wjpls, 2019, Vol. 5, Issue 12, 06-21 Review Article ISSN 2454-2229

Ogbodo et al. World Journal of Pharmaceutical World Journal and ofLife Pharmaceutical Sciences and Life Sciences WJPLS

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THYROID HORMONE PROFILING AND ENZYMATIC STATUS IN DIAGNOSIS AND MANAGEMENT OF TYPE-II-DIABETES MELLITUS: A REVIEW OF LITERATURE

E.C. Ogbodo*1, C.C. Okafor1, H.G.O. Ogah2, I.P. Ezeugwunne3, Igwebuobi CF4; Okezie AO2, Agada U.N5, A. K. Amah6, I.O. Odumodu1

1Department of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Nnewi, Nigeria. 2Department of Chemical Pathology, Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Nigeria. 3Department of Biochemistry, Faculty of Basic Medical Sciences, Nnamdi Azikiwe University, Nnewi, Nigeria. 4Department of Nursing Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Nnewi, Nigeria. 5Histopathology unit, Department of Medical Laboratory Services, Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria. 6Department of Human Physiology, College of Medicine, Imo State University, Owerri, Nigeria.

*Corresponding Author: E.C. Ogbodo Department of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikiwe University, Nnewi, Nigeria.

Article Received on 24/09/2019 Article Revised on 14/10/2019 Article Accepted on 04/11/2019

ABSTRACT Diabetes mellitus (DM) is a chronic metabolic disease resulting from diminished or absent secretion of insulin or due to reduced tissue sensitivity to insulin and has a global health burden especially in developing countries like

Nigeria. The present review focuses on the role of thyroid hormone profiling and enzymatic antioxidant status in diagnosis and management of type-II-diabetes mellitus. Diabetes Mellitus and thyroid disorders are the two most

common endocrine disorders encountered in clinical practice and this is as a result of interaction between thyroid hormones and insulin. The clinical relationship between diabetes mellitus and thyroid function is becoming more widely recognized with hypothyroidism among diabetes mellitus patient. Type 2 diabetes is accompanied with increased formation of free radicals otherwise called reactive oxygen species (ROS) leading to oxidative damage of

cell components. ROS production in diabetes plays a key role in the pathogenesis of diabetic complications by accelerating important molecular mechanisms involved in hyperglycaemia induced oxidative damage. Thus,

increased ROS and impaired antioxidant defense contribute to the initiation and progression of micro- and macrovascular complications experienced in diabetics. Hyperinsulinamia initiates a negative feedback mechanism leading to hypothyroidism in Type 2 Diabetes Mellitus. Also, a decrease in enzymatic increases the risk of Type 2 Diabetes mellitus. Therefore, thyroid hormone function profiling and antioxidant assays may be

incorporated as part of routine tests for Type 2 Diabetes Mellitus.

KEY WORDS: Diabetes Mellitus, Thyroid Hormone, , Free Radicals, Enzymatic Antioxidants.

INTRODUCTION world, with stroke, myocardial infarction and other

cardiovascular diseases being the most common causes Diabetes mellitus (DM) is a chronic metabolic disease of death for adults with diabetes, with its main which results from diminished or absent secretion of pathophysiological features been impaired insulin insulin or even by reduced tissue sensitivity to insulin secretion and increased insulin resistance (Kaku, 2010). (International Diabetes Federation, 2015; American A number of factors including less glycemic control, Diabetes Association, 2016). It is a diverse group of smoking, high blood pressure, elevated cholesterol diseases with different group of etiology such as social, levels, obesity, and lack of regular exercise are environmental and genetic factors which acts considered to be risk factors that accelerate the concurrently or mutually. Diabetes is a global endemic deleterious effects of diabetes (Elfaki et al., 2014). with rapidly increasing prevalence in developing

countries such as Nigeria and Type 2 diabetes mellitus is one of the leading causes of preventable death in the

