Targeted Regulation of Pancreatic Islet Function by Natural Products Against Type 2 Diabetes Mellitus: Advances and Prospects.

Type 2 diabetes mellitus (T2DM) is a major global health challenge, with insulin resistance (IR) and islet dysfunction as its core pathophysiology. Current glucose-lowering agents, including insulin secretagogues, insulin sensitizers, DPP-IV inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists, effectively control blood glucose and may partly improve β-cell function indirectly, but they do not directly target the functional defects of pancreatic β cells. Developing drugs that precisely modulate islet function is therefore a key direction. Natural products, with their structural diversity, established glucose-lowering activity, and derivation from medicinal plants with long clinical use, have become an important source of lead compounds for drugs targeting these mechanisms. The main pathways through which natural products act include: (1) promoting insulin secretion through direct and indirect secretagogue mechanisms (modulating ion channels, metabolic enzymes, incretin signaling); (2) preserving β-cell function and mass by maintaining the differentiated phenotype, promoting regeneration, alleviating oxidative stress, inhibiting apoptosis and pyroptosis, attenuating inflammation, and suppressing hIAPP toxic aggregation and endoplasmic reticulum stress; and (3) other pathways with incompletely elucidated mechanisms that also contribute to islet protection. This article delineates these molecular mechanisms and highlights the limited ability of current agents to directly restore and protect β-cell function. It provides a theoretical basis for developing novel drugs that integrate glycemic control with islet restoration based on natural lead compounds, and offers a framework for further mechanistic studies. In addition, it encourages the exploration of unidentified active constituents and unique pathways, while also addressing challenges such as target identification and structure-activity relationships.