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

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• Type 2 diabetes affects over 30 million Americans, with diabetic kidney disease as a major complication.
• Lipotoxicity plays a role in diabetic kidney disease pathogenesis.
• Fatty acid transport protein-2 (FATP2) was investigated for its role in glucose metabolism.

Purpose of the Study:

• To elucidate the mechanism by which FATP2 gene deletion reduces plasma glucose in diabetic mice.
• To determine if FATP2 influences insulin secretion and GLP-1 release.

Main Methods:

• Utilized db/db mouse models with global FATP2 gene deletion (FATP2KO).
• Assessed islet FATP2 expression and localization in α-cells.
• Investigated GLP-1 secretion using FATP2 inhibitors in cell lines and human islets.
• Performed glucose tolerance tests and measured plasma GLP-1 levels after oral and intraperitoneal glucose loading.

Main Results:

• FATP2 gene deletion markedly reduced plasma glucose in db/db mice, linked to sustained insulin secretion.
• FATP2 expression was found exclusively in pancreatic α-cells and was functional.
• FATP2 deletion or inhibition increased GLP-1 secretion from α-cells, leading to paracrine insulin release from β-cells.
• Enteroendocrine GLP-1 secretion was ruled out as the mechanism.

Conclusions:

• FATP2 deletion or inhibition lowers blood glucose levels.
• The glucose-lowering effect is mediated by enhanced GLP-1 secretion from α-cells.
• This leads to increased insulin release from β-cells via a paracrine mechanism.