An Evaluation of Role of Vitamin D in The Pathophysiology of Streptozotocin induced Type-II Diabetes Mellitus in Rats and its Impact on Oral Hypoglycemic/Antidiabetic Agents.

Abstract

Diabetes mellitus is a metabolic illness with several underlying causes which is defined by chronic hyperglycemia and altered carbohydrate, lipid, and protein metabolism as a result of a problem with insulin secretion, action, or both. (1). There are currently four types of diabetes mellitus based on pathophysiology, type-1 insulin dependent diabetes mellitus; type-2, non-insulin dependent diabetes mellitus; type 3 other; type 4 gestational diabetes mellitus (Expert Committee 2019). However, type 1 and type 2 are the most prevalent. One of the biggest hazards to human health in the twenty-first century is diabetes mellitus (DM), which the World Health Organization (WHO) originally regarded as a condition of least importance (2). The number of people with diabetes mellitus has increased significantly during the past few years, particularly in emerging nations like India. In India, the prevalence of type 2 diabetes is currently 2.4% in rural areas and 11.4% in cities. Globally, more than 150 million individuals have diabetes, a number that is expected to rise to 300 million by 2025. Indians made up more than one fifth of them. India has been designated as the world's diabetic capital by the International Diabetes Federation. (3). This syndrome often manifests quickly in childhood and is brought on by T cell-mediated death of pancreatic beta cells, which results in total insulin insufficiency (5). 5–10% of persons with diabetes mellitus have type 1 illness (6). Contrarily, type 2 illness, sometimes known as adult-onset diabetes, is non insulin-dependent.diabetes mellitus (NIDDM); type 2 diabetes is becoming more common (7). Insulin resistance and reduced insulin production are features of type 2 illness (8), which can range from predominant insulin resistance with relative insulin deficiency to predominant secretory deficiency with insulin resistance. About 85–90% of diabetic patients have type 2 disease (9–11), which is particularly common in Asian people (12). Type 2 diabetes mellitus is largely 2 caused by insulin resistance, which is characterised as a state of diminished responsiveness to normal circulating levels of insulin. Insulin levels fall in the presence of insulin resistance. Insufficient signalling results in post-receptor abnormalities, such as decreased glucose transporter 4 translocation, due to an increase in insulin receptor number and insulin receptor kinase activity. The reduction of first-phase insulin secretion, an increase in proinsulin production, a deficiency in pulsatile insulin secretion, and the deposition of islet amyloid polypeptide are all indicators of impaired islet -cell function (13,14). Acute and chronic problems are both possible in diabetic patients. Ketoacidosis and ketoacidotic coma are examples of acute complications. Macrovascular and microvascular problems are two general categories for chronic complications. More than 70% of diabetic mortality is caused by macrovascular disorders, primarily myocardial ischaemia, congestive heart failure, and stroke. Stroke, a common cause of morbidity and mortality in diabetic patients, is also connected with diabetes and increases risk for the condition (15). Patients with type 1 or type 2 diabetes have a much higher risk of stroke when they have high morbidity.(16, 17) In the early stages of stroke, elevated blood sugar is typical, and a glucose level greater than 155 mg/dl within 48 hours of the beginning of stroke is linked to a high risk of mortality (18). One of the main causes of death among diabetic individuals is cardiovascular disease, especially myocardial infarction. Myocardium and coronary vasculature exhibit aberrant morphological and structural alterations in diabetic cardiomyopathy (19). The underlying mechanism involves the excessive production of highly reactive free radicals, mostly brought on by hyperglycemia, which subsequently leads to oxidative stress and worsens the onset, progression, and consequences of diabetes (20). Diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy are examples of microvascular problems. The most prevalent 3 diabetic consequence is diabetic neuropathy, which affects up to 50% of people with type 1 or type 2 diabetes. (21) Progressive nerve fibre loss, together with both positive and negative clinical signs and symptoms like pain, paraesthesia, and loss of feeling, are the hallmarks of diabetic neuropathy. All retinal cell types experience