- Email: [email protected]
Insulin may cause deterioration of proliferative diabetic retinopathy
Medical Hypotheses 72 (2009) 306–308
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Insulin may cause deterioration of proliferative diabetic retinopathy Peng Zhang a, Na Liu b, Yusheng Wang a,* a b
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 15 West Changle Street, Xi’an, Shaanxi Province 710032, PR China State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, PR China
a r t i c l e
i n f o
Article history: Received 12 September 2008 Accepted 2 October 2008
s u m m a r y Diabetes mellitus (DM) can cause many systemic complications, including proliferative diabetic retinopathy (PDR). Retinal neovascularization (RNV) is the typical symptom of PDR, representing an important risk factor for severe vision loss in patients with DM. Diabetic hyperglycemia plays a major role in the destruction of retinal capillary walls, resulting in retinal ischemia and up-regulation of vascular endothelial growth factor (VEGF), leading to neovascularization. The transcriptional regulation of VEGF is mediated by transcription factor hypoxia-inducible factor 1 (HIF-1). Insulin is the mainstay of treatment for DM, but some studies have demonstrated that insulin had the ability to stimulate VEGF and HIF-1 expression in retinal pigment epithelial cells, retinal epithelial cells and vascular smooth muscle cells. In addition to the mitogenic effect of insulin makes it as an assistant agent has long been used in vitro cell culture. Other studies confirmed that insulin increased leukostasis in retinal microcirculation. Based on these experimental results, we hypothesize that long-term insulin therapy maybe improves the expression of VEGF and increase the risk of RNV, eventually deteriorates PDR in patients with DM. Ó 2008 Elsevier Ltd. All rights reserved.
Background Diabetes mellitus and diabetic retinopathy Diabetes mellitus (DM) is a syndrome of disordered metabolism; main symptom is abnormally high blood glucose levels. The two most common forms of DM are due to either a diminished production of insulin (type 1), or diminished response by the body to insulin (type 2 and gestational). DM can cause many complications. Acute complications include ketoacidosis, hypoglycemia, or nonketotic hyperosmolar coma. Long-term complications include chronic renal failure, cardiovascular disease, diabetic retinopathy (DR), diabetic cataract and diabetic neuropathy, etc. [1]. DR is a common ocular complication of DM and is the most common cause of blindness in people of working age. DR represents a major socioeconomic problem. Around 2% of diabetic patients become legally blind and 10% have a severe visual handicap because of proliferative diabetic retinopathy (PDR) and/ or development of macular edema, despite the availability of several effective therapeutic options such as laser photocoagulation or vitrectomy [2]. The development of PDR is a multifactorial process. Most of the etiology is now understood to result from diabetic hyperglycemia, which promotes sorbitol production from glucose via aldose reductase [3]. Sorbitol plays a major role in the destruction of intramural
* Corresponding author. Tel./fax: +86 29 84775371. E-mail address: [email protected] (Y. Wang). 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.10.014
pericyte of retinal capillaries, resulting in leakage of plasma and proteinaceous material from these impaired vessels [4,5]. As the disease progresses, eventual closure of the retinal capillaries occurs, leading to retinal hypoxia, which triggers the production of vasoproliferative factors that stimulate retinal neovascularization (RNV). These new vessels arise mainly from the retinal venule may penetrate the internal limiting membrane into vitreous body [6,7]. The delicate RNV are disrupted easily by vitreous traction, which leads to vitreous hemorrhage. More severely, as the fibrosis of neovascularization, it may exert tractional force on the retina and cause tractional retinal detachment and retinal tear with subsequent detachment [8]. Insulin, vascular endothelial growth factor and hypoxiainducible factor 1 The major goal in treating DM is to minimize any elevation of blood glucose; insulin is the mainstay of treatment for patients with type 1 DM. For type 2 DM, when blood glucose levels can not be controlled by diet, weight loss, exercise, and oral medications, insulin is also crucial [9,10]. Insulin is synthesized in the pancreas b-cells and released into blood when any of several stimuli are detected, such as protein ingestion and increased glucose in the blood. The function of insulin is relative to glycogen synthesis, fatty acid synthesis, esterification of fatty acids, increased amino acid uptake, increased potassium uptake, etc. [9–11]. In the etiology of PDR, vascular endothelial growth factor (VEGF) as a major mediator of RNV and plays a key role. The
