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[Preprint]. 2025 Feb 6:2025.01.31.635976.
doi: 10.1101/2025.01.31.635976.

Fatty Acid Transport Protein-2 (FATP2) Inhibition Enhances Glucose Tolerance through α-Cell-mediated GLP-1 Secretion

Fatty Acid Transport Protein-2 (FATP2) Inhibition Enhances Glucose Tolerance through α-Cell-mediated GLP-1 Secretion

Shenaz Khan et al. bioRxiv. .

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Abstract

Type 2 diabetes affects more than 30 million people in the US, 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 α-cell FATP2 was functional. Direct evidence of FATP2KO-induced α-cell-mediated GLP-1 secretion included increased GLP-1-positive α-cell mass in FATP2KO 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 FATP2KO mice following oral versus intraperitoneal glucose loading, non-overlapping FATP2 and preproglucagon mRNA expression, and lack of FATP2/GLP-1 co-immunolocalization in intestine. We conclude that FATP2 deletion or inhibition exerts glucose-lowering effects through α-cell-mediated GLP-1 secretion and paracrine β-cell insulin release.

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