Please cite this paper as:

Banerjee, A., Chattopadhyay, A. and Bandyopadhyay, D. 2022. Prevention of diabetic cardiomyopathy through metabolic amendments of myocardium by melatonin: a role beyond antioxidative efficiency. Melatonin Research. 5, 2 (Jun. 2022), 133-153. DOI:https://doi.org/https://doi.org/10.32794/mr112500125.


Review 

Prevention of diabetic cardiomyopathy through metabolic amendments of myocardium by melatonin: a role beyond antioxidative efficiency 

Adrita Banerjee1, 2, Aindrila Chattopadhyay2, Debasish Bandyopadhyay1* 

1Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata-700009, India

2Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata-700006, India

*Correspondence: debasish63@gmail.com, Tel: +91-9433072066 

Running Title: Melatonin modulates metabolic pathways to prevent diabetic cardiomyopathy

Received: February 26, 2022; Accepted: June 4, 2022


ABSTRACT

     The alarming rise in diabetes throughout the world brings the scientists at the brink of finding the suitable remedies which can impede glucotoxicity and insulin resistance involved in initiation and progression of diabetes. Either devoid of insulin or resistance to insulin makes the pancreatic tissue a most vulnerable target. However, cardiac tissue, is another target of hyperglycaemia. The remodelling of cardiac tissue in insulin resistant individuals often includes cardiac hypertrophy along with misaligned diastolic and systolic functions. All these amendments reduce cardiac contractility and cause heart failure. Both carbohydrate and fatty acid metabolism are altered in diabetes with declined glycolysis and elevated lipolysis leading to rise in fatty acid oxidation. Melatonin, as a potent antioxidant, reduces the excessive reactive oxygen species (ROS) generation induced by glucotoxicity, therefore, prevents diabetes associated cellular injury. The reduced ROS production, in turn, lowers both glucose and fatty acid accumulation by augmenting glycolysis and diminishing lipolysis. Melatonin also inhibits gluconeogenesis and glycogenesis pathways in diabetic myocardium. The regulation of important metabolic pathways by melatonin assists the myocardium to maintain energy balance, the primary need for heart contraction. Hence, this review focuses on metabolic modulatory actions of melatonin in diabetic myocardium, which may encourage its usage as a saviour for diabetic cardiomyopathy.

Key words: diabetic cardiomyopathy, carbohydrate metabolism, fatty acid metabolism, melatonin, cardiac function

________________________________________________________________________________


1. INTRODUCTION

     Among metabolic disorders, diabetes mellitus (DM) is a leading cause of death worldwide (1). Pancreatic oxidative stress, high glucose intake, obesity- any of them or all in combination lead to glucose intolerance (2, 3). As a typical physiological response, pancreas secretes more insulin and manages to neutralize the hyperglycaemia (4). However, this long-lasting excessive insulin secretion makes the pancreatic tissue exhausted with mitochondrial and endoplasmic reticulum stress (5, 6). On the other hand, the surplus of insulin secretion fails to ameliorate hyperglycaemia which is referred as insulin resistance (7). The prevalence and progression of diabetes give rise to various life-threatening disorders (8-10). The excessive blood glucose is the biomarker of diabetes; thus, red blood cells are the first to expose to high glucose (11) followed by cardiac tissue. As a result, the diabetic cardiac anomalies emerge as a primary cause of morbidity as well as the mortality (12). The alterations in cardiac structure and functions are collectively named as ‘Diabetic Cardiomyopathy’ (DCM) featured as left ventricular hypertrophy, fibrosis, changes in cardiac contractility, myocardial ischaemia, etc. (13, 14). These cardiac abnormalities other than those observed in coronary artery disease are signature marks of DCM which has been considered as a multifactorial disease.

     Among the factors responsible for DCM, oxidative stress can be considered as one of the initial causes. High plasma glucose mediated excessive ROS generation is unavoidable for diabetic patients (15), especially in their myocardium (16). Under hyperglycaemia, the myocardium responds to reduction in glucose oxidation (17) and find the alternative source for ATP production. Insulin resistance in diabetes gives rise to excess of free fatty acids in plasma by accelerating the process of lipolysis (18). Thus, fatty acid becomes the central source of energy for diabetic myocardium and as a consequence, the rate of fatty acid oxidation surges with lipid accumulation (19, 20). Overload of fatty acids and escalation in beta-oxidation prompt mitochondrial ROS generation (21) and reduced contractility of cardiomyocytes (22). Moreover, the long chain free fatty acids can alter plasma membrane composition and fluidity which may cause release of cytochrome C from mitochondria with succeeding cellular death (23).

     Since a fine weaving between excessive ROS generation and metabolic perturbation is prominent as aetiology of diabetes, a mitochondria-targeted stress reliever which can bring about normalcy in metabolic pathways can be the best preventive approach. Melatonin seems as such a reliever, by its virtue, acting as an antioxidant and also as a metabolic regulator (24, 25). The contribution of melatonin as an antioxidant in impediment of diabetes and associated disorders like DCM has been well documented but, its metabolic modulatory roles on this issue remains less cultivated. As to its metabolic activities, melatonin enhances the glucose uptake in adipose tissue by influencing the expression of GLUT(s) (Glucose transporter) to lower the plasma glucose load (26) and escalates the aerobic oxidative rate of glucose (27) as well as suppresses gluconeogenesis from non-carbohydrate sources (28). In addition, melatonin regulates fatty acid metabolism by interacting with enzymes which are involved in rate limiting steps of fatty acid synthesis (29). Therefore, melatonin reduces excessive fatty acid burden and assists the cells to rely upon carbohydrates instead of lipids as energy source under hyperglycaemia. These actions of melatonin in cardiac cells lower likelihood of ROS generation and facilitates cells to avert the fatty acid metabolism associated mitochondrial uncoupling (30). Hence, melatonin instigated preferential selection of energy source to avoid insulin resistance, mitochondrial uncoupling and excessive ROS generation, preserves the cardiac structure, function and the integral contractile nature of heart in diabetes patients.

 

2. DCM

     The exclusive risk factors for DCM are independent for those in coronary arterial disease, hypertension, congenital heart disease or cardiac valvular disease (31). Hyperglycaemia and insulin resistance contribute equally in the progression of DCM, the alterations of vascular structure and metabolism (14, 32, 33). If not screened and diagnosed at appropriate time, especially in the asymptomatic type 2 diabetes, the gradual progression of disease leads to heart failure (34, 35). Alterations in cardiac systolic and diastolic functions in diabetes are the primary causes behind such detrimental outcomes (33), where early-onset diastolic dysfunction followed by systolic dysfunction cause cardiac hypertrophy, and fibrosis, and finally failure (36). The early diastolic filling with escalated atrial filling is the biomarker of type 1 diabetes (37) whereas, left ventricular hypertrophy is the primary pathophysiology behind ventricular dysfunction in type 2 diabetes (38). The insulin resistance and enhanced left ventricular mass indicate a strong linkage between cardiac hypertrophy and heart failure (39, 40). Additionally, the action of insulin as a growth factor in cardiac tissue has been substantiated in type 2 diabetes where augmented insulin signalling participates in progression of cardiac hypertrophy (41). Interstitial and perivascular fibrosis are also the causative factors of cardiac hypertrophy (42). In type 2 diabetic patients with hyperinsulinemia, collagen, and especially collagen type III deposits in intramural vessels and myofibres, indicating fibrosis in diabetes (43). Hyperglycaemia also activates renin-angiotensin-aldosterone system and the resulted augmentation in angiotensin II level promotes cardiovascular proliferation and cardiac hypertrophy (44, 45). The occurrence of myocardial infarction, myocardial ischaemia and heart failure are often observed in both type 1 and 2 diabetes (46, 47). Moreover, defective cardiac insulin metabolic signalling strengths the correlation between hyperglycaemia and cardiac abnormalities, a leading cause of death among diabetic patients (48, 49).

     Various factors, associated with diabetic cardiac incongruities have been identified. These include oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial structural and functional disorientation, advanced glycation end products (AGE) mediated extracellular matrix stiffness (48, 50) and all of these can cause myocardial infarction and heart failure (51, 52). The metabolic amendments involved in cardiac structural and functional modifications have been extensively studied (13, 53, 54). A disturbed homoeostasis of substrate utilisation and energy production has been considered as the key aetiology of DCM (54, 55). Declined energy level lowers efficiency of heart contractability and jeopardizes its diastolic and systolic functions (35). The inability of diabetic heart to utilise more glucose as substrate to generate ATP becomes the sole pathophysiological factor of initiation and progression of DCM (54). This low glucose oxidation makes the cardiac tissue less efficient in substrate use (56) and leads the myocardium to be more dependent on fatty acid oxidation (57, 58). This substrate shift alarmingly enhances the chance of malfunction in oxidative phosphorylation pathway with excess of proton leakage from mitochondria (48) which triggers ROS generation (59). The mitochondrial uncoupling further lowers ATP production and the ATP dependent contractile efficiency of cardiac cells (60, 61). This is a vicious cycle of high glucose instigated metabolic alterations and excess oxidative stress generation associated with DCM.


