Diabetes mellitus type 1 pathophysiology: Difference between revisions

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Latest revision as of 10:31, 31 August 2020

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]Vishal Devarkonda, M.B.B.S [4] Anahita Deylamsalehi, M.D.[5]

Overview

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. Type 1 diabetes 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. Currently, 58 genomic regions are known to be associated with type 1 DM. There are environmental factors that can play a protective role in Type 1 diabetes like higher maternal vitamin D, probiotic and omega-3 fatty acids intake during prenatal period. Conversely, environmental factors such as caesarean section, congenital rubella, maternal enteroviral infection and abnormal microbiome are among environmental factors that are able to trigger Type 1 DM. Furthermore, some immunological components are responsible for type 1 DM pathogenesis.

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.
Possible thymus and bone marrow deficiency includes defective thymic selection, faulty self antigen presentation, thymic VNTR and Aire expression, mobilopathy and defective lymphocyte precursors are some possible proceeding triggers that underlie type 1 DM.^[1]

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.

Genetics

Genes associated with Diabetes mellitus include the following: ^[2]^[3]^[4]^[5]^[6]^[7]
- Currently, 58 genomic regions are known to be associated with Type 1 DM.
- Major susceptibility gene for type 1 diabetes is located on HLA region of chromosome 6. It accounts for 40-50% of the genetic risk for type 1 diabetes. This region encodes for class II major histocompatibility complex (MHC) molecules. major histocompatibility complex (MHC) molecules play an important role in presenting antigen to T helper cell 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, Insulin-VNTR, AIRE, FoxP3, STAT3, HIP14 and PTPN22 etc.^[8]^[9]
- 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 diabetes.
- There is a relationship between some human leukocyte antigens (HLA) and type 1 diabetes, such as DQB1, DQA1, and DRB1. There are some supporting data on DR4-linked haplotypes transmission from type 2 diabetes parents to offspring with type 1 diabetes. Patients with latent autoimmune diabetes of adults also have been related to HLA alleles DQB1*0302 and 02. ^[9]

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 cell 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 were found to influence Diabetes mellitus type 1 through various pathways. Some were found to confer protection against Diabetes mellitus type 1, while others were associated with the progression and promotion of Diabetes mellitus type 1, including:^[10]^[11]

	Triggers	Protective factors
Prenatal triggers	Congenital rubell a Maternal Enteroviral infection Cesarean section Higher birth weight Older maternal age Low maternal intake of vegetables	Higher maternal vitamin D intake or vitamin D 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 Enteroviral 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 Diabetes mellitus type 1, these include:^[12]^[13]^[14]^[15]^[16]^[1]
- Deficiency in immune regulation, such as effector T cells (Teff) resistance to Regulatory T cells (Treg) or Regulatory T cells (Treg) abnormalities
- Islet cell autoantibodies
- Defective cellular trafficking and adhesion
- Activated lymphocytes in the islets, peripancreatic lymph nodes, and systemic circulation
- Chronic activation of Antigen-presenting cells
- T lymphocytes that proliferate when stimulated with islet proteins
- Release of cytokines within the insulitis
- An enzyme named glutamic acid decarboxylase (GAD65) found in β cells has similar amino acid sequence with the Coxsackie B4 P2-C protein, which augments the response of humoral immunity.
- Autoantibodies against IA-2 and zinc transporter (ZnT8) have been positive in 60% and 60-80% of Diabetes mellitus type 1 at the time of diagnose, respectively.

Associated conditions

Conditions associated with diabetes mellitus type 1 include:^[7]^[17]
- Autoimmune thyroid disease (ATD)
- Celiac disease (CD)
- Autoimmune gastritis (AIG)
- Pernicious anemia (PA)
- Vitiligo
- Addison's disease
The following table is a summary of some associated autoimmune conditions and their prevalence among type 1 diabetic patients and normal population.^[18]


Associated autoimmune conditions	Prevalence in patients with diabetes mellitus type 1 (%)	95% CI	Prevalence in the general population (%)
Hypothyroidism	9.8	7.5–12.3	2–4.6
Positive TPO and or TG antibodies	18.9	17.2–20.6	Unknown
Positive TPO antibodies	18.3	15.8–21.0	11.3–12.8
Positive TG antibodies	12.3	10.0–14.9	10.4
Hyperthyroidism	1.3	0.9–1.8	1.0–4.0
Positive TSH receptor antibodies and or Thyroid stimulating immunoglobulin	9.5	1.4–22.7	Unknown
Celiac disease	4.7	4.0–5.5	0.5–1.0
Presence of any gluten related antibodies	10.2	8.4–12.7	Unknown
Positive tissue transglutaminase antibodies (IgA)	9.8	8.2–11.6	1.5
Positive tissue transglutaminase antibodies (IgA/IgG)	9.8	8.4–11.3	2.1
Positive anti-endomysial antibodies (IgA)	5.3	4.3–6.4	0.8
Positive antigliadin antibodies (IgA)	9.7	5.1–15.5	1.6
Positive antigliadin antibodies (IgG)	12.7	6.1–21.0	7.1
Pernicious anemia	4.3	1.6–8.2	0.2
Positive anti-parietal cell antibodies	9.3	5.4–14.1	3–10
Vitiligo	2.4	1.2–3.9	0.4
Adrenal gland insufficiency	0.2	0.0–0.4	0.012
Positive anti-adrenal antibodies (AAA/21-OHab)	1.4	0.8–2.2	Unknown

Gross Pathology

On gross pathology, pancreas may demonstrated the following changes:^[1]
- Decreased overall weight and size
- Dorsal region atrophy
- Possible hypertrophy (related to hydrophic changes)

Microscopic Pathology

On microscopic histopathological analysis, the following changes can be detected in islet cells:^[1]
- Insulitis
- Beta cell loss due to necrosis or apoptosis
- Major histocompatibility complex class one hyperexpression
- Reduction in insulin in remnant beta cells
- Interferon alpha expression in beta cells
- CD3-positive cells in Islet cell

