Role of synaptic plasticity and EphA5-ephrinA5 interaction within the ventromedial hypothalamus in response to recurrent hypoglycemia.

  1. Robert S. Sherwin1
  1. 1Yale University School of Medicine, Department of Internal Medicine and Endocrinology, New Haven, Connecticut, United States
  2. 2Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  1. Corresponding author: Robert S. Sherwin, MD, E-mail: robert.sherwin{at}


Hypoglycemia stimulates counterregulatory hormone release to restore euglycemia. This protective response is diminished by recurrent hypoglycemia, limiting the benefits of intensive insulin treatment in patients with diabetes. Previously we have reported that EphA5 receptor-ephrinA5 interactions within the ventromedial hypothalamus (VMH) influence counterregulatory hormone responses during acute hypoglycemia in non-diabetic rats. In this study we examined whether recurrent hypoglycemia alters the capacity of the ephrinA5 ligand to activate VMH EphA5 receptors, and if so whether these changes could contribute to pathogenesis of defective glucose counterregulation in response to a standard hypoglycemic stimulus. The expression of ephrinA5, but not EphA5 receptors within the VMH was found to be reduced by antecedent recurrent hypoglycemia. In addition, there was an increase in the number of synaptic connections as well as reduced astroglial synaptic coverage. Activation of VMH EphA5 receptors via targeted microinjection of ephrinA5-Fc prior to hyperinsulinemic hypoglycemic clamp study caused a reduction in the glucose infusion rate in non-diabetic rats exposed to recurrent hypoglycemia. The increase in the counterregulatory response to insulin- induced hypoglycemia was associated with a 150% increase in glucagon release (p<0.001). These data suggest that changes in ephrinA5/EphA5 interactions and synaptic plasticity within the VMH, a key brain glucose-sensing region, may contribute to the impairment in glucagon secretion and counterregulatory responses caused by recurrent hypoglycemia.

  • Received August 15, 2013.
  • Accepted November 5, 2013.

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