pharmacogenetics of type-2 diabetes...pharmacogenetics of type-2 diabetes thessaloniki, may 17 th...

Prof. Dr. Harald Staiger

Institute of Pharmaceutical Sciencesof the Eberhard Karls University Tübingen

and

Institute for Diabetes Research and Metabolic Diseases (IDM)of the Helmholtz Center Munich at the Eberhard Karls University Tübingen

Pharmacogenetics of Type-2 Diabetes

Thessaloniki, May 17th 2019

Diabetes mellitus – Recent Data (Germany)

7.5 million people with diabetes(>95 % T2D)

+ 2 million undiagnosed cases

16 billion €/year therapy costs(10 % of total health care costs)

Diabetes mellitus – Recent Data (Germany)

need of cost-effective useof anti-diabetic medication

7.5 million people with diabetes(>95 % T2D)

+ 2 million undiagnosed cases

16 billion €/year therapy costs(10 % of total health care costs)

Aims of Pharmacogenetics

impact of genetic variation on

treatment response

o genetically determined non-response

o genetically determined adverse response

side effects

to contribute to patient stratificationand precision medicine

reduction of therapy costs

Antidiabetic Drugs and Target Organs

metformin

sulfonylureasmeglitinidesGLP1R agonistsDPP4 inhibitors

thiazolidindiones

α-glucosidase inhibitors

SGLT2 inhibitors

insulininsulin analogues

oral applicationsubcutaneous application

Pharmacokinetic Genes

transport proteinsenzymes ofbiotransformation

transport proteins

transport proteins

Pharmacodynamic Genes

drug (class) molecular target downstream elements (examples)

metformin ETC complex I AMPK, ADCY, FBPase

sulfonylureas KATP channel L-type Ca2+ channel

meglitinides KATP channel L-type Ca2+ channel

GLP1R agonists GLP1 receptor Gs, ADCY, PKA, TCF7L2, CREB, …

DPP4 inhibitors DPP4 -

SGLT2 inhibitors SGLT2 -

α-glucosidaseinhibitors α-glucosidase -

insulin/insulinanalogues insulin receptor IRS, PI3K, AKT, GSK3, GLUT4, …

Pharmacogenetics of Metformin

metformin

Antidiabetic Actions of Metformin

hepatocyte

Treatment Response to Metformin

Genetics of Diabetes and Audit Research TaysideStudy (GoDARTS)

Treatment Response to Metformin

Genetics of Diabetes and Audit Research TaysideStudy (GoDARTS)

non-responseadverse response

Pharmacokinetics of Metformin

absorption

enterocyte

blood

hepatocyte renaltubular cell

bile urine

metformin

metformin

metformin

metformin metformin

ENT4 OCT3

OCT1

OCT3OCT1 OCT2

MATE1 MATE1MATE2-K

distribution

eliminationOCT1

gut

OCT1 Mutations

23 coding variants in the gene

7 coding variants with 40-100 % reduced transport activity in vitro

Shu Y et al., J. Clin. Invest. 2007

Consequences of OCT1 Mutations

absorption

enterocyte

blood

hepatocyte renaltubular cell

bile urine

metformin

metformin

metformin

metformin metformin

ENT4 OCT3

OCT1

OCT3OCT1 OCT2

MATE1 MATE1MATE2-K

distribution

eliminationOCT1

gut

Pharmacogenetic Importance of OCT1 Mutations

SDDS (N=160)R61C, S189L, G401S, M420del, G465R→ reduced plasma metformin levels→ limited treatment response (HbA1c reduction)

GoDARTS (N=1530)R61C, M420del→ no effects on treatment response→ compound heterozygous carriers have 2.4-fold

higher risk of metformin intolerance

MetGen consortium (N=8000)R61C, M420del→ no effects on treatment response

Christensen MM et al., Pharmacogenet. Genomics 2011Zhou K et al., Diabetes 2009Dujic T et al., Diabetes 2015Dujic T et al., Clin. Pharmacol. Ther. 2016

