GENETIC FACTORS IN

DIABETES MELLITUS

Birmingham Study

A random sample of 4886 birth.

Comparison between the most valid data:2432 North European babies 956 British Pakistani babies

Couple family relation in the two group:0.4% North European 69% British Pakistani

Prevalence of congenital and genetic disorders:4.3% North European 7.9% British Pakistani

0

20

40

60

80

North European British Pakistani

Corrected congenital malformation

Disability

Death 1 month - 5 years

Death <1 month (lethal malformation)

Genetic abortion

IDDM 1

HLA alleles documented in the 1970s.

Locus contains many diabetes susceptibility genes.

The most important alleles are DQB1 & DRB1.

Sequences in DQB1 gene that code for an amino acid other than aspartic acid at position 57 (non-ASP57) are highly associated with type 1 diabetes.

Protective HLA haplotypes is: DQA1*0102,DQB1*0602

Chromosome 6Q p

DP DQ DR B C A

Class II Class III Class I

CLIIA2 DP DN DM LMP2 LMP7 DO DQ DR

B2 A2 B1 A1 A A B B B2A2B1A1 B1B2B3B9 A

Class II

Class III

CYP21 Hsp70 G7a TNF

C4BC4ABfC2 2 1Hom A B

Class I B C X E J A H G F

Genetic Factors in Type 1 Diabetes

18 regions of the genome have been linked with influencing type 1 diabetes risk.

The most well studied HLA gene is IDDM 1.

Non-HLA genes like: IDDM 2 (insulin gene)CTLA4 (immune response)

Designation Nature Chromosome

IDDM 1IDDM 2

MHCInsulin

611

IDDM 3

IDDM 4

IDDM 5

?

?

?

15

11

6

Weaker susceptibility loci:

Diabetes susceptibility loci

18 regions of the genome have been linked with influencing type 1 diabetes risk.

Chromosome 2 Chromosome 5 Chromosome 6 Chromosome 10

IDDM10

IDDM17

IDDM1

IDDM15

IDDM5IDDM8

IDDM18

IDDM7IDDM12IDDM13

Chromosome 11 Chromosome 14 Chromosome 15 Chromosome 18

IDDM17

IDDM3

IDDM11

IDDM2

IDDM4

Genetic Factors in Type 1 Diabetes

Empiric Risk of type 1 Diabetes

Relative with Modifying Risk ofType 1 Diabetes Factor Diabetes (%)

Identical twin70Father 6Mother 2Sibling 5First degree relatives HLA DR3 & DR4 20

HLA DR3 or DR4 5HLA DR2 with DQB1*0502 5HLA DR2 with DQB1*0602

<0.2

Genetic Factors in Type 1 Diabetes

The Bart’s Oxford population-based family study:

• To examine familial risk of disease in relation to age at onset in 1,299 families.

The cumulative risk of type 1 diabetes by age 20 years

Age %

Siblings (No 1,430):Before age 5 years 11.75 – 9 years 3.610 – 14 years 2.3

Parents (No 2,419):Before age 5 years 5.95 – 9 years 3.710 – 14 years 3.7

Genetic Factors in Type 2 Diabetes

• Strong family history of diabetes add to other factor like obesity and it’s distribution.

• Ethnicity and family history show the genetic factor in type 2 diabetes.

4

5

6

7

8

9

10

11

12

90 100 110 120 130 140 150 160 170 180

Ideal body weight (%)

Insu

lin s

ensiv

ity ControlsOffspring of type 2

diabetes subjects

Impact of diabetogenes on obesity induced insulin

resistance

Genetic Factors in Type 2 Diabetes

The sulfonylurea Receptor (ABCC8):

Chromosome 11.

KATP channels is found in the pancreas.

Activation of the KATP channel regulate the release of insulin.

Mutation in ABCC8 can result in up-regulation of insulin secretion ( Familial persistent hyperinsulinemic hypoglycemia of infancy).

Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.

K+

Sulphonylureas

Dépolarisation

KATP Channel closex

Ca 2+

Ca 2+

Ca

2+ Influx

Ashcroft, Gribble, Diabetologia (1999) 42: 903-919

Insuline

secretion

through

exocytosis

Insulin

17400k

17410k

17420k

17430k

17440k

17450k

ABCC811P15

11P1411P1311P1211P11

Chromosome 11

Who should not develop Diabetes

• Age

• Sex

• Ethnicity

• Family history

• Metabolic syndrome