3. DCM AND ALTERED CARDIAC METABOLISM 

3.1. Substrate shifting in DCM.

     The substrate switching of diabetic heart was highlighted as a major concern for cardiac morphological as well as pathophysiological alterations even though the preferential switching of normal cardiac tissue from glucose to fatty acid occurs just after birth depending on the plasma fatty acid content (61, 62). However, hyperglycaemia makes cardiac tissue to use fatty acid as the exclusive substrate for energy generation in diabetes (58, 63) where insulin resistance acts as the signal for such biased shifting (64, 65) and thus, β-oxidation of free fatty acids becomes the sole ATP generating pathway of diabetic heart (57). Two possible factors may relate to this metabolic amendment. First, less glucose has been uptaken by cardiac cells and second, excessive fatty acid accumulated within cardiac cells which might drive the tissue to restrict its energy generation from fatty acid oxidation.

3.2. Alterations in carbohydrate metabolism.

     The myocardial metabolic substrate shift in diabetes has been attributed to insulin mediated reduction in glucose uptake (66). The insulin instigated depletion of glucose transporter protein type 4 (GLUT4) in diabetic myocardium is responsible for its lower uptake from plasma (67). Along with GLUT4, glucose transporter protein type 1 (GLUT1) expression was also abated in diabetic cardiac tissue (68). Apart from low GLUT content of myocardial cells, the abated translocation of GLUT4 to the sarcolemma in hyperglycaemia, makes cardiomyocytes more averted from plasma glucose (69). A clinical trial showed a significant downregulation of GLUT4 expression in diabetic patients with cardiac ailments (70). The non-availability of glucose causes suppression of glycolytic cycle (32) leading to a drastic decline in glucose oxidation. The depressed glucose oxidation level in type1 diabetic patients has also been observed (17, 61, 71) as in type2 diabetes (72, 73), which may be due to the reduction in pyruvate dehydrogenase (PDH) flux toward mitochondria (74). 

3.3. Modifications of lipid metabolism.

     On other hand, in hyperglycaemia, an increase in free fatty acid content (75) and subsequent augmentation of its flux in cardiomyocytes (61) compel myocardium to utilize fatty acid over glucose. This excessive fatty acid uptake has been observed in both type1 (22, 76) and 2 (17) diabetic patients. Insulin resistance in diabetes induces excessive lipolysis of adipose tissue. The accumulation of free fatty acids and triglycerides (19, 74) become high cardiac risk factor in type1 diabetic patients (77). Moreover, the free fatty acid uptake into cardiomyocytes is a dynamic process with several routes. These include passive diffusion, through fatty acid translocase and/or fatty acid binding protein (FABP) mediated translocation which provide the lipid entry into myocardium a supremacy over glucose (78). The preference of cardiomyocytes for fatty acids is more obvious when the expressions of FABP4 and FABP5 augment in type2 diabetes with cardiovascular abnormalities (79, 80) and this has been substantiated in animal studies (81, 35). Free fatty acids of plasma not only compete with glucose entry to myocardium, but also hinders glucose oxidation by impeding the action of PDH, a crucial enzyme for glucose metabolism (82, 83). Excess fatty acid oxidation increases the ratio of acetyl coA/coA with a concomitant rise in NAD+ cofactor, which in turn impedes the action of PDH and hampers glucose oxidation (84). Additionally, the ascended expression of peroxisome proliferator-activated receptor-gamma coactivator-1 α (PGC-1α) (85) in diabetic heart in turn elevates the expression of peroxisome proliferator-activated receptor α (PPARα) (86), a transcriptional factor accountable for induction of enzymes involved in beta oxidation (87, 88). PPARα not only positively regulates fatty acid oxidation, but also elevates the rate of beta oxidation by hindering glucose oxidation through pyruvate dehydrogenase kinase (PDK4) actuation, responsible for PDH inactivation (35, 12).

     The selection of fatty acid as the major energy source by diabetic myocardium makes   its uptake over its oxidising capacity (89- 91) with fatty acid accumulation, leading to cardiac lipotoxicity (92-94). Overload of fatty acid also triggers synthesis and further cumulation of a potent cardiotoxin ceramide, (32, 95, 96) which induces myocardial apoptosis in diabetic patients (95, 97). Thus, this lipotoxicity induced lipoapoptosis (98, 61) triggers morphological (99-101) and functional (102-104) alterations of cardiac tissue. The suppressed contractility (99) and hindered myocardial performance (105) are the consequences of the altered lipid metabolism under the state of hyperglycaemia in diabetes (19, 105, 106).

 

4. LIPID METABOLISM INVOLVED OXIDATIVE STRESS IN DCM

     Oxidative stress has been identified as a keynote factor behind occurrence of hyperglycaemia (107, 108) and this excessive ROS is detrimental for diabetic myocardium (109-111). Oxidative stress alters metabolism and morpho-functions in the myocardium (55, 111-114). In addition to insulin resistance, high glucose is considered as the principal metabolic anomaly to cause most pernicious outcome of diabetes, i.e., DCM. The accumulation and oxidation of fatty acid is another important factor behind redox imbalance in cardiac tissue of diabetes (99, 115, 116). The hindrance of glucose utilization in diabetic myocardium causes excess fatty acid oxidation (69) and lipid accumulation with subsequent stress in DCM. Hence, lowering lipid and subsequent stress level has been recommended as a therapeutic measure for DCM (36). Mitochondria are the major site of ROS generation. The morphologically altered and malfunctional mitochondria have been reported in the DCM (117, 118). Overexpression of mitochondrial superoxide dismutase (MnSOD) provides protection to DCM (119). In patients with diabetes, the augmented fatty acid mediated excessive mitochondrial ROS generation are supportive to cardiac lipid metabolism involved oxidative stress (120, 121). In diabetic heart, metabolic substrate switching and subsequent excessive fatty acid oxidation leads to hampered oxidative phosphorylation with excessive free radical generation (120, 122). The excessive β-oxidation causes electron leakage in mitochondria to produce superoxide anion radical (123), the hydrogen peroxide and hydroxyl radical (124). Moreover, fatty acid induced mitochondrial uncoupling causes less ATP production and incomplete reduction and thus it indicates lipid metabolism related declined cardiac efficiency (12, 125-127). The escalation of uncoupling has been reported in diabetic myocardial cells of mice with overloaded ROS and lipid peroxides (20, 128).

 

5. MELATONIN: A METABOLIC REGULATOR

     Melatonin, a naturally occurring molecule, has been drawn a great attention due to its ability to redeem multiple arrays of metabolic hazards and disorders (24, 129). The antioxidant property of melatonin takes the ascendancy over its other properties in providing protective effects to stress stricken morpho-functionally altered tissues and/or cells. Not only its antioxidative activity, but also its anti-inflammatory and anti-apoptotic properties render this molecule as one of the best remedies for metabolic syndrome (130, 131).

     Randomized control and double-blind clinical studies have authenticated the harmonizing effects of melatonin on metabolic syndrome components like fasting glucose, blood pressure, cholesterol level etc (132, 133). Diabetes is the most prevalent metabolic disorder with imbalance in plasma glucose and insulin level (134, 135). Melatonin exhibits anti-hyperglycaemic property with the potency to balance both insulin and glucose levels via endocrine signalling and metabolic modifications. Apart from protecting cells/tissues from high glucose stress and insulin resistance (136), melatonin shows enormous effects on carbohydrate metabolism by controlling the blood glucose and maintaining energy homoeostasis (24). Melatonin enhances the glucose uptake both in adipocytes and skeletal muscle to lower blood glucose load (137, 138). It also inhibits the rate of hepatic gluconeogenesis (28) through silent information regulator 1 (SIRT1) activation (139). Pinealectomy in rats abated GLUT4 expression and increased insulin resistance and this can be rescued by melatonin administration (140, 141). In alloxan induced diabetic rats, melatonin steers the glucose metabolism toward aerobic mode by decreasing the activity of lactate dehydrogenase (LDH) (142). A more favourable action of melatonin toward energy balance comes through normalization of the activity of glucose-6-phosphate-dehydrogenase (G6PDH) in diabetic kidney, which leads to escalation in level of reduced nicotinamide adenine di-nucleotide phosphate (NADPH2), an integral factor of aerobic oxidation of glucose (143).

