Biphasic glucose-stimulated insulin secretion over decades: a journey from measurements and modeling to mechanistic insights

Glucose-stimulated insulin release from pancreatic beta-cells is critical for maintaining blood glucose homeostasis. An abrupt increase in blood glucose concentration evokes a rapid and transient rise in insulin secretion followed by a prolonged, slower phase. A diminished first phase is one of the earliest indicators of beta-cell dysfunction in individuals predisposed to develop type 2 diabetes. Consequently, researchers have explored the underlying mechanisms for decades, starting with plasma insulin measurements under physiological conditions and advancing to single-vesicle exocytosis measurements in individual beta-cells combined with molecular manipulations. Based on a chain of evidence gathered from genetic manipulation to in vivo mouse phenotyping, a widely accepted theory posits that distinct functional insulin vesicle pools in beta-cells regulate biphasic glucose-stimulated insulin secretion (GSIS) via activation of different metabolic signal pathways. Recently, we developed a high-resolution imaging technique to visualize single vesicle exocytosis from beta-cells within an intact islet. Our findings reveal that beta-cells within the islet exhibit heterogeneity in their secretory capabilities, which also differs from the heterogeneous Ca2+ signals observed in islet beta-cells in response to glucose stimulation. Most importantly, we demonstrate that biphasic GSIS emerges from the interactions among alpha-, beta-, and delta-cells within the islet and is driven by a small subset of hypersecretory beta-cells. Finally, we propose that a shift from reductionism to holism may be required to fully understand the etiology of complex diseases such as diabetes.