Insulin-like growth factor-2 regulates basal retinal insulin receptor activity

Abstract

The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina. The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina. Peptide growth factors are essential for the proliferation and differentiation of neuroprogenitor cells and for survival of fully differentiated retinal neurons, particularly under stress conditions (1Chaum E. Retinal neuroprotection by growth factors: A mechanistic perspective.J. Cell Biochem. 2003; 88: 57-75Crossref PubMed Scopus (115) Google Scholar). The evolutionarily conserved roles of insulin-like growth factors (IGFs) and insulin predate the development of the pancreas (2LeRoith D. Delahunty G. Wilson G.L. Roberts Jr., C.T. Shemer J. Hart C. Lesniak M.A. Shiloach J. Roth J. Evolutionary aspects of the endocrine and nervous systems.Recent Prog. Horm. Res. 1986; 42: 549-587PubMed Google Scholar), and these ligands have prominent effects on retina and brain development and function. For example, deletion of the insulin receptor (IR) causes morphologic defects in the eye and brain of zebrafish (3Toyoshima Y. Monson C. Duan C. Wu Y. Gao C. Yakar S. Sadler K.C. LeRoith D. The role of insulin receptor signaling in zebrafish embryogenesis.Endocrinology. 2008; 149: 5996-6005Crossref PubMed Scopus (52) Google Scholar) and Drosophila (4Broglio W. Stocker H. Ikeya T. Rintelen F. Fernandez R. Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.Curr. Biol. 2001; 11: 213-221Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar), and deletion of the mouse insulin responsive substrate gene, Irs-2, impairs retinal ganglion cell and photoreceptor maturation (5Yi X. Schubert M. Peachey N.S. Suzuma K. Burks D.J. Kushner J.A. Suzuma I. Cahill C. Flint C.L. Dow M.A. Leshan R.L. King G.L. White M.F. Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells.J. Neurosci. 2005; 25: 1240-1248Crossref PubMed Scopus (62) Google Scholar). The rat retina exhibits a high level of basal IR kinase activity equivalent to that in the liver of fed animals but does not fluctuate with feeding or fasting (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). also that insulin administration the retinal IR and the IGF-1 receptor (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). These findings role of the in the and nervous causes of retinal A.J. E. Antonetti D.A. Gardner T.W. in the retina and diabetes. onset and of PubMed Scopus Google Scholar) in with reduced basal activity of the IR Akt kinase of kinase activity A.J. Antonetti D.A. Gardner T.W. The mouse a of retinal in 2005; PubMed Scopus Google Wu X. Sandirasegarane L. M. Antonetti D.A. Gardner T.W. Diabetes basal retinal insulin receptor with and PubMed Scopus Google M. M. Diabetes of retinal insulin receptor and PubMed Scopus Google C.E. M. Barber A.J. Gardner T.W. roles of and in induced retinal cell for retinal insulin PubMed Scopus Google Scholar). Insulin and IGF-1 are for retinal of the Akt a specifically by in the retina and metabolic stress conditions in A.J. M. Wolpert E.B. Antonetti D.A. Gardner T.W. Insulin retinal from by a that the of Biol. 2001; Full Text Full Text PDF PubMed Scopus Google M. Barber A.J. Antonetti D.A. Gardner T.W. the of insulin and in retinal Biol. 2001; Full Text Full Text PDF PubMed Scopus Google D. L. E. S. Gardner T.W. growth factor 1 retinal from phosphorylation of Res. PubMed Scopus Google Scholar). and administration of insulin prosurvival IR and Akt kinase and retinal cell with Wu X. Sandirasegarane L. M. Antonetti D.A. Gardner T.W. Diabetes basal retinal insulin receptor with and PubMed Scopus Google C.E. M. Barber A.J. Gardner T.W. roles of and in induced retinal cell for retinal insulin PubMed Scopus Google Scholar). it is the basal IR activity in normal animals is and the basal of retinal IR activity by insulin to retinal feeding and fasting does not retinal IR activity it does in the liver (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). we it was that the high basal retinal IR activity and are in the liver and brain rats to and in the brain with liver of IGF-2 is in W. K. M. M. regulation and of the insulin growth factor PubMed Scopus Google C. J. and of the in retinal and in PubMed Scopus Google Scholar) that the of ligands and is in the mouse retina. mRNA is to than or insulin and receptor is than the role of IGF-2 in fully differentiated have increased to D. M. M.F. survival in after PubMed Scopus Google Scholar). the effects of IGF-2 development are the IR D. of