| Description |
Insulin injection into peripheral tissues inefficiently controls elevated fasting blood glucose in type 1 diabetes mellitus (DM1) patients. Peripheral insulin lacks the signaling of healthy β-cell insulin, which directs adjacent pancreatic α-cells to stop production of glucagon, a hormone releasing glucose from the liver into the blood. Since peripheral insulin injection to treat DM1 poorly inhibits pancreatic glucagon secretion, fasting blood glucose remains persistently elevated in DM1. Glucagon receptor antagonism (GRA) therapies aim to reduce glucagon activity by blocking glucagon receptors in the liver, thereby increasing the efficacy of injected insulin. GRA is currently unviable since it promotes dysregulated α-cell proliferation and glucagon secretion, in the long-term. Similar α-cell growth and blood glucagon levels were identified in animal models expressing the transcriptional repressor protein FOXN3 in the liver. This paper aims to characterize mice with the liver-specific deletion of Foxn3 to determine whether the gene's expression is necessary for pancreatic α-cell growth, and whether its deletion mitigates adverse effects of GRA therapy. Results validated that liver-specific deletion of Foxn3 causes α-cell expansion and decreases glucose utilization during fasting, resulting in elevated blood glucose. Mechanistically, Foxn3 is shown to act independently from GRA since its expression does not alter liver amino acid metabolism and losing Foxn3 in the liver does not reduce dysregulated α-cell proliferation and glucagon secretion during GRA therapy. Future insights into liver FOXN3-directed activation of pancreatic α- and β-cell development in a diabetic mouse may elucidate mechanisms of glucagon action in the absence of pancreatic insulin signaling |
