REVIEW OF LITERATURE

INTRODUCTION

Our focus in this chapter is to critically examine relevant literature that would assist in explaining the research problem and furthermore recognize the efforts of scholars who had previously contributed immensely to similar research. The chapter intends to deepen the understanding of the study and close the perceived gaps.

Precisely, the chapter will be considered in three sub-headings:

Conceptual Framework

Empirical Review

2.1 CONCEPTUAL FRAMEWORK

Definition Of Diabetes Mellitus

Diabetes mellitus (DM) is a clinical syndrome characterized by hyperglycemia due to absolute or relative deficiency of insulin (Sukha and Rubin, 2007). Deficiency in insulin production by the pancreas or inability of the insulin produced to bind effectively to its receptor on the cell surface results to chronic hyperglycemia and the attendant metabolic disregulation may be associated with secondary damage in multiple organ systems, especially the .kidneys, eyes, nerves, and blood vessels (Virella et al., 2003). Insulin has several functions in the human body. In the liver insulin increases the storage of glucose as glycogen. This involves the insertion of additional GLUT2 glucose transport molecules in cell plasma membranes.

In the muscle, insulin stimulates glycogen and protein synthesis. Glucose transport into muscle cells is facilitated by insertion of additional GLUT4 transport molecules into cell plasma membrane. In adipose tissue, insulin facilitates triglyceride storage by

activating plasma lipoprotein lipase, increasing glucose transport into cells via GLUT4 transporters and reducing intracellular lipolysis (Jagessar et al., 2015).

The primary symptoms are hyperglycemia and glucosuria, polyuria, polydipsia and polyphagia, sudden weight loss, ketonuria and ketonemia in acute episodes which results from inability to regulate glucose metabolism (Brownlee, 2001). In the later stage of diabetes, lipid metabolism is affected and is seen as hyperlipidemia and hypercholesterolemia, a risk factor in atherosclerosis (Ross, 1999; Schwartz, 2006; WHO, 2006).

Insulin deficiency may arise in various ways such as destruction of β-cells of the pancreas, an organ responsible for the production of insulin (Leslie et al., 2008) and although the exact cause of the disease is uncertain, genetic and secondary predisposing factors contribute to the onset of the disease (Shafee et al., 2008). Any other abnormality in the glucose metabolism pathway may result in hyperglycemia.

Epidemiology Of Diabetes Mellitus

Diabetes mellitus and its complications constitute a significant public health problem worldwide and an important cause of morbidity and mortality. Increase in obesity rates is to blame for much of the increase especially of type 2 DM. In the USA, two thirds of the adults are reported to be overweight or obese, and as a result, predictions show that one in three US citizens born in 2000 will develop diabetes mellitus. Habits characterized by low daily energy expenditure daily and by excessive ingestion of foods rich in carbohydrates and lipids, result in positive energy balance leading to increase of the body mass index (BMI) and prevalence of obesity in developed as well as developing countries (Mukundi et al., 2015).

Classification Of Diabetes Mellitus

Previous classification schemes of diabetes mellitus were based on the age at onset of the disease or on the mode of therapy (WHO, 1985). In contrast, the recent revised classification reflects the greater understanding of the pathogenesis of each variant (WHO, 1997). The vast majority of cases of diabetes fall into one of 3 broad classes: Type I diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas leading to insulin deficiency. This type of diabetes can be further classified as immune-mediated or idiopathic (ADA, 2007). The majority of type I diabetes is of the immune-mediated nature, where beta cell loss is a T-cell mediated autoimmune attack. The HLA genes encode proteins called major histocompatibility complex (MHC), and there are two main classes of MHC proteins, both of which display chains of amino acids. The chains are called antigens, and immune cells (called T cells) analyze them. MHC class 1 present chains from inside the cells, whereas MHC class 2 present chains from outside the cells. If T cells bind to the chain presented on an MHC, the T cell immediately orchestrates powerful attacks by the body's other immune cells (ADM, 2007). Ideally, the body only contains T cells that bind to chains from infectious organisms (Viruses, bacteria, etc.) and tumor cells. The alternative is found in autoimmune diseases such as diabetes where T cells bind to chains from the body's healthy cells.

There are many different alleles of the HLA genes, leading to many different variants of MHC proteins and allowing a variety of chains to be presented to cells. The inheritance of particular HLA alleles can account for over half of the genetic risk of developing type 1 diabetes (Frier and Fisher, 2010). The genes encoding class II MHC proteins are most strongly linked with diabetes, and these genes are called HLA-DR, HLA-DQ, and HLA-DP. There is no known preventive measure against type 1 diabetes, which causes approximately 10 % of diabetes mellitus cases in North America and Europe. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type I diabetes can affect children or adults but was traditionally termed "juvenile diabetes" because it represented a majority of the diabetic cases in children (WHO, 1999).

Diabetogenic agents such as chemicals, biological agents, peptides, potentiators and steroids are known to induce diabetes. Alloxan is an oxygenated pyrimidine and toxic analog of glucose. Alloxan destroys β cells and is used in research models to induce diabetes. It selectively destroys insulin-producing cells in the pancreas when administered to rodents and many other animal species. This compound does not affect human cells. It causes an insulin-dependent diabetes mellitus (called "alloxan diabetes") in these animals, with similar characteristics to type 1 diabetes in humans. It preferentially accumulates in beta cells through uptake via the GLUT2 glucose transporter (Danilova, 2014).

Alloxan, in the presence of intracellular thiols, generates reactive oxygen species (ROS) in a cyclic reaction with its reduction product, dialuric acid. The beta cell toxicity action is initiated by free radicals formed in this redox reaction. The selective uptake of the compound is due to its structural similarity to glucose as well as the beta-cell's highly efficient uptake mechanism (GLUT2). In addition, alloxan has a high affinity to SH- containing cellular compounds and, as a result, reduces glutathione content. In addition, alloxan inhibits glucokinase, a SH-containing protein essential for insulin secretion induced by glucose (Szkudelski, 2001). Some studies have shown that alloxan is not toxic to the human beta-cells, even in very high doses, probably because of differing glucose uptake mechanisms in humans and rodents (Tyrberg et al., 2001, Lenzen 2008). It is, however, toxic to the liver and the kidneys in high doses.

Type II diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β-cell (relative insulin deficiency). Approximately 80 % to 90 % of diabetic patients have type 2 diabetes, while variety of monogenic and secondary causes are responsible for the remaining cases (WHO, 1999). Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance that is first recognized during pregnancy and affects approximately 4 % of all pregnancies. GDM generally resolves postpartum, although women who have experienced gestational diabetes are at higher risk of developing type 2 diabetes mellitus (ADM, 2007). Hormones produced during pregnancy causes insulin resistance that is normally compensated for by increased insulin secretion. Similar to individuals with type 2 diabetes, women with GDM are unable to meet the increased demand for insulin due to an underlying insulin secretory defect (Beaser, 2001). Despite major types of diabetes having different pathogenic mechanism, the long - term complications in kidneys, eyes, nerves and blood vessels are the same, as are the principle causes of morbidity and death.

Other types include impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG). IGT and IFG are intermediate conditions in the transition between normality and diabetes. People with IGT or IFG are at high risk of progressing to type 2 diabetes although this is not inevitable. Obesity has been associated with insulin resistance which precedes type 2 diabetes mellitus. Insulin stimulates production of leptin when adipocytes are exposed to glucose to encourage satiety while leptin via negative feedback decreases the secretion of insulin (Carey et. al., 1997).

