Role of Brain in Counterregulation of Insulin-Induced Hypoglycemia in Dogs

Abstract

The role of the brain in directing counterregulation during hypoglycemia induced by insulin infusion was assessed in overnight-fasted conscious dogs. Concomitant brain and peripheral hypoglycemia was induced in one group of dogs (n = 5) by infusing insulin peripherally at a rate of 3.5 mU.kg-1.min-1. In another group (n = 4), insulin was infused as described above to induce peripheral hypoglycemia, and brain hypoglycemia was minimized by infusing glucose bilaterally into the carotid and vertebral arteries to maintain the brain glucose level at a calculated concentration of 85 mg/dl. Glucose was also infused peripherally as needed so that the peripheral glucose levels in both of the protocols were similar (45 +/- 2 mg/dl with and 48 +/- 3 mg/dl without brain glucose infusion, both P less than .05). The responses (in terms of change of area under the curve) of epinephrine, norepinephrine, cortisol, and pancreatic polypeptide when brain glycemia was controlled during insulin infusion were only 14 +/- 6, 39 +/- 12, 17 +/- 8, and 9 +/- 4%, respectively, of those present during insulin infusion without concomitant brain glucose infusion (all P less than .05). Of particular interest was the glucagon response that occurred when head hypoglycemia was minimized; the glucagon level was only 21 +/- 8% of that present when marked brain hypoglycemia accompanied insulin infusion (P less than .05). During hypoglycemia resulting from insulin infusion, endogenous glucose production (EGP), as assessed with [3-3H]glucose, rose from 2.6 +/- 0.1 to 4.4 +/- 0.5 mg.kg-1.min-1 (P less than .05). In contrast, EGP decreased from 2.7 +/- 0.2 to 2.0 +/- 0.3 mg.kg-1.min-1 when brain hypoglycemia was minimized. In an additional set of studies, when insulin was infused at 3.5 mU.kg-1.min-1 and glucose was infused peripherally to maintain both the head and peripheral glucose concentrations at 88 +/- 6 mg/dl, EGP decreased from 2.6 +/- 0.1 to 1.2 +/- 0.2 mg.kg-1.min-1. These results suggest that under marked hyperinsulinemic conditions the brain is the primary director of glucagon release and that it is responsible for approximately 75% of the life-sustaining glucose production.

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

“…Glucagon and sympathoadrenal activation is important in the early counter-regulatory responses to hypoglycaemia. On the other hand, cortisol and growth hormone responses, which occur after a prolonged and severe decrease in circulating glucose concentrations, are important for the long-term maintenance of blood glucose concentrations [1,2].…”

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

“…Finally, neural pathways stimulated by hypoglycemia induce feeding behavior [2]. Hormone responses and symptoms of hypoglycemia tend to be blunted in DM patients treated with insulin, and it is likely that deficient responses to hypoglycemia result from recurrent severe hypoglycemia sustained over many years of insulin replacement [1] CNS mechanisms of autonomic and endocrine responses to hypoglycemia have been studied in dogs and in rodents, and these studies indicate participation of structures in brainstem as well as hypothalamus [3][4][5][6][7][8][9][10][11][12]. Although these animal studies have proven useful in elucidating aspects of neural circuitry underlying counterregulatory hormone secretion, symptom thresholds, per se, cannot be directly assessed in an animal model.…”

The role of hepatic portal glucose sensing in modulating responses to hypoglycaemia in man

“…For a long time, the major mammalian hypoglycaemia sensor has been considered to be within the brain, particularly including the hypothalamus. The evidence for this includes the inhibition of neuroendocrine counterregulatory responses to systemic hypoglycaemia when brain glucose concentrations are maintained by selective glucose infusion [8,9]; the development of hyperglycaemia after hypothalamic lesions [10]; the induction of a counterregulatory response in euglycaemic animals by localised glucoprivation in the ventromedial hypothalamus [11] and the amelioration of counterregulatory responses to acute hypoglycaemia in animals when hypothalamic glucose concentrations are sustained by microdialysis of glucose solutions into the area [12]. However, the primacy of the cranial hypoglycaemia sensor has been challenged by studies showing similar suppression of counterregulatory responses to acute hypoglycaemia when portal vein and hepatic glucose concentrations are sustained by local infusion in rats and dogs [14,15,16].…”

“…Selective catheterisation studies in dogs showed a reduction in the counterregulatory hormone responses to systemic hypoglycaemia when brain glucose concentrations were maintained artificially, suggesting that the hypoglycaemia sensor is in the brain [8,9]. More recent studies using microdialysis catheters in rats localised the glucose sensor to the ventromedial nuclei of the hypothalamus (VMH) [10,11,12,13].…”