INTRODUCTION:

Diabetes mellitus (DM) constitutes a group of metabolic disorders marked by inadequate insulin secretion, impaired insulin action, or a concurrent manifestation of both dysfunctions. This disorder can cause persistent injury, impairment, and eventually failure of many organs, such as the eyes, nerves, kidneys, heart, and blood vessels^1,2.

DM is associated with various long-term complications, particularly microvascular issues. These complications encompass peripheral neuropathy, which increases the possibility of foot ulcers and Charcot joints; retinopathy, which poses a threat to vision; and nephropathy, which may result in kidney failure. Additionally, autonomic neuropathy can initiate cardiovascular, genitourinary, and gastrointestinal complications, including persistent sexual dysfunction^3,4. Coronary artery disease (CAD), cardiomyopathy (CM), arrhythmias that cause sudden death, cerebrovascular diseases, and peripheral vascular disease are all macrovascular consequences of type 2 diabetes (T2DM).

Cardiovascular disorders are the leading cause of death in patients with diabetes mellitus. Evidence from multiple studies highlights the strong link between T2DM and vascular complications. In addition, people with diabetes frequently present with other comorbidities, including hypertension, obesity, and abnormal lipid profiles⁵.

DM can cause a variety of problems, which are generally divided into two categories: "microvascular disease," referring to damage to small blood vessels, and "macrovascular disease," which affects larger blood vessels. Microvascular complications encompass retinopathy (eye damage), nephropathy (kidney damage), and neuropathy (nerve damage)^6,7. The major macrovascular complications involve the rapid advancement of cardiovascular disease, potentially leading to myocardial infarction, as well as cerebrovascular disease, a key factor in stroke occurrence. Although the exact mechanisms are not yet fully clarified, substantial evidence suggests a close relationship between diabetes mellitus and cardiac impairment, which can develop irrespective of atherosclerosis⁸.

DM impacts the heart in three significant ways: it can lead to cardiac autonomic neuropathy, cause CAD due to rapid atherosclerosis, and result in diabetic cardiomyopathy (DCM)⁹. Cardiac muscle dysfunction (CMD) is presently characterized as a condition affecting individuals with DM who are free from hypertension or any structural heart disorders like CAD or valvular heart disease¹⁰.

Diabetic Cardiomyopathy:

The exact pathophysiological mechanisms underlying chronic metabolic syndrome remain incompletely elucidated; nonetheless, it is postulated to result from a multifactorial interplay (Figure 1) involving insulin resistance, microvascular impairment, subcellular structural abnormalities, metabolic dysregulation, dysfunction of the cardiac autonomic nervous system, perturbations in the renin-angiotensin-aldosterone axis, and aberrant immune responses⁵.

Figure 1: Pathophysiological Basis and Mechanistic Insights into Diabetic Cardiomyopathy.

Impact of Hyperglycemia on Cardiac Health:

Prolonged periods of elevated blood sugar lead to alterations in the metabolism and molecular structure of cardiac muscle cells. The heightened glucose metabolism linked to high blood sugar levels increases oxidative stress due to the generation of reactive oxygen species (ROS) by mitochondria¹¹. Excessive generation of superoxide from the mitochondrial respiratory chain, along with the consequent oxidative stress, disrupts the contractile ability of heart muscle and eventually results in fibrosis within cardiac cells^12,13. ROS and oxidative stress can damage cellular DNA and hasten cardiomyocyte apoptosis^14,15.

Oxidative stress-induced DNA damage activates DNA repair enzymes, notably poly(ADP-ribose) polymerase (PARP). Upon activation, PARP diverts glucose metabolism from the conventional glycolytic pathway toward alternative metabolic routes, resulting in the generation of various harmful intermediates and contributing to cellular injury under hyperglycemic conditions. These deleterious effects include enhanced flux through the hexosamine and polyol pathways, activation of protein kinase C, and elevated levels of advanced glycation end products^16-19.