Type 1 diabetes mellitus

Type 1 DM is an autoimmune disease. An autoimmune disease results when the bodys system for fighting infection; the immune system, turns against a part of the body. In diabetes, the immune system attacks and destroys the insulin-producing beta cells in the pancreas. The pancreas then produces little or no insulin. A person who has type 1 DM must take insulin daily to live (WHO, 2007). Figure 1 shows the normal appearance of beta cell while Figure 2 shows the appearance of beta cells in type 1 DM.

At present, scientists do not know exactly what causes the bodys immune system to attack the beta cells, but they believe that autoimmune, genetic, and environmental factors, possibly viruses, are involved. Type 1 DM accounts for about 5 to 10% of diagnosed diabetes in the United States. It develops most often in children and young adults but can appear at any age (WHO, 2007). Symptoms of type 1 DM usually develop over a short period, although beta cell destruction can begin years earlier. Symptoms may include increased thirst and urination, constant hunger, weight loss, blurred vision, and extreme fatigue. If not diagnosed and treated with insulin, a person with type 1 DM can lapse into a life-threatening diabetic coma, also known as diabetic ketoacidosis (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 2003; WHO, 2007).

Figure 1: Appearance of normal beta cells

Type 2 diabetes

The most common form of DM is T2DM. About 90% of people with DM have type 2. This form of DM is most often associated with older age, obesity, family history of DM (Balletshofer et al., 2000), previous history of gestational diabetes, physical inactivity, and certain ethnicities. About 80% of people with T2DM are overweight. T2DM is increasingly being diagnosed in children and adolescents, especially among African American, Mexican American, and Pacific Islander youth. When T2DM is diagnosed, the pancreas is usually producing enough insulin, but for unknown reasons the body cannot use the insulin effectively, a condition called insulin resistance. After several years, insulin production decreases. The result is the same as for type 1 DM, glucose builds up in the blood and the body cannot make efficient use of its main source of fuel (NIH, 2008).The symptoms of T2DM develop gradually. Their onset is not as sudden as in type 1 DM. Symptoms may include fatigue, frequent urination, increased thirst and hunger, weight loss, blurred vision, and slow healing of wounds or sores. Some people have no symptoms (WHO, 2007). Figure one shows the appearance of beta cell in T2DM

Gestational diabetes mellitus

Some women develop gestational DM late in pregnancy. Although this form of DM usually disappears after the birth of the baby, women who have had gestational DM have a 40 to 60 percent chance of developing T2DM within 5 to 10 years. Maintaining a reasonable body weight and being physically active may help prevent development of T2DM (Alberti and Zimmet, 1998). About 3 to 8% of pregnant women in the United States develop gestational diabetes. As with T2DM, gestational diabetes occurs more often in some ethnic groups and among women with a family history of DM. Gestational DM is caused by the hormones of pregnancy or a shortage of insulin. Women with gestational DM may not experience any symptoms (WHO, 2007; NIH, 2008).

Epidemiology

Diabetes Mellitus is not contagious; however, certain factors can increase the risk of developing it. Type 1 DM occurs equally among males and females but is more common in whites (NIH, 2008). Data from the World Health Organizations Multinational Project for Childhood DM indicated that type 1 diabetes is rare in most African, American Indian, and Asian populations (Rewers et al., 1988). However, some Northern European countries, including Finland and Sweden, have high rates of type 1 DM (NIH, 2008). The reasons for these differences are unknown. Type 1 DM develops most often in children but can occur at any age (NIH, 2008).

Type 2 diabetes is more common in older people, especially in people who are overweight, and occurs more often in African Americans, American Indians, some Asian Americans, Native Hawaiians and other Pacific Islander Americans, and Hispanics/Latinos (Patrick et al., 1989). National survey data in 2007 indicate a range in the prevalence of diagnosed and undiagnosed diabetes in various populations ages 20 years or older in United States: Age 20 years or older recorded 23.5 million, or 10.7 percent, of all people in this age group have DM. Age 60 years or older recorded a prevalence of 12.2 million, or 23.1 percent, of all people in this age group. For men, 12.0 million or 11.2 percent, of all men ages 20 years or older have diabetes while the prevalence of DM in women was 11.5 million or 10.2 percent, of all women ages 20 years or older. Non-Hispanic whites have a prevalence of 14.9 million or 9.8 percent, of all non-Hispanic whites ages 20 years or older while non-Hispanic blacks recorded 3.7 million or 14.7 percent, of all non-Hispanic blacks ages 20 years or older (NIH, 2008).

Diabetes Mellitus prevalence in the United States is likely to increase for several reasons. First, a large segment of the population is aging. Also, Hispanics/Latinos and other minority groups at increased risk make up the fastest-growing segment of the U.S. population. Finally, Americans are increasingly overweight and sedentary. According to recent estimates from the Centre for Disease Control (CDC), DM will affect one in three people born in 2000 in the United States. The centre for disease control (CDC) also projects that the prevalence of diagnosed DM in the United States will increase 165 percent by 2050 (NIH, 2008).There are an estimated 23.6 million people in the U.S. (7.8% of the population) with diabetes with 17.9 million being diagnosed (American Diabetes Association, 2009) 90% of whom are type 2 with prevalence rates doubling between 1990 and 2005, CDC has characterized the increase as an epidemic (Gerberding, 2007). According to CDC, about 23.613 million people in the United States, or 8% of the population, have DM (Gerberding, 2007). The total prevalence of DM increased 13.5% from 2005-2007(American Diabetes Association, 2008). It was thought that only 24% of DM is now undiagnosed, down from an estimated 30% in 2005 and from the previously estimated 50% in 1995 (Gerberding, 2007). About 9095% of all North American cases of DM are type 2 and about 20% of the population over the age of 65 has T2DM (Zimmet et al., 1997).

The fraction of people with T2DM in other parts of the world varies substantially, almost certainly for environmental and lifestyle reasons, though these are not known in detail. DM affects over 150 million people worldwide and this number is expected to double by 2025 (Zimmet et al., 2001). Crude prevalence rates were 7.7 and 5.7% were estimated for males and females Port Harcourt in Nigeria. In Nigeria, the national prevalence of DM was estimated to be 6.8% in adult Nigerians older than 40 years (Abubakari and Bhopalb, 2008), making it the second common non-communicable disease after hypertension (Akinkugbe, 1997; Familoni et al., 2008).

Pathology

Diabetes Mellitus is characterized by hyperglycaemia due to disturbances in the metabolism of carbohydrate, fat and protein because of abnormalities in the availability of insulin or insulin-action (WHO, 2007). Even though DM is an endocrine disease in origin, its major manifestations are those of a metabolic disease. The characteristics symptoms are excessive thirst, polyuria, pruritus, and otherwise unexplained weight loss (American Diabetes Association, 2003a). DM also brings about the progression of secondary complications through the thickening of basement membrane (WHO, 2007). The most dominant feature of the metabolism in DM is an abnormally high concentration of blood glucose. This can be either due to an abnormally high rate of glucose production or of impaired glucose utilization. It is now accepted that the high blood glucose level is the result of combination of both these processes.