with the insulin receptor mouse Biol. PubMed Scopus Google Scholar), and the retinal IR is highly sensitive to IGF-2 in Gardner T.W. Retinal insulin and insulin for diabetic Res. 2003; PubMed Scopus Google these data to that IGF-1 IGF-2 may ligands of the retinal IR and a prosurvival role in retinal neurons, a function by diabetes. studies and IR levels in the retina and liver development and diabetes. the basal retinal IR kinase we demonstrated that intravitreal administration of a IGF-2 specifically retinal IR kinase activity in normal rats. we that retinal mRNA content and IGF-2 content in the Finally, we that intravitreal administration of retinal prosurvival signaling in diabetic rats. Collectively, these findings the regulation of prosurvival signaling in the retina and are by diabetes. C. J. and of the in retinal and in PubMed Scopus Google Scholar) the high of retinal with insulin mRNA in normal mouse but is and role in the retina. studies have that IGF-1 and IGF-2 are for cell growth D. M. M. W. growth factor 2 in development and A PubMed Scopus (115) Google Scholar), levels were by in pups and rats. that mRNA content is 10-fold higher in retina than in liver is than in These data are with of high content in brain with brain J. J. and of the insulin-like growth factor 2 PubMed Scopus Google X. G. Insulin growth factor 2 in the rat brain in basal and from the PubMed Scopus Google Scholar). liver mRNA was higher in than and retinal content was equivalent in and and reveal in is mRNA in liver versus but retina is higher than in liver. content in liver is higher than in and in by a factor of These reveal that the retina IGF-1 and IGF-2, function in or W. K. M. M. regulation and of the insulin growth factor PubMed Scopus Google Scholar). of IR that retinal and liver IR mRNA are and animals and IR mRNA content is to higher in liver than retina and is a in mRNA in with is a in liver, to retinal orders of higher than liver in and Collectively, these data a high level of retinal IR and in retina. the of reduced retinal IR kinase activity in was for and and the ligands in control and rats after of but not mRNA content decreased in diabetic rat mRNA decreased in the diabetic rat liver, but was not in and mRNA were not by in and are in that insulin, and IGF-2 IR in ex vivo (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar), but to the ligand(s) of the retinal IR in the we a of to the role of insulin in the regulation of retinal IR serum insulin concentrations were in pups and in control and diabetic rats. the 10-fold greater serum insulin in fed control versus animals after of insulin-deficient in of insulin, the of insulin in vitreous fluid of rats. A and retinal insulin mRNA content and pancreas insulin mRNA content was orders of magnitude greater than in retina. The in insulin mRNA content is of the of in the rat pancreas M.A. of the mouse pancreas for and metabolic PubMed Scopus Google Scholar). the that the level of retinal insulin ligand to the retinal that retinal insulin content not with fasting or and of retinal are equivalent to by LeRoith D. Lesniak M.A. S. J. Roth J. Insulin in brain and of and PubMed Google Scholar) for brain and suggest a level in the these the regulation of basal retinal IR activity from the IR activity in and suggest the that ligands may retinal IR The studies to a a cell to the effects of and on IR phosphorylation retinal neurons, for signaling studies D. L. E. S. Gardner T.W. growth factor 1 retinal from phosphorylation of Res. PubMed Scopus Google X. C.E. Antonetti D.A. Gardner T.W. Insulin rat retinal cell survival in a Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the effects of serum from and diabetic rats on IR and and to the of of serum on receptor with serum from fed rats induced prominent IR and that was greater than that from serum of rats fasted and increased in a from to cells with serum from insulin-deficient diabetic rats not control the diabetic serum determine the ligand(s) for the of the of insulin, insulin-like growth factor and IGF-2 was from control serum antibodies in serum in to insulin not IR to of IGF-2, reduced IR and by but depletion of IGF-1 and IGF-2 of and IGF-1 not IR or The insulin, and IGF-2 antibodies were for antibodies the IR insulin to was to the in The of that IGF-2, and insulin have equivalent effects on These data the of IGF-2 on retinal IR of retinal cells a of IR and in response to serum from control but not diabetic animals these studies the role of IGF-2 a ligand of retinal