October 1, 2009Open Access

Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction

Q: What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Type 2 diabetes and left-ventricular dysfunction (n=63). Intervention: Type 2 diabetes and left-ventricular dysfunction vs. Patients with normal ventricular function without diabetes. Primary outcome: Myocardial IRS1-PI3K activity and sarcolemmal GLUT4 expression.

Key Result

Patients with type 2 diabetes and left-ventricular dysfunction both exhibited increased myocardial IRS1-PI3K activity, but sarcolemmal GLUT4 was reduced in diabetes and increased in left-ventricular dysfunction.

Study Design

Type

Cross-Sectional (n=63)

PICO

Population

63 patients aged 35-75 years awaiting routine cardiac surgery, categorized into controls, those with type 2 diabetes, and those with left-ventricular dysfunction, who underwent myocardial biopsy.

Exposure / Comparator

Type 2 diabetes and left-ventricular dysfunction vs Patients with normal ventricular function without diabetes

Primary Outcome

Myocardial IRS1-PI3K activity and sarcolemmal GLUT4 expression

Limitations

In vivo glucose utilization measurements were compared with ex vivo molecular analysis on surgical samples.
Control subjects were affected by cardiovascular disease, an unavoidable limitation in human heart studies.
The ob/ob mouse model exhibits an extreme body habitus phenotype that may not perfectly mimic all aspects of human disease.

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.

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Cite This Study

Cook et al. (Thu,) conducted a cross-sectional in Type 2 diabetes and left-ventricular dysfunction (n=63). Type 2 diabetes and left-ventricular dysfunction vs. Patients with normal ventricular function without diabetes was evaluated on Myocardial IRS1-PI3K activity and sarcolemmal GLUT4 expression. Patients with type 2 diabetes and left-ventricular dysfunction both exhibited increased myocardial IRS1-PI3K activity, but sarcolemmal GLUT4 was reduced in diabetes and increased in left-ventricular dysfunction.

synapsesocial.com/papers/6a1fff697110a651dc04d39c https://doi.org/https://doi.org/10.1093/eurheartj/ehp396