TABLE 1:

GENES ASSOCIATED WITH METFORMIN PHARMACOKINETICS OR RESPONSE

Gene	Study Population	Metformin dose	Variant	Phenotype
SLC22A1 (OCT1)	20 healthy volunteers	2 doses 1000mg and 850 mg	R61C (rs12208357), G401S (rs34130495), 420del (rs72552763 and G4665R/rs34059508)	Impaired response to oral glucose tolerance test (Shu et al., 2007)
	20 healthy volunteers	2 doses 1000mg and 850 mg	R61C (rs12208357), G401S (rs34130495), 420del (rs72552763 and G4665R/rs34059508)	Higher AUC, higher Cmax, lower oral volume of distribution (Shu et al., 2008)
	103 healthy male Caucasian volunteers	1 dose of 500 mg	G465R	Increased renal clearance and decreased hepatic uptake (Tzvetkov et al., 2009)
	1531 GoDARTS subjects with type 2 diabetes	Average dose 1260 mg/day	R61C and M420del	No effect on HbA1c reduction(K. Zhou et al., 2009)
	159 Danish South Danish Diabetes Study participants with type 2 diabetes	1000 mg twice a day	R61C (rs12208357), G401S (rs34130495), 420del (rs72552763 and G4665R/rs34059508)	Decrease in trough-steady state metformin concentration and less change in HbA1c over 6 months (Christensen et al., 2011)
	1915 metformin tolerant and 251 metformin intolerant GoDARTS participants	Average dose 1000 mg/day	R61C (rs12208357), G401S (rs34130495), 420del (rs72552763 and G4665R/rs34059508)	2 reduced function alleles associated with metformin intolerance. Higher odds of intolerance in the presence of OCT-1 interacting drugs (Dujic et al., 2015)
	102 subjects with type 2 diabetes from Rotterdam Study	Average dose 677 mg/day	rs622342	Less reduction in HbA1c level(Becker et al., 2009b)
	148 drug naïve Caucasian patients with type 2 diabetes	Average dose ~ 1400mg/day	rs622342	No effect on HbA1c reduction (Tkac et al., 2013)
	990 multi-ethnic DPP participants with pre-diabetes	850 mg twice a day	rs622342	No evidence of interaction with metformin (Jablonski et al., 2010)
SLC22A2(OCT2)	15 healthy Chinese participants	A single dose of 500 mg	808G>T	Reduced metformin renal tubular clearance (Wang et al., 2008)
	26 healthy Korean subjects	A single dose of 500 mg of metformin	596C>T, 602C>T, and 808G>T	Higher Cmax, AUC and lower renal clearance (Song et al., 2008)
	23 healthy Caucasian and African American volunteers	A single dose of 850 mg of metformin	808G>T	Decreased renal clearance and renal clearance by secretion of metformin (Chen et al., 2009)
	371 Danish participants with type 2 diabetes from South Danish Diabetes Study	1000 mg twice a day	rs316019	No effect on metformin concentration or HbA1c response (Christensen et al., 2011)
	990 multi-ethnic DPP participants with pre-diabetes	850 mg twice a day	rs316019	No evidence of interaction with metformin (Jablonski et al., 2010)
SLC47A1(MATE1) and SLC47A2(MATE2)	57 healthy volunteers	2 doses 1000mg and 850 mg	rs2252281 (MATE1) rs12943590 (MATE2)	Renal and secretory clearance of metformin higher in MATE2 carriers who were MATE1 reference. Enhanced OGTT response with MATE1, reduced response with MATE2 (Stocker et al., 2013)
	145 patients with type 2 diabetes	Average dose 938 mg/day	rs2252281 (MATE1)	Greater change in HbA1c level with MATE1(Stocker et al., 2013)
	253 Caucasian and African American subjects with type 2 diabetes	Average dose 938 mg/day	rs12943590 (MATE2-K)	Less reduction in HbA1c (Choi et al., 2011)
	116 Caucasian subjects with type 2 diabetes	Average dose 741 mg	rs2289669 (MATE1)	Decrease in HbA1c (Becker et al., 2009a)
	148 drug naïve Caucasian patients with type 2 diabetes	Average dose ~ 1400mg/day	rs2289669 (MATE1)	Greater reduction in HbA1c(Tkac et al., 2013)
	990 multi-ethnic DPP participants with pre-diabetes	850 mg twice a day	rs8065082 (In LD r2 0.8 with rs2289669) (MATE1)	Poorer response to metformin(Jablonski et al., 2010)
	371 Danish participants with type 2 diabetes from South Danish Diabetes Study	1000 mg twice a day	rs2252281, rs2289669 (MATE1) rs34399035 (MATE2)	No effect on metformin concentration or change in HbA1c (Christensen et al., 2011)
ATM	1,024 Scottish subjects with type 2 diabetes (GWAS Discovery cohort) 2,896 Caucasian subjects with type 2 diabetes (2 Replication cohorts)	The average daily dose during the 3 months prior to the minimum HbA1c was achieved	rs11212617 (intron of C11orf65), in LD with r2>0.8 with SNPs in several genes including ATM, NPAT, KDELC2.	Minor C-allele of rs11212617 is associated with treatment success (K. Zhou et al., 2011). Treatment success was defined as achieving HbA1c <7% in the first 18 months of metformin initiation (n = 3,920, P = 2.9×10−9, odds ratio = 1.35).
SLC2A2 (GLUT2)	3,103 Scottish subjects with type 2 diabetes (GWAS Discovery cohort) 7,454 Caucasian subjects with type 2 diabetes (9 Replication cohorts) 2,526 Non-European subjects with type 2 diabetes (3 different ethnic groups)	The average daily dose during the 3 months prior to the minimum HbA1c was achieved	rs8192675 (intron of SLC2A2)	Minor C-allele of rs8192675 is associated with greater response to metformin (K. Zhou et al., 2016). Response to metformin was defined as baseline HbA1c minus the minimum treatment HbA1c in the first 18 months of metformin initiation (n = 10,557 Caucasians, P = 2.0×10−8, beta = 0.075 (baseline-adjusted model); P=6.6×10−14, beta=0.17 (baseline non-adjusted model)). Also significant in the combined non-European subjects (n = 2,566 Non-Europeans, P = 0.006, beta = 0.077 (baseline-adjusted model); P = 0.005, beta = 0.15 (baseline non-adjusted model)). Minor C-allele of rs8192675 is associated with lower SLC2A2 transcript levels in human liver tissue samples (n=1,226, P<5×10−8)) and other tissues (fibroblasts, islet, intestine) (K. Zhou et al., 2016)