, A. Kumar, L. E. Eberly, J. Kim, R. Roberts, and E. R. Seaquist, “Hypoglycemia-associated autonomic failure in healthy humans: Comparison of two vs three periods of hypoglycemia on hypoglycemia-induced counterregulatory and symptom response 5 days later,” Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 2, pp. 664–670, 2014. View at Publisher · View at Google Scholar · View at Scopus
  22. P. A. Goldberg, R. Weiss, R. J. McCrimmon, E. V. Hintz, J. D. Dziura, and R. S. Sherwin, “Antecedent hypercortisolemia is not primarily responsible for generating hypoglycemia-associated autonomic failure,” Diabetes, vol. 55, no. 4, pp. 1121–1126, 2006. View at Publisher · View at Google Scholar · View at Scopus
  23. J. Leu, M.-H. Cui, H. Shamoon, and I. Gabriely, “Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade,” The Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 9, pp. 3372–3380, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. J. Klement, B. Mergelkuhl, J. Born, H. Lehnert, and M. Hallschmid, “Role of γ-aminobutyric acid signalling in the attenuation of counter-regulatory hormonal responses after antecedent hypoglycaemia in healthy men,” Diabetes, Obesity and Metabolism, vol. 16, no. 12, pp. 1274–1278, 2014. View at Publisher · View at Google Scholar · View at Scopus
  25. R. Ramanathan and P. E. Cryer, “Adrenergic mediation of hypoglycemia-associated autonomic failure,” Diabetes, vol. 60, no. 2, pp. 602–606, 2011. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Klement, I. Pais, J. Strube et al., “NMDA receptor blockade by memantine does not prevent adaptation to recurrent hypoglycaemia in healthy men,” Diabetes, Obesity and Metabolism, vol. 15, no. 4, pp. 310–315, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. S. N. Davis, C. Shavers, F. Costa, and R. Mosqueda-Garcia, “Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans,” The Journal of Clinical Investigation, vol. 98, no. 3, pp. 680–691, 1996. View at Publisher · View at Google Scholar · View at Scopus
  28. N. M. Sanders, D. P. Figlewicz, G. J. Taborsky Jr., C. W. Wilkinson, W. Daumen, and B. E. Levin, “Feeding and neuroendocrine responses after recurrent insulin-induced hypoglycemia,” Physiology & Behavior, vol. 87, no. 4, pp. 700–706, 2006. View at Publisher · View at Google Scholar
  29. S. A. Paranjape and K. P. Briski, “Recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation,” Neuroscience, vol. 130, no. 4, pp. 957–970, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. E. F. LaGamma, N. Kirtok, O. Chan, and B. B. Nankova, “Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats,” American Journal of Physiology—Endocrinology and Metabolism, vol. 307, no. 7, pp. E580–E588, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. O. Chan, S. A. Paranjape, A. Horblitt, W. Zhu, and R. S. Sherwin, “Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes,” Diabetes, vol. 62, no. 12, pp. 4239–4246, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. B. O. Orban, V. H. Routh, B. E. Levin, and J. R. Berlin, “Direct effects of recurrent hypoglycaemia on adrenal catecholamine release,” Diabetes and Vascular Disease Research, vol. 12, no. 1, pp. 2–12, 2015. View at Publisher · View at Google Scholar · View at Scopus
  33. D. E. Flanagan, T. Keshavarz, M. L. Evans et al., “Role of corticotrophin-releasing hormone in the impairment of counterregulatory responses to hypoglycemia,” Diabetes, vol. 52, no. 3, pp. 605–613, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. R. J. McCrimmon, M. L. Evans, X. Fan et al., “Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats,” Diabetes, vol. 54, no. 11, pp. 3169–3174, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. N. C. Tkacs, Y. Pan, R. Raghupathi, A. A. Dunn-Meynell, and B. E. Levin, “Cortical Fluoro-Jade staining and blunted adrenomedullary response to hypoglycemia after noncoma hypoglycemia in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 12, pp. 1645–1655, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. M. A. Osundiji, P. Hurst, S. P. Moore et al., “Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats,” Metabolism: Clinical and Experimental, vol. 60, no. 4, pp. 550–556, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. W. I. Sivitz, J. A. Herlein, D. A. Morgan, B. D. Fink, B. G. Phillips, and W. G. Haynes, “Effect of acute and antecedent hypoglycemia on sympathetic neural activity and catecholamine responsiveness in normal rats,” Diabetes, vol. 50, no. 5, pp. 1119–1125, 2001. View at Publisher · View at Google Scholar · View at Scopus
  38. N. Kudrick, O. Chan, E. F. La Gamma et al., “Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia,” Physiological Reports, vol. 3, no. 2, Article ID e12307, 2015. View at Publisher · View at Google Scholar
  39. L. Kang, N. M. Sanders, A. A. Dunn-Meynell et al., “Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 294, no. 3, pp. R784–R792, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. M. G. de Vries, M. A. Lawson, and J. L. Beverly, “Dissociation of hypothalamic noradrenergic activity and sympathoadrenal responses to recurrent hypoglycemia,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 286, no. 5, pp. R910–R915, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. R. I. Herzog, O. Chan, S. Yu, J. Dziura, E. C. McNay, and R. S. Sherwin, “Effect of acute and recurrent hypoglycemia on changes in brain glycogen concentration,” Endocrinology, vol. 149, no. 4, pp. 1499–1504, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. S. Al-Noori, N. M. Sanders, G. J. Taborsky Jr. et al., “Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 295, no. 5, pp. R1446–R1454, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. S. B. Evans, C. W. Wilkinson, K. Bentson, P. Gronbeck, A. Zavosh, and D. P. Figlewicz, “PVN activation is suppressed by repeated hypoglycemia but not antecedent corticosterone in the rat,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 281, no. 5, pp. R1426–R1436, 2001. View at Google Scholar · View at Scopus
