IGF-2 Lr3 1200mcg

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IGF-2 Lr3

IGF-2 is a protein hormone/peptide that is endogenous to the human body and, like IGF-1 and relaxin, shares structural and functional similarities to insulin.[4][5]  The IGF-2 gene is genetically imprinted from the father, always.  Genetic imprinting is an epigenetic process meaning that the gene's expression is heavily influenced by methylation and histone modification.  In the body IGF-2 binds to and exerts effect on the IGF-1 receptor, and may bind to the IGF-2 receptor; the IGF-2 receptor primarily acts as a signalling antagonist, meaning it primarily prevents the primary effects of IGF-2 (with regard to the IGF-1 receptor).[1][2][4][5]


IGF-2 administered or experienced in supra-physiological levels causes hypoglycemia, such as that experienced by sufferers of Doege-Potter syndrome, a disease resulting from excessive IGF-2 production from tumorous cells.


IGF-2 has been demonstrated to interact with IGFBP3, IGF-binding protein 3.  IGFBP3, IGFALS (IGF-acid labile-subunit), and IGF-2 bind to form a ternary complex which is thought to function, primarily, to increase circulating life of IGF-2.[1][2][3]


MacDonald writes:

 GF-I and IGF-II receptors are expressed in the small intestine of mammalian species, as are the genes to synthesize both peptides.... IGF-I and IGF-II receptor binding to the small intestine is higher in newborn animals and decreases with age. Both receptors are more concentrated in the crypt than villus regions, but IGF-II binding is higher than IGF-I in all regions. IGF-I receptors are associated with the submucosal region of the small intestine, whereas IGF-II receptors are more abundant in the mucosal cells. Administration of IGF-I either orally or by osmotic pump generally has no affect on small intestinal weight or length, but does increase mucosal cellularity. LR3-IGF-I administration by osmotic pump affects the small intestine similarly to IGF-I, although with a higher potency. In the few studies in which IGF-II was administered, increased gut mass was observed in adult rats, but not newborn rats or pigs. Significant effects on mucosal expression of disaccharidases was achieved with either oral or subcutaneous IGF-I or oral IGF-II. [6]


From a study investigating the role of IGF-II and IGF-IIR in myocardial tissue, Chu et al infer conclusions that may be useful in preventing myocardial apoptosis following heart failure:


Our results revealed that IGF-II synergistically increased the cell apoptosis induced by suppressing of IGF-IR in neonatal rat ventricular myocytes. After binding of Leu27IGF-II, IGF-IIR became associated with alpha-q polypeptide, acted like a protein-coupled receptor to activate calcineurin, led to the translocation of Bad into mitochondria and release of cytochrome c into cytoplasm, and contributed to mitochondrial-dependent apoptosis in neonatal rat ventricular myocytes. Furthermore, inhibition of IGF-IIR, alpha-q polypeptide, or calcineurin by RNA interference could block the Leu27IGF-II-induced cell apoptosis. Together, this study provides a new insight into the effects of the IGF-IIR and its downstream signaling in myocardial apoptosis. Suppression of IGF-IIR signaling pathways may be a good strategy for both the protection against myocardial cell apoptosis and the prevention of heart failure progression.[7]


Tong et al speculate that in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, resistance in the brain to IGF-I and IGF-II may play a role in dementia, and that this may be tied in with manganese toxicity:


IGF-I and IGF-II resistance was present in DLB but not PD frontal cortex, and associated with reduced expression of Hu, nerve growth factor, and Trk neurotrophin receptors, and increased levels of glial fibrillary acidic protein, alpha-synuclein, dopamine-beta-hydroxylase, 4-hydroxy-2-nonenal (HNE), and ubiquitin immunoreactivity. MnCl2 treatment reduced survival, ATP, and insulin, IGF-I and IGF-II receptor expression, and increased alpha-synuclein, HNE, and ubiquitin immunoreactivity in cultured neurons. The results suggest that: 1) IGF-I, IGF-II, and neurotrophin signaling are more impaired in DLB than PD, corresponding with DLB's more pronounced neurodegeneration, oxidative stress, and alpha-synuclein accumulation; 2) MnCl2 exposure causes PD/DLB associated abnormalities in central nervous system neurons, and therefore may contribute to their molecular pathogenesis; and 3) molecular abnormalities in PD/DLB overlap with but are distinguishable from Alzheimer's disease.[8]


