Mechanism, temporal patterns, and magnitudes of the metabolic responses to the KATP channel agonist diazoxide

• Published in: American journal of physiology: endocrinology and metabolism 2005-01, Vol.288 (1), p.E80-E85
• Main Authors: Raju, Bharathi, Cryer, Philip E
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Administration, Oral; Adult; Blood Glucose - drug effects; Blood Glucose - metabolism; Diazoxide - administration & dosage; Epinephrine - blood; Fatty Acids, Nonesterified - blood; Female; Glucagon - blood; Glucagon - metabolism; Humans; Injections, Intravenous; Insulin - blood; Insulin - metabolism; Insulin Secretion; Male; Potassium Channels - agonists; Potassium Channels - physiology; Vasodilator Agents - administration & dosage
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00188.2004

Division of Endocrinology, Metabolism, and Lipid Research, The General Clinical Research Center and the Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri Submitted 30 April 2004 ; accepted in final form 30 August 2004 To assess the mechanism, temporal patterns, and magnitudes of the metabolic responses to the ATP-dependent potassium channel agonist diazoxide, neuroendocrine and metabolic responses to intravenous diazoxide (saline, 1.0 and 2.0 mg/kg) and oral diazoxide (placebo, 4.0 and 6.0 mg/kg) were assessed in healthy young adults. Intravenous diazoxide produced rapid, but transient, decrements ( P = 0.0023) in plasma insulin (e.g., nadirs of 2.8 ± 0.5 and 1.8 ± 0.3 µU/ml compared with 7.0 ± 1.0 µU/ml after saline at 4.0–7.5 min) and C-peptide ( P = 0.0228) associated with dose-related increments in plasma glucose ( P = 0.0044) and serum nonesterified fatty acids ( P < 0.0001). After oral diazoxide, plasma insulin appeared to decline, as did C-peptide, again associated with dose-related increments in plasma glucose ( P < 0.0001) and serum nonesterified fatty acids ( P = 0.0141). Plasma glucagon, as well as cortisol and growth hormone, was not altered. Plasma epinephrine increased ( P = 0.0215) slightly only after intravenous diazoxide. There were dose-related increments in plasma norepinephrine ( P = 0.0038 and P = 0.0005, respectively), undoubtedly reflecting a compensatory sympathetic neural response to vasodilation produced by diazoxide, but these would not raise plasma glucose or serum nonesterified fatty acid levels. Thus selective suppression of insulin secretion, without stimulation of glucagon secretion, raised plasma glucose and serum nonesterified fatty acid concentrations. These findings define the temporal patterns and magnitudes of the metabolic responses to diazoxide and underscore the primacy of regulated insulin secretion in the physiological regulation of postabsorptive carbohydrate and lipid metabolism. glucose; insulin; glucagon; epinephrine; norepinephrine; adenosine 5'-triphosphate-dependent potassium channel Address for reprint requests and other correspondence: P. E. Cryer, Campus Box 8127, Washington Univ. School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110 (E-mail: pcryer{at}wustl.edu )