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Atkinson MA, Eisenbarth GS, Michels AW (2014). "Type 1 diabetes". Lancet. 383 (9911): 69–82. doi:10.1016/S0140-6736(13)60591-7. PMC 4380133. PMID 23890997.
↑ Pociot F, Lernmark Å (2016). "Genetic risk factors for type 1 diabetes". Lancet. 387 (10035): 2331–9. doi:10.1016/S0140-6736(16)30582-7. PMID 27302272.
↑ Safari-Alighiarloo N, Taghizadeh M, Tabatabaei SM, Shahsavari S, Namaki S, Khodakarim S; et al. (2016). "Identification of new key genes for type 1 diabetes through construction and analysis of protein-protein interaction networks based on blood and pancreatic islet transcriptomes". J Diabetes. doi:10.1111/1753-0407.12483. PMID 27625010.
↑ Brorsson CA, Pociot F, Type 1 Diabetes Genetics Consortium. Shared genetic basis for type 1 diabetes, islet autoantibodies, and autoantibodies associated with other immune-mediated diseases in families with type 1 diabetes. Diabetes Care 2015; 38 (suppl 3): S8–13.
↑ Ahlqvist E, van Zuydam NR, Groop LC, McCarthy MI. The genetics of diabetic complications. Nat Rev Nephrol 2015; 11: 277–87.
↑ Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14: 661–73.
↑ ^7.0 ^7.1 Type 1 Diabetes mellitus "Dennis Kasper, Anthony Fauci, Stephen Hauser, Dan Longo, J. Larry Jameson, Joseph Loscalzo"Harrison's Principles of Internal Medicine, 19e Accessed on December 27th,2016
↑ Paschou, Stavroula A; Papadopoulou-Marketou, Nektaria; Chrousos, George P; Kanaka-Gantenbein, Christina (2018). "On type 1 diabetes mellitus pathogenesis". Endocrine Connections. 7 (1): R38–R46. doi:10.1530/EC-17-0347. ISSN 2049-3614.
↑ ^9.0 ^9.1 Tuomi, T. (2005). "Type 1 and Type 2 Diabetes: What Do They Have in Common?". Diabetes. 54 (Supplement 2): S40–S45. doi:10.2337/diabetes.54.suppl_2.S40. ISSN 0012-1797.
↑ Volume 387, Issue 10035, 4–10 June 2016, Pages 2340–2348 Series Environmental risk factors for type 1 diabetes Prof Marian Rewers, MD^a, Prof Johnny Ludvigsson, MD
↑ Butalia S, Kaplan GG, Khokhar B, Rabi DM (2016). "Environmental Risk Factors and Type 1 Diabetes: Past, Present, and Future". Can J Diabetes. 40 (6): 586–593. doi:10.1016/j.jcjd.2016.05.002. PMID 27545597.
↑ Jaberi-Douraki M, Pietropaolo M, Khadra A (2015). "Continuum model of T-cell avidity: Understanding autoreactive and regulatory T-cell responses in type 1 diabetes". J Theor Biol. 383: 93–105. doi:10.1016/j.jtbi.2015.07.032. PMC 4567915. PMID 26271890.
↑ Rydén A, Ludvigsson J, Fredrikson M, Faresjö M (2014). "General immune dampening is associated with disturbed metabolism at diagnosis of type 1 diabetes". Pediatr Res. 75 (1–1): 45–50. doi:10.1038/pr.2013.167. PMID 24105410.
↑ Type 1 Diabetes mellitus "Dennis Kasper, Anthony Fauci, Stephen Hauser, Dan Longo, J. Larry Jameson, Joseph Loscalzo"Harrison's Principles of Internal Medicine, 19e Accessed on December 27th,2016
↑ Paschou, Stavroula A; Papadopoulou-Marketou, Nektaria; Chrousos, George P; Kanaka-Gantenbein, Christina (2018). "On type 1 diabetes mellitus pathogenesis". Endocrine Connections. 7 (1): R38–R46. doi:10.1530/EC-17-0347. ISSN 2049-3614.
↑ Ellis TM, Schatz DA, Ottendorfer EW, Lan MS, Wasserfall C, Salisbury PJ; et al. (1998). "The relationship between humoral and cellular immunity to IA-2 in IDDM". Diabetes. 47 (4): 566–9. doi:10.2337/diabetes.47.4.566. PMID 9568688.
↑ Witek PR, Witek J, Pańkowska E (2012). "[Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management]". Med Wieku Rozwoj. 16 (1): 23–34. PMID 22516771.
↑ Nederstigt, C; Uitbeijerse, B S; Janssen, L G M; Corssmit, E P M; de Koning, E J P; Dekkers, O M (2019). "Associated auto-immune disease in type 1 diabetes patients: a systematic review and meta-analysis". European Journal of Endocrinology. 180 (2): 135–144. doi:10.1530/EJE-18-0515. ISSN 0804-4643.

Template:WH Template:WS Template:WH Template:WS

Template:WH Template:WS

[pmid23890997-1] 1.0 ^1.1 ^1.2 ^1.3 Atkinson MA, Eisenbarth GS, Michels AW (2014). "Type 1 diabetes". Lancet. 383 (9911): 69–82. doi:10.1016/S0140-6736(13)60591-7. PMC 4380133. PMID 23890997.

[pmid27302272-2] Pociot F, Lernmark Å (2016). "Genetic risk factors for type 1 diabetes". Lancet. 387 (10035): 2331–9. doi:10.1016/S0140-6736(16)30582-7. PMID 27302272.

[pmid27625010-3] Safari-Alighiarloo N, Taghizadeh M, Tabatabaei SM, Shahsavari S, Namaki S, Khodakarim S; et al. (2016). "Identification of new key genes for type 1 diabetes through construction and analysis of protein-protein interaction networks based on blood and pancreatic islet transcriptomes". J Diabetes. doi:10.1111/1753-0407.12483. PMID 27625010.

[4] Brorsson CA, Pociot F, Type 1 Diabetes Genetics Consortium. Shared genetic basis for type 1 diabetes, islet autoantibodies, and autoantibodies associated with other immune-mediated diseases in families with type 1 diabetes. Diabetes Care 2015; 38 (suppl 3): S8–13.

[5] Ahlqvist E, van Zuydam NR, Groop LC, McCarthy MI. The genetics of diabetic complications. Nat Rev Nephrol 2015; 11: 277–87.

[6] Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14: 661–73.

[:0-7] 7.0 ^7.1 Type 1 Diabetes mellitus "Dennis Kasper, Anthony Fauci, Stephen Hauser, Dan Longo, J. Larry Jameson, Joseph Loscalzo"Harrison's Principles of Internal Medicine, 19e Accessed on December 27th,2016

[PaschouPapadopoulou-Marketou2018-8] Paschou, Stavroula A; Papadopoulou-Marketou, Nektaria; Chrousos, George P; Kanaka-Gantenbein, Christina (2018). "On type 1 diabetes mellitus pathogenesis". Endocrine Connections. 7 (1): R38–R46. doi:10.1530/EC-17-0347. ISSN 2049-3614.

