Effect of Metformin on Glycemic Control Regarding Carriers of the SLC22A1/OCT1 (rs628031) Polymorphism and Its Interactions with Dietary Micronutrients in Type 2 Diabetes

Figures & data

Table 1 Clinical Features and Biochemical Profile of Patients with T2D According to Anti-Hyperglycemic Therapy

n=240	Reference Values	Metformin (Monotherapy)	Dual Therapy (Met+Glib & Met+Ins)	Triple Therapy (Met+Glib+Ins)	p-value
n (%)		112 (47)	108 (45)	20 (8)
Age (years)	-	57.0 ± 12.0	58.5 ± 10.0	54.8 ± 9.6	0.314
Years with T2D	-	4.5 ± 5.4	10.6 ± 9.5	12.8 ± 10.4	5x10-7^a
Sex F/M	-	71/41	66/42	14/6	0.835
Therapy time (years)	-	4.3 ± 5.2	9.3 ± 8.0	12.4 ± 10.2	1x10-8^a
Anthropometric profile
BMI (kg/m^2)	18.5–24.9	30.5 ± 6.3	30.4 ± 6.9	29.8 ± 6.2	0.638
Normal weight n(%)	-	15 (13.4)	17 (15.7)	3 (15.0)	0.526
Overweight n(%)	-	34 (30.4)	33 (30.5)	8 (40.0)
Obesity n(%)	-	43 (38.4)	36 (33.3)	7 (35.0)
Total body fat (%)	M:12–20 F:20–30	34.8 ± 8.6	33.6 ± 8.5	32.8 ± 8.0	0.449
WC (cm)	M:<90 F:<80	101.5 ± 14.6	101.3 ± 12.9	99.0 ± 12.6	0.720
Glycemic profile
Glucose (mg/dL)	<110	126 ± 40.0	166 ± 69.3	161 ± 57.5	2x10-4^b
HbA1c (%)	<6.5	6.6 ± 1.5	8.2 ± 2.2	8.6 ± 1.6	7x10-7^a
TyG index (ratio)	<8.31	9.0 ± 0.5	9.4 ± 0.7	9.5 ± 0.7	0.001^a
I.R (TyG ratio)	-	103 (92.0)	106 (98.1)	18 (90.0)	0.049^b
Glyc Ctrl (HbA1c%)	<7.0	86 (76.8)	38 (35.2)	3 (15)	6x10-8^a
Lipid profile
TC (mg/dL)	<200	174 ± 31.0	179 ± 31.2	184 ± 27.4	0.671
TG (mg/dL)	<150	142 ± 56.5	167 ± 80.7	192 ± 100.7	0.152^b
HDL-c (mg/dL)	>50	46.9 ± 10.9	45.4 ± 10.6	45.9 ± 9.4	0.569
Non-HDL-c (mg/dL)	<130	127.8 ± 28.5	133.4 ± 30.4	138.0 ± 27.6	0.458
LDL-c (mg/dL)	<100	100.3 ± 25.1	100.4 ± 26.3	100.7 ± 25.0	0.989

Notes: Values are presented as mean ± standard deviations, frequencies, and percentages. ^aBy post hoc tests: Metformin monotherapy vs dual therapy and triple therapy, p<0.001. ^bBy post hoc tests: Metformin monotherapy vs dual therapy: Glucose, p<0.001; Insulin Resistance (TyG index), p=0.029; Triglycerides, p=0.025. The one-way ANOVA for quantitative variables and Chi-square test for qualitative variables were the statistical approach. The variables of age and years with T2D were used to fit the analysis.

Abbreviations: T2D, Type 2 Diabetes; Met, Metformin; Glib, Glibenclamide; Ins, Insulin; F, Female; M, Male; BMI, Body Mass Index; WC, Waist Circumference; HbA1c, Glycated haemoglobin; TyG index, Triglyceride-Glucose index; I.R, Insulin Resistance; Glyc Ctrl, Glycemic control; TC, Total-cholesterol; TG, Triglycerides; HDL-c, High-density lipoprotein cholesterol; Non-HDL-c, Non-high-density lipoprotein cholesterol; LDL-c, Low-density lipoprotein cholesterol.