IR and The intravitreal of antibodies against insulin, and IGF-2 to determine the retinal IR that with and that intravitreal insulin and IGF-1 antibodies not IR kinase the IGF-2 reduced IR kinase activity by are of These that from deletion of retinal These data that IGF-2 is the ligand to the basal activity of the retinal the of the IR for insulin and on the mRNA F. G. L. R. R. Insulin receptor a insulin-like growth factor receptor in and Biol. PubMed Scopus Google Scholar). IR were by from normal rat and liver. the liver and the retina and brain the A is sensitive to IGF-2 (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). These with the to higher level IGF-2 mRNA to insulin or IGF-1 C. J. and of the in retinal and in PubMed Scopus Google Scholar), suggest of the retinal IR by IGF-2, with the high basal activity of feeding and that insulin and IGF-2 the IR in normal ex vivo rat (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). we basal in vivo IR and by after we and Wu X. Sandirasegarane L. M. Antonetti D.A. Gardner T.W. Diabetes basal retinal insulin receptor with and PubMed Scopus Google G. F. R. L. R. growth factor have on the insulin receptor Biol. Full Text Full Text PDF PubMed Scopus Google S. D. K. Characterization of of the insulin receptor and and the to ligand and receptor J. PubMed Scopus Google Scholar) have to the than (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar), the from liver than that from retina and the rat liver we the G.L. growth factor to and is by deletion of the or of for in J. PubMed Scopus Google Scholar) in normal rats and receptor The in a greater in retinal than in response to IGF-2 versus the IR is a for IGF-2 in the retina. IGF-2 in adults J. of insulin-like growth factor and in Res. 42: PubMed Scopus Google we the effects of and in ex vivo IGF-2 in Akt and the effects were by with and These data the retina IR to IGF-2 a insulin concentrations in control and diabetic animals are in IGF-2 content was by from of control and diabetic animals after of diabetes. by and M. of of insulin-like growth in and rats and of levels in PubMed Scopus Google Scholar). and is a serum from a control rat and control and diabetic rats. reveal levels of IGF-2 in rats and the animals levels of are in were by from a of IGF-2 but IGF-2, with from and of serum content of IGF-1 and The concentrations of ligands were also in vitreous from the a higher content and from the diabetic rat of of R. of the and retinal in Res. PubMed Scopus Google Scholar). reduced rat vitreous IGF-2 content by and IGF-2 by and vitreous content was reduced by the and vitreous IGF-1 content was reduced by increased a and to serum rat vitreous does not IGF-1 rats with of and have equivalent serum IGF-2 IGF-1 is reduced in the animals the of serum and vitreous IGF-2 and IGF-1 by is to the in vitreous and not of Diabetes impairs the retinal IR signaling and insulin signaling and normal of cell and C.E. M. Barber A.J. Gardner T.W. roles of and in induced retinal cell for retinal insulin PubMed Scopus Google S. Gardner T.W. of retinal in 1 PubMed Scopus Google Scholar). we and in rats with diabetes. ligand in retinal IR and kinase A and These the to prosurvival signaling and in the retina of insulin-deficient The of was to determine the basal regulation of retinal IR activity and it is by insulin-deficient diabetes. The factors that of the retina and are by are we for the retinal IGF-2 levels remain high in role in basal retinal IR kinase activity on IGF-2 than insulin or retinal IGF-2 mRNA content and IGF-2 content vitreous and intravitreal IGF-2 prosurvival IR kinase and kinase activity in diabetic rat these findings understanding of the regulation of the retinal IR and it may by diabetes. has that the retinal IR and effects of are for development of and retinal and the (3Toyoshima Y. Monson C. Duan C. Wu Y. Gao C. Yakar S. Sadler K.C. LeRoith D. The role of insulin receptor signaling in zebrafish embryogenesis.Endocrinology. 2008; 149: 5996-6005Crossref PubMed Scopus (52) Google W. Stocker H. Ikeya T. Rintelen F. Fernandez R. Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.Curr. Biol. 2001; 11: 213-221Abstract Full Text Full Text PDF PubMed Scopus (848) Google X. Schubert M. Peachey N.S. Suzuma K. Burks D.J. Kushner J.A. Suzuma I. Cahill C. Flint C.L. Dow M.A. Leshan R.L. King G.L. White M.F. Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells.J. Neurosci. 