The Effect of Vitamin D Supplementation on Glycemic Control and Body Mass Index in the Obese, Vitamin D Deficient Adult with Type 2 Diabetes Mellitus: A Systematic Review Protocol

Abstract

Review question/objective The objective of this review is to identify the effectiveness of Vitamin D supplementation on glycemic control and body mass index (BMI) in the non-pregnant, obese, Vitamin D deficient (VDD) adult with Type 2 Diabetes Mellitus (T2DM). More specifically, the objective is to identify: The dose dependent effect of Vitamin D supplementation of 600IU/day or more on glycemic control in the non-pregnant, obese, VDD adult with T2DM. Background In regards to Type 2 Diabetes Mellitus (T2DM) and Obesity, there is a worldwide pandemic causing great concern over these evolving and increasing diseases. 1 Statistics reflect that T2DM accounts for 85-90% of all cases of diabetes 1 around the world and one in ten adults are considered obese. 2 Worldwide approximations also reveal that 50% of the world's population is at risk of being vitamin D deficient. 3 The global rise in T2DM can be attributed to a change toward a western lifestyle leading to increases in overweight and obesity, which in turn promote insulin resistance. 4 Evidence of micronutrient deficiencies such as vitamin D deficiency may also affect endocrine cells thus possibly leading to the increased risk of developing T2DM. 4 Epidemiological evidence supporting an inverse relationship between T2DM, obesity, and vitamin D deficiency (VDD), 5-11 may reveal a common denominator in regards to risk for metabolic processes. Diabetes Mellitus (DM) refers to impairment in insulin secretion and differing degrees of peripheral insulin resistance leading to hyperglycemia. 15 Terms for DM classification have changed due to overlap in the age groups and respective treatments. 12 Outdated terms such as juvenile or adult onset diabetes have been replaced with Type 1 Diabetes Mellitus (T1DM) and T2DM.12 The international committee has determined that a Hemoglobin A1C (HGA1C) of 6.5% or above should be used for the diagnosis of diabetes. 14 There are two main types of DM; Type 1 Diabetes Mellitus (TIDM) and T2DM. 15 Symptomatic hyperglycemia and diabetic ketoacidosis are typical of T1DM however, T2DM may not present with outright hyperglycemia. 15 Many times T2DM is detected during routine testing. 15 This review will use the HGA1C assay to determine glycemic control. Type 2 Diabetes Mellitus The estimated worldwide incidence of individuals with diabetes was approximately 366 million in 2011 and is expected to rise to 552 million by 2030. 1 The growing epidemic of T2DM has prompted global concern 1,2 with a call for awareness, prevention and improved management of the disease. Experts speculate that the increased incidence in T2DM is a product of globalization, sedentary lifestyle, obesity, and genetics. 1 The estimated worldwide incidence of diabetes was approximately 366 million in 2011 and is expected to rise to 552 million by 2030. 1 Type 2 Diabetes Mellitus can lead to illness and a taxing financial burden, with T2DM contributing to over 20% of all deaths after the age of 49 for all regions of the world during 2011. 1 Worldwide estimates of health expenditures in 2010 accounted for $376 billion in T2DM related illnesses. 1 Projected costs by 2030 are expected to reach $490 billion without a concerted effort to control this disease. 1 In 2010, 1.9 million new cases of T2DM were diagnosed in the United States 12 and currently there are 25.8 million adults and children with all types of diabetes with at least 7.0 million people not yet diagnosed. 12The growing epidemic of T2DM is the leading cause of new cases of blindness among people between the ages of 20 and 74 years of age. 12 People living with T2DM suffer from multiple complications such as heart disease, stroke, blindness, kidney disease, and neuropathies associated with the disease. 12The total cost of T2DM in the U.S. for the year 2007 was $174 billion 12and costs continue to rise in spite of educational programs. Worldwide efforts to reduce the financial and physiological burden of T2DM 1,2,12,13 exist, but have been unsuccessful. Researchers have been working diligently toward an efficient and economical alternative to the current status quo when it comes to traditional anti-diabetic treatment. Latest guideline changes to diagnosing and monitoring diabetes were announced during the 69th American Diabetic Association's (ADA) annual Scientific Session in 2009. 