Table 2 Nutrient Intakes of T2D Patients According to Anti-Hyperglycemic Therapy

n=199	Reference Values	Metformin (Monotherapy)	Dual Therapy (Met+Glib & Met+Ins)	Triple Therapy (Met+Glib+Ins)	p-value
n= (%)		90 (45)	91 (46)	18 (9)
Macronutrients
Total energy (Kcal/d)	-	1,575.3 ± 403.3	1,583.9 ± 452.5	1,659.7 ± 393.8	0.858
Total CHO (%E/d)	50–60	51.0 ± 9.6	49.1 ± 9.9	50.3 ± 9.2	0.448
Sugar Total (g/d)	<25	59.7 ± 31.1	51.1 ± 28.9	60.6 ± 29.2	0.108
Total protein (%E/d)	15	17.7 ± 3.4	17.5 ± 2.9	17.4 ± 2.6	0.988
Total fat (%E/d)	<30	30.8 ± 6.1	31.3 ± 6.4	31.0 ± 6.2	0.911
SFA (%E/d)	<7	8.3 ± 2.4	8.5 ± 2.5	9.1 ± 2.6	0.706
MUFA (%E/d)	10–15	10.3 ± 2.8	10.0 ± 2.8	10.1 ± 2.5	0.519
PUFA (%E/d)	>10	7.5 ± 2.5	7.7 ± 2.4	7.4 ± 2.5	0.872
Dietary Chol (mg/d)	<200	245.8 ± 133.5	280.3 ± 174.2	268.5 ± 138.4	0.341
Dietary Fiber (g/d)	>30	20.7 ± 7.1	19.7 ± 7.0	21.8 ± 6.0	0.564
Micronutrients
Sodium (g/d)	2	1.4 ± 0.47	1.5 ± 0.63	1.5 ± 0.48	0.148
Calcium (mg/d)	800	604.2 ± 236.3	618.0 ± 260.0	676.1 ± 251.2	0.545
Potassium (mg/d)	1800	2,491.6 ± 719.9	2,508.9 ± 733.8	2,585.4 ± 914.1	0.982
Magnesium (mg/d)	350	291.6 ± 86.7	291.7 ± 83.0	312.8 ± 94.6	0.718
Zinc (mg/d)	15	8.5 ± 2.8	8.7 ± 4.4	9.0 ± 2.6	0.927
Vitamin D (IU)	400	136.9 ± 90.6	140.7 ± 92.0	168.3 ± 94.1	0.364

Notes: Values are presented as mean ± Standard deviations. The one-way ANOVA was the statistical approach. The variables of age and years with T2D were used to fit the analysis.

Abbreviations: Met, Metformin; Glib, Glibenclamide; Ins, Insulin; CHO, Carbohydrates; SFA, Saturated fatty acids; MUFA, Monounsaturated fatty acids; PUFA, Polyunsaturated fatty acids; chol, cholesterol; Kcal, kilocalories; d, day; mg, milligrams; g, grams.

Table 3 SLC22A1/OCT1 (rs628031) Genotype and Allele Distribution Among Patients with T2D According of the Glycemic and Type of Anti-Hyperglycemic Therapy

		Genotypes				Alleles
	n	GG	GA	AA	p-value	G	A	p-value
n (%)	107	82 (76.6)	23 (21.5)	2 (1.9)		93.5 (87.4)	13.5 (12.6)
Glycemic control
Glycemic control (HbA1c<7%)	63	48 (76.2)	15 (23.8)	0 (0.0)	0.204	55 (88)	8 (12)	1.000
No glycemic control (HbA1c ≥7%)	44	34 (77.3)	8 (18.2)	2 (4.5)		38 (86)	6 (14)
Type of anti-hyperglycemic therapy
Monotherapy (Metformin)	83	63 (75.9)	19 (22.9)	1 (1.2)	0.142	72 (87)	11 (13)	0.208
Dual therapy (Met+Glib/Met+Ins)	23	19 (82.6)	3 (13.0)	1 (4.4)		20 (89)	3 (11)
Triple Therapy (Met+Glib+Ins)	1	0 (0)	1 (100)	0 (0)		1 (100)	0 (0)

Notes: Values are presented as frequencies and percentages. The Chi-square Test was the statistical approach.

Abbreviations: G, Guanine; A, Adenine; Met, Metformin; Glib, Glibenclamide; Ins, Insulin; HbA1c, Glycated hemoglobin.

Table 4 Clinical Features and Biochemical Profile of T2D Patients According to Alleles of Met408Val (rs628031) SLC22A1/OCT1 Polymorphism in Monotherapy with Metformin

