Type 1 DM prevention what's new

1. Type 1 DM prevention what's new Professor/ Mohammed Ahmed Bamashmos Professor if Internal Medicine and Endocrinology Faculty of Medicine ( Sanaa University)

2. Introduction • Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic beta cell destruction in which genetic susceptibility combined with environmental factors, mostly in early life, plays a crucial role. Several studies have been focusing on the identification of individuals at risk for T1D, early in the natural history of the disease, using prediction models in which the genetic factors are considered to be important for their time-independence in all subjects. These results have offered the possibility of identifying people at risk and to follow them during the years, in order to try to prevent or revert the progression of T1D. Nevertheless, genetic factors do not provide a sufficient explanation regarding the development of the disease. In the last decade, the Eisenbarth model has tried to explain the progression of T1D (1), suggesting three main stages in the natural history of T1D.

4. Risk factors

5. Risk factors 1- genetic factors ; genetic predisposition might explain up to 50% of the risk (5). Relatives of T1D patients have higher risk of developing T1D (about 15–20 times, since the risk is about 0.4% among the general population) (6, 7). The concordance rate for T1D is, respectively, 25–50% in identical twins and 6–7% in dizygotic twins and siblings types of genes - HLA both - class 1 gene (HLA-A, HLA-B, and HLA-C, ) - class 2 gene (HLA-DP, HLA-DQ, and HLA-DR. ) 50% of type 1 DM has HLA gene Importance of HLA genes in pathogenesis of type 1 DM

6. 2- Environmental factors - viral infection Enterovirus (coxsackie B viruses , rotavirus , mumps , cytomegalovirus - stress 3- Dietary factors ; - Cow's milk proteins have been proposed as triggers of an autoimmune response in hosts at genetic risk, leading to pancreatic beta cell destruction - vitamin D deficiency function of Vitamin D ; it regulate the innate and the adaptive immune system it important in induction of immunological tolerance it reduce the expansion of MHC class 1 and 2 it decrease costimulatory molecules

7. stages of type 1 DM 1- pre stage 1 Criteria for diagnosis ; - HLA genotype - positive FH - no autoantibodies - Beta cell function is 100%

8. 2- Stage 1 Criteria for diagnosis ; - the presence of two or more autoantibodies - no dysglycemia - clinically asymptomatic chance of progression to type 1 For children who were screened for genetic risk at birth , the 5 years and 10 years risk of symptomatic diseases are approximately 44 and 70% respectively and the life time risk are approximately 100% Method of prevention ; primary

9. 3- stage 2 Criteria for diagnosis ; - the presence of two or more autoantibodies - dysglycemia as manifested by 1- impaired FBG 2- IGTT - imaging insulitis ( MRI, US, Computed tomography , bioluminescence and fluorescence imaging - beta cell dysfunction ( manifested by low c- peptide . Failure of c- peptide to increase after OGTT - clinically asymptomatic The 5 years risk of symptomatic diseases is 75% and the life time risk are approximately 100% Method of prevention ; secondary

10. 4- stage 3 Criteria for diagnosis ; - the presence of two or more autoantibodies - clinically symptomatic - hyperglycemia - beta cell mass 10-20 % - method of prevention ; tertiary

12. Serological markers • Types of autoantibodies ; There are five primary types of islet autoantibodies: autoantibodies against insulin (IAA), autoantibodies against insulinoma-associated antigen-2 (IA-2), autoantibodies against glutamic acid decarboxylase (GAD), autoantibodies against zinc-transporter 8 (ZnT8), and islet cell • Time of appearance these autoantibodies could appear at any age, they rarely appear before the age of 6 months (43). The peak incidence of appearance of a first islet autoantibody is before the age of 3 years (43–45). After this age the risk of developing islet autoimmunity declines. The risk factors of developing type 1 diabetes depends on 1- age of appearance before age of 3years the progression of diseases was faster 2- presence of multiple antibodies ; 14.5% with single antibodies , 69.6% with multiple antibodies 3- the titer

13. types and indication of prevention Aim 1- to avoid the development of autoimmunity processes in subjects at risk of T1D. 2- to stop the natural progression of the disease. Level of prevention 1-primary prevention, intended for individuals at high risk of developing T1D and aimed at preventing the autoimmunity against islet autoantigens; 2- secondary prevention, which relates to individuals with multiple islet autoantibodies with the aim of halting autoimmunity processes and possibly avoid the clinical onset of diabetest 3=tertiary prevention of T1D that is focused on complications of the disease, attempting to reduce or minimize these with the main goal at least of delaying their onset

14. 1- Primary Indication - no sign of autoimmunity - no metabolic impairment - Positive family history - positive HLA Types A- Dietary interventions; Aim , to maintain gut epithelial cell integrity Types - breast feeding - avoid cows milk ; it reduce the risk of beta cell auto immunity - use of casetin hydrolysate formula - use of formula free of bovine insulin start from first 6 month of life until age of 3 years - use of gluten free diet Prospective observational studies suggest that the age at introduction of solid food, such as gluten-containing foods or cereals, affects the development of islet autoimmunity in children who are genetically susceptible to Type 1 diabetes [16,17]. In a pilot study in islet autoantibody-positive children, β-cell function seemed to be improved by deprivation of gluten for 6 months [18].