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Interestingly, thyroid disorders have been implicated in (Krishnamurthy and Wadhwani, 2012). SOD is Type-2-Diabetes Mellitus. Diabetes Mellitus and thyroid considered a first-line defense against ROS and is disorders are an endocrine disorder that are interrelated present in nearly all cells. It converts ion (O2- to each other (Rahman et al., 2007) and have a ) to (H2O2). H2O2 may still react with propensity to appear together and this is as a result of other free radicals; it is thus degraded by either one of interaction between thyroid hormones and insulin (Feely the other two antioxidant , GPx or CAT. GPx and Isles, 1979). Thyroid diseases and diabetes mellitus removes H2O2 by coupling its reduction with the are the two most common endocrine disorders oxidation of glutathione (GSH). GPx can also reduce encountered in clinical practice. They have been shown other peroxides, such as fatty acid hydroperoxides. CAT to mutually influence each other and associations which is localized primarily in peroxisomes, detoxifies between both conditions have been reported previously the H2O2 converting it into water and molecular oxygen (Tiwari and Rao, 2002). The clinical relationship (Krishnamurthy and Wadhwani, 2012). However, several between diabetes mellitus and thyroid function is studies have shown decreased enzymatic antioxidants becoming more widely recognized with hypothyroidism (SOD, GPX and CAT) activities in type 2 diabetes among diabetes mellitus patient (Ghazali and mellitus than in the non diabetic population jordjevi Abbiyesuku, 2010; Singh et al., 2011; Demitrost and et al., 2011; Rains and Jain, 2011; Bigagli et al., 2012; Ranabir, 2012; Yadav et al., 2012; Valerie et al., 2014; Hisalkar et al., 2012; Brown and Briggs, 2016; Ngaski, Datchinamoorthi et al., 2016; Afrin et al., 2017). Thyroid 2018). Therefore, the present review seeks to evaluate disease is common in the general population and the the Thyroid hormone profiling and enzymatic prevalence increases with age (Wu, 2000). However, antioxidant status in diagnosis and management of type- there is reported higher prevalence of thyroid 2-diabetes mellitus. dysfunction in type 2 diabetics than in the general population (Vondra et al., 2005). Type 2 diabetes mellitus Classification is based on the production of insulin by the Type 2 diabetes is accompanied with increased formation pancreas or the cells of the body response properly of free radicals otherwise called reactive oxygen species towards the insulin production. The relative importance (ROS) leading to oxidative damage of cell components of defects in insulin secretion or in the peripheral action (Bashan et al., 2009; Noori, 2012). ROS production in of the hormone in the occurrence of type 2 diabetes diabetes plays a key role in the pathogenesis of diabetic mellitus has been and will continue to be cause for complications (Van Campenhout et al., 2006). ROS discussion. In type 2 diabetes, the body does not create accelerates important molecular mechanisms involved in enough insulin to address its own particular issues or cell hyperglycaemia induced oxidative damage; it increases does not respond properly against the insulin. This is the stress signalling pathways that lead to beta-cell known as insulin resistance (Arthur, 2016; Zain, 2016). apoptosis (Rhodes, 2005). Different studies have Insulin resistance, which is the inability of cells to provided evidences of increased oxidative stress with respond adequately to normal levels of insulin, occurs depleted antioxidant enzymes in type 2 diabetes primarily within the muscles, liver, and fat tissue (Likidlilid et al., 2010; Al-Rawi, 2011; Bigagli et al., (Lippincott and Wilkins, 2007). In the liver, insulin 2012). Hyperglycemia, a hallmark of diabetic condition, normally suppresses glucose release. However, in the depletes natural antioxidants and facilitates the setting of insulin resistance, the liver inappropriately production of ROS, which has the ability to react with all releases glucose into the blood (Melmed et al., 2011). biological molecules like lipids, proteins, carbohydrates, The proportion of insulin resistance versus beta cell DNA and exert cytotoxic effects on cellular components dysfunction differs among individuals, with some having (Dincer et al., 2002). Thus, increased ROS and impaired primarily insulin resistance and only a minor defect in antioxidant defense contribute for initiation and insulin secretion and others with slight insulin resistance progression of micro- and macrovascular complications and primarily a lack of insulin secretion (Gardner et al., in diabetics (Ceriello and Motz, 2004). 2011).

Antioxidant enzymes are endogenous proteins that work Type 2 diabetes is also known as Non-Insulin-Dependent in combination to protect cells from reactive oxygen Diabetes Mellitus (NIDDM) or "adult-onset diabetes species (ROS) damage. Antioxidants are instrumental in (Batra and Singh, 2016) and has a prevalence of 75 to repairing damages caused by free radicals and the 90% occurring in all instances of diabetes globally. Type resulting oxidation; these enzymes action occurs by 2 diabetes as a rule grows steadily after some time. Most triggering chemical reactions that rid the body of free people with the condition might be ignorant of their radicals and ROS (Kulbacka et al., 2012). Of all the ailment particularly at early stages as there might be no enzymes, (SOD), Glutathione particular side effects (Nishimura, 2016). Most Peroxidase (GPx) and Catalase (CAT) are the ones with individuals with Type 2 diabetes exhibit intra-abdominal the most antioxidant activity and thus considered the (visceral) obesity, which is closely related to the main antioxidant enzymes that regulate free radical presence of insulin resistance. In addition, hypertension activity (Giacco and Brownlee, 2010). They constitute a and dyslipidemia (high triglyceride and low HDL- mutually supportive team of defense against ROS cholesterol levels; postprandial hyperlipidemia) often are

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present in these individuals. This is the most common cellular utilization of glucose results in lowering of blood form of diabetes mellitus and is highly associated with a glucose levels. Lower glucose levels then result in family history of diabetes, alcoholism, older age, obesity decreased insulin secretion. If insulin production and and lack of exercise. secretion are altered by disease, blood glucose dynamics will also change. If insulin production is decreased, PATHOPHYSIOLOGY OF DIABETES MELLITUS glucose entry into cells will be inhibited, resulting in An understanding of the pathophysiology of diabetes hyperglycaemia. The same effect will be seen if insulin rests upon knowledge of the basics of carbohydrate is secreted from the pancreas but is not used properly by metabolism and insulin action. Following the target cells. If insulin secretion is increased, blood consumption of food, carbohydrates are broken down glucose levels may become very low (hypoglycemia) as into glucose molecules in the gut. Glucose is absorbed large amounts of glucose enter tissue cells and little into the bloodstream elevating blood glucose levels. This remains in the bloodstream. Multiple hormones may rise in glycemia stimulates the secretion of insulin from affect glycemia. Insulin is the only hormone that lowers the beta cells of the pancreas. Insulin is needed by most blood glucose levels. The counter-regulatory hormones cells to allow glucose entry. Insulin binds to specific such as glucagon, catecholamines, growth hormone, cellular receptors and facilitates entry of glucose into the thyroid hormone, and glucocorticoids all act to increase cell, which uses the glucose for energy. The increased blood glucose levels, in addition to their other effects insulin secretion from the pancreas and the subsequent (Meley et al., 2006).

