The insulin receptor family in the heart: new light on old insights

Abstract

Insulin was discovered over 100 years ago. Whilst the first half century defined many of the physiological effects of insulin, the second emphasised the mechanisms by which it elicits these effects, implicating a vast array of G proteins and their regulators, lipid and protein kinases and counteracting phosphatases, and more. Potential growth-promoting and protective effects of insulin on the heart emerged from studies of carbohydrate metabolism in the 1960s, but the insulin receptor (and the related receptor for insulin-like growth factors 1 and 2) were not defined until the 1980s. A related third receptor, the insulin receptor-related receptor (INSRR) remained an orphan receptor for many years until it was identified as an alkali-sensor. The mechanisms by which these receptors and the plethora of downstream signalling molecules confer cardioprotection remain elusive. Here, we review important aspects of the effects of the three insulin receptor family members in the heart. Metabolic studies are set in the context of what is now known of insulin receptor family signalling and the role of protein kinase B (PKB, or Akt), and the relationship between this and cardiomyocyte survival versus death is discussed. PKB/Akt phosphorylates numerous substrates with potential for cardioprotection in the contractile cardiomyocytes and cardiac non-myocytes. Our overall conclusion is that the effects of insulin on glucose metabolism that were initially identified remain highly pertinent in managing cardiomyocyte energetics and preservation of function. This alone provides a high level of cardioprotection in the face of pathophysiological stressors such as ischaemia and myocardial infarction.

Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy

“… 44 Classically, phosphoinositide 3-kinase alpha engagement occurs after insulin receptor and\or insulin like growth factor receptor stimulation. 45 It is known that insulin receptor stimulation is cardioprotective likely mediated to a large extent via a phosphoinositide 3-kinase alpha and the consequent metabolic adaptations. 45 Phosphoinositide 3-kinase alpha is known to be important in determining cardiomyocyte size and in maintaining contractility through downstream actions on akt protein kinase.…”

“… 45 It is known that insulin receptor stimulation is cardioprotective likely mediated to a large extent via a phosphoinositide 3-kinase alpha and the consequent metabolic adaptations. 45 Phosphoinositide 3-kinase alpha is known to be important in determining cardiomyocyte size and in maintaining contractility through downstream actions on akt protein kinase. 46 Furthermore, direct activation of phosphoinositide 3-kinase alpha is known to be protective in heart disease.…”