     The modulatory activity of melatonin has not only been evidenced in carbohydrate metabolism, but also in fatty acid metabolism (144). Long term melatonin administration influences the fatty acid metabolism along with alterations of lipid profile in type 2 diabetic rats (145). In DCM, the overload of fatty acids drives the cellular metabolic load toward beta oxidative pathway, as evidenced while melatonin hinders the synthesis of fatty acids directly to rescue cells from lipid burden. Melatonin impedes activities of acetyl-CoA carboxylase and fatty acid synthase in hyperlipidemic hamsters causing retardation in fatty acid production and concomitant decrease in triglyceride and cholesterol levels (29, 146). This has also been observed in in vitro condition. Alterations of lipid content in high concentration oleic acid exposed HepG2 has been prevented with melatonin pre-treatment where it acts by inhibiting acetyl-CoA carboxylase and other enzymes, involved in lipogenesis (147).

Figure 1.jpg

Fig.1. The potentially protective mechanisms of melatonin on DCM.

     The protective effects of melatonin on diabetes and DCM are to reduce many of severe symptoms among which metabolic amendment is a major one. Both carbohydrate and fatty acid metabolism pathways have drastically affected in diabetic heart, where melatonin rescues from those alterations to maintain convention in ATP level in order to normalize cardiac structure and function.

 

6. MELATONIN DEFICIENCY AND DISORGANISED METABOLISM

     A strong correlation between compromised melatonin synthesis and hyperglycaemia (148, 149) has put forward the goal for scientists to inspect the involvement of biorhythm and pineal gland function behind disastrous ailments of diabetes. The disarray in circadian rhythm remains excused for long as a responsible factor behind metabolic alterations associated with hyperglycaemia. The disturbed biorhythm has been considered experimentally as a causative factor behind the development of metabolic syndrome (150) such as in type 2 diabetes (143). Thus, targeting the circadian rhythm becomes a potential approach to treat diabetes (151). It was shown that a fine harmony between biorhythmic melatonin and insulin secretion is a protective measure for diabetes (152, 153). The maintenance of circadian rhythm entrained metabolic pathways is also equally considerable in terms of a preventive measure towards development of hyperglycaemia (154, 155). The correlation between circadian rhythm misalignment and disturbed plasma glucose level comprehensibly indicates their association with glucose intolerance (154), such as in the shift workers (150). Advancement toward type 2 diabetes in patients with sleep deprivation, disrupted circadian rhythm also suggested this crucial association (156, 157). For example, pinealectomy with circulatory melatonin deficiency leads to night-time high blood glucose concentration (158) which induces surged insulin resistance and glucose intolerance (159, 160). Those metabolic amendments toward glucose overload and ensuing glucose intolerance have also been noted in melatonin receptor knockout mouse model (161) which again substantiates crucial involvement of the pineal indole in metabolic regulations. The decline in the level of melatonin with night time light exposure was also found responsible for metabolic disturbances (162), specifically, increase in the rate of gluconeogenesis (163). Melatonin supplementation maintained the glucose homoeostasis (164) which improves metabolic status of obesity associated pre-diabetic rat heart and impedes occurrence of myocardial ischaemia (165). The relevance of melatonin biorhythm in preserving metabolic status in normalcy became more prominent with 24 hour rhythmic melatonin exposure on primary adipocytes in vitro (166). Here, melatonin administration has shown to keep balance in fatty acid level by enhancing free fatty acid incorporation within adipocytes along with reduction in lipolysis rate. An association between melatonin rhythm disruption and occurrence of diabetic autonomic neuropathy also endorsed the effective role of pineal indole in retarding the development of diabetic symptoms (167). Hence, in addition to its antioxidative activity, melatonin biorhythm and associated metabolic modulations in high glucose system have enlightened the effect of this indolamine on both carbohydrate and lipid metabolism (158, 168, 169).

 

7. ALLEVIATION OF METABOLIC PERTURBATIONS IN DCM BY MELATONIN

     The metabolic modulatory actions of melatonin add some feathers to its highly potent antioxidative role in amelioration of diabetes and associated disorders. Since, both metabolic pathways and oxidative stress are related to mitochondria, functional mitochondria are essential in mitigating metabolic disarray caused by glucotoxicty. Melatonin preserves stress stricken mitochondrial structure and thus revives functional status of cardiac mitochondria in DCM patients (170), otherwise, dysfunctional mitochondria in myocardium drastically lower functional mitochondrial content and energy production (171). Melatonin hinders the development of DCM (130) in multitudinous ways (172). Melatonin pre-treatment reduces glucose load by scavenging ROS (165, 173) and it also can rescue from the deleterious outcomes of diabetes by obstructing advancements of the disease toward heart failure (131).

     Melatonin stimulates PGC-1α to increase SIRT3 level of diabetic cardiac tissue which contributes in mitochondrial biogenesis with an obvious rise in activities at complex I, III and IV (174). Hence, melatonin keeps energy balance by preserving oxidative phosphorylation. Melatonin also contributes in arresting excessive fatty acid oxidation and facilitates the cellular environment to rely upon glucose oxidation pathways (175). Fatty acid overload in myocardium of hyperglycaemics with insulin resistance is due to excessive fatty acid uptake. This is mediated by PPARα, the transcription factor responsible for activation of enzymes related to β-oxidative pathway (176). Melatonin upregulates the expression of PPARα mRNA in hepatic and adipose tissue and accelerates fatty acid metabolism in those tissues to lower free fatty acid load (177, 178). These protective activities may be mediated by its receptor since mutated MTNR1B (Melatonin receptor 1B) gene is associated with diabetes (179, 180). The downregulation of melatonin nuclear receptor, RORα, is correlated with progression of DCM while melatonin application reduces cardiac hypertrophy and fibrosis associated with diabetes (181).

     Hence, apart from the antioxidative and mitochondria preserving actions, the modulation of cardiac metabolism by melatonin effectively retards the occurrence of DCM. The key metabolic improvement by melatonin is to decrease glucose level and fatty acid load and lipolysis. The potency of melatonin to keep metabolic balance is the prime factor behind maintenance of non-oxidative environment in myocardial tissue. Thus, the role of melatonin particularly in carbohydrate and fatty acid metabolism regulation of diabetic myocardium is nothing but an indication of fostering the usage of melatonin as an aid for DCM.

 

ACKNOWLEDGEMENTS

     A Junior Research Fellowship (JRF) under WBDST [304(Sanc.)/STP/S&T/1G-67/2017 DATED 29.03.2018] is greatly acknowledged by AB. Dr. AC is supported by funds available to her from Department of Science and Technology, Govt. of West Bengal. Dr. DB also gratefully acknowledges the support he received from Departmental BI Grant and DST-PURSE Program awarded to the University of Calcutta.


CONFLICT INTEREST

     The author(s) declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article.


AUTHORSHIP

     DB contributed to the conception. AB drafted the first version of the manuscript and figures and performed editing works. AC and DB critically reviewed the manuscript and approved it.

 

REFERENCE

 

  1. Salehidoost R, Mansouri A, Amini M, Aminorroaya Yamini S, Aminorroaya A (2020) Diabetes and all-cause mortality, a 18-year follow-up study. Sci. Rep. 10 (1): 1-8. DOI: 10.1038/s41598-020-60142-y.

  2. Miyazaki Y, Kawano H, Yoshida T, Miyamoto S, Hokamaki J, Nagayoshi Y, Yamabe H, Nakamura H, Yodoi J, Ogawa H (2007) Pancreatic B‐cell function is altered by oxidative stress induced by acute hyperglycaemia. Diab. Med. 24 (2): 154-160. DOI: 10.1111/j.1464-5491.2007.02058.x.

  3. Dominiczak MH (2003) Obesity, glucose intolerance and diabetes and their links to cardiovascular disease. Implications for laboratory medicine. Clin. Chem. Lab. Med. 41 (9): 1266-1278. DOI: 10.1515/CCLM.2003.194.

  4. Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr. Diabetes Rev. 9 (1): 25-53. DOI: 10.2174/157339913804143225.

  5. Haythorne E, Rohm M, van de Bunt M, Brereton MF, Tarasov AI, Blacker TS, Sachse G, Silva dos Santos M, Terron Exposito R, Davis S, Baba O (2019) Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nat. Commun. 10 (1): 1-7. DOI: 10.1038/s41467-019-10189-x.

  6. Oyadomari S, Araki E, Mori M (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells. Apoptosis 7 (4): 335-345. DOI: 10.1023/A:1016175429877.

  7. Petersen MC, Shulman GI (2018) Mechanisms of insulin action and insulin resistance. Phys. Rev. 98 (4): 2133-2223. DOI: 10.1152/physrev.00063.2017.

