Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

SMOC1 – A new therapeutic target for glycaemic control? (#10)

Magdalene K Montgomery 1 , Ruth Meex 1 , Cheng Huang 2 , Ralf B Schittenhelm 2 , Matthew J Watt 1
  1. Department of Physiology, Monash University, Clayton, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

Introduction: Current medications for the treatment of type 2 diabetes (T2D) have side effects or are not effective in all patients, necessitating the development of new medications. We have recently identified the protein ‘secreted modular calcium-binding protein 1’ (SMOC1) as a liver-secreted factor whose secretion is increased in non-alcoholic fatty liver disease and is responsive to glucose and insulin, suggesting a role in glycemic control.

Objective: This study aimed to further investigate the role of SMOC1 in glucose metabolism and its potential as a therapeutic for T2D.

Methods: Lean, obese insulin-resistant C57BL/6 mice and diabetic db/db mice were injected with SMOC1 recombinant protein (2 mg/kg) either acutely (2h before metabolic assessment) or chronically (daily injections for 14d). Additionally, we used adeno-associated virus (AAV) to overexpress SMOC1 in livers of db/db mice with the view to achieving a stable increase in circulating SMOC1. Metabolic outcome measures included oral glucose tolerance, insulin sensitivity (insulin tolerance test and euglycemic hyperinsulinemic clamps) and liver function. Phosphoproteomics and targeted cell signalling analysis were carried out to gain mechanistic insights into the function of SMOC1 in the liver.

Results: Acute injection of SMOC1 substantially improved glucose tolerance in all three mouse models. AAV-induced hepatic overexpression increased liver and plasma SMOC1, and improved glucose tolerance and insulin sensitivity. Clamp studies as well as glucose tolerance testing using [6,6-2H]glucose indicated that the improvements in glycemic control were predominantly due to SMOC1 effects on hepatic glucose output. Phosphoproteomic analysis of SMOC1-mediated signalling in HepG2 hepatocytes as well as targeted functional analysis suggested that SMOC1 decreases glucose output by increasing glycolytic flux acutely and inhibiting gluconeogenesis via a AMPK-HNF4a-Foxo mediated pathway.

Conclusion: We have uncovered a striking and previously unknown role for SMOC1 in the regulation of glucose metabolism and are investigating SMOC1 as a possible novel therapeutic for T2D.