P. Zhang et al. / Medical Hypotheses 72 (2009) 306–308
upregulation of VEGF is associated with retinal ischemia, i.e. VEGF expression is mainly regulated by tissue oxygen content [12–14]. Pathologically, VEGF is closely related to proliferation of endothelial cell growth and breakdown of blood-retina barrier, resulting in RNV and retinal edema. The transcriptional regulation of VEGF is mediated by the transcription factor hypoxia-inducible factor 1 (HIF-1) [15–17]. HIF-1 is composed of two proteins: HIF-1a and HIF-1b. There are two transcriptional activation domains in HIF-1a referred to as the N-terminal activation domain (NAD) and the C-terminal activation domain (CAD). Between these two domains is an oxygen-dependent degradation domain (ODD), which, when deleted, confers stability of the protein in the presence of oxygen [18–20]. HIF-1b expresses constitutively under normoxia or hypoxia. The stability and activity of HIF-1a are regulated by hypoxia. Under normoxia, the HIF-1a subunit is rapidly degraded via the ubiquitin-proteasome pathway. On the contrary, in the hypoxia condition, HIF-1a subunit becomes stable and interacts with HIF-1b subunit to form HIF-1, to modulate its transcriptional activity. Once activated by hypoxia, HIF-1 binds to the consensus HIF-1 DNA binding site (HBS), which presents in the hypoxia-response elements (HREs) of many oxygen-regulated genes. HIF-1 target genes include those related to vasomotor control (such as NOS2), angiogenesis (such as VEGF), blood and iron metabolism (such as EPO, transferrin, transferrin receptor, ceruloplasmin), cell proliferation [such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-b] and many others [20–24]. Mounting evidence indicates that insulin stimulating VEGF expression in cultured retinal epithelial cells [25]. More importantly, insulin activates HIF-1a protein expression in a dosedependent manner, augments HIF-1 DNA binding activity, and stimulates HIF-1-mediated reporter gene transcription in retinal pigment epithelial cell, epithelial cells and vascular smooth muscle cells through phosphatidylinositol-3 kinase (PI3-K) and mitogenactivated protein kinase (MAPK) pathways [22,25,26]. Insulin and cell culture For the mitogenic effect, insulin has been used in cell culture since 1924 [27]. It has predominantly been used for the culture of non-malignant cells, such as human fibroblasts and endothelial cells. Commonly, insulin is added to medium to enhance cell survival and protein production. Evidences showed that at high concentrations of insulin, human hepatoma cells grow faster [27]. A study observed human retinal endothelial cells and neutrophils co-cultured in medium with insulin. The adhesion of neutrophils to endothelial cells and surface expression of intercellular adhesion molecule-1 (ICAM-1) significantly increased. In another study, rats continually received subcutaneous injection of insulin, leukocyte entrapment in the retina was significantly elevated. These results suggested that insulin may enhance leukostasis in retinal microcirculation [28,29]. Hypothesis Although the etiology of DM is of diversity, the primary target of treatment still is normalizing blood sugar with insulin. Based on our review, we hypothesize that long-term insulin therapy maybe deteriorates PDR. In the eye of PDR, insulin contacts with retinal vascular endothelium, and stimulates IGF-I, VEGF and other growth factors production from endothelial cells and others. IGF1 protects epithelial cells from apoptosis, and stimulates the growth of vascular smooth muscle cells. VEGF as the most important angiosis factor increases retinal vascular permeability resulting in more serous retinal edema. Furthermore, upregulated VEGF expedites the proliferation, migration and tube formation
307