[Tuomi2005-9] 9.0 ^9.1 Tuomi, T. (2005). "Type 1 and Type 2 Diabetes: What Do They Have in Common?". Diabetes. 54 (Supplement 2): S40–S45. doi:10.2337/diabetes.54.suppl_2.S40. ISSN 0012-1797.

[10] Volume 387, Issue 10035, 4–10 June 2016, Pages 2340–2348 Series Environmental risk factors for type 1 diabetes Prof Marian Rewers, MD^a, Prof Johnny Ludvigsson, MD

[pmid27545597-11] Butalia S, Kaplan GG, Khokhar B, Rabi DM (2016). "Environmental Risk Factors and Type 1 Diabetes: Past, Present, and Future". Can J Diabetes. 40 (6): 586–593. doi:10.1016/j.jcjd.2016.05.002. PMID 27545597.

[pmid26271890-12] Jaberi-Douraki M, Pietropaolo M, Khadra A (2015). "Continuum model of T-cell avidity: Understanding autoreactive and regulatory T-cell responses in type 1 diabetes". J Theor Biol. 383: 93–105. doi:10.1016/j.jtbi.2015.07.032. PMC 4567915. PMID 26271890.

[pmid24105410-13] Rydén A, Ludvigsson J, Fredrikson M, Faresjö M (2014). "General immune dampening is associated with disturbed metabolism at diagnosis of type 1 diabetes". Pediatr Res. 75 (1–1): 45–50. doi:10.1038/pr.2013.167. PMID 24105410.

[14] Type 1 Diabetes mellitus "Dennis Kasper, Anthony Fauci, Stephen Hauser, Dan Longo, J. Larry Jameson, Joseph Loscalzo"Harrison's Principles of Internal Medicine, 19e Accessed on December 27th,2016

[PaschouPapadopoulou-Marketou20182-15] Paschou, Stavroula A; Papadopoulou-Marketou, Nektaria; Chrousos, George P; Kanaka-Gantenbein, Christina (2018). "On type 1 diabetes mellitus pathogenesis". Endocrine Connections. 7 (1): R38–R46. doi:10.1530/EC-17-0347. ISSN 2049-3614.

[pmid9568688-16] Ellis TM, Schatz DA, Ottendorfer EW, Lan MS, Wasserfall C, Salisbury PJ; et al. (1998). "The relationship between humoral and cellular immunity to IA-2 in IDDM". Diabetes. 47 (4): 566–9. doi:10.2337/diabetes.47.4.566. PMID 9568688.

[pmid22516771-17] Witek PR, Witek J, Pańkowska E (2012). "[Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management]". Med Wieku Rozwoj. 16 (1): 23–34. PMID 22516771.

[NederstigtUitbeijerse2019-18] Nederstigt, C; Uitbeijerse, B S; Janssen, L G M; Corssmit, E P M; de Koning, E J P; Dekkers, O M (2019). "Associated auto-immune disease in type 1 diabetes patients: a systematic review and meta-analysis". European Journal of Endocrinology. 180 (2): 135–144. doi:10.1530/EJE-18-0515. ISSN 0804-4643.

