Diabetes mellitus type 1 pathophysiology

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Case #1

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]

Overview

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels.Type 1 DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency.

Pathophysiology

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of sugar in the blood.

Pathogenesis

• Type 1 DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency

• Concordance of type 1 DM in identical twins ranges between 40 and 60%, indicating the presence of additional modifying factors.
  
  

Type-1-diabetes pathophysiology

Genetics

Genes associated with Diabetes mellitus include the following:

• Currently, 58 genomic regions are found to be associated with Type 1 DM.

• Major susceptibility gene for type 1 DM is located on HLA region of chromosome 6. It accounts for 40-50% of the genetic risk for type 1 DM. This region encodes for class II major histocompatibility complex (MHC) molecules. Class II major histocompatibility complex (MHC) molecules play an important role in presenting antigen to helper T cells and initiating immune response.

• Other major susceptibility genes which were associated with Type 1 DM include polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, CTLA4, and PTPN22 etc
• Presence of certain genes confer protection against the development of the disease. Haplotype DQA1*0102, DQB1*0602 is extremely rare in individuals with type 1 DM (<1%) and appears to provide protection from type 1 DM.

Genes important to type 1 diabetes pathogenesis	Region	Odds ratio	Gene funtion
PTPN22	1p13.2	1·89	Regulation of innate immune response, T-cell activation, and natural killer cell proliferation
IL10	1q32.1	0·86	Cytokines and inflammatory response
AFF3	2q11.2	1·11	Regulation of transcription
IFIH1	2q24.2	0·85 0·85 0·59	Innate immune system NF-κB activation
STAT4	2q32.3	1·10§	Cytokine-mediated signalling pathway
CTLA4	2q33.2	0·82 0·84	T-cell activation
CCR5	3p21.31	0·85	Th1 cell development and chemokine-mediated signalling pathway
IL21, IL2	4q27	1·13 1·12 1·14 1·15	Cytokines and inflammatory response and Th1 or Th2 cell differentiation
IL7R	5p13.2	1·11	T-cell-mediated cytotoxicity, immunoglobulin production, and antigen binding
BACH2	6q15	1·10 0·88 1·20	Transcription
TNFAIP3	6q23.3	1·12	Inflammatory response
TAGAP	6q25.3	0·92	Signal transduction
IKZF1	7p12.2	0·89	Immune-cell regulation
GLIS3	9p24.2	1·12 1·12 0·90	Regulation of transcription
IL2RA	10p15.1	1·20 0·73 0·52 0·62 0·82	Alternative mRNA splicing Th1 or Th2 cell differentiation
PRKCQ	10p15.1	0·69	Apoptotic process, inflammatory response, innate immune response, and T-cell-receptor signalling pathway
NRP1	10p11.22	1·11	Signal transduction
INS	11p15.5	0·42 0·63 0·63	Insulin signalling pathway
BAD	11q13.1	0·92	Apoptosis
CD69	12p13.31	0·87 1·10	Signal transduction
ITGB7	12q13.13	1·19	Response to virus and regulation of immune response
ERBB3	12q13.2	1·25	Regulation of transcription, innate immune response, and lipid metabolism
CYP27B1	12q14.1	0·82	Metabolism of lipids, lipoproteins, steroid hormones, and vitamin D
SH2B3	12q24.12	1·24 0·76 0·76	Signal transduction
GPR183	13q32.3	1·12	Humoral immune response
DLK1	14q32.2	0·88 0·90	Regulation of gene expression
RASGRP1	15q14	0·85 1·15	Inflammatory response to antigenic stimulus and cytokine production
CTSH	15q25.1	0·81 0·78 0·90	Immune response-regulating signalling pathway T-cell-mediated cytotoxicity adaptive immune response
CLEC16A	16p13.13	0·83 0·82 1·14	Unknown
IL27	16p11.2	1·19 0·90 1·24	Inflammatory response and regulation of defence response to virus
ORMDL3	17q12	0·90	Protein binding
PTPN2	18p11.21	1·20	Cytokine signalling and B-cell and T-cell differentiation
CD226	18q22.2	1·13	Immunoregulation and adaptive immune system
TYK2	19p13.2	0·82 0·87 0·67	Cytokine-mediated signalling pathway, intracellular signal transduction, and type I interferon signalling pathway
FUT2	19q13.33	0·87 0·75 0·87	Metabolic pathways
UBASH3A	21q22.3	1·16	Regulation of cytokine production Regulation of T-cell receptor signalling pathway
C1QTNF6	22q12.3	1·11	B-cell receptor signalling pathway, chemokine signalling pathway, and natural killer cell-mediated cytotoxicity

Environment

Environmental factors through various pathways were found to influence type 1 DM. Some were found to confer protection against type 1 DM, while others associated with progression and promotion of Type 1 DM, these include :

	Triggers	Protective factors
Prenatal triggers	Congenital rubella Maternal entero-viral infection Cesarean section Higher birth weight Older maternal age Low maternal intake of vegetables	Higher maternal vitamin D intake or concentrations in late pregnancy
Postnatal triggers	Enteroviral infection Frequent respiratory or enteric infections Abnormal microbiome Early exposure to cereals, root vegetables, eggs and cow's milk Infant weight gain Serious life events	Probiotic in first month Higher omega-3 fatty acids introduction of solid foods while breastfeeding and after age 4 months
Promoters of progression	Persistent or recurrent entero-viral infections Overweight or increased height velocity High glycemic load, fructose intake Dietary nitrates or nitrosamines Puberty Steroid treatment Insulin resistance Psychological stress

Immunological

Several studies have found that abnormalities in the humoral and cellular arm of the immune system, were identified to be associated with Type 1 DM, these include:

• Islet cell autoantibodies
• Activated lymphocytes in the islets, peripancreatic lymph nodes, and systemic circulation
• T lymphocytes that proliferate when stimulated with islet proteins
• Release of cytokines within the insulitis

Associated conditions

• Autoimmune thyroid disease (ATD)
• Celiac disease (CD)
• Autoimmune gastritis (AIG)
• Pernicious anemia (PA)
• Vitiligo
• Addison's disease