of endothelial cells. On the other hand, nonperfusion of retinal capillary results in hypoxia of endothelial cells, which in turn stimulates accumulation of HIF-1a in endothelial cells, enhances the activation of the transcription factor leading to increased expression of VEGF and other growth factor genes. More importantly, upregulated VEGF and IGF-1 improve the sensitivity of insulin binding its receptor in endothelial cells. Consequently, the abnormal retinal cells, such as proliferating endothelial cells will migrate and proliferate more quickly, that is to say, the growth rate of RNV is enhanced. In addition, blood insulin increases the chance of leukocyte–endothelial cell adhesion in retinal microcirculation through surface expression of ICAM-1. Inflammatory response mediated by leukocytes, therefore, vascular permeability is aggravated and retinal edema is more grievous. These molecular events facilitate each other; result would be an amplification of the angiogenic signal leading to further progression of PDR. Conclusion In order to elucidate the affect of extraneous insulin on the development of RNV of PDR, long-term and large sample test of clinic outcome is necessary. DM is currently a chronic disease, except for pancreas or a kidney-pancreas transplant (long-term immunosuppressive drugs generally remain)[30], without a cure. Sensible exercise, diet control and weight loss is good way of keeping blood glucose levels and reducing diabetic complications for type 2 DM. External insulin still is the mainstay of controlling hyperglycemia, especially for type 1 DM. The paradoxical use of insulin potentially deteriorate PDR, facilitates retinal edema and neovascularization. Hence, how to weaken the side effect of insulin in frail retina of diabetic patient is a worthwhile target. References [1] Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, et al. Testosterone: and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036–41. [2] Massin P. Ocular complications in diabetes: towards standardizing screening and care. Rev Prat 2001;51:1776–82. [3] Gillies MC, Su T, Stayt J, Simpson JM, Naidoo D, Salonikas C. Effect of high glucose on permeability of retinal capillary endothelium in vitro. Invest Ophthalmol Vis Sci 1997;38:635–42. [4] Amano S, Yamagishi S, Kato N, Inagaki Y, Okamoto T, Makino M, et al. Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes. Biochem Biophys Res Commun 2002;299:183–8. [5] Ola MS, Berkich DA, Xu Y, King MT, Gardner TW, Simpson I, et al. Analysis of glucose metabolism in diabetic rat retinas. Am J Physiol Endocrinol Metab 2006;290:E1057–67. [6] Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy. Diabetes 2004;53:2931–8. [7] Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118:445–50. [8] Okamoto F, Okamoto Y, Fukuda S, Hiraoka T, Oshika T. Vision-related quality of life and visual function following vitrectomy for proliferative diabetic retinopathy. Am J Ophthalmol 2008;145:1031–6. [9] Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr 2003;22:487–93. [10] Bonadonna RC, De Fronzo RA. Glucose metabolism in obesity and type 2 diabetes. Diabete Metab 1991;17:112–35. [11] Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev 1998;19:608–24. [12] Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 1995;270:19761–6. [13] Levy AP, Levy NS, Wegner S, Goldberg MA. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 1995;270:13333–40. [14] Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 2003;44:2155–62. [15] Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306–9.
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P. Zhang et al. / Medical Hypotheses 72 (2009) 306–308
[16] Arjamaa O, Nikinmaa M. Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. Exp Eye Res 2006;83:473–83. [17] Zhang P, Wang Y, Hui Y, Hu D, Wang H, Zhou J, et al. Inhibition of VEGF expression by targeting HIF-1 alpha with small interference RNA in human RPE cells. Ophthalmologica 2007;221:411–7. [18] Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15:551–78. [19] Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basichelix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510–4. [20] Ratcliffe PJ, O’Rourke JF, Maxwell PH, Pugh CW. Oxygen sensing, hypoxiainducible factor-1 and the regulation of mammalian gene expression. J Exp Biol 1998;201:1153–62. [21] Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, et al. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem 2001;276:2292–8. [22] Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 2000;275:25130–8. [23] Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249–57. [24] Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ ARNT. EMBO J 1998;17:5085–94.
