VITAMIN D DEFICIENCY IN TYPE 1 DIABETIC PATIENT

Transcription

1 VITAMIN D DEFICIENCY IN TYPE 1 DIABETIC PATIENT Thesis Submitted for Fulfillment of Master Degree in Pediatrics Presented by Ahmed Mahmoud Aly Abdelaziz (M.B.B.Ch).2003 Faculty of Medicine Cairo University Under supervision of Prof. Dr. Noura Elsaid Badawy Ass Professor of Pediatrics Faculty of Medicine Cairo University Prof. Dr Azza Abdelkader Elhamshary Ass Professor of Pediatrics Faculty of Medicine Cairo University Dr. Gamal Thabet Aly Lecturer of Clinical Pathology Cairo University Faculty of Medicine Cairo University 2012

2 Acknowledgement. First and foremost, all thanks and gratefulness to "ALLAH ALLAH", the most beneficial and merciful. It is a great honour to me to express my deepest gratitude and appreciation to Prof. Dr. Nora Badawy Ass professor of Pediatrics, Faculty of Medicine, Cairo University for her continuous supervision, fruitful guidance and generous support. Indeed, this work would not be accomplished without her efforts and advice. I am deeply grateful and forever indebted to Dr. Azza Elhamshary, Ass professor of Pediatrics, Faculty of Medicine, Cairo University, Dr. Gamal thabet, Lecture of Clinical pathology for their valuable effort, supervision and guidance. My special thanks to all my patients and their parents who agreed to share in this study. I'm thankful to them for their effort, time and cooperation. Last but not least, I would like to express my endless gratitude to my family esp my grandfather,father,mother,wife for their support. Ahmed Mahmoud Aly Abdelaziz

3 Abstract Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Vitamin D deficiency continues to be a public health problem in many countries despite the availability of cheap and effective means to prevent this disease, Vitamin D deficiency in now considered pandemic. The actions of vitamin D are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. Pancreatic insulin secretion is selectively inhibited by hypovitaminosis D. Several reports have demonstrated an active role for vitamin D and especially its bioactive form, 1,25(OH)2D3, in the regulation of endocrine pancreas function, especially the beta cell. An important role for vitamin D is suggested by the presence of the VDR in pancreatic beta cells. Key words : Dendritic cell - cytochrome P450 - Inter leukin.

4 List of Contents Page Introduction & Aim of work 1 Review of Literature. Ch 1 Type-1 Diabetes Mellitus Ch 2 Vitamin D Ch 3 Vitamin D relation to diabetes Subjects & Methods Results: Discussion: Summary& Conclusion Recommendations References Arabic Summary

5 List of Tables No Title Page Table (1) Etiological classification of DM 6 Table (2) The Clinical and biological characteristic of the different subtype of type 1 diabetes. 8 Table (3) Vitamin D and Its Metabolites. 31 Table (4) Vitamin D Content of Some Foods 43 Table (5) Table (6) Table (7) Table (8) Table (9) Table( 10) Table (11) Tolerable Upper Intake Level of Vitamin D for Infant and Children. Physical characteristics of patients in both groups (A&B). Mean and ±SD, t and P values of Vitamin D for diabetic and control groups. Mean and ±SD, t and P values of Ca level for diabetic and control groups Mean and ±SD, t and P values of Ca level for diabetic and control groups. Mean and ±SD, t and P values of Alkaline phosphatase for diabetic and control groups. Mean and ±SD, t and P values of Creatinine for diabetic and control groups Table (12) Mean and ±SDof HbA1C for diabetic group. 101 I

6 Table (13) Table (14) Table (15) Table (16) Table (17) Correlation Analysis between the Vitamin D and HbA1C. Correlation Analysis between the Vitamin D and Ca level. Correlation Analysis between the Vitamin D and P level. Correlation Analysis between the Vitamin D and Alkaline phosphatase Correlation Analysis between the Vitamin D and Creatinine I

