Genetics of Diabetes

Genetics of Diabetes 

Melissa Fries, MD 

Clinical Geneticist/Obstetrician- 

Gynecology

In your Jeans or your Genes?

Definition of genetics 

Study of inherited characteristics 

� Viewed in context of an individual and his/her 

family 

� Infinitely broad scope 

� Molecular genetics and the nature of genes 

� Medical genetics and the nature of illness 

� Clinical genetics and the diagnosis of disorders

Classic Medical Genetics 

� Single gene disorders: 

� Over 3000 

� Often expressed in the pediatric population 

� Resources: 

� www.genetests.org 

� On-line Mendelian Inheritance in Man 

� www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM 

� New Focus in Genetics: Complex common 

disease

Single gene abnormalities 

� Usually identified through a recognizable 

abnormality 

� “Treasure your exceptions” 

� Easier to recognize a visible abnormality than 

an abnormal gene 

� Inheritance patterns of these abnormalities is 

a clue to their genetic make-up and valuable 

to the family

Family inheritance patterns 

� Mendelian (single gene) disorders 

� Autosomal dominant 

� Autosomal recessive 

� X-linked 

� Multi-factorial disorders 

� Mitochondrial disorders 

� Abnormalities of mitochondrial DNA

Multifactorial inheritance 

� Condition is related to the interaction of 

multiple genes and environmental factors 

� No predictable pattern of recurrence 

� Recurrence risks based on empiric data of 

population studies 

� Usually is the square root of the population 

frequency--3-4% 

� Most likely involved in common, complex 

diseases such as diabetes

Multifactorial disorders 

� Higher recurrence risks if 

� more family members are affected 

� affected person is of the less commonly affected 

sex 

� more severe initial condition 

� Reduced recurrence risk with 

� more distant relationship (negligible in 3degree 

relatives) 

� Concerns to recognize both genetic 

predisposition AND environmental triggers

Diabetes mellitus 

� Extremely common disorder of glucose 

metabolism related to a failure of adequate 

insulin production 

� T1D: autoimmune destruction of beta cells 

� T2D: Impaired insulin effectiveness along 

with failure to produce adequate insulin 

� Affects over 18 million people in the US

Permutt, 

2005

Epidemiology of DM 

� Lifetime risk for development of DM 

� 33% for males 

� 39% for females 

� 53% for Hispanic females 

� Related also to age 

� 10 times more common >65 than

Genetics of T1D (10% of DM) 

� Disease requires predisposing genetic 

background and 

� Interaction with other environmental factors 

� End result: T cell mediated destruction of beta 

cells 

� Most cases are sporadic 

� No standard Mendelian pattern of inheritance 

� Susceptibility to disease, rather than disease itself 

appears to be inherited

Autoimmune triggers: T-cells 

may directly target insulin 

� Kent, et al Nature 435, 2005: 

� Examined T cells from pancreatic draining lymph 

nodes in diabetic patients with DR4 susceptability 

allele 

� Specific clone of T cells which recognized the 

insulin A1-15 epitope 

� Strongly supports autoimmune effect from 

stimulated T-cells

Autoimmune Triggers: GAD 

� Glutamic acid decarboxylase 1/2 (GAD 1 and 

2) 