  8. Baena-Díez JM, Peñafiel J, Subirana I, Ramos R, Elosua R, Marín-Ibañez A, Guembe MJ, Rigo F, Tormo-Díaz MJ, Moreno-Iribas C, Cabré JJ (2016) Risk of cause-specific death in individuals with diabetes: a competing risks analysis. Diabetes Care 39 (11): 1987-1995. DOI: 10.2337/dc16-0614.

  9. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA (2018) Association between insulin resistance and the development of cardiovascular disease. Cardiovasc. Diabetol. 17 (1): 1-4. DOI: 10.1186/s12933-018-0762-4.

  10. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M, McGuire DK, Sattar N, Rosengren A, Gudbjörnsdottir S (2017) Mortality and cardiovascular disease in type 1 and type 2 diabetes. N. Engl. J. Med. 376 (15): 1407-1418. DOI: 10.1056/NEJMoa1608664.

  11. Banerjee A, Chattopadhyay A, Pal PK, Bandyopadhyay D (2020) Melatonin is a potential therapeutic molecule for oxidative stress induced red blood cell (RBC) injury: A review. Melatonin Res. 3 (1): 1-31. DOI: 10.32794/mr11250045.

  12. Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev. Endocr. Metab. Disord. 11 (1): 31-39. DOI: 10.1007/s11154-010-9131-7.

  13. Hayat SA, Patel B, Khattar RS, Malik RA (2004) Diabetic cardiomyopathy: mechanisms, diagnosis and treatment. Clin. Sci. 107 (6): 539-557. DOI: 10.1042/CS20040057.

  14. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am. J. Card. 30 (6): 595-602. DOI: 10.1016/0002-9149(72)90595-4.

  15. Robertson RP, Harmon JS (2006) Diabetes, glucose toxicity, and oxidative stress: a case of double jeopardy for the pancreatic islet β cell. Free Radic. Biol. Med. 41 (2): 177-184. DOI: 10.1016/j.freeradbiomed.2005.04.030.

  16. Ansley DM, Wang B (2013) Oxidative stress and myocardial injury in the diabetic heart. J. Pathol. 229 (2): 232-241. DOI: 10.1002/path.4113.

  17. Doria A, Nosadini R, Avogaro A, Fioretto P, Crepaldi G (1991) Myocardial metabolism in type 1 diabetic patients without coronary artery disease. Diab. Med. 8 (S2): S104-S107. DOI: 10.1111/j.1464-5491.1991.tb02168.x.

  18. Kenno KA, Severson DL (1985) Lipolysis in isolated myocardial cells from diabetic rat hearts. Am. J. Physiol. Heart Circ. Physiol. 249 (5): H1024-H1030.

  19. Herrero P, Peterson LR, McGill JB, Matthew S, Lesniak D, Dence C, Gropler RJ (2006) Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J. Am. Coll. Cardiol. 47 (3): 598-604. DOI: 10.1016/j.jacc.2005.09.030.

  20. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, Aziz S, Johnson JI, Bugger H, Zaha VG, Abel ED (2007) Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56 (10): 2457-2466. DOI: 10.2337/db07-0481.

  21. Bugger H, Abel ED (2009) Rodent models of diabetic cardiomyopathy. Dis. Model Mech. 2 (9-10): 454-466. DOI: 10.1242/dmm.001941.

  22. Karwi QG, Sun Q, Lopaschuk GD (2021) The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity. Cells 10 (11): 3259. DOI: 10.3390/cells10113259.

  23. Ostrander DB, Sparagna GC, Amoscato AA, McMillin JB, Dowhan W (2001) Decreased cardiolipin synthesis corresponds with cytochromec release in palmitate-induced cardiomyocyte apoptosis. J. Biol. Chem. 276 (41): 38061-38067. DOI: 10.1074/jbc.M107067200.

  24. Drăgoi CM, Arsene AL, Dinu-Pîrvu CE, Dumitrescu IB, Popa DE, Burcea-Dragomiroiu GT, Udeanu DI, Timnea OC, Velescu BȘ, Nicolae AC (2017) Melatonin: a silent regulator of the glucose homeostasis, eds Caliskan M, Kavakli IH, Oz GC (IntechOpen, London) pp 99. DOI: 10.5772/66625.

  25. Zhu T, Guan S, Lv D, Zhao M, Yan L, Shi L, Ji P, Zhang L, Liu G (2021) Melatonin modulates lipid metabolism in porcine cumulus–oocyte complex via its receptors. Front. Cell Dev. Biol. 9: 648209. DOI: 10.3389/fcell.2021.648209.

  26. Sun H, Wang X, Chen J, Gusdon AM, Song K, Li L, Qu S (2018) Melatonin treatment improves insulin resistance and pigmentation in obese patients with acanthosis nigricans. Int. J. Endocrinol. 2018: 2304746. DOI: 10.1155/2018/2304746.

  27. Wright JJ, Kim J, Buchanan J, Boudina S, Sena S, Bakirtzi K, Ilkun O, Theobald HA, Cooksey RC, Kandror KV, Abel ED (2009) Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc. Res. 82 (2): 351-360. DOI: 10.1093/cvr/cvp017.

  28. Faria JA, Kinote A, Ignacio-Souza LM, de Araújo TM, Razolli DS, Doneda DL, Paschoal LB, Lellis-Santos C, Bertolini GL, Velloso LA, Bordin S (2013) Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am. J. Physiol. Endocrinol. Metab. 305 (2): E230-E242. DOI: 10.1152/ajpendo.00094.2013.

  29. Ou TH, Tung YT, Yang TH, Chien YW (2019) Melatonin improves fatty liver syndrome by inhibiting the lipogenesis pathway in hamsters with high-fat diet-induced hyperlipidemia. Nutrients 11 (4): 748. DOI: 10.3390/nu11040748.

  30. Agil A, El‐Hammadi M, Jiménez‐Aranda A, Tassi M, Abdo W, Fernández‐Vázquez G, Reiter RJ (2015) Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats. J. Pineal Res. 59 (1): 70-79. DOI: 10.1111/jpi.12241.

  31. Lundbæk K (1954) Diabetic angiopathy: a specific vascular disease. Lancet 263 (6808): 377-379. DOI: 10.1016/S0140-6736(54)90924-1.

  32. Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M (2018) Diabetic cardiomyopathy: current and future therapies. Beyond glycemic control. Front. Physiol. 9: 1514. DOI: 10.3389/fphys.2018.01514.

  33. Fein FS, Sonnenblick EH (1985) Diabetic cardiomyopathy. Prog. Cardiovasc. Dis. 27 (4): 255-270. DOI: 10.1016/0033-0620(85)90009-X.

  34. Schocken DD, Benjamin EJ, Fonarow GC, Krumholz HM, Levy D, Mensah GA, Narula J, Shor ES, Young JB, Hong Y (2008) Prevention of heart failure: a scientific statement from the American Heart Association Councils on epidemiology and prevention, clinical cardiology, cardiovascular nursing, and high blood pressure research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 117 (19): 2544-2565. DOI: 10.1161/CIRCULATIONAHA.107.188965.

  35. Gilca GE, Stefanescu G, Badulescu O, Tanase DM, Bararu I, Ciocoiu M (2017) Diabetic cardiomyopathy: current approach and potential diagnostic and therapeutic targets. J. Diabetes Res. 2017: 1310265. DOI: 10.1155/2017/1310265.

  36. Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L (2020) Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat. Rev. Cardiol. 17 (9): 585-607. DOI: 10.1038/s41569-020-0339-2.

  37. Schannwell CM, Schneppenheim M, Perings S, Plehn G, Strauer BE (2002) Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology 98 (1-2): 33-39. DOI: 10.1159/000064682.

  38. Bell DS (2003) Diabetic cardiomyopathy. Diabetes care 26 (10): 2949-5291. DOI: 10.2337/diacare.26.10.2949.

  39. Karason K, Sjöström L, Wallentin I, Peltonen M (2003) Impact of blood pressure and insulin on the relationship between body fat and left ventricular structure. Eur. Heart J. 24 (16): 1500-1505. DOI: 10.1016/S0195-668X(03)00312-9.

  40.  Ingelsson E, Sundström J, Ärnlöv J, Zethelius B, Lind L (2005) Insulin resistance and risk of congestive heart failure. JAMA. 294 (3): 334-341. DOI: 10.1001/jama.294.3.334.

  41. Cook SA, Varela-Carver A, Mongillo M, Kleinert C, Khan MT, Leccisotti L, Strickland N, Matsui T, Das S, Rosenzweig A, Punjabi P (2010) Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction. Eur. Heart J. 31 (1): 100-111. DOI: 10.1093/eurheartj/ehp396.

  42. Tate M, Grieve DJ, Ritchie RH (2017) Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin. Sci. 131 (10): 897-915. DOI: 10.1042/CS20160491.

  43. Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, Haider B (1977) Evidence for cardiomyopathy in familial diabetes mellitus. J. clin. Invest. 60 (4): 885-899. DOI: 10.1172/JCI108843.

