type 1 diabetes mellitus - etiology
TRANSCRIPT
Etiology of Type 1 Diabetes Mellitus
Dr. Shashikiran UmakanthProfessor & HeadDepartment of Internal MedicineDr. TMA Pai Hospital - Udupi, MMMCManipal University, INDIA
Type 1 diabetes mellitus (T1DM)
Characterized by absolute insulin deficiency
Result of pancreatic beta cell destruction Prone to ketosis
Etiology of T1DM
Genetic predisposition
Isletautoimmunity
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
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
Genetic factors in T1DM
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
Familial clusteringRisk 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 T2DMWarram. Genetics & Diabetes, Diabetes Information. Joslin Diabetes Center and Joslin Clinic
Environmental factors in T1DM
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 UKBorchers AT et al. The geoepidemiology of type 1 diabetes. Autoimmun Rev. 2010 Mar;9(5):A355-65.
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?
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
Models for etiopathogenesis of T1DM
T1DM may be a relapsing-remitting disease
van Belle TL, et al. Physiol Rev. 2011;91:79-118.
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
Mejía-León ME, Barca AM. Nutrients. 2015 Nov 6;7(11):9171-84
Microbiome and Immune System
Other factors
GlutenCow’s milkLack of sunshine - vitamin D deficiencyLack of breast feedingDrugs and food additivesVaccinations *
T1DM is increasing
0
10
20
30
40
50
60
70
1950 1960 1970 1980 1990 2000
Finland
Sweden
Colorado
Germany
Why is T1DM increasing?
Reason not clear, but 3-5% per year rise in incidencePossibly 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
Summary
Overview & ScreeningGenetic
predisposition Isletautoimmunity
Dysglycemia Onset of T1DM
GeneticHLA class IIHLA class I
Non-HLA genes
ImmunologicIAA, GAD
IA-2 (ICA512), ZnT8, T cell assays
MetabolicIV GTTOGTTHbA1cSC
REEN
ING
Orban T et al. Diabetes Care 2009;32(12):2269-2274Taplin 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
Thank you
Questions
Question 1
The most accepted etiology for T1DM isA. Drug induced destruction of pancreatic β-cellsB. An environmental trigger activating autoimmunity in a
genetically susceptible individualC. Vitamin D deficiency in countries that do not have
adequate exposure to sunlightD. Obesity triggering hyperstimulation of pancreatic β-
cells causing their destruction
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 deficiencyC. Improved survival in T1DM with increased potential for
them to reproduce and transmit genetic susceptibilityD. Increased detection of T1DM patients due to advanced
diagnostic methods