Diabetic retinopathy results from altered insulin receptor signaling. Based on previous studies demonstrating an interaction between β-adrenergic receptors and insulin signaling in hyperglycemic conditions, we hypothesized that β-adrenergic receptor stimulation and insulin stimulation would act synergistically to inhibit one of the hallmarks of diabetic retinopathy, namely retinal endothelial cell apoptosis. To test this hypothesis, human retinal endothelial cells were grown in high glucose (25 mM) medium and treated with a β-1-adrenergic receptor agonist (xamoterol, 10 μM) alone, insulin alone (10 nM) or xamoterol + insulin. We then assessed changes in the levels of insulin receptor, insulin-like growth factor (IGF-1) receptor, and Akt phosphorylation, as well as cleaved caspase 3. Xamoterol alone significantly decreased insulin receptor, IGF-1 receptor and Akt phosphorylation, whereas insulin alone increased insulin receptor, IGF-1 receptor, and Akt phosphorylation. Xamoterol significantly decreased apoptosis of retinal endothelial cells. This data suggests that both β-adrenergic receptors and insulin can inhibit retinal endothelial cell apoptosis in hyperglycemic conditions, but inhibition occurs through independent pathways. These findings have implications for treatments of diabetic retinopathy.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Frank RN (2004) Diabetic retinopathy. N Engl J Med 350:48–58
Klein R (1996) Diabetic retinopathy. Annu Rev Public Health 17:137–158
Wiley LA, Rupp GR, Steilnle JJ (2005) Sympathetic innervation regulates basement membrane thickening and pericyte number in rat retina. Invest Ophthalmol Vis Sci 46:744–748
Williams KP, Steinle JJ (2009) Maintenance of beta-adrenergic receptor signaling can reduce fas signaling in human retinal endothelial cells. Exp Eye Res 89:448–455
Steinle JJ, Kern TS, Thomas SA et al (2009) Increased basement membrane thickness, pericyte ghosts, and loss of retinal thickness and cells in dopamine beta hydroxylase knockout mice. Exp Eye Res 88:1014–1019
Panjala SR, Thomas SA, Steinle JJ (2009) Effects of insulin-like growth factor-1 (IGF-1) receptor signaling on rates of apoptosis in retina of dopamine beta hydroxylase (Dbh(-/-)) knockout mice. Auton Neurosci 15:21–26
Steinle JJ, BooZ GW, Meininger CJ et al (2003) Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation. J Biol Chem 278:20681–20686
Steinle JJ, Chin VC, Williams KP et al (2008) Beta-adrenergic receptor stimulation modulates iNOS protein levels through p38 and ERK1/2 signaling in human retinal endothelial cells. Exp Eye Res 87:30–34
Miura S, Ohno I, Suzuki J et al (2003) Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by beta-adrenergic stimulation in rats. J Cardiovasc Pharmacol 42:174–181
Rosenfeld RG, Charles T, Roberts J (1999) The IGF system: Molecular Biology, Physiology, Clinical application. Contemporary Endocrinology. Humana Press, NJ
Feik E, Baierl A, Hieger B et al (2010) Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk. Cancer Causes Control 21:91–97
Yamada PM, Lee KW (2009) Perspectives in mammalian IGFBP-3 biology: local versus systemic action. Am J Physiol Cell Physiol 296:C954–C976
Barber AJ, Nakamura M, Wolpert EB et al (2001) Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J Biol Chem 276:32814–32821
Nakamura M, Barber AJ, Antonetti DA et al (2001) Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons. J Biol Chem 276:43748–43755
Steinle JJ (2007) Sympathetic neurotransmission modulates expression of inflammatory markers in the rat retina. Exp Eye Res 84:118–125
Jiang Y, Steinle JJ (2010) Systemic propranolol reduces B-wave amplitude in the ERG and increases IGF-1 receptor phosphorylation in rat retina. Invest Ophthalmol Vis Sci 51:2730–2735
Reiter CE, Gardner TW (2003) Functions of insulin and insulin receptor signaling in retina: possible implications for diabetic retinopathy. Prog Retin Eye Res 22:545–562
Nitert MD, Chisalita SI, Olsson K et al (2005) IGF-I/insulin hybrid receptors in human endothelial cells. Mol Cell Endocrinol 229:31–37
Cotlier E, Davidson C (1983) Insulin receptors in calf and human retinal blood vessels. Ophthalmic Res 15:29–37
Haskell JF, Meezan E, Pillion DJ (1984) Identification and characterization of the insulin receptor of bovine retinal microvessels. Endocrinology 115:698–704
Das A, Pansky B, Budd GC et al (1984) Immunocytochemistry of mouse and human retina with antisera to insulin and S-100 protein. Curr Eye Res 3:1397–1403
Reiter CE, Sandirasegarane L, Wolpert EB et al (2003) Characterization of insulin signaling in rat retina in vivo and ex vivo. Am J Physiol Endocrinol Metab 285:E763–E774
Reiter CE, Wu X, Sandirasegarane L et al (2006) Diabetes reduces basal retinal insulin receptor signaling: reversal with systemic and local insulin. Diabetes 55:1148–1156
Das A, Pansky B, Budd GC (1987) Demonstration of insulin-specific mRNA in cultured rat retinal glial cells. Invest Ophthalmol Vis Sci 28:1800–1810
Pessin JE, Gitomer W, Oka Y et al (1983) Beta-adrenergic regulation of insulin and epidermal growth factor receptors in rat adipocytes. J Biol Chem 258:7386–7394
Baltensperger K, Karoor V, Paul H et al (1996) The beta-adrenergic receptor is a substrate for the insulin receptor tyrosine kinase. J Biol Chem 271:1061–1064
Walker R, Steinle J (2007) Role of beta-adrenergic receptors in inflammatory marker expression in muller cells. Invest Ophthalmol Vis Sci 48:5276–5281
Joussen AM, Doehmen S, Le ML et al (2009) TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Mol Vis 15:1418–1428
White MF (2002) IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 283:E413–E422
Grounds MD, Radley HG, Gebski BL et al (2008) Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle. Clin Exp Pharmacol Physiol 35:846–851
Ferry RJ Jr, Katz LE, Grimberg A et al (1999) Cellular actions of insulin-like growth factor binding proteins. Horm Metab Res 31:192–202
Yi HK, Kim SY, Hwang PH et al (2005) Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochem Biophys Res Commun 330:760–767
Lofqvist C, Chen J, Connor KM et al (2007) IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc Natl Acad Sci USA 104:10589–10594
Lofqvist C, Willett KL, Aspegren O et al (2009) Quantification and localization of the IGF/insulin system expression in retinal blood vessels and neurons during oxygen-induced retinopathy in mice. Invest Ophthalmol Vis Sci 50:1831–1837
The authors would like to thank Dr. Dianna Johnson for her help in editing the text. This work is supported by a Career Development Award from JDRF 2-2006-114 (JJS), JDRF Translational Award 17-2008-1044 (JJS), the William and Mary Greve Special Scholars Award from Research to Prevent Blindness and a departmental award from the Research to Prevent Blindness (Dr. Barrett Haik, chair), NEI Vision Core Grant: PHS 3P30 EY013080 (PI: Dianna Johnson).
Special issue article in honor of Dr. Dianna Johnson.
About this article
Cite this article
Panjala, S.R., Steinle, J.J. Insulin and β-adrenergic Receptors Inhibit Retinal Endothelial Cell Apoptosis Through Independent Pathways. Neurochem Res 36, 604–612 (2011). https://doi.org/10.1007/s11064-010-0303-3
- β-adrenergic receptors
- Insulin-like growth factor 1 (IGF-1)