Fig. 1: Hormonal regulation of blood glucose. Key: +, stimulation; -, inhibition. Cortisol, growth, and epinephrine also antagonize the effect of insulin (Burtis and Bruns, 2015).

Pathogenesis and Pathophysiology of type 2 Diabetes resistance, the plasma insulin concentration could be Mellitus insufficient to maintain normal glucose homeostasis. In type 2 diabetes these mechanisms break down, with Keeping in mind the intimate relationship between the the consequence that the two main pathological defects secretion of insulin and the sensitivity of hormone action in type 2diabetes are impaired insulin secretion through a in the complicated control of glucose homeostasis, it is dysfunction of the pancreatic β-cell, and impaired insulin practically impossible to separate the contribution of action through insulin resistance (American Diabetes each to the etiopathogenesis of DM2 (Kumar and Clark, Association, 2010). In situations where resistance to 2002). Insulin resistance and hyperinsulinemia insulin predominates, the mass of β-cells undergoes a eventually lead to impaired glucose tolerance (Mahler transformation capable of increasing the insulin supply and Adler, 1999). and compensating for the excessive and anomalous demand. In absolute terms, the plasma insulin Aetiology of type 2 diabetes concentration (both fasting and meal stimulated) usually Type 2 diabetes results from an imbalance between is increased, although ―relative‖ to the severity of insulin insulin sensitivity and insulin secretion. Both

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longitudinal and cross-sectional studies have THYROID HORMONES demonstrated that the earliest detectable abnormality in All cells in the body are targets for thyroid hormones. type 2 diabetes is an impairment of the body's ability to While not strictly necessary for life, thyroid hormones respond to insulin. have profound effects on big time physiologic processes, such as development, growth and metabolism, and Impaired insulin action is observed in several tissues e.g., deficiency in the thyroid hormones is not compatible skeletal muscle, adipose tissue and the liver. It leads to with normal health. Additionally, many of the effects of increased insulin secretion from the pancreas to thyroid hormones have been delineated by study of overcome impaired insulin action. Compensatory deficiency and excess states. The primary function of the hyperinsulinemia maintains glucose level within normal thyroid is the production of the iodine-containing thyroid range, but in individual at high risk of developing hormones, triiodothyronine (T3) and thyroxine (T4) and diabetes, beta cells function eventually declines and the peptide hormone calcitonin. T3 is so named because leads to the development of impaired glucose tolerance it contains three atoms of iodine per molecule and T4 and eventually overt diabetes mellitus (Bloomgarden, contains four atoms of iodine per molecule (Guyton and 1998; Stumvoll et al., 2005). A number of factors Hall, 2011). The major form of thyroid hormone in the including less glycemic control, family history of blood is thyroxine (T4), which has a longer half-life than diabetes, alcoholism, older age, smoking, high blood T3 (Irizarry et al., 2014). In , the ratio of T4 to T3 pressure, elevated cholesterol levels, obesity, and lack of released into the blood is approximately 14:1. T4 is regular exercise are considered to be risk factors that converted to the active T3 (3-4 times more potent than accelerate the deleterious effects of diabetes. T4) within the cell by deiodinases. Thyroxine is believed to be a prohormone and a reservoir for the most active Signs and symptoms of diabetes and main thyroid hormone T3 (Irizarry et al., 2014). The - Excessive thirst (polydipsia) - Excessive urination hormonal output from the thyroid is regulated by the (polyuria) and dehydration thyroid-stimulating hormone (TSH) secreted from the - Excessive hunger or appetite (polyphagia) anterior pituitary gland, which itself is regulated by - Unexplained weight loss thyrotropin–releasing hormone (TRH) produced by the - Blurred vision, nearsightedness or other vision hypothalamus (Boron and Boulapep, 2012). problems - Frequent infections, including skin infections, thrush, BIOSYNTHESIS OF THYROID HORMONES gingivitis, urinary tract infections and yeast infections Iodide is actively taken up by thyroid gland under the - Slow healing of sores control of thyroid-stimulating hormone (TSH) via a - Skin problems, such as itchiness sodium iodide (Na/I-) symporter. The concentration of I- - Fatigue, lethargy or drowsiness in the gland is at least 20 times that in plasma. Iodide is - Shakiness or trembling rapidly converted to iodine within the thyroid gland, - Mood swings or irritability catalyzed by thyroid peroxidase (TPO). Iodination of - Dizziness or fainting tyroxine residue in thyroglobulin takes place to form - Numbness, tingling or pain in the feet, legs or hands mono-iodotyroxine (MIT) and di-iodotyroxine (DIT) (American Diabetes Association; 2005; Rother, 2007). mediated by the TPO (Crook, 2012). Iodo- tyroxines are coupled to T4 (DIT and DIT) and T3 (DIT Epidemiology of type 2 diabetes mellitus and MIT) which are stored in the lumen of the follicular According to International Diabetes Federation (IDF), in cells. Normally, much more T4 than T3 is synthesized, 2017, approximately 425 million adults were living with but if there is an inadequate supply of iodide, the ratio of diabetes and it is estimated to affect up to 629 million T3 to T4 increases. The thyroid hormones still people by the year 2045 (IDF, 2017). Diabetes Mellitus incorporated in thyroglobulin are stored in collid of the has become a major public health problem in Nigeria thyroid follicule. Prior to the secretion thyroid hormones, accounting for a prevalence of 2.4% with total number of thyroglobulin is taken up by the follicular cells, by a mortality amounting to 3028 deaths in 2017 (IDF, process involving endocytosis and phagocytosis, and T4 2017).In the world, WHO estimates that, globally, 422 and T3 are released by proteolytic enzymes into the blood million adults aged over 18 years were living with stream. This process is stimulated by TSH and inhibited diabetes in 2014 accounting for a prevalence of 8.5% by iodide. The thyroid hormones are immediately bound among the adult population, of which 90% have type 2 to plasma proteins. MIT and DIT, released at the same diabetes mellitus (T2DM), largely the result of physical time are de-iodinated and the iodine is reused. Each step inactivity and excess body weight (WHO, 2016). T2DM is controlled by specific enzymes and congenital accounts for well over 90% of diabetes mellitus in Sub- deficiency of any of these enzymes can lead to goiter Saharan Africa, and population prevalence proportions and, if severe, hypothyroidism. The uptake of iodide, as ranged from 1% in rural areas to 12% in urban (Hall et well as synthesis and secretion of thyroid hormones, is al., 2011). regulated by TSH, secreted from the anterior pituitary gland. About 10 times more T4 than T3 is formed, with most of the latter being formed by de-iodination in the liver, kidney and muscle (Crook, 2012).