  44. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P (2000) Myocardial cell death in human diabetes. Circ. Res. 87 (12): 1123-1132. DOI: 10.1161/01.RES.87.12.1123.

  45. Kumar R, Yong QC, Thomas CM, Baker KM (2012) Intracardiac intracellular angiotensin system in diabetes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302 (5): R510-R517. DOI: 10.1152/ajpregu.00512.2011.

  46. Krentz AJ, Clough G, Byrne CD (2007) Interactions between microvascular and macrovascular disease in diabetes: pathophysiology and therapeutic implications. Diabetes Obes. Metab. 9 (6): 781-791. DOI: 10.1111/j.1463-1326.2007.00670.x.

  47. Calcutt NA, Cooper ME, Kern TS, Schmidt AM (2009) Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat. Rev. Drug Discov. 8 (5): 417-430.

  48. Jia G, Hill MA, Sowers JR (2018) Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ. Res. 122 (4): 624-638. DOI: 10.1161/CIRCRESAHA.117.311586.

  49. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: US department of health and human services, centers for disease control and prevention. 201 (1): 2568-2569.

  50. Huynh K, Bernardo BC, McMullen JR, Ritchie RH (2014) Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol. Ther. 142 (3): 375-415. DOI: 10.1016/j.pharmthera.2014.01.003.

  51. Kannel WB (2011) Framingham study insights on diabetes and cardiovascular disease. Clin. Chem. 57 (2): 338-239. DOI: 10.1373/clinchem.2010.149740.

  52. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB (2004) The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care 27 (8): 1879-1884. DOI: 10.2337/diacare.27.8.1879.

  53. Karnik AA, Fields AV, Shannon RP (2007) Diabetic cardiomyopathy. Curr. Hypertens Rep. 9 (6): 467-473.

  54. Athithan L, Gulsin GS, McCann GP, Levelt E (2019) Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date. World J. Diabetes 10 (10): 490-510. DOI: 10.4239/wjd.v10.i10.490.

  55. Isfort M, Stevens SC, Schaffer S, Jong CJ, Wold LE (2014) Metabolic dysfunction in diabetic cardiomyopathy. Heart Fail. Rev. 19 (1): 35-48. DOI: 10.1007/s10741-013-9377-8.

  56. Levelt E, Gulsin G, Neubauer S, McCann GP (2018) MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review. Eur. J. Endocrinol. 178 (4): R127-R139. DOI: 10.1530/EJE-17-0724.

  57.  Rodrigues B, Cam MC, McNeill JH (1995) Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J. Mol. Cell Cardiol. 27 (1): 169-179. DOI: 10.1016/S0022-2828(08)80016-8.

  58. Guo CA, Guo S (2017) Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure. J. Endocrinol. 233 (3): R131-R143. DOI: 10.1530/joe-16-0679.

  59. Wold LE, Ceylan‐Isik AF, Ren J (2005) Oxidative stress and stress signaling: menace of diabetic cardiomyopathy. Acta Pharmacol. Sin. 26 (8): 908-917. DOI: 10.1111/j.1745-7254.2005.00146.x.

  60.  Bugger H, Abel ED (2010) Mitochondria in the diabetic heart. Cardiovasc. Res. 88 (2): 229-240. DOI: 10.1093/cvr/cvq239.

  61. Rider OJ, Cox P, Tyler D, Clarke K, Neubauer S (2012) Myocardial substrate metabolism in obesity. Int. J. Obes. 37 (7): 972-979. DOI: 10.1038/ijo.2012.170.

  62. Bing RJ, Siegel A, Ungar I, Gilbert M (1954) Metabolism of the human heart: II. Studies on fat, ketone and amino acid metabolism. Am. J. Med. 16 (4): 504-515. DOI: 10.1016/0002-9343(54)90365-4.

  63. Wall SR, Lopaschuk GD (1989) Glucose oxidation rates in fatty acid-perfused isolated working hearts from diabetic rats. Biochim. Biophys. Acta. 1006 (1): 97-103. DOI: 10.1016/0005-2760(89)90328-7.

  64. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109 (18): 2191-2196. DOI: 10.1161/01.CIR.0000127959.28627.F8.

  65. Lopaschuk GD, Russell JC (1991) Myocardial function and energy substrate metabolism in the insulin-resistant JCR: LA corpulent rat. J. Appl. Physiol. 71 (4): 1302-1308. DOI: 0.1152/jappl.1991.71.4.1302.

  66. Zou MH, Xie Z (2013) Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy 9 (4): 624-625. DOI: 10.4161/auto.23577.

  67. Kolter TH, Uphues IN, Eckel JU (1997) Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats. Am. J. Physiol. 273 (1): E59-E67. DOI: 10.1152/ajpendo.1997.273.1.E59.

  68. Randle PJ, Kerbey AL, Espinal J (1988) Mechanisms decreasing glucose oxidation in diabetes and starvation: role of lipid fuels and hormones. Diabetes Metab. Rev. 4 (7): 623-638. DOI: 10.1002/dmr.5610040702.

  69. Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 281 (7285): 785-789. DOI: 10.1016/S0140-6736(63)91500-9.

  70. Camps M, Castello A, Munoz P, Monfar M, Testar X, Palacin M, Zorzano A (1992) Effect of diabetes and fasting on GLUT-4 (muscle/fat) glucose-transporter expression in insulin-sensitive tissues. Heterogeneous response in heart, red and white muscle. Biochem. J. 282 (3): 765-772. DOI: 10.1042/bj2820765.

  71. Razeghi P, Young ME, Cockrill TC, Frazier OH, Taegtmeyer H (2002) Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C–regulated gene expression in diabetic patients with nonischemic heart failure. Circulation 106 (4): 407-411. DOI: 10.1161/01.CIR.0000026392.80723.DC.

  72. Avogaro A, Nosadini R, Doria A, Fioretto P, Velussi M, Vigorito C, Sacca L, Toffolo G, Cobelli C, Trevisan R (1990) Myocardial metabolism in insulin-deficient diabetic humans without coronary artery disease. Am. J. Physiol. 258 (4): E606-E618. DOI: 10.1152/ajpendo.1990.258.4.E606.

  73. Monti LD, Lucignani G, Landoni C, Moresco RM, Piatti P, Stefani I, Pozza G, Fazio F (1995) Myocardial glucose uptake evaluated by positron emission tomography and fluorodeoxyglucose during hyperglycemic clamp in IDDM patients: role of free fatty acid and insulin levels. Diabetes 44 (5):537-542. DOI: 10.2337/diab.44.5.537.

  74. Hällsten K, Virtanen KA, Lönnqvist F, Janatuinen T, Turiceanu M, Rönnemaa T, Viikari J, Lehtimäki T, Knuuti J, Nuutila P (2004) Enhancement of insulin‐stimulated myocardial glucose uptake in patients with type 2 diabetes treated with rosiglitazone. Diabet. Med. 21 (12): 1280-1287. DOI: 10.1111/j.1464-5491.2004.01332.x.

  75. Lautamaki R, Airaksinen KJ, Seppanen M, Toikka J, Luotolahti M, Ball E, Borra R, Harkonen R, Iozzo P, Stewart M, Knuuti J (2005) Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study. Diabetes 54 (9): 2787-2794. DOI: 10.2337/diabetes.54.9.2787.

  76. Harmancey R, Lam TN, Lubrano GM, Guthrie PH, Vela D, Taegtmeyer H (2012) Insulin resistance improves metabolic and contractile efficiency in stressed rat heart. FASEB J. 26 (8): 3118-3126. DOI: 10.1096/fj.12-208991.

  77. Peterson LR, Saeed IM, McGill JB, Herrero P, Schechtman KB, Gunawardena R, Recklein CL, Coggan AR, DeMoss AJ, Dence CS, Gropler RJ (2012) Sex and type 2 diabetes: Obesity‐independent effects on left ventricular substrate metabolism and relaxation in humans. Obesity 20 (4):802-810. DOI: 10.1038/oby.2011.208.

  78. How OJ, Larsen TS, Hafstad AD, Khalid A, Myhre ES, Murray AJ, T. Boardman N, Cole M, Clarke K, Severson DL, Aasum E (2007) Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice. Arch. Physiol. Biochem. 113 (4-5): 211-220. DOI: 10.1080/13813450701783281.

  79. Koivisto VA, Stevens IK, Mattock M, Ebeling P, Muggeo M, Stephenson J, Idzior-Walus B (1996) EURODIAB IDDM Complications Study Group. Cardiovascular disease and its risk factors in IDDM in Europe. Diabetes care 19 (7): 689-697. DOI: 10.2337/diacare.19.7.689.