� Catalyzes gamma aminobutyric acid from Lglutamic 

acid 

� Found to act as autoantigen in T1D as well as stiff 

person syndrome 

� Gene is at 10p11.23 

� 2 common isotypes: GAD65 and 67 in brain and 

pancreatic islet cells

Autoimmune effects 

� GAD 65 

� Shares 24 AA segment with P2-C protein of 

coxsackie virus 

� 17 viruses identified with some homology to 

various segments of GAD65 

� De Aizpurua, 1992: anti-GAD found in most 

subjects with pre-clinical IDDM 

� Antibodies against common viruses may also 

target GAD 

� End result: gradual beta islet cell failure

Genetic predisposition: HLA 

genotypes 

� DR and DQ loci on chromosome 6p major 

genetic influences for T1D 

� DR1,3,4,8, and 2(16) increase susceptibility 

� DR 5 and 2(15) provide protection 

� DQ 0602 provides dominant protection against 

T1D 

� Strong susceptibility to narcolepsy

HLA genes 

Chromosome 

6p

HLA subtypes and 

susceptibility 

� Exaggerated susceptibility to T1D in 

DR3/DR4 heterozygotes 

� Appears to relate to production of unique 

hybrid molecules which lead to altered 

functional immune response in DR4 subtypes

Norwegian studies 

� One of the highest world frequencies of T1D 

� Ronningen, et al: Diabetes, 1997 

� Specific HLA genotype at high risk 

� DR4-DQ8/DR3-DQ2 

� Confers RR of 20 for T1D development 

� Absolute risk of 7% by age 15 

� In Norway, tested in neonatal screening 

� 2.1% of newborns carry this genotype

MIDIA study: Environmental 

Triggers of Type 1 Diabetes 

� Rasmussen et al, Diabetes Care, 2009 

� Followed 1003 newborns screen positive (in 46,939 

newborns screened) for high risk genotype 

� 885 tested serially for autoantibodies to insulin, GAD, and 

insulinoma-associated protein 2 

� Followed for 6 years 

� 36 developed islet autoimmunity (4%) 

� 10 developed diabetes 

� Maternal BMI >30kg/m 2 and wt gain of >15 kg in pregnancy 

increased risk for islet autoimmunity in offspring by 2-3fold 

� ?Increased maternal/fetal glucose may increase fetal insulin 

production and growth of islet cells

PANDA study 

� Prospective Assessment in Newborns for 

Diabetes Autoimmunity 

� NIH Observational study (still recruiting) 

� Initiated in early 2000 

� U of FL and Georgia 

� Evaluate risk for development of T1D 

� Measure genetic risk factors (HLA) 

� Autoimmunity markers 

� Family history

PANDA study 

� No diabetes outcome data reported yet 

� 3 published reports on psychosocial factors 

related to the study 

� Genet Med, 2003: 73% of mothers recall infant’s 

diabetes risk accurately 

� Diabetes Care, 2005: No overall increase in maternal 

depression regarding infant’s diabetes risk 

� Increased depression if mother is of ethnic minority, limited 

education, or with post partum depresssion 

� Diabetes Care, 2005: 67% of mothers of at risk 

infants reported 1 or more diabetes prevention 

behaviors

Single nucleotide polymorphism 

(SNP) studies 

� European Consortium for IDDM Genome 

studies 

� Identified susceptibility loci on 2p, 5q, 16p 

� Suggest non-HLA genes also involved 

� Interaction between HLA and non-HLA loci may be 

etiologic 

� No clear pattern at this time

Family risk for T1D(Schatz and Winter, 

Current opinions in Pediatrics, 1995; 7:459-465) 

General population .2% 

Any 1 st degree relative 5% 

Sibling: no HLA shared 1-2% 

1 HLA haplotype shared 5-7% 

2 HLA haplotypes shared 16-17 % 

Both HLA haplotypes 20-25% 

DR3/DR4 

Monozygotic twins 33%

Other genes involved 

� CTLA4 cytoxic T-lymphocyte associated 

protein 4 

� PTPN22 Protein tyrosine phosphate nonreceptor 

type 22 

� INS (Variable number of tandem repeats) 

� Permutt, J Clin Invest, Vol 115(6), June 2005: 

1431-1439

T2D (90% of DM) 

� Increase in frequency follows increase in 

obesity, urbanization, and wealth 

� “Thrifty genotype” postulated 

� Genetic advantage of accelerated fat deposition in 

time of restricted calories 

� Disadvantage in time of unrestricted calories 

� “Thrifty phenotype” (Barker hypothesis) 

� Malnourishment (IUGR) leads to impaired beta cell 

development, insulin resistance, and predisposition to 

adult diabetes and metabolic syndrome

Genetics of T2D 

� Still very poorly understood 

� May relate to susceptibility issues to obesity as 

well as insulin resistance 

� Combined inherited/environmental features 

not well understood

Triggers: Obesity 

� Sargeant, NIH, 2003: 38% of the excess risk 

associated with a family history of diabetes 

could be avoided if BMI was not allowed to 

be greater than 30kg/m 2 . 

