Authors : Ahamed Syedh K.; Dr. A. Pandiselvi; Aravindhan N.; Poovarasan B.; Sarankarthikeyan S.; Miruthungupta R. B.; Harish Kumar E.; Arulmani T.

Volume/Issue : Volume 10 - 2025, Issue 8 - August

Google Scholar : https://tinyurl.com/mvn222cw

Scribd : https://tinyurl.com/52kwy3nt

DOI : https://doi.org/10.38124/ijisrt/25aug1181

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Note : Google Scholar may take 30 to 40 days to display the article.

Abstract : Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is a complex metabolic disorder frequently accompanied by a wide array of comorbidities that significantly increase morbidity and mortality. These comorbidities encompass cardiovascular diseases (e.g., hypertension, atherosclerosis, stroke), renal dysfunction (diabetic nephropathy), hepatic disorders (non-alcoholic fatty liver disease), neurological complications (diabetic neuropathy and cognitive decline), and reproductive disturbances (male and female infertility). The shared pathophysiological mechanisms underlying these complications include chronic hyperglycemia, insulin resistance, oxidative stress, low-grade systemic inflammation, and advanced glycation end-product (AGE) formation. These factors contribute to endothelial dysfunction, mitochondrial impairment, and multiorgan cellular injury. Moreover, the presence of comorbidities further complicates glycemic control and worsens clinical outcomes, creating a vicious cycle of disease progression. Early detection and integrated management strategies targeting both hyperglycemia and comorbid conditions are essential for improving the quality of life and reducing the long-term burden of diabetes. This review aims to elucidate the major diabetic comorbidities, their underlying mechanisms, and the importance of comprehensive care in diabetic patients.

Keywords : RAGE, AGE, PAD, TIDM, T2DM, PKC, IDF, TNF-α, IL-1β, and IL-6, CVD, AGE.

References :

