FATP2 at the crossroads of fatty acid transport, lipotoxicity, and complex disease

Type 2 diabetes mellitus affects over 38 million Americans, with diabetic kidney disease as a major complication partly driven by lipotoxicity. Fatty acid transport protein 2 (FATP2) regulates uptake and activation of long-chain fatty acids, making it a therapeutic target in metabolic disease. In this issue of the JCI, Khan et al. investigated FATP2 in glycemic control. In db/db mice, global FATP2 deletion reduced plasma glucose via sustained insulin secretion, with expression restricted to pancreatic α cells. FATP2-deficient db/db mice also showed suppressed glucagon and reduced alanine-stimulated gluconeogenesis, implicating α cell FATP2 in systemic glucose regulation. The FATP2-specific inhibitor lipofermata enhanced α cell-derived glucagon-like peptide 1 (GLP-1) secretion, expanded GLP-1-positive α cell mass, and promoted paracrine insulin release - effects reversed by GLP-1 receptor antagonism. These findings identify FATP2 as a key regulator linking lipid handling to α cell hormone secretion and glucose control, positioning its inhibition as a potential complement to incretin-based therapies.