� However, relatives of non-obese T2D may 

have greater risk for disease development 

� Implies possible greater genetic burden if disease 

development in absence of obesity

Obese 

Not Obese 

Goldfine, Proc Nat Aca Sci, 2003 

Fm Hx Diabetes 

Diabetes 

development: 

16.7/1000 

person years 


development: 

8.8/1000 person 

years 

No family Hx of 



development: 

1.8/1000 person 

years 


development: 

1.6/1000 person 

years

Possible Genes associating 

with T2D 

� Genes involved in insulin secretion 

� ABCC8 (sulfonylurea receptor) and KCNJ11 

� Components of the K ATP channel on beta cells 

� Uncoupling protein UCP2 

� Mitochondrially encoded NADH dehydrogenase 

� Variants will be inherited only maternally 

� Transcription factor 7-like 2 (TCF7L2)


with T2D 

� Insulin and Insulin signaling genes 

� INS insulin gene 

� Insulin receptor (INSR) 

� Insulin-like growth factor IGF2(adjacent to INS gene) 

� Insulin receptor substrate IRS1 

� Note: All studied changes are related to 

polymorphisms—variations in sequence not 

associated with protein malformation or absence but 

which may vary protein efficiency or adaptation 

� Defects in insulin expression or insulin receptor expression 

would probably be lethal.


with T2D 

� Lipid and glucose metabolism genes 

� Peroxisome proliferative activated receptor 

gamma (PPARG) 

� Transcription factor which regulates adipocyte 

development as well as lipid and glucose metabolism 

� Common variant: Pro12Ala (substitutes alanine for 

proline) which alters binding affinity 

� Confers moderately increased risk for T2D 

� May also influence obesity


with T2D 

� Peroxisome proliferative activated receptor-gamma 

coactivator 1-alpha (PPARGC1A) 

� Beta 3 adrenergic receptor 

� Glucose transporter 1 

� Adiponectin 

� Forkhead box C2 (FOXC2) 

� Mannose-binding lectin (protein C)2 

� Calpain 10 

� Plasminogen activator inhibitor type 1

MODY-maturity onset diabetes 

of the young 

� Early onset T2D less than age 25 in non-obese 

patients 

� Defects in insulin secretion 

� AD inheritance pattern, 2-5% of T2D 

� Different subtypes related to different genes 

� HNF4alpha (hepatocyte nuclear factor): 5% 

� GCK (glucokinase) 12.5% 

� HNF1A(hepatocyte nuclear factor 1a): 65% 

� IPF1 

� HNF1B 

� NEU-ROD1 

� Genetic testing available

Genetests.org search for genetic testing for Diabetes mellitus 

Search Result for Disease Name Containing 'diabetes mellitus' 

ABCC8-Related Transient Neonatal Diabetes Mellitus 2 

Diabetes Mellitus, 6q24-Related Transient Neonatal 

Diabetes Mellitus, Insulin-Resistant, with Acanthosis Nigricans 

Diabetes Mellitus, KCNJ11-Related Transient Neonatal 

Diabetes Mellitus, Neonatal, with Congenital Hypothyroidism 

Diabetes Mellitus, Noninsulin-Dependent, with Acanthosis Nigricans and Hypertension 

Diabetes Mellitus, Permanent Neonatal, with Cerebellar Agenesis 

Maturity-Onset Diabetes of the Young Type 1 [Diabetes Mellitus, MODY Type 1] 

More Links 

HNF4A-Related Maturity-Onset Diabetes of the Young Type 1 [HNF4A-Related Diabetes Mellitus, MODY Type 

1] 

More Links 

INS-Related Maturity-Onset Diabetes of the Young Type 1 [INS-Related Diabetes Mellitus, MODY Type 

1] 

More Links 


Links 




Multiple Epiphyseal Dysplasia with Early-Onset Diabetes Mellitus 

Permanent Neonatal Diabetes Mellitus 

ABCC8-Related Permanent Neonatal Diabetes Mellitus 

GCK-Related Permanent Neonatal Diabetes Mellitus 

INS-Related Permanent Neonatal Diabetes Mellitus 

KCNJ11-Related Permanent Neonatal Diabetes Mellitus 

PDX1-Related Permanent Neonatal Diabetes Mellitus 

Pineal Hyperplasia, Insulin-Resistant Diabetes Mellitus, and Somatic Abnormalities 

Renal Cysts and Diabetes Syndrome [Diabetes Mellitus, MODY Type 5] 

Items 1 - 16 of 16 

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Family Risk for T2D (Groop, J Int Med 1997: 

241:95-101) 

