Aging Drives Excess Glucagon and Raises Diabetes Risk Even Before Insulin Resistance Appears

Aging is already recognized as a leading risk factor for type 2 diabetes, but research has focused almost entirely on beta-cell failure and peripheral insulin resistance. This study, published in Aging Cell, makes the case that pancreatic alpha-cells and their hormone glucagon are equally important — and equally disrupted — during normal aging. The researchers systematically characterized alpha-cell biology across young (3-month-old) and aged (20-month-old) male C57BL/6 mice, and validated findings in a human clinical cohort.

To separate the direct effects of aging from those driven by insulin resistance, aged mice were stratified using the QUICKI index into a high-insulin-sensitive (HIS) group and a low-insulin-sensitive (LIS) group. Both groups were compared against young controls. Critically, even the aged HIS mice — those with preserved insulin sensitivity — exhibited fasting hyperglucagonemia relative to young animals. Fasting plasma glucagon was elevated in both aged groups, and the arginine stimulation test revealed exaggerated glucagon responses, confirming excess secretory capacity. Ex vivo perifusion experiments showed that isolated islets from aged mice failed to properly suppress glucagon secretion when glucose concentrations were raised from low (1 mM) to high (16.7 mM) levels, a fundamental defect that mirrors the alpha-cell dysfunction seen in type 2 diabetes patients.

Histological and morphometric analyses demonstrated that aged mice had significantly increased alpha-cell mass — driven by both a greater number and larger size of alpha-cells — as well as higher intracellular glucagon content per cell. This expanded alpha-cell compartment was associated with marked remodeling of islet architecture: alpha-cells, normally confined to the islet periphery in mice, were found increasingly dispersed throughout the islet core in aged animals. This spatial disorganization was more pronounced in LIS mice. At the molecular level, alpha-cells in aged mice showed elevated markers of endoplasmic reticulum (ER) stress, including increased expression of the unfolded protein response sensors GRP78/BiP and CHOP, suggesting that proteostatic failure contributes to secretory dysregulation. RNA-sequencing and immunofluorescence data also indicated moderate but significant alterations in alpha-cell identity markers — including changes in the transcription factors Arx and Pax6 — pointing to partial transdifferentiation or dedifferentiation processes analogous to those reported in aged beta-cells.

To assess human relevance, the team analyzed data from the CORDIOPREV study, a large Spanish cardiovascular prevention clinical trial that prospectively followed adults with coronary heart disease. Among the participants with insulin resistance, older age was independently associated with higher fasting plasma glucagon. Crucially, a longitudinal analysis over approximately five years of follow-up revealed that individuals with higher baseline plasma glucagon levels had a significantly elevated risk of developing new-onset type 2 diabetes, and this association was particularly strong in older participants. This dose-response relationship between glucagon and diabetes incidence strengthens the causal inference from the mouse mechanistic data.

Taken together, these findings establish aging as a direct perturbation of alpha-cell biology, independent of — though compounded by — peripheral insulin resistance. The study is notable for distinguishing intrinsic aging effects on alpha-cells from secondary effects of metabolic deterioration. Limitations include use of only male mice (precluding sex-specific conclusions) and the observational nature of the human CORDIOPREV analysis. Nevertheless, the convergence of mouse mechanistic data with human longitudinal epidemiology makes a compelling case that hyperglucagonemia should be considered a biomarker and potential therapeutic target in age-associated diabetes.