Type 1 Diabetes Mellitus is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. Genetic factors are believed to be a major com- ponent for the development of type 1diabetes, but the con- cordance rate for the development of diabetes in identical twins is only about 40%, suggesting that non-genetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of type 1 diabetes mellitus.
Shashikiran Umakanth made this presentation at the "First Endocrine Update Program” – ENDO EGYPT 2015, from 17-20 December 2015 in the Historic City of Luxor, Egypt. This endocrine update was organised by the Egyptian Association of Endocrinology , Diabetes and Atherosclerosis (EAEDA) in collaboration with the Endocrine Society, USA.
1. Etiology of
Type 1 Diabetes Mellitus
Dr. Shashikiran Umakanth
Professor & Head
Department of Internal Medicine
Dr. TMA Pai Hospital - Udupi, MMMC
Manipal University, INDIA
2. Type 1 diabetes mellitus (T1DM)
Characterized by absolute insulin deficiency
Result of pancreatic beta cell destruction
Prone to ketosis
3. Etiology of T1DM
Genetic
predisposition
Islet
autoimmunity
Dysglycemia Onset of
T1DM
Orban T et al. Diabetes Care 2009;32(12):2269-2274
Environmental factors suggested by
Seasonality
Increasing incidence
Epidemics of T1DM
? Viral infections
Genetic factors alone cannot explain
etiology
Genetic markers
Can identify varying risk
Poor positive predictive value in the
absence of autoantibodies
Environmental
4. Models for Pathogenesis of T1DM
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
Atkinson MA. Diabetes. 2005;54:1253-1263.
▶ IAA - insulin autoantibodies
▶ GAD - glutamic acid
decarboxylase antibodies
▶ IA-2 (ICA512) - tyrosine
phosphatase antibodies
▶ ZnT8 - Zinc transporter 8
autoantibodies
▶ T cell assays - cellular
autoimmunity
6. HLA association with T1DM
About 50% of genetic risk for T1DM attributed to
HLA region
HLA-DR3/4 DQB1 genotype shown to be high-risk
for β-cell autoimmunity
More than 50 genes associated with T1DM
Dominant or recessive
Low penetrance
7. Familial clustering
Risk when first degree relatives have T1DM
Dizygous twin/
Non-twin sibling
8-15 %
Monozygous twin >50 % Father 12 %
Mother 6 %
Sibling with T1DM Parent with T1DM
Both parents
>30 %
>90 %*
10 %*
15 %*
15 %*
>75 %*
* For T2DM Warram. Genetics & Diabetes, Diabetes Information. Joslin Diabetes Center and Joslin Clinic
9. Geographic location
Striking geographic variability
0.73/100,000 in China
60/100,000 in Finland
Increasing incidence 3-5% per year
More common in Northern
hemisphere
Migrants from a low-incidence country have higher
incidence of the adopted country
Example: South Asian children in UK
Borchers AT et al. The geoepidemiology of type 1 diabetes. Autoimmun Rev. 2010 Mar;9(5):A355-65.
10. Seasonal incidence
In Northern hemisphere
Incidence declines in warm summer months
In Southern hemisphere
Incidence declines in warm December-January
? Climatic factor, Vitamin D?
? Related to school attendance, viral infections?
