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Straub, L.G.* ; Efthymiou, V.* ; Grandl, G. ; Balaz, M.* ; Challa, T.D.* ; Truscello, L.* ; Horvath, C.* ; Moser, C.* ; Rachamin, Y.* ; Arnold, M.* ; Sun, W.* ; Modica, S.* ; Wolfrum, C.*

Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity.

Diabetologia 62, 2094-2105 (2019)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Aims/hypothesis In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy. Methods We studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant's effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism. Results Acute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia. Conclusions/interpretation We conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acetovanillone ; Adipocyte ; Adipocyte Quantification ; Adipocyte-specific ; Adipose Tissue ; Antioxidants ; Apocynin ; Creert2 ; Diet-induced Obesity ; Fat ; Hyperglycaemia ; Hyperinsulinaemic-euglycaemic Clamp ; Hyperphagia ; Ifirko ; Insulin Receptor ; Insulin Resistance ; Leptin Deficiency ; Lipolysis ; N-acetylcysteine ; Ob ; Ob ; Obesity Resistance ; Polydipsia Obesity ; Tamoxifen ; Type 2 Diabetes; Metabolic Syndrome; Oxidative Stress; Leptin; Fat; Steatohepatitis; Lipotoxicity; Glutathione; Activation; Apocynin; Health
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Zeitschrift Diabetologia
Quellenangaben Band: 62, Heft: 11, Seiten: 2094-2105 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Berlin ; Heidelberg [u.a.]
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)