  80. van der Vusse GJ, van Bilsen M, Glatz JF (2000) Cardiac fatty acid uptake and transport in health and disease. Cardiovasc. Res. 45 (2): 279-293. DOI: 10.1016/S0008-6363(99)00263-1.

  81. Bagheri R, Qasim AN, Mehta NN, Terembula K, Kapoor S, Braunstein S, Schutta M, Iqbal N, Lehrke M, Reilly MP (2010) Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus. Am. J. Cardiol. 106 (8): 1118-1123. DOI: 10.1016/j.amjcard.2010.06.028.

  82. Coort SL, Hasselbaink DM, Koonen DP, Willems J, Coumans WA, Chabowski A, van der Vusse GJ, Bonen A, Glatz JF, Luiken JJ (2004) Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes 53 (7): 1655-1663. DOI: 10.2337/diabetes.53.7.1655.

  83.  Carley AN, Atkinson LL, Bonen A, Harper ME, Kunnathu S, Lopaschuk GD, Severson DL (2007) Mechanisms responsible for enhanced fatty acid utilization by perfused hearts from type 2 diabetic db/db mice. Arch. Physiol. Biochem. 113 (2): 65-75. DOI: 10.1080/13813450701422617.

  84. Liedtke AJ, DeMaison L, Eggleston AM, Cohen LM, Nellis SH (1988) Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ. Res. 62 (3): 535-542. DOI: 10.1161/01.RES.62.3.535.

  85. Falcão-Pires I, Leite-Moreira AF (2012) Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev. 17 (3): 325-344. DOI: DOI 10.1007/s10741-011-9257-z.

  86. Bowker-Kinley Mm, Davis Iw, Wu P, Harris Ar, Popov M (1998). Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem. J. 329 (1): 191-196. DOI: 10.1042/bj3290191.

  87. Carley AN, Severson DL (2005) Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim. Biophys. Acta 1734 (2): 112-126. DOI: 10.1016/j.bbalip.2005.03.005.

  88. Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP (2003) A critical role for PPARα-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc. Natl. Acad. Sci. 100 (3): 1226-1231. DOI: 10.1073/pnas.0336724100.

  89. Hopkins TA, Sugden MC, Holness MJ, Kozak R, Dyck JR, Lopaschuk GD (2003) Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-α transgenic mice. Am. J. Physiol. Heart Circ. Physiol. 285 (1): H270-H276. DOI: 10.1152/ajpheart.00852.2002.

  90. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146 (12): 5341-5349. DOI: 10.1210/en.2005-0938.

  91. Sharma V, Dhillon P, Wambolt R, Parsons H, Brownsey R, Allard MF, McNeill JH (2008) Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin-diabetic rat. Am. J. Physiol. Heart Circ. Physiol. 294 (4): H1609-H1620. DOI: 10.1152/ajpheart.00949.2007.

  92. Onay-Besikci A, Guner S, Arioglu E, Ozakca I, Ozcelikay AT, Altan VM (2007) The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts. Can. J. Physiol. Pharmacol. 85 (5): 527-535. DOI: 10.1139/Y07-036.

  93.  Rijzewijk LJ, van der Meer RW, Lamb HJ, de Jong HW, Lubberink M, Romijn JA, Bax JJ, de Roos A, Twisk JW, Heine RJ, Lammertsma AA (2009) 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. 54 (16): 1524-1532.

  94. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc. Natl. Acad. Sci. 97 (4): 1784-1789. DOI: 10.1073/pnas.97.4.1784.

  95. Chun L, Junlin Z, Aimin W, Niansheng L, Benmei C, Minxiang L (2011) Inhibition of ceramide synthesis reverses endothelial dysfunction and atherosclerosis in streptozotocin-induced diabetic rats. Diabetes Res. Clin. Pract. 93 (1): 77-85. DOI: 10.1016/j.diabres.2011.03.017.

  96. Ussher JR, Koves TR, Cadete VJ, Zhang L, Jaswal JS, Swyrd SJ, Lopaschuk DG, Proctor SD, Keung W, Muoio DM, Lopaschuk GD (2010) Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59 (10): 2453-2464. DOI: 10.2337/db09-1293.

  97. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED, Goldberg IJ (2008) Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid Res. 49 (10): 2101-2112. DOI: 10.1194/jlr.M800147-JLR200.

  98. Ljubkovic M, Gressette M, Bulat C, Cavar M, Bakovic D, Fabijanic D, Grkovic I, Lemaire C, Marinovic J (2019) Disturbed fatty acid oxidation, endoplasmic reticulum stress, and apoptosis in left ventricle of patients with type 2 diabetes. Diabetes 68 (10): 1924-1933. DOI: 10.2337/db19-0423.

  99. Pappachan JM, Varughese GI, Sriraman R, Arunagirinathan G (2013) Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. World J. Diabetes 4 (5): 177-189. DOI: 10.4239/wjd.v4.i5.177.

  100. Van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P (2011) Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc. Res. 92 (1): 10-18. DOI: 10.1093/cvr/cvr212.

  101. Nakayama H, Morozumi T, Nanto S, Shimonagata T, Ohara T, Takano Y, Kotani J, Watanabe T, Fujita M, Nishio M, Kusuoka H (2001) Abnormal myocardial free fattyacid utilization deteriorates with morphological changes in the hypertensive heart. Jpn. Circ. J. 65 (9): 783-787. DOI: 10.1253/jcj.65.783.

  102. Rodrigues B, Cam MC, McNeill JH (1998) Metabolic disturbances in diabetic cardiomyopathy. Mol. Cell Biochem. 180 (1): 53-57.

  103. Yazaki Y, Isobe M, Takahashi W, Kitabayashi H, Nishiyama O, Sekiguchi M, Takemura T (1999) Assessment of myocardial fatty acid metabolic abnormalities in patients with idiopathic dilated cardiomyopathy using 123I BMIPP SPECT: correlation with clinicopathological findings and clinical course. Heart 81 (2): 153-159. DOI: 10.1136/hrt.81.2.153.

  104. Takeda N, Nakamura I, Hatanaka T, Ohkubo T, Nagano M (1988) Myocardial mechanical and myosin isoenzyme alterations in streptozotocin-diabetic rats. Jpn. Heart J. 29 (4): 455-463. DOI: 10.1536/ihj.29.455.

  105. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, Tsuji T, Kohzuki H, Suga H, Taniguchi S, Takaki M (2002) Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am. J. Physiol. Heart Circ. Physiol. 282 (1): H138-H148. DOI: 10.1152/ajpheart.2002.282.1.H138.

  106.  McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, Levine BD, Raskin P, Victor RG, Szczepaniak LS (2007) Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116 (10): 1170-1175. DOI: 10.1161/CIRCULATIONAHA.106.645614.

  107.  Ceriello A (2000) Oxidative stress and glycemic regulation. Metabolism 49 (2): 27-29. DOI: 10.1016/S0026-0495(00)80082-7.

  108. Banerjee A, Chattopadhyay A, Bandyopadhyay D (2021) Potentially synergistic effects of melatonin and metformin in alleviating hyperglycaemia: a comprehensive review. Melatonin. Res. 4 (4): 522-550. DOI: 10.32794/mr112500110.

  109. Cai LU, Kang YJ (2001) Oxidative stress and diabetic cardiomyopathy. Cardiovasc. Toxicol. 1 (3): 181-193.

  110. Khullar M, Al-Shudiefat AA, Ludke A, Binepal G, Singal PK (2010) Oxidative stress: a key contributor to diabetic cardiomyopathy. Can. J. Physiol. Pharmacol. 88 (3): 233-240. DOI: 0.1139/Y10-016.

  111. Nunes S, Rolo AP, Palmeira CM, Reis F (2017) Diabetic cardiomyopathy: Focus on oxidative stress, mitochondrial dysfunction and inflammation. In: Kirali K, editor. Cardiomyopathies-Types and Treatments. London: IntechOpen. 235-257. DOI: 10.5772/65915.

  112.  González-Vı́lchez F, Ayuela J, Ares M, Pi J, Castillo L, Martı́n-Durán R (2005) Oxidative stress and fibrosis in incipient myocardial dysfunction in type 2 diabetic patients. Int. J. Cardiol. 101 (1): 53-58. DOI: 10.1016/j.ijcard.2004.03.009.

  113. Seddon M, Looi YH, Shah AM (2007) Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93 (8): 903-907. DOI: 10.1136/hrt.2005.068270.

  114. De Rosa S, Arcidiacono B, Chiefari E, Brunetti A, Indolfi C, Foti DP (2018) Type 2 diabetes mellitus and cardiovascular disease: genetic and epigenetic links. Front. Endocrinol. 9:2. DOI: 10.3389/fendo.2018.00002.

  115. Carpentier AC (2018) Abnormal myocardial dietary fatty acid metabolism and diabetic Cardiomyopathy Can. J. Cardiol. 34 (5): 605-614. DOI: 10.1016/j.cjca.2017.12.029.