7 List of Figures No Title Page Figure (1) Steps of Vitamin D Activation 44 Figure (2) Mean and ±SD of the age for groups (A, B). 92 Figure (3) Mean and ±SD of the weight for groups (A, B). 92 Figure (4) Mean and ±SD of the height for groups (A, B). 93 Figure (5) Mean and ±SD of the BMI for groups (A, B). 93 Figure (6) Mean and ±SD of Vitamin D for diabetic and control groups. 95 Figure (7) Mean and ±SD of Ca level for diabetic and control groups 96 Figure (8) Mean and ±SD of P level for diabetic and control groups 97 Figure (9) Mean and ±SD of Alkaline phosphatase for diabetic and control groups. 99 Figure (10) Mean and ±SD of Creatinine for diabetic and control groups 100 Figure (11) Mean and ±SD of the HbA1C for diabetic group. 101 Figure (12) Correlation between vitamin d and hba1c. 102 Figure (13) Correlation between vitamin d and ca level. 103 Figure (14) Correlation between vitamin d and p level. 104 Figure (15) Correlation between vitamin d and alkaline phosphatase. 105 Figure (16) Correlation between vitamin d and creatinine 106

8 Abbreviations 1,25 (OH)2D dihydroxycholecalciferol 1,25(OH)2D3 1α,25-dihydroxyvitamin D3 ADA American Diabetes Association BB biobreeding BMI Body mass index CYP cytochrome P450 DC Dendritic cell DKA Diabetic Ketoacidosis DM Diabetes mellitus DPB vitamin-d-binding protein ER FBG GDM GFR HbA1c HLA IFN IGF-1 IL endoplasmic reticulum fasting blood glucose Gestational diabetes mellitus glomerular filtration rate disease glycoselated hemoglobin human leukocyte antigen interferon Insulin-like growth factor-1 Inter leukin NOD non-obese diabetic T1DM type 1 diabetes mellitus TNF Tumor necrotic factor VDBP vitamin D-binding proteins VDR Vitamin D receptor

9 Introduction INTRODUCTION Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemic resulting from defects in insulin secretion, insulin action or both. The chronic hyperglycemia of diabetes is associated with long term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels (American Diabetes Association, 2011). In 1985 an estimated 30 million people worldwide had diabetes & in 2000, little over a decade later, the figure had risen to over 150 millions. This figure is expected to rise to almost 350 millions by 2025 (Stern et al., 2005). The etiology of type I diabetes is unknown, but it is recognized to be due to both genetics and environmental determinants (Sperling, 2000). Type I diabetes mellitus is usually due to autoimmune destruction of B cells of langerhans in individuals with genetic predisposition, when exposed to enviromental factors, which are still poorly understood (Sperling,2000). The Linus Pauling Institute (institute of nutrition) recommends a daily intake of IU for healthy adults, especially for individuals that are at high risk for vitamin D deficiency such as the elderly and individuals with dark skin, such as Africans Americans. 1

10 Introduction According to the Institute of Medicine, the acceptable upper intake level of vitamin D for infants 0-12 months is IU, for children 1-18 years is 2000 IU (Linus Pauling Institute at Oregon state university 2008). Vitamin D deficiency in now considered pandemic, (Holick and Michael, 2006). Alack of vitamin D results in increase osteoclasts which break down bone, thus increasing the risk of osteoporosis (Holick and Michael, 2006).. Sever vitamin D deficiency also negatively affects children by adversely bone development and reducing mineralization, resulting in rickets which leads to deformity and reduced bone tensile strength. it causes bowed legs, and knock knees. (Holick and Michael, 2006). There are receptors for vitamin D in 30 different type of tissue, and vitamin D is involved in the transcription of more than 200 different DNA sequences. It supports the production of insulin at the pancreas, proving throughly beneficial in both type 1 and type 2 diabetes. A study of more than Finish children given 2000 IU/day for a year showed 78% reduction in the incidence of type 1 diabetes in the 31 years of study, and even a lower intake of just 800 IU/day has been shown to reduce risk of type 2 diabetes by a third. On a day to day basis, vitamin D improves insulin sensitivity. Vitamin D also improves leptin sensitivity. It reverses and blood 2

