In the setting of insulin therapy, patients with Type 1 diabetes (T1D) are at particularly high risk for hypoglycemia (low blood sugar) because of an impaired ability of the brain to sense and respond appropriately to hypoglycemia. The physiologic basis of this impairment is, however, unclear. The laboratories of Simon Fisher, MD, Owen Chan, PhD, and Candace Reno, PhD, demonstrated that brain glucose sensing was impaired in rats with recurrent hypoglycemia as a result of defective glucose and lactate metabolism within the neurons and astrocytes in the hypothalamus. The resultant abnormal release of neurotransmitters—such as GABA, glutamate and dopamine—led to inadequate activation of hormonal responses to hypoglycemia. This detrimental effect, however, could be prevented by treatment with the beta-blocker carvedilol in rats. They further demonstrated that severe hypoglycemia led to coma, brain damage and fatal cardiac arrhythmias, and these effects were mediated by excessive activation of the autonomic nervous system. Based on these results, the investigators have launched a clinical trial to examine the efficacy of the drug metoclopramide to restore the neurotransmitter and hormonal responses and awareness to hypoglycemia in people with T1D.
Brain glut4 knockout mice have impaired glucose tolerance, decreased insulin sensitivity, and impaired hypoglycemic counterregulation. Reno CM, Puente EC, Sheng Z, Daphna-Iken D, Bree AJ, Routh VH, Kahn BB, Fisher SJ. Diabetes. 2017 March;66(3):587. https://doi.org/10.2337/db16-0917
Impaired glutamatergic neurotransmission in the ventromedial hypothalamus may contribute to defective counterregulation in recurrently hypoglycemic rats. Chowdhury GMI, Wang P, Ciardi A, Mamillapalli R, Johnson J, Zhu W, Eid T, Behar, Chan O. Diabetes. 2017 July;66(7):1979. https://doi.org/10.2337/db16-1589
Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia. Reno CM, VanderWeele J, Bayles J, Litvin M, Skinner A, Jordan A, Daphna-Iken D, Fisher S. Diabetes. 2017 December;66(12):3091. https://doi.org/10.2337/db17-0306
Prevention of severe hypoglycemia-induced brain damage and cognitive impairment with verapamil. Jackson DA, Michael T, Vieira de Abreu A, Agarwal R, Bortolato M, Fisher SJ. Diabetes. 2018 October;67(10):2107. https://doi.org/10.2337/db18-0008
Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in sprague-dawley rats. Farhat R, Su G, Sejling AS, Knight N, Fisher SJ, Chan O. Diabetologia. 2019 April;62(4):676. https://doi.org/10.1002/edm2.226
Severe hypoglycemia-induced fatal cardiac arrhythmias are mediated by the parasympathetic nervous system in rats. Reno CM, Bayles J, Huang Y, Oxspring M, Hirahara AM, Dosdall DJ, Fisher SJ. Diabetes. 2019 November;68(11):2107. http://doi.org/10.2337/db19-0306