Lipid droplet dynamics in type 2 diabetes and its complications: pathophysiological insights and therapeutic options

Patients with type 2 diabetes mellitus (T2DM) often exhibit dysregulated lipid metabolism, which contributes to the development and progression of complications, such as cardiomyopathy and nephropathy. Lipid droplet (LD) dynamics involve several processes, such as synthesis, lipolysis, and lipophagy. They also interact with organelles, such as the endoplasmic reticulum, mitochondria, and Golgi apparatus. These dynamic behaviors are essential for the maintenance of cellular energy homeostasis. Under physiological conditions, LDs in pancreatic β-cells are involved in lipid metabolism that regulates insulin secretion, while also isolating harmful lipids to protect β-cells from damage due to nutrient excess. In the adipose tissue, LDs respond to nutrient fluctuations by modulating lipolysis and releasing free fatty acids (FFAs) and glycerol. Glycerol can enter the liver for gluconeogenesis and changes in FFA levels affect systemic insulin sensitivity, thereby influencing glucose uptake by skeletal muscles and contributing to whole-body glucose homeostasis. Under pathological conditions, abnormal LD accumulation can lead to ectopic lipid deposition and lipotoxicity, exacerbating T2DM and its complications in target organs, such as the heart, kidneys, retina, and brain. Lifestyle interventions, such as diet and exercise, influence LD homeostasis in tissues affected by T2DM. Pharmacological agents, including certain antidiabetic and lipid-lowering drugs as well as bioactive natural products, have demonstrated tissue-specific regulatory effects on LD dynamics. Emerging therapeutic strategies targeting LDs, such as photodynamic therapy, gene editing, and gut microbiota modulation, are also being investigated. In summary, a deeper understanding of the physiological and pathological roles of LDs in different organs may offer targeted and integrated treatment options for T2DM and its associated complications.