The heart muscle can be negatively affected by advanced glycation end products through their interaction with and stimulation of specific receptors, including those for advanced glycation end products and galectin-311; this triggers the activation of transcription factors such as nuclear factor-kappa B (NF-kB). Genes regulated by NF-kB subsequently initiate various pathways that enhance the synthesis of pro-inflammatory cytokines, including tumor necrosis factor, leading to damage in the myocardium^20-23. Research conducted on diabetic murine models found that NF-κB inhibitors were found to reduce mitochondrial oxidative stress and protect against cardiac dysfunction^24,25.

Prolonged high blood sugar levels may result in an increased influx of glucose into the hexosamine metabolic pathway. The increased glucose metabolism within the hexosamine pathway correlates with the disruption of normal calcium dynamics in cardiomyocytes, which in turn is related to reduced calcium storage in the sarcoplasmic reticulum²⁶. The reduction in myocardial function and the impairment of diastolic relaxation are significant clinical concerns, which are possible mechanisms for CM.

Elevated blood sugar levels can activate the polyol pathway, converting glucose into sorbitol through the action of the enzyme aldose reductase, which requires nicotinic acid adenine dinucleotide phosphate (NADPH). The resulting sorbitol is then oxidized to NADP+. NADPH is a crucial cofactor for the regeneration of reduced glutathione and plays a vital role as an ROS scavenger in the body. An increase in NADPH consumption in the polyol pathway may disturb cellular redox balance²⁷. The resulting increase in oxidative stress can lead to DNA damage and cardiomyocyte apoptosis²⁸. Sorbitol can also glycate proteins, forming advanced glycation end products that act as mediators of diabetic tissue injury²⁹^,³⁰.

Abnormalities in Subcellular Components:

The overproduction of ROS adversely affects the endoplasmic reticulum (ER) by disrupting post-translational modifications and impairing protein folding processes within the rough ER³¹. Excessive consumption of fats and carbohydrates, particularly in the context of insulin resistance, can result in nutrients overflowing into cells. This mechanism promotes electron transport to oxygen without the creation of adenosine triphosphate (ATP). This process also produces more ROS, which can cause oxidative damage to mitochondria. As a result, the ROS produced by mitochondria can damage DNA, proteins, and lipid membranes, and the buildup of fibrosis caused by ROS can lead to diastolic dysfunction, potentially resulting in heart failure^32,33.

The regulation of calcium levels can be influenced by stress within the endoplasmic reticulum (ER) and oxidative stress, leading to issues such as diastolic dysfunction and cardiomyopathy (CM). The presence of ROS, long-chain acylcarnitines, and abnormal lipid profiles in mitochondrial membranes, particularly through cardiolipin, can disrupt calcium regulation by impacting various transporter proteins. This disruption can result in delayed diastolic relaxation and reduced intracellular calcium absorption. The interaction of abnormal calcium handling, ROS, and ER stress plays a crucial role in the malfunctioning of subcellular components, eventually leading to processes such as autophagy, necrosis, and apoptosis^34,35.

Pathophysiological Consequences of Insulin Resistance and Hyperinsulinemia:

Insulin resistance and high insulin levels are common pathophysiological features associated with T2DM and prediabetes. Increased insulin levels facilitate the proliferation of cardiomyocytes through multiple mechanisms. The diabetic state fosters the hypertrophy of cardiomyocytes, a process regulated at the transcriptional level³⁶. Hyperinsulinemia induces a range of epigenetic and genetic modifications that activate transcription factors essential for regulating protein expression both extracellularly and intracellularly. The stimulation of transcription factors is a key driver of extracellular matrix protein deposition and cardiomyocyte enlargement, ultimately leading to localized myocardial fibrosis in the context of diabetes mellitus³⁶.

Impairment of Microcirculation in the Myocardium:

Injury to the microcirculation across the body is a characteristic of vascular issues associated with DM. Conditions such as diabetic nephropathy, neuropathy, and retinopathy exemplify these microvascular complications⁹. Patients diagnosed with type 2 diabetes mellitus (T2DM), characterized by insulin resistance, often exhibit compromised coronary microvasculature. This impairment is primarily attributed to a deficiency in bioavailable nitric oxide^37,38. Nitric oxide is vital for the activation of kinases and guanylyl cyclase in the smooth muscle cells of coronary vessels, which is necessary for promoting relaxation in the coronary arteries³⁹. The degradation of nitric oxide is increased while its production is decreased in conditions of reduced insulin sensitivity.

