Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes

Abstract

Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.

Keywords: Androgens; Brain integrity; Cognition; Diabetes; Estrogen; Insulin; Insulin-like growth factor 1; Neuroprotection.

Figure 1

Similar signaling cascades involved with neuroprotection for insulin-like peptides and sex hormones. The insulin receptor (IR), insulin-like growth factor 1 receptor (IGF1R), and insulin-IGF1 hybrid receptor enact their neuroprotection through the mitogen-activated protein kinases-extracellular signal-related kinase (MAPK-ERK) or phosphoinositide 3-kinase (PI3K)-Akt pathways signaling cascades. Although IGF1R can directly activate the RAS-ERK pathway, both the insulin-like peptide receptors and the estrogen receptor alpha (ERα) firstly interact with insulin receptor substrate 1 (IRS-1) scaffolding proteins. ERα and the androgen receptor (AR) can also directly modulate PI3K-Akt and MAPK-ERK signaling. Both IRS-1 and p85 binding of PI3K are increased with ERα activation, leading to downstream Akt-derived inhibition of glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR). GSK3, specifically, is involved with glycogen synthesis, while both effectors are involved in apoptosis. A similar effect may occur with AR’s ability to modulate p85 binding to PI3K. AR-induced MAPK-ERK signaling also results in ribosomal S6 kinase (Rsk) expression that can inhibit the pro-apoptosis bcl-2-associated death promoter protein, as well as effects on the ER, GSK3, and the ETS-like transcription factor, ELK1. Solid black arrows indicate downstream interaction. Dashed black arrows represent the influence of kinases or proteins on the cellular environment. Dashed blue arrows represent the binding capabilities of IGF1 and insulin across all three receptor types.