  44. D. P. Figlewicz, G. Van Dijk, C. W. Wilkinson, P. Gronbeck, M. Higgins, and A. Zavosh, “Effects of repetitive hypoglycemia on neuroendocrine response and brain tyrosine hydroxylase activity in the rat,” Stress, vol. 5, no. 3, pp. 217–226, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. E. C. McNay and R. S. Sherwin, “Effect of recurrent hypoglycemia on spatial cognition and cognitive metabolism in normal and diabetic rats,” Diabetes, vol. 53, no. 2, pp. 418–425, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. K. E. Inouye, J. T. Y. Yue, O. Chan et al., “Effects of insulin treatment without and with recurrent hypoglycemia on hypoglycemic counterregulation and adrenal catecholamine-synthesizing enzymes in diabetic rats,” Endocrinology, vol. 147, no. 4, pp. 1860–1870, 2006. View at Publisher · View at Google Scholar · View at Scopus
  47. L. Jacobson, T. Ansari, and O. P. McGuinness, “Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice,” American Journal of Physiology—Endocrinology and Metabolism, vol. 290, no. 4, pp. E678–E684, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. M. M. Poplawski, J. W. Mastaitis, and C. V. Mobbs, “Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure,” Diabetes, vol. 60, no. 1, pp. 39–46, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. P. E. Cryer, “Mechanisms of hypoglycemia-associated autonomic failure in diabetes,” The New England Journal of Medicine, vol. 369, no. 4, pp. 362–372, 2013. View at Publisher · View at Google Scholar · View at Scopus
  50. J. E. Gerich, M. Langlois, C. Noacco, J. H. Karam, and P. H. Forsham, “Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect,” Science, vol. 182, no. 4108, pp. 171–173, 1973. View at Publisher · View at Google Scholar · View at Scopus
  51. G. Bolli, P. De Feo, P. Compagnucci et al., “Abnormal glucose counterregulation in insulin-dependent diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion,” Diabetes, vol. 32, no. 2, pp. 134–141, 1983. View at Publisher · View at Google Scholar · View at Scopus
  52. P. E. Cryer, “Hypoglycemia: still the limiting factor in the glycemic management of diabetes,” Endocrine Practice, vol. 14, no. 6, pp. 750–756, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. E. R. Seaquist, J. Anderson, B. Childs et al., “Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society,” Diabetes Care, vol. 36, no. 5, pp. 1384–1395, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. L. Diedrich, D. Sandoval, and S. N. Davis, “Hypoglycemia associated autonomic failure,” Clinical Autonomic Research, vol. 12, no. 5, pp. 358–365, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. P. E. Cryer, “Hypoglycemia in type 1 diabetes mellitus,” Endocrinology and Metabolism Clinics of North America, vol. 39, no. 3, pp. 641–654, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. E. George, N. Harris, C. Bedford, I. A. Macdonald, C. A. Hardisty, and S. R. Heller, “Prolonged but partial impairment of the hypoglycaemic physiological response following short-term hypoglycaemia in normal subjects,” Diabetologia, vol. 38, no. 10, pp. 1183–1190, 1995. View at Publisher · View at Google Scholar · View at Scopus
  57. P. E. Cryer, S. N. Davis, and H. Shamoon, “Hypoglycemia in diabetes,” Diabetes Care, vol. 26, no. 6, pp. 1902–1912, 2003. View at Publisher · View at Google Scholar · View at Scopus
  58. S. A. Amiel, R. S. Sherwin, D. C. Simonson, and W. V. Tamborlane, “Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release,” Diabetes, vol. 37, no. 7, pp. 901–907, 1988. View at Publisher · View at Google Scholar · View at Scopus
  59. S. N. Davis, C. Shavers, R. Mosqueda-Garcia, and F. Costa, “Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans,” Diabetes, vol. 46, no. 8, pp. 1328–1335, 1997. View at Publisher · View at Google Scholar · View at Scopus
  60. S. N. Davis, S. Mann, P. Galassetti et al., “Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans,” Diabetes, vol. 49, no. 11, pp. 1897–1903, 2000. View at Publisher · View at Google Scholar · View at Scopus
  61. O. Chan, H. Cheng, R. Herzog et al., “Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory reponses after antecedent hypoglycemia,” Diabetes, vol. 57, no. 5, pp. 1363–1370, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Senthilkumaran, M. E. Johnson, and L. Bobrovskaya, “The effects of insulin-induced hypoglycaemia on tyrosine hydroxylase phosphorylation in rat brain and adrenal gland,” Neurochemical Research, vol. 41, no. 7, pp. 1612–1624, 2016. View at Publisher · View at Google Scholar
  63. P. Lucidi, P. Rossetti, F. Porcellati et al., “Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis,” Diabetes, vol. 59, no. 6, pp. 1349–1357, 2010. View at Publisher · View at Google Scholar · View at Scopus