Diabetic patients' heart circulation demonstrates lower capillary length density and hyaline-related alterations in the medial arteriolar layers^40,41. Diabetes causes reduced blood flow due to microcirculation dysfunction, which affects the vasa vasorum and damages the small and medium arterioles in the diabetic heart. Additional vascular alterations contributing to cardiac microvascular ischemia in diabetes encompass perivascular fibrosis, remodeling of the interstitial matrix, formation of microaneurysms within small arteries, and thickening of the capillary basement membrane. In the setting of cardiomyopathy, these ischemic changes further promote myocardial fibrosis, enhance ventricular stiffness, and compromise cardiac performance. Insulin resistance, high insulin levels, and the rigidity of both small and big blood arteries are all related⁴². Excess insulin promotes the phenotypic shift of vascular smooth muscle cells into osteoblast-like cells, thereby contributing to vascular rigidity. This effect is mediated through elevated osteocalcin expression, enhanced alkaline phosphatase activity, and the formation of mineralized nodules in vascular smooth muscle cells, primarily driven by activation of the nuclear factor κB receptor pathway⁴³. Impaired function of vascular smooth muscle cells and endothelial cells is correlated with a heightened risk of developing CAD in the context of CM.

Lipid Metabolism and Myocardial Function:

DM leads to accumulation of lipids in tissues other than fat, including skeletal muscle, liver, and heart, as a result of increased stress on the ability of cells to oxidize. The condition known as cardiac steatosis, characterized by elevated lipid levels in the heart muscle, has been suggested as a significant factor contributing to CM due to impaired metabolism of substrates in the heart^44,45. The typical metabolic issues associated with T2DM that contribute to cardiac fat accumulation include high insulin levels, increased blood sugar, and raised concentrations of plasma free fatty acids (FFA). It was observed that DM, obesity, and reduced glucose tolerance are all linked to different levels of cardiac fat deposition^44,46,47.

In individuals suffering from obesity and T2DM, the role of glucose oxidation in cardiac energy production is diminished compared to normal levels, while the metabolism of fatty acids is heightened to fulfill the energy requirements of the heart^48,49. In individuals with T2DM and obesity, elevated free fatty acid (FFA) levels contribute to increased fatty acid uptake by the heart, leading to triglyceride accumulation. This excessive influx and absorption of fatty acids can exceed the oxidative capacity of mitochondria, causing lipotoxic damage to cardiac tissue. Some of the excess fatty acids are diverted into nonoxidative pathways, producing detrimental byproducts like ceramide. These toxic compounds disrupt normal cellular signaling, resulting in mitochondrial dysfunction, cellular damage, programmed cell death, and ultimately, myocardial fibrosis and compromised heart function.

Recent research has shown that patients with high myocardial triglyceride levels have biventricular systolic and diastolic dysfunction⁵⁰. Since triglyceride is generally stable, its buildup within cells is probably not the reason for heart damage. Conversely, the intermediate byproducts from non-oxidative pathways of lipid processing inside cells are more likely to contribute to tissue injury due to lipotoxicity and ultimately lead to cell death.

The rise in fatty acid oxidation within mitochondria correlates with heightened production of ROS, which in turn oxidizes cytoplasmic lipids, transforming them into lipid peroxides. These ROS and lipid peroxides subsequently lead to damage in both cellular structures and mitochondria, as well as disrupt mitochondrial oxidative metabolism⁵¹ As a result, myocardial energy generation is impaired, and cardiac contractility is reduced. Decreased energy generation additionally results in compromised calcium management within mitochondria, leading to heart dysfunction⁵². Lipoapoptosis is the term used to describe cell apoptosis caused by lipotoxicity.