2005; 25: 1240-1248Crossref PubMed Scopus (62) Google E. regulation of PubMed Scopus Google Insulin receptor signaling and function in 2008; Full Text Full Text PDF PubMed Scopus Google M. S. S. M. Retinal in the insulin receptor Res. PubMed Scopus Google Scholar), but the regulation of basal IR activity in has not been fully that basal retinal IR kinase activity is higher in the retina versus the liver and of fasted rats and does not fluctuate with feeding and fasting (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). of insulin in control rats increased of but not retina (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). Insulin and IGF-2 IR in ex vivo (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar), but the control of basal kinase activity in has not been we to the we found that retinal insulin constant feeding and fasting and insulin-deficient induced by These findings are with of LeRoith D. Lesniak M.A. S. J. Roth J. Insulin in brain and of and PubMed Google Scholar) studies insulin concentrations in brain and and a of with fasting or IR activity is from that of liver, and and the that ligands contribute to the high basal retinal IR we found that serum from insulin-deficient rats to IR in retinal in to serum from fed or fasted rats. from animals to and fasting the conditions are by serum insulin concentrations and conditions and of IGF-2 but not or IGF-1 from the serum reduced the to IR and by and was of IGF-2 and IGF-1 IGF-2 and insulin induced of and these effects are in cells from the was to basal IR the effects are from the in vivo in the IR kinase activity and are a role of IGF-2 to the IR from retinal cells. A role for IGF-2 in the retina is by of IGF-2 mRNA in the normal rat liver IGF-2 declines after rat to high levels of IGF-2 and These findings are in with the by C. J. and of the in retinal and in PubMed Scopus Google Scholar) that the retina to IGF-2 than are also with high of IGF-2 in brain and cells M.A. M. A.J. growth and insulin-like growth in rat and Biol. 1986; Full Text PDF PubMed Google S. E. M. I. T. K. Gao growth factor An essential cell in brain and Cell Full Text Full Text PDF PubMed Scopus Google Scholar) of increased from the X. G. Insulin growth factor 2 in the rat brain in basal and from the PubMed Scopus Google Scholar). retina has of the levels of IGF-2 mRNA in to the the in vivo role of IGF-2 was the of antibodies to insulin, and IGF-2 in normal rats. The IGF-2 IGF-2 by IGF-2 antibodies decreased basal IR kinase activity in and the in activity is equivalent to the in diabetic rats Wu X. Sandirasegarane L. M. Antonetti D.A. Gardner T.W. Diabetes basal retinal insulin receptor with and PubMed Scopus Google Scholar). IR activity to in vivo regulation of in retina phosphorylation of the insulin receptor Biol. Full Text Full Text PDF Scopus Google Scholar) or of the to the retina. These findings not the that of insulin or IGF-1 may contribute to retinal IR basal The of the of mRNA in the the is with a role for IGF-2 and a of IR regulation in the nervous versus that fluctuate with LeRoith (2LeRoith D. Delahunty G. Wilson G.L. Roberts Jr., C.T. Shemer J. Hart C. Lesniak M.A. Shiloach J. Roth J. Evolutionary aspects of the endocrine and nervous systems.Recent Prog. Horm. Res. 1986; 42: 549-587PubMed Google D. Lesniak M.A. S. J. Roth J. Insulin in brain and of and PubMed Google Scholar) have that the evolutionarily in the of and in the development of the brain growth factor control of with liver, that to IGF-1 IGF-2 in or of the retina for and cell survival than Collectively, the data that the retinal IR is by and The is to A insulin receptor signaling in retinal photoreceptor Biol. PubMed Scopus Google Scholar), the is on retinal cells. IGF-2 the IR we the of IGF-1 and IGF-2 in by M. of of insulin-like growth in and rats and of levels in PubMed Scopus Google Scholar) of of IGF-2 that by or of serum prominent in rats retina prominent and and a prominent but to IGF-2 in the retina. Diabetes not the content or of IGF-2 in the retina. of the IGF-1 in response to diabetes. The of IGF-2 in the rat retina from receptor and M. and of the insulin-like growth factor receptor and insulin receptor receptor Endocrinol. PubMed Scopus Google Scholar) and to the vitreous fluid. the vitreous was greater in diabetic animals than the and IGF-2 was reduced by Diabetes also reduced the vitreous content by in not for the of IGF-1 content was reduced in the vitreous to of the retinal IR was of and greater of than in retina and prominent but in liver. also found that intravitreal of IGF-2 increased retinal activity with ex vivo