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ResearchIn-Press PreviewEndocrinologyMetabolism Open Access | 10.1172/JCI202344

Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis

Simran Singh,1 Ashish Kumar,1 Sudipta Paul,1 Mriganka Sarkar,1 Santhosh Duraisamy,2 Ganesh Timalsina,1 Raashidha Farhath,1 Harender Yadav,1 Seema Kuldeep,1 Soumita Bhaumik,1 Kunj Kumar Prajapati,1 Saahiba Thaleshwari,1 Anuj Gargya,1 Tamojit Santra,3 Sonal Amit,4 Rashmi Parihar,5 Santosh K. Misra,3 Hamim Zafar,3 Luiz F. Barella,6 Michael A. Kalwat,7 Dharmaraja Allimuthu,2 and Sai Prasad Pydi1

1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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1Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India

2Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

3Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India

4Autonomous State Medical College, Kanpur, India

5Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India

6Penguin Bio Corp., New York, United States of America

7Indiana Biosciences Research Institute, Indianapolis, United States of America

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Published September 15, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202344.
Copyright © 2026, Singh 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 15, 2026 - Version history
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Abstract

Obesity-associated inflammation impairs pancreatic β-cell function, yet the mechanisms by which immune cells acutely regulate insulin secretion remain poorly defined. Here, we identify myeloid Gq signaling as an immunometabolic node linking macrophage lipid sensing to impaired insulin secretion. Using chemogenetic DREADD-mediated activation of myeloid Gq, we show that acute macrophage Gq activation impairs glucose-stimulated insulin secretion (GSIS) in vivo, whereas myeloid Gαq ablation enhances GSIS. Mechanistically, Gq activation rapidly induced AMPK phosphorylation and sphingolipid remodeling independently of canonical inflammatory cytokines. Macrophage-derived sphingolipids impaired β-cell insulin signaling and GSIS through CD36-PKCζ, while inhibition of CD36, AMPK, or sphingolipid metabolism restored β-cell function. We further identified GPR18, a Gq-coupled endocannabinoid-responsive GPCR, as an upstream regulator. GPR18 activation with N-arachidonoyl glycine (NAGly) recapitulated this phenotype, whereas myeloid Gαq deletion or Gpr18/AMPK silencing abolished it. GPR18 signaling predominantly engaged Gq rather than Gi pathways. In human tissues, GPR18 was enriched in islet macrophages, and NAGly suppressed GSIS in primary human islets. Thus, a conserved macrophage GPR18-Gαq-AMPK-sphingolipid axis dynamically regulates β-cell function and represents a potential therapeutic target in obesity and type 2 diabetes.

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