Table 1

Target genes and pathways of nine classes of FDA-approved antidiabetes medications

Medication classMechanism of actionPhysiological effectTissueNumber of target genes*Target genes of antidiabetes medication class*Target genes in LD to known T2D or glycemic trait–associated SNPsReferences
InsulinDownstream signaling from insulin/IGF-I receptorSignals glucose uptakeLiver, muscle, fat17ACACA, AKT1, FOXO1, GAB1, INSR, IRS1, IRS2, IRS4, PIK3CA, PIK3R1, SLC2A1, SLC2A2, SLC2A3, SLC2A4, SLC2A5, SHC1, TRIB3IRS1: T2D, fasting insulin, insulin resistance; SLC2A2 (GLUT2): fasting glucose11,19,42
Metformin (biguanide)AMP-activated protein kinase pathway; complex I inhibitionImproves insulin sensitivity; reduces gluconeogenesisLiver, muscle6PRKAA2, SLC22A1, SLC22A2, SLC2A1, SLC2A4, STK1120,30
TZDsPPARG receptor pathwayFat, muscle, liver42ABCA1, ACSL1, ADIPOQ, ADIPOR1, ADIPOR2, APOA1, APOC3, CCL2, CD36, CPT1A, CPT1B, CPT2, CRP, EDN1, F3, FACL2, FGB, GK, HSD11B1, ICAM1, IL6, IRS1, IRS2, MMP9, NFKB1, NFKB2, NOS2A, PDK4, PIK3CA, PIK3R1, PPARA, PPARD, PPARG, PTGS1, RETN, RXRA, SCARB1, SLC2A4, SLC27A1, SORBS1, TNF, VCAM1PPARG: T2D; IRS1: T2D, fasting insulin11,21,22,42
SulfonylureasATP-sensitive K channel inhibitionIncreases insulin production and secretion from β-cells in pancreas and/or decreases glucagon secretion from α-cells in pancreasPancreas, liver, fat5ABCC8, ABCC9, KCNJ11, SLC2A4, TNFKCNJ11: T2D ABCC8: T2D2325
GLP-1 receptor agonistsGLP-1 receptor pathwayPancreas, GI tract18ATF4, BCL2, CASP12, CPA1, DDIT3, EIF2S1, GCG, GLP1R, HSPA5, JUNB, NGFB, NGFR, PDX1, PPP1R15A, PPYR1, PRKACA, XBP1, XIAPPDX1: fasting glucose1618
DPP4 inhibitorsInhibits DPP4 degradation (i.e., GLP-1, GIP)Diffuse20ADCYAP1, CCL11, CCL5, CCL22, CXCL9, CXCL10, CXCL11, CXCL12, DPP4, DPP8, DPP9, FAP, GHRH, GIP, GIPR, GRP, GLP2R, NPY, PYY, TAC1GIPR: T2D, fasting glucose, 2-h glucose, 2-h insulin18,26
Amylin mimeticsAmylin receptor pathwayPancreas, GI tract2IAPP, IDEIDE: T2D27
MeglitinidesATP-sensitive K channel inhibitionPancreas, liver, fat2ABCC8, KCNJ11KCNJ11/ABCC8: T2D28
α-Glucosidase inhibitorsInhibits α-glucosidase enzymes, α-amylase inhibitionAffects sugar absorption in gut by preventing digestion of carbohydratesSmall intestine, pancreas2AMY2A, GAA29
  • GI, gastrointestinal.

  • *Genes involved in pathways targeted by antidiabetes medications were compiled from the literature.

  • †Validated SNP associations are based on GWAS of European descent individuals; details of associations are in Supplementary Table 1.

  • ‡These genes were added to our drug target gene list before their association with T2D or a related glycemic trait was reported (3). Genes in boldface refer to drug targets in LD to SNPs associated with T2D or glycemic traits.