[25] Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 2002;277:27975–81. [26] Doronzo G, Russo I, Mattiello L, Riganti C, Anfossi G, Trovati M. Insulin activates hypoxia-inducible factor-1alpha in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling. Diabetologia 2006;49:1049–63. [27] Motoo Y, Kobayashi K, Hattori N. Effect of insulin on the growth of a human hepatoma cell line PLC/PRF/5: a possible role of insulin receptor. Tohoku J Exp Med 1988;156:351–7. [28] Hirata F, Yoshida M, Niwa Y, Okouchi M, Okayama N, Takeuchi Y, et al. Insulin enhances leukocyte–endothelial cell adhesion in the retinal microcirculation through surface expression of intercellular adhesion molecule-1. Microvasc Res 2005;69:135–41. [29] Okouchi M, Okayama N, Shimizu M, Omi H, Fukutomi T, Itoh M. High insulin exacerbates neutrophil-endothelial cell adhesion through endothelial surface expression of intercellular adhesion molecule-1 via activation of protein kinase C and mitogen-activated protein kinase. Diabetologia 2002;45:556–9. [30] O’Gorman D, Kin T, Murdoch T, Richer B, McGhee-Wilson D, Ryan EA, et al. The standardization of pancreatic donors for islet isolations. Transplantation 2005;80:801–6.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Insulin may cause deterioration of proliferative diabetic retinopathy Peng Zhang a, Na Liu b, Yusheng Wang a,* a b
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 15 West Changle Street, Xi’an, Shaanxi Province 710032, PR China State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, PR China
a r t i c l e
i n f o
Article history: Received 12 September 2008 Accepted 2 October 2008
s u m m a r y Diabetes mellitus (DM) can cause many systemic complications, including proliferative diabetic retinopathy (PDR). Retinal neovascularization (RNV) is the typical symptom of PDR, representing an important risk factor for severe vision loss in patients with DM. Diabetic hyperglycemia plays a major role in the destruction of retinal capillary walls, resulting in retinal ischemia and up-regulation of vascular endothelial growth factor (VEGF), leading to neovascularization. The transcriptional regulation of VEGF is mediated by transcription factor hypoxia-inducible factor 1 (HIF-1). Insulin is the mainstay of treatment for DM, but some studies have demonstrated that insulin had the ability to stimulate VEGF and HIF-1 expression in retinal pigment epithelial cells, retinal epithelial cells and vascular smooth muscle cells. In addition to the mitogenic effect of insulin makes it as an assistant agent has long been used in vitro cell culture. Other studies confirmed that insulin increased leukostasis in retinal microcirculation. Based on these experimental results, we hypothesize that long-term insulin therapy maybe improves the expression of VEGF and increase the risk of RNV, eventually deteriorates PDR in patients with DM. Ó 2008 Elsevier Ltd. All rights reserved.
Background Diabetes mellitus and diabetic retinopathy Diabetes mellitus (DM) is a syndrome of disordered metabolism; main symptom is abnormally high blood glucose levels. The two most common forms of DM are due to either a diminished production of insulin (type 1), or diminished response by the body to insulin (type 2 and gestational). DM can cause many complications. Acute complications include ketoacidosis, hypoglycemia, or nonketotic hyperosmolar coma. Long-term complications include chronic renal failure, cardiovascular disease, diabetic retinopathy (DR), diabetic cataract and diabetic neuropathy, etc. [1]. DR is a common ocular complication of DM and is the most common cause of blindness in people of working age. DR represents a major socioeconomic problem. Around 2% of diabetic patients become legally blind and 10% have a severe visual handicap because of proliferative diabetic retinopathy (PDR) and/ or development of macular edema, despite the availability of several effective therapeutic options such as laser photocoagulation or vitrectomy [2]. The development of PDR is a multifactorial process. Most of the etiology is now understood to result from diabetic hyperglycemia, which promotes sorbitol production from glucose via aldose reductase [3]. Sorbitol plays a major role in the destruction of intramural
* Corresponding author. Tel./fax: +86 29 84775371. E-mail address: [email protected] (Y. Wang). 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.10.014
pericyte of retinal capillaries, resulting in leakage of plasma and proteinaceous material from these impaired vessels [4,5]. As the disease progresses, eventual closure of the retinal capillaries occurs, leading to retinal hypoxia, which triggers the production of vasoproliferative factors that stimulate retinal neovascularization (RNV). These new vessels arise mainly from the retinal venule may penetrate the internal limiting membrane into vitreous body [6,7]. The delicate RNV are disrupted easily by vitreous traction, which leads to vitreous hemorrhage. More severely, as the fibrosis of neovascularization, it may exert tractional force on the retina and cause tractional retinal detachment and retinal tear with subsequent detachment [8]. Insulin, vascular endothelial growth factor and hypoxiainducible factor 1 The major goal in treating DM is to minimize any elevation of blood glucose; insulin is the mainstay of treatment for patients with type 1 DM. For type 2 DM, when blood glucose levels can not be controlled by diet, weight loss, exercise, and oral medications, insulin is also crucial [9,10]. Insulin is synthesized in the pancreas b-cells and released into blood when any of several stimuli are detected, such as protein ingestion and increased glucose in the blood. The function of insulin is relative to glycogen synthesis, fatty acid synthesis, esterification of fatty acids, increased amino acid uptake, increased potassium uptake, etc. [9–11]. In the etiology of PDR, vascular endothelial growth factor (VEGF) as a major mediator of RNV and plays a key role. The