14 During this session, the ADA, the International Diabetes Federation (IDF), and European Association for the Study of Diabetes (EASD) joined forces in creating new guidelines in the diagnosis of Diabetes Mellitus (DM). 14 The recommendation to use theHGA1C assay for initial diagnosis, in addition to fasting glucose and 2-hour glucose tolerance test, was announced 14 This is the first change in 30 years to the existing ADA guidelines for diagnosing diabetes. 12,14 Overweight, Obesity, and Body Mass Index The substantial impact of obesity on subsequent metabolic disorders is a complex situation that requires further investigation. Obesity, now considered a chronic disease, is linked to hypertension, T2DM, insulin resistance, joint issues, and obstructive sleep apnea. 16 An energy imbalance is the best way to describe obesity; it means that the energy consumption out weights the energy expenditure 17 Overweight and obesity are defined as “abnormal or excessive fat accumulation that may impair health”. 2 BMI is determined by a person's weight in kilograms divided by the square of his/her height in meters. 1The World Health Organization (WHO) defines overweight as a body mass index (BMI) of greater than or equal to 25 (kilograms per meters squared) kg/m2 and obesity as greater than or equal to 30 kg/m2. In 1980, over 1.5 million adults across the globe were considered overweight and the numbers have doubled. 2 Approximately 2.8 million deaths, 13 44% of diabetes, and 23% of heart disease cases are attributed to overweight and obesity across the globe.13 Disparities across all countries reflect that women with less education were two to three times more likely to be obese or overweight versus women with higher education. 18 Approximately 25% of the population in England are obese as well as 18% in Hungary and 15% in Spain and Ireland. 18 Adult Americans with a BMI of 25 kg/m2 or greater are estimated at about 149.3 million. 16 The worldwide financial burden accounts for approximately 0.7% - 2.8% of total health-care costs 16 and American health-care costs related to obesity estimated to reach $861-957 billion by 2030. 13 By lowering BMI by 5 %, millions of dollars in healthcare costs could be saved. 18 Vitamin D Vitamin D, discovered in the 1700s, was not only used to cure rickets and improve osteomalacia 19 but since then has been associated with a reduction in cancer risk, infectious diseases, cardiovascular diseases, autoimmune diseases, neurological disorders, T1DM, and T2DM. 20 Investigators have also found increased levels of Vitamin D3 to be associated with reduced mortality rates of all causes. 20 In 1940, a physician researcher investigating skin cancer and sunlight discovered an inverse relationship between increased sunlight exposure and decreased incidence of all types of cancers except skin cancer. 21 That introduction into the biological effects of sunlight on cancer mortality rates, spurred interest in Vitamin D. The impetus for further investigation of Vitamin D began to evolve in 1970, when Holick 8 isolated 25-hydroxyvitamin D3 into the active form 1,25-dihydroxivitamin D3. 22 His seminal work 22 in this field revealed that many tissues and cells in the body have Vitamin D receptors (VDR) and thus have the ability of converting circulating Vitamin D or 25-hydroxyvitamin (D 25(OH)D3) to the active form, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). 8 There are two forms of Vitamin D; 19 they are Vitamin D2 or ergocalciferol and Vitamin D3 (cholecalciferol). Plants synthesize ergocalciferol and the skin, when exposed to ultraviolet sunlight, synthesizes cholecalciferol. 19 Vitamin D3 deficiency is linked to a lack of ultraviolet B rays from the sun, use of sun block, increased skin pigmentation, seasonal variation, location of the sun, latitude, aging, and obesity. 23 Metabolism of Vitamin D involves conversion in the liver and the kidneys. Sufferers of chronic diseases such as diabetes, pancreatitis, celiac disease, and diseases taxing the liver and kidneys are at greater risk of Vitamin D deficiency. 19 Vitamin D status is classified as: 25(OH)D deficiency < 20 ng/ml, insufficiency 21-29ng/ml; and a normal level at 30ng/ml. 8 The recommended daily allowance (RDA) for adults aged 18-70 is 600IU/day and for those over 70, the RDA is 800IU/day. 24 The RDA upper limit for Vitamin D supplementation in adults over 18 years of age is 4000IU/day. 24 The best predictor of Vitamin D status is determined by measuring 25(OH)D3 in the blood. The circulating form of Vitamin D, 25(OH)D3, in the blood exists for approximately 2-3 weeks, thus providing a more accurate serum Vitamin D level than the active form 1,25-(OH)2D38 which is only available for measurement for about 2-4 hours. 