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Fig. 2: structure of thyroid hormones.

GENERAL FUNCTIONS OF THYROID 4. Development: Normal levels of thyroid hormone HORMONES are essential for development. They increase the METABOLISM: thyroid hormones stimulate diverse growth rate of young people, and cells of the metabolic activities in most tissues, leading to an developing brain are a major target for the thyroid increase in basal metabolic rate. One consequence of this hormones. Thyroid hormone plays a crucial role in activity is to increase body heat production, which seems brain maturation during fetal development and few to result, at least in part, increased oxygen consumption years of postnatal life (Guyton and Hall,2011). and rates of ATP hydrolysis. Mechanism of Action of Thyroid Hormones Some of the metabolic effects of thyroid hormone T3 and T4 bind to nuclear receptors (thyroid hormone include receptors) (Lazar and Chin, 1990). T3 and T4, although 1. Lipid metabolism: Increased thyroid hormone being lipophilic, are not able to passively diffuse through levels stimulate fat mobilization, leading to the phospholipid bilayers of target cells (Dietrich et al., increased concentrations of fatty acids in many 2008), instead relying on transmembrane iodothyronine tissues. Despite increasing free fatty acids, thyroid transporters. The lipophilicity of T3 and T4 requires their hormones decreases cholesterol levels, perhaps by binding to the protein carrier thyroid-binding protein increasing the rate of secretion of cholesterol in bile. (TBG) (thyroxine-binding globulins, thyroxine binding Plasma concentration of cholesterol and prealbumins, and albumins) for transport in the blood. triglycerides are inversely correlated with thyroid The thyroid receptors bind to response elements in hormone levels (Guyton and Hall, 2011) promoters, thus enabling them to activate or inhibit 2. Carbohydrate metabolism: Thyroid hormones transcription. The sensitivity of a tissue to T3 is stimulate almost all aspects of carbohydrate modulated through the thyroid receptors. When metabolism, including enhancement of insulin- triiodothyronine (T3) binds a receptor, it induces a dependent entry of glucose into cells and increased conformational change in the receptor, displacing the gluconeogenesis and glycogenolysis to generate free corepressor from the complex. This leads to recruitment glucose. of coactivator proteins and RNA polymerase, activating 3. Growth: Thyroid hormones are clearly necessary transcription of the gene (Wu and Koenig, 2000). for normal growth in children and young animals, as Although this general functional model has considerable evidenced by growth-retardation observed in thyroid experimental support, there remain many open questions deficiency. Not surprisingly, the growth promoting (Ayers and Stephen, 2014). effects of thyroid hormones is intimately intertwined with that of growth hormone; a clear indication that Regulation of Thyroid Hormones (Hypothalamic– complex physiologic processes like growth depends Pituitary–Thyroid Axis) upon multiple endocrine controls. The hypothalamic pituitary thyroid axis (HPT axis) also known as thyroid homeostasis or thyrotropic feedback

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control is part of the neuroendocrine system responsible secrete thyroxine (T4) and, to a lesser degree, for the regulation of metabolism. As its name suggests, it triiodothyronine(T3). The major portion of T3, however, depends upon the hypothalamus, the pituitary gland, and is produced in peripheral organs, e.g. liver, adipose the thyroid gland. The hypothalamus senses low tissue, glia and skeletal muscle by deiodination from circulating levels of thyroid hormone (Triiodothyronine circulating T4. Deiodination is controlled by numerous (T3) and Thyroxine (T4)) and responds by releasing hormones and nerve signals including TSH, vasopressin thyrotropin releasing hormone (TRH). The TRH and catecholamines. Both peripheral thyroid hormones stimulates the pituitary to produce thyroid-stimulating (iodothyronines) inhibit thyrotropin secretion from the hormone (TSH). The TSH, in turn, stimulates the thyroid pituitary (negative feedback). Consequently, equilibrium to produce thyroid hormone until levels in the blood concentrations for all hormones are attained. TSH return to normal. Thyroid hormone exerts negative secretion is also controlled by thyrotropin releasing feedback control over the hypothalamus as well as hormone (thyroliberin, TRH), whose secretion itself is anterior pituitary, thus controlling the release of both again suppressed by plasma T4 and T3. Recent research TRH from hypothalamus and TSH from anterior suggested the existence of an additional feed forward pituitary gland (Dietrich et al., 2012). Thyroid motif linking TSH release to deiodinase activity in homeostasis results from a multi-loop feedback system human (Hoermann et al., 2014; Dietrich et al., 2015; that is found in virtually all higher vertebrates. Proper Hoermann et al., 2015).The existence of this TSH-T3 function of thyrotropic feedback control is indispensable shunt could explain why deiodinase activity is higher in for growth, differentiation, reproduction and intelligence. hypothyroid patients and why a minor fraction of The pituitary gland secretes thyrotropin (TSH; Thyroid affected individuals may benefit from substitution Stimulating Hormone) that stimulates the thyroid to therapy with T3 (Hoerman et al., 2015).