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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Diabetes mellitus type 1}}
-{{Diabetes mellitus}}
-{{CMG}}; {{AE}} [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com]; {{CZ}}
+{{CMG}}; {{AE}} [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com]; {{CZ}}{{VD}} {{Anahita}}
 ==Overview==
+[[Type 1 diabetes]] is a disorder characterized by abnormally high [[blood sugar]] levels. [[Type 1 diabetes]] is the result of interactions of [[Genetics|genetic]], [[Environmental Science|environmental]], and [[Immunology|immunologic]] factors that ultimately lead to the destruction of the pancreatic [[Beta cell|beta cells]] and [[insulin]] deficiency. Currently, 58 [[Genomics|genomic regions]] are known to be associated with [[Type 1 diabetes|type 1 DM]]. There are [[Environmental Science|environmental]] factors that can play a protective role in [[Type 1 diabetes]] like higher maternal [[vitamin D]], probiotic and [[omega-3 fatty acids]] intake during [[Obstetrics|prenatal]] period. Conversely, [[Environmental Science|environmental]] factors such as [[caesarean section]], [[Congenital rubella syndrome|congenital rubella]], maternal enteroviral infection and abnormal [[microbiome]] are among [[Environmental Science|environmental]] factors that are able to trigger [[Type 1 diabetes|Type 1 DM]]. Furthermore, some immunological components are responsible for [[Type 1 diabetes|type 1 DM]] pathogenesis.
 ==Pathophysiology==
-The cause of Type 1 diabetes is still not understood. Type 1 diabetes could be a virally induced autoimmune response. Autoimmunity is a condition where one's own immune system "attacks" structures in one's own body either destroying the tissue or decreasing its functionality. In the proposed scenario, pancreatic [[beta cells]] in the [[Islets of Langerhans]] are destroyed or damaged sufficiently to abolish endogenous [[insulin]] production. This etiology makes type 1 distinct from type 2 diabetes mellitus. It should also be noted that the use of insulin in a patient's diabetes treatment protocol does ''not'' render them as having type 1 diabetes, the type of diabetes a patient has is determined only by disease etiology. The [[autoimmune]] attack may be triggered by reaction to an infection, for example by one of the viruses of the [[Coxsackie B4 virus|Coxsackie virus]] family or German measles, although the evidence is inconclusive.
+*[[Type 1 diabetes]] is a disorder characterized by abnormally high [[blood sugar]] levels.
+*In this form of [[diabetes]], specialized [[Cell (biology)|cells]] in the [[pancreas]] called [[Beta cells|beta cells]] stop producing [[insulin]]. [[Insulin]] controls how much [[glucose]] (a type of [[sugar]]) is passed from the [[blood]] into [[Cell (biology)|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]].
+*Possible [[thymus]] and [[bone marrow]] [[deficiency]] includes defective thymic selection, faulty self [[antigen]] presentation, thymic [[Variable number tandem repeat|VNTR]] and Aire [[Gene expression|expression]], mobilopathy and defective [[lymphocyte]] precursors are some possible proceeding triggers that underlie [[Diabetes Mellitus|type 1 DM]].<ref name="pmid23890997">{{cite journal| author=Atkinson MA, Eisenbarth GS, Michels AW| title=Type 1 diabetes. | journal=Lancet | year= 2014 | volume= 383 | issue= 9911 | pages= 69-82 | pmid=23890997 | doi=10.1016/S0140-6736(13)60591-7 | pmc=4380133 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23890997  }} </ref>
+===Pathogenesis===
+*[[Diabetes Mellitus|Type 1 DM]] is the result of interactions of [[Genetics|genetic]], [[Environmental Science|environmental]], and [[Immunology|immunologic]] factors that ultimately lead to the destruction of the [[pancreas|pancreatic]] [[beta cells]] and [[insulin]] deficiency.
+*Concordance of [[Diabetes Mellitus|type 1 DM]] in identical [[twins]] ranges between 40 and 60%, indicating  the presence of additional modifying factors.<br><br>
+[[File:Type-1-diabetes pathophysiology.jpg|600px|Type-1-diabetes pathophysiology|center]]<br><br>
-This vulnerability is not shared by everyone, for not everyone infected by these organisms develops Type 1 diabetes. This has suggested a genetic vulnerability<ref>{{cite web |url="http://jcem.endojournals.org/cgi/content/abstract/82/1/143" |title="CTLA4 Alanine-17 Confers Genetic Susceptibility to Graves’ Disease and to Type 1 Diabetes Mellitus" |accessdate=2008-02-06 |last="Donner"|first="Horst" |coauthors="Harald Rau, Paul G. Walfish, Jens Braun, Thorsten Siegmund, Reinhard Finke, Jürgen Herwig, Klaus H. Usadel and Klaus Badenhoop" |date="2007" |work="The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 143-146"|publisher="The Journal of Clinical Endocrinology & Metabolism"}}</ref> and there is indeed an observed inherited tendency to develop Type 1. It has been traced to particular [[human leukocyte antigen|HLA]] phenotypes, though the connection between them and the triggering of an auto-immune reaction is poorly understood.
+===Genetics===
+*[[Genes]] associated with [[Diabetes mellitus]] include the following: <ref name="pmid27302272">{{cite journal| author=Pociot F, Lernmark Å| title=Genetic risk factors for type 1 diabetes. | journal=Lancet | year= 2016 | volume= 387 | issue= 10035 | pages= 2331-9 | pmid=27302272 | doi=10.1016/S0140-6736(16)30582-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27302272  }}</ref><ref name="pmid27625010">{{cite journal| author=Safari-Alighiarloo N, Taghizadeh M, Tabatabaei SM, Shahsavari S, Namaki S, Khodakarim S et al.| title=Identification of new key genes for type 1 diabetes through construction and analysis of protein-protein interaction networks based on blood and pancreatic islet transcriptomes. | journal=J Diabetes | year= 2016 | volume=  | issue=  | pages=  | pmid=27625010 | doi=10.1111/1753-0407.12483 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27625010  }}</ref><ref>Brorsson CA, Pociot F, Type 1 Diabetes Genetics Consortium. Shared genetic basis for type 1 diabetes, islet autoantibodies, and autoantibodies associated with other immune-mediated diseases in families with type 1 diabetes. Diabetes Care 2015; 38 (suppl 3): S8–13.</ref><ref>Ahlqvist E, van Zuydam NR, Groop LC, McCarthy MI. The genetics of diabetic complications. Nat Rev Nephrol 2015; 11: 277–87.</ref><ref>Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14: 661–73.</ref><ref name=":0">Type 1 Diabetes mellitus "Dennis Kasper, Anthony Fauci, Stephen Hauser, Dan Longo, J. Larry Jameson, Joseph Loscalzo"Harrison's Principles of Internal Medicine, 19e Accessed on December 27th,2016</ref>