8 Obesity, Vitamin D, and Type 2 diabetes Mellitus It is believed that Vitamin D may assist in improving glycemic control by improving insulin production and secretion. 20 It is hypothesized that vitamin D may inhibit pancreatic beta cell dysfunction by protecting islet cells from destruction. 7 Preliminary research has found an inverse relationship between Vitamin D status and obesity. 5 Vitamin D deficiency in the obese population offers an intriguing perspective. Vitamin D is fat-soluble, behaves like a hormone, and is sequestered in adipose tissue. 23, 25 It has been hypothesized that the greater the fat mass the greater the Vitamin D deficiency. 5 Obesity, a disease associated in the pathophysiology of T2DM, is a consequence of over nutrition and sedentary life-style in those with a genetic predisposition. 26 Demise of the islet beta cell is said to be caused by over nutrition and inactivity. 27 Type 2 Diabetes Mellitus is a metabolic disorder characterized by hyperglycemia and pancreatic beta cell dysregulation. 4 Commonalities between T2DM and obesity involve systemic vascular inflammation. 28 Over nutrition promotes adipose tissue inflammation and beta cell stress; these cellular responses cause insulin signaling impairment and possible subsequent development of T2DM. 17, 28 Cellular responses in organs stemming from inflammation may play a role in the pathogenesis of T2DM. 28 Other contributing factors to this inflammation 28 involve changes in environment, lifestyle, sleep deprivation, and diets low in fiber. Systemic vascular inflammation increases with age and is more pronounced and prolonged in those at risk for T2DM. 28 Vitamin D activity in the beta cells is potentiated by the activation of Vitamin D receptors (VDR) located in the pancreas, this in turn allows for a reduction in systemic inflammation. 29 The global increase in obesity and the possible relationship to VDD may present a unique opportunity to impact T2DM at the onset. 5 Current medications such as Byetta and Victoza, which affect both glycemic control and obesity, may present obstacles to treatment such as unfavorable side effects like nausea, emesis, headache, diarrhea 30,31 and a potential risk for pancreatitis, 30 renal insufficiency, 30 and/or thyroid tumor. 31 In a commentary on the link between Vitamin D deficiency and T2DM, the reviewer reports that Vitamin D depletion may have dose related effects on glucose homeostasis, insulin secretion, and insulin resistance. 32 Vitamin D supplemented at the higher dose limit 23 may be a less expensive and effective treatment to harness obesity in the T2DM adult. A preliminary search of the Joanna Briggs Library of Systematic Reviews, Cochrane Library, CINAHL, Pub Med, and PROSPERO has revealed a number of reviews covering the link between VDD and various disease processes which include T2DM and obesity. Mitri et al. 6 conducted a meta-analysis that included different levels of evidence correlating high levels of Vitamin D with a 43% lower risk of developing T2DM. In 2010, Renzaho et al. 9 conducted a review focusing on VDD and its relation to obesity, T2DM, and/or cardiovascular disease in which they 9 reported that ethnic minorities from various countries had significant VDD. The results also showed an inverse relation between Vitamin D status and obesity; however, the strength of the studies was limited due to the various tools used for determining body fat and not necessarily BMI. 9 A recent review 3 included a mix of multi-level research and147 systematic reviews. The data revealed a clearer association of VDD to insulin resistance than to fasting glucose. A review conducted by Alvarez et al. 10 also found an inverse relationship between Vitamin D and T2DM; however, dose-dependent glycemic control was not detailed. Another review 11 on the relationship between VDD, obesity, and T2DM found that women who received Vitamin D and Calcium supplementation had less weight gain and smaller waist circumference at a 7 year follow-up versus the placebo group. The results from this were difficult to isolate due to the inclusion of Calcium-Vitamin D supplementation combinations. 11 As there have been several systematic reviews to gain understanding of the relationship between Vitamin D and Type 2 Diabetes Mellitus, this systematic review will narrow its focus to investigate the effect of Vitamin D in the non-pregnant, obese, VDD adult with T2DM. This review aims to determine what effect vitamin D supplementation has on glycemic control and obesity in the T2DM adult by measurements of HGA1C and BMI, respectively.