Michael German, MDUCSF Diabetes Center

An Update on the Genetics of Diabetes

Diabetes in the US

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

Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk

Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk2. Insulin Gene

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.

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.

MODY2: GlucokinaseGlucose

GlucokinaseGlucokinaseGT-2GT-2

GlycolysisGlycolysis

MitochondriaMitochondriaATPATP

KK++ CaCa++++

SignalSignalinsulininsulin

secretionsecretion

β-cell

MODY2: Glucokinase

InsulinSensitivity

β-cellSensitivity

[Glucose]

[Insulin]

glucokinasemutation

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.

MODY3: HNF1A/TCF1

RNApolymerase

HNF1A

MODY3: HNF1A

• β-cell defect.Impaired insulin secretion.

• Severe hyperglycemia.

• Disease progression.

• High incidence of complications.

MODY Genes

MODY1: HNF4AMODY2: GlucokinaseMODY3: HNF1A / TCF1

MODY: β-cell Dysfunction

Fajans, Bell, and Polonsky, NEJM, 2001

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

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

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.

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

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ßce

ll fu

nctio

n (%

)

0

20

40

60

80

100

0 1 2 3 4 5 6 7

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n (%

)

Years from randomization

Conventional Sulfonylurea Metformin

Non-obese Obese

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

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)

Rfx6 Expression at E10

Nina Kishimoto

Rfx6-/- Mice at P1

Stuart Smith & David Scheel

Rfx6-/- Mice at E17.5

Stuart Smith & David Scheel

Diabetolgia, 2004.

Am. J. Med. Genetics, 2008.

Human Neonatal Diabetes with Intestinal Atresia

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

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)

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

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

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.

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.