11 Introduction sugar swings and reduces over eating and thus will help weight loss. (Borkar, 2009). 3

12 Aim of the Work AIM OF THE WORK Is to evaluate the level of vitamin D in type 1 diabetic patient, and the effect of vitamin D deficiency on the long term blood glucose control as reflected by Hb A1C. 4

13 Review of o f Literature DIABETES MELLITUS Definition of Diabetes: Diabetes mellitus is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The hyperglycemia of diabetes is associated with long term damage, dysfunction and failure of various organs, especially the eye, kidney, nerves and blood vessels (ADA, 2011). Etiological classification of DM: The classification of diabetes includes four clinical classes as stated by American Diabetes Association (ADA), 2008: 1- Types 1 Diabetes. 2- Types 2 Diabetes. 3- Other specific types. 4- Gestational diabetes mellitus (GDM). 5

14 Review of o f Literature Table (1): Etiological classification of DM: I- Type 1 diabetes (B-cell destruction, usually leading to absolute insulin deficiency). A. Immune mediated. B. Idiopathic. II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretary defect with insulin resistance). III. Other specific types: A. Genetic defects of B-cell function: (MODY3), (MODY2), (MODY1), (IPF-1; MODY4), (MODY5) and (MODY6). B. Genetic defects in insulin action: Type A insulin resistance, Leprechauns and Robson- Mendenhall syndrome. C. Disease of the exocrine pancreas: Pancreatitis, Trauma, Pancreatectomy, Neoglasia, Cystic fibrosis and Homochromatic. D. Endocrineyathy: Acromegally, Cushing's syndrome, Glucagonoma, Pheochromocytoma, Hyperthyroidism and Somatostatinoma. E. Drug - or Chemical - Induced: Glucocoricoids. F. Infections: Congenital rubella and Cytomegalovirus. G. Uncommon forms of immune mediated diabetes: "Still-man" syndrome. H. Other genetic syndromes sometimes associated with diabetes: Daun's Syndrome, Klinefelter's syndrome, Turners's syndrome, Wolfram's syndrome, Friedreich's ataxia and Preder-will syndrome. IV. Gestational diabetes mellitus (GDM): (ADA, 2008) 6

15 Review of o f Literature Type 1 Diabetes mellitus: Type 1 diabetes was previously called insulin dependant diabetes mellitus or juvenile onset. Type 1 diabetes is a chronic autoimmune disease characterized by selective destruction of the insulin producing beta cells in the pancreatic islet cells, accompanied by antibody formation against beta-cells components (Alemzadeh & Wyatt, 2004). It accounts for 5% to 10% of all diagnosed cases of diabetes and may include autoimmune, genetic, and environmental factors (National Diabetes fact sheet United State, 2005). 1- Type 1a (The autoimmune form): Autoimmune destruction of pancreatic B-cells representing about 90% of type 1 cases in Europe. The presence of other autoimmune disorders is highly raised (ADA, 2005). 2- Type 1b (The idiopathic form): In which there is no evidence of autoimmunity, it represents about 10% of cases of type 1 DM in Europe (Salma, 2003). 3- Type 1c: A publication from Japan has described what is thought to be another new form of the disease where the onset was explosive with 4-5 days of symptoms, HbA1c levels were still almost normal at diagnosis, there was a profound lack of insulin, extremely high blood glucose level and full ketoacidosis but there were no anti-islet autoantibody (Imagawa et al, 2000). 7