Fig. 3: regulation of thyroid hormone synthesis and secretion (hypothalamic–pituitary–thyroid axis). Retrieved from: http://www.pathwaymedicine.org/thyroid-hormone-regulation.

Oxidative stress metabolism. Increased oxidative stress at the cellular The shift in the balance between oxidants and level can come about as a consequence of many factors, antioxidants in favor of oxidants is termed ―oxidative including exposure to alcohol, cigarette smoke, stress.‖ As remarkable as our antioxidant defense system medications, trauma, cold, infections, poor diet, toxins, is, it may not always be adequate. The term ―oxidative radiation, or strenuous physical activity. Protection stress‖ has been coined to represent a shift towards the against all of these processes is dependent upon the pro-oxidants in the pro-oxidant/antioxidant balance that adequacy of various antioxidant substances that are can occur as a result of an increase in oxidative derived either directly or indirectly from the diet.

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Consequently, an inadequate intake of antioxidant TYPES OF ENZYMATIC ANTIOXIDANTS nutrients may compromise antioxidant potential, thus 1. Superoxide Dismutase compounding overall oxidative stress. Oxidative damage Superoxide dismutase (SOD) is the antioxidant enzyme − to DNA, proteins, and other macromolecules has been that catalyses the dismutation of superoxide anion (O2 ) implicated in the pathogenesis of a wide variety of into hydrogen peroxide and molecular oxygen (Wang et diseases, most notably heart disease and cancer al., 2012). SOD plays important protective roles against (Halliwell, 1994) . Oxidative stress causes damage to cellular and histological damages that are produced by proteins, nucleic acids and lipids due to lipid ROS. It facilitates the conversion of superoxide radicals peroxidation, which in turn leads to changes in the into hydrogen peroxide, and in the presence of other cellular structure and function, and ultimately cell death enzymes it converted into oxygen and water (Davari et via apoptosis or necrosis (Jancsó, 2015). The term al., 2013). All mammalian tissues contain three forms of ―oxidative stress‖ is used to describe the condition of SOD: Cu-Zn-SOD, Mn-SOD, and extracellular EC-SOD, oxidative damage resulting when the critical balance and each of them is a product of a distinct gene (Li et al., between free radical generation and antioxidant defenses 2012). Cu-Zn-SOD or SOD 1 (EC 1.15.1.1) is localized is unfavorable (Rock et al., 1996). Oxidative stress, in cytosol, Mn-SOD or SOD 2 (EC 1.15.1.1) in arising as a result of an imbalance between free radical mitochondria, and EC-SOD or SOD 3 (EC 1.15.1.1) in production and antioxidant defenses, is associated with (Zelko et al., 2002). Superoxide damage to a wide range of molecular species including reacts rapidly with nitric oxide (NO), reducing NO lipids, proteins, and nucleic acids (McCord, 2000). bioactivity and producing the oxidative peroxynitrite Excessive free radical formation and/or a reduction in the radical (Guzik et al., 2002). SOD, a major defender antioxidant capacity may upset the balance between against superoxide, in the kidneys during the prooxidants and antioxidants, leading to oxidative stress. development of murine diabetic nephropathy and down regulation of renal SOD (SOD 1 and SOD 3) may play a The mitochondria are the energy power houses of the key role in the pathogenesis of diabetic nephropathy cell. It has been suggested that certain chronic illnesses (Fujita et al., 2009). Over expression of SOD or the related to muscle pain and chronic fatigue, e.g., supplements of antioxidants including SOD mimetics, myofascial pain syndrome (MPS), fibromyalgia targeted to overcome oxidative stress, reduce ROS, and syndrome, and chronic fatigue immunodeficiency increase antioxidant enzymes, has been shown to prevent syndrome (CFIDS), are disorders in which there is an diabetes mellitus (Wang et al., 2012). EC-SOD is found aberration or dysfunction of mitochondrial energy in the of various tissues including production. It has been suggested that mitochondrial pancreas, skeletal muscle, and blood vessels, and is dysfunction is related to damage caused by ROS themajor extracellular scavenger of superoxide radicals produced as a consequence of increased oxidative stress (Fattman et al., 2003). The higher level of EC-SOD and insufficient antioxidant defenses. Levels of ROS resulted in a 6-fold increase in the total superoxide produced within the mitochondria are reported to dismutase activity of the islets; therefore, superoxide increase with age. Consequently, oxidative damage to radicals secreted to the extracellular space does not mitochondria would also appear to increase with age. contribute to the 훽-cell destruction (Sandstr¨om et al., This damage results in a decrease in energy production 2002). The elevated level of SOD is shown to reduce by some of the cell’s mitochondria. Mitochondrial oxidative stress; decrease mitochondrial release of function is supported by a broad spectrum of nutritional cytochrome C and apoptosis in neurons; and, in mice, modulators including antioxidants and antioxidant prevent diabetes-induced glomerular injury, thus support systems. suggesting a major role of SOD in the regulation of apoptosis (Kowluru et al., 2006). Decline in the level of ANTIOXIDANTS SOD in diabetic tissue and blood has been reported in Antioxidants are the substance that when present in low many studies (He et al., 2011; Shukla et al., 2012). concentration compared to those of the oxidisable Recently Kim (2013) reported that diabetic skin tissues substrates significantly delay or inhibit the oxidation of express a relatively small amount of extracellular protein that substance. Antioxidants defense, both enzymatic and and concluded that extracellular SOD is related to the non enzymatic reactions protect the body against altered metabolic state in diabetic skin, which elevates oxidative damage. The term ―antioxidant‖ refers to any ROS production (Kim, 2013). Study performed by molecule capable of stabilizing or deactivating free Lucchesi and colleagues (Lucchesi et al., 2013) to radicals before they attack cells. Humans have evolved observe the oxidative balance of diabetic rats reported highly complex antioxidant systems (enzymic and diminished activity of SOD and other antioxidative nonenzymic), which work synergistically, and in enzymes in in the liver tissue. combination with each other to protect the cells and organ systems of the body against free radical damage 2. Glutathione (Lobo et al., 2010). Therefore, it is imperative to X-ray Glutathione (GSH), a tripeptide, 훾-Lglutamyl-L- the underlying events ―free radicals‖ and ―oxidative cysteinylglycine, is present in all mammalian tissues at stress‖ which antioxidants seeks to ameliorate its 1–10mM concentrations (highest concentration in liver) deleterious effects. as the most abundant nonprotein thiol that defends

