Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction
- PMID: 19797329
- PMCID: PMC2800920
- DOI: 10.1093/eurheartj/ehp396
Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction
Abstract
Aims: Whole body and myocardial insulin resistance are features of non-insulin-dependent diabetes mellitus (NIDDM) and left-ventricular dysfunction (LVD). We determined whether abnormalities of insulin receptor substrate-1 (IRS1), IRS1-associated PI3K (IRS1-PI3K), and glucose transporter 4 (GLUT4) contribute to tissue-specific insulin resistance.
Methods and results: We collected skeletal muscle (n = 27) and myocardial biopsies (n = 24) from control patients (n = 7), patients with NIDDM (n = 9) and patients with LVD (n = 8), who were characterized by euglycaemic-hyperinsulinaemic clamp and positron emission tomography. Comparative studies were carried out in three mouse models. We demonstrate an unrecognized reduction of IRS1 in skeletal muscle of LVD patients and an unexpected increase in cardiac IRS1-PI3K activity in NIDDM and LVD patients. In NIDDM, there was a concomitant reduction in sarcolemmal GLUT4, whereas in patients with LVD sarcolemmal GLUT4 was increased. We confirm activation of IRS1-PI3K and reduction in sarcolemmal GLUT4 in the insulin resistant ob/ob mouse heart where we also demonstrate perturbation of GLUT4 docking and fusion. A direct relationship between PI3K and GLUT4 was demonstrated in mice expressing activated PI3K in the heart and increased GLUT4 at the sarcolemma was confirmed in a mouse model of LVD.
Conclusion: Our data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39601.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39602.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39603.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39604.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39605.gif)
![Figure 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39606.gif)
![Figure 7](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39607.gif)
![Figure 8](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39608.gif)
![Figure 9](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2800920/bin/ehp39609.gif)
Similar articles
-
Panax notoginseng saponins alleviate skeletal muscle insulin resistance by regulating the IRS1-PI3K-AKT signaling pathway and GLUT4 expression.FEBS Open Bio. 2019 May;9(5):1008-1019. doi: 10.1002/2211-5463.12635. Epub 2019 Apr 26. FEBS Open Bio. 2019. PMID: 30945455 Free PMC article.
-
Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.Dan Med J. 2014 Jul;61(7):B4890. Dan Med J. 2014. PMID: 25123125 Review.
-
Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng.J Endocrinol. 2009 Oct;203(1):65-74. doi: 10.1677/JOE-09-0026. Epub 2009 Jul 8. J Endocrinol. 2009. PMID: 19587264 Free PMC article.
-
Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes.Diabetologia. 2006 Dec;49(12):2983-92. doi: 10.1007/s00125-006-0457-3. Epub 2006 Sep 26. Diabetologia. 2006. PMID: 17019595
-
Lilly lecture 1995. Glucose transport: pivotal step in insulin action.Diabetes. 1996 Nov;45(11):1644-54. doi: 10.2337/diab.45.11.1644. Diabetes. 1996. PMID: 8866574 Review.
Cited by
-
Ferroptosis: A New Mechanism in Diabetic Cardiomyopathy.Int J Med Sci. 2024 Jan 21;21(4):612-622. doi: 10.7150/ijms.88476. eCollection 2024. Int J Med Sci. 2024. PMID: 38464828 Free PMC article. Review.
-
Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine.J Cardiothorac Surg. 2024 Feb 16;19(1):99. doi: 10.1186/s13019-024-02543-y. J Cardiothorac Surg. 2024. PMID: 38365663 Free PMC article.
-
Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis.iScience. 2024 Jan 17;27(2):108927. doi: 10.1016/j.isci.2024.108927. eCollection 2024 Feb 16. iScience. 2024. PMID: 38327776 Free PMC article.
-
A comprehensive review of the novel therapeutic targets for the treatment of diabetic cardiomyopathy.Ther Adv Cardiovasc Dis. 2023 Jan-Dec;17:17539447231210170. doi: 10.1177/17539447231210170. Ther Adv Cardiovasc Dis. 2023. PMID: 38069578 Free PMC article. Review.
-
Molecular Processes Involved in the Shared Pathways between Cardiovascular Diseases and Diabetes.Biomedicines. 2023 Sep 23;11(10):2611. doi: 10.3390/biomedicines11102611. Biomedicines. 2023. PMID: 37892985 Free PMC article. Review.
References
-
- Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607. - PubMed
-
- Doehner W, Rauchhaus M, Ponikowski P, Godsland IF, von Haehling S, Okonko DO, Leyva F, Proudler AJ, Coats AJ, Anker SD. Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure. J Am Coll Cardiol. 2005;46:1019–1026. - PubMed
-
- Ingelsson E, Sundstrom J, Arnlov J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA. 2005;294:334–341. - PubMed
-
- Bjornholm M, Kawano Y, Lehtihet M, Zierath JR. Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes. 1997;46:524–527. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous