Central but not systemic lipid infusion augments the counterregulatory response to hypoglycemia

• Published in: American journal of physiology: endocrinology and metabolism 2009-07, Vol.297 (1), p.E50-E56
• Main Authors: Haywood, Samuel C, Bree, Adam J, Puente, Erwin C, Daphna-Iken, Dorit, Fisher, Simon J
• Format: Article
• Language: English
• Subjects: Adrenal Glands - drug effects; Adrenal Glands - physiology; Animals; Brain - drug effects; Brain - metabolism; Epinephrine - blood; Fatty acids; Fatty Acids, Nonesterified - cerebrospinal fluid; Glucagon - blood; Hypoglycemia; Hypoglycemia - metabolism; Hypoglycemia - physiopathology; Infusions, Intravenous; Injections, Intraventricular; Insulin; Lipids; Lipids - administration & dosage; Lipids - pharmacology; Norepinephrine - blood; Rats; Rats, Sprague-Dawley; Rodents; Studies; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - physiology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.90673.2008

1 Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine; and 2 Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri Submitted 6 August 2008 ; accepted in final form 1 May 2009 This study tests the hypothesis that lipids could act as an alternative fuel source in the brain during insulin-induced hypoglycemia. Male Sprague-Dawley rats were subjected to hyperinsulinemic (5 mU·kg –1 ·min –1 ) hypoglycemic ( 50 mg/dl) clamps. In protocol 1 , intralipid (IL), a fat emulsion, was infused intravenously to prevent the fall in free fatty acid levels that occurs in response to hyperinsulinemic hypoglycemia. Intravenous lipid infusion did not alter the counterregulatory responses to hypoglycemia. To test whether IL could have central effects in mediating the counterregulatory response to hypoglycemia, in protocol 2 the brains of precannulated rats were intracerebroventricularly (icv) infused with IL or artificial cerebrospinal fluid (aCSF) as control. Unexpectedly, the epinephrine and glucagon response to hypoglycemia was significantly augmented with icv IL infusion. To determine whether central IL infusion could restore defective counterregulation, in protocol 3 rats were made recurrently hypoglycemic (RH) for 3 days and on the 4th day underwent hyperinsulinemic hypoglycemic clamps with icv IL or aCSF infusion. RH rats had the expected impaired epinephrine response to hypoglycemia, and icv IL infusion again significantly augmented the epinephrine response in RH rats to normal. With regard to our experimental model of hypoglycemic counterregulation, we conclude that 1 ) systemic lipid infusion did not alter the counterregulatory response to hypoglycemia, 2 ) the icv infusion of lipids markedly increased CSF FFA levels and paradoxically augmented the epinephrine and glucagon responses, and 3 ) the blunted sympathoadrenal response in recurrently hypoglycemic rats was completely normalized with the icv lipid infusion. It is concluded that, in the setting of insulin-induced hypoglycemia, increased brain lipids can enhance the sympathoadrenal response. intralipid; intracerebroventricular Address for reprint requests and other correspondence: S. Fisher, Div. of Endocrinology, Metabolism, & Lipid Research, Washington University in St. Louis, 660 South Euclid Ave., St. Louis, MO 63110 (e-mail: sfisher{at}dom.wustl.edu )