Elsevier

Biochemical Pharmacology

Volume 93, Issue 4, 15 February 2015, Pages 409-417
Biochemical Pharmacology

Research update
The insulin-like growth factor I system: Physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome

https://doi.org/10.1016/j.bcp.2014.12.006Get rights and content

Abstract

Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca2+ handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF-1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1-associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed.

Section snippets

Metabolic syndrome and cardiovascular health

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Epidemiological study has projected up to 23.3 million mortality in 2030 due to cardiovascular diseases because of the aging populations [1], [2]. Despite the intensive management for cardiovascular diseases, many patients fail to achieve a satisfactory clinical outcome of managements and interventions against cardiovascular diseases. This may be attributed to, in part, the ever-rising prevalence of obesity and

Insulin-like growth factor 1 (IGF-1)

IGF-1 is primarily produced in the liver from GH metabolism, prior to secretion into circulation. IGF-1 possesses insulin-like metabolic action (short-term) and growth factor-like long-term effects on cell proliferation and differentiation [2], [26], [27]. IGF-1 activity is regulated by IGF binding proteins (IGFBP), with IGFBP-3 carrying majority (>80%) of circulating IGF-1. At least six IGFBPs are identified to regulate the levels and biological activities of IGF-1 through IGF-1 receptor

Genetic variation of igf-1, igf-1r and human health

Genetic polymorphisms in the IGF-1 genes have been reported to influence human health such as statue, longevity, cognition, vision and hearing [33], [34], [35], [36] although inconsistent data are present. Meta-analysis examining the association between polymorphisms in IGF-1 or IGF-1R genes and longevity revealed little correlation between the single nucleotide polymorphisms (SNPs) of IGF-1 and human longevity. However, a tight association is identified between the IGF-1R polymorphism

Metabolic syndrome and heart disease

Metabolic syndrome such as in the form of obesity and hypertension is often associated with myocardial contractile anomalies manifested as prolonged contraction and relaxation duration, reduced velocity of myocardial contraction and relaxation, and depressed myocardial compliance [56], [57], [58]. A number of machineries have been postulated for myocardial dysfunction under metabolic syndrome including reduced energy production as a result of depressed mitochondrial respiration and pyruvate

Current therapeutic options and limitations

The inverse correlation between circulating IGF-1 levels and cardiometabolic prevalence has dictated the clinical need for the pluripotential IGF-1 and its analogues in clinical use. The clinical application of recombinant human IGF-1 children with severe primary IGF-1 deficiency three decades ago led to the 2005 US Food and Drug Administration (FDA) approval of recombinant human IGF-1 for treatment of severe primary IGF-1 deficiency [41]. A complementary aspect of the recombinant human IGF-1

Conclusion and future directions

In summary, regulation of IGF-1 signaling cascade is an intriguing paradigm with significant physiological and pathophysiological implications in cardiac growth, function and tissue remodeling. Low circulating IGF-1 levels have been speculated to play a unique role in the increased prevalence of obesity and metabolic syndrome [12]. Both free IGF-1 and IGF-1/IGFBP-3 ratio, a rough estimate of free IGF-1 levels, are significantly decreased in obesity and are deemed useful in the monitoring of

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