and increased Akt activity in a basal retinal IR activity may by and of insulin substrate and and in and and insulin causes of and of insulin E. of Diabetes Google Scholar). with reduced serum insulin concentrations Jr., J. Jr., PubMed Scopus Google Scholar) is not to a that insulin is not the retinal IR ligand the that retinal insulin content does not with feeding and fasting or from insulin-deficient in of serum levels and high retinal activity in fasted animals (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google Scholar). we the roles of IGF-1 and IGF-2 and found that intravitreal administration of IGF-2 but not insulin or IGF-1 decreased basal retinal IR kinase activity in normal rats. The that retina the of the IR has high for IGF-2 (6Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. 2003; PubMed Scopus Google J. of insulin-like growth factor and in Res. 42: PubMed Scopus Google M. of serum of insulin-like growth factor in the development of in with S. PubMed Scopus Google Scholar) a role of IGF-2 in the normal retina. insulin to kinase activity in diabetic rat C.E. M. Barber A.J. Gardner T.W. roles of and in induced retinal cell for retinal insulin PubMed Scopus Google S. Gardner T.W. of retinal in 1 PubMed Scopus Google H. Wu L. Gardner T.W. for insulin to retinal cell in diabetic PubMed Scopus Google Scholar), but the data in suggest that IGF-2 than insulin may to prosurvival kinase activity and diabetic retinal IGF-2 mRNA content is reduced in the of diabetic rats L. growth factor is reduced in and liver from rats with and diabetic Google Scholar), and the K. Y. W. G. Insulin receptor in rat and Res. PubMed Scopus Google Scholar). of a of in diabetes. Collectively, is to the metabolic and cell survival of the high basal IR activity in normal retina and to retinal function and in diabetes. were in with the for in and on the and of and by the of with to were under and to a rat and and were under conditions and photoreceptor insulin were by by regulation of the insulin receptor in the 2003; PubMed Scopus Google Scholar). Diabetes was induced by of in and control rats equivalent of S. Gardner T.W. of retinal in 1 PubMed Scopus Google Scholar). rats were diabetic levels after and levels were animals were after feeding with a the of of the retinas, the rats were with and by for of retinas, and were in and vitreous was from on for and the IGF-2 was by the by M. of of insulin-like growth in and rats and of levels in PubMed Scopus Google Scholar). the to the of IGF-2, or were 2 2 2 and and were by the and to the with IGF-2 was a primary were with the to the antibodies were and to the and were from was from and and and and and and and and were from Cell For were from For IGF-2 the antibodies from were For antibodies from were antibodies or antibodies and growth were a control for cells were with 2 cell for in The cells were with and in serum for with under conditions for in The studies were in with rat serum and after with for C. was in with for C. For of with of antibodies to serum insulin for 1 were insulin with and and antibodies rat and was IGF-1 and IGF-2 on a control for the we and rat serum with the of we insulin in concentrations in the in the conditions to with with and insulin or were for and in cells. with to with The of the rat serum were in to to IR and in cells after and from was with of and and was with a on the for were and from was to antibodies against insulin, and IGF-2 were of control rats in a of The were with a of and with high levels of ligand and were 1 after and were and were for IR and kinase of 1 or were in control and were vivo rat were with or of receptor insulin-like growth or and for with or were for and Insulin concentrations from and retina were with the to and C.E. M. Barber A.J. Gardner T.W. roles of and in induced retinal cell for retinal insulin PubMed Scopus Google Scholar). Retinal insulin receptor kinase and kinase were in retinal C.E. M. Barber A.J. Gardner T.W. roles of and in induced retinal cell for retinal insulin PubMed Scopus Google S. Gardner T.W. of retinal in 1 PubMed Scopus Google Scholar). were in and of were or the kinase activity was the peptides for and for of the was by of the after of the were by with For were were by with a were data are in the The that have of with the of to C. and for the E. F. and T. W. G. and the S. H. M. K. and R. S. J. S. the S. and T. W. G. the and the The was by the of the of The and from to and W. G. and E. and

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