Victoria Svop Jensen1,2, Christian Fledelius3, Christina Zachodnik3, Jesper Damgaard3, Helle Nygaard3, Kristina Steinicke Tornqvist3, Rikke Kaae Kirk4, Birgitte Martine Viuff4, Erik Max Wulff5, Jens Lykkesfeldt6, Henning Hvid4. 1. Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. victoriasvop@gmail.com. 2. Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark. victoriasvop@gmail.com. 3. Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark. 4. Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark. 5. Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark. 6. Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark.
Abstract
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabetic patients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia. METHODS:Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or human insulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps. RESULTS:NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group. CONCLUSIONS: These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.
RCT Entities:
BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabeticpatients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia. METHODS: Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or humaninsulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps. RESULTS:NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group. CONCLUSIONS: These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.
Authors: H Shimano; N Yahagi; M Amemiya-Kudo; A H Hasty; J Osuga; Y Tamura; F Shionoiri; Y Iizuka; K Ohashi; K Harada; T Gotoda; S Ishibashi; N Yamada Journal: J Biol Chem Date: 1999-12-10 Impact factor: 5.157
Authors: April D Lake; Petr Novak; Craig D Fisher; Jonathan P Jackson; Rhiannon N Hardwick; D Dean Billheimer; Walter T Klimecki; Nathan J Cherrington Journal: Drug Metab Dispos Date: 2011-07-07 Impact factor: 3.922