Diabetes mellitus and its clinical association with dry eye and ocular surface are becoming a frequent and sometimes complicate problem in Ophthalmology. Epidemiological data show that an increase in the number of patients with this association is expected following the trend to rise of the disease. The present work reviews the clinical and functional aspects of this problem. The observations indicate that metabolic, neuropathic and vascular tissue damages lead to an inflammatory process and functional degeneration. The physiopathological mechanism include hyperglycemia, advanced glycated end product accumulation, oxidative stress and inflammation mediated by NF-κB signaling pathways. Potential treatments enlightened by those findings would include antioxidant, anti-inflammatory, secretagogues and/or anabolic agents that would mimic insulin effects.716 SUPP96103Moss, S.E., Klein, R., Klein, B.E., Prevalence of and risk factors for dry eye syndrome (2000) Arch Ophthalmol, 118 (9), pp. 1264-1268Moss, S.E., Klein, R., Klein, B.E., Incidence of dry eye in an older population (2004) Arch Ophthalmol, 122 (3), pp. 369-373Ramos-Remus, C., Suarez-Almazor, M., Russell, A.S., Low tear production in patients with diabetes mellitus is not due to Sjögren's syndrome (1994) Clin Exp Rheumatol, 12 (4), pp. 375-380Goebbels, M., Tear secretion and tear film function in insulin dependent diabetics (2000) Br J Ophthalmol, 84 (1), pp. 19-21Dogru, M., Katakami, C., Inoue, M., Tear function and ocular surface changes in noninsulin-dependent diabetes mellitus (2001) Ophthalmology, 108 (3), pp. 586-592Kaiserman, I., Kaiserman, N., Nakar, S., Vinker, S., Dry eye in diabetic patients (2005) Am J Ophthalmol, 139 (3), pp. 498-503Zimmet, P., Alberti, K.G., Shaw, J., Global and societal implications of the diabetes epidemic (2001) Nature, 414 (6865), pp. 782-787King, H., Aubert, R.E., Herman, W.H., Global burden of diabetes, 1995-2025: prevalence, numerical estimates and projections (1998) Diabetes Care, 21 (9), pp. 1414-1431Saad, M.J., Molecular mechanisms of insulin resistance (1994) Braz J Med Biol Res, 27 (4), pp. 941-957Kahn, B.B., Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance (1998) Cell, 92 (5), pp. 593-596Kahn, C.R., Vicent, D., Doria, A., Genetics of non-insulin-dependent (type-II) diabetes mellitus (1996) Annu Rev Med, 47, pp. 509-531Brownlee, M., Biochemistry and molecular cell biology of diabetic complications (2001) Nature, 414 (6865), pp. 813-820The Diabetes Control and Complications Trial Research Group (1993) N Engl J Med, 329 (14), pp. 977-986. , The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitusUK Prospective Diabetes Study (UKPDS) Group (1998) Lancet, 352 (9131), pp. 837-853. , Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)Ebara, T., Conde, K., Kako, Y., Liu, Y., Xu, Y., Ramakrishnan, R., Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice (2000) J Clin Invest, 105 (12), pp. 1807-1818Ginsberg, H.N., Insulin resistance and cardiovascular disease (2000) J Clin Invest, 106 (4), pp. 453-458Wei, M., Gaskill, S.P., Haffner, S.M., Stern, M.P., Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality (1998) The San Antonio Heart Study. Diabetes Care., 21 (7), pp. 1167-1172Ishida, N., Rao, G.N., del Cerro, M., Aquavella, J.V., Corneal nerve alterations in diabetes mellitus (1984) Arch Ophthalmol, 102 (9), pp. 1380-1384Azar, D.T., Spurr-Michaud, S.J., Tisdale, A.S., Gipson, I.K., Altered epithelialbasement membrane interactions in diabetic corneas (1992) Arch Ophthalmol, 110 (4), pp. 537-540Hsueh, W.A., Law, R.E., Cardiovascular risk continuum: implications of insulin resistance and diabetes (1998) Am J Med, 105 (1 A), pp. 4S-14SJiang, Z.Y., Lin, Y.W., Clemont, A., Feener, E.P., Hein, K.D., Igarashi, M., Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats (1999) J Clin Invest, 104 (4), pp. 447-457Zecchin, H.G., Bezerra, R.M., Carvalheira, J.B., Carvalho-Filho, M.A., Metze, K., Franchini, K.G., Insulin signalling pathways in aorta and muscle from two animal models of insulin resistance-the