title: Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.
abstract: Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA.
authors: Thomas H
authors: TH
authors: Meek
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA.
authors: Mauricio D
authors: MD
authors: Dorfman
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA.
authors: Miles E
authors: ME
authors: Matsen
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA.
authors: Jonathan D
authors: JD
authors: Fischer
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA.
authors: Alexis
authors: A
authors: Cubelo
authors: University of South Alabama College of Medicine, Mobile, AL.
authors: Monica R
authors: MR
authors: Kumar
authors: VA Puget Sound Health Care System, Department of Veterans Affairs Medical Center, Seattle, WA.
authors: Gerald J
authors: GJ
authors: Taborsky
authors: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA gjmorton@u.washington.edu.
authors: Gregory J
authors: GJ
authors: Morton
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D005934:Glucagon / Q000097:blood* / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology*; D007328:Insulin / Q000494:pharmacology; D007657:Ketone Bodies / Q000097:blood; D007662:Ketosis / Q000097:blood / Q000209:etiology*; D000069450:Liraglutide; D008099:Liver / Q000378:metabolism*; D008297:Male; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000502:physiology; D013311:Streptozocin
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D007657:Ketone Bodies; D018027:Receptors, Glucagon; D013311:Streptozocin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose
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