SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control
Authors: David Roberts
Luke A Selth
Jacqueline Bayliss
Gregory R Steinberg
Ralf B Schittenhelm
Trevor J Biden
Andrew Ryan
Dorit Samocha-Bonet
Matthew J Watt
Ayenachew Bezawork-Geleta
Camille Devereux
Ruth C R Meex
Scott L Townley
Magdalene K Montgomery
Cheng Huang
Journal: Science Translational Medicine (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Intertissue communication; liver; SMOC1; glucose homeostasis; insulin sensitivity
Affiliations: Department of Physiology, University of Melbourne, Melbourne, VIC 3010, Australia., Department of Physiology, Monash University, Melbourne, VIC 3800, Australia., Proteomics and Metabolomics Facility, Monash University, Melbourne, VIC 3800, Australia., TissuPath, Mount Waverley, VIC 3149, Australia., Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, University of Adelaide, SA 5005, Australia., Flinders Centre for Innovation in Cancer and Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia., Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia., Division of Endocrinology and Metabolism, Department of Medicine, the Department of Biochemistry and Biomedical Sciences and the Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON L8S 4L8, Canada., St. Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2052, Australia., Department of Human Biology, Maastricht University Medical Centre, Maastricht 6229, Netherlands., Department of Physiology, University of Melbourne, Melbourne, VIC 3010, Australia. .

Abstract:  Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes. 

Retracted: No

PubPeer comments:
 Considering the clamps were done on lean mice, the controls were unusually insulin resistant in their ability to suppress EGP. Normally EGP is suppressed by around 80-90% in lean mice when insulin is infused at the rate used here (4 mU kg min). But it was only suppressed by around 40% which is similar to what is seen in fat-fed mice. Just a thought but perhaps the SMOC treated mice are actually normal and there is an issue with the controls which is driving the effect? ![file] , 
 Could the authors give the exact data for this panel (Fig. 1L, I believe)? The p-value must be desperately close to 0.05, maybe even greater. , 
 Agree with #1 about the clamp data. Also, why havenu2019t the basal EGP data been presented along with the real time glucose and GIR curves? This is just good practice when reporting clamp data. Otherwise how can we tell if it really was a clamp? ,