The identification of new pathways to prevent ß-cell failure is crucial to finding a cure for autoimmune diabetes (AD). The study of subjects naturally protected from ß-cell deficiency despite the presence of islet autoimmunity may reveal new protective mechanisms in AD. Subjects with Latent Autoimmune Diabetes of the Adults (LADA) are characterized by an adult onset and by a slow progression of ß-cell destruction, compared to type 1 diabetes (T1D).The study of AD heterogeneity in terms of genetic and humoral differences between T1D and LADA may therefore highlight new potential therapeutic pathways.
In this research project we will study the heterogeneity of genetic polymorphisms of risk (in human leukocyte antigen -HLA, Cytotoxic T-Lymphocyte Antigen 4 -CTLA4, Protein tyrosine phosphatase non-receptor type 22 -PTPN22, insulin genes) and protection (calcyphosine-like-Interleukin-7 receptor, Interlunkin-10 and Solute Carrier Family 30 Zinc Transporter Member 6 genes) for autoimmune disorders and the differences between T1D and LADA. Moreover, we will evaluate the differential role of autoantibodies to Interferon alfa (AbIFNa) in T1D and LADA patients and the involvement of oxidative post-translational modifications (oxPTM) of three main ß-cell antigens (insulin, GAD, IA-2). Differences in microvascular complication will be evaluated. To these aims we will collect data from validated dataset and biobank of more than 800 patients with AD already available to this investigator. Further adult and pediatric patients with T1D and LADA will be enrolled.
We expect to show that polymorphisms associated with protection from autoimmune disorders and AbIFNa are differentially associated with less aggressive forms of AD. New pathophysiological pathways leading to AD will be explored investigating the role of oxPTM in patients with LADA.
This project will provide new insights into the mechanisms of ß-cell failure and/or protection, revealing potential targets for AD treatment.
Expected outcomes: We expect to show that 1) polymorphisms associated with protection from autoimmune disorders are differentially associated with less aggressive forms of AD revealing new protective pathways; 2) AbIFNa are associated to less aggressive phenotypes of AD characterized by ß-cell, suggesting new molecular targets for AD therapies; 3) different "genetic and humoral loads" are associated with different risks of diabetes complications, allowing a more precise microvascular risk stratification of people with AD.
Relevance of the study: AD is a chronic disease not yet curable. People with AD spend most of their life with the disease, lasting for decades thanks to the significant increase in life-expectancy, which is however still 10 years shorter compared to controls [26]. AD causes disability in work skills, social activity, patients' and families' life due to daily challenges, including multiple insulin injections and glucose monitoring. This burden leads to decreased quality of life, psychological problems and loss of independence. Progression to insulin dependence represents the end stage of the autoimmune process leading to ß-cell destruction. Results from the DCCT study [27] highlights the importance of maintaining ß-cell function for preventing the development of long term complications. Therefore, the process towards a cure for AD should encompass the identification of new pathways to prevent ß-cell failure. The aims of this project will help to increase a successful management of AD, through a personalized medicine approach taking into account the different characteristics of each patient. This project will provide new crucial insights in the mechanisms of ß-cell failure.
A deep knowledge of AD heterogeneity is essential to understand and tackle the processes leading to disease onset and progression. The proposed project has been specifically designed to investigate the determinants, in terms of genetic and autoimmunity, of AD natural history by looking into the disease heterogeneity. The identification of new differences in immunogenetic between LADA and T1D gives the great opportunity to discover new predictors of AD.
This in-depth characterization of genetic and humoral differences between slowly and rapidly progressive AD is crucial to elaborate a precision medicine approach.
The identification of new Ab specificities to oxPTM antigens and presence of AbIFNa may provide a paradigm shift in the concept of AD immunopathogenesis.
AD contribute to a huge economic burden due to both direct and indirect costs. Direct costs are caused by treatment and monitoring of AD. Acute and chronic complications, insulin therapy, glucose monitoring, health care and hospital access represent a significant economic burden for the Health care system [28]. In the last ten years, the cost of insulin therapies have increased of more than 500% [29]. Indirect costs arise from factors such as work absenteeism, reduced productivity and decreased quality of life [30]. Hypoglycemia, a direct consequence of insulin therapy, also increases the costs of AD by direct economic impact on hospitalisation and medical care [31] and by indirect cost on work productivity and AD management [32]. New strategies of preventing AD and slowing down ß-cell depletion will delay the need of insulin therapy and the onset of chronic complications, resulting in the reduction of both direct and indirect cost of AD, decreasing economic burden for health care system and for whole society.
Bibliography
1.Mishra R (2017)BMC Med 15:88;
2.Buzzetti R (2017)Nat Rev Endocrinol 13:674-686;
3.Thomas NJ (2018)Lancet Diabetes Endocrinol 6:122-129;
4.Sun JK (2011)Diabetes Care 34:968-74;
5.Fourlanos S (2005)Diabetologia 48:2206-12;
6.Newton J (2004)Genes Immun 5:151-157;
7.Strollo R (2013)Diabetologia 56:563-72;
8.Strollo R (2013)Arthritis Rheum 65:1702-12;
9.Ciccacci C (2016)Clin Exp Immunol 186:157-163;
10.Adelino JE (2017)Scand J Rheumatol 46:326-327;
11.Santiago JL (2008)Diabetologia 51:1653-8;
12.Liao KP (2009)Arthritis Rheum 60:653-60;
13.Strollo R (2017)Diabetologia 60:1467-1474;
14.Strollo R (2015)Diabetologia 58:2851-60;
15.Tiberti C (2008)Diabetes 57:1276-83;
16.Buzzetti R (2015)Diabetes Care 38:513-20;
17.Meyer S (2016)Cell 166:582-595;
18. No authors (1998)Ann Intern Med 128:517-23;
19.Hernández M, (2017)Cardiovasc Diabetol 16:94;
20. Radtke MA, (2009)Diabetes Metab 35:273-279;
21.Zampetti S (2014)Eur J Endocrinol 171:697-704;
22.Petrone A (2008)Diabetes Care 31:534-8;
23.Crinó A (2005)J Pediatr Endocrinol Metab 18:749-54;
24.Pitocco D (2006)Diabet Med 23:920-3;
25.Bizzarri C (2010)Diabetes Care 33:1962-3;
26.Livingstone SJ (2015)JAMA 313:37-44;
27.Subramanian S (2018)Endocrinol Metab Clin North Am 47:65-79;
28.McEwan P (2018)Diabet Med. 35:557-566;
29.Osservatorio ARNO (2017) Rapporti ARNO-volume XXX;
30.Hex N, (2012)Diabet Med 29:855-62;
31.Aronson R (2018)Diabetes Res Clin Pract 138:35-43;
32.Brod M (2011)Value Health 14:665-71.