title: Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice.
abstract: Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM). Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of T2DM and complications, and that removal of the metabolic overload with dietary interventions may be more efficacious. We explored the efficacy and systems effects of pharmaceutical interventions versus dietary lifestyle intervention (DLI) in developing T2DM and complications. To mimic the situation in humans, high fat diet (HFD)-fed LDLr-/- mice with already established disease phenotype were treated with ten different drugs mixed into HFD or subjected to DLI (switch to low-fat chow), for 7 weeks. Interventions were compared to untreated reference mice kept on HFD or chow only. Although most of the drugs improved HFD-induced hyperglycemia, drugs only partially affected other risk factors and also had limited effect on disease progression towards microalbuminuria, hepatosteatosis and atherosclerosis. By contrast, DLI normalized T2DM risk factors, fully reversed hepatosteatosis and microalbuminuria, and tended to attenuate atherogenesis. The comprehensive beneficial effect of DLI was reflected by normalized metabolite profiles in plasma and liver. Analysis of disease pathways in liver confirmed reversion of the metabolic distortions with DLI. This study demonstrates that the pathogenesis of T2DM towards complications is reversible with DLI and highlights the differential effects of current pharmacotherapies and their limitation to resolve the disease.
authors: Microbiology and Systems Biology, TNO, Zeist, The Netherlands.
authors: Marijana
authors: M
authors: Radonjic
authors: Peter Y
authors: PY
authors: Wielinga
authors: Suzan
authors: S
authors: Wopereis
authors: Thomas
authors: T
authors: Kelder
authors: Varshna S
authors: VS
authors: Goelela
authors: Lars
authors: L
authors: Verschuren
authors: Karin
authors: K
authors: Toet
authors: Wim
authors: W
authors: van Duyvenvoorde
authors: Bianca
authors: B
authors: van der Werff van der Vat
authors: Johanna H M
authors: JH
authors: Stroeve
authors: Nicole
authors: N
authors: Cnubben
authors: Teake
authors: T
authors: Kooistra
authors: Ben
authors: B
authors: van Ommen
authors: Robert
authors: R
authors: Kleemann
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000178:diet therapy* / Q000188:drug therapy* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects; D017353:Gene Deletion; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008019:Life Style; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000235:genetics; D049490:Systems Biology
chemical_list: D007004:Hypoglycemic Agents; D020543:Proteome; D018110:Receptors, Lipoprotein