16 Review of o f Literature Table (2): Clinical and biological characteristics of the different subtypes of type 1 diabetes: Type 1a Type 1b Type 1c Signs of anti-islet autoimmunity Duration of symptoms before diagnosis 8 months 7 months < 1 week Ketosis, Ketoacidosis at Frequent Frequent Constant diagnosis Blood glucose level at diagnosis HBA1c at diagnosis Normal or slightly elevated (Imagawa et al, 2000) Diagnosis of Diabetes Mellitus: The classic symptoms and signs of type 1 diabetes include: polyuria, polydipsia, polyphagia, and weight loss-rarely give doubt about the diagnosis of diabetes in childhood or adolescence (ADA, 2008). The diagnosis is dependent on demonstration of hyperglycemia in association with glucosuria with or without ketonuria. The glucose tolerance test is not needed to support the diagnosis when classical symptoms are associated with hyperglycemia and glucosuria (Sperling, 2000). 8

17 Review of o f Literature Criteria for the diagnosis of diabetes: 1- FBG >126 mg /d1 ( 7 mmol/l). Fasting is defined as no caloric intake for at least 5h. Or 2- Symptoms of hyperglycemia and a casual random plasma glucose > 200 mg /d1 (11.1 mmol/1). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and weight loss. Or 3-2-hPP plasma glucose > 200 mg /d1 (11.1 mmol/1) during in OGTT The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. (Expert Committee on the diagnosis and classification of diabetes mellitus, 2003). 9

18 Review of o f Literature Complications Of Diabetes Short term complication can happend quickly such as hypoglycemia, hyperglycemia, ketoacidosis, and hyperosmolar syndrome. Patients need to be aware of their signs and symptom and what to do to reverse them. The long term vascular compilations of diabetes include retinopathy, nephropathy and neuropathy and macro vascular disease. The outcomes are: Visual impairment and blindness due to diabetic retinopathy Renal failure and hypertension due to diabetic nephropathy. Pain, Parasthesia, muscle weakness and autonomic dysfunction due to diabetic neuropathy. Cardiac disease, peripheral vascular disease and stroke due to macro vascular disease. Clinically evident diabetes related vascular complications should be rare in childhood and adolescence, however, early functional and structural abnormalities may be present a few years after the onset of diabetes. Childhood and adolescence is a period during which intensive education and treatment may prevent or delay the onset and progression of complications. (DCCT Research Group, 1994). 10

19 Review of o f Literature 1- Acute metabolic complications: A. Hyperglycemic states: 1. Diabetic Ketoacidoisis: Diabetes Ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Mortality is predominantly related to the occurrence of cerebral odema; only a minority of deaths in DKA is attributed to other causes. It is a state of absolute or relative insulin deficiency aggravated by ensuring hyperglycemia, dehydration, and acidosis - producing derangements in intermediately metabolism. The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes. (Berthold & Krone, 2006). 2- Non Ketotic hyperosmolar coma: HHS is manifested by marked elevation of blood glucose hyperosmolality and little or no ketosis. Precipitating causes of HHS are infection, undiagnosed diabetes and substance abuse. The mortality rates of the HHS remain high 15%. (Berthold & Krone, 2006). 11

20 Review of o f Literature B. Hypoglycemia: Hypoglycemia is the most common acute complication in insulin-` treated type 1 diabetic patients. Most surveys have demonestrated that the tighter the glycemic control, and the younger the patient, the greater the frequency of both mild and severe hypoglycemia. However, people in poor metabolic control, with high glycosylated hemoglobin levels, are not protected from experiencing severe hypoglycemia. (Becker and Ryan, 2000). 2. Chronic diabetic complication: 1- Microvascular angiopathy: Mainly affecting vessels of the eye causing diabetic retinopathy, of kidney causing diabetic nephropathy and nervous system causing diabetic neuropathy. (Canadian Diabetes Association, 2003) Diabetic retinopathy: Adolescents have a higher risk of progression to vision threatening retinopathy compared to adult patients with diabetes The progression may be rapid, especially in those with poor glycemic control (Maguire et al, 2005) Progression of retinopathy: 12