  116. Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation. 115 (25): 3213-3223. DOI: 10.1161/CIRCULATIONAHA.106.679597.

  117. Galloway CA, Yoon Y (2015) Mitochondrial dynamics in diabetic cardiomyopathy. Antioxid. Redox Signal. 22 (17): 1545-1562. DOI: 10.1089/ars.2015.6293.

  118. Jarosz J, Ghosh S, Delbridge LM, Petzer A, Hickey AJ, Crampin EJ, Hanssen E, Rajagopal V (2017) Changes in mitochondrial morphology and organization can enhance energy supply from mitochondrial oxidative phosphorylation in diabetic cardiomyopathy. Am. J. Physiol. Cell Physiol. 312 (2): C190-C197. DOI: 10.1152/ajpcell.00298.2016.

  119. Shen X, Zheng S, Metreveli NS, Epstein PN (2006) Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes 55 (3): 798-805. DOI: 10.2337/diabetes.55.03.06.db05-1039.

  120. Tsushima K, Bugger H, Wende AR, Soto J, Jenson GA, Tor AR, McGlauflin R, Kenny HC, Zhang Y, Souvenir R, Hu XX (2018) Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ. Res. 122 (1): 58-73. DOI: 10.1161/CIRCRESAHA.117.311307.

  121. Cacicedo JM, Benjachareowong S, Chou E, Ruderman NB, Ido Y (2005) Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P)H oxidase, oxidant stress, and ceramide. Diabetes 54 (6): 1838-1845. DOI: 10.2337/diabetes.54.6.1838.

  122. An D, Rodrigues B (2006) Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 291 (4): H1489-H1506. DOI: 10.1152/ajpheart.00278.2006.

  123. Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39: 359-407. DOI: 10.1146/annurev.genet.39.110304.095751.

  124. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J. Physiol. 552 (2): 335-344. DOI: 10.1111/j.1469-7793.2003.00335.x.

  125. Vettor R, Fabris R, Serra R, Lombardi AM, Tonello C, Granzotto M, Marzolo MO, Carruba MO, Ricquier D, Federspil G, Nisoli E (2002) Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle. Int. J. obes. 26 (6): 838-847. DOI: 10.1038/sj.ijo.0802005.

  126. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K (2004) Uncoupling proteins in human heart. Lancet 364 (9447): 1786-1788. DOI: 10.1016/S0140-6736(04)17402-3.

  127. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED (2021) Cardiac energy metabolism in heart failure. Circ. Res. 128 (10): 1487-1513. DOI: 10.1161/CIRCRESAHA.121.318241.

  128. Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otín M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ, Brand MD (2003) A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J. 22 (16): 4103-4110. DOI: 10.1093/emboj/cdg412.

  129. Korkmaz A, Topal T, Tan DX, Reiter RJ (2009) Role of melatonin in metabolic regulation. Rev. Endocr. Metab. Disord. 10 (4): 261-270. DOI: 10.1007/s11154-009-9117-5.

  130. Aksoy N, Vural H, Sabuncu T, Aksoy S (2003) Effects of melatonin on oxidative–antioxidative status of tissues in streptozotocin‐induced diabetic rats. Cell Biochem. Funct. 21 (2): 121-125. DOI: 10.1002/cbf.1006.

  131. Amin AH, El-Missiry MA, Othman AI (2015) Melatonin ameliorates metabolic risk factors, modulates apoptotic proteins, and protects the rat heart against diabetes-induced apoptosis. Eur. J. Pharmacol. 747: 166-173. DOI: 10.1016/j.ejphar.2014.12.002.

  132. Bahrami M, Cheraghpour M, Jafarirad S, Alavinejad P, Cheraghian B (2019) The role of melatonin supplement in metabolic syndrome: A randomized double blind clinical trial. Nutr. Food Sci. 49 (5): 965-977. DOI: 10.1108/NFS-01-2019-0018.

  133. Goyal A, Terry PD, Superak HM, Nell-Dybdahl CL, Chowdhury R, Phillips LS, Kutner MH (2014) Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial. Diabetol. Metab. Syndr. 6 (1): 1-1. DOI: 10.1186/1758-5996-6-124.

  134. 134.          Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030 (2010) Diabetes Res. Clin. Pract. 87 (1): 4-14. DOI: 10.1016/j.diabres.2009.10.007.

  135. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res. Clin. Pract. 103 (2): 137-149. DOI: 10.1016/j.diabres.2013.11.002.

  136. Teodoro BG, Baraldi FG, Sampaio IH, Bomfim LH, Queiroz AL, Passos MA, Carneiro EM, Alberici LC, Gomis R, Amaral FG, Cipolla‐Neto J (2014) Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle. J. Pineal Res. 57 (2): 155-167. DOI: 10.1111/jpi.12157.

  137. Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, Baik HH (2006) Melatonin stimulates glucose transport via insulin receptor substrate‐1/phosphatidylinositol 3‐kinase pathway in C2C12 murine skeletal muscle cells. J. Pineal Res. 41 (1): 67-72. DOI: 10.1111/j.1600-079X.2006.00334.x.

  138.  Lima FB, Matsushita DH, Hell NS, Dolnikoff MS, Okamoto MM (1994) The regulation of insulin action in isolated adipocytes. Role of the periodicity of food intake, time of day and melatonin. Braz. J. Med. Biol. Res. 27 (4): 995-1000. PMID: 8087099.

  139. Chen J, Xia H, Zhang L, Zhang H, Wang D, Tao X (2019) Protective effects of melatonin on sepsis-induced liver injury and dysregulation of gluconeogenesis in rats through activating SIRT1/STAT3 pathway. Biomed. Pharmacother. 117: 109150. DOI: 10.1016/j.biopha.2019.109150.

  140. Rodrigues SC, Pantaleão L, Lellis‐Santos C, Veras K, Amaral F, Anhê G, Bordin S (2013) Increased corticosterone levels contribute to glucose intolerance induced by the absence of melatonin. Feder Am Soc Exp Biol. 27 (S1): 1161. DOI: 10.1096/fasebj.27.1_supplement.1161.1.

  141. Pourhanifeh MH, Hosseinzadeh A, Dehdashtian E, Hemati K, Mehrzadi S (2020) Melatonin: new insights on its therapeutic properties in diabetic complications. Diabetol. Metab. Syndr. 12 (1): 1-20. DOI: 10.1186/s13098-020-00537-z.

  142. Sanchez‐Campos S, Arévalo M, Mesonero MJ, Esteller A, González‐Gallego J, Collado PS (2001) Effects of melatonin on fuel utilization in exercised rats: role of nitric oxide and growth hormone. J. Pineal Res. 31 (2): 159-166. DOI: 10.1034/j.1600-079x.2001.310210.x.

  143. Kushnir OY, Yaremii IM, Shvetsv VI, Shvets NV (2017) Influence of melatonin on carbohydrate metabolism in the kidney of alloxan diabetic rats. Fiziol Zh. 63 (4): 64-71.

  144. Liu W, Zhang Y, Chen Q, Liu S, Xu W, Shang W, Wang L, Yu J (2020) Melatonin alleviates glucose and lipid metabolism disorders in Guinea pigs caused by different artificial light rhythms. J. Diab. Res. 2020: 4927403. DOI: 10.1155/2020/4927403.

  145. Nishida S, Segawa T, Murai I, Nakagawa S (2002) Long‐term melatonin administration reduces hyperinsulinemia and improves the altered fatty‐acid compositions in type 2 diabetic rats via the restoration of Δ‐5 desaturase activity. J. Pineal Res. 32 (1): 26-33. DOI: 10.1034/j.1600-079x.2002.10797.x.

  146. Chen X, Zhang C, Zhao M, Shi CE, Zhu RM, Wang H, Zhao H, Wei W, Li JB, Xu DX (2011) Melatonin alleviates lipopolysaccharide‐induced hepatic SREBP‐1c activation and lipid accumulation in mice. J. Pineal Res. 51 (4): 416-425. DOI: 10.1111/j.1600-079X.2011.00905.x.

  147. Mi Y, Tan D, He Y, Zhou X, Zhou Q, Ji S (2018) Melatonin modulates lipid metabolism in HepG2 cells cultured in high concentrations of oleic acid: AMPK pathway activation may play an important role. Cell Biochem. Biophys. 76 (4): 463-470. DOI: 10.1007/s12013-018-0859-0.

  148. Frese T, Bach AG, Mühlbauer E, Pönicke K, Brömme HJ, Welp A, Peschke E (2009) Pineal melatonin synthesis is decreased in type 2 diabetic Goto–Kakizaki rats. Life Sci. 85 (13-14): 526-533. DOI: 10.1016/j.lfs.2009.08.004.

