Fatty acid transport protein 2 inhibition enhances glucose tolerance through α cell-mediated GLP-1 secretion.

Type 2 diabetes affects more than 38 million people in the United States, and a major complication is kidney disease. During the analysis of lipotoxicity in diabetic kidney disease, global fatty acid transport protein 2 (FATP2) gene deletion was noted to markedly reduce plasma glucose in db/db mice due to sustained insulin secretion. To identify the mechanism, we observed that islet FATP2 expression was restricted to α cells and that α cell FATP2 was functional. Basal glucagon and alanine-stimulated gluconeogenesis were reduced in FATP2-KO db/db mice compared with db/db mice. Direct evidence of FATP2-KO-induced α cell-mediated glucagon-like peptide 1 (GLP-1) secretion included increased GLP-1+ α cell mass in FATP2-KO db/db mice, small-molecule FATP2 inhibitor enhancement of GLP-1 secretion in αTC1-6 cells and human islets, and exendin[9-39]-inhibitable insulin secretion in FATP2 inhibitor-treated human islets. FATP2-dependent enteroendocrine GLP-1 secretion was excluded by demonstration of similar glucose tolerance and plasma GLP-1 concentrations in db/db FATP2-KO mice following oral versus i.p. glucose loading, nonoverlapping FATP2 and preproglucagon mRNA expression, and lack of FATP2 and GLP-1 coimmunolocalization in the intestines. We conclude that FATP2 deletion or inhibition exerts glucose-lowering effects through α cell-mediated GLP-1 secretion and paracrine β cell insulin release.