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against oxidative stress (Lu, 2013). GSH can maintain this organelle might be a source of ROS (G´oth and SH groups of proteins in a reduced state, participate in Eaton, 2000). amino acid transport, detoxify foreign radicals, act as coenzyme in several enzymatic reactions, and also Catalase protects pancreatic 훽-cells from damage by prevent tissue damage (Tsai et al., 2012). It is an hydrogen peroxide (Tiedge et al., 1998). Low catalase efficient antioxidant present in almost all living cells and activities, which have been reported in patients with is also considered as a biomarker of redox imbalance at schizophrenia and atherosclerosis (G´oth and Vitai, cellular level (Rizvi and Chakravarty, 2011). There are 1996), are consistent with the hypothesis that long-term several reports that claim reduced level of GSH in oxidative stress may contribute to the development of a diabetes (Rahigude et al., 2012; Calabrese et al., 2012). variety of late-onset disorders, such as type 2 diabetes Decreased GSH level may be one of the factors in the (G´oth, 2000). Deficiency of catalase increases oxidative DNA damage in type 2 diabetics (Dinc et al., mitochondrial ROS and fibronectin expression in 2002). As a consequence of increased oxidative status, response to free fatty acids, which were effectively GSH showed the frequent alteration in its concentration. restored by catalase over expression or N-acetyl cysteine Plasma GSH/GSSG showed a significant decrease in (Hwang et al., 2012). Low catalase activities can cause type 2 diabetes as compared to normal (Calabrese et al., methemoglobinaemia and hemolytic anemia which may 2012). Hyperlipidemia, inflammation, and altered be attributed either to deficiency of glucose-6-phosphate antioxidant profiles are the usual complications in dehydrogenase or to other unknown circumstances and diabetes mellitus as results decreased GSH/GSSG ratio also may damage heme proteins, cause cell death, and, (Das et al., 2012). Abnormal GSH status is involved in together with redox active metal ions, produce highly 훽-cell dysfunction and in the pathogenesis of long-term toxic hydroxyl radicals (G´oth and Bigler, 2007). Patel complications of diabetes. The dysregulation is widely and coworkers (Patel et al., 2013), during investigation implicated in disease states (Livingstone and Davis, of hyperglycemia- induced functional changes: 2007). Glutathione reductase (GSR) plays an important superoxide, hydrogen peroxide production, role through the reduction of GSSG to GSH and mitochondrial membrane polarization, and gene oxidation of NADPH to NAD+. GSSG is unable to expression fingerprints of related enzymes in endothelial perform antioxidant functions; however, GSH can be cells, have reported that hyperglycemia increased reclaimed from GSSG through the use of glutathione hydrogen peroxide production, hyperpolarized reductase (GSR) by the use of NADPH as a cofactor. mitochondrial membrane, and down regulated CAT gene Unfortunately, this GSH system can be overwhelmed if expression. ROS are produced in excess (Morris et al., 2013). Uncontrolled type 2 diabetes has severely deficient PATHOPHYSIOLOGY OF THYROID HORMONE synthesis of GSH attributed to limited precursor PROFILE IN T2DM availability. Dietary supplementation with GSH The thyrotrophin-releasing hormorne (TRH) released precursor amino acids can restore GSH synthesis and from the hypothalamus signals the pituitary gland to lower oxidative stress and oxidant damage in the face of produce and release Thyroid Stimulating Hormone persistent hyperglycemia (Sekhar et al., 2011). It has (TSH). TSH stimulates the synthesis and release of been observed that GSH deficiency in diabetics increased thyroid hormones from the thyroid gland (Crook, 2012). their susceptibility to melioidosis. It is hypothesized that The physiological function of thyroid hormones requires maintenance of GSH redox state may be a new the interaction of THs and their nuclear receptors (TRs). therapeutic avenue to protect diabetic patients against There are two major TR isoforms, encoded on separate some intracellular bacterial pathogens (Tan et al., 2012). (Sap et al., 1986; Weinberger et al., 1986): TRα and TRβ. The TRβ gene encodes three TRβ isoforms: 3. Catalase TRβ1, TRβ2, and TRβ3. All TRβ isoforms bind to their Catalase is an antioxidative enzyme present nearly in all cognate ligand T3 with high affinity to mediate target living organisms. It plays an important role against . In contrast, among the three TRα oxidative stress-generated complications such as diabetes isoforms, only TRα1 is able to bind to T3 in order to and cardiovascular diseases (Chelikani, 2004). Catalase activate or repress target genes, whereas TRα2 and TRα3 acts as main regulator of hydrogen peroxide metabolism. do not bind T3, antagonizing T3 action. The Hydrogen peroxide is a highly reactive small molecule musculoaponeurotic fibrosarcoma oncogene family A formed as natural by-product of energy metabolism. (MaFA) is present in the human pancreas and promotes β Excessive concentration of hydrogen peroxide may cause cell maturation and proliferation through its target genes significant damages to proteins, DNA, RNA, and lipids after birth (Eto et al., 2014). In pancreas, there are (Takemoto et al., 2009). Catalase enzymatically receptors of TH which are important for a normal processes hydrogen peroxide into oxygen and water and development of the islets. MAF gene encode thus neutralizes it. Increased risk of diabetes has been transcription factors, and the expression of MafA isotype documented in patients with catalase deficiency. The has as its main objective to regulate the growth, deficiency of this enzyme leads, in the 훽-cell, to an proliferation and development of β pancreatic cells increase in oxidative stress and ultimately to a failure of (Aramata et al., 2007) which in turn results in the this cell type. 훽-cells are rich in mitochondria, and thus secretion of insulin. Hyperinsulinemia triggers the