+** Currently, 58 [[Genomics|genomic regions]] are known to be associated with [[Type 1 diabetes|Type 1 DM]].
+** Major susceptibility [[gene]] for [[Type 1 diabetes|type 1 diabetes]] is located on [[HLA]] region of [[Chromosome 6 (human)|chromosome 6]]. It accounts for  40-50% of the genetic risk for [[Type 1 diabetes|type 1 diabetes]]. This region encodes for class  II [[major histocompatibility complex]] ([[major histocompatibility complex|MHC]]) [[molecule|molecules]]. [[major histocompatibility complex]] ([[major histocompatibility complex|MHC]]) [[molecule|molecules]] play an important role in presenting [[antigen]] to [[T helper cell]] and initiating immune response.
+** Other major susceptibility [[genes]] which were associated with [[Type 1 diabetes|Type 1 DM]] include [[polymorphisms]] in the [[promoter region]] of the [[insulin]] [[gene]], the [[CTLA-4|CTLA-4 gene]], [[IL-2|interleukin 2 receptor]], [[Insulin]]-[[Variable number tandem repeat|VNTR]], AIRE, [[FOXP3|FoxP3]], [[STAT3]], HIP14 and [[PTPN22]] etc.<ref name="PaschouPapadopoulou-Marketou2018">{{cite journal|last1=Paschou|first1=Stavroula A|last2=Papadopoulou-Marketou|first2=Nektaria|last3=Chrousos|first3=George P|last4=Kanaka-Gantenbein|first4=Christina|title=On type 1 diabetes mellitus pathogenesis|journal=Endocrine Connections|volume=7|issue=1|year=2018|pages=R38–R46|issn=2049-3614|doi=10.1530/EC-17-0347}}</ref><ref name="Tuomi2005">{{cite journal|last1=Tuomi|first1=T.|title=Type 1 and Type 2 Diabetes: What Do They Have in Common?|journal=Diabetes|volume=54|issue=Supplement 2|year=2005|pages=S40–S45|issn=0012-1797|doi=10.2337/diabetes.54.suppl_2.S40}}</ref>
+** 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 diabetes|type 1 DM]] (<1%) and appears to provide protection from [[Type 1 diabetes|type 1 diabetes]].
+** There is a relationship between some [[human leukocyte antigen|human leukocyte antigens]] ([[human leukocyte antigen|HLA]]) and [[Type 1 diabetes|type 1 diabetes]], such as DQB1, DQA1, and DRB1. There are some supporting data on DR4-linked haplotypes transmission from [[Diabetes mellitus type 2|type 2 diabetes]] parents to offspring with [[Type 1 diabetes|type 1 diabetes]]. Patients with latent autoimmune diabetes of adults also have been related to [[human leukocyte antigen|HLA]] alleles DQB1*0302 and 02. <ref name="Tuomi2005">{{cite journal|last1=Tuomi|first1=T.|title=Type 1 and Type 2 Diabetes: What Do They Have in Common?|journal=Diabetes|volume=54|issue=Supplement 2|year=2005|pages=S40–S45|issn=0012-1797|doi=10.2337/diabetes.54.suppl_2.S40}}</ref>
+<SMALL><SMALL>
+{| class="wikitable"
+![[Genes]] important to [[Type 1 diabetes|type 1 diabetes]] [[pathogenesis]]
+!Region
+!Odds ratio
+!Gene funtion
+|-
+| colspan="1" rowspan="1" |PTPN22
+| colspan="1" rowspan="1" |1p13.2
+| colspan="1" rowspan="1" |1·89
+| colspan="1" rowspan="1" |Regulation of innate immune response, [[T cell]] activation, and [[natural killer cell]] [[Cell growth|proliferation]]
+|-
+| colspan="1" rowspan="1" |IL10
+| colspan="1" rowspan="1" |1q32.1
+| colspan="1" rowspan="1" |0·86
+| colspan="1" rowspan="1" |[[Cytokine|Cytokines]] and inflammatory response
+|-
+| colspan="1" rowspan="1" |AFF3
+| colspan="1" rowspan="1" |2q11.2
+| colspan="1" rowspan="1" |1·11
+| colspan="1" rowspan="1" |Regulation of [[Transcription (genetics)|transcription]]
+|-
+| colspan="1" rowspan="1" |IFIH1
+| colspan="1" rowspan="1" |2q24.2
+| colspan="1" rowspan="1" |0·85
+·85
+·59
+| colspan="1" rowspan="1" |[[Innate immune system]] [[NF-κB]] activation
+|-
+| colspan="1" rowspan="1" |STAT4
+| colspan="1" rowspan="1" |2q32.3
+| colspan="1" rowspan="1" |1·10§
+| colspan="1" rowspan="1" |[[Cytokine]]-mediated signalling pathway
+|-
+| colspan="1" rowspan="1" |CTLA4
+| colspan="1" rowspan="1" |2q33.2
+| colspan="1" rowspan="1" |0·82
+·84
+| colspan="1" rowspan="1" |[[T cell]] activation
+|-
+| colspan="1" rowspan="1" |CCR5
+| colspan="1" rowspan="1" |3p21.31
+| colspan="1" rowspan="1" |0·85
+| colspan="1" rowspan="1" |[[T helper cell|Th1 cell]] development and [[chemokine]]-mediated signalling pathway
+|-
+| colspan="1" rowspan="1" |IL21, IL2
+| colspan="1" rowspan="1" |4q27
+| colspan="1" rowspan="1" |1·13
+·12
+·14
+·15
+| colspan="1" rowspan="1" |[[cytokine|Cytokines]] and inflammatory response and [[T helper cell|Th1 cell]] or [[T helper cell|Th2 cell]] [[differentiation]]
+|-
+| colspan="1" rowspan="1" |IL7R
+| colspan="1" rowspan="1" |5p13.2
+| colspan="1" rowspan="1" |1·11
+| colspan="1" rowspan="1" |[[T cell]]-mediated [[cytotoxicity]], [[immunoglobulin]] production, and [[antigen]] binding
+|-
+| colspan="1" rowspan="1" |BACH2
+| colspan="1" rowspan="1" |6q15
+| colspan="1" rowspan="1" |1·10
+·88
+·20
+| colspan="1" rowspan="1" |[[Transcription (genetics)|transcription]]
+|-
+| colspan="1" rowspan="1" |TNFAIP3
+| colspan="1" rowspan="1" |6q23.3
+| colspan="1" rowspan="1" |1·12
+| colspan="1" rowspan="1" |Inflammatory response
+|-
+| colspan="1" rowspan="1" |TAGAP
+| colspan="1" rowspan="1" |6q25.3
+| colspan="1" rowspan="1" |0·92
+| colspan="1" rowspan="1" |[[Signal transduction]]
+|-
+| colspan="1" rowspan="1" |IKZF1
+| colspan="1" rowspan="1" |7p12.2
+| colspan="1" rowspan="1" |0·89
+| colspan="1" rowspan="1" |Immune-cell regulation
+|-
+| colspan="1" rowspan="1" |GLIS3
