by Nicholas Pokoluk
Human cellular functions and lifecycles are very rigorously controlled. This control is carried out by intra and extracellular signals that effect proliferation, senescence and apoptosis. There are many nutrient signaling pathways including AKT, mTOR, FOXO and Insulin/Insulin-like Growth Factor 1 (IGF-1) pathways that are all interconnected at some point. The I/IGF-1 glucose sensing pathway is the one we will focus on in this post. I/IGF-1 in simple terms, is the pathway that signals cells of the presence of glucose. Since glucose is the major energy source for mammalian cells this pathway influences a myriad of processes that have profound effects on the action of cells, tissues and organs. Those that have followed the course of these blogs on Hallmarks of Aging and the Role of Glycation can anticipate the way this signaling pathway plays a role in health and disease, and as such, the role it plays in the aging phenotype.
I/IGF-1, and an another closely linked signaling element, growth hormone (GH) have a significant role in the development and functioning of cells in the human body. During adulthood the levels of these signaling elements decline as we age significantly. Thus, their role in regulating cellular functioning changes. This decline in IGF-1 and GH is sometime called the “somatopause” indicating the loss of the robust activity of these two important signaling elements.
While insulin is produced in the pancreatic beta cells, IGF-1 comes from liver via the action of GH on liver GH receptor. IGF-1 is the “channel” through which GH’s influences are mediated. GH produced in the anterior pituitary, is released into the blood stream, and ultimately stimulates the liver to produce IGF-1. Insulin signals through the insulin receptors and IGF-1 via IGF-1 receptor. Since insulin products an increase in GH, hyperglycemia leading to hypersulinemia may also lead to elevated IGF-1 expression.
Diabetes is characterized by chronic hyperglycemia, which in turn facilitates the formation of advanced glycation end products (AGEs). AGEs activate signaling proteins including AKT (also know as protein kinase B). AKT signaling pathway is involved in cellular survival pathways by inhibiting apoptosis and is also able to induce protein synthesis pathways and as such may play a role in both tumorigenesis and proliferation. IGF-1 is a very strong activator of the AKT pathway.
The GH and IGF-1 signaling actions are quite diverse in their locations of action, but we can see the way it is affected by glycation by looking at two specific examples. One example is the glycation of fibronectin and the increases of IGF-I induced proliferation of human aortic smooth muscle cells. The other example involves the binding proteins of IGF-1 and their glycation and resulting modulation of IGF-1 functioning.
AGEs, as we have indicated throughout this series of posts, contribute to long-termed complications of diabetes mellitus, including macroangiopathy, where smooth muscle cells (SMC) proliferate stimulated by insulin-like growth factor-I (IGF-I). In their study, Correa-Geannella et al (1), investigated the effect of an AGE-modified extracellular matrix protein on IGF-I induced SMC proliferation and on the IGF-I binding protein 4 (IGFBP-4) axis under basal conditions and after stimulation. IGF-I resulted in significantly higher thymidine incorporation in SMC seeded on AGE-modified fibronectin (AGE-FN) in comparison to cells seeded on fibronectin (FN). This augmented proliferation could not be accounted for by increased expression of IGF-IR (IGF-1 receptor), by decreased secretion of IGFBP-4, a binding protein that inhibits IGF-I mitogenic effects or by increased IGF-IR autophosphorylation. These findings strongly suggest that one mechanism by which AGE-modified proteins is involved in the pathogenesis of diabetes-associated atherosclerosis is by increasing SMC susceptibility to IGF-I mitogenic effects via an upstream glycation reaction.
The second example considers the role of glycation on the binding proteins associated with IGF-1 control. IGF-1 stimulates growth in tissue cells by accessing cell surface receptors. This linkage is controlled by several IGF-1 binding proteins. Synthesis of binding proteins is a tightly controlled process as is the binding to IGF-1. Since IGF-1 and the binding proteins are subject to glycation it is not surprising that they can become deregulated and thus present downstream signaling problems.
We know in diabetes there is an increase in the content of AGEs in various tissues, including bone. This increase can lead to a local imbalance in the secretion of cytokines and growth factors, and has been implicated in the pathophysiology of the longterm complications of diabetes. The McCarthy research (2) was based on previously shown proliferation and differentiation of rat osteosarcoma affected by AGE-modified proteins. In the cited study, they investigated the effects of AGEs on the secretion of insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) by osteoblast cell lines. The cells were studied throughout their successive stages of development: proliferation, differentiation and mineralisation. For every condition, cells were incubated 24 hours with increasing concentrations of either bovine serum albumin (BSA) or AGE-BSA. Results showed low doses of AGE-BSA significantly decreased the secretion of both IGF-I. In proliferating preosteoblastic cells, AGE-BSA decreased the secretion of IGF-I (34%-37% of control) while increasing the secretion of IGFBP (124%-127% of control). On the other hand, secretion of these components of the IGF system by mature (differentiated) cells was unaffected by the presence of AGE-BSA. When these cells finally attained mineralisation, incubation with AGE-modified BSA provoked an increase both in IGFBP (131%-169% of control) and in IGF-I secretion (119%-123% of control).
This evidence strongly suggests that the modulation of growth and development by AGE-modified proteins could significantly impact the IGF-IGFBP signaling system. Taken together both these examples show the far reaching effects of AGE-modified proteins in yet another Hallmark of Aging.
- Correa-Geannella, M., et al, Fibronectin glycation increases IGF-1 induced proliferation of human aortic smooth muscle cells, 2012, Diabetology and Metabolic Syndrome, 4:19
- McCarthy, AD, et al, Effects of advanced glycation end products on the secretion of
Insulin-like growth factor-1 and its binding protines: role in osteoblast development,
2001, Acta Diabetol, 38(3):113-22
Nick Pokoluk is a biochemist, Six Sigma Black Belt of Transformational Change Methodology and Spencer Institute certified wellness coach. He can be reached at npokoluk@wwtpi.com or openlcr@yahoo.com