The secondary complications seen in patients with DM are found to involve alterations in vascular basement membrane composition as well as accumulation of glucose derived reaction products due to over utilization of glucose in insulin independent tissues (Laaksonen, 2003). Various authors have shown that hyperglycaemia leads to an increase in serum glycated proteins (Gordon et al., 2008; Delimaris et al., 2008) along with alterations in other atherogenic risk factors. Further, disturbances in mineral metabolism are also noticed (Walter, 1991; Ditzel and Lervang, 2009) and it is not known whether differences in trace element status are a consequence to the expression of the disease (Laaksonen, 2003).

Insulin resistance means that body cells do not respond appropriately when insulin is present. Unlike type 1 DM, the insulin resistance is generally "post-receptor", meaning it is a problem with the cells that respond to insulin rather than a problem with production of insulin (American Diabetes Association, 2003a).Other important contributing factors to T2DM are; increased hepatic glucose production (e.g., from glycogen to glucose conversion), especially at inappropriate times (typical cause is deranged insulin levels, as those levels control this function in liver cells) (Laaksonen, 2003), decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects) and impaired beta cell function loss of early phase of insulin release in response to hyperglycaemic stimuli (Gavin, 2008). Figure 4 shows a schematic representation of regulation of blood glucose. These factors are more complex problem in T2DM, but is sometimes easier to treat, especially in the early years when insulin is often still being produced internally (Laaksonen, 2003). T2DM may go unnoticed for years before diagnosis, since symptoms are typically milder (e.g. no ketoacidosis, coma, etc.) and can be sporadic (Laaksonen, 2003). However, severe complications can result from improperly managed T2DM, including renal failure, erectille dysfunction, blindness, slow healing wounds (including surgical incisions), and arterial disease, including coronary artery disease. The onset of T2DM has been most common in middle age and later life (Zimmet et al., 1997), although it is being more frequently seen in adolescents and young adults due to an increase in child obesity and inactivity (Zimmet et al., 1997). There is also a strong inheritable genetic connection in T2DM. Having relatives (especially first degree) with T2DM increases risks of developing T2DM very substantially. In addition, there is a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes (Jansson et al., 2002). About 55% of T2DM patients are obese (WHO, 2000). Long standing obesity leads to increased insulin resistance that can develop into diabetes. This can be attributed to the fact that adipose tissue (especially that in the abdomen around internal organs) is a source of several chemical signals to other tissues (hormones and cytokines). Other research shows that T2DM causes obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance (Camastra et al., 1999). However, genetics play a relatively small role in the widespread occurrence of T2DM. This can be logically deduced from the huge increase in the occurrence of T2DM which has correlated with the significant change in western lifestyle (Hu, 2003).

Symptoms

Early symptoms may be chronic fatigues, generalized weakness and malaise (feeling of unease), excessive urine production, excessive thirst and increased fluid intake, blurred vision (typically from lens shape alterations, due to osmotic effects, e.g., high blood glucose levels), unexplained weight loss, lethargy and itching of external genitalia (American Diabetes Association, 2003a).

Diagnosis Of Diabetes Mellitus

Diabetes Mellitus is a disease which may complicate and affect all organ systems in the body. Prevention, timely diagnosis, and treatment are important in patients with diabetes mellitus. Many of the complications associated with diabetes, such as nephropathy, retinopathy, neuropathy, cardiovascular disease, stroke, and death, can be delayed or prevented with appropriate treatment by controlling elevated blood pressure, lipids, and blood glucose (Albert et al., 1998).

The body, under normal circumstances, is able to keep glucose concentrations stable within the range of 4-7 mmol/L. The normal fasting blood sugar is usually between 2-5 mmol/L. After a meal it would rarely exceed 8.0 mmol/L. In normal condition, there is no glucose in urine since the normal threshold above which glucose would appear in the urine would be 10 mmol/L. Any value below a concentration of 10 mmol/L allows the kidneys to reabsorb glucose back into the blood stream and so glucose does not appear in the urine unless the blood concentration of glucose is high (Ta et al., 2014).

The criterion of diagnosis of diabetes mellitus is based on presence of signs and symptoms and on three major laboratory findings according to ADA, (2012).

a) A fasting plasma glucose test of ≥ 90 mg/dL (5.0 mmol/L).

Blood glucose is measured after 8 to 14 hrs of fasting preferably after an overnight fast.

b) Oral Glucose Tolerance Test (OGTT) of 200 mg/dL (11.1 mmol/L) 2 hours after glucose load.

The oral glucose tolerance test evaluates clearance from the circulation after glucose loading under defined and controlled conditions (Mari et al., 2001). The patient needs to have been fasting 8 to 14 hours prior to sampling. Before oral administration of the glucose solution within 5 minutes, a zero time (baseline) blood sample is drawn. Blood is then drawn at 1-hour intervals for the next 2hrs for measurement of glucose, and sometimes insulin levels. In a non-diabetic, the blood glucose level increases immediately after a high sugar or carbohydrate drink and then decreases gradually since high blood sugar levels stimulates insulin release from the beta cells that enhances uptake of glucose by peripheral tissues from the blood stream resulting to its low levels (Tietz, 2002). In a diabetic, the glucose in the blood continues to go up and stays high after drinking the sweetened liquid. Therefore, a plasma glucose level of 200 mg/dL or higher at two hours after drinking the sweetened syrup and at one other point during the two hour test period confirms the diagnosis of diabetes mellitus (Ta, 2014).

c) Glycosylated hemoglobin value of 6.5% indicates diabetes.

Pre-diabetes individuals present with values of 5.7 % to 5.99 %. Normal glucose levels give values less than 5.7 %. In diabetes mellitus, a minor hemoglobin derivative called HbA1c is produced by glycosylation. Since this reaction is spontaneous and erythrocytes are completely permeable to glucose, the quantity of HbA1c formed is directly proportional to the average plasma glucose concentration that the erythrocytes are exposed to during their 120-day life span (4 to 6 weeks before sampling) (Selvin et al., 2010).

For normoglycemic persons, HbA1c constitutes 4 to 5 % of total hemoglobin whereas in diabetics, HbA1c levels are significantly elevated. The elevations are directly proportional to the long-term degree of hyperglycemia. Glycosylated hemoglobin is most useful in monitoring diabetes mellitus. However, they are not sufficiently sensitive to effectively detect borderline cases of diabetes mellitus. Serum albumin is also glycosylated to a degree proportional to plasma glucose levels. The short half-life for albumin of 15 days makes it a good monitor of short-term blood plasma glucose levels (Selvin et al., 2010).

d) Intravenous glucose tolerance test

The intravenous glucose tolerance test is used for persons with malabsorptive disorders or previous gastric or intestinal surgery. Glucose is administered intravenously over 30 minutes, using a 20 % solution. A glucose load of 0.5 g/kg of body weight is used. Non- diabetics respond with plasma glucose level of 11.1-13.9 mmol/L. Discontinuation of the glucose loading leads to a decrease in plasma level with fasting levels reached at about 90 minutes. Diabetics demonstrate plasma glucose level of 13.9 mmol/L and above during administration of the load. On discontinuation of the loading, plasma glucose levels of diabetics also return to fasting levels at about 90 minutes. An alternative procedure called the Soskin method uses 50 % glucose delivered intravenously within 3 to 5 minutes. The glucose load used is 0.3 g/kg of body weight. Non-diabetics re-establish fasting levels in less than 60 minutes after discontinuing the glucose infusion. In diabetics fasting levels are established significantly later than 60 minutes (Dods, 2010).

e) O’Sullivan-Mahan glucose challenge test.