+| colspan="1" rowspan="1" |9p24.2
+| colspan="1" rowspan="1" |1·12
+·12
+·90
+| colspan="1" rowspan="1" |Regulation of [[Transcription (genetics)|transcription]]
+|-
+| colspan="1" rowspan="1" |IL2RA
+| colspan="1" rowspan="1" |10p15.1
+| colspan="1" rowspan="1" |1·20
+·73
+·52
+·62
+·82
+| colspan="1" rowspan="1" |Alternative [[Messenger RNA|mRNA]] splicing [[T helper cell|Th1]] or [[T helper cell|Th2 cell]] [[differentiation]]
+|-
+| colspan="1" rowspan="1" |PRKCQ
+| colspan="1" rowspan="1" |10p15.1
+| colspan="1" rowspan="1" |0·69
+| colspan="1" rowspan="1" |Apoptotic process, inflammatory response, [[innate immune response]], and [[T cell]]-receptor signalling pathway
+|-
+| colspan="1" rowspan="1" |NRP1
+| colspan="1" rowspan="1" |10p11.22
+| colspan="1" rowspan="1" |1·11
+| colspan="1" rowspan="1" |[[Signal transduction]]
+|-
+| colspan="1" rowspan="1" |INS
+| colspan="1" rowspan="1" |11p15.5
+| colspan="1" rowspan="1" |0·42
+·63
+·63
+| colspan="1" rowspan="1" |[[Insulin]] signalling pathway
+|-
+| colspan="1" rowspan="1" |BAD
+| colspan="1" rowspan="1" |11q13.1
+| colspan="1" rowspan="1" |0·92
+| colspan="1" rowspan="1" |[[Apoptosis]]
+|-
+| colspan="1" rowspan="1" |CD69
+| colspan="1" rowspan="1" |12p13.31
+| colspan="1" rowspan="1" |0·87
+·10
+| colspan="1" rowspan="1" |[[Signal transduction]]
+|-
+| colspan="1" rowspan="1" |ITGB7
+| colspan="1" rowspan="1" |12q13.13
+| colspan="1" rowspan="1" |1·19
+| colspan="1" rowspan="1" |Response to [[virus]] and regulation of immune response
+|-
+| colspan="1" rowspan="1" |ERBB3
+| colspan="1" rowspan="1" |12q13.2
+| colspan="1" rowspan="1" |1·25
+| colspan="1" rowspan="1" |Regulation of [[Transcription (genetics)|transcription]], [[Innate immune system|innate immune response]], and [[lipid metabolism]]
+|-
+| colspan="1" rowspan="1" |CYP27B1
+| colspan="1" rowspan="1" |12q14.1
+| colspan="1" rowspan="1" |0·82
+| colspan="1" rowspan="1" |[[lipid metabolism|Metabolism of lipids]], [[lipoprotein|lipoproteins]], steroid [[hormone|hormones]], and [[vitamin D]]
+|-
+| colspan="1" rowspan="1" |SH2B3
+| colspan="1" rowspan="1" |12q24.12
+| colspan="1" rowspan="1" |1·24
+·76
+·76
+| colspan="1" rowspan="1" |[[Signal transduction]]
+|-
+| colspan="1" rowspan="1" |GPR183
+| colspan="1" rowspan="1" |13q32.3
+| colspan="1" rowspan="1" |1·12
+| colspan="1" rowspan="1" |[[Humoral immunity|Humoral immune response]]
+|-
+| colspan="1" rowspan="1" |DLK1
+| colspan="1" rowspan="1" |14q32.2
+| colspan="1" rowspan="1" |0·88
+·90
+| colspan="1" rowspan="1" |Regulation of [[gene expression]]
+|-
+| colspan="1" rowspan="1" |RASGRP1
+| colspan="1" rowspan="1" |15q14
+| colspan="1" rowspan="1" |0·85
+·15
+| colspan="1" rowspan="1" |Inflammatory response to [[antigen|antigenic]] stimulus and [[cytokine]] production
+|-
+| colspan="1" rowspan="1" |CTSH
+| colspan="1" rowspan="1" |15q25.1
+| colspan="1" rowspan="1" |0·81
+·78
+·90
+| colspan="1" rowspan="1" |Immune response-regulating signalling pathway [[T cell]]-mediated [[cytotoxicity]] adaptive immune response
+|-
+| colspan="1" rowspan="1" |CLEC16A
+| colspan="1" rowspan="1" |16p13.13
+| colspan="1" rowspan="1" |0·83
+·82
+·14
+| colspan="1" rowspan="1" |Unknown
+|-
+| colspan="1" rowspan="1" |IL27
+| colspan="1" rowspan="1" |16p11.2
+| colspan="1" rowspan="1" |1·19
+·90
+·24
+| colspan="1" rowspan="1" |Inflammatory response and regulation of defence response to [[virus]]
+|-
+| colspan="1" rowspan="1" |ORMDL3
+| colspan="1" rowspan="1" |17q12
+| colspan="1" rowspan="1" |0·90
+| colspan="1" rowspan="1" |[[Protein]] binding
+|-
+| colspan="1" rowspan="1" |PTPN2
+| colspan="1" rowspan="1" |18p11.21
+| colspan="1" rowspan="1" |1·20
+| colspan="1" rowspan="1" |[[Cytokine]] signalling and [[B cell]] and [[T cell]] [[differentiation]]
+|-
+| colspan="1" rowspan="1" |CD226
+| colspan="1" rowspan="1" |18q22.2
+| colspan="1" rowspan="1" |1·13
+| colspan="1" rowspan="1" |Immunoregulation and [[adaptive immune system]]
+|-
+| colspan="1" rowspan="1" |TYK2
+| colspan="1" rowspan="1" |19p13.2
+| colspan="1" rowspan="1" |0·82
+·87
+·67
+| colspan="1" rowspan="1" |[[Cytokine]]-mediated signalling pathway, intracellular [[signal transduction]], and type I [[interferon]] signalling pathway
+|-
+| colspan="1" rowspan="1" |FUT2
+| colspan="1" rowspan="1" |19q13.33
+| colspan="1" rowspan="1" |0·87
+·75
+·87
+| colspan="1" rowspan="1" |Metabolic pathways
+|-
+| colspan="1" rowspan="1" |UBASH3A
+| colspan="1" rowspan="1" |21q22.3
+| colspan="1" rowspan="1" |1·16
+| colspan="1" rowspan="1" |Regulation of [[cytokine]] production
+Regulation of [[T cel]]l receptor signalling pathway
+|-
+| colspan="1" rowspan="1" |C1QTNF6
+| colspan="1" rowspan="1" |22q12.3
+| colspan="1" rowspan="1" |1·11
+| colspan="1" rowspan="1" |[[B cell]] receptor signalling pathway, [[chemokine]] signalling pathway, and [[natural killer cell]]-mediated [[cytotoxicity]]
+|}
+</SMALL></SMALL>
-Some researchers believe that the autoimmune response is influenced by [[antibodies]] against cow's milk proteins. A large retrospective controlled study published in 2006 strongly suggests that infants who were never breast fed had twice the risk for developing Type 1 diabetes as infants who were breast fed for at least three months. The mechanism, if any, is not understood. No connection has been established between [[autoantibody|autoantibodies]], antibodies to cow's milk proteins, and Type 1 diabetes. A subtype of Type 1 (identifiable by the presence of antibodies against beta cells) typically develops slowly and so is often confused with Type 2. In addition, a small proportion of Type 1 cases have the hereditary condition [[maturity onset diabetes of the young]] (MODY) which can also be confused with Type 2.
+=== Environment ===
+*Environmental factors were found to influence [[Diabetes mellitus type 1]] through various pathways. Some were found to confer protection against [[Diabetes mellitus type 1]], while others were associated with the progression and promotion of [[Diabetes mellitus type 1]], including:<ref>Volume 387, Issue 10035, 4–10 June 2016, Pages 2340–2348
