GLP-1-based therapies for type 2 diabetes: from single, dual and triple agonists to endogenous GLP-1 production and L-cell differentiation.
This review paper provides a broad overview of glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily by intestinal L-cells, pancreatic α-cells, and the central nervous system, and its therapeutic relevance in type 2 diabetes mellitus (T2DM). The authors describe how GLP-1 promotes glucose homeostasis by stimulating insulin secretion, slowing gastric emptying, reducing food intake, and supporting β-cell proliferation. The paper surveys existing GLP-1-based pharmacological strategies, including GLP-1 receptor agonists (single, dual, and triple agonists) and dipeptidyl peptidase-4 (DPP-4) inhibitors, noting that both preclinical and clinical evidence supports their role in improving glycemic control. The review then shifts focus to emerging, non-pharmacological-style strategies: enhancing endogenous GLP-1 production through various physiological and molecular stimuli, and promoting intestinal L-cell differentiation as a means to expand the body's own GLP-1-secreting capacity. The authors frame L-cell differentiation as a particularly promising future therapeutic avenue. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and its conclusions are limited by the scope and quality of the studies it cites.
Why this grade: This is a narrative review synthesizing preclinical and clinical literature on GLP-1-based therapies; it generates no original primary data and therefore receives a review-level evidence grade.
Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone mainly secreted by enteroendocrine intestinal L-cells. GLP-1 is also secreted by α-cells of the pancreas and the central nervous system (CNS). GLP-1 secretion is stimulated by nutrient intake and exerts its effects on glucose homeostasis by stimulating insulin secretion, gastric emptying confiding the food intake, and β-cell proliferation. The insulinotropic effects of GLP-1, and the reduction of its effects in type 2 diabetes mellitus (T2DM), have made GLP-1 an attractive option for the treatment of T2DM. Furthermore, GLP-1-based medications such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have been shown to improve diabetes control in preclinical and clinical trials with human subjects. Importantly, increasing the endogenous production of GLP-1 by different mechanisms or by increasing the number of intestinal L-cells that tend to produce this hormone may be another effective therapeutic approach to managing T2DM. Herein, we briefly describe therapeutic agents/compounds that enhance GLP-1 function. Then, we will discuss the approaches that can increase the endogenous production of GLP-1 through various stimuli. Finally, we introduce the potential of L-cell differentiation as an attractive future therapeutic approach to increase GLP-1 production as an attractive therapeutic alternative for T2DM.
Educational summary of published research — not medical advice. License: cc by-nc-nd. Full text is shown only where licensing permits.