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Type 1 Diabetes (T1D)
Type 1 Diabetes Caused by the destruction of the pancreatic beta cells
– Insulin is no longer produced– Leads to hyperglycemia, ketoacidosis and
potentially death if not treated with insulin
Treatment goals for T1D– Maintaining near normal levels of blood
glucose– Avoidance of long-term complications
Type 1 Diabetes 2nd most common chronic childhood
disease
Peak age at onset is around puberty– But T1D can occur at any age
Incidence is increasing worldwide by ~3% per year– Related to increase in T2D?
T1D Incidence Worldwide
Importance of Environmental Risk Factors in T1D Seasonality at diagnosis
Migrants assume risk of host country
Risk factors from case-control studies– Infant/childhood diet– Viruses – exposures as early as in utero– Hormones– Stress– Improved hygiene– Vitamin D
Importance of Genetic Risk Factors in T1D Concordance in identical twins greater
in MZ versus DZ twins
15-fold increased risk for 1st degree relatives– Risk is ~6% through age 30 years– Risk increases in presence of susceptibility
genes
MHC Region – Chromosome 6p21
Predisposition to T1D is Better Determined by Haplotypes DRB1-DQB1 haplotypes more accurately
determine T1D risk
Testing for both genes is more expensive– Most screening is based only on DQA1-DQB1
High risk T1D haplotypes– DQA1*0501-DQB1*0201– DQA1*0301-DQB1*0302
Relative Increase in T1D Risk by Number of High Risk Haplotypes
Number of High Risk DQA1-DQB1 haplotypes
Ethnicity Two OneCaucasians 16 4African Americans 45 7Asians 11 4
Absolute T1D Risk (to age 30) by Number of High Risk Haplotypes
Number of High Risk DQA1-DQB1 Haplotypes
Ethnicity Two One ZeroCaucasians 2.6% 0.7% 0.2%African Americans 3.1% 0.5% 0.1%Asians 0.2% 0.1% 0.02%
Absolute T1D Risk for Siblings of Affected Individuals
Number of High Risk DQA1-DQB1 Haplotypes
Two One ZeroRisk of developing T1D 25% 8.3% 1%
Genome Screens for T1DIDDM1 6p21 IDDM13 2q34-q35IDDM2 11p15 IDDM15 6q21IDDM3 15q26 IDDM17 10q25IDDM4 11q13 IDDM18 5q31-q33IDDM5 6q25-q27 PTPN22 1p13IDDM6 18q21 8q24IDDM7 2q31 VDR, INFγ 12q12-qterIDDM8 6q27-qter 16p11-p13IDDM9 3q21-q25 16q22-q24IDDM10 10p11-q11 17q24-qterIDDM11 14q24-q31 TGFβ1 19p13-q13IDDM12 2q33 Xp11
IDDM2 Insulin (INS) gene
Chromosome 11p15, OMIM: 176730
Variable number of tandem repeats (VNTR)– Class I: 26-63 repeats– Class II: ~80 repeats– Class III: 141-209 repeats– Relative increase in risk ~2-fold with two class I alleles
(compared to 0 class I alleles)
Class I is associated with lower mRNA in the thymus – may reduce tolerance to insulin and its precursors
IDDM12 Cytotoxic T Lymphocyte Associated-4 (CTLA-4)
Chromosome 2q33, OMIM: 123890– ICOS and CD28 flank
Encodes a T cell receptor that plays are role in T cell apoptosis– A49G polymorphism (Thr17Ala)– Relative increase in risk ~ 1.2
Dysfunction of CTLA-4 is consistent with development of T1D
PTPN22 Lymphoid specific tyrosine phosphatase (LYP)
Chromosome 1p13, OMIM: 600716
Encodes a LPY that is important in negative T-cell activation and development– C858T polymorphism (Arg620Trp)– Relative increase in risk ~ 1.8
May alter binding of LYP to cytoplasmic tyrosine kinase, which regulates the T-cell receptor signaling kinases
Intervention Trials for T1D
StudyIntervention Target /ScreenTRIGR Avoid CM FDR / geneticDIPP Insulin (N) GP / geneticTrialNet Immunosuppressive FDR / antibodies
agents and genetic
CM = cows milk, N = nasalCM = cows milk, N = nasal,,FDR = first degree relatives, GP = general FDR = first degree relatives, GP = general populationpopulation
Natural History Studies for T1D
Conducted in the general population–DAISY - Colorado–PANDA - Florida–TEDDY – US and Europe
Based on newborn genetic screening–Concerns about proper informed consent–Parents are notified of the results by mail–General population at ‘high’ risk (5-8%) recruited for follow-up
