In aged mice, pancreatic α-cells showed increased mass, higher glucagon content, impaired suppression of glucagon secretion, and endoplasmic reticulum stress, producing elevated circulating glucagon independent of insulin sensitivity. Insulin resistance amplified these changes. Human data from the CORDIOPREV cohort confirmed hyperglucagonemia in older adults with insulin resistance and linked higher plasma glucagon to greater risk of type 2 diabetes.
Key Points
- Aging raises glucagon secretion independent of insulin sensitivity in mice
- Aged α-cells show increased mass, ER stress, altered islet organization
- Higher plasma glucagon predicted type 2 diabetes risk in older adults
Longevity Analysis
Age-related glucose dysregulation has been framed almost entirely around failing insulin secretion, yet the opposing arm of islet control deteriorates in parallel and may precede clinical disease. Measuring fasting glucagon alongside insulin and glucose gives a more complete reading of how metabolic signaling is drifting with age, well before fasting glucose moves. The endoplasmic reticulum stress and loss of cell identity seen in aged α-cells also place this squarely within the broader machinery of cellular repair and protein-handling capacity, which responds to reduced metabolic load, consistent energy demands on tissue, and sustained insulin sensitivity.
Original published by Wiley Aging Cell, by Eva Tudurí, Lucía Almagro, Ana Ojeda‐Rodríguez, Raquel Pascua‐Maestro, Henver S. Brunetta, Sergi Soriano, Alejandro López‐Moreno, Talía Boronat‐Belda, Sergio Velasco‐Avilés, Joel Alves da Silva Junior, Manuel Castellano‐Muñoz, Alex Rafacho, Irene Cózar‐Castellano, Ángel Nadal, Paloma Alonso‐Magdalena, Beatriz Merino, José López‐Miranda, Ivan Quesada .