functional and structural alterations as a result of the neurodegenerative illness known as diabetic retinopathy (22). In wealthy nations, this ailment continues to be the predominant contributor of blindness. Patients with type 1 diabetes are expected to develop sight threatening retinopathy in 50% of cases and type 2 diabetes patients in 30% of cases (23). Diabetes-related vision loss is mostly brought about by diabetic macular oedema and consequences from aberrant retinal blood vessel development (angiogenesis). Increased retinal blood flow, which results from angiogenesis, contributes to the development of diabetic retinopathy(24). The majority of diabetic individuals (20– 30%) will eventually develop some form of diabetic nephropathy, which can advance from microalbuminuria to overt nephropathy or macroalbuminuria to end-stage renal failure with a significant mortality rate (24). Approximately 20-30%of all diabetic patients will develop some form of diabetic nephropathy, which may progress from micro albuminuria to overt nephropathy or macro- albuminuria, to end stage renal failure with high mortality (25). Diabetic nephropathy is marked by an excessive build-up of extracellular matrix, thickening of the glomerular and tubular basement membranes, and an increase in the mesangial matrix. Glomerulosclerosis and tubulo interstitial fibrosis eventually result from this condition (26). In diabetics, improved glycaemic management enhances lipid metabolism, lowering risk factors for numerous related disorders. Currently, the cornerstone of treatment is insulin and oral anti-diabetic medications, but they have limitations of their own. Cost and parenteral delivery of insulin, weight gain from sulfonylureas and meglitinides, hepatic 4 impairment, increased risk of heart failure, increased risk of bone fractures from thiazolidinediones, and gastrointestinal problems from acarbose are only a few of the side effects (27). Allowing patients to live normal lives while achieving a normal metabolic state in order to slow down or prevent long-term effects of diabetes is the main objective of treating diabetes mellitus. The continual quest for novel, efficient, safer, and more affordable medications has been undertaken in order to meet these objectives. To date, a number of studies have been conducted to determine natural treatments for dominant diabetic disease and its complications. A fatsoluble vitamin, Vitamin D plays a key role in bone mineralization and calcium homeostasis. Rickets in infancy and osteomalacia in older age are both skeletal symptoms of Vitamin D deficiency, which is currently thought to be a pandemic. Wide-ranging extra-skeletal symptoms of Vitamin D insufficiency include cardiovascular, neuropsychiatric, endocrine, gastrointestinal, and renal impacts. (28). On the other hand, type 2 diabetes mellitus (T2DM) is one of the most illnesses that are common and have significant burdens and rates of complications. T2DM, in contrast to type 1 diabetes mellitus, is primarily characterised by decreased sensitivity to the insulin released by pancreatic beta cells that are still functional. Despite the extensive research done, increased insulin resistance is still not fully understood because of the intricate relationship between insulin receptors (IR), glucose transporters (GLUTs) in various tissues, fluidity of the plasma membrane, intracellular signalling, and transcriptional control of metabolism (29). Over the past ten years, mounting evidence has shown a connection between Vitamin D insufficiency and type 2 diabetes (30). The risk factors for Vitamin D insufficiency and type 2 diabetes (T2DM) include obesity, age, and a lack of physical activity (31). Based on research relating to the role of Vitamin D in glucose homeostasis, insulin secretion, and insulin sensitivity, reports have proposed a 5 causal relationship between Vitamin D deficiency and type 2 diabetes (T2DM) (32,33). The possible involvement of Vitamin D as a glucostatic and insulin secretagogue is becoming more and more popular (33). With varying results from research to study, the precise significance of Vitamin D in diabetes mellitus, particularly T2DM, is still up for debate. Additionally, the precise physiological and molecular mechanisms underlying the reported beneficial results are still not completely understood. In order to explore the impact on glycemic control and to highlight the underlying pathophysiological mechanisms, this study evaluated the role of Vitamin D in a T2DM-rat model produced by streptozotocin injection in combination with oral anti-diabetic medications.