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negative feedback mechanism which down regulates the occurs in hyperthyroidism, reducing the secretion of synthesis and secretion of TSH that results in subsequent insulin stimulated by glucose (Stanick et al., 2005; decrease in the synthesis and secretion of thyroid Mitrou et al., 2010). This is in consonance with several hormones (T3 and T4) leading to hypothyroidism. In studies (Udiong et al., 2007; Yadav et al., 2012; hypothyroidism, there is an increase of insulin secretion Datchinamoorthi et al., 2016; Afrin et al., 2017). stimulated by glucose in the β cells, and the opposite

Fig. 5: Role of insulin in control of thyroid hormones through hypothalamic-pituitary axis (da Silva et al., 2017).

OXIDATIVE STRESS AND EZYMATIC •NO mediates endothelium-dependent vasorelaxation by ANTIOXIDANT ROLE IN T2DM its action on guanylate cyclase in vascular smooth Oxidative stress is defined in general as excess formation muscle cells (VSMC), initiating a cascade that leads to and/or insufficient removal of highly reactive molecules vasorelaxation. •NO also displays antiproliferative such as reactive oxygen species (ROS) and reactive properties and inhibits platelet and leukocyte adhesion to nitrogen species (RNS) (Maritim et al., 2003). ROS vascular endothelium (Turko et al., 2001). Therefore, • - • include free radicals such as superoxide ( O2 ), hydroxyl NO is considered a vasculoprotective molecule. • • • - • ( OH), peroxyl ( RO2), hydroperoxyl ( HRO2 ) as well as However, NO easily reacts with superoxide, generating - nonradical species such as hydrogen peroxide (H2O2) and the highly reactive molecule ONOO , and triggering a hydrochlorous acid (HOCl) (Evans et al., 2002). cascade of harmful events as discussed below (Vega- Lopez et al., 2004). Therefore its chemical environment, • • - • RNS include free radicals like nitric oxide ( NO) and i.e. presence of O2 , determines whether NO exerts • - nitrogen dioxide ( NO2 ), as well as nonradicals such as protective or harmful effects. Production of one ROS or - peroxynitrite (ONOO ), nitrous oxide (HNO2) and alkyl RNS may lead to the production of others through radical • - peroxynitrates (RONOO) (Evans et al., 2002). Of these chain reactions. As summarized in Fig. 6: O2 is • - • - reactive molecules, O2 , NO and ONOO are the most produced by one electron reduction of oxygen by several widely studied species and play important roles in the different oxidases including NAD(P)H oxidase, xanthine diabetic cardiovascular complications. •NO is normally oxidase, cyclooxygenase and even eNOS under certain produced from L-arginine by endothelial nitric oxide conditions as well as by the mitochondrial electron synthase (eNOS) in the vasculature (Turko et al., 2001). transport chain during the course of normal oxidative www.wjpls.org 14 Ogbodo et al. World Journal of Pharmaceutical and Life Sciences

phosphorylation, which is essential for generating ATP elements like iron and copper. A previous study • - (Evans et al., 2003). Under normal conditions, O2 is demonstrated that hyperglycemia-induced generation of - quickly eliminated by antioxidant defense mechanisms. •O2 at the mitochondrial level is the initial trigger of • - O2 is dismutated to H2O2 by manganese superoxide vicious cycle of oxidative stress in diabetes (Brownlee, dismutase (Mn-SOD) in the mitochondria and by copper 2001). Previously, a number of studies have shown (Cu)-SOD in the cytosol (Evans et al., 2003). H2O2 is depleted antioxidant status (SOD, GPX and CAT) in type converted to H20 and O2 by glutathione peroxidase 2 diabetic patients (Verma et al., 2013; Briggs et al., (GSH-Px) or catalase in the mitochondria and lysosomes, 2016; Medhini et al., 2016; Brown and Briggs, 2016; respectively. H2O2 can also be converted to the highly Kayalvizhi, 2017; Ngaski, 2018). reactive •OH radical in the presence of transition