  149. Amaral FG, Turati AO, Barone M, Scialfa JH, do Carmo Buonfiglio D, Peres R, Peliciari‐Garcia RA, Afeche SC, Lima L, Scavone C, Bordin S, Reiter RJ, Menna-Barreto L, Cipolla-Neto J (2014) Melatonin synthesis impairment as a new deleterious outcome of diabetes‐derived hyperglycemia. J. Pineal Res. 57 (1): 67-79. DOI: 10.1111/jpi.12144.

  150. Karlsson B, Knutsson A, Lindahl B (2001) Is there an association between shift work and having a metabolic syndrome? Results from a populationbased study of 27 485 people. Occup. Environ. Med. 58 (11): 747-752. DOI: 10.1136/oem.58.11.747.

  151. Thomas AP, Hoang J, Vongbunyong K, Nguyen A, Rakshit K, Matveyenko AV (2016) Administration of melatonin and metformin prevents deleterious effects of circadian disruption and obesity in male rats. Endocrinology 157 (12): 4720-4731. DOI: 10.1210/en.2016-1309.

  152. Banerjee A, Chattopadhyay A, Bandyopadhyay D (2020) Biorhythmic and receptor mediated interplay between melatonin and insulin: its consequences on diabetic erythrocytes. Melatonin. Res. 3 (2): 243-263. DOI: 10.32794/mr12250060.

  153.  Peschke E, Peschke D (1998) Evidence for a circadian rhythm of insulin release from perifused rat pancreatic islets. Diabetologia 41 (9): 1085-1092. DOI: 10.1007/s001250051034.

  154. Scheer FA, Hilton MF, Mantzoros CS, Shea SA (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl. Acad. Sci. 106 (11): 4453-4458. DOI: 10.1073/pnas.0808180106.

  155. Espino J, Pariente JA, Rodríguez AB (2011) Role of melatonin on diabetes-related metabolic disorders. World J. Diabetes 2 (6): 82. DOI: 10.4239/wjd.v2.i6.82.

  156. Knutson KL, Ryden AM, Mander BA, Van Cauter E (2006) Role of sleep duration and quality in the risk and severity of type 2 diabetes mellitus. Arch. Intern. Med. 166 (16): 1768-1774. DOI: 10.1001/archinte.166.16.1768.

  157. Laposky AD, Bass J, Kohsaka A, Turek FW (2008) Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS lett. 582 (1): 142-151. DOI: 10.1016/j.febslet.2007.06.079.

  158. La Fleur SE, Kalsbeek A, Wortel J, Van Der Vliet J, Buijs RM (2001) Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night‐time glucose concentrations. J. Neuroendocrinol. 13 (12): 1025-1032. DOI: 10.1046/j.1365-2826.2001.00717.x.

  159. Diaz B, Blazquez E (1986) Effect of pinealectomy on plasma glucose, insulin and glucagon levels in the rat. Horm. Metab. Res. 18 (04): 225-229. DOI: 10.1055/s-2007-1012279.

  160. Rodríguez V, Mellado C, Alvarez E, De Diego JG, Blázquez E (1989) Effect of pinealectomy on liver insulin and glucagon receptor concentrations in the rat. J. Pineal Res. 6 (1): 77-88. DOI: 10.1111/j.1600-079X.1989.tb00405.x.

  161. Contreras‐Alcantara S, Baba K, Tosini G (2010) Removal of melatonin receptor type 1 induces insulin resistance in the mouse. Obesity 18 (9): 1861-1863. DOI: 10.1038/oby.2010.24.

  162. Fonken LK, Weil ZM, Nelson RJ (2013) Dark nights reverse metabolic disruption caused by dim light at night. Obesity 21 (6): 1159-1164. DOI: 10.1002/oby.20108.

  163. Nogueira TC, Lellis-Santos C, Jesus DS, Taneda M, Rodrigues SC, Amaral FG, Lopes AM, Cipolla-Neto J, Bordin S, Anhê GF (2011) Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response. Endocrinology 152 (4): 1253-1263. DOI: 10.1210/en.2010-1088.

  164. Agil A, Rosado I, Ruiz R, Figueroa A, Zen N, Fernández‐Vázquez G (2012) Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats. J. Pineal Res. 52 (2): 203-210. DOI: 10.1111/j.1600-079X.2011.00928.x.

  165. Nduhirabandi F, Du Toit EF, Blackhurst D, Marais D, Lochner A (2011) Chronic melatonin consumption prevents obesity‐related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet‐induced obesity. J. Pineal Res. 50 (2): 171-182. DOI: 10.1111/j.1600-079X.2010.00826.x.

  166. Alonso‐Vale MI, Andreotti S, Mukai PY, Borges‐Silva CD, Peres SB, Cipolla‐Neto J, Lima FB (2008) Melatonin and the circadian entrainment of metabolic and hormonal activities in primary isolated adipocytes. J. Pineal Res. 45 (4): 422-429. DOI: 10.1111/j.1600-079X.2008.00610.x.

  167. O'brien IA, Lewin IG, O'hare JP, Arendt J, Corrall RJ (1986) Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy. Clin. Endocrinol. 24 (4): 359-364. DOI: 10.1111/j.1365-2265.1986.tb01639.x.

  168. Morgan LM, Aspostolakou F, Wright J, Gama R (1999) Diurnal variations in peripheral insulin resistance and plasma non-esterified fatty acid concentrations: a possible link? Ann. Clin. Biochem. 36 (4): 447-450. DOI: 10.1177/000456329903600407.

  169. Onaolapo AY, Onaolapo OJ (2018) Circadian dysrhythmia-linked diabetes mellitus: Examining melatonin’s roles in prophylaxis and management. World J. Diabetes 9 (7): 99-114. DOI: 10.4239/wjd.v9.i7.99.

  170. Yu LM, Dong X, Xue XD, Xu S, Zhang X, Xu YL, Wang ZS, Wang Y, Gao H, Liang YX, Yang Y (2021) Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6. J. Pineal Res. 70 (1): e12698. DOI: 10.1111/jpi.12698.

  171. Hu Y, Suarez J, Fricovsky E, Wang H, Scott BT, Trauger SA, Han W, Hu Y, Oyeleye MO, Dillmann WH (2009) Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J. Biol. Chem. 284 (1): 547-555. DOI: 10.1074/jbc.M808518200.

  172. Song YJ, Zhong CB, Wu W (2020) Cardioprotective effects of melatonin: Focusing on its roles against diabetic cardiomyopathy. Biomed. Pharmacother. 128: 110260. DOI: 10.1016/j.biopha.2020.110260.

  173. Nduhirabandi F, Huisamen B, Strijdom H, Lochner A (2017) Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats. Cardiovasc. J. Afr. 28 (6): 362-369. DOI: https://hdl.handle.net/10520/EJC-b2b7bfd2b.

  174. Yu L, Gong B, Duan W, Fan C, Zhang J, Li Z, Xue X, Xu Y, Meng D, Li B, Zhang M (2017) Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling. Sci. Rep. 7 (1): 1-3. DOI: 10.1038/srep41337.

  175. Amaral N, Okonko DO (2015) Metabolic abnormalities of the heart in type II diabetes. Diab. Vasc. Dis. Res. 12 (4): 239-248. DOI: 10.1177/1479164115580936.

  176. Watanabe K, Fujii H, Takahashi T, Kodama M, Aizawa Y, Ohta Y, Ono T, Hasegawa G, Naito M, Nakajima T, Kamijo Y (2000) Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor α associated with age-dependent cardiac toxicity. J. Biol. Chem. 275 (29): 22293-22299. DOI: 10.1074/jbc.M000248200.

  177. Ferré P (2004) The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 53 (suppl_1): S43-S50. DOI: 10.2337/diabetes.53.2007.S43.

  178. Huang K, Luo X, Zhong Y, Deng L, Feng J (2022) New insights into the role of melatonin in diabetic cardiomyopathy. Pharmacol. Res. Perspect. 10 (1): e00904. DOI: 10.1002/prp2.904.

  179. Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spégel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B (2009) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat. Genet. 41 (1): 82-88. DOI: 10.1038/ng.288.

  180. Garaulet M, Gómez-Abellán P, Rubio-Sastre P, Madrid JA, Saxena R, Scheer FA (2015) Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism 64 (12): 1650-1657. DOI: 10.1016/j.metabol.2015.08.003.

  181. Zhao Y, Xu L, Ding S, Lin N, Ji Q, Gao L, Su Y, He B, Pu J (2017) Novel protective role of the circadian nuclear receptor retinoic acid‐related orphan receptor‐α in diabetic cardiomyopathy. J. Pineal Res. 62 (3): e12378. DOI: 10.1111/jpi.12378.

     CCBY.png

         This work is licensed under a Creative Commons Attribution 4.0 International License