Activation of the renin-angiotensin-aldosterone system:

Recent evidence from animal and human experiments has shown that RAS plays a significant role in DM-induced cardiac dysfunction^53,54. Hyperglycemia stimulates intracardiac RAS, which has a variety of effects on myocardial cells. Intracellular AGT II levels were found to be 3.4-fold higher in diabetic cardiomyocytes compared to nondiabetics⁵⁵.

AGT II has been shown to stimulate cell proliferation in a number of animal experiments. This substance has a direct impact on cell signaling pathways, which causes cardiac myocytes to enlarge and cardiac fibroblasts to proliferate⁵⁶. Other factors, such as oxidative stress, inflammation, and aldosterone, may contribute to AGT II's detrimental effects on the heart, resulting in myocardial damage in DM⁵⁴.

Changes in Attributes and Structure:

CM substantially alters the form and function of heart muscle, leading to a variety of pathological and clinical effects. The disease's early primary effects on the myocardial interstitium cause disturbances in heart contractility. Next, heart microcirculation dysfunction, interstitial and perivascular fibrosis, and ventricular myocardial hypertrophy are identified. Systolic dysfunction only appears later in the course of the illness, whereas diastolic dysfunction is the first aberration in heart microcirculation to be noticed^57,58. Common factors contributing to diastolic dysfunction include ventricular fibrosis and hypertrophy induced by CM. As systolic dysfunction develops, there is a gradual decline in cardiac output as the condition advances.

Participation in concomitant high blood pressure and coronary artery disease:

CM is diagnosed only when HPT and CAD have been ruled out. However, there may be a quick development to advanced heart failure when these conditions coexist with pre-existing CM. Coexisting HPT was found in 50% to 80% of individuals with T2DM and almost 30% of patients with T1DM in the US^59,60. According to reports, HPT made cardiac dysfunction worse in CM animal models⁶¹. Diastolic dysfunction in diabetic individuals was independently linked to HPT presence⁶².

Changes in heart structure associated with diabetes-related heart disease:

In the initial phases of cardiomyopathy, metabolic disturbances including insulin resistance and hyperglycemia exert minimal influence on cardiac structure and systolic function^35,63. At advanced stages of CM, numerous cellular alterations drive the progression of cardiac fibrosis, leading to marked impairments in both systolic and diastolic function⁴⁰. The earliest aberration in CM is impaired diastolic function; systolic dysfunction does not show up until much later in the course of the disease⁵⁸. Diastolic dysfunction occurs when the ventricular muscle does not relax during the diastole phase of the cardiac cycle, resulting in diastolic heart failure and an increase in ventricular filling pressure. The basic causes of diastolic dysfunction include CM-related ventricular hypertrophy and fibrosis.

As the disease progresses and systolic dysfunction sets in, cardiac output gradually decreases. The degree of heart failure and systolic dysfunction is accurately represented by the LV systolic ejection fraction. Further degradation of coronary microcirculation and systolic and diastolic function arises from alterations in neurohumoral activation, metabolism, and the development of myocardial fibrosis in the late stage of CM^35,64.

CONCLUSION:

In people with DM, DCM is a distinct cardiac disorder characterized by myocardial dysfunction that happens apart from CAD and HPT. This review has outlined the intricate pathophysiological processes that contribute to this condition, highlighting how prolonged high blood sugar levels trigger a series of harmful effects on the heart muscle. The complex origins of this condition include heightened oxidative stress due to the production of ROS, abnormalities in subcellular components, impaired microcirculation, changes in lipid metabolism, insulin resistance, and the activation of the renin-angiotensin-aldosterone system.

Two important biological variables that affect cardiomyocyte function are mitochondrial malfunction and endoplasmic reticulum stress. The oxidative stress brought on by elevated blood sugar levels triggers the hexosamine and polyol pathways, among other metabolic pathways, activates protein kinase C, and promotes the production of advanced glycation end products. By disrupting normal calcium control, causing the release of pro-inflammatory cytokines, and accelerating apoptotic processes, these molecular changes result in myocardial fibrosis and impaired contractility.