15. B - Omega-3 fatty acids An observational study suggested that dietary intake of omega-3 fatty acids is associated with reduced risk of islet autoimmunity in children at increased genetic risk for Type 1 diabetes [21]. Its importance ; - maintain gut epithelial integrity - promoting anti-inflammatory response - regulating the activity of regulatory T – cells c- Vitamin D Vitamin D has been shown to prevent insulitis and Type 1 diabetes in several mouse models of Type 1 diabetes [23]. Vitamin D supplementation in early childhood may offer protection against the development of Type 1 diabetes. Several retrospective studies found beneficial effects

16. 2- Secondary prevention trials Indication Types A- Nicotinamide is a water-soluble vitamin (B6) derived from nicotinic acid. In animal models of spontaneous and induced diabetes, nicotinamide has been shown to increase insulin synthesis and if administered before onset, to prevent development of diabetes. As long ago as 1947, nicotinamide was shown to inhibit the development of diabetes in alloxan-treated rats [30]. It was subsequently found to be effective in preventing streptozotocin-induced diabetes [31] and to prevent the spontaneous development of diabetes in the non-obese diabetic (NOD) mouse Cohort study was conducted in in school children aged year 5-10 s . Those with high ICA and impaired first phase insulin release treated with Nicotinomide at dose of 1.5 gl day . The rate of development of type 1 diabetes wsa 8.1/ 105 per year in nicotinomode treated group VS 20.1/ 105 per year in comparison group Other two study ; German Nicotinamide Diabetes Intervention study and The European Nicotinamide Diabetes Intervention study ; showed no benefit

17. B- Antigen specific therapy ; Aim ; is the holy grail of immunotherapy for prevention of type 1 MD - it control the immune response - induction of immunological tolerance - it induce beta cell rest The concept is that appropriate administration of diabetes auto antigen has the potential to control the auto immune response by diverting the immune system to protective rather than destructive response they are quite safe they are specific for type 1 diabetes Types ; 1- insulin therapy ; - parenteral insulin ; indication ; in individual projected 5 years risk of at least 50% dose ; twice daily injection of long acting insulin ( total daily dose of 0.25units lkg ) plus 96 h of continuous IV insulin infusion at base line and annually result no benefit

18. - Mucosal insulin ( intra nasal and oral ) - oral insulin 9 7.5 mg of insulin crystals ) Benefit ; - no benefit - other study showed decrease in rate of development of type 1 diabetes by 35% over 5 years also there is delay in onset of type 1 diabetes by 4.5-5 years 2- proinsulin the study still under way 3- glutamic acid decarboxylase ; vaccine using GAD with an aluminum hydroxide adjuvant C- immunomodulation a- cyclosporine ; Indication ; - first degree relative of patients with type 1 DM - two or more autoantibodies - reduced first phase insulin response - IGT

19. Dose ; 7.5 mg / kg / day and tapered at end of first year Response 30% Immunotherapy ; using monoclonal antibodies ; benefit ; it cause transient improvement of beta cell function types ; - antiCD 3 monoclonal antibodies ( Teplizumab) It targeted CD receptor in surficeot T lymphocytes dose ; single 14 days course benefit ; it delay development of type 1DM for 2 years - Abatacept ; its immunomodulatory molecules blocking T cell co- stimulation this lead to decrease in T – lymphocyte activation and proliferation it reduce the rate of reduction of beta cell function - Golimumab ; ; its tumor necrosis factor inhibitor

21. Tertiary prevention ; Indication ; In newly diagnosed type 1DM Aim ; to preserve the remaining beta cell to induce and prolong partial remission Types ; 1- use of immunosuppressive drugs A- cyclosporine ; Definition of complete remission - FBG less than 140mg - PPDG less than 200 - HbA1C less than 7,5 - absence of insulin therapy

22. definition of partial remission - same plus the need of less than 0 .2 iu / kg insulin per day Period of remission is about 1 year duration of therapy it should progressively declined and stopped if remission is not achieved B- corticosteroid and azathioprine 10 weeks course of corticosteroid followed by azathioprine for 1 year the majority of type 1 diabetic subject achieve remission c- li mnomide ; it activate or modulate regulatory T cell D- oral insulin

23. E- immunomodulatory drug 1- antiCD5 Monoclonal Antibody ; action ; it targeted T lymphocytes Indication ; new diagnosed type 1 diabetes within 5 days of diagnoses Result ; slower decline in beta cell function over 1 year 2- anti CD 3 monoclonal antibodies ( Otelixizumab and teplizumab action indication ; within 4 weeks of diagnosis of stage 3 type 1 DM treatment course ; 6 days and followed for 18 months result ; improvement of Beta cell function for 4 years ; by using hyperglycemic clamp followed by glucagon stimulation 3- anti CD 20 ( Rituximab ) 4- drugs that inhibit release of T- cells costimulatory molecules - Abatacept - Alefacept