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Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARgamma and c-Jun.
Diabetologia. 2005 Nov; 48(11):2412-21.D

Abstract

AIMS/HYPOTHESIS

Insulin resistance is concomitant with metabolic syndrome, oxidative stress and cardiac contractile dysfunction. However, the causal relationship between oxidative stress and cardiac dysfunction is unknown. This study was designed to determine the impact of overexpression of the cardiac antioxidant metallothionein on cardiac dysfunction induced by insulin resistance in mice.

METHODS

Whole-body insulin resistance was generated in wild-type FVB and metallothionein transgenic mice by feeding them with sucrose for 12 weeks. Contractile and intracellular Ca(2+) properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analysed included: peak shortening (PS), time to 90% PS (TPS(90)), time to 90% relengthening (TR(90)), half-width duration, maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), fura-fluorescence intensity change (DeltaFFI) and decay rate (tau).

RESULTS

The sucrose-fed mice displayed glucose intolerance, enhanced oxidative stress, hyperinsulinaemia, hypertriglyceridaemia and normal body weight. Compared with myocytes in starch-fed mice, those from sucrose-fed mice exhibited depressed PS, +dL/dt, -dL/dt, prolonged TR(90) and decay rate, and reduced DeltaFFI associated with normal TPS(90) and half-width duration. Western blot analysis revealed enhanced basal, but blunted insulin (15 mU/g)-stimulated Akt phosphorylation. It also showed elevated expression of insulin receptor beta, insulin receptor tyrosine phosphorylation, peroxisome proliferator-activated receptor gamma, protein tyrosine phosphatase 1B and phosphorylation of the transcription factor c-Jun, associated with a reduced fold increase of insulin-stimulated insulin receptor tyrosine phosphorylation in sucrose-fed mice. All western blot findings may be attenuated or ablated by metallothionein.

CONCLUSIONS/INTERPRETATION

These data indicate that oxidative stress may play an important role in cardiac contractile dysfunction associated with glucose intolerance and possibly related to alteration in insulin signalling at the receptor and post-receptor levels.

Authors+Show Affiliations

Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071-3375, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16172869

Citation

Fang, C X., et al. "Metallothionein Alleviates Cardiac Contractile Dysfunction Induced By Insulin Resistance: Role of Akt Phosphorylation, PTB1B, PPARgamma and C-Jun." Diabetologia, vol. 48, no. 11, 2005, pp. 2412-21.
Fang CX, Dong F, Ren BH, et al. Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARgamma and c-Jun. Diabetologia. 2005;48(11):2412-21.
Fang, C. X., Dong, F., Ren, B. H., Epstein, P. N., & Ren, J. (2005). Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARgamma and c-Jun. Diabetologia, 48(11), 2412-21.
Fang CX, et al. Metallothionein Alleviates Cardiac Contractile Dysfunction Induced By Insulin Resistance: Role of Akt Phosphorylation, PTB1B, PPARgamma and C-Jun. Diabetologia. 2005;48(11):2412-21. PubMed PMID: 16172869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance: role of Akt phosphorylation, PTB1B, PPARgamma and c-Jun. AU - Fang,C X, AU - Dong,F, AU - Ren,B H, AU - Epstein,P N, AU - Ren,J, Y1 - 2005/09/20/ PY - 2005/01/05/received PY - 2005/06/17/accepted PY - 2005/9/21/pubmed PY - 2006/1/27/medline PY - 2005/9/21/entrez SP - 2412 EP - 21 JF - Diabetologia JO - Diabetologia VL - 48 IS - 11 N2 - AIMS/HYPOTHESIS: Insulin resistance is concomitant with metabolic syndrome, oxidative stress and cardiac contractile dysfunction. However, the causal relationship between oxidative stress and cardiac dysfunction is unknown. This study was designed to determine the impact of overexpression of the cardiac antioxidant metallothionein on cardiac dysfunction induced by insulin resistance in mice. METHODS: Whole-body insulin resistance was generated in wild-type FVB and metallothionein transgenic mice by feeding them with sucrose for 12 weeks. Contractile and intracellular Ca(2+) properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analysed included: peak shortening (PS), time to 90% PS (TPS(90)), time to 90% relengthening (TR(90)), half-width duration, maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), fura-fluorescence intensity change (DeltaFFI) and decay rate (tau). RESULTS: The sucrose-fed mice displayed glucose intolerance, enhanced oxidative stress, hyperinsulinaemia, hypertriglyceridaemia and normal body weight. Compared with myocytes in starch-fed mice, those from sucrose-fed mice exhibited depressed PS, +dL/dt, -dL/dt, prolonged TR(90) and decay rate, and reduced DeltaFFI associated with normal TPS(90) and half-width duration. Western blot analysis revealed enhanced basal, but blunted insulin (15 mU/g)-stimulated Akt phosphorylation. It also showed elevated expression of insulin receptor beta, insulin receptor tyrosine phosphorylation, peroxisome proliferator-activated receptor gamma, protein tyrosine phosphatase 1B and phosphorylation of the transcription factor c-Jun, associated with a reduced fold increase of insulin-stimulated insulin receptor tyrosine phosphorylation in sucrose-fed mice. All western blot findings may be attenuated or ablated by metallothionein. CONCLUSIONS/INTERPRETATION: These data indicate that oxidative stress may play an important role in cardiac contractile dysfunction associated with glucose intolerance and possibly related to alteration in insulin signalling at the receptor and post-receptor levels. SN - 0012-186X UR - https://www.unboundmedicine.com/medline/citation/16172869/Metallothionein_alleviates_cardiac_contractile_dysfunction_induced_by_insulin_resistance:_role_of_Akt_phosphorylation_PTB1B_PPARgamma_and_c_Jun_ L2 - https://doi.org/10.1007/s00125-005-1940-y DB - PRIME DP - Unbound Medicine ER -