There is a clear pattern to the development of DCM, with diastolic dysfunction being the first functional abnormality and systolic impairment occurring later. Fundamental to these functional changes are the structural abnormalities, which are typified by hypertrophied ventricles and increased interstitial and perivascular fibrosis. Interestingly, the onset of severe heart failure and cardiac dysfunction is considerably accelerated when DCM is combined with HPT or CAD.

Abnormalities in lipid metabolism play a major role in myocardial damage through cardiac steatosis and the buildup of harmful fatty acid intermediates. The result of this lipotoxicity is mitochondrial malfunction, which hampers energy production and ultimately results in lipoapoptosis. In addition, the renin-angiotensin-aldosterone system's activation exacerbates cardiac damage by directly affecting cell signaling, which results in fibroblast proliferation and myocyte hypertrophy.

Grasping these complex pathophysiological processes is critical for formulating targeted treatment approaches for diabetic CM. In order to successfully prevent or lessen cardiac dysfunction in diabetic individuals, future research should focus on identifying therapies that address several pathogenic pathways. Additionally, early identification through innovative biomarkers and imaging methods may enable prompt intervention before irreversible cardiac remodeling takes place. Addressing DCM is a critical challenge in reducing cardiovascular morbidity and mortality in this at-risk population, given the increased incidence of DM worldwide.

REFERENCES:

1. Tripathi BK, Srivastava AK. Diabetes mellitus: complications and therapeutics. Med Sci Monit. 2006; 12(7): RA130-47. doi: PMID: 16810145.

2. Premkumar B. Antioxidant defense and disease activity in rheumatoid arthritis. Research Journal of Pharmacy and Technology. 2018;11(5):1810-4.

3. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011; 34 Suppl 1(Suppl 1): S62-S9. doi: 10.2337/dc11-S062

4. Alta'ee AH, Majeed HA, Hadwan MH. The levels of vitamin E in seminal fluids and their association with male infertility: Short review. Research Journal of Pharmacy and Technology. 2018; 11(5): 2152-6.

5. Viigimaa M, Sachinidis A, Toumpourleka M, Koutsampasopoulos K, Alliksoo S, Titma T. Macrovascular Complications of Type 2 Diabetes Mellitus. Curr Vasc Pharmacol. 2020; 18(2): 110-6. doi: 10.2174/1570161117666190405165151

6. Muhjoub NM, Alrasheed SH, Gammoh Y, Elmadina AM. Clinical characteristics and associated factors of diabetic retinopathy in Sudanese patients. African Vision and Eye Health. 2024; 83(1): 913. doi: 10.2337/dc21-S002

7. Abdelhamid AM, Ali LS, Fansa HA, Srag El-Din ASG. Microwave-Assisted Synthesis of Selenium Nanoparticles: A Comprehensive Review on Optimizing Parameters for Enhanced Bioavailability and Therapeutic Potential. Research Journal of Pharmacy and Technology. 2025; 18(5): 2003-9. doi: 10.52711/0974-360X.2025.00286

8. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013; 93(1): 137-88. doi: 10.1152/physrev.00045.2011

9. Pappachan JM, Varughese GI, Sriraman R, Arunagirinathan G. Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. World J Diabetes 2013; 4(5): 177-89. doi: 10.4239/wjd.v4.i5.177

10. Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME. Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med. 2008; 121(9): 748-57. doi: 10.1016/j.amjmed.2008.03.046

11. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002; 51(6): 1938-48. doi: 10.2337/diabetes.51.6.1938

12. Aragno M, Mastrocola R, Medana C, Catalano MG, Vercellinatto I, Danni O, et al. Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes. Endocrinology. 2006; 147(12): 5967-74. doi: 10.1210/en.2006-0728

13. Chitra V, Narayanan J. In vitro screening for anti-cholinesterase and anti oxidant activity of extract of garcinia hanburyi. Research Journal of Pharmacy and Technology.. 2018; 11(7): 2918-21.

14. Al-Hatamleh MAI, Al-Shajrawi OM, Khan SU, Nadeem MI, Simbak NB, Latif AZA, et al. Effects of Oxidative Stress on Alzheimer's Disease, Haematological Perspective. Research Journal of Pharmacy and Technology. 2018; 11(9): 3881-6.