+Series
+Environmental risk factors for type 1 diabetes
+Prof Marian Rewers, MD<sup>a</sup>,
+Prof Johnny Ludvigsson, MD
+</ref><ref name="pmid27545597">{{cite journal| author=Butalia S, Kaplan GG, Khokhar B, Rabi DM| title=Environmental Risk Factors and Type 1 Diabetes: Past, Present, and Future. | journal=Can J Diabetes | year= 2016 | volume= 40 | issue= 6 | pages= 586-593 | pmid=27545597 | doi=10.1016/j.jcjd.2016.05.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27545597  }}</ref>
+{| class="wikitable"
+!
+!Triggers
+!Protective factors
+|-
+|[[Obstetrics|Prenatal]] triggers
+|
-[[Vitamin D]] in doses of 2000 IU per day given during the first year of a child's life has been connected in one study in Northern Finland (where intrinsic production of Vitamin D is low due to low natural light levels) with a reduction in the risk of getting Type 1 diabetes later in life (by 80%).
+* [[Congenital rubella|Congenital rubell]]<nowiki/>[[Congenital rubella|a]]
+* Maternal [[Enterovirus|Enteroviral]] [[infection]]
+* [[Caesarean section|Cesarean section]]
+* Higher [[birth weight]]
+* Older maternal age
+* Low maternal intake of vegetables
+|
+* Higher maternal [[vitamin D]] intake or [[vitamin D]] concentrations in late [[pregnancy]]
+|-
+|[[Postnatal]] triggers
+|
+* [[Enterovirus|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 acid|omega-3 fatty acids]]
+* introduction of solid foods while [[breastfeeding]] and after age 4 months
+|-
+|Promoters of progression
+|
+* Persistent or recurrent [[Enterovirus|Enteroviral infections]]
+* [[Overweight]] or increased height velocity
+* High glycemic load, [[fructose]] intake
+* Dietary [[nitrates]] or [[Nitrosamine|nitrosamines]]
+* [[Puberty]]
+* [[Steroid]] [[treatment]]
+* [[Insulin resistance]]
+* [[Stress (medicine)|Psychological stress]]
+|
+|}
-Some suggest that Vitamin D3 (one of several related chemicals with Vitamin D activity) may be an important pathogenic factor in Type 1 diabetes independent of geographical latitude.
+=== Immunological ===
+*Several studies have found that abnormalities in the [[Humoral immunity|humoral]] and [[Cell-mediated immunity|cellular arm]] of the [[immune system]], were identified to be associated with [[Diabetes mellitus type 1]], these include:<ref name="pmid26271890">{{cite journal| author=Jaberi-Douraki M, Pietropaolo M, Khadra A| title=Continuum model of T-cell avidity: Understanding autoreactive and regulatory T-cell responses in type 1 diabetes. | journal=J Theor Biol | year= 2015 | volume= 383 | issue=  | pages= 93-105 | pmid=26271890 | doi=10.1016/j.jtbi.2015.07.032 | pmc=4567915 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26271890  }}</ref><ref name="pmid24105410">{{cite journal| author=Rydén A, Ludvigsson J, Fredrikson M, Faresjö M| title=General immune dampening is associated with disturbed metabolism at diagnosis of type 1 diabetes. | journal=Pediatr Res | year= 2014 | volume= 75 | issue= 1-1 | pages= 45-50 | pmid=24105410 | doi=10.1038/pr.2013.167 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24105410  }}</ref><ref>Type 1 Diabetes mellitus "Dennis Kasper, Anthony Fauci, Stephen Hauser, Dan Longo, J. Larry Jameson, Joseph Loscalzo"Harrison's Principles of Internal Medicine, 19e Accessed on December 27th,2016</ref><ref name="PaschouPapadopoulou-Marketou20182">{{cite journal|last1=Paschou|first1=Stavroula A|last2=Papadopoulou-Marketou|first2=Nektaria|last3=Chrousos|first3=George P|last4=Kanaka-Gantenbein|first4=Christina|title=On type 1 diabetes mellitus pathogenesis|journal=Endocrine Connections|volume=7|issue=1|year=2018|pages=R38–R46|issn=2049-3614|doi=10.1530/EC-17-0347}}</ref><ref name="pmid9568688">{{cite journal| author=Ellis TM, Schatz DA, Ottendorfer EW, Lan MS, Wasserfall C, Salisbury PJ | display-authors=etal| title=The relationship between humoral and cellular immunity to IA-2 in IDDM. | journal=Diabetes | year= 1998 | volume= 47 | issue= 4 | pages= 566-9 | pmid=9568688 | doi=10.2337/diabetes.47.4.566 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9568688  }}</ref><ref name="pmid23890997">{{cite journal| author=Atkinson MA, Eisenbarth GS, Michels AW| title=Type 1 diabetes. | journal=Lancet | year= 2014 | volume= 383 | issue= 9911 | pages= 69-82 | pmid=23890997 | doi=10.1016/S0140-6736(13)60591-7 | pmc=4380133 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23890997  }} </ref>
+** Deficiency in immune regulation, such as effector [[T cell|T cells]] (Teff) resistance to Regulatory [[T cell|T cells]] (Treg) or Regulatory [[T cell|T cells]] (Treg) abnormalities
+** [[Islets of Langerhans|Islet cell]] [[Autoantibody|autoantibodies]]
+** Defective cellular trafficking and adhesion
+** Activated [[lymphocytes]] in the [[Islets of Langerhans|islets]], peripancreatic [[lymph node|lymph nodes]], and systemic circulation
+** Chronic activation of [[Antigen-presenting cell|Antigen-presenting cells]]
+** [[T lymphocytes]] that proliferate when stimulated with [[Islets of Langerhans|islet]] [[protein|proteins]]
+** Release of [[cytokines]] within the insulitis
+** An [[enzyme]] named [[Glutamate decarboxylase|glutamic acid decarboxylase]] ([[Glutamate decarboxylase|GAD65]]) found in [[Beta cell|β cells]] has similar [[amino acid sequence]] with the [[Coxsackie virus|Coxsackie]] B4 P2-C [[protein]], which augments the response of [[humoral immunity]].
+** [[Autoantibody|Autoantibodies]] against IA-2 and [[zinc]] transporter (ZnT8) have been positive in 60% and 60-80% of [[Diabetes mellitus type 1]] at the time of [[Diagnosis|diagnose]], respectively.
-Some chemicals and drugs specifically destroy pancreatic cells. Vacor (N-3-pyridylmethyl-N'-p-nitrophenyl urea), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in Type 1 diabetes after accidental or intentional ingestion. Vacor was withdrawn from the U.S. market in 1979. Zanosar is the trade name for [[streptozotocin]], an [[antibiotic]] and [[antineoplastic]] agent used in chemotherapy for [[pancreatic cancer]], that kills beta cells, resulting in loss of insulin production.