n= 83	Reference Values	Allele G	Allele A	p-value
n (%)	–	63 (76)	20 (24)
Age (years)	–	58.6 ± 11.8	55.0 ± 11.8	0.170
Sex, F/M	–	39/24	14/6	0.600
Years with T2D	–	5.3 ± 6.4	2.5 ± 2.7	0.047^a
Therapy time (years)	–	5.0 ± 5.9	2.2 ± 2.1	0.038^a
Anthropometric
BMI (Kg/m^2)	18.5–24.9	29.4 ± 4.9	32.1 ± 8.3	0.426
Normal weight n (%)	–	10 (16)	2 (10)
Overweight n (%)	–	15 (24)	10 (50)	0.215
Obesity n (%)	–	22 (35)	8 (40)
Total body fat (%)	M: 12–20 F: 20–30	34.3 ± 7.9	36.1 ± 8.5	0.476
WC (cm)	M:<90 F:<80	99.3 ± 11.9	106.2 ± 20.0	0.567
Glycemic profile
Glucose (mg/dL)	< 110	127 ± 43.2	124 ± 43.7	0.454
HbA1c (%)	< 6.5	6.6 ± 1.3	6.7 ± 1.9	0.496
Glyc Ctrl (%HbA1c)	<7.0	51 (81)	15 (75)	1.000
TyG index (ratio)	< 8.31	9.0 ± 0.5	8.9 ± 0.5	0.532
I.R. (TyG index)	-	58 (92.1)	19 (95.0)	0.568
Lipid Profile
TC (mg/dL)	< 200	176 ± 30.8	174 ± 31.9	0.717
TG (mg/dL)	< 150	143 ± 63.3	132 ± 40.3	0.862
HDL-c (mg/dL)	>50	49 ± 11.1	46 ± 9.9	0.696
Non-HDL-c (mg/dL)	<130	127 ± 29.6	128 ± 28.7	0.949
LDL-c (mg/dL)	<100	100 ± 26.8	102 ± 23.0	0.746

Notes: Values are presented as mean ± standard deviations, frequencies, and percentages. ^aThe t-student test was the statistical approach, p<0.05.

Abbreviations: T2D, Type 2 Diabetes; F, Female; M, Male; BMI, Body Mass Index; WC, Waist Circumference; HbA1c, Glycated hemoglobin; TyG index, Triglyceride-Glucose index; I.R, Insulin Resistance; Glyc Ctrl, Glycemic control; TC, Total-cholesterol; TG, Triglycerides; HDL-c, High-density lipoprotein cholesterol; Non-HDL-c, Non-high-density lipoprotein cholesterol; LDL-c, Low-density lipoprotein cholesterol; mg, milligrams; dL, deciliters.

Table 5 Nutrient Intake of T2D Patients According to Alleles of the SLC22A1/OCT1 (rs628031) Polymorphism in Monotherapy with Metformin

n= 83	Reference Values	Allele G	Allele A	p-value
n (%)	-	63 (76)	20 (24)
Macronutrients
Total energy (kcal/d)	-	1,603.0 ± 418.2	1,585.0 ± 368.5	1.000
Total CHO (%E/d)	50–60	49.5 ± 10.2	51.1 ± 8.8	0.531
Sugar total (g/d)	<25	55.5 ± 22.3	68.6 ± 46.2	0.133
Total protein (%E/d)	15	17.6 ± 3.8	18.2 ± 3.0	0.551
Total fat (%E/d)	<30	31.6 ± 6.2	30.6 ± 5.9	0.345
SFA (%E/d)	<7	8.4 ± 2.6	8.2 ± 1.8	0.701
MUFA (%E/d)	10–15	10.6 ± 2.7	9.9 ± 2.3	0.330
PUFA (%E/d)	10	7.6 ± 2.3	8.3 ± 3.2	0.851
Dietary Chol (mg/d)	<200	258.4 ± 132.7	257.8 ± 138.7	0.946
Dietary Fiber (g/d)	>30	20.0 ± 7.1	21.1 ± 6.1	0.369
Micronutrients
Sodium (g/d)	2	1.4 ± 0.48	1.5 ± 0.38	0.300
Calcium (mg/d)	800	608.4 ± 252.7	659.2 ± 219.2	0.330
Potassium (mg/d)	1800	2,414.3 ± 589.0	2,425.1 ± 512.5	0.667
Magnesium (mg/d)	350	290.6 ± 92.4	296.5 ± 59.8	0.635
Zinc (mg/d)	15	8.6 ± 2.9	8.3 ± 1.6	0.780
Vitamin D (IU)	400	127 ± 72.6	192 ± 92.6	0.004^a

Notes: Values are presented as mean ± Standard deviations. ^aThe T-student Test was the statistical method approach. p<0.05.

Abbreviations: %E/d, Percentage of Energy /day; CHO, Carbohydrates; SFA, Saturated fatty acids; MUFA, Monounsaturated fatty acids; PUFA, Polyunsaturated fatty acids; chol, cholesterol; Kcal, kilocalories; d, day; mg, milligrams; g, grams.

Figure 1 Interaction and correlation between dietary calcium and OCT1 polymorphism regarding HbA1c. (A) Interaction between dietary calcium and OCT1 polymorphism regarding HbA1c values. (B) Correlation between dietary calcium and HbA1c values within risk allele A carriers + metformin monotherapy adjusted by age, sex and energy intake.

Figure 2 Interaction and correlation between dietary potassium and OCT1 polymorphism regarding the TyG index. (A) Interaction between dietary Potassium and OCT1 polymorphism regarding the TyG index values. (B) Correlation between dietary potassium and TyG index values within risk allele A carriers + metformin monotherapy, adjusted by age, s ex and energy intake.