15. Al-Rubaei SH, Jubair S, Al-Sharifi AN. The impact of oxidative stress in primary congenital glaucoma. Research Journal of Pharmacy and Technology. 2018; 11(11):5013-6.

16. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003; 112(7): 1049-57. doi: 10.1172/jci18127

17. Lee W-S, Kim J. Diabetic cardiomyopathy: where we are and where we are going. The Korean Journal of Internal Medicine. 2017; 32(3): 404-21. doi: 10.3904/kjim.2016.208

18. Alhyasat RA-E, Khleifat K, Khlaifat AM, Za'al Alsarayreh A, Al Qaisi YT, Hajleh MNA, et al. Oxidative Stress and its connection to Jordanians' Red Blood Cell Storage. Research Journal of Pharmacy and Technology. 2024; 17(9): 4304-10. doi: 10.52711/0974-360X.2024.00665

19. Srag El-Din ASG, Yehia A, Hamza E, A-Elgadir TME, Abd El-Fattah EE. Selenium nanoparticle ameliorates LPS-induced acute lung injury in rats through inhibition of ferroptosis, inflammation, and HSPs. Journal of Drug Delivery Science and Technology. 2024; 95: 105626. doi: 10.1016/j.jddst.2024.105626

20. Burgess ML, McCrea JC, Hedrick HL. Age-associated changes in cardiac matrix and integrins. Mech Ageing Dev. 2001; 122(15): 1739-56. doi: 10.1016/s0047-6374(01)00296-2

21. Gardouh AR, Srag El-Din AS, Salem MS, Moustafa Y, Gad S. Starch nanoparticles for enhancement of oral bioavailability of a newly synthesized thienopyrimidine derivative with anti-proliferative activity against pancreatic cancer. Drug Design, Development and Therapy. 2021: 3071-93. doi: 10.2147/DDDT.S321962

22. Samuel G, Nazim U, El-Din AS. Physicochemical characterization of Novel Particulate Delivery Systems for Antitumor/metastatic Therapeutics. Research Journal of Pharmacy and Technology. 2021; 14(9): 4837-44. doi: 10.52711/0974-360X.2021.00840

23. Samuel G, Nazim U, El-Din AS. Optimization of PLGA nanoparticles for delivery of Novel anticancer CK-10 peptide. Research Journal of Pharmacy and Technology. 2021; 14(10): 5371-9. doi: 10.52711/0974-360X.2021.00937

24. Mariappan N, Elks CM, Sriramula S, Guggilam A, Liu Z, Borkhsenious O, et al. NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res. 2010; 85(3): 473-83. doi: 10.1093/cvr/cvp305

25. Gardouh AR, El-Din ASS, Mostafa Y, Gad S. Starch Nanoparticles Preparation and Characterization by in situ combination of Sono-precipitation and Alkali hydrolysis under Ambient Temperature. Research Journal of Pharmacy and Technology. 2021; 14(7): 3543-52.

26. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, et al. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 2003; 278(45): 44230-7. doi: 10.1074/jbc.M303810200

27. Pappachan JM, Varughese GI, Sriraman R, Arunagirinathan G. Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. World Journal of Diabetes. 2013; 4(5): 177-89. doi: 10.4239/wjd.v4.i5.177

28. Galvez AS, Ulloa JA, Chiong M, Criollo A, Eisner V, Barros LF, et al. Aldose reductase induced by hyperosmotic stress mediates cardiomyocyte apoptosis: differential effects of sorbitol and mannitol. J Biol Chem. 2003; 278(40): 38484-94. doi: 10.1074/jbc.M211824200

29. Sohn EJ, Kim CS, Kim YS, Jung DH, Jang DS, Lee YM, et al. Effects of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) on diabetic nephropathy in type 2 diabetic Goto-Kakizaki rats. Life Sci. 2007; 80(5): 468-75. doi: 10.1016/j.lfs.2006.09.037

30. Hashim Z, Zarina S. Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes. J Diabetes Complications. 2012; 26(4): 275-9. doi: 10.1016/j.jdiacomp.2012.04.005

31. Factor SM, Minase T, Cho S, Fein F, Capasso JM, Sonnenblick EH. Coronary microvascular abnormalities in the hypertensive-diabetic rat. A primary cause of cardiomyopathy? Am J Pathol. 1984;116(1):9-20.