>50% of children who will develop T1D not eligible
Genetics and Prevention of T1D Type 1 diabetes cannot be prevented
Ethical concerns regarding genetic testing for T1D, especially in children
Education programs are need for parents who consent to have their children involved in such studies because risk estimation is– Dependent on genes/autoantibodies used for
assessment– Is not sensitive or specific
Type 2 Diabetes (T2D)
Type 2 Diabetes Is group of genetically heterogeneous metabolic disorders that cause glucose intolerance
– Involves impaired insulin secretion and insulin action ~90% of individuals with diabetes have T2D Considerations
– May be treated with diet / oral medications / physical activity
– T2D individuals may be asymptomatic for many years
– Associated with long-term complications
Polygenic and multifactorial– Caused by multiple genes that may interact– Caused by genetic and environmental risk factors
Insulin secretionand
Insulin resistance
Environmental effects
Genetic effects
Fatty acid
levels
Blood glucose
levels
From McIntyre and Walker, 2002
Thrifty Genotype Had a selective advantage In primitive times, individuals who were
‘metabolically thrifty’ were– Able to store a high proportion of energy as fat when food
was plentiful– More likely to survive times of famine
In recent years, most populations have – A continuous supply of calorie-dense processed foods– Reduced physical activity
These changes likely explain the rise in T2D worldwide
Revised Classification Criteria for T2D
Fasting plasma glucose– > 7.0 mmol/L– > 126 mg/dl
Random blood glucose – > 11.1 mmol/L– > 200 mg/dl
T2D Prevalence Worldwide
Estimated Number of Adults with Diabetes – Developing Countries
www.who.int/diabetes/actionnow/en/diabprev.pdf
Estimated Number of Adults with Diabetes – Developed Countries
www.who.int/diabetes/actionnow/en/diabprev.pdf
Increase in T2D in Children Most T2D children
were females from minority populations
Mean age at onset was around puberty
Many had a family history of T2D
Environmental Risk Factors in T2D
Obesity– Increases risk of developing T2D
– Defined as:• > 120% of ideal body weight• Body mass index (BMI) > 30 k / m2
– Likely related to the increase in T2D• ~80% newly diagnosed cases due to obesity
– Higher association with abdominal or central obesity
• Assessed by measuring the waist-to- hip ratio
Environmental Risk Factors in T2D
Physical Activity– Increases risk of developing T2D
– Exercise • Controls weight• Improves glucose and lipid metabolism• Is inversely related to body mass index
– Lifestyle interventions decreased risk of progression of impaired glucose tolerance to T2D by ~60%
Genetics and T2D Individuals with a positive family history are
about 2-6 times more likely to develop T2D than those with a negative family history– Risk ~40% if T2D parent; ~80% if 2 T2D parents
Higher concordance for MZ versus DZ twins
Has been difficult to find genes for T2D– Late age at onset– Polygenic inheritance– Multifactorial inheritance
Finding Genes for T2D Candidates selected because they are involved in
– Pancreatic beta cell function– Insulin action / glucose metabolism– Energy intake / expenditure– Lipid metabolism
Genome wide screens– Nothing is assumed about disease etiology
Genome wide association studies– Current approach based on thousands of cases and
controls
Challenges in Finding Genes Inadequate sample sizes
– Multiplex families– Cases and controls
Difficult to define the phenotype Reduced penetrance
– Influence of environmental factors– Gene-gene interactions
Variable age at onset Failure to replicate findings Genes identified have small effects
CAPN10 – NIDDM1 Chromosome 2q37.3 (OMIM 601283)
– Encodes an intracellular calcium-dependent cytoplasmic protease that is ubiquitously expressed