P. Zhang et al. / Medical Hypotheses 72 (2009) 306–308
upregulation of VEGF is associated with retinal ischemia, i.e. VEGF expression is mainly regulated by tissue oxygen content [12–14]. Pathologically, VEGF is closely related to proliferation of endothelial cell growth and breakdown of blood-retina barrier, resulting in RNV and retinal edema. The transcriptional regulation of VEGF is mediated by the transcription factor hypoxia-inducible factor 1 (HIF-1) [15–17]. HIF-1 is composed of two proteins: HIF-1a and HIF-1b. There are two transcriptional activation domains in HIF-1a referred to as the N-terminal activation domain (NAD) and the C-terminal activation domain (CAD). Between these two domains is an oxygen-dependent degradation domain (ODD), which, when deleted, confers stability of the protein in the presence of oxygen [18–20]. HIF-1b expresses constitutively under normoxia or hypoxia. The stability and activity of HIF-1a are regulated by hypoxia. Under normoxia, the HIF-1a subunit is rapidly degraded via the ubiquitin-proteasome pathway. On the contrary, in the hypoxia condition, HIF-1a subunit becomes stable and interacts with HIF-1b subunit to form HIF-1, to modulate its transcriptional activity. Once activated by hypoxia, HIF-1 binds to the consensus HIF-1 DNA binding site (HBS), which presents in the hypoxia-response elements (HREs) of many oxygen-regulated genes. HIF-1 target genes include those related to vasomotor control (such as NOS2), angiogenesis (such as VEGF), blood and iron metabolism (such as EPO, transferrin, transferrin receptor, ceruloplasmin), cell proliferation [such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-b] and many others [20–24]. Mounting evidence indicates that insulin stimulating VEGF expression in cultured retinal epithelial cells [25]. More importantly, insulin activates HIF-1a protein expression in a dosedependent manner, augments HIF-1 DNA binding activity, and stimulates HIF-1-mediated reporter gene transcription in retinal pigment epithelial cell, epithelial cells and vascular smooth muscle cells through phosphatidylinositol-3 kinase (PI3-K) and mitogenactivated protein kinase (MAPK) pathways [22,25,26]. Insulin and cell culture For the mitogenic effect, insulin has been used in cell culture since 1924 [27]. It has predominantly been used for the culture of non-malignant cells, such as human fibroblasts and endothelial cells. Commonly, insulin is added to medium to enhance cell survival and protein production. Evidences showed that at high concentrations of insulin, human hepatoma cells grow faster [27]. A study observed human retinal endothelial cells and neutrophils co-cultured in medium with insulin. The adhesion of neutrophils to endothelial cells and surface expression of intercellular adhesion molecule-1 (ICAM-1) significantly increased. In another study, rats continually received subcutaneous injection of insulin, leukocyte entrapment in the retina was significantly elevated. These results suggested that insulin may enhance leukostasis in retinal microcirculation [28,29]. Hypothesis Although the etiology of DM is of diversity, the primary target of treatment still is normalizing blood sugar with insulin. Based on our review, we hypothesize that long-term insulin therapy maybe deteriorates PDR. In the eye of PDR, insulin contacts with retinal vascular endothelium, and stimulates IGF-I, VEGF and other growth factors production from endothelial cells and others. IGF1 protects epithelial cells from apoptosis, and stimulates the growth of vascular smooth muscle cells. VEGF as the most important angiosis factor increases retinal vascular permeability resulting in more serous retinal edema. Furthermore, upregulated VEGF expedites the proliferation, migration and tube formation
307