Pharmacogenomic Hit ATM

meta-analysis of GoDARTS (N=1020), a Scottish cohort (N=1780) and

UKPDS (N=1110)

Zhou K et al., Nat. Genet. 2011

meta-analysis of GoDARTS (N=1020), a Scottish cohort (N=1780) and

UKPDS (N=1110)


Major problems of genomic studies:• genome-wide p-value <5·10-8 (10 million SNPs)

• mostly non-coding variants

• mostly genes with no described link to the disease


ATM rs11212617 increases treatment response 1.35-fold (target HbA1c <7 %) and enhances absolute HbA1c reductionby 0.11 HbA1c units (%) per minor allele

identification of super-responders!

replicated in a meta-analysis of DCS West-Frisia (N=930), Rotterdam Study (N=180) and CARDS (N=250)

Zhou K et al., Nat. Genet. 2011Van Leeuwen N et al., Diabetologia 2012


MetGen consortium


HbA1c reduction (N=10.620) hepatic GLUT2 expression (N=1200)

Pharmacogenomic Hit SLC2A2

Zhou K et al., Nat. Genet. 2016Rathmann W et al., Diabetologia 2019

SLC2A2 rs8192675 enhances absolute HbA1c reductionby 0.08 HbA1c units (%) per minor allele

identification of super-responders again!

SLC2A2 rs8192675 enhances reduction in fasting plasmaglucose in GDS (N=500)


Zhou K et al., Nat. Genet. 2016Rathmann W et al., Diabetologia 2019

SLC2A2 rs8192675 enhances absolute HbA1c reductionby 0.08 HbA1c units (%) per minor allele

identification of super-responders again!

SLC2A2 rs8192675 enhances reduction in fasting plasmaglucose in GDS (N=500)


non-response and adverse reponseto metformin therapy a result oflifestyle/environmental factors?

Pharmacogenetics of Modern Antidiabetic Drugs

DPP4 inhibitors&

TCF7L2

SGLT2 inhibitors&

SLC5A2

Zimdahl H, …, Staiger H, Pharmacogenet. Genomics 2017Ordelheide AM, …, Staiger H, PLoS One 2017

Haupt A, …, Staiger H, Diabetes 2010 Heni M, …, Staiger H et al., Diabetes 2010Müssig K, Staiger H et al., Diabetologia 2010Ordelheide AM., …, Staiger H, Mol. Metab. 2013Wagner R, Staiger H et al. Mol. Metab. 2014

Reviews:Staiger H et al., Pharmacogenetics 2015Ordelheide AM, …, Staiger H, Pharmacogenomics 2018

Renal Glucose Reabsorption

Chao EC and Henry RR, Nat. Rev. Drug Discov. 2010

Actions of SGLT2 Inhibitors

SGLT2 inhibitors‚gliflozins‘

glucose~70 g/day

~280 kcal/day

dapagliflozincanagliflozinempagliflozin

SGLT2 inhibitors‚gliflozins‘

glucose~70 g/day

~280 kcal/day

blood glucose reductionblood pressure reduction(osmotic diuresis)weight loss

dapagliflozincanagliflozinempagliflozin

Actions of SGLT2 Inhibitors

Effects of SLC5A2 rs3116150

2230 prediabetic subjects (TÜF Study)


2230 prediabetic subjects (TÜF Study)

980 T2D patients (pool of 4 phase-III studies)


Effects of SLC5A2 rs3116150

Pharmacogenetic Importance of SLC5A2 rs3116150

980 T2D patients, empagliflozin 1x10 mg, 24 weeks

Zimdahl H, …, Staiger H, Pharmacogenet. Genomics 2017

980 T2D patients, empagliflozin 1x10 mg, 24 weeks

Zimdahl H, …, Staiger H, Pharmacogenet. Genomics 2017

Pharmacogenetic Importance of SLC5A2 rs3116150

11.4 % of drug-treated T2D patients on SGLT2 inhibitors (2017, Germany)frequency of A/A = 5 %

