Human pancreatic alpha cells – long known for producing glucagon – also generate significant amounts of bioactive GLP-1, a hormone critical to insulin secretion and blood sugar regulation, research has revealed. The findings, published in Science Advances, challenge conventional views of alpha cell function and advance understanding of endogenous mechanisms of glucose control in type 2 diabetes, potentially informing future therapeutic strategies.
Using high-specificity mass spectrometry, researchers at Duke University School of Medicine quantified levels of GLP-1(7–36)amide – the active form of the hormone – in pancreatic tissue from humans and mice. Their analysis showed that alpha cells naturally produce more bioactive GLP-1 than previously assumed, and that this production can compensate for glucagon loss under certain conditions.
“Alpha cells are more flexible than we imagined,” said lead author Jonathan Campbell in a press release. “They can adjust their hormone output to support beta cells and maintain blood sugar balance.”
The team developed a targeted LC-MS/MS assay to distinguish between bioactive GLP-1 and its inactive cleavage fragments, which often confound antibody-based assays. This enabled direct quantification of GLP-1(7–36)amide in islets and whole pancreas samples. In both mouse and human tissues, GLP-1 levels were strongly correlated with insulin secretion and improved glucose tolerance – particularly when glucagon production was suppressed.
In genetic mouse models lacking prohormone convertase 2 (PC2), which drives glucagon synthesis, the researchers observed a compensatory increase in PC1/3 activity, the enzyme responsible for GLP-1 biosynthesis. This enzymatic switch led to higher local GLP-1 levels, enhanced insulin output, and improved glycemic control. When both PC1 and PC2 were knocked out, however, insulin secretion dropped and hyperglycemia ensued, confirming the functional relevance of alpha cell–derived GLP-1.
“We thought that removing glucagon would impair insulin secretion by disrupting alpha-to-beta cell signaling,” said Campbell. “Instead, it improved it. GLP-1 took over, and it turns out, it’s an even better stimulator of insulin than glucagon.”
Although GLP-1 is primarily produced in the intestinal L-cells following food intake, the study shows that alpha cells contribute to circulating GLP-1 under physiological and metabolic stress conditions. This "hormonal flexibility" could represent an intrinsic glucose-buffering mechanism, particularly relevant in the context of beta-cell dysfunction in type 2 diabetes.
The researchers suggest that future therapies might aim to amplify alpha cell-derived GLP-1 production, offering an alternative to exogenous GLP-1 receptor agonists. However, further work is needed to determine how this mechanism can be modulated safely and effectively in humans they conclude.
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