11. Viruses
β-cell infection Systemic infection
Autoimmune β-cell damage
T1DM
Direct cytolytic
effects
Indirect immune effects
• Viral antigen
expression
• β-cell antigens altered
• HLA antigens or
cytokines expressed
• Activation of immune
response
• Breakdown of immune
tolerance
• Molecular mimicry with β-cell
antigens
Possible mechanisms for
virus-induced T1DM
Jun HS, Yoon JW. Diabetes Metab Res Rev. 2003 Jan-Feb;19(1):8-31
14. Models for
etiopathogenesis
of T1DM
Fertile Field Hypothesis
Time-window following a
viral infection
Initial infection - normal T cell
response
Subsequent - autoreactive T
cells
Molecular mimicry
Bystander activation
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
Initial
infection
Subsequent
infection
15. Mejía-León ME, Barca AM. Nutrients. 2015 Nov 6;7(11):9171-84
Microbiome and Immune System
16. Other factors
Gluten
Cow’s milk
Lack of sunshine - vitamin D deficiency
Lack of breast feeding
Drugs and food additives
Vaccinations *
18. Why is T1DM increasing?
Reason not clear, but 3-5% per year rise in incidence
Possibly due to
Increased survival of T1DM individuals due to insulin
treatment
Health promotion and increased life span, and potential to
have children
Transmission of genetic susceptibility
Jaakko Tuomilehto. Curr Diab Rep (2013) 13:795–804
20. Overview & Screening
Genetic
predisposition Islet
autoimmunity
Dysglycemia Onset of
T1DM
Genetic
HLA class II
HLA class I
Non-HLA genes
Immunologic
IAA, GAD
IA-2 (ICA512),
ZnT8, T cell assays
Metabolic
IV GTT
OGTT
HbA1c
SCREENING
Orban T et al. Diabetes Care 2009;32(12):2269-2274
Taplin CE et al. Autoimmunity. 2008 Feb;41(1):11-8
The number of
antibodies, not the
individual antibody,
is most predictive of
progression to T1DM
Environmental
factors
23. Question 1
The most accepted etiology for T1DM is
A. Drug induced destruction of pancreatic β-cells
B. An environmental trigger activating autoimmunity in a
genetically susceptible individual
C. Vitamin D deficiency in countries that do not have
adequate exposure to sunlight
D. Obesity triggering hyperstimulation of pancreatic β-
cells causing their destruction
24. Question 2
The most likely reason for rising incidence of
T1DM in most parts of the world is
A. Increasing vaccination coverage resulting in triggering
of autoimmunity in genetically susceptible individuals
B. Increasing vitamin D deficiency
C. Improved survival in T1DM with increased potential for
them to reproduce and transmit genetic susceptibility
D. Increased detection of T1DM patients due to advanced
diagnostic methods
Editor's Notes
Model for linear beta-cell mass decay. With genetic predisposition, an environmental trigger induces islet autoimmunity and beta-cell death leading to a sequence of prediabetic stages and eventually clinical onset.
In this concept of T1D as a relapsing-remitting disease, dependent on cyclical disruption and restoration of the balance between effector and regulatory T cells and potentially counteracted by beta-cell proliferation. This model also provides a mechanistic rationale for its variable course.
The fertile field hypothesis postulates the existence of a time window following viral infection during which at-risk individuals may develop autoimmunity. Infection with certain viruses temporarily create a fertile field. Whereas initial exposure to virus (e.g., via APC presentation; purple cells) will generate a normal antiviral response (green T cells), subsequent generation of autoreactive cells (red T cells) may occur via cross-reactivity with viral antigens (molecular mimicry) or direct recognition of autoantigens (bystander activation). Bystander activation is thought to be mediated by APC that process and present self-antigens, with the potential to raise autoreactive T cells only in the presence of viral “danger” signals.
The lactate model appears to be the strongest possible explanation for understanding the link between T1DM and dysbiosis. According to this model, the presence of lactic acid- and butyrate-producing bacteria such as Prevotella and Akkermansia helps to maintain a healthy epithelium. This is because butyrate contributes to mucin synthesis and to the assembly of tight junctions. These bacteria were common in the microbiota of healthy children around the world. In contrast, when microorganisms such as Bacteroides and Veillonella are harbored in abundance, this substrate follows the pathway to succinate, acetate, and propionate. These products compromise mucin synthesis and increase paracellular permeability by altering the tight junctions.
In addition, butyrate may contribute to maintaining the anti-inflammatory response in the healthy gut by inhibiting the activation of NF-κB. High-fiber diets have been associated with a decreased risk of inflammatory immune-related diseases. However, it is unknown whether this effect is due to the butyrate itself or to the associated microbial profile.