Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells

• Published in: Pflügers Archiv 2024-11
• Main Authors: Ruiz-Pino, Antonia, Goncalves-Ramírez, Arianna, Jiménez-Palomares, Margarita, Merino, Beatriz, Castellano-Muñoz, Manuel, Vettorazzi, Jean F, Rafacho, Alex, Marroquí, Laura, Nadal, Ángel, Alonso-Magdalena, Paloma, Perdomo, Germán, Cózar-Castellano, Irene, Quesada, Ivan
• Format: Article
• Language: English
• ISSN: 0031-6768; 1432-2013; 1432-2013
• DOI: 10.1007/s00424-024-03045-5

Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.