1. American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33(Suppl 1):S62–S69.
2. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358(9277):221–229.
3. Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia. 2019;62(1):3–16.
4. International Diabetes Federation. IDF Diabetes Atlas. 10th ed. Brussels, Belgium: IDF; 2021.
5. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
6. Anjana RM, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, et al. Prevalence of diabetes and prediabetes in urban and rural India: Phase I results of the Indian Council of Medical Research–INdia DIABetes (ICMR-INDIAB) study. Diabetologia. 2011;54(12):3022–3027.
7. Knip M, Siljander H. Autoimmune mechanisms in type 1 diabetes. Lancet. 2008;371(9626):1776–1783.
8. Ziegler AG, Bonifacio E, Hyek M, Winkler C, Lauber E, Naserke HE, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. J Clin Invest. 2009;119(4):1068–1076.
9. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Diabetes Care. 2015;38(9):1778–1785.
10. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. Ann Intern Med. 2001;134(2):96–105.
11. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Diabetes. 2006;55(11):2998–3007.
12. Ling C, Rönn T. Epigenetic adaptation to regular exercise in humans. Nat Rev Endocrinol. 2019;15(2):71–72.
13. Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154. https://doi.org/10.2337/dc16-2042
14. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathies. Med Clin North Am. 2013;97(1):99–120. https://doi.org/10.1016/j.mcna.2012.10.002
15. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521–534. https://doi.org/10.1016/S1474-4422(12)70065-0
16. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–2293. https://doi.org/10.2337/dc10-1303
17. Thomas MC, Cooper ME, Zimmet P. Diabetic nephropathy. Nat Rev Nephrol. 2015;11(3):129–138.
18. Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):556–563.
19. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93(1):137–188.
20. International Diabetes Federation. IDF Diabetes Atlas. 10th ed. Brussels, Belgium: IDF; 2021.
21. United States Renal Data System. USRDS 2023 Annual Data Report: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2023.
22. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124–136.
23. Stitt AW, Curtis TM, Chen M, Medina RJ, McKay GJ, Jenkins A, et al. The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res. 2016;51:156–186.
24. International Diabetes Federation. IDF Diabetes Atlas. 10th ed. Brussels, Belgium: IDF; 2021.
25. Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556–564.
26. GBD 2020 Blindness and Vision Impairment Collaborators. Global estimates on the number of people blind or visually impaired by diabetic retinopathy. Lancet Glob Health. 2021.
27. Pop-Busui, R. et al. (2017). Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care, 40(1), 136–154.
28. Armstrong, D. G., Boulton, A. J., & Bus, S. A. (2017). Diabetic Foot Ulcers and Their Recurrence. New England Journal of Medicine, 376, 2367–2375.
29. International Diabetes Federation. IDF Diabetes Atlas, 10th Edition, 2021.
30. Singh, N., Armstrong, D. G., & Lipsky, B. A. (2005). Preventing Foot Ulcers in Patients With Diabetes. JAMA, 293(2), 217–228.
31. American Heart Association (2020). Adults with diabetes are two to four times more likely to die from heart disease than adults without diabetes. AHA - Cardiovascular Disease & Diabetes.
32. Brownlee M. (2001). Biochemistry and molecular cell biology of diabetic complications. Nature, 414(6865), 813–820.
33. Goldin A. et al. (2006). Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation, 114(6), 597–605.
34. Howard BV, et al. (2002). Dyslipidemia in type 2 diabetes and the metabolic syndrome. Current Diabetes Reports, 2(6), 477–483.
35. Beckman JA, Creager MA, Libby P. (2002). Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA, 287(19), 2570–2581.
36.  American Heart Association. Cardiovascular disease and diabetes. Dallas: American Heart Association; 2020. Available from: https://www.heart.org/en/health-topics/diabetes/why-diabetes-matters/cardiovascular-disease--diabetes
37. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114(6):597–605.
38.  Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.
39.  Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, et al. LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals. Curr Diab Rep. 2002;2(6):477–83.
40.  Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19):2570–81.
41. Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Lancet Neurol. 2018;17(11):987–1000.
42. Fowkes FG, et al. "Peripheral artery disease: epidemiology and global perspectives." Nat Rev Cardiol. 2017;14(3):156-170.
43. Beckman JA, et al. "Diabetes and vascular disease." Circulation. 2002;105(18):2136-2143.
44. Giacco F, Brownlee M. "Oxidative stress and diabetic complications." Circ Res. 2010;107(9):1058-1070.
45. Ramasamy R, et al. "AGE-RAGE in diabetes and inflammatory diseases." Nat Rev Endocrinol. 2009;5(5):261-275.
46. Bierhaus A, et al. "Understanding RAGE signaling." J Mol Med. 2005;83(11):876-886.
47. Hansson GK. "Inflammation, atherosclerosis, and coronary artery disease." N Engl J Med. 2005;352(16):1685-1695.
48. Howard BV, et al. "Dyslipidemia in type 2 diabetes." Endocrinol Metab Clin North Am. 2001;30(4):987-1009.
49. Montagnani M, et al. "Insulin resistance and endothelial dysfunction: mechanisms and implications." Am J Physiol. 2002;283:E1003–E1012.
50. Santilli F, et al. "Inflammation in vascular disease in diabetes." Clin Chem Lab Med. 2008;46(7):934-942.
51. Vazzana N, et al. "Diabetes mellitus and thrombosis." Thromb Res. 2012;129(3):371-377.
52. Jude EB, et al. "Peripheral arterial disease in diabetic and nondiabetic patients." Diabet Med. 2001;18(7): 478-484.
53. Prompers L, et al. "High prevalence of ischemia in diabetic foot patients." Diabetes Care. 2008;31(5): 961–965.
54. Aboyans V, et al. "Measurement and interpretation of the ankle–brachial index." Circulation. 2012;126(24):2890-2909.
55. Norgren L, et al. "Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)." Eur J Vasc Endovasc Surg. 2007;33(Suppl 1):S1–S75.
56. Bainbridge KE, et al. “Diabetes and hearing impairment in the United States.” Ann Intern Med. 2008;149(1):1–10.
57. Cullen JR, et al. “Hearing loss in diabetes.” J Laryngol Otol. 1975;89(3):217–224.