of endothelial cells. On the other hand, nonperfusion of retinal capillary results in hypoxia of endothelial cells, which in turn stimulates accumulation of HIF-1a in endothelial cells, enhances the activation of the transcription factor leading to increased expression of VEGF and other growth factor genes. More importantly, upregulated VEGF and IGF-1 improve the sensitivity of insulin binding its receptor in endothelial cells. Consequently, the abnormal retinal cells, such as proliferating endothelial cells will migrate and proliferate more quickly, that is to say, the growth rate of RNV is enhanced. In addition, blood insulin increases the chance of leukocyte–endothelial cell adhesion in retinal microcirculation through surface expression of ICAM-1. Inflammatory response mediated by leukocytes, therefore, vascular permeability is aggravated and retinal edema is more grievous. These molecular events facilitate each other; result would be an amplification of the angiogenic signal leading to further progression of PDR. Conclusion In order to elucidate the affect of extraneous insulin on the development of RNV of PDR, long-term and large sample test of clinic outcome is necessary. DM is currently a chronic disease, except for pancreas or a kidney-pancreas transplant (long-term immunosuppressive drugs generally remain)[30], without a cure. Sensible exercise, diet control and weight loss is good way of keeping blood glucose levels and reducing diabetic complications for type 2 DM. External insulin still is the mainstay of controlling hyperglycemia, especially for type 1 DM. The paradoxical use of insulin potentially deteriorate PDR, facilitates retinal edema and neovascularization. Hence, how to weaken the side effect of insulin in frail retina of diabetic patient is a worthwhile target. References [1] Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, et al. Testosterone: and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036–41. [2] Massin P. Ocular complications in diabetes: towards standardizing screening and care. Rev Prat 2001;51:1776–82. [3] Gillies MC, Su T, Stayt J, Simpson JM, Naidoo D, Salonikas C. Effect of high glucose on permeability of retinal capillary endothelium in vitro. Invest Ophthalmol Vis Sci 1997;38:635–42. [4] Amano S, Yamagishi S, Kato N, Inagaki Y, Okamoto T, Makino M, et al. Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes. Biochem Biophys Res Commun 2002;299:183–8. [5] Ola MS, Berkich DA, Xu Y, King MT, Gardner TW, Simpson I, et al. Analysis of glucose metabolism in diabetic rat retinas. Am J Physiol Endocrinol Metab 2006;290:E1057–67. [6] Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy. Diabetes 2004;53:2931–8. [7] Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118:445–50. [8] Okamoto F, Okamoto Y, Fukuda S, Hiraoka T, Oshika T. Vision-related quality of life and visual function following vitrectomy for proliferative diabetic retinopathy. Am J Ophthalmol 2008;145:1031–6. [9] Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr 2003;22:487–93. [10] Bonadonna RC, De Fronzo RA. Glucose metabolism in obesity and type 2 diabetes. Diabete Metab 1991;17:112–35. [11] Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev 1998;19:608–24. [12] Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 1995;270:19761–6. [13] Levy AP, Levy NS, Wegner S, Goldberg MA. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 1995;270:13333–40. [14] Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 2003;44:2155–62. [15] Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306–9.
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P. Zhang et al. / Medical Hypotheses 72 (2009) 306–308
[16] Arjamaa O, Nikinmaa M. Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. Exp Eye Res 2006;83:473–83. [17] Zhang P, Wang Y, Hui Y, Hu D, Wang H, Zhou J, et al. Inhibition of VEGF expression by targeting HIF-1 alpha with small interference RNA in human RPE cells. Ophthalmologica 2007;221:411–7. [18] Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15:551–78. [19] Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basichelix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510–4. [20] Ratcliffe PJ, O’Rourke JF, Maxwell PH, Pugh CW. Oxygen sensing, hypoxiainducible factor-1 and the regulation of mammalian gene expression. J Exp Biol 1998;201:1153–62. [21] Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, et al. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem 2001;276:2292–8. [22] Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 2000;275:25130–8. [23] Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249–57. [24] Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ ARNT. EMBO J 1998;17:5085–94.
[25] Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 2002;277:27975–81. [26] Doronzo G, Russo I, Mattiello L, Riganti C, Anfossi G, Trovati M. Insulin activates hypoxia-inducible factor-1alpha in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling. Diabetologia 2006;49:1049–63. [27] Motoo Y, Kobayashi K, Hattori N. Effect of insulin on the growth of a human hepatoma cell line PLC/PRF/5: a possible role of insulin receptor. Tohoku J Exp Med 1988;156:351–7. [28] Hirata F, Yoshida M, Niwa Y, Okouchi M, Okayama N, Takeuchi Y, et al. Insulin enhances leukocyte–endothelial cell adhesion in the retinal microcirculation through surface expression of intercellular adhesion molecule-1. Microvasc Res 2005;69:135–41. [29] Okouchi M, Okayama N, Shimizu M, Omi H, Fukutomi T, Itoh M. High insulin exacerbates neutrophil-endothelial cell adhesion through endothelial surface expression of intercellular adhesion molecule-1 via activation of protein kinase C and mitogen-activated protein kinase. Diabetologia 2002;45:556–9. [30] O’Gorman D, Kin T, Murdoch T, Richer B, McGhee-Wilson D, Ryan EA, et al. The standardization of pancreatic donors for islet isolations. Transplantation 2005;80:801–6.