• May modulate activity of enzymes and/or apoptosis– Likely involves insulin secretion and resistance– Stronger influence in Mexican Americans than
other ethnic groups• Responsible for ~40% if familial clustering
– Genetic variant: A43G, Thr50Ala, Phe200Thr– Estimated relative risk: ~2
PPARγ Peroxisome proliferator-activated receptor-γ
(chromosome 3p25, OMIM: 601487)– Transcription factors that play an important role
in adipocyte differentiation and function– Is associated with decreased insulin sensitivity – Target for hypoglycemic drugs -thiazolidinediones– Genetic variant: Pro12Ala, Pro is risk allele
(common)– Estimated relative risk = 1 - 3– Variant is common – May be responsible for ~25% of T2D cases
ABCC8 and KCNJ11 ATP-binding cassette, subfamily C member 8
(chromosome 11p15.1, OMIM 600509)
Potassium channel, inwardly rectifying, subfamily J, member 11 (chromosome 11p15.1, OMIM 600937)– ABCC8 encodes the sulfonylurea receptor (drug
target )– Is coupled to the Kir6.2 subunit (encoded by KCNJ11 –
4.5 kb apart & near INS )– Part of the ATP-sensitive potassium channel
• Involved in regulating insulin and glucagon• Mutations affect channel’s activity and insulin secretion
– Site of action of sulfonylureal drugs– Genetic variants: Ser1369Ala & Glu23Lys, respectively– Estimated relative risk = 2 – 4
TCF7L2 Transcription factor 7-like 2 (chromosome 10q25,
OMIM 602228)– Related to impaired insulin release of glucagon-like
peptide-1 (islet secretagogue), reduced β-cell mass or β-cell dysfunction• Stronger among lean versus obese T2D
– 10% of individuals are homozygous have 2-fold increase in risk relative to those with no copy of the variant
– Responsive to sulfunynlureals not metformin– Genetic variant: re7901695 and others in LD– Estimated relative risk ~ 1.4
GWAS New Loci Identified FTO – chr 16q12
– Fat mass and obesity associated gene– Governs energy balance; gene expression is regulated by
feeding and fasting– Estimated relative risk ~ 1.23
HHEX/IDE – chr 10q23-24; near TCF7L2– HHEX - Haematopoietically expressed homeobox
• Transcription factor in liver cells– IDE - Insulin degrading enzyme
• Has affinity for insulin; inhibits IDE-mediated degradation of other substances
– Estimated relative risk ~ 1.14
GWAS New Loci Identified CDKAL1 – chr 6p22
– Cyclin-dependent kinase regulatory subunit associated protein 1-like 1
– Likely plays role in CDK5 inhibition and decreased insulin secretion
– Estimated relative risk ~ 1.12
SLC30A8 – chr 8q24– Solute carrier family 30 zinc transporter– May be major autoantigen for T1D– Estimated relative risk ~ 1.12
GWAS New Loci Identified IGF2BP2 – chr 3q28
– Insulin-like growth factor 2 mRNA binding protein 2– Regulates IGF2 translation; stimulates insulin action– Estimated relative risk ~ 1.17
CDKN2A/B – chr 9p21– Clycin dependent kinase inhibitor 2A– Plays role in pancreatic development and islet
proliferation– Estimated relative risk ~ 1.2
T2D Genes are Drug Targets PPARγ, ABCC8 and KCNJ11 are the targets of
drugs used routinely in the treatment of T2D– Pharmacogenetic implications – Response to oral agents may be related to one’s
genotype– Genetic testing may
• Identify individuals at high risk for T2D• Guide treatment regimens for T2D
– Individualize therapy
Genetics and Prevention of T2D T2D is preventable
– Maintaining age-appropriate body weight– Physical activity
New genes will provide insight to etiology
Public health messages may have a greater influence on genetically susceptible
Will genetic testing prevent T2D?– Unclear whether knowledge of one’s genetic risk will lead to
behavior modifications
Genetics and Prevention of T2D Challenges include:
– Predictive values of most test is low– How to communicate risk information?– Health care professionals may not be able to