obese middle-aged and the spontaneously hypertensive rats (2003) Diabetologia, 46 (4), pp. 479-491Zecchin, H.G., Priviero, F.B., Souza, C.T., Zecchin, K.G., Prada, P.O., Carvalheira, J.B., Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats (2007) Diabetes, 56 (4), pp. 1014-1024Du, X.L., Edelstein, D., Rossetti, L., Fantus, I.G., Goldberg, H., Ziyadeh, F., Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation (2000) Proc Natl Acad Sci U S A, 97 (22), pp. 12222-12226Yagyu, H., Kitamine, T., Osuga, J., Tozawa, R., Chen, Z., Kaji, Y., Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia (2000) J Biol Chem, 275 (28), pp. 21324-21330Temelkova-Kurktschiev, T.S., Koehler, C., Henkel, E., Leonhardt, W., Fuecker, K., Hanefeld, M., Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level (2000) Diabetes Care, 23 (12), pp. 1830-1834Vlassara, H., Bucala, R., Striker, L., Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging (1994) Lab Invest, 70 (2), pp. 138-151Alves, M., Calegari, V.C., Cunha, D.A., Saad, M.J., Velloso, L.A., Rocha, E.M., Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats (2005) Diabetologia, 48 (12), pp. 2675-2681Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P.M., Chen, J., Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB (2001) Diabetes, 50 (12), pp. 2792-2808Evans, J.L., Goldfine, I.D., Maddux, B.A., Grodsky, G.M., Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes (2002) Endocr Rev, 23 (5), pp. 599-622Stitt, A.W., Advanced glycation: an important pathological event in diabetic and age related ocular disease (2001) Br J Ophthalmol, 85 (6), pp. 746-753Leslie, R.D., United Kingdom prospective diabetes study (UKPDS): what now or so what? (1999) Diabetes Metab Res Rev, 15 (1), pp. 65-71Chung, H., Tolentino, F.I., Cajita, V.N., Acosta, J., Refojo, M.F., Reevaluation of corneal complications after closed vitrectomy (1988) Arch Ophthalmol, 106 (7), pp. 916-919Taylor, H.R., Kimsey, R.A., Corneal epithelial basement membrane changes in diabetes (1981) Invest Ophthalmol Vis Sci, 20 (4), pp. 548-553Kaji, Y., Prevention of diabetic keratopathy (2005) Br J Ophthalmol, 89 (3), pp. 254-255Foulks, G.N., Thoft, R.A., Perry, H.D., Tolentino, F.I., Factors related to corneal epithelial complications after closed vitrectomy in diabetics (1979) Arch Ophthalmol, 97 (6), pp. 1076-1078Hyndiuk, R.A., Kazarian, E.L., Schultz, R.O., Seideman, S., Neurotrophic corneal ulcers in diabetes mellitus (1977) Arch Ophthalmol, 95 (12), pp. 2193-2196Kenyon, K.R., Stark, W.J., Stone, D.L., Corneal endothelial degeneration and fibrous proliferation after plana vitrectomy (1976) Am J Ophthalmol, 81 (4), pp. 486-490Friend, J., Thoft, R.A., The diabetic cornea (1984) Int Ophthalmol Clin, 24 (4), pp. 111-123Cousen, P., Cackett, P., Bennett, H., Swa, K., Dhillon, B., Tear production and corneal sensitivity in diabetes (2007) J Diabetes Complications, 21 (6), pp. 371-373Lockwood, A., Hope-Ross, M., Chell, P., Neurotrophic keratopathy and diabetes mellitus (2006) Eye, 20 (7), pp. 837-839Seifart, U., Strempel, I., The dry eye and diabetes mellitus (1994) Ophthalmologe, 91 (2), pp. 235-239Rieger, G., The importance of the precorneal tear film for the quality of optical imaging (1992) Br J Ophthalmol, 76 (3), pp. 157-158Inoue, K., Kato, S., Ohara, C., Numaga, J., Amano, S., Oshika, T., Ocular and systemic factors relevant to diabetic keratoepitheliopathy (2001) Cornea, 20 (8), pp. 798-801Nepp, J., Abela, C., Polzer, I., Derbolav, A., Wedrich, A., Is there a correlation between the severity of diabetic retinopathy and keratoconjunctivitis sicca? (2000) Cornea, 19 (4), pp. 487-491Henricsson, M., Nilsson, A., Janzon, L., Groop, L., The effect of glycaemic control and the introduction of insulin therapy on retinopathy in non-insulin-dependent diabetes mellitus (1997) Diabet Med, 14 (2), pp. 123-131Rakieten, N., Rakieten, M.L., Nadkarni, M.V., Studies on the diabetogenic action of streptozotocin (NSC-37917) (1963) Cancer Chemother Rep, 29, pp. 91-98Junod, A., Lambert, A.E., Orci, L., Pictet, R., Gonet, A.E., Renold, A.E., Studies