O’Sullivan-Mahan glucose challenge test is used frequently to detect gestational diabetes. A 50g load of glucose is given to a fasting patient and a blood glucose measurement is made 1 hour after dosage. A plasma glucose value of above 7.8 mmol/L suggests gestational diabetes, and a full oral glucose tolerance test is recommended for such patients (Dods, 2010).

f) Plasma insulin test.

Fasting plasma insulin levels in type I diabetics are usually low. Those of type II diabetics are low only when fasting plasma glucose levels exceed 13.9 mmol/L otherwise, they are normal or even elevated. A glucose challenge separates type I diabetics from type II diabetics. Glucose loading elicits no significant insulin response for type I diabetics and a delayed, exaggerated response in type II diabetics (Dods, 2010).

g) Urine tests.

Urine tests are undertaken to analyze glucose, ketone bodies, and proteins in the urine (Piero et al., 2012b). Testing urine for glucose with dipsticks is a common screening procedure for detecting diabetes. If possible, testing should be performed on urine passed 1-2 hours after a meal to maximize sensitivity (Frier and Fisher, 2010). However urinary glucose is a poor marker for diabetes. The normal renal threshold for glucose is 10 mmol/L. Blood glucose levels must exceed this value before excessive glucose is apparent in the urine. Further complicating this picture is the fact that the renal threshold in persons with diabetes often is increased to levels above 16.7 mmol/L (Dods, 2010).

Complications of Diabetes Mellitus

Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic syndrome These conditions represent decompensation in diabetic control and require immediate treatment. Careful evaluation of the patient for associated or precipitating events must be undertaken, for example infection, medical and vascular events and the associated problems must be treated (ADA, 1999).

Diabetic retinopathy

Diabetic retinopathy can result into any level of macular edema, severe non- proliferative retinopathy or any proliferative retinopathy and these requires prompt care of an ophthalmologist.

It is a serious micro-vascular complication of diabetes and a leading cause of visual impairment in people with diabetes. WHO estimates that diabetic retinopathy accounts for approximately 5 % of the global prevalence of blindness with estimates of 15-17 % in developed countries (Lee et al., 2010; Nwaobi, 2011). It is reported to be the leading cause of blindness in people aged 20-74 years in industrialized nations (Jabbour et al., 2008). Studies have established that duration of type 1 diabetes is the best predictor of developing diabetic retinopathy. Evidence suggests that hyperglycemia is the primary cause of diabetic retinopathy.

Diabetic nephropathy

The earliest stage of diabetic nephropathy is persistent microalbuminuria at range of 30- 299 mg/24hr and is a significant risk marker for cardiovascular disease. This can likely progress to clinical albuminuria (>300mg/24hr) and decreasing GFR over a period of years. It has been classically defined by the presence of proteinuria (> 0.5 g/24h) or persistent albuminuria (> 300 mg/24hr) (Osiogo et al., 2006). Incidence of diabetic nephropathy is about 1-2 % per year in patients with type 1 DM. Recent studies have shown substantial reduction in incidence of diabetes nephropathy in type 1 DM. The decline is attributed to the adoption in clinical practice of measures that contribute to early diagnosis and prevention of the disease. There is a marked racial, ethnic and international disparity in the epidemiology of diabetic nephropathy (Jabbour et al., 2008). These disparities have been extensively reported in the United States, with African Americans having the highest reported incidence and prevalence of treated end stage renal disease (Gheith et al., 2016).

Neuropathy

Peripheral diabetic neuropathy may result in pain, loss of sensation and muscle weakness. Autonomic involvement can affect gastrointestinal, cardiovascular and genitourinary functions. It is a condition that is associated with nerve damage. Diabetic neuropathy can be classified as peripheral, autonomic, proximal or focal, depending on the affected body part, focal neuropathy is the less prevalent and is generally acute and self-limiting (Jabbour et al., 2008; Moura et al., 2013). Peripheral neuropathy is the most common manifestation with chronic sensor motor symptoms and signs, the onset of which is usually insidious, it may be asymptomatic in about 50 % of patients, 10 % to 20 % of patients may have sensory symptoms necessitating treatment (Smith et al., 2012). Diabetic neuropathy is more frequent in older people, on average neuropathy symptoms begin to appear within 10 –20 years of the diagnosis of diabetes, and approximately 50% of diabetic patients will develop nerve damage (Moura et al., 2013).

Neuropathy is the most common cause of foot ulcers in diabetic population, and it is associated with increased likelihood of amputations especially in western countries (Llorente and Malphurs, 2007). Diabetic neuropathies develop as a result of hyperglycemia which inhibits the normal uptake of myoinositol, leading to a decrease in the myoinositol within the nerve. This action prolongs nerve conduction, causing nerve dysfunction. Long-term hyperglycemia also activates the polyol pathways (Xu et al., 2012). The excess glucose is converted to sorbitol and fructose, causing the accumulation of sorbitol and fructose in nerve cell. Their accumulation leads to intracellular osmotic stress (Xu et al., 2012).

Diabetic foot

Foot infection involving the skin and soft tissues is a common complication of diabetic individuals and represents a major cause of morbidity and mortality and is a major reason for lower-limb amputation (Crouzet et al., 2011). The feet of diabetic patients become susceptible to both ischemic and neuropathic ulceration. Neuropathic ulceration is the consequence of traumatic damage to the skin in the presence of sensory loss, especially when accompanied by mechanical derangement of the foot (Scobie, 2002).

The estimated annual total cost of diabetes related to foot complications in the UK is approximately $252 million inclusive of $8459 for every single amputation (Paton et al., 2011). Patients with diabetes have a 12-25 % life time risk of developing foot ulcers. Major amputations are done when the ulcerated foot either threatens patient survival or when reasonable function can no longer be expected (Leung, 2007).

Dyslipidemia

Diabetes increases the risk of atherosclerotic vascular disease. A common abnormal lipid pattern in such patients is an elevation of VLDL, a reduction in HDL and an LDL fraction that contains a greater proportion of small dense LDL particles (American Diabetes Association, 2001).

Hypertension

Hypertension contributes to the development and progression of chronic complications of diabetes mellitus. In type 1 diabetes mellitus, persistent hypertension is often a manifestation of diabetic as indicated by concomitant elevated levels of urinary albumin and in later stages by a decrease in glomerular filtration rate (GFR). Isolated systolic hypertension may occur with long duration of either type of DM due to inelasticity of atherosclerotic large vessels (ADA, 2001). Control of hypertension has been demonstrated conclusively to reduce the rate of progression of diabetic nephropathy and to reduce the complications of hypertension nephropathy, cerebrovascular disease and cardiovascular disease (ADA, 2001).

Psychiatric disorders

Schizophrenia is a chronic psychiatric disorder, characterized by abnormalities in thinking, emotions and behavior. Studies have found association between schizophrenia and diabetes. Reasons given for the increased risk for type 2 diabetes mellitus in this population include inadequate healthcare, less healthy lifestyle and side effects of antipsychotics (Llorente and Malphurs, 2007). Also, stigma associated with serious mental illness as well as general medical community’s discomfort and fear related to working with patients who have serious mental illness render such patients unwelcome in medical clinics and thus influence the care they receive. Schizophrenia may thus be considered an independent risk factor for diabetes mellitus (Jabbour et al., 2008). People with schizophrenia are more likely than the general population to be overweight and obese even before the age of antipsychotic treatments. Use of both typical and anti psychotic medications has been associated with weight gain and glucose intolerance (Jabbour et al., 2008).

