Aging Affects Pancreatic α‐Cell Function and Promotes Hyperglucagonemia: Implications in Age‐Associated Diabetes

Abstract

ABSTRACT Aging is a major risk factor in the development of type 2 diabetes mellitus (T2DM). With age, pancreatic β‐cells undergo functional and cell identity changes that can compromise insulin secretion, thereby contributing to impaired glucose tolerance and T2DM. However, glucose homeostasis also depends on pancreatic α‐cells. Excessive plasma glucagon levels, along with impaired regulation of α‐cell secretion, are involved in the pathophysiology of T2DM. Despite their importance, the effects of aging on α‐cells have been overlooked. In the present study, we analyzed pancreatic α‐cells in aged mice with normal insulin sensitivity and in those with peripheral insulin resistance. Regardless of insulin sensitivity, aged mice exhibited hyperglucagonemia and increased glucagon release. Ex vivo, these alterations were associated with increased α‐cell mass, higher glucagon content, impaired suppression of glucagon secretion, and endoplasmic reticulum stress. Furthermore, aged mice showed remodeling of islet cellular composition and changes in the spatial organization of α‐cells within the islet. Additionally, moderate alterations in α‐cell identity were noted. While most of these alterations were already present in aged mice with normal insulin sensitivity, they were generally more pronounced with insulin resistance. Examination of the CORDIOPREV clinical study revealed the presence of hyperglucagonemia in older adults with insulin resistance. Additionally, an increased risk of developing T2DM was also found in older people with higher plasma glucagon levels. The findings described here indicate that aging affects the biology of α‐cells and glucagon, positioning them as active players in impaired glucose tolerance and diabetes associated with aging.