of the diabetogenic action of streptozotocin (1967) Proc Soc Exp Biol Med, 126 (1), pp. 201-205Reed, M.J., Meszaros, K., Entes, L.J., Claypool, M.D., Pinkett, J.G., Gadbois, T.M., A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat (2000) Metabolism, 49 (11), pp. 1390-1394Kuriyama, H., Sasaki, K., Fukuda, M., Studies on diabetic cataract in rats induced by streptozotocin II. Biochemical examinations of rat lenses in relation to cataract stages (1983) Ophthalmic Res, 15 (4), pp. 191-197Stitt, A.W., Anderson, H.R., Gardiner, T.A., McIntyre, I., Archer, D.B., The combined effects of diabetes and ionising radiation on the rat retina: an ultrastructural study (1994) Curr Eye Res, 13 (1), pp. 79-86Cutler, L.S., Pinney, H.E., Christian, C., Russotto, S.B., Ultrastructural studies of the rat submandibular gland in streptozotocin induced diabetes mellitus (1979) Virchows Arch A Pathol Anat Histol, 382 (3), pp. 301-311Zagon, I.S., Sassani, J.W., McLaughlin, P.J., Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats (2006) Diabetes, 55 (4), pp. 1141-1147Cunha, D.A., de Alves, M.C., Stoppiglia, L.F., Jorge, A.G., Modulo, C.M., Carneiro, E.M., Extra-pancreatic insulin production in RAt lachrymal gland after streptozotocin-induced islet beta-cells destruction (2007) Biochim Biophys Acta, 1770 (8), pp. 1128-1135Toda, I., Sullivan, B.D., Rocha, E.M., da Silveira, L.A., Wickham, L.A., Sullivan, D.A., Impact of gender on exocrine gland inflammation in mouse models of Sjogren's syndrome (1999) Exp Eye Res, 69 (4), pp. 355-366Barabino, S., Dana, M.R., Animal models of dry eye: a critical assessment of opportunities and limitations (2004) Invest Ophthalmol Vis Sci, 45 (6), pp. 1641-1646Wakuta, M., Morishige, N., Chikama, T., Seki, K., Nagano, T., Nishida, T., Delayed wound closure and phenotypic changes in corneal epithelium of the spontaneously diabetic Goto-Kakizaki rat (2007) Invest Ophthalmol Vis Sci, 48 (2), pp. 590-596Rocha, E.M., de, M.L.M.H., Carvalho, C.R., Saad, M.J., Velloso, L.A., Characterization of the insulin-signaling pathway in lacrimal and salivary glands of rats (2000) Curr Eye Res, 21 (5), pp. 833-842Hann, L.E., Kelleher, R.S., Sullivan, D.A., Influence of culture conditions on the androgen control of secretory component production by acinar cells from the rat lacrimal gland (1991) Invest Ophthalmol Vis Sci, 32 (9), pp. 2610-2621Adeghate, E., Hameed, R.S., Immunohistochemical localization of orexin-B, orexin-1 receptor, ghrelin GHS-R in the lacrimal gland of normal and diabetic rats (2005) Peptides, 26 (12), pp. 2585-2589Mahay, S., Adeghate, E., Lindley, M.Z., Rolph, C.E., Singh, J., Streptozotocininduced type 1 diabetes mellitus alters the morphology, secretory function and acyl lipid contents in the isolated rat parotid salivary gland (2004) Mol Cell Biochem, 261 (1-2), pp. 175-181Nogueira, F.N., Carvalho, A.M., Yamaguti, P.M., Nicolau, J., Antioxidant parameters and lipid peroxidation in salivary glands of streptozotocin-induced diabetic rats (2005) Clin Chim Acta, 353 (1-2), pp. 133-139Nishida, T., Nakagawa, S., Manabe, R., Superoxide dismutase activity in diabetic rat retina (1984) Jpn J Ophthalmol, 28 (4), pp. 377-382Zoukhri, D., Hodges, R.R., Byon, D., Kublin, C.L., Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia (2002) Invest Ophthalmol Vis Sci, 43 (5), pp. 1429-1436Rocha, E.M., Wickham, L.A., Huang, Z., Toda, I., Gao, J., da Silveira, L.A., Presence and testosterone influence on the levels of antiand pro-inflammatory cytokines in lacrimal tissues of a mouse model of Sjogren's syndrome (1998) Adv Exp Med Biol, 438, pp. 485-491Fukushi, S., Merola, L.O., Tanaka, M., Datiles, M., Kinoshita, J.H., Reepithelialization of denuded corneas in diabetic rats (1980) Exp Eye Res, 31 (5), pp. 611-621Azar, D.T., Gipson, I.K., Repair of the corneal epithelial adhesion structures following keratectomy wounds in diabetic rabbits (1989) Acta Ophthalmol Suppl, 192, pp. 72-79Fowler, S.A., Wound healing in the corneal epithelium in diabetic and normal rats (1980) Exp