Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions

Abstract

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for—and an intervention to improve—IGF-1 function.

Role of the Insulin-like Growth Factor System in Neurodegenerative Disease

“…This cleavage is inhibited when IGF-I is associated with IGFBPs. Although GPE is cleared rapidly from the circulation, it crosses the BBB and has a longer half-life in the brain where it has neuroprotective effects, a property that is being explored for the management of brain injury [14] and as a diagnostic tool in PD [15]. The role of IGF-II in the brain is less well understood.…”

Is Deuterium Fractionation a Major Controlling Factor in Human Metabolism and Cancer? An Essential Role for Proline

“…cGP is produced naturally from the N-terminal tripeptide of the endogenous hormone insulin-like growth factor-1 (IGF-1), and it circulates freely in the circulation. cGP has shown promise as a therapy to treat various conditions associated with aging [34].…”

Exploring Sources, Biological Functions, and Potential Applications of the Ubiquitous Marine Cyclic Dipeptide: A Concise Review of Cyclic Glycine-Proline

“…Moreover, the absorption of cGP is enhanced in human tissues, and cGP efficiently and directly crosses the blood–brain barrier into the cerebrospinal fluid. Activation of IGF-1 receptors in capillaries promotes astrocyte plasticity and vascular formation to enhance memory ( Figure 7 b) [ 74 ]. According to Fan et al, the intake of exogenous cyclic dipeptide is associated with reduced cardiovascular systolic pressure and improved stroke recovery [ 29 ].…”

“… Proposed mechanisms for the effects of cyclic glycine-proline: ( a ) induction of apoptosis in human foetal neural stem cells; ( b ) regulation of IGF-1 homeostasis in the circulatory system and brain tissue. Akt, protein kinase B; cGP , cyclic glycine-proline; ERK, extracellular signal-regulated kinase; IGF-1 or IGF1, insulin-like growth factor 1; IGFBP-3 or IGFBP 3 , insulin-like growth factor-binding protein 3; IGF-1R, insulin-like growth factor 1 receptor; MDM2, mouse double minute 2 homologous protein (Note: Redrawn graphics are based on original artwork by Murotomi [ 67 ] and Guan [ 74 ]. The red arrows on the left indicate the up-regulated levels of related proteins, while the red arrows on the right indicate changes in their relative amounts).…”