Depression symptoms have negative impact on symptom burden, functional impairment, adherence to medication regimens and self management of illness (Llorente and Malphurs, 2007). Evidence has shown that persons with diabetes and depression symptoms have mortality rates nearly twice as high as persons with diabetes and no depression symptoms (Llorente and Malphurs, 2007).

Cognitive impairment: Diabetes mellitus also increases the risk of cognitive impairment, a process that affects the deposition of amyloid beta (A) in the brain, which is the putative culprit in the pathogenesis of Alzheimer’s disease (AD) (Llorente and Malphurs, 2007). Diabetes mellitus increases cognitive impairment which raises concerns about the ability of persons with this disorder to follow proper treatment. There is evidence to suggest that better diabetes treatment control improves recognition (Llorente and Malphurs, 2007).

Sexual dysfunction

Both physiological and psychological factors can contribute to sexual dysfunction among patients with diabetes mellitus. Normal human sexual activity is composed of four stages; desire, arousal, orgasm and resolution. Sexual dysfunction is prevalent among men with diabetes occurring two to four times more often than in persons without diabetes. Whereas sexual dysfunction most commonly develops after the age of 60 years, it tends to occur 5-10 years earlier among men with diabetes. Diabetes may affect arousal due to decreased genital sensation and lubrication. Women with type two diabetes mellitus are also predisposed to vaginal dryness and infections which can lead to dyspareunia (Llorente and Malphurs, 2007).

Prevalence of Diabetes in Nigeria

Researchers have raised alarm over the increasing rate of diabetes among Nigerians; saying over 5.5 per cent of the country’s population was suffering from the ailment. According to IDF, an estimated 15.5 (9.8-27.8) million adults aged 20-79 years have diabetes in Africa (AFR), representing a regional prevalence of 2.1 (6%). The highest prevalence of diabetes in AFR is between ages 55 and 64. AFR has the highest proportion of undiagnosed diabetes; over two-thirds (69.2%) of people with diabetes are unaware they have the disease. Some of AFR’s most populous countries have the highest numbers of people with diabetes, including Ethiopia [2.6 (1.1-3.8) million], South Africa [1.8 (1.1-3.6) million], Democratic Republic of Congo [1.7 (1.4-2.1) million], and Nigeria [1.7 (1.2-3.9) million]. About 45.1% of all adults, aged 20-79 years, with diabetes in the region live in these four countries and in terms of mortality, in 2017, more than 298,160 deaths (6% of all mortality) in AFR are attributed to diabetes with the highest percentage of all-cause mortality due to diabetes in age group 30-39. Regardless of the obvious huge burden of diabetes faced in Nigeria, Nigeria is still not listed among African countries with largest percentage of healthcare budget allocation. The countries in sub-Sahara Africa with the largest percentage of healthcare budget allocated to diabetes in 2017 are the Seychelles and Comoros. However, it is widely perceived that prevalence figures reported by the IDF grossly under-report the true burden of DM in Nigeria, given that they are derived through the extrapolation of data from other countries. Vis-à-vis morbidity, diabetes contributes to the development of heart failure, stroke, renal disease, pneumonia, bacteremia, and tuberculosis (TB)[24,25,26,27]; and it is known that people with diabetes are 3 times more likely to develop tuberculosis and approximately 15% of TB globally is thought to have background diabetes as a predisposing factor[24].

Diabetes has a wide range of prevalence across the country. In the rural areas of Nigeria, diabetes is prevalent in 0%-2% of the population, whereas in the urban regions the figures are much higher at 5%-10%. The difference in prevalence values is often seen as a result of westernization and demographic transition and the progressive shift in the population from rural to urban centers (Mukundi et al., 2015).

Management of Diabetes mellitus

Management of diabetes mellitus has been achieved through oral and intraperitoneal agents. The primary aim of the treatment is to save life and alleviate symptoms. Secondary aims are to prevent long-term diabetic complications and, by eliminating various risk factors, to increase longevity. Insulin replacement therapy is the mainstay for patients with type 1 DM while diet and lifestyle modifications are considered the corner stone for the treatment and management of type 2 DM. Insulin is also important in type 2 DM when blood glucose levels cannot be controlled by diet, weight loss, exercise and oral medications.

Oral hypoglycemic agents including sulphonylureas, biguanides, alpha glucosidase inhibitors and thiazolidenediones have been successfully used in the management of DM. The main objective of these drugs is to correct the underlying metabolic disorder, such as insulin resistance and inadequate insulin secretion. They are prescribed in combination with an appropriate diet and lifestyle changes to reduce weight, improve glycaemic control and reduce the risk of cardiovascular complications, which account for 70 to 80% of deaths among those with diabetes. Diabetes is best controlled either by diet alone and exercise (non-pharmacological), or diet with herbal or oral hypoglycemic agents or insulin (Bastaki, 2005; ADM, 2012).

Insulin Therapy

Insulin is the cornerstone of pharmacotherapy in persons with type 1 DM. Progressively more aggressive targeted glycemic, blood pressure, and LDL cholesterol treatment strategies impact both micro-vascular and macro-vascular diabetes complications and co-morbidities (Jabbour et al., 2008). Studies have demonstrated that improved glycemic control with intensive insulin therapy in patients with type 1 DM leads to gradual reduction in retinopathy, nephropathy and neuropathy. Individual insulin regiment should be tailored for each person with type 1 DM to enable targeted blood glucose control. With advances in recombinant DNA technology, it is now possible to produce large quantities of insulin with an amino acid structure identical to that of human insulin using strains of genetically altered Escherichia coli, bacteria or yeast (Jabbour et al., 2008). The main undesirable effect of insulin is that hypoglycemia can cause brain damage, swelling, erythema and stinging occurs especially in the beginning. Insulin allergy to human is unusual but can occur. Some patients develop short lived dependent edema (Patil et al., 2011).

In type 1 diabetics, most studies have not found any benefit from exercise because of the likelihood of type 1 diabetics to consume additional carbohydrates in an effort to prevent hypoglycemia which often develops during light to moderate exercise unless the insulin dose is reduced or extra carbohydrate consumed (Bastaki, 2005).

Oral Hypoglycemic Agents

Sulfonylureas

They stimulate insulin secretion from the β-cell. They also appear to sensitize the β-cell to various other insulin secretagogues, such as glucose. An improvement in insulin resistance may also be observed with sulfonylureas. The commonest adverse effects of sulfonylureas are hypoglycemia, which can be severe and prolonged. Allergic skin rashes can occur as well as bone marrow damage although very rare (Patil et al., 2011). Sulfonylureas have a tendency to produce weight gain, although intervention that improves diabetic control in a patient following an isocaloric diet would be expected to result in such an effect (Scobie, 2002).

Biguanides

Biguanides lowers plasma glucose levels by enhancing the sensitivity of peripheral tissue to insulin. They do not usually cause hypoglycemia, but accumulates as it is excreted through the renal causing lactic acidosis and therefore it should not be used in patients with renal impairment. It should not also be used in patients with hepatic disease, hypoxic pulmonary disease, heart failure or shock. Vitamin B12 deficiency

may occur due to interference with its absorption when a high dose of metformin is used (Scobie, 2002; Patil et al., 2011). The commonest unwanted side effects of metformin are gastrointestinal disturbances, abdominal pain, and metallic taste (Patil et al., 2011).