Offspring of one parent with 

T2D 

Offspring of two parents with 

T2D 

Siblings of individuals with 

T2D 

Monozygotic twins 

concordancy 

40% lifetime risk 

80-100% lifetime risk 

35% lifetime risk 

70-80%* 

May be 100% if index 

case has disease onset 

after age 45

Genetics of Diabetic 

nephropathy 

� Diabetic nephropathy is a subtype, affecting 

1/3 of those with T1D after 40 years 

� Familial aggregation seen in those with diabetic 

nephropathy 

� Black ethnicity and early onset of ESRD also clustered 

� Genome wide linkage scans survey genome 

for regions coinherited with a trait 

� Linkage found to 7q35,3q26,9q22,20p12

Special inheritance pattern in 

diabetes 

� Mitochondrial effects

Mitochondrial Inheritance 

� Occurs from mutation in mitochondrial DNA 

� circular double stranded DNA found in multiple 

copies in each mitochondrion 

� Mitochondria are tiny energy producing 

organelles of the cell 

� 1000’s in each cell 

� Passed in the cytoplasm of the ovum 

� Exclusive maternal transmission 

� If mother is affected, disease is passed to all her 

offspring

Mitochondrial Inheritance 

� Displays heteroplasmy 

� Different mitochondria may or may not have the 

mutation 

� Severity of disease is proportional to the relative 

proportions of normal and abnormal mitochondrial 

DNA 

� Affected males cannot transmit the disease 

� Affected females transmit to all their children

Mitochondrial disease in 

diabetes 

� MIDD: Maternally inherited diabetes and 

deafness 

� Mutation in mitochondrial DNA (3243tRNA leu) 

� Same mutation associated with MELAS 

� Mitochondrial myopathy, encephalopathy, lactic 

acidosis, and stroke-like episodes 

� Usually not obese, with deafness preceding DM 

� Appears to lead to defect in insulin release

Gestational diabetes 

� Permutt, 2005 

� Gestational diabetes is “state of glucose 

intolerance in pregnancy . . . With major 

implications for subsequent development of T2D 

as pregnancy serves as an ‘environmental 

stressor’ that reveals a genetic predisposition.”

Genetic susceptibility to GDM 

� Any parental history of T2D diabetes 

increases risk for GDM 2.3x 

� Mothers with a diabetic sibling have 8.4 fold 

higher risk of GDM than women with no 

diabetic siblings 

� Lifetime risk for T2D after having GDM is 15- 

60%

What is the heritability for 

GDM? 

� May relate to epigenetic changes in the in-utero environment 

leading to future predisposition 

� Epigenetic changes: Changes in gene activation or suppression 

by methylation of DNA or deacetylation of histones—not DNA 

sequence changes 

� 2 older studies showing that GDM is more frequent in the 

mothers of women who themselves later develop GDM 

� Also greater likelihood for GDM in women whose mothers, not 

fathers have T2D 

� No paternal or maternal influence seen in T1D parents for GDM 

� Implication that prenatal exposure to diabetic intrauterine 

environment may lead to increased predisposition to GDM in 

adult pregnant state

Effects of Gestational Diabetes 

on offspring 

� J MatFetNeonatal Med, 2008: Vohr,et al 

� Pediatrics, 2004, Boney et al 

� Development of metabolic syndrome in children 

related to 

� Maternal gestational diabetes mellitus 

� Maternal glycemia in the 3 rd trimester 

� Maternal obesity 

� Neonatal macrosomia 

� Perpetuating cycle of increasing obesity, insulin 

resistance and abnormal lipid metabolism

Relationship of GDM and T2D 

� Parallels in inheritance features and increase 

in lifetime risk for T2D after GDM suggests 

probable common variants in genes 

predisposing to both

Genetics of Common 

Disorders 

� Key research effort at present 

� Diabetes high on priorities of studies 

� Research to investigate 

� Complications 

� Pharmacogenetics 

� Environmental triggers 

� Etiologic factors

Suggested references 

� Robitaille, J and Grant AM. The genetics of 

gestational diabetes mellitus. Genet Med 

2008, 10(4):240-250 

� Permutt MA, Wasson J, and Cox N. Genetic 

epidemiology of diabetes. J Clin Invest, 

2005, 115(6): 1431-1439. 

� Newell AM. Genetics for targeting disease 

prevention: diabetes. Primary Care: Clinics in 

Office Practice 2004, 31(3)

Jeans or Genes? 

� Genes In Jeans!

Genetics of Diabetes

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