Association between glucose-lowering drugs and circulating insulin antibodies induced by insulin therapy in patients with type 2 diabetes

Table 1 Clinical characteristics, n (%)/95%CI

	IA ≤ 5% (n = 961)	IA > 5% (n = 902)	P value	IA ≤ 1% (n = 278)	IA > 10% (n = 581)	P value
Age (yr)	63.1 (62.3-63.9)	64.5 (63.7-65.2)	0.029	62.6 (61.1-64.2)	65.4 (64.5-66.4)	0.004
Gender (male)	532 (55.4)	472 (52.3)	0.193	155 (55.8)	293 (50.4)	0.175
Smoking	176 (18.3)	120 (13.3)	0.003	69 (24.8)	68 (11.7)	< 0.001
Family history	219 (22.8)	187 (20.7)	0.287	71 (25.5)	121 (20.8)	0.145
BMI (kg/m2)	24.8 (24.6-25)	24.8 (24.6-25)	0.998	24.6 (24.2-25.1)	24.7 (24.4-25.0)	0.854
Duration of insulin use (yr)	8.05 (7.23-8.84)	6.71 (5.99-7.43)	0.011	9.11 (7.42-10.79)	6.80 (5.81-7.78)	0.005
ALT (U/L)	26.7 (24.5-28.9)	23.5 (21.9-25.1)	0.049	30.4 (26.0-34.7)	23.8 (21.6-25.9)	< 0.001
AST (U/L)	20.7 (19.3-22.2)	18.9 (18-19.7)	0.691	21.7 (19.0-24.4)	19.1 (18.1-20.2)	0.513
Creatinine (μmol/L)	77.3 (74.7-80)	80.1 (76.9-83.3)	0.475	79.3 (73.7-84.8)	78.9 (75.4-82.3)	0.820
Uric acid (μmol/L)	308.5 (302.2-314.8)	307.6 (300.1-315)	0.361	310.8 (299.4-322.2)	302.3 (293.1-311.5)	0.083
Total cholesterol (mmol/L)	4.7 (4.4-5.1)	4.8 (4.4-5.1)	0.032	4.3 (4.1-4.4)	4.6 (4.4-4.8)	0.004
Triglyceride (mmol/L)	2 (1.9-2.2)	1.8 (1.7-1.9)	0.058	2.3 (1.8-2.7)	1.7 (1.5-1.8)	0.015
LDL-c (mmol/L)	2 (2-2.1)	2.1 (2.1-2.2)	0.003	1.8 (1.7-1.9)	2.2 (2.1-2.2)	< 0.001
HDL-c (mmol/L)	1.2 (1.2-1.2)	1.2 (1.2-1.3)	0.053	1.2 (1.2-1.3)	1.3 (1.2-1.3)	0.675
White blood cell (× 109)	6 (5.9-6.1)	6 (5.9-6.1)	0.984	5.9 (5.8-6.1)	6.0 (5.9-6.1)	0.922
Neutrophil ratio	59.4 (58.6-60.1)	59.6 (58.9-60.4)	0.829	58.7 (57.3-60.1)	59.6 (58.7-60.6)	0.339
Hemoglobin (g/L)	130.5 (129-132)	129.2 (127.9-130.5)	0.315	129.7 (127.6-131.8)	128 (126.5-129.5)	0.248
FBG (mmol/L)	8.4 (8.2-8.7)	9.1 (8.8-9.4)	< 0.001	7.9 (7.5-8.3)	9.0 (8.7-9.4)	< 0.001
Fasting insulin (mU/L)	22.2 (18.9-25.6)	41.4 (34.2-48.6)	< 0.001	27.4 (21.5-33.2)	54.0 (43.8-64.3)	< 0.001
Insulin-120 min (mU/L)	54.4 (49-59.7)	93 (79-107)	< 0.001	60.7 (52.7-68.7)	115.6 (96.2-134.9)	< 0.001
Fasting CP (ng/mL)	1.5 (1.3-1.6)	1.4 (1.3-1.5)	0.451	1.4 (1-1.8)	1.4 (1.3-1.5)	0.049
CP-120 min (ng/mL)	3.1 (3-3.3)	3 (2.9-3.2)	0.361	3.0 (2.7-3.3)	3.0 (2.8-3.1)	0.569
HOMA2-IR	1.5 (1.4-1.6)	1.7 (1.5,2)	0.191	1.3 (1.2-1.4)	1.7 (1.5-2)	0.025
HOMA2-β	49.1 (46.3-51.8)	46.6 (43.6-49.6)	0.082	48.6 (43.9-53.2)	46.5 (42.7-50.3)	0.107
HbA1c	9 (8.8-9.1)	8.8 (8.7-9)	0.177	8.6 (8.4-8.8)	8.8 (8.7-9.0)	0.102
GAD-Ab (IU/mL)	4.5 (4.2-4.9)	5.6 (5.2-6)	< 0.001	3.3 (2.7-3.9)	5.5 (5.0-6.0)	< 0.001
IA	2.2 (2.1-2.3)	20.4 (19.3-21.5)	< 0.001	0.3 (0.3-0.3)	27.8 (26.7-29.3)	< 0.001
Hypertension	566 (58.9)	547 (60.6)	0.450	176 (63.3)	346 (59.6)	0.297
Fatty liver	291 (30.3)	246 (27.3)	0.167	86 (30.9)	152 (26.2)	0.166
Cancer	36 (3.7)	63 (7)	0.002	5 (1.8)	44 (7.6)	< 0.001
DKD	191 (19.9)	207 (22.9)	0.113	55 (19.8)	124 (21.3)	0.654
Neuropathy	257 (26.7)	273 (30.3)	0.100	72 (25.9)	168 (28.9)	0.372
Retinopathy	263 (27.4)	258 (28.6)	0.570	79 (28.4)	178 (30.6)	0.525
Atherosclerosis	662 (68.9)	638 (70.7)	0.391	188 (67.6)	416 (71.6)	0.233

IA: Insulin antibody; BMI: Body mass index; ALT: Alanine transferase; AST: Aspartate transferase; LDL-c: Low density lipoprotein cholesterol; HDL-c: High density lipoprotein cholesterol; FBG: Fasting blood glucose; CP: C peptide; HOMA2-IR: Homeostasis model assessment 2 of insulin resistance; HOMA2-β: Homeostasis model assessment 2 of β cell function; HbA1c: Hemoglobin A1c; GAD-Ab: Glutamic acid decarboxylase antibody; DKD: Diabetic kidney disease.

Table 2 Logistics regression analysis for risk factors of insulin antibodies

	OR	95%CI	P value
Diabetes duration	1.019	1.001-1.037	0.042
Types of OHAs	0.875	0.771-0.991	0.036
ALT	0.996	0.992-1.000	0.053
Triglyceride	0.920	0.867-0.976	0.005
FBG	1.069	1.029-1.111	0.001
GAD-Ab	1.025	1.004-1.047	0.021
With cancer	0.533	0.310-0.917	0.023

OR: Odds ratio; OHAs: Oral hypoglycemic agents; ALT: Alanine transferase; FBG: Fasting blood glucose; LDL-c: Low density lipoprotein cholesterol; GAD-Ab: Glutamic acid decarboxylase antibody.