Brain insulin infusion does not augment the counterregulatory response to hypoglycemia or glucoprivation

Abstract

Although high dosages of insulin can cause hypoglycemia, several studies suggest that increased insulin action in the head may paradoxically protect against severe hypoglycemia by augmenting the sympathoadrenal response to hypoglycemia. We hypothesized that a direct infusion of insulin into the third ventricle and/or the mediobasal hypothalamus (MBH) would amplify the sympathoadrenal response to hypoglycemia. Nine week-old male rats had insulin (15 mU) or artificial cerebrospinal fluid (aCSF- control) infused bilaterally into the MBH or directly into the third ventricle. During the final two hours of the brain insulin or aCSF infusions, the counterregulatory response to either a hyperinsulinemic hypoglycemic (~50 mg/dl) clamp or to a 600 mg/kg IV bolus of 2-deoxy-glucose (2DG) was measured. 2DG was used to induce a glucoprivic response without peripheral insulin infusion. In response to insulin-induced hypoglycemia, epinephrine rose more than 60-fold, norepinephrine rose more than 4-fold, glucagon 8 fold, and corticosterone almost 2-fold, but these increments were not different in aCSF versus insulin treatment groups with either ICV or bilateratal MBH insulin protocols. ICV insulin infusion stimulated insulin signaling as noted by a 5-fold increase in AKT phosophorylation. In the absence of systemic insulin infusion, 2DG-induced glucopenia resulted in an equal counterregulatory response with brain aCSF and insulin infusions. Under the conditions studied, although insulin infusion acted to stimulate hypothalamic insulin signaling neither intrahypothalmic nor intracerebroventricular insulin infusion augmented the counterregulatory response to hypoglycemia nor to 2DG-induced glucoprivation. Therefore, it is proposed that the previously noted acute actions of insulin to augment the sympathoadrenal response to hypoglycemia are likely mediated via mechanisms exterior to the central nervous system.

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

“…Roles in glucoprivic feeding have been reported for the glucose transporter GLUT2 [595], the glucose-sensing glucokinase [596,597], mu (m) opiod receptors [597e599], and the orexigenic neuropeptides NPY [597,600e602] and orexin-A [603]. Interestingly, during glucoprivation, central insulin flips from being an appetite suppressor into a further stimulant of feeding [604], even though a separate report indicates that insulin-induced phosphorylation of AKT remains intact within the brain during glucoprivation [605] (see Fig. 4).…”

“…4). Centrally administered insulin does not appear to affect other counter-regulatory responses to glucoprivation [605]. Regarding the fourth additional regulatory effect, there is evidence that most neurons sense hormones in the extracellular fluid via receptors on the primary (solitary) cilium that protrudes, like an antenna, from these cells through their dense glycocalxy and unstirred water layer, to reach miscible liquid [606,607].…”

Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation

“…Following surgical recovery, rats underwent a hyperinsulinemic (20 mU · kg −1 · min −1 )–hypoglycemic (∼45 mg/dL) clamp, as previously described (20). Three hours before and throughout the clamp, indinavir (IDV) (10 μg/min; Merck, Whitehouse Station, NJ; n = 9) or vehicle (artificial cerebrospinal fluid [aCSF]; n = 6) was infused into the third ventricle (−2.8 mm from the bregma; Plastics One Inc., Roanoke, VA).…”

Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In Vivo

“…Whether insulin acts centrally to influence glucose counterregulation is also uncertain. In animal studies, insulin delivered directly into the brain in very large doses has been reported to amplify counterregulatory hormone secretion ( 22 – 24 ) or to have no direct effect ( 25 ).…”