interpret genetic tests– Genetic testing may lead to distress, etc.– Insurance and employment discrimination– Confidentiality and stigmatization– Direct to consumer marketing for genetic
testing
Maturity Onset Diabetes of the Young (MODY)
MODY Account for ~ 5% of type 2 diabetes
Single gene defects– Autosomal dominant inheritance– Multiple generations affected
Early age at onset (< age 25 years)
Characterized by the absence of obesity, no ketosis and no evidence of beta cell autoimmunity
Hyperglycemia often corrected by diet
MODY Genes
Type Gene Locus Protein
# Mutatio
ns
% MOD
YMODY1
HNF4A 20q12-q13.1
Hepatocyte nuclear factor 4-alpha
12 ~5%
MODY2
GCK 7p15-p13 Glucokinase ~200 ~15%
MODY3
HNF1A 12q24.2 Hepatocyte nuclear factor 1-alpha
>100 ~65%
MODY4
IPF1 13q12.1 Insulin promotor factor-1
Few
MODY5
HNF1B 17cen-q21.3
Hepatocyte nuclear factor 1-beta
Few <3%
MODY6
NEUROD1 2q32 Neurogenic differentiation factor 1
Few
MODY1 is HNF4A (hepatocyte nuclear factor 4-alpha) on 20q12-q13.1
Transcription factor – Expressed in the liver, kidney, intestine and pancreatic islet
cells– Has been associated with T2D
Controls genes involved in glucose, cholesterol and fatty acid metabolism
Controls transcription of HNF1A (MODY3)
Several mutations/splicing defects identified– Account for ~5% of all MODY cases
MODY2 is GCK (glucokinase) on 7p15-p13 Only MODY gene that is not a transcription factor
Required for glucose metabolism and insulin secretion; acts as a glucose ‘sensor’
MODY2 is generally a mild form of diabetes
~ 200 mutations have been identified – VNTR, nonsense and missense mutations– Account for ~15% of all MODY cases
MODY3 is HNF1A (hepatocyte nuclear factor 1-alpha) on 12q24.2 Regulates expression of insulin and other genes
involved in glucose transport / metabolism– Influences expression of HNF4A (MODY1)
Results in a severe insulin secretory defect– May contribute to abnormal islet cell development
More than 100 genetic variants have been identified
Mutations in MODY3 are the most common cause of MODY– Account for ~65% of all MODY cases– Sensitive to sulphonylureas
MODY4 is IPF1 (insulin promoter factor-1) on 13q12.1 Transcription factor that regulates expression of insulin, somatostatin and other genes
– Involved in the development of the pancreas– In adults, expressed only in pancreatic cells
Mutations lead to decreased binding activity to the insulin promoter– Reduced activation of insulin gene in response to
glucose
Genetic variants include frameshift, insertions and missense mutations– Accounts for a very small proportion of MODY cases
MODY5 is HNF1B (hepatocyte nuclear factor 1-beta) on 17cen-q21.3 Transcription factor required for liver-specific
expression of a variety of genes
Is highly homologous to HNF1A (MODY3)– Recognizes same binding site as HNF1A
HNF1A and HNF1B likely interact to regulate gene expression
Individuals have lower renal threshold to glucose
Is a rare cause of MODY
MODY6 is NEUROD1 (neurogenic differentiation factor 1) on 2q32 Is a transcription factor involved in the
differentiation of neurons
Regulates insulin gene expression by binding to a critical motif on the insulin promoter
Few genetic variants identified– Missense and nonsense mutations– Account for ~1% of all MODY cases
Summary of MODY Genetics All MODY genes are expressed in the pancreas, and
play a role in:– The metabolism of glucose– The regulation of insulin or other genes involved in glucose
transport– The development of the fetal pancreas
MODY phenotype depends on the MODY genotype (on next slide)
Knowing the genotype is important to determine treatment
MODY PhenotpesType Onset Complications Treatment
MODY1 Severe Frequent D, O, IMODY2 Mild Rare DMODY3 Severe Frequent D, O, IMODY4 Moderate Little data O, IMODY5 Severe Renal disease O, IMODY6 Severe Little Data D, O, O
D = Diet, O = Oral agents, I = Insulin