Eye Res, 31 (2), pp. 167-179Zagon, I.S., Klocek, M.S., Sassani, J.W., McLaughlin, P.J., Use of topical insulin to normalize corneal epithelial healing in diabetes mellitus (2007) Arch Ophthalmol, 125 (8), pp. 1082-1088Gonul, B., Koz, M., Ersoz, G., Kaplan, B., Effect of EGF on the corneal wound healing of alloxan diabetic mice (1992) Exp Eye Res, 54 (4), pp. 519-524Yamada, N., Yanai, R., Kawamoto, K., Nagano, T., Nakamura, M., Inui, M., Promotion of corneal epithelial wound healing by a tetrapeptide (SSSR) derived from IGF-1 (2006) Invest Ophthalmol Vis Sci, 47 (8), pp. 3286-3292Yanai, R., Yamada, N., Inui, M., Nishida, T., Correlation of proliferative and antiapoptotic effects of HGF, insulin, IGF-1, IGF-2, and EGF in SV40-transformed human corneal epithelial cells (2006) Exp Eye Res, 83 (1), pp. 76-83Cunha, D.A., Carneiro, E.M., Alves Mde, C., Jorge, A.G., de Sousa, S.M., Boschero, A.C., Insulin secretion by rat lacrimal glands: effects of systemic and local variables (2005) Am J Physiol Endocrinol Metab, 289 (5), pp. E768-E775Kern, T.S., Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy (2007) Exp Diabetes Res, 95, p. 103Tracey, K.J., Physiology and immunology of the cholinergic antiinflammatory pathway (2007) J Clin Invest, 117 (2), pp. 289-296Nguyen, D.H., Beuerman, R.W., Meneray, M., Toshida, H., Sensory denervation modulates eIF-2 alpha kinase expression in the rabbit lacrimal gland (2006) Curr Eye Res, 31 (4), pp. 287-295Carter, D.A., Wobken, J.D., Dixit, P.K., Bauer, G.E., Immunoreactive insulin in rat salivary glands and its dependence on age and serum insulin levels (1995) Proc Soc Exp Biol Med, 209 (3), pp. 245-250Westrom, B.R., Ekman, R., Svendsen, L., Svendsen, J., Karlsson, B.W., Levels of immunoreactive insulin, neurotensin, and bombesin in porcine colostrum and milk (1987) J Pediatr Gastroenterol Nutr, 6 (3), pp. 460-465Rocha, E.M., Cunha, D.A., Carneiro, E.M., Boschero, A.C., Saad, M.J., Velloso, L.A., Identification of insulin in the tear film and insulin receptor and IGF-1 receptor on the human ocular surface (2002) Invest Ophthalmol Vis Sci, 43 (4), pp. 963-967Habib, T., Hejna, J.A., Moses, R.E., Decker, S.J., Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein (1998) J Biol Chem, 273 (29), pp. 18605-18609Degenhardt, T.P., Alderson, N.L., Arrington, D.D., Beattie, R.J., Basgen, J.M., Steffes, M.W., Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat (2002) Kidney Int, 61 (3), pp. 939-950Peponis, V., Bonovas, S., Kapranou, A., Peponi, E., Filioussi, K., Magkou, C., Conjunctival and tear film changes after vitamin C and E administration in noninsulin dependent diabetes mellitus (2004) Med Sci Monit, 10 (5), pp. CR213-CR217Yin, M.J., Yamamoto, Y., Gaynor, R.B., The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta (1998) Nature, 396 (6706), pp. 77-80Shoelson, S.E., Lee, J., Yuan, M., Inflammation and the IKK beta/I kappa B/NFkappa B axis in obesityand diet-induced insulin resistance (2003) Int J Obes Relat Metab Disord, 27 (SUPPL 3), pp. S49-52Beauregard, C., Brandt, P.C., Peroxisome proliferator-activated receptor agonists inhibit interleukin-1beta-mediated nitric oxide production in cultured lacrimal gland acinar cells (2003) J Ocul Pharmacol Ther, 19 (6), pp. 579-587Bonini, S., Lambiase, A., Rama, P., Caprioglio, G., Aloe, L., Topical treatment with nerve growth factor for neurotrophic keratitis (2000) Ophthalmology, 107 (7), pp. 1347-1351. , discussion 1351-2Brown, S.M., Lamberts, D.W., Reid, T.W., Nishida, T., Murphy, C.J., Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1 (1997) Arch Ophthalmol, 115 (7), pp. 926-927Watanabe, M., Yamagishi-Wang, H., Kawaguchi, M., Lowered susceptibility of muscarinic receptor involved in salivary secretion of streptozotocin-induced diabetic rats (2001) Jpn J Pharmacol, 87 (2), pp. 117-124Schulze, S., Sekundo, W., Kroll, P., Autologous serum versus hyaluronic acid eye drops for the treatment of corneal erosions after vitrectomy in diabetic patients (2005) A prospective randomized study. Ophthalmologe., 102 (9), pp. 863-868