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Michael German, MDUCSF Diabetes Center
An Update on the Genetics of Diabetes
Diabetes in the US
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Diabetes: Genetics
Concordance Rates in Identical Twins:
Type 1 Diabetes: ~40%.
Type 2 Diabetes: ~90%.
But What Are the Genes?
Diabetes: Genetics1. Type 1 Diabetes Genes2. Monogenic Diabetes
• Maturity Onset Diabetes of the Young (MODY)
• Neonatal Diabetes• Mitochondrial Diabetes• Rare forms of severe insulin resistance
3. Type 2 Diabetes• Genome Wide Association Studies
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Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk
Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk2. Insulin Gene
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Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk2. Insulin Gene3. Others
Mehers, K. L. et al. Br Med Bull 2008 88:115-129; doi:10.1093/bmb/ldn045
Type 2 Diabetes:The Search for Genes
• Although type 2 diabetes runs in families, the inheritance in most families is complex.
• Therefore, focus on families with simple, Mendelian inheritance patterns -- monogenic diabetes.
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MODY: Maturity Onset Diabetes of the Young
• Autosomal dominant inheritance pattern. --Every generation, 50%
• Onset before age 25.
• Not obese.
• Islet autoantibodies negative.
MODY2: Glucokinase
• Combined β-cell and liver defect.Impaired insulin secretion in response to glucose.
• Moderate hyperglycemia.
• No disease progression.
• Low incidence of complications.
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MODY2: GlucokinaseGlucose
GlucokinaseGlucokinaseGT-2GT-2
GlycolysisGlycolysis
MitochondriaMitochondriaATPATP
KK++ CaCa++++
SignalSignalinsulininsulin
secretionsecretion
β-cell
MODY2: Glucokinase
InsulinSensitivity
β-cellSensitivity
[Glucose]
[Insulin]
glucokinasemutation
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MODY2: Glucokinase
InsulinSensitivity
β-cellSensitivity
[Glucose]
[Insulin]
MODY2: GlucokinaseLessons
• Modest changes in the sensitivity of the β-cell to glucose can cause big changes in glucose levels.
• Much larger changes in insulin sensitivity are required to cause similar changes in glucose levels.
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MODY3: HNF1A/TCF1
RNApolymerase
HNF1A
MODY3: HNF1A
• β-cell defect.Impaired insulin secretion.
• Severe hyperglycemia.
• Disease progression.
• High incidence of complications.
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MODY Genes
MODY1: HNF4AMODY2: GlucokinaseMODY3: HNF1A / TCF1
MODY: β-cell Dysfunction
Fajans, Bell, and Polonsky, NEJM, 2001
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MODY: β-cell Dysfunction
InsulinSensitivity
β-cellSensitivity
[Glucose]
[Insulin]
MODY2
MODY1/3
MODY GenesMODY1: HNF4AMODY2: GlucokinaseMODY3: HNF1A / TCF1MODY4: PDX1 / IPF1MODY5: HNF1B / TCF2MODY6: NEUROD1MODY7: KLF11MODY8: CEL
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Act
E47PDX1
Act TF IID RNAPol II
Co-Act
NEUROD1
HMG I(Y)
Insulin Promoter Model
Islet Cell Lineage
PDX1
NGN3
NeuroD1
Nkx2.2
Nkx6.1Pax4
Pax6Isl1Lmx1a - HB9PDX1Sox4 Pet1
Brn4 Arx Irx
P48
Sox9
HNF1a,bHNF4aHNF6FoxA
HB9Lmx1a
Sox2 Sox9HNF6HNF1bFoxA
PDX1
NeuroD1
Lmx1a -PDX1Sox4
HNF1a,bHNF4aHNF6FoxA
Lmx1a
Sox9HNF6
FoxA
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Islet Cell Lineage
PDX1
NGN3
NeuroD1
Nkx2.2
Nkx6.1Pax4
Pax6Isl1Lmx1a - HB9PDX1Sox4 Pet1
Brn4 Arx Irx
P48
Sox9
HNF1a,bHNF4aHNF6FoxA
HB9Lmx1a
Sox2 Sox9HNF6HNF1bFoxA
PDX1
NGN3
NeuroD1
Nkx2.2
Nkx6.1Pax4
Pax6Isl1Lmx1a - HB9PDX1Sox4 Pet1
Brn4 Arx Irx
P48
Sox9
HNF1a,bHNF4aHNF6FoxA
HB9Lmx1a
Sox9HNF6HNF1bFoxA
MODY: HNF1ALessons
• Decreases in the maximal β-cell capacity can cause big increases in glucose levels, especially as demand (insulin resistance) increases.
• Decreases in β-cell mass could cause such decreases in maximal β-cell capacity.
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β Cell Mass in Adult Humans
A. Butler, et al. Diabetes 2003
Progressive Hyperglycemia:Secondary to Beta Cell Failure
UKPDS 16. Diabetes. 1995; 44:1249-1258.