58. Frisina ST, et al. “Characterization of hearing loss in aged type II diabetics.” Hear Res. 2006;211(1–2):103–113.
59. Fukushima H, et al. “Diabetes-induced microangiopathy in the cochlea.” Acta Otolaryngol Suppl. 2004;(552):30–35.
60. Prazma J, et al. “Insulin and microvascular reactivity in diabetic guinea pigs.” Arch Otolaryngol Head Neck Surg. 1999;125(10):1125–1129.
61. Vincent AM, et al. “Oxidative stress in diabetic neuropathy.” Endocr Rev. 2004;25(4):612–628.
62. Wu HP, et al. “Increased cochlear oxidative stress in streptozotocin-induced diabetic mice.” Neurotox Res. 2012;21(3):312–318.
63. Ramasamy R, et al. “Receptor for advanced glycation endproducts (RAGE) and implications for the pathogenesis of diabetic complications.” Cell Mol Life Sci. 2005;62(20):2339–2350.
64. Vaughan N, et al. “Sensorineural hearing loss in diabetes mellitus.” Arch Otolaryngol Head Neck Surg. 2006;132(9):929–933.
65. Axelsson A, et al. “Hearing in diabetics.” Acta Otolaryngol Suppl. 1978;356:1–23.
66. Lisowska G, et al. “Early identification of hearing impairment in patients with type 1 diabetes mellitus.” Otol Neurotol. 2001;22(3):316–320.
67. National Institute on Deafness and Other Communication Disorders (NIDCD). “Diabetes and Hearing Loss.” NIH Publication. 2011.
68. Horikawa C, et al. “Gender differences in the association between diabetes and hearing loss.” Diabet Med. 2013;30(9):1051–1055.
69. Kumar A, et al. “Hearing status in type 2 diabetes mellitus.” Indian J Otolaryngol Head Neck Surg. 2015;67(1):30–34.
70. Seidman MD, et al. “The protective role of antioxidants in hearing loss.” Otolaryngol Head Neck Surg. 1999;120(5):659–664.
71. Romano G, et al. "Skin lesions in diabetes mellitus: prevalence and clinical correlations." Diabetes Res Clin Pract. 1998;39(2):101–106.
72. Huntley AC. "Diabetic dermopathy." Cutis. 1977;19(6):701–702.
73. Rashed H. "Diabetic dermopathy: a marker of underlying microvascular complications." Saudi Med J. 2001;22(8):707–710.
74. Sinha S, Schwartz RA. "Acanthosis nigricans: a sign of systemic disease." J Am Acad Dermatol. 2007;56(5): 659–662.
75. Muller SA, Winkelmann RK. "Necrobiosis lipoidica diabeticorum: a clinical and pathological investigation." Arch Dermatol. 1966;93(3):272–281.
76. Erfurt-Berge C, et al. "Necrobiosis lipoidica – A review of the literature." J Dtsch Dermatol Ges. 2015;13(4):360–365.
77. Lafferty K, et al. "Bullosis diabeticorum." Arch Dermatol. 1983;119(12):909–911.
78. Delamaire M, et al. "Impaired leucocyte functions in diabetic patients." Diabet Med. 1997;14(1):29–34.
79. Wheat LJ. "Infections in diabetic patients." Diabetes Care. 1980;3(1):187–197.
80. Ghosh SK, et al. "Pruritus in diabetes: a study from eastern India." J Eur Acad Dermatol Venereol. 2010;24(5):531–534.
81. Jeffcoate WJ, et al. "Wound healing and treatments for diabetic foot ulcers." BMJ. 2005;330(7490):1389–1393.
82. Gkogkolou P, Böhm M. "Advanced glycation end products: Key players in skin aging?" Dermatoendocrinol. 2012;4(3):259–270.
83. Caballero AE. "Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease." Obes Res. 2003;11(11):1278–1289.
84. Geerlings SE, et al. "Infections in patients with diabetes mellitus: A review of pathogenesis." Lancet Infect Dis. 2004;4(10): 599–604.
85. Delamaire M, et al. "Impaired leukocyte functions in diabetic patients." Diabetes Med. 1997;14(1): 29–34.
86. Joshi N, et al. "Infections in patients with diabetes mellitus." N Engl J Med. 1999;341(25): 1906–1912.
87. Hirji I, et al. "Diabetes and the risk of infections: A cohort study." BMJ Open Diabetes Res Care. 2012; 2(1): e000033.
88. Nitzan O, et al. "Urinary tract infections in patients with type 2 diabetes mellitus: Review of prevalence, diagnosis, and management." Diabetes Metab Syndr Obes. 2015;8:129–136.
89. Wheat LJ. "Infections in diabetic patients." Diabetes Care. 1980;3(1):187–197.
90. Lavery LA, et al. "Diabetic foot infections: Pathophysiology and treatment." J Foot Ankle Surg. 2006;45(5): 356–364.
91. Shah BR, Hux JE. "Quantifying the risk of infectious diseases for people with diabetes." Diabetes Care. 2003;26(2): 510–513.
92. Kornum JB, et al. "Diabetes, glycemic control, and risk of hospitalization with pneumonia: A population-based case–control study." Diabetes Care. 2008;31(8):1541–1545.
93. Roden MM, et al. "Epidemiology and outcome of zygomycosis: A review of 929 reported cases." Clin Infect Dis. 2005;41(5):634–653.
94. Prabhu RM, Patel R. "Mucormycosis and entomophthoramycosis: A review of the clinical manifestations, diagnosis and treatment." Clin Microbiol Infect. 2004;10(s1):31–47.
95. Soysa NS, et al. "Candida infections in diabetes mellitus." J Diabetes Res. 2012;2012:439062.
96. Pearson-Stuttard J, et al. "Diabetes and infection: assessing the association with glycaemic control in population-based studies." Lancet Diabetes Endocrinol. 2016;4(2):148–158.
97. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115(3):387–97.
98. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil. 2007;19(12):951–60.
99. Camilleri M. Gastrointestinal dysfunction in diabetes. N Engl J Med. 2007;356(9):921–30..
100.  Horowitz M, Edelbroek MA, Wishart JM, Straathof JW. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia. 1993;36(9):857–62.
101. Maleki D, Locke GR, Camilleri M, et al. Gastrointestinal complications of diabetes. Endocrinol Metab Clin North Am. 1996;25(2):361–78.
     Parkman HP, Hasler WL, Fisher RS. Gastroparesis and functional dyspepsia: excerpts from the ACG Task Force. Am J Gastroenterol. 2006;101(2):513–23.
102. Enck P, Rathmann W, Spiekermann M, et al. Diabetic autonomic neuropathy of the gastrointestinal tract. J Gastroenterol. 1994;32(6):820–6.
103. Bharucha AE, Batey-Schaefer B, Cleary PA, et al. American Gastroenterological Association Technical Review on Gastroparesis. Gastroenterology. 2013;146(5):e1–e15
104. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.
     Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–871.
105. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118(3):829–838.
106. Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146(3):726–735.
107. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion. 2006;6(1):1–28.
108. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900–917.
109. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–1846.
110. Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62(12):1787–1794.