Counterregulation During Hypoglycemia Is Directed by Widespread Brain Regions

Abstract

Previous studies have demonstrated the importance of the brain in directing counterregulation during insulin-induced hypoglycemia in dogs. The capability of selective carotid or vertebrobasilar hypoglycemia in triggering counterregulation was assessed in this study using overnight-fasted dogs. Insulin (21 pM.kg-1.min-1) was infused for 3 h to create peripheral hypoglycemia in the presence of 1) selective carotid hypoglycemia (vertebral glucose infusion, n = 5), 2) selective vertebrobasilar hypoglycemia (carotid glucose infusion, n = 5), 3) the absence of brain hypoglycemia (carotid and vertebral glucose infusion, n = 4), or 4) total brain hypoglycemia (no head glucose infusion, n = 5). Glucose was infused via a leg vein as needed in each group to minimize the differences in peripheral glucose levels (2.6 +/- 0.1, 3.0 +/- 0.2, 2.7 +/- 0.1, and 2.5 +/- 0.1 mM, respectively). The humoral responses (cortisol, glucagon, catecholamines, and pancreatic polypeptide) to hypoglycemia were minimally attenuated (< 40%) by selective carotid or vertebrobasilar euglycemia. In addition, the increase in hepatic glucose production, as assessed using [3-3H]glucose, was attenuated by only 41 and 34%, respectively, during selective carotid or vertebrobasilar hypoglycemia. These observations offer support for the hypothesis that more than one center is important in hypoglycemic counterregulation in the dog and that they are located in brain regions supplied by the carotid and vertebrobasilar arteries, because significant counterregulation occurred when hypoglycemia developed in either of these circulations. Counterregulation during hypoglycemia, therefore, is probably directed by widespread brain regions that contain glucose-sensitive neurons such that the sensing sites are redundant.

Activation of Hindbrain Neurons Is Mediated by Portal-Mesenteric Vein Glucosensors During Slow-Onset Hypoglycemia

“…In this capacity, central glucose sensors might also act primarily to suppress CRRs once euglycemia is reestablished following a hypoglycemic event. This would further explain why clamping either portal-mesenteric or brain glycemia during general systemic hypoglycemia is equally effective in blunting the CRR (47,48). …”

Modulation of β-Adrenergic Receptors in the Ventromedial Hypothalamus Influences Counterregulatory Responses to Hypoglycemia

“…It is now recognized that hypoglycemia is detected by specialized glucose-sensing neurons located within a variety of brain regions (6,7) as well as periphery (5). Watts and Donovan, in a recent review (14), proposed that brainstem catecholaminergic neurons receive neural input from peripheral glucose sensors and then transmit this information to hypothalamic glucose-sensing neurons, including those in the VMH.…”

“…Detection of hypoglycemia by glucose-sensing cells/neurons peripherally (5) and centrally (6) is critical in the defense against hypoglycemia and the prevention of brain injury. One brain region in particular, the ventromedial hypothalamus (VMH), appears to play a key role in hypoglycemia sensing (7).…”

Insulin in the brain: There and back again

“…Reduction in blood glucose levels below that for which GLUT-1 can compensate results immediately in the signs and symptoms of hypoglycemia. The brain responds by increasing sympathetic outflow and releasing hypothalamic regulatory factors, all of which directly or indirectly result in the release of counter-regulatory hormones that oppose the action of insulin (Frizzell, et al, 1993). …”