0
20
40
60
80
100
0 1 2 3 4 5 6 7
ßce
ll fu
nctio
n (%
)
0
20
40
60
80
100
0 1 2 3 4 5 6 7
ßce
ll fu
nctio
n (%
)
Years from randomization
Conventional Sulfonylurea Metformin
Non-obese Obese
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Diabetes: Genetics1. Type 1 Diabetes Genes2. Monogenic Diabetes
• Maturity Onset Diabetes of the Young (MODY)
• Neonatal Diabetes• Mitochondrial Diabetes• Rare forms of severe insulin resistance
3. Type 2 Diabetes• Genome Wide Association Studies
Neonatal Diabetes
Transient (<1yr)-vs.-
Permanent
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Neonatal Diabetes
Aguilar-Bryan, L. et al. Endocr Rev 2008;29:265-291
Neonatal DiabetesTransient: 6q24 (paternal isodisomy)Trans/Perm: KCNJ11/Kir6.2 (activating/dominant)Trans/Perm: ABCC8/SUR1 (activating/dominant)Permanent: PDX1 / IPF1 (recessive)Permanent: PTF1 (recessive)Permanent: RFX6 (recessive)Permanent: GCK (recessive)Permanent: EIF2AK3/PERK (recessive)Permanent: INS (dominant)Autoimmune: FoxP3 (recessive)
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Rfx6 Expression at E10
Nina Kishimoto
Rfx6-/- Mice at P1
Stuart Smith & David Scheel
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Rfx6-/- Mice at E17.5
Stuart Smith & David Scheel
Diabetolgia, 2004.
Am. J. Med. Genetics, 2008.
Human Neonatal Diabetes with Intestinal Atresia
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Mutations in Human Patients.5 Probands tested:
4 Homozygous RFX6 mutations.1 Compound heterozygote.Splicing site and missense mutations.
DNA BINDING DIMERIZATIONRFX6
Arg>Gln Ser>Pro
Wild Type Arg58Gln Constantin PolychronakosStuart Smith
RFX6DNABinding
Diabetes: Genetics1. Type 1 Diabetes Genes2. Monogenic Diabetes
• Maturity Onset Diabetes of the Young (MODY)
• Neonatal Diabetes• Mitochondrial Diabetes• Rare forms of severe insulin resistance
3. Type 2 Diabetes• Genome Wide Association Studies
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Mitochondrial Diabetes•Maternally inherited•Non-obese• Insulin deficiency•Associated with deafness and other neural defects
•Caused by mutations in the mitochondrial genome
Severe insulin Resistance
INSR (Insulin signaling)AKT2 (Insulin signaling)LMNA (Lipodystrophy)LMNB2 (Lipodystrophy)AGPAT2 (Lipodystrophy)BSCL2 (Lipodystrophy)PPARG (Lipodystrophy)
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Diabetes: Genetics1. Type 1 Diabetes Genes2. Monogenic Diabetes
• Maturity Onset Diabetes of the Young (MODY)
• Neonatal Diabetes• Mitochondrial Diabetes• Rare forms of severe insulin resistance
3. Type 2 Diabetes• Genome Wide Association Studies
Type 2 Diabetes: Genome Wide Association Studies
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Type 2 Diabetes: Genome Wide Association Studies
Doria, et al. Cell Metab. 2008
Type 2 Diabetes: Genome Wide Association Studies
Common low risk varients
-vs.-Rare high risk
mutations
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German Lab Support
Hillblom Islet Genesis Network (Larry L. Hillblom Foundation)
Nora Eccles Treadwell Foundation
Juvenile Diabetes Research Foundation
American Diabetes Association
NIH/NIDDK, UCSF DERC
References
•Aguilar-Bryan, L., and Bryan, J. (2008). Neonatal diabetes mellitus. Endocr Rev 29, 265-291.
•Dickson, S.P., Wang, K., Krantz, I., Hakonarson, H., and Goldstein, D.B. Rare variants create synthetic genome-wide associations. PLoS Biol 8, e1000294.
•Doria, A., Patti, M.E., and Kahn, C.R. (2008). The emerging genetic architecture of type 2 diabetes. Cell Metab 8, 186-200.
•Florez, J.C. (2008). Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51, 1100-1110.
•Lupski, J.R., Reid, J.G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D.C., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D.A., McGuire, A.L., Zhang, F., Stankiewicz, P., Halperin, J.J., Yang, C., Gehman, C., Guo, D., Irikat, R.K., Tom, W., Fantin, N.J., Muzny, D.M., and Gibbs, R.A. Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth Neuropathy. N Engl J Med.
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References
•McCarthy, M.I., and Zeggini, E. (2009). Genome-wide association studies in type 2 diabetes. Curr Diab Rep 9, 164-171.
•Mehers, K.L., and Gillespie, K.M. (2008). The genetic basis for type 1 diabetes. Br Med Bull 88, 115-129.
•Roach, J.C., Glusman, G., Smit, A.F., Huff, C.D., Hubley, R., Shannon, P.T., Rowen, L., Pant, K.P., Goodman, N., Bamshad, M., Shendure, J., Drmanac, R., Jorde, L.B., Hood, L., and Galas, D.J. Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing. Science.
•Vaxillaire, M., and Froguel, P. (2008). Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 29, 254-264.