Abstract
BackgroundGlucagon is an important hormone in the regulation of glucose homeostasis, particularly in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM), glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Efforts to discover and evaluate glucagon receptor antagonists for the treatment of T2DM have been ongoing for approximately two decades, with the challenge being to identify an agent with appropriate pharmaceutical properties and efficacy relative to potential side effects. We sought to determine the hepatic & systemic consequence of full glucagon receptor antagonism through the study of the glucagon receptor knock-out mouse (Gcgr-/-) compared to wild-type littermates.ResultsLiver transcriptomics was performed using Affymetric expression array profiling, and liver proteomics was performed by iTRAQ global protein analysis. To complement the transcriptomic and proteomic analyses, we also conducted metabolite profiling (~200 analytes) using mass spectrometry in plasma. Overall, there was excellent concordance (R = 0.88) for changes associated with receptor knock-out between the transcript and protein analysis. Pathway analysis tools were used to map the metabolic processes in liver altered by glucagon receptor ablation, the most notable being significant down-regulation of gluconeogenesis, amino acid catabolism, and fatty acid oxidation processes, with significant up-regulation of glycolysis, fatty acid synthesis, and cholesterol biosynthetic processes. These changes at the level of the liver were manifested through an altered plasma metabolite profile in the receptor knock-out mice, e.g. decreased glucose and glucose-derived metabolites, and increased amino acids, cholesterol, and bile acid levels.ConclusionsIn sum, the results of this study suggest that the complete ablation of hepatic glucagon receptor function results in major metabolic alterations in the liver, which, while promoting improved glycemic control, may be associated with adverse lipid changes.
Highlights
Glucagon is an important hormone in the regulation of glucose homeostasis, in the maintenance of euglycemia and prevention of hypoglycemia
Five animals from each group were selected for transcript profiling based on their RNA quality
No outliers were found during principal component analysis (PCA) and correlation mapping analysis
Summary
Glucagon is an important hormone in the regulation of glucose homeostasis, in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM), glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Mice lacking the glucagon receptor gene (Gcgr-/mice) exhibit a phenotype of improved glucose tolerance with decreased glucose levels under both fed and fasted conditions compared to control mice, but they do not have overt hypoglycemia under these conditions. In the fed but not fasted state, hepatic glycogen levels increase by 65%, suggesting the Gcgr-/-mice do not mobilize glycogen as efficiently as wild-type or favor glycogenesis [3]. While the Gcgr-/- mice have been well-characterized physiologically, we performed a comprehensive analysis of transcriptomic and proteomic changes in the liver of these animals, as well as metabolic profiling of the plasma, to more thoroughly understand the consequence of glucagon receptor ablation at the molecular level. Major biological alterations were seen in Gcgr-/- animals affecting carbohydrate metabolism, lipid metabolism, and protein metabolism with many of the pathways being affected at both the mRNA and protein level
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