+=== Associated conditions ===
+* Conditions associated with [[diabetes mellitus type 1]] include:<ref name=":0" /><ref name="pmid22516771">{{cite journal| author=Witek PR, Witek J, Pańkowska E| title=[Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management]. | journal=Med Wieku Rozwoj | year= 2012 | volume= 16 | issue= 1 | pages= 23-34 | pmid=22516771 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22516771  }}</ref>
+** [[Autoimmunity|Autoimmune]] [[thyroid disease]] (ATD)
+** [[Celiac disease|Celiac disease]] ([[Celiac disease|CD]])
+** [[Gastritis|Autoimmune gastritis]] (AIG)
+** [[Pernicious anemia]] ([[Pernicious anemia|PA]])
+** [[Vitiligo]]
+** [[Addison's disease]]
+* The following table is a summary of some associated [[Autoimmunity|autoimmune]] conditions and their prevalence among [[type 1 diabetes mellitus|type 1 diabetic]] patients and normal population.<ref name="NederstigtUitbeijerse2019">{{cite journal|last1=Nederstigt|first1=C|last2=Uitbeijerse|first2=B S|last3=Janssen|first3=L G M|last4=Corssmit|first4=E P M|last5=de Koning|first5=E J P|last6=Dekkers|first6=O M|title=Associated auto-immune disease in type 1 diabetes patients: a systematic review and meta-analysis|journal=European Journal of Endocrinology|volume=180|issue=2|year=2019|pages=135–144|issn=0804-4643|doi=10.1530/EJE-18-0515}}</ref>
+{| class="wikitable"
+|+
+!Associated [[Autoimmunity|autoimmune]] conditions
+![[Prevalence]] in patients with [[diabetes mellitus type 1]] (%)
+!95% [[Confidence interval|CI]]
+![[Prevalence]] in the general population (%)
+|-
+|[[Hypothyroidism]]
+|9.8
+|7.5–12.3
+|2–4.6
+|-
+|Positive [[Thyroid peroxidase|TPO]] and or [[Thyroglobulin|TG]] [[antibody|antibodies]]
+|18.9
+|17.2–20.6
+|Unknown
+|-
+|Positive [[Thyroid peroxidase|TPO]] [[antibody|antibodies]]
+|18.3
+|15.8–21.0
+|11.3–12.8
+|-
+|Positive [[Thyroglobulin|TG]] [[antibody|antibodies]]
+|12.3
+|10.0–14.9
+|10.4
+|-
+|[[Hyperthyroidism]]
+|1.3
+|0.9–1.8
+|1.0–4.0
+|-
+|Positive [[Thyrotropin receptor|TSH receptor]] [[antibody|antibodies]] and or Thyroid stimulating immunoglobulin
+|9.5
+|1.4–22.7
+|Unknown
+|-
+|[[Celiac disease]]
+|4.7
+|4.0–5.5
+|0.5–1.0
+|-
+|Presence of any [[gluten]] related [[antibody|antibodies]]
+|10.2
+|8.4–12.7
+|Unknown
+|-
+|Positive [[tissue transglutaminase]] [[antibody|antibodies]] ([[Immunoglobulin A|IgA]])
+|9.8
+|8.2–11.6
+|1.5
+|-
+|Positive [[tissue transglutaminase]] [[antibody|antibodies]] ([[Immunoglobulin A|IgA]]/[[Immunoglobulin G|IgG]])
+|9.8
+|8.4–11.3
+|2.1
+|-
+|Positive anti-endomysial [[antibody|antibodies]] ([[Immunoglobulin A|IgA]])
+|5.3
+|4.3–6.4
+|0.8
+|-
+|Positive antigliadin [[antibody|antibodies]] ([[Immunoglobulin A|IgA]])
+|9.7
+|5.1–15.5
+|1.6
+|-
+|Positive antigliadin [[antibody|antibodies]] ([[Immunoglobulin G|IgG]])
+|12.7
+|6.1–21.0
+|7.1
+|-
+|[[Pernicious anemia]]
+|4.3
+|1.6–8.2
+|0.2
+|-
+|Positive anti-[[parietal cell]] [[antibody|antibodies]]
+|9.3
+|5.4–14.1
+|3–10
+|-
+|[[Vitiligo]]
+|2.4
+|1.2–3.9
+|0.4
+|-
+|[[Adrenal insufficiency|Adrenal gland insufficiency]]
+|0.2
+|0.0–0.4
+|0.012
+|-
+|Positive anti-adrenal [[antibody|antibodies]] (AAA/21-OHab)
+|1.4
+|0.8–2.2
+|Unknown
+|}
-Other pancreatic problems, including trauma, [[pancreatitis]] or tumors (either malignant or benign), can also lead to loss of insulin production. The exact cause(s) of Type 1 diabetes are not yet fully understood, and research on those mentioned, and others, continues.
+==Gross Pathology==
+*On [[gross pathology]], [[pancreas]] may demonstrated the following changes:<ref name="pmid23890997">{{cite journal| author=Atkinson MA, Eisenbarth GS, Michels AW| title=Type 1 diabetes. | journal=Lancet | year= 2014 | volume= 383 | issue= 9911 | pages= 69-82 | pmid=23890997 | doi=10.1016/S0140-6736(13)60591-7 | pmc=4380133 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23890997  }} </ref>
+** Decreased overall weight and size
+** Dorsal region [[atrophy]]
+** Possible [[Hypertrophy (medical)|hypertrophy]] (related to hydrophic changes)
-In December 2006, researchers from Toronto [[Hospital for Sick Children]] revealed research that shows a link between type 1 diabetes and the immune and nervous system. Using mice, the researchers discovered that a control circuit exists between insulin-producing cells and their associated sensory (pain-related) nerves <ref>{{cite web |url=http://www.cbc.ca/canada/calgary/story/2006/12/14/diabetes-neuron.html |title=Canadian scientists reverse diabetes in mice |accessdate=2007-06-04 |format= |work=}}</ref>. It's being suggested that faulty nerves in the pancreas could be a cause of type 1 diabetes.
+==Microscopic Pathology==
+*On microscopic [[Histopathology|histopathological]] [[analysis]], the following changes can be detected in [[Islets of Langerhans|islet cells]]:<ref name="pmid23890997">{{cite journal| author=Atkinson MA, Eisenbarth GS, Michels AW| title=Type 1 diabetes. | journal=Lancet | year= 2014 | volume= 383 | issue= 9911 | pages= 69-82 | pmid=23890997 | doi=10.1016/S0140-6736(13)60591-7 | pmc=4380133 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23890997  }} </ref>
+** Insulitis
+** [[Beta cell]] loss due to [[necrosis]] or [[apoptosis]]
+** [[Major histocompatibility complex]] class one hyperexpression
+** Reduction in [[insulin]] in remnant [[Beta cell|beta cells]]
+** [[Interferon type I|Interferon alpha]] [[Gene expression|expression]] in [[Beta cell|beta cells]]
+** [[CD3 (immunology)|CD3]]-positive cells in [[Islets of Langerhans|Islet cell]]
 ==References==
+{{reflist|2}}{{WH}} {{WS}} {{WH}} {{WS}}
+__NOTOC__
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-[[Category:Needs content]]
-[[Category:Endocrinology]]
-[[Category:Emergency medicine]]
-[[Category:Primary care]]
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