Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Acute administration the IL-6-CNTF chimera IC7 improves glucose tolerance via suppression of hepatic gluconeogenesis (#20)

Tamara L Allen 1 , Helene Kammoun 1 , Darren Henstridge 1 , Sandra Barre 1 , Guy Krippner 1 , Tim Adams 2 , Lindsey Sparrow 2 , Judy Scoble 2 , Stefan Rose-John 3 , Mark Febbraio 1
  1. BakerIDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. CSIRO, Materials Science & Engineering, Parkville, Victoria, Australia
  3. Department of Biochemistry, Christian-Albrechts-Universit├Ąt zu Kiel, Kiel, Germany

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 peptide (IC7), an IL-6:CNTF chimera designed to retain the positive metabolic effects of both proteins, whilst avoiding the adverse effects. In a previous communication to this society (Allen et al. ADS Scientific Meeting 2013, unpublished) we demonstrated that treatment of mice with IC7 daily for 7 d reduces total weight and fat mass, food intake and fasting blood glucose. Glucose tolerance is improved along with decreased hepatic lipid deposition and glycogen storage. The present study aimed to investigate the acute effects of IC7 treatment in chow and high fat fed (HFF) mice. A single injection of IC7 significantly reduced blood glucose 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. This reduction in liver glycogen was seen at a time point when blood glucose levels were unchanged from vehicle, indicating a drop in blood glucose is not the cause for glycogen breakdown. Phosphorylation and activation of glycogen phosphorylase in the liver was increased by IC7 indicating a direct activation on the glycogen breakdown pathway. Administration of IC7 30 min prior to an oral glucose tolerance test led to an improvement. Similarly, administration 30 min prior to a pyruvate tolerance test also showed improvement, suggesting IC7 may reduce hepatic gluconeogenesis. These data show IC7 has robust acute effects in lowering blood glucose after administration and improved glucose tolerance after an oral bolus of glucose in both chow and HFF mice. These effects are due in part to reduced hepatic glucose production.

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  3. Febbraio, M.A. gp130 receptor ligands as potential therapeutic targets for obesity. J Clin Invest 117, 841-849 (2007).