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