The effects of brain-derived neurotrophic factor on insulin signal transduction in the liver of diabetic mice

Aim/hypothesis. We previously reported that repeated subcutaneous or intracerebroventricular injection of brain-derived neurotrophic factor (BDNF) reduces blood glucose concentrations in obese diabetic C57BL/KsJ-db/db mice. In this study, we assessed the effects of BDNF on insulin action in peripheral tissues of diabetic mice. Methods. First, brain-derived neurotrophic factor (20 mg/kg) was subcutaneously given to male db/db mice for 14 days and then the insulin-stimulated tyrosine phosphorylation of insulin receptors and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in peripheral tissues was assessed. Second, we examined the effects of a single subcutaneous or intracerebroventricular brain-derived neurotrophic factor injection on insulin responsiveness in liver and skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Third, the effects of brain-derived neurothrophic factor on insulin action were also examined in cultured cells. Results. Repeated injection of BDNF to db/db mice for 14 days enhanced insulin-stimulated tyrosine phosphorylation of insulin receptors in liver and insulin-stimulated PI 3-kinase activity in liver, skeletal muscle and interscapular brown adipose tissue. We then examined the rapid effect of BDNF on insulin signalling in vivo. A single subcutaneous or intracerebroventricular injection of BDNF rapidly increased insulin-stimulated tyrosine phosphorylation of insulin receptors and PI 3-kinase activity in liver of STZ-mice. No direct effect of brain-derived neurothrophic factor was observed on insulin signalling in primary cultured hepatocytes, L6 muscle cells or 3T3-L1 adipocytes. Brain-derived neurothrophic factor did not affect either glucose uptake or gluconeogenesis in these cells. Conclusion/interpretation. These data indicate that brain-derived neurothrophic factor rapidly enhances insulin signal transduction in liver and shows hypoglycaemic action in diabetic mice. [Diabetologia (2001) 44: 555–566]

Authors and Affiliations

1. Sumitomo Pharmaceuticals, Osaka, Japan, , , , , , JP

   A. Tsuchida, T. Nakagawa, Y. Itakura, J. Ichihara, M. Taiji & H. Noguchi

2. The Second Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan, , , , , , JP

   W. Ogawa & M. Kasuga

Received: 10 July 2000 and in revised form: 28 December 2000

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