Alpha-glucosidase inhibitors

They include acarbose and miglitol and are widely used as first line agents in countries like Japan. They slow the absorption of complex carbohydrates from the gastrointestinal tract and are important in controlling post-prandial hyperglycemia, but their blood glucose lowering effect is lower than those of metformin or the sulfonylureas and the side effects of flatulence and bloating limit their tolerability (Scobie, 2002).

Meglitinides

They include repaglinide and nateglinide and they act like the sulfonylureas via closure of the K+-ATP channels in the β-cells, although their receptor binding characteristics are different. They produce a short lived insulin release that is dependent on concentration of glucose. Thus taken before meals, they act to restore the delayed and impaired insulin response to meals seen in type 2 DM, without causing hypoglycemia. Meglitinides may safely be used in combination with biguanides (Scobie, 2002).

Thiazolinidiones (Glitazones)

Their exact mode of action is not well understood, but is mediated by activation of the nuclear receptor peroxisome proliferator activated receptor gamma, this leads to

stimulation of insulin sensitive proteins with a reduction of hepatic glucose production and an increase in peripheral glucose uptake. As a monotherapy, these agents are comparable with sulfonylureas and metformin. They reduce intra-abnominal fat deposition but also promote peripheral fat deposition. This latter effect and their tendency to produce edema are associated with weight gain. Thiazolidinediones also causes serious hepatotoxicity effect (Scobie, 2002; Patil et al., 2011).

Exercise

Exercise training raises high density lipoprotein cholesterol, lowers blood pressure, and leads to a 20 to 40% increase in insulin sensitivity by enhancing insulin action in skeletal muscles (Jabbour et al., 2007). All diabetic patients should be encouraged to engage in 30 minutes of modest aerobic exercise 3-4 times per week. The intensity should be gauged to produce an increase in pulse rate to 60-70% of maximum which can be calculated as 220-minus age (Jabbour et al., 2007). However exercise may not be ideal for long term care because it is associated with potential risks such as cardiac ischemia, musculoskeletal injuries and hypoglycemia in patients treated with insulin or secretagogues (Fieldman et al., 2009).

Dietary Management

In type 1 DM, a diet of low fat, high complex carbohydrates, high fiber and low salt intake is recommended. Total fat intake should not exceed 30% of total energy intake, and less than 10% should come from saturated fats. Complex carbohydrates should comprise more than 50% of the total energy intake. Simple sugars such as sucrose should only be consumed in moderate amounts, as they do not cause acute hyperglycemia unlike glucose. Dietary fiber should be increased to more than 30g/day, preferably taken in the form of natural soluble fiber as found in legumes, grains, cereals, or fruit. Protein should comprise 10-15% of total energy intake (Scobie, 2002).

There should be calorie restriction and avoidance of sweet foods and drinks for type 2 DM. A long term strategy should be formulated whose goals is to correct obesity, as weight loss will improve blood glucose control, lower blood pressure and lower blood lipid concentrations. A diet of low fat, high complex carbohydrate, high fiber and low calorie intake is recommended. Dietary failure is common in the treatment of obesity associated with type 2 diabetes mellitus; avoidance of fat in the diet should be stressed. An increase in the regular exercise and avoidance of smoking are advisable (Scobie, 2002).

Cell Replacement.

There are three general clinical situations that justify this approach. The first is recurrent hypoglycemia with poor symptom recognition despite optimal medical care (Jabbour et al., 2008). The second general indication of -cell replacement is increase in secondary complications of diabetes for example in patients who have developed kidney failure and are candidates for kidney transplantation. The third indication is psychiatric or emotional disability that prevents patients from cooperating with insulin based therapy (Jabbour et al., 2008).

Mineral elements and antidiabetic activity Chromium (Cr)

Chromium, in the form of naturally occurring dinicotinic acid -glutathione complex, also known as glucose tolerance factor (GTF), is vital for carbohydrate metabolism as it potentiates the action of insulin. Isolated from brewer’s yeast, the active component of GTF was subsequently found to contain trivalent chromium, nicotinic acid, glycine, glutamic acid and cysteine. As such, it normalizes blood sugar levels in subjects with tendencies toward blood sugar fluctuations associated with diabetes (hyperglycemia) and low blood sugar (hypoglycemia) (Anderson, 1980). Chromium increases the number of insulin receptors, enhances receptor binding, and potentiates insulin action (Siddiqui et al., 2014).

Selenium (Se)

As with other trace elements, early researchers concentrated on the role of selenium in animal disease conditions. The role of selenium in animal physiology was first established when it was found that it could prevent liver necrosis in vitamin E-deficient rats. Selenium is able to prevent exudative diathesis and pancreatic fibrosis in poultry, hepatosis dietetica in pigs and muscular dystrophy in lambs, calves and other species. It is a vital element for growth and for maintaining optimum fertility status. In humans, selenium increases the growth of fibroblasts in culture. It is also a vital component of an antioxidant enzyme known as glutathione peroxidase. Furthermore, it prevents the occurence of Keshan disease and juvenile cardiomyopathy, found in countries where the soil is low in this essential mineral. An ever increasing number of epidemiological

surveys are linking low dietary selenium with the development of cancer and cardiovascular disorders (Levander et al., 1982)

Zinc (Zn)

The function of zinc in the body metabolism is based on its enzymatic affinity and way of a zinc-enzyme complex or metallo-enzyme. In humans and animals, diabetes causes disturbances in this vital trace element (Kowluru et al., 2000). Zinc is required for insulin synthesis and storage and insulin is secreted as zinc crystals. It maintains the structural integrity of insulin (Chausma, 1998). Zinc has an important role in modulating the immune system and its dysfunction in diabetes mellitus may be related in part to the status of zinc (Mocchegianai et al., 1989).

Toxic metals like lead (Pb), nickel (Ni), cadmium (Cd) and arsenic (As) deposit in tissues and are non-degradable. Toxic metals react with various proteins in the body that may modify their functions and kinetics. Moreover, when diet is low in essential metals, the body absorbs and makes use of more toxic metals. An abundance of a toxic metal competes with essential metal for enzymes activity and various body physiological functions (Flora, 2009). For example, Zn is required for the activity of many enzymes. In case of Zn deficiency and increased exposure to toxic metals such as lead (Pb), body will use Pb instead of Zn (Duruibe, 2007).

Magnesium (Mg)

Magnesium has an important role in the phosphorylation reactions of glucose and its metabolism. Its deficiency has been implicated in insulin resistance, carbohydrate

intolerance, dyslipidemia and complications of diabetes (Praveena et al., 2013). The association between diabetes mellitus and hypomagnesaemia is compelling, because of its wide ranging impact on diabetic control.

Potassium (K)

Normal potassium concentration is necessary for optimal insulin secretion. Deficiency of potassium results more often from excessive losses than from insufficient intakes. Deficiencies arise in abnormal conditions such as diabetic acidosis. Potassium depletion can result in reduced glucose tolerance. Sodium and potassium ions play an important role in the disease related disorder (Rajendra et al., 2007). Lower levels of potassium have been found to be associated with a higher risk of diabetes in some studies (Ranee et al., 2012).The results of this experiment (Hales and Milner, 1967) showed that a rise in the potassium concentration of the incubation medium caused a reversible stimulation of insulin secretion.

Vanadium (V)

Numerous investigations have demonstrated the beneficial effect of vanadium salts on diabetes in diabetic rats, in rodents with genetically determined diabetes and in human subjects. In 1980 vanadium was reported to mimic the metabolic effects of insulin in rat adipocytes. Vanadium therapy was shown to normalize blood glucose levels in diabetic induced rats and to cure many hyperglycemia related deficiencies (Rajendra et al., 2007).