32. Liu J, Shen W, Zhao B, Wang Y, Wertz K, Weber P, et al. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients. Adv Drug Deliv Rev. 2009; 61(14): 1343-52. doi: 10.1016/j.addr.2009.06.007

33. Abdelhamid AM, Amir Mohamed A, Rania RA, Rania RA, Hatem AS, Hatem AS. Vildagliptin/pioglitazone combination improved the overall glycemic control in type I diabetic rats. Canadian Journal of Physiology and Pharmacology. 2018. doi: 10.1139/cjpp-2017-0680

34. Adameova A, Dhalla NS. Role of microangiopathy in diabetic cardiomyopathy. Heart Fail Rev. 2014; 19(1): 25-33. doi: 10.1007/s10741-013-9378-7

35. Adeghate E, Singh J. Structural changes in the myocardium during diabetes-induced cardiomyopathy. Heart Fail Rev. 2014; 19(1): 15-23. doi: 10.1007/s10741-013-9388-5

36. Feng B, Chen S, Chiu J, George B, Chakrabarti S. Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level. Am J Physiol Endocrinol Metab. 2008; 294(6): E1119-26. doi: 10.1152/ajpendo.00029.2008

37. Zhou X, Ma L, Habibi J, Whaley-Connell A, Hayden MR, Tilmon RD, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat. Hypertension. 2010; 55(4): 880-8. doi: 10.1161/hypertensionaha.109.145136

38. El-Beltagy AE-FB, Mohamed G, Saad Ali L, El-Mansy AA, Soliman MF, Gadallah AA, et al. Propolis extract attenuates cisplatin-induced nephrotoxicity in female rats and their offspring. Egyptian Journal of Basic and Applied Sciences. 2025; 12(1): 1-21. doi: 10.1080/2314808X.2024.2446871

39. Hayden MR, Habibi J, Joginpally T, Karuparthi PR, Sowers JR. Ultrastructure Study of Transgenic Ren2 Rat Aorta - Part 1: Endothelium and Intima. Cardiorenal Med. 2012; 2(1): 66-82. doi: 10.1159/000335565

40. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004; 25(4): 543-67. doi: 10.1210/er.2003-0012

41. Campbell DJ, Somaratne JB, Jenkins AJ, Prior DL, Yii M, Kenny JF, et al. Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease. Cardiovasc Diabetol. 2011; 10: 80. doi: 10.1186/1475-2840-10-80

42. Blaha MJ, DeFilippis AP, Rivera JJ, Budoff MJ, Blankstein R, Agatston A, et al. The relationship between insulin resistance and incidence and progression of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2011; 34(3): 749-51. doi: 10.2337/dc10-1681

43. Yuan LQ, Zhu JH, Wang HW, Liang QH, Xie H, Wu XP, et al. RANKL is a downstream mediator for insulin-induced osteoblastic differentiation of vascular smooth muscle cells. PLoS One 2011; 6(12): e29037. doi: 10.1371/journal.pone.0029037

44. McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation. 2007; 116(10): 1170-5. doi: 10.1161/circulationaha.106.645614

45. Winhofer Y, Krssák M, Jankovic D, Anderwald CH, Reiter G, Hofer A, et al. Short-term hyperinsulinemia and hyperglycemia increase myocardial lipid content in normal subjects. Diabetes. 2012; 61(5): 1210-6. doi: 10.2337/db11-1275

46. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. 2008; 52(22): 1793-9. doi: 10.1016/j.jacc.2008.07.062

47. Iozzo P, Lautamaki R, Borra R, Lehto HR, Bucci M, Viljanen A, et al. Contribution of glucose tolerance and gender to cardiac adiposity. J Clin Endocrinol Metab. 2009; 94(11): 4472-82. doi: 10.1210/jc.2009-0436

48. Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda). 2006; 21: 250-8. doi: 10.1152/physiol.00008.2006.

