IC7, a designer cytokine, improves glucose tolerance in an insulin dependent manner in high fat fed mice and non human primates — ASN Events
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IC7, a designer cytokine, improves glucose tolerance in an insulin dependent manner in high fat fed mice and non human primates (#193)

Tamara L Allen 1 , Maria Findeisen 1 , Helene Kammoun 1 , Darren C Henstridge 1 , Guy Krippner 1 , Tim Adams 2 , Stefan Rose-John 3 , Mark A Febbraio 4
  1. BakerIDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. CSIRO, Materials Science & Engineering, Parkville, Victoria, Australia
  3. Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
  4. Garvan Institute, Sydney, New South Wales, Australia

We have previously shown that the gp130 cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) can improve obesity and insulin resistance in both mice and humans1,2, but neither cytokine has clinical utility3.  As a result we have generated a novel protein (IC7), an IL-6:CNTF chimera designed to retain the positive metabolic effects of both proteins, whilst avoiding the adverse effects.  Previous findings have demonstrated that treatment of high fat fed (HFF) mice with IC7 daily for 7 d reduces total weight and fat mass, food intake, fasting blood glucose (BG) and hepatic lipid and glycogen levels. A single injection of IC7 significantly reduced BG in chow and HFF mice, reaching significance at 90 min after injection and maintaining this reduction for 12 h.  Liver glycogen also decreased by 30 min in HFF IC7 treated mice with a concomitant increase in circulating glucagon. By 2 hours, both glucagon and insulin were significantly elevated. To investigate if insulin was required for the BG lowering effects of IC7, HFF and STZ diabetic mice were treated daily with 1 mg/kg IC7 for 2 days and their BG levels closely monitored.  IC7 was ineffective at reducing blood BG levels in diabetic mice but as expected was effective at reducing BG levels in HFF mice, clearly illustrating this reduction in BG was insulin dependent. To further investigate the therapeutic utility of IC7, long tail macaques were injected with IC7 0.3 mg/kg 30 minutes before an intravenous glucose tolerance test (IVGTT).  IC7 treatment significantly improved glucose clearance during the IVGTT, with no evidence of changes to immune cell populations or elevation in CRP.  These findings further support the ongoing investigation of IC7 for the treatment of high fat diet-induced glucose intolerance and hepatic steatosis in individuals with at least partial pancreatic function.

  1. Carey, A.L., et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688-2697 (2006).
  2. Watt, M.J., et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12, 541-548 (2006).
  3. Febbraio, M.A. gp130 receptor ligands as potential therapeutic targets for obesity. J Clin Invest 117, 841-849 (2007).