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ResearchIn-Press PreviewEndocrinologyMetabolism Open Access | 10.1172/JCI192011

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

Shenaz Khan,1 Robert J. Gaivin,1 Zhiyu Liu,1 Vincent Li,1 Ivy Samuels,2 Jinsook Son,3 Patrick Osei-Owusu,1 Jeffrey L. Garvin,1 Domenico Accili,3 and Jeffrey R. Schelling1

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Khan, S. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Gaivin, R. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Liu, Z. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Li, V. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Samuels, I. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Son, J. in: PubMed | Google Scholar |

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Osei-Owusu, P. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Garvin, J. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Accili, D. in: PubMed | Google Scholar

1Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, United States of America

2Louis Stokes Cleveland VA Medical Center, VA Northeast Ohio Healthcare System, Cleveland, United States of America

3Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, United States of America

Find articles by Schelling, J. in: PubMed | Google Scholar

Published September 16, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI192011.
Copyright © 2025, Khan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 16, 2025 - Version history
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Abstract

Type 2 diabetes affects more than 38 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. Basal glucagon and alanine-stimulated gluconeogenesis were reduced in FATP2KO db/db compared to db/db mice. Direct evidence of FATP2KO-induced α-cell-mediated glucagon-like peptide-1 (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 ß-cell insulin release.

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  • Version 1 (September 16, 2025): In-Press Preview
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