49. Rijzewijk LJ, van der Meer RW, Lamb HJ, de Jong HW, Lubberink M, Romijn JA, et al. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol. 2009; 54(16): 1524-32. doi: 10.1016/j.jacc.2009.04.074

50. Ng AC, Delgado V, Bertini M, van der Meer RW, Rijzewijk LJ, Hooi Ewe S, et al. Myocardial steatosis and biventricular strain and strain rate imaging in patients with type 2 diabetes mellitus. Circulation. 2010; 122(24): 2538-44. doi: 10.1161/circulationaha.110.955542

51. van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011; 92(1): 10-8. doi: 10.1093/cvr/cvr212

52. Balaban RS. Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol. 2002; 34(10): 1259-71. doi: 10.1006/jmcc.2002.2082

53. Guleria RS, Choudhary R, Tanaka T, Baker KM, Pan J. Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system. J Cell Physiol. 2011; 226(5): 1292-307. doi: 10.1002/jcp.22457

54. Kurdi M, Booz GW. New take on the role of angiotensin II in cardiac hypertrophy and fibrosis. Hypertension. 2011; 57(6): 1034-8. doi: 10.1161/hypertensionaha.111.172700

55. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, et al. Myocardial cell death in human diabetes. Circ Res. 2000; 87(12): 1123-32. doi: 10.1161/01.res.87.12.1123

56. Kumar R, Yong QC, Thomas CM, Baker KM. Intracardiac intracellular angiotensin system in diabetes. Am J Physiol Regul Integr Comp Physiol. 2012; 302(5): R510-7. doi: 10.1152/ajpregu.00512.2011

57. Voulgari C, Papadogiannis D, Tentolouris N. Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies. Vasc Health Risk Manag 2010; 6: 883-903. doi: 10.2147/vhrm.S11681

58. Nunes S, Soares E, Fernandes J, Viana S, Carvalho E, Pereira FC, et al. Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker. Cardiovasc Diabetol. 2013; 12: 44. doi: 10.1186/1475-2840-12-44

59. Landsberg L, Molitch M. Diabetes and hypertension: pathogenesis, prevention and treatment. Clin Exp Hypertens. 2004;26(7-8):621-8. doi: 10.1081/ceh-200031945

60. Alahmari LA, Ali LS, Fansa HA, Alshaya DS, Al‐Salmi FA, El‐Hallous EI, et al. Antioxidant and Antiapoptotic Effects of Selenium And Nano Selenium‐Loaded Exosomes on Hepatic Dysfunction of Type 1 Diabetic Rats. Journal of Experimental Zoology Part A: Ecological and Integrative Physiology. 2025; 343(2): 211-9. doi: 10.1002/jez.2881

61. Mathis DR, Liu SS, Rodrigues BB, McNeill JH. Effect of hypertension on the development of diabetic cardiomyopathy. Can J Physiol Pharmacol. 2000; 78(10): 791-8.

62. Mathis DR, Liu SSL, Rodrigues BB, McNeill JH. Effect of hypertension on the development of diabetic cardiomyopathy. Canadian Journal of Physiology and Pharmacology 2000; 78(10): 791-8. doi: 10.1139/y00-058

63. Falcão-Pires I, Leite-Moreira AF. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev. 2012; 17(3): 325-44. doi: 10.1007/s10741-011-9257-z

64. Battiprolu PK, Gillette TG, Wang ZV, Lavandero S, Hill JA. Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets. Drug Discov Today Dis Mech. 2010; 7(2): e135-e43. doi: 10.1016/j.ddmec.2010.08.001

Received on 09.05.2025 Revised on 08.09.2025

Accepted on 17.11.2025 Published on 20.05.2026

Available online from May 25, 2026

Research J. Pharmacy and Technology. 2026;19(5):2390-2396.

DOI: 10.52711/0974-360X.2026.00342

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.