Fig. 6: Generation of reactive species in type 2 diabetes mellitus (Jeanette et al., 2005). .

Highlighted in gray are some of the most important ROS glycemic indices, the American Diabetes Association • - and RNS in vascular cells. Oxygen is converted to O2 recommends glycated hemoglobin (HbA1c) testing in all via the activation of enzymatic and nonenzymatic diabetic patients as an initial assessment and then as a pathways, which is then dismutated to H2O2 by SOD. part of continuing care (ADA, 2014). This H2O2 can be converted to H2O by catalase or glutathione recommendation is derived from clinical data that shows peroxidase (GSH-Px) or to •OH after reaction with Cu or that HbA1c reflects average glycemic status over 2-3 Fe. Glutathione reductase regenerates glutathione (GSH). months and predicts diabetic complications (Lee et al., • - • - In addition, O2 reacts rapidly with NO to form ONOO . 2013). Currently, glycated albumin is been used along side with glycated hemoglobin. Albumin is one of the LABORATORY DIAGNOSIS OF TYPE 2 most abundant plasma proteins (Tiwari et al., 2015).The DIABETES MELLITUS glycation of albumin to form glycated albumin (GA) is In individuals diagnosed of diabetes mellitus, glucose ten times more than the glycation of hemoglobin in type monitoring is essential for glycemic control (Yoon et al., 2 DM (Tahara et al., 1995). GA is a marker which 2015). Currently, the laboratory tests used to diagnose reflects a short-term glycemic control (Yoon et al., Diabetes Mellitus are glycated hemoglobin (HbA1C), 2015). One advantage of utilizing serum albumin as a fasting plasma glucose (FG) and two-hour plasma measure of glycemic control is its shorter half-life of 21 glucose (2HPPG) after a 75g oral glucose tolerance test days, which renders its serum concentration more (OGTT) (Sacks et al., 2011; ADA, 2016). Of the sensitive to recent change in average blood glucose level

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than HbA1C (Guerin-Dubourg et al., 2012). Studies have levels of the antioxidant enzymes SOD and GPx are shown decreased albumin levels associated with usually significantly reduced in the diabetic subjects. increased HbA1c and total protein (Malawadi and Adiga, Hyperglycaemia, an inevitable consequence of Type 2 2016; Nazki et al., 2017). The following laboratory tests diabetes and increased generation of ROS depresses the is thus pivotal in the diagnosis of type 2 diabetes mellitus endogenous antioxidant defence system, exposing cells and they include: Urinalysis, blood glucose estimation to damage from oxidative stress which could lead to the (FBS, 2HPP, OGTT), HBA1c, glycated albumin development of diabetic complications. estimation. Hyperinsulinamia initiates a negative feedback mechanism leading to hypothyroidism in Type 2 Importantly, the use of thyroid function testing to assay Diabetes Mellitus. Also, a decrease in enzymatic the levels of TSH, T3 and T4, fT3 and fT4 index as well antioxidants increases the risk of Type 2 Diabetes as T3/T4 ratio which are not used routinely by many mellitus. laboratories may be included. I. Thyroid-stimulating hormone assay (TSH): TSH RECOMMENDATION produced by the pituitary is decreased in 1. Balanced diet, healthy life style and regular medical hyperthyroidism. Thus, the diagnosis of check are encouraged. hyperthyroidism is nearly always associated with a 2. Awareness creation by medical personnel is low (suppressed) TSH level. If the TSH levels are essential in the prevention and management of Type not low, then other tests must be run. 2 Diabetes Mellitus. II. Triiodothyronine (T3) Estimation 3. Thyroid hormone function profiling and antioxidant Thyroid hormones themselves (T3, T4) are assays should be incorporated as part of routine tests increased. For a patient to have hyperthyroidism, for Type 2 Diabetes Mellitus. they must have high thyroid hormone levels. Sometimes all of the different thyroid hormones are REFERENCES not high and only one or two of the different thyroid 1. ADA (American Diabetes Association), (2005). hormone measurements are high. This is not too Diagnosis and classification of Diabetes Mellitus. common, as most people with hyperthyroidism will Diabetes Care; 28(Suppl. 1): S37–S43. have all of their thyroid hormone measurements 2. ADA. (2010). Diagnosis and classification of high (except TSH). diabetes mellitus. Diabetes Care; 33(Suppl 1): S62- III. Free Triiodothyronine (Ft3) Estimation: 69. Triiodothyronine, a thyroid hormone, circulates in 3. Afrin, S., Sarkar, A.T.M.C.R., Zahid, Z.R. and blood almost completely bound (>99.5%) to carrier Ahmed, N. (2017). Thyroid function in type 2 proteins (Wild, 1994). The main transport protein is diabetes mellitus. 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