Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis

Zewen Jiang1, Meng Zhao1, Laetitia Voilquin1, Yunshin Jung1, Mari A Aikio2, Tanushi Sahai1, Florence Y Dou2, Alexander M Roche2, Ivan Carcamo-Orive3, Joshua W Knowles4, Martin Wabitsch5, Eric A Appel6, Caitlin L Maikawa7, Joao Paulo Camporez8, Gerald I Shulman9, Linus Tsai10, Evan D Rosen10, Christopher D Gardner11, Bruce M Spiegelman2, Katrin J Svensson12

  1. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
  2. Department of Cell Biology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  3. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  4. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Prevention Research Center, Stanford University, Stanford, CA 94305, USA.
  5. Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany.
  6. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Materials Science & Engineering, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics (Endocrinology), Stanford University, Stanford, CA 94305, USA.
  7. Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  8. Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo, Brazil; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
  9. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06519, USA.
  10. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  11. Stanford University, Stanford, CA 94305, USA.
  12. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: katrinjs@stanford.edu.

Abstract

With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.

Presented By Meng Zhao

MetabolismNicholas Liao2021-09 (Sep)