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Title:The Role of Insulin and Glucagon in Mammalian Ammonia Homeostasis. Studies With Ammonia-Induced Orotic Aciduria in Rats
Author(s):Ulman, Edward Allen
Department / Program:Food Science
Discipline:Food Science
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Health Sciences, Nutrition
Abstract:Ammonia is a neural toxin, and this thesis proposes that the prevention of ammonia intoxication is a primary metabolic "concern" of mammals. The infrequency of ammonia intoxication indicates that an effective mechanism for controlling ammonia homeostasis exists. Extensive review of the literature on ammonia metabolism, glucose metabolism, urea synthesis and insulin and glucagon function has provided a basis for proposing a simple model accounting for ammonia homeostasis.
Only three enzymes initiate the removal of ammonia. These are: carbamyl phosphate synthetase I (CPS I), glutamate dehydrogenase (GDH), and glutamine synthetase (GS). Their tissue distribution underlies a basic pattern of ammonia metabolism. CPS I is the first enzyme in the synthesis of urea, which accounts for most of the nitrogen loss by mammals. However, urea synthesis is limited primarily to the liver. Therefore, transport of ammonia from extrahepatic tissues, especially the brain, to the liver must occur to prevent ammonia intoxication. This removal and transport of ammonia depends on GDH, GS and related transaminase activity. These reactions require a supply of (alpha)-ketoacids, which depends principally upon the availability of glucose. Therefore, the prevention of ammonia intoxication depends on the controlled presentation of glucose to extrahepatic tissues, its metabolism to (alpha)-ketoacids, their use with ammonia in the synthesis of amino acids and the return of these amino acids to the liver. Hepatic ureagenesis and gluconeogenesis then allow for the final removal of ammonia and the return of glucose for further peripheral ammonia removal. This thesis hypothesizes that ammonia homeostasis depends on the control of glucose metabolism and urea synthesis and that insulin and glucagon initiate control of these to provide for appropriate removal of ammonia.
This proposal was tested in studies with fed and fasted mature male rats, using ammonia-induced orotic aciduria (AIOA) as an index. Extensive evidence reviewed in this thesis show that AIOA results because mitochondrially generated carbamyl phosphate is shunted into hepatic pyrimidine synthesis following ammonia intoxication or loss of ureagenic capacity. Data presented show that AIOA is an inverse function of the in vivo ureagenic capacity and is directly related to the degree of ammonia intoxication. Thus the evidence suggests that AIOA may be useful in assessing ureagenic capacity and ammonia status in vivo. These characteristics of AIOA were exploited in studies designed to test the role of glucose metabolism and insulin and glucagon in maintaining ammonia homeostasis.
In general the evidence is consistent with the interpretation that glucose, insulin and glucagon play a central role in ammonia homeostasis. That is, glucagon, by increasing peripheral glucose availability and hepatic ureagenesis, and insulin, by causing the reverse, have the capacity to control ammonia homeostasis. Also, the literature reviewed and data presented support the conclusion that changes in ammonia supply are associated with changes in glucose, insulin and glucagon which are appropriate for control of ammonia removal. That is, increased ammonia leads to increased glucagon and/or decreased insulin.
In short, this thesis proposes that the control of glucose metabolism is related to its role in ammonia removal and that insulin and glucagon, by appropriately controlling the availability of glucose and the capacity for ureagenesis, lead to the maintenance of ammonia homeostasis. This proposal demands significant reevaluation of the role of glucose, insulin and glucagon in mammals, giving emphasis to their relation to ammonia homeostasis. If valid, this proposed reinterpretation has broad implications of ammonia in mammalian health and disease.
Issue Date:1980
Description:237 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1980.
Other Identifier(s):(UMI)AAI8018210
Date Available in IDEALS:2015-05-13
Date Deposited:1980

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