J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://jocmr.elmerjournals.com

Short Communication

Volume 16, Number 10, October 2024, pages 503-508

Elevated Serum Growth Differentiation Factor 15 Levels as a Potential Biomarker of the Efficacy of Imeglimin in Individuals With Type 2 Diabetes Mellitus: An Exploratory Study

Figure 1. Correlation between Δgrowth differentiation factor 15 (GDF15) and Δglycoalbumin (GA), Δbody mass index (BMI), diabetes history, baseline HbA1c, baseline GA, baseline BMI. Correlation between ΔGDF15 and each parameter is shown as “r”. ΔGDF15 vs. each parameter, *P < 0.05. ns: not significant; HbA1c: glycated hemoglobin.

Figure 2. GDF15 released from imeglimin-treated HepG2 cells. Control (n = 3), 1 µg/mL imeglimin-treated (n = 3), 2 µg/mL imeglimin-treated HepG2 cells (n = 3). Data are mean ± SD. Control vs. imeglimin-treated, *P < 0.05, ns: not significant; SD: standard deviation.

**Table 1.** Profile of the Subjects and Laboratory Data Before, 3, and 6 Months After Initiation of Imeglimin Treatment, and Adverse Effects of Imeglimin During the Study
	Before (n = 16)	3 months (n = 16)	6 months (n = 13)	P value (before vs. 3 months)	P value (before vs. 6 months)
BMI: body mass index; DPP-4i: dipeptidyl peptidase 4 inhibitor; SGLT2i: sodium-glucose cotransporter 2 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; NDR: no diabetic retinopathy; NPDR: non-proliferative diabetic retinopathy; PPDR: pre-proliferative diabetic retinopathy; PDR: proliferative diabetic retinopathy; HbA1c: glycated hemoglobin; GA: glycoalbumin; CPI: C-peptide index; HOMA-β: homeostatic model assessment of β-cell function; HOMA-IR: homeostasis model assessment-insulin resistance; QUICKI: quantitative insulin check index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transpeptidase; LDL-CHO: low-density lipoprotein cholesterol; HDL-CHO: high-density lipoprotein cholesterol; Cre: creatinine; FGF21: fibroblast growth factor 21; GDF15: growth differentiation factor 15; CRP: C-reactive protein: 8-OHdG: 8-hydroxy-2′-deoxyguanosine.
Age (year)	67.5 ± 13.0
Male (%)	43.8
Height (cm)	159.1 ± 10.1
Weight (kg)	64.4 ± 11.0
BMI (kg/m²)	25.4 ± 3.2
Duration of diabetes (year)	11.3 ± 13.1
Concomitant anti-diabetic medications
Metformin (%)	56.3
DPP-4i (%)	37.5
SGLT2i (%)	25
GLP-1RA (%)	12.5
Sulfonylurea (%)	12.5
Glinide (%)	6.3
α-glucosidase inhibitor (%)	0
Complications
Retinopathy (NDR/NPDR/PPDR/PDR) (%)	87.5/12.5/0/0
Nephropathy (stage 1/2/3/4/5) (%)	68.5/26.3/5.2/0/0
Coronary artery disease (%)	12.5
Body weight (kg)	64.4 ± 11.0	63.4 ± 10.1		0.80
BMI (kg/m²)	25.4 ± 3.2	25.0 ± 3.0		0.74
Waist-hip ratio	0.97 ± 0.04	0.96 ± 0.04		< 0.05
HbA1c (%)	7.3 ± 0.7	7.0 ± 0.6	6.7 ± 0.4	< 0.01	< 0.001
GA (%)	17.4 ± 3.7	15.9 ± 2.8	15.1 ± 1.9	< 0.001	< 0.05
Fasting CPI	1.6 ± 0.6	2.3 ± 1.5		< 0.01
HOMA-β	44.0 ± 35.6	66.9 ± 50.6		< 0.05
HOMA-IR	2.4 ± 1.4	3.2 ± 4.2		0.63
QUICKI	0.35 ± 0.04	0.34 ± 0.04		0.56
AST (U/L)	24.3 ± 9.4	24.8 ± 14.3		0.30
ALT (U/L)	30.6 ± 19.9	27.0 ± 16.1		0.16
γGTP (U/L)	28.4 ± 15.6	25.3 ± 14.0		0.23
TG (mg/dL)	143.8 ± 54.5	150.4 ± 66.2		0.62
LDL-CHO (mg/dL)	98.1 ± 27.1	101.2 ± 30.9		0.49
HDL-CHO (mg/dL)	57.7 ± 13.3	55.7 ± 12.6		0.41
Cre (mg/dL)	0.75 ± 0.13	0.79 ± 0.18		0.17
Serum FGF21 (pg/mL)	794.0 ± 1,236.2	483.1 ± 382.9		0.11
Serum GDF15 (ng/mL)	308.5 ± 134.0	425.7 ± 171.3		< 0.05
Urine 8-OHdG (ng/mL)	7.2 ± 3.5	7.0 ± 2.5		0.81
Type IV collagen (ng/mL)	3.4 ± 0.8	3.3 ± 0.8		0.33
Ferritin (ng/mL)	93.1 ± 57.7	89.5 ± 58.3		0.32
CRP (mg/dL)	0.17 ± 0.24	0.17 ± 0.25		0.77
Skeletal muscle mass (kg)	22.7 ± 5.4	22.7 ± 5.2		0.99
Body fat percentage (%)	31.5 ± 8.1	31.7 ± 9.6		0.97
Resting metabolic rate (kcal)	1,284.0 ± 319.9	1,198.0 ± 216.5		0.45
Total energy expenditure (kcal)	1,491.0 ± 371.4	1,391.3 ± 251.4		0.44
Adverse effects of imeglimin during the study
Metabolic and nutritional disorders		Loss of appetite (6.3%, n = 1/16)
Gastrointestinal disorders		Diarrhea (18.8%, n = 3/16), nausea (6.3%, n = 1/16), constipation (6.3%, n = 1/16), soft stool (6.3%, n = 1/16), abdominal bloating (6.3%, n = 1/16)
Laboratory abnormalities		AST elevation (6.3%, n = 1/16)