40,000 T2D patients with blood pressure increase

The Major T2D Gene TCF7L2

Franks PW et al., Diabetes Care 2013

rs7903146

Incretin-Stimulated Insulin Secretion

insulin

TCF7L2

Gs PKAATP

cAMP

glucose

ATPCa2+-

KATP

+

L-type Ca2+

[Ca2+]i ↑GLP-1

GIP

K+

insulinGIP-RGLP-1-RPC1PC2

L-cells: GLP-1(ileum + colon)

K-cells: GIP(duodenum + jejunum)

+

AC

pancreaticβ-cell

inactivationdegradation

DPP4

glucose

Actions of GLP1R Agonists and DPP4 Inhibitors

insulin ⇑

TCF7L2

Gs PKAATP

cAMP

glucose

ATPCa2+-

KATP

+

[Ca2+]i ⇑GLP-1 ⇑

GIP ⇑

K+

insulin ⇑GIP-R ⇑GLP-1-R ⇑PC1 ⇑PC2 ⇑

L-/K-cells

DPP4inactivationdegradation

+

AC

pancreaticβ-cell

DPP4 inhibitors‚gliptins‘sitagliptin

vildagliptinsaxagliptin

GLP1R agonistsincretin mimetics

exenatideliraglutidedulaglutide

glucose

L-type Ca2+

insulin

TCF7L2

Gs PKAATP

cAMP

glucose

ATPCa2+-

KATP

+

[Ca2+]i ↑GLP-1

GIP

K+

insulin ⇓GIP-R ⇓GLP-1-R ⇓PC1 ⇓PC2 ⇓

+

AC

pancreaticβ-cell

glucose

Effects of TCF7L2 rs7903146

L-/K-cells

Schäfer S et al., Diabetologia 2007Haupt A, …, Staiger H, Diabetes 2010 Heni M, …, Staiger H et al., Diabetes 2010Müssig K, Staiger H et al., Diabetologia 2010Heni M et al., Diabetes Care 2012Ordelheide A., …, Staiger H, Mol. Metab. 2013Wagner R, Staiger H et al. Mol. Metab. 2014

L-type Ca2+

insulin ⇓

TCF7L2

Gs PKAATP

cAMP

glucose

ATPCa2+-

KATP

+

[Ca2+]i ↑GLP-1

GIP

K+

insulin ⇓GIP-R ⇓GLP-1-R ⇓PC1 ⇓PC2 ⇓

+

AC

pancreaticβ-cell

glucose

L-/K-cells

Schäfer S et al., Diabetologia 2007Haupt A, …, Staiger H, Diabetes 2010 Heni M, …, Staiger H et al., Diabetes 2010Müssig K, Staiger H et al., Diabetologia 2010Heni M et al., Diabetes Care 2012Ordelheide A., …, Staiger H, Mol. Metab. 2013Wagner R, Staiger H et al. Mol. Metab. 2014

L-type Ca2+

Effects of TCF7L2 rs7903146

Incretin Resistance due to TCF7L2 rs7903146

CC

CT+TT

Schäfer S et al., Diabetologia 2007

Zimdahl H et al., Diabetologia 2014

Pharmacogenetic Importance of TCF7L2 rs7903146

960 T2D patients, linagliptin 1x5 mg, 24 weeks

placebo

linagliptin



placebo

linagliptin


27.6 % of drug-treated T2D patients on DPP4 inhibitors (2017, Germany)frequency of T/T = 16 %

330,000 T2D patients with limited treatment response



placebo

linagliptin


33.2 % of drug-treated T2D patients on DPP4 inhibitors or GLP1R agonistsfrequency of T/T = 16 %

