title: Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes.
abstract: Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug. Increased vanin activity was observed in plasma and liver of high fat diet (HFD)-induced obese mice, as well as ZDF-diabetic rats. Ablation of vanin-1 (Vnn1(-/-) mice) mildly improved glucose tolerance and insulin sensitivity in HFD-fed mice, but had no effects on body weight, hepatic steatosis or circulating lipid levels. Oral administration of RR6 for 8 days completely inhibited plasma vanin activity, but did not affect hepatic glucose production, insulin sensitivity or hepatic steatosis in ZDF-diabetes rats. In conclusion, absence of vanin-1 activity improves insulin sensitivity in HFD-fed animals, yet short-term inhibition of vanin activity may have limited value as an anti-diabetic strategy.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, 6525 GA Nijmegen, The Netherlands.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Jansen
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Dov B
authors.initials: DB
authors.lastname: Ballak
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.affiliation: Institute for Molecules and Materials, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands.
authors.forename: Floris P J T
authors.initials: FP
authors.lastname: Rutjes
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, 6525 GA Nijmegen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.|Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6703 HA, Wageningen, the Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000201:enzymology / Q000473:pathology; D017208:Rats, Wistar; D011924:Rats, Zucker
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D007328:Insulin; D008055:Lipids; D000581:Amidohydrolases; C000613246:Vnn1 protein, rat; C022314:pantetheinase