A novel [13C9,15N1]-glucagon tracer study in 12 healthy individuals undergoing multi-rate clamp visits demonstrates that glucose, not insulin, appears to be the main regulator of glucagon secretion, with implications for understanding alpha-cell biology and the broader pathophysiology of glucagon dysregulation in diabetes where established teaching has emphasized insulin’s role in glucagon suppression.
The relative contribution of circulating glucose and insulin concentrations to glucagon secretion in healthy individuals has been unknown, despite the foundational importance of glucagon regulation for understanding diabetes pathophysiology and for developing glucagon-modulating therapeutics. The current study addresses this directly through innovative tracer methodology.
Conventional teaching has emphasized insulin’s role in suppressing glucagon secretion through the islet paracrine system, with beta cell insulin output regulating alpha cell glucagon output in a coordinated islet response. The conventional framework supports the view that insulin deficiency in diabetes drives the inappropriate glucagon secretion contributing to hyperglycemia.
However, glucose concentration itself directly affects alpha cell function through cellular glucose-sensing mechanisms parallel to those operating in beta cells. The relative importance of direct glucose sensing versus insulin-mediated paracrine suppression has been difficult to isolate experimentally.
The current study assessed glucagon secretion using [13C9,15N1]-glucagon tracer at varying insulin and glucose concentrations in healthy individuals, providing isolation of insulin and glucose effects through the controlled clamp design. The tracer methodology directly quantifies glucagon production rather than relying on plasma glucagon measurements alone.
After overnight fast, twelve healthy individuals underwent three separate clamp visits (hypogly-cemia, euglycemia, hyperglycemia) in random order at two insulin infusion rates. Five participants received insulin at 0.25 and 0.75 mU/kg/min; remaining received insulin at 0.5 and 1 mU/kg/min over 90-minute intervals each.
Simultaneously, [13C9,15N1]-glucagon tracer was infused to enable direct calculation of glucagon secretion rate using tracer dilution methodology. The framework provides quantitative dissection of insulin- and glucose-mediated effects on glucagon secretion that conventional plasma measurement methodology cannot achieve.
Findings indicated that glucose, not insulin, appears to be the main regulator of glucagon secretion in healthy individuals. The result challenges conventional teaching and supports alpha cell intrinsic glucose sensing as the dominant regulatory mechanism rather than insulinmediated paracrine control.
Take-home: in healthy individuals, glucose appears to be the main regulator of glucagon secretion rather than insulin, challenging conventional islet paracrine teaching. The findings reframe understanding of glucagon regulation and have implications for interpreting the inappropriate glucagon secretion in diabetes and developing glucagon-modulating therapeutic strategies.
“Glucose, not insulin, drives glucagon secretion in healthy adults, alpha cell intrinsic glucose sensing supersedes the conventional islet paracrine model.”