400,000 T2D patients with limited treatment response

Nor-1 – A Novel Incretin-Sensitive Transcription Factor

Ordelheide A, …, Staiger H, Mol. Metab. 2013

insulin

Gs

PKA

ATP

cAMP

Glucose

ATPCa2+-

KATP

+

[Ca2+]i ↑

K+

AC

pancreaticβ-cell

GLP-1GIP

Nor-1

Nor-1

TCF7L2

+

CREB

+

L-type Ca2+


insulin

PKA

ATP

cAMP

Glucose

ATPCa2+-

KATP

+

[Ca2+]i ↑

K+

pancreaticβ-cell

GLP-1GIP

L-type Ca2+

Nor-1 – A Novel Incretin-Sensitive Transcription Factor

TCF7L2

+

Nor-1

+

AC

Gs

insulinVAMP3SYT11HPCANLGN3

Effect of NR4A3 rs12686676

insulin

Gs

PKA

ATP

cAMP

Glucose

ATPCa2+-

KATP

+

[Ca2+]i ↑

K+

insulin ⇓VAMP3 ⇓SYT11 ⇓HPCA ⇓NLGN3 ⇓

AC

pancreaticβ-cell

GLP-1GIP

+

Weyrich P, Staiger H et al., BMC Med. Genet. 2009Ordelheide A, …, Staiger H, Mol. Metab. 2013

TCF7L2

+

Nor-1

L-type Ca2+

Effects of TCF7L2 rs7903146 and NR4A3 rs12686676


T TTGGG

Interaction between TCF7L2 rs7903146 and NR4A3 rs12686676


T TT GGG

TCF7L2 RNR4A3 NR

TCF7L2 NRNR4A3 NR

TCF7L2 NRNR4A3 R

TCF7L2 RNR4A3 R

diabetes risk [RR]rel. Insulin secretion [%] 1 1,510090

R = risk alleleNR = non-risk allele

EPIC-Potsdam, N=2700690 incident T2D cases

Schulze MB, Staiger H, unpublished


Spread of Treatment Response of TCF7L2 SNP Carriers

TT + GG ?

TT

TT

TTTT + AA ?


working hypothesis

TT + GG ?

TT

TT

TTTT + AA ?


working hypothesis

33.2 % of drug-treated T2D patients on DPP4 inhibitors or GLP1R agonistsfrequency of T/T + G/G = 7 %

175,000 T2D patients with markedly limited treatment response

Acknowledgements

Transl. DiabetologyAnna-Maria OrdelheideAnja BöhmJohannes KrierMichaela KeuperLucia Berti

IDM/UKTHans-Ulrich HäringAndreas FritscheNorbert StefanAndreas PeterMartin HeniRobert WagnerKonstantinos KantartzisStefan Lutz

DIfEMatthias Schulze

HMGUMartin Hrabě de AngelisHarald GrallertJennifer Kriebel

Boehringer IngelheimHans-Jürgen WörleHeike Zimdahl-Gelling

Lilly GermanyAxel Haupt

Prescription Frequency of OAD (Germany)

Bohn B et al., Diabetologe 2019

Metformin

blood sugar lowering biguanide, since 1958

T2D first-line drug: safe, cheap & efficacious

2x500 mg - 3x1000 mg/day

contraindicated in cases of severe renal and hepaticinsufficiency (lactic acidosis)

gastrointestinal side effects in 25 % of patients, mostlytransient upon dose reduction

discontinuation in 5 % of patients

Galega officinalisgoat‘s-rue

Functional Studies of Gene Variants

carrier of gene variant


Wang X, …, Staiger H et al., Mol. Metab. (in Druck)Wang X, …, Staiger H et al., Stem Cell Res. 2016aWang X, …, Staiger H et al., Stem Cell Res. 2016bBader E, …, Staiger H et al., Nature 2016



Wang X, …, Staiger H et al., Mol. Metab. (in Druck)Wang X, …, Staiger H et al., Stem Cell Res. 2016aWang X, …, Staiger H et al., Stem Cell Res. 2016bBader E, …, Staiger H et al., Nature 2016

generation of isogenic wild-type controls by gene editing(CRISPR/Cas9-based)


Association of NR4A3 with Insulin Secretion

Nor-1 Effects on Insulin Gene Expression and Insulin Secretion


Nor-1 Binding Sites in Insulin Gene Loci


Incretin Responsiveness of Nor-1


pharmacogenetics of type-2 diabetes...pharmacogenetics of type-2 diabetes thessaloniki, may 17 th...

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