Iron (Fe)

Iron has several vital functions in the body which are involved in oxidation- reduction reactions, Heamoglobin oxygen transport and also a cofactor for numerous other enzymes (Rajendra et al., 2007).

Manganese (Mn)

Manganese functions as a key constituent of metallo-enzymes activator. In experimental animals, pancreatectomy and diabetes have been correlated with decreased manganese levels in blood. Manganese supplements have reversed the impaired glucose utilization induced by manganese deficiency in guinea pigs. Manganese may act like insulin in increasing the transport of glucose into adipose tissue by enhancing an existing low level of insulin. Manganese requirements are low, and many plant foods contain significant amounts of this trace mineral (Rajendra et al., 2007).

Copper (Cu)

The primary function of copper in the body is to serve as constituents of many biologically important enzymes. Thus enzymes which contain copper in the active site catalyze the oxidation of ferrous iron to ferric iron. Copper is required for absorption and transport of iron and it plays a key role in heamoglobin synthesis. High plasma copper concentrations are found in people with diabetes mellitus (Rajendra et al., 2007).

Thyroid Disorders

Thyroid hormones (TH) play a vital role in the normal growth and metabolism. Thyroid disorders can have a significant impact on wellbeing and quality of life (QoL) of individuals and on the healthcare system of the country. Therefore, evidence based, up to date guidelines on investigation and management of these disorders, adapted to the local setting are a timely requirement.

Thyroid disorders can present with hypofunction or hyperfunction of the gland, as well as benign or malignant thyroid nodules. Focus of this clinical practice guideline is on hypothyroidism and thyrotoxicosis.

Epidemiology

Global situation

Global distribution of thyroid disorders varies based on several factors, including gender, iodine status, predisposition to autoimmunity, smoking, alcohol consumption and genetic factors. Overall, thyroid disorders are more common among females. Nodular thyroid disorders are more frequently found in iodine deficient areas, while autoimmune thyroid disorders are common in iodine replete areas.

Hypothyroidism

Iodine deficiency and thyroid autoimmunity (Hashimoto thyroiditis) are the commonest causes for hypothyroidism. In iodine sufficient areas, prevalence of overt hypothyroidism is 1-2% and is 10 times commoner among females than males, with an increasing prevalence with age (2). Worldwide annual incidence of Hashimoto thyroiditis is estimated to be 0.3-1.5 cases per 1000 persons.

Hyperthyroidism

Overall prevalence of hyperthyroidism is estimated to be 1.3% and incidence is 2.7% in females and 0.7% in males (Mukundi et al., 2015). Graves disease (GD) is the most common cause for hyperthyroidism, followed by toxic multi-nodular goitre (MNG) (4). GD contributes to 70-80% of all cases of hyperthyroidism in iodine sufficient countries while in iodine deficient countries it contributes to 50% of all cases (6)(7). Toxic MNG and solitary toxic nodule (STN) are more prevalent in iodine deficient areas.

Hypothyroidism is a syndrome that results from abnormally low secretion of THs from the thyroid gland, leading to a decrease in basal metabolic rate and multisystem dysfunction. The most severe form is known as myxoedema.

Overt hypothyroidism (OH)

Elevated TSH with sub-normal FT4

Subclinical hypothyroidism (SH)

TSH above the upper reference limit and a normal FT4

Note: This is only applicable when thyroid function has been stable for 3 months or more, the hypothalamo-pituitary function is normal, and there is no recent or on-going

severe illness

Hypothyroidism may be primary, secondary or tertiary due to thyroid disease, pituitary disease, or hypothalamic dysfunction respectively. Primary hypothyroidism can be overt or subclinical.

Causes of primary hypothyroidism

Congenital

Thyroid agenesis / dysplasia

Defects in thyroid hormone synthesis

Acquired

Chronic autoimmune thyroiditis / Hashimoto’s thyroiditis

Post-thyroidectomy Iodine deficiency

Post radio-iodine thyroid ablation

External beam radiotherapy for non-thyroidal head and neck malignancy

Drugs inhibiting the synthesis or release of thyroxine – Lithium, iodide, over treatment of hyperthyroidism

Infiltrative diseases – e.g.: sarcoidosis

Thyroid Disorders and Diabetes Mellitus

Thyroid diseases and diabetes mellitus are the two most common endocrine disorders encountered in clinical prac- tice. Diabetes and thyroid disorders have been shown to mutually influence each other and associations between both conditions have long been reported. On one hand, thyroid hormones contribute to the regulation of carbohydrate metabolism and pancreatic function, and on the other hand, diabetes affects thyroid function tests to variable extents. This paper demonstrates the importance of recognition of this interdependent relationship between thyroid disease and diabetes which in turn will help guide clinicians on the optimal screening and management of these conditions (Amira, & Okubadejo, 2007).

Frequency of Thyroid Disorders in the General Population and in Patients with Diabetes

Thyroid disorders are widely common with variable preva- lence among the different populations. Data from the Whickham survey conducted in the late 1970s in the north of England revealed a prevalence of 6.6% of thyroid dysfunction in the adult general population. In the Colorado Thyroid Disease Prevalence study involving 25,862 participants attending a state health fair, 9.5% of the studied population were found to have an elevated TSH, while 2.2% had a low TSH [4]. In the NHANES III study, a survey of 17,353 subjects representing the US population, hypothyroidism was found in 4.6% and hyperthyroidism in 1.3% of subjects. The latter further observed an increased frequency of thyroid dysfunction with advancing age and a higher prevalence of thyroid disease in women compared to men and in diabetic subjects compared to nondiabetic (Amira, & Okubadejo, 2007).

Several reports documented a higher than normal preva- lence of thyroid dysfunction in the diabetic population. Particularly, Perros et al. demonstrated an overall prevalence of 13.4% of thyroid diseases in diabetics with the highest prevalence in type 1 female diabetics (31.4%) and lowest prevalence in type 2 male diabetics (6.9%). Recently, a prevalence of 12.3% was reported among Greek diabetic patients and 16% of Saudi patients with type 2 diabetes were found to have thyroid dysfunction. In Jordan, a study reported that thyroid dysfunction was present in 12.5% of type 2 diabetic patients. However, thyroid disorders were found to be more common in subjects with type 1 diabetes compared to those with type 2 diabetes. Additionally, a 3.5-fold increased risk of autoimmune thy- roiditis was noticed in GADA positive patients. Thyroid disorders remain the most frequent autoimmune disorders associated with type 1 diabetes. This was shown in a cross- sectional study involving 1419 children with type 1 diabetes mellitus, where 3.5% had Hashimoto’s thyroiditis. In addition, positive TPO antibodies have been reported in as high as 38% of diabetic individuals and have been shown to be predictive for the development of clinical and subclinical hypothyroidism. Very recently, Ghawil et al. documented that 23.4% of type 1 diabetic Libyan subjects had positive TPO antibodies and 7% had positive TG antibodies. The association between AITD and T1DM has been recognized as a variant of APS3 referred to as APS3 variant. Common susceptibility genes have been acknowledged to confer a risk for development of both AITD and type 1 diabetes mellitus. Currently, at least four shared genes have been identified including HLA, CTLA-4 [23], PTPN22, and FOXP3 genes (Amira, & Okubadejo, 2007).