Regarding the potential of the IGF-II receptor in acting as a delivery system for tumor-targeting drugs, Prakash et al write:

 Tumor-targeting of anticancer drugs is an interesting approach for the treatment of cancer since chemotherapies possess several adverse effects. ...We developed a drug carrier against M6P/IGF-II receptor by modifying human serum albumin (HSA) with M6P moieties. M6P-HSA specifically bound and internalized into M6P/IGF-IIR-expressing B16 melanoma cells as demonstrated with radioactive studies and anti-HSA immunostaining. In vivo, M6P-HSA rapidly accumulated in subcutaneous tumors in tumor and stromal components after an intravenous injection. ... In conclusion, M6P-HSA is a suitable carrier for delivery of anticancer drugs to tumors through M6P/IGF-IIR. Improved antitumor effects of the targeted doxorubicin by M6P-HSA suggest that this novel approach may be applied to improve the therapeutic efficacy of anticancer drugs.[9]


IGF-II is most important during gestational phases of mammals; Napoli demonstrates an important link between IGF-II and choline intake: "prenatal choline supplementation produced alterations in IGF2 signaling, via increased levels of IGF2 and IGF2R, which may enhance cholinergic neurotransmission and confer neuroprotection against insult."[10]



[1]Storch, S; Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T (Dec. 2001). "Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3". FEBS Lett. (NL) 509 (3): 395–8.

[2]Buckway, C K; Wilson E M, Ahlsén M, Bang P, Oh Y, Rosenfeld R G (Oct. 2001). "Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding". J. Clin. Endocrinol. Metab. USA 86 (10): 4943–50.

[3]Twigg, S M; Baxter R C (Mar. 1998). "Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit". J. Biol. Chem. USA 273 (11): 6074–9. 

[4]Firth, S M; Ganeshprasad U, Baxter R C (Jan. 1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". J. Biol. Chem. USA 273 (5): 2631–8.

[5]Cubbage ML, Suwanichkul A, Powell DR (July 1990). "Insulin-like growth factor binding protein-3. Organization of the human chromosomal gene and demonstration of promoter activity". J. Biol. Chem. USA 265 (21): 12642–9.

[6] MacDonald RS.  The role of insulin-like growth factors in small intestinal cell growth and development.  Horm Metab Res. 1999 Feb-Mar;31(2-3):103-13.

[7]Chu CH, Tzang BS, Chen LM, Liu CJ, Tsai FJ, Tsai CH, Lin JA, Kuo WW, Bau DT, Yao CH, Huang CY. Activation of insulin-like growth factor II receptor induces mitochondrial-dependent apoptosis through G(alpha)q and downstream calcineurin signaling in myocardial cells.Endocrinology. 2009 Jun;150(6):2723-31.

[8]Tong M, Dong M, de la Monte SM. Brain insulin-like growth factor and neurotrophin resistance in Parkinson's disease and dementia with Lewy bodies: potential role of manganese neurotoxicity.  J Alzheimers Dis. 2009 Mar;16(3):585-99.

[9] Prakash J, Beljaars L, Harapanahalli AK, Zeinstra-Smith M, de Jager-Krikken A, Hessing M, Steen H, Poelstra K. Tumor-targeted intracellular delivery of anticancer drugs through the mannose-6-phosphate/insulin-like growth factor II receptor. Int J Cancer. 2010 Apr 15;126(8):1966-81.

[10] Napoli I, Blusztajn JK, Mellott TJ.  Prenatal choline supplementation in rats increases the expression of IGF2 and its receptor IGF2R and enhances IGF2-induced acetylcholine release in hippocampus and frontal cortex. Brain Res. 2008 Oct 27;1237:124-35.


*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.


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