Table 1. Profile of the Subjects and Laboratory Data Before, 3, and 6 Months After Initiation of Imeglimin Treatment, and Adverse Effects of Imeglimin During the Study

Before (n = 16)

3 months (n = 16)

6 months (n = 13)

P value (before vs. 3 months)

P value (before vs. 6 months)

BMI: body mass index; DPP-4i: dipeptidyl peptidase 4 inhibitor; SGLT2i: sodium-glucose cotransporter 2 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; NDR: no diabetic retinopathy; NPDR: non-proliferative diabetic retinopathy; PPDR: pre-proliferative diabetic retinopathy; PDR: proliferative diabetic retinopathy; HbA1c: glycated hemoglobin; GA: glycoalbumin; CPI: C-peptide index; HOMA-β: homeostatic model assessment of β-cell function; HOMA-IR: homeostasis model assessment-insulin resistance; QUICKI: quantitative insulin check index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γGTP: γ-glutamyl transpeptidase; LDL-CHO: low-density lipoprotein cholesterol; HDL-CHO: high-density lipoprotein cholesterol; Cre: creatinine; FGF21: fibroblast growth factor 21; GDF15: growth differentiation factor 15; CRP: C-reactive protein: 8-OHdG: 8-hydroxy-2′-deoxyguanosine.

Age (year)

67.5 ± 13.0

Male (%)

43.8

Height (cm)

159.1 ± 10.1

Weight (kg)

64.4 ± 11.0

BMI (kg/m²)

25.4 ± 3.2

Duration of diabetes (year)

11.3 ± 13.1

Concomitant anti-diabetic medications

Metformin (%)

56.3

DPP-4i (%)

37.5

SGLT2i (%)

GLP-1RA (%)

12.5

Sulfonylurea (%)

12.5

Glinide (%)

6.3

α-glucosidase inhibitor (%)

Complications

Retinopathy (NDR/NPDR/PPDR/PDR) (%)

87.5/12.5/0/0

Nephropathy (stage 1/2/3/4/5) (%)

68.5/26.3/5.2/0/0

Coronary artery disease (%)

12.5

Body weight (kg)

64.4 ± 11.0

63.4 ± 10.1

0.80

BMI (kg/m²)

25.4 ± 3.2

25.0 ± 3.0

0.74

Waist-hip ratio

0.97 ± 0.04

0.96 ± 0.04

< 0.05

HbA1c (%)

7.3 ± 0.7

7.0 ± 0.6

6.7 ± 0.4

< 0.01

< 0.001

GA (%)

17.4 ± 3.7

15.9 ± 2.8

15.1 ± 1.9

< 0.001

< 0.05

Fasting CPI

1.6 ± 0.6

2.3 ± 1.5

< 0.01

HOMA-β

44.0 ± 35.6

66.9 ± 50.6

< 0.05

HOMA-IR

2.4 ± 1.4

3.2 ± 4.2

0.63

QUICKI

0.35 ± 0.04

0.34 ± 0.04

0.56

AST (U/L)

24.3 ± 9.4

24.8 ± 14.3

0.30

ALT (U/L)

30.6 ± 19.9

27.0 ± 16.1

0.16

γGTP (U/L)

28.4 ± 15.6

25.3 ± 14.0

0.23

TG (mg/dL)

143.8 ± 54.5

150.4 ± 66.2

0.62

LDL-CHO (mg/dL)

98.1 ± 27.1

101.2 ± 30.9

0.49

HDL-CHO (mg/dL)

57.7 ± 13.3

55.7 ± 12.6

0.41

Cre (mg/dL)

0.75 ± 0.13

0.79 ± 0.18

0.17

Serum FGF21 (pg/mL)

794.0 ± 1,236.2

483.1 ± 382.9

0.11

Serum GDF15 (ng/mL)

308.5 ± 134.0

425.7 ± 171.3

< 0.05

Urine 8-OHdG (ng/mL)

7.2 ± 3.5

7.0 ± 2.5

0.81

Type IV collagen (ng/mL)

3.4 ± 0.8

3.3 ± 0.8

0.33

Ferritin (ng/mL)

93.1 ± 57.7

89.5 ± 58.3

0.32

CRP (mg/dL)

0.17 ± 0.24

0.17 ± 0.25

0.77

Skeletal muscle mass (kg)

22.7 ± 5.4

22.7 ± 5.2

0.99

Body fat percentage (%)

31.5 ± 8.1

31.7 ± 9.6

0.97

Resting metabolic rate (kcal)

1,284.0 ± 319.9

1,198.0 ± 216.5

0.45

Total energy expenditure (kcal)

1,491.0 ± 371.4

1,391.3 ± 251.4

0.44

Adverse effects of imeglimin during the study

Metabolic and nutritional disorders

Loss of appetite (6.3%, n = 1/16)

Gastrointestinal disorders

Diarrhea (18.8%, n = 3/16), nausea (6.3%, n = 1/16), constipation (6.3%, n = 1/16), soft stool (6.3%, n = 1/16), abdominal bloating (6.3%, n = 1/16)

Laboratory abnormalities

AST elevation (6.3%, n = 1/16)