Effects of Thyroid Hormones on Glucose Homeostasis

Thyroid hormones affect glucose metabolism via several mechanisms. Hyperthyroidism has long been recognized to promote hyperglycemia. During hyperthyroidism, the half-life of insulin is reduced most likely secondary to an increased rate of degradation and an enhanced release of biologically inactive insulin precursors.

In untreated Graves’ disease, increased proinsulin levels in response to a meal were observed in a study by Bech et al.. In addition, untreated hyperthyroidism was associated with a reduced C-peptide to proinsulin ratio suggesting an underlying defect in proinsulin processing. Another mechanism explaining the relationship between hyperthy- roidism and hyperglycemia is the increase in glucose gut absorption mediated by the excess thyroid hormones.

Endogenous production of glucose is also enhanced in hyperthyroidism via several mechanisms. Thyroid hormones produce an increase in the hepatocyte plasma membrane concentrations of GLUT2 which is the main glucose trans- porter in the liver, and consequently, the increased levels of GLUT-2 contribute to the increased hepatic glucose output and abnormal glucose metabolism. Additionally, increased lipolysis is observed in hyperthyroidism resulting in an increase in FFA that stimulates hepatic gluconeogene- sis. The increased release of FFA could partially be explained by an enhanced catecholamine-stimulated lipolysis induced by the excess thyroid hormones. Moreover, the nonox- idative glucose disposal in hyperthyroidism is enhanced resulting in an overproduction of lactate that enters the Cori cycle and promotes further hepatic gluconeogenesis. The increase in GH, glucagon and catecholamine levels associated with hyperthyroidism further contributes to the impaired glucose tolerance.

It is well known that diabetic patients with hyper- thyroidism experience worsening of their glycemic control and thyrotoxicosis has been shown to precipitate diabetic ketoacidosis in subjects with diabetes (Amira, & Okubadejo, 2007).

As for hypothyroidism, glucose metabolism is affected as well via several mechanisms. A reduced rate of liver glucose production is observed in hypothyroidism and accounts for the decrease in insulin requirement in hypothyroid diabetic patients. Recurrent hypoglycemic episodes are the presenting signs for the development of hypothyroidism in patients with type 1 diabetes and replacement with thyroid hormones reduced the fluctuations in blood glucose levels as demonstrated by Leong et al.. In a case control study involving type 1 diabetic patients, those with subclinical hypothyroidism experienced more frequent episodes of hypoglycemia during the 12 months prior to the diagnosis of hypothyroidism compared to euthyroid diabetics. On the other hand, both clinical and subclinical hypothyroidisms have been recognized as insulin resistant states. In vivo and in vitro studies have shown that this is due to impaired insulin stimulated glucose utilization in peripheral tissues. A recent study involving subjects from a Chinese population found a higher TSH level in patients with metabolic syndrome compared to that in the nonmetabolic syndrome group suggesting that subclinical hypothyroidism may be a risk factor for metabolic syndrome. More recently, Erdogan et al. found an increased frequency of metabolic syndrome in subclinical and overt hypothyroidism compared to healthy controls. There- fore, it seems prudent to consider hypothyroidism in newly diagnosed metabolic syndrome patients. This raises the issue whether routine screening for thyroid disease in all patients newly diagnosed with metabolic syndrome will be cost effective. Furthermore, an increased risk of nephropathy was shown in type 2 diabetic patients with subclinical hypothy- roidism which could be explained by the decrease in cardiac output and increase in peripheral vascular resistance seen with hypothyroidism and the resulting decrease in renal flow and glomerular filtration rate. In 2005, Den Hollander et al. reported that treating hypothyroidism improved renal function in diabetic patients. As for retinopathy, Yang et al. demonstrated recently that diabetic patients with subclinical hypothyroidism have more severe retinopathy than euthyroid patients with diabetes. The increased risk of retinopathy and nephropathy observed in diabetic patients with subclinical hypothy- roidism provides evidence in favor of screening patients with type 2 diabetes for thyroid dysfunction and treating when present (Amira, & Okubadejo, 2007).

Effects of Diabetes Mellitus on Thyroid Hormones and Thyroid Diseases

Altered thyroid hormones have been described in patients with diabetes especially those with poor glycemic control. In diabetic patients, the nocturnal TSH peak is blunted or abolished, and the TSH response to TRH is impaired. Reduced T3 levels have been observed in uncontrolled diabetic patients. This “low T3 state” could be explained by an impairment in peripheral conversion of T4 to T3 that normalizes with improvement in glycemic control. However, in a study by Coiro et al. involving type 1 diabetes patients with absent residual pancreatic beta cell function, an amelioration in glycemic control did not restore the normal nocturnal TSH peak suggesting a diabetes- dependent alteration in the central control of TSH. Higher levels of circulating insulin associated with insulin resistance have shown a proliferative effect on thyroid tissue resulting in larger thyroid size with increased formation of nodules. A higher prevalence of type 1 diabetes is observed in patients with Grave’s orbitopathy than in the normal population. Furthermore, the vasculopathic changes associated with diabetes renders the optic nerve more susceptible to the pressure exerted by the enlarged extraocular muscles. Consequently, a higher incidence of dysthyroid optic neuropathy is observed in diabetic sub- jects with Graves ophthalmopathy compared to nondiabetic.

2.2 EMPIRICAL REVIEW

A study on “Evaluation of thyroid dysfunction among type 2 diabetic patients by Raghuwanshi et al (2014) showed that Diabetes mellitus is a very common endocrinal disorders and incidence of thyroid dysfunction also rising in India and world over. Thyroid hormones directly control insulin secretion and insulin clearance. Diabetes also may affect the thyroid function to variable extent first at the level of hypothalamic control of TSH release and second at peripheral tissue by converting T4 to T3. The study was carried out aiming to evaluate thyroid dysfunction among type 2 diabetes mellitus patients. Study included total 80 subjects. Thyroid dysfunction was evaluated by investigating the subjects for Total tri-iodo-thyronine (T3), Total thyroxine (T4) and thyroid stimulating hormone (TSH). Plasma glucose was estimated by- GOD-POD method and Thyroid profile was estimated by- CLIA (chemiluminescence immunoassay) system. Statistical analysis was performed using software statistical package for social sciences (SPSS) version 20, unpaired T test, Pearson’s correlation. In type 2 diabetic patients the prevalence of hypothyroidism and subclinical hypothyroidism was found to be 4(10.00%) and 6(15.00%) respectively, while the prevalence of subclinical hyperthyroidism and hyperthyroidism was found to be 0(0.0%) and 1(2.5%) respectively. In non diabetic healthy subjects the prevalence of hypothyroidism and subclinical hypothyroidism was found to be 1(2.5%) and 3(7.5%) respectively while the prevalence of subclinical hyperthyroidism and hyperthyroidism was found to be 0(0.0%) and 0(0.0%) respectively. In conclusion, the prevalence of thyroid dysfunction was found to be higher in type 2 diabetes mellitus subjects as compared to non-diabetic subjects.

A similar study on “Thyroid Disorders and Diabetes Mellitus by Hage, Zantout, & Azar (2020) found out that Studies have found that diabetes and thyroid disorders tend to coexist in patients. Both conditions involve a dysfunction of the endocrine system. Thyroid disorders can have a major impact on glucose control, and untreated thyroid disorders affect the management of diabetes in patients. Consequently, a systematic approach to thyroid testing in patients with diabetes is recommended.