Evaluation of cytokines in type 1 diabetes patients with and without retinopathy

Diabetes mellitus is one of the greatest public health problems in the world; the numerous complications of this disease are the focus of great concern, as they are related to high morbidity and mortality. Among the complications of diabetes, diabetic retinopathy is the most common microvascular complication.

Objectives:

Evaluate the association of plasma levels of inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), and anti-inflammatory cytokine interleukin-10 (IL-10) with diabetic retinopathy and the correlation of plasma levels of these cytokines together.

Material and method:

125 patients with type 1 diabetes mellitus were included in this study - 55 with retinopathy and 70 without retinopathy. Cytokines IL-6, TNF-α, IFN-γ and IL-10 were determined by flow cytometry.

Results and discussion:

A significant association of the levels of cytokines IL-6, TNF-α, IFN-γ and IL-10 with retinopathy was not observed, possibly because measurements were performed on plasma samples, but not on vitreous humor. However, a positive correlation of cytokines among themselves (p < 0.001) was observed.

Conclusion:

Cytokines IL-6, TNF-α, IFN-γ and IL-10 presented a positive correlation among themselves, what suggests that they may act together in the development and progression of vascular complications in diabetes patients.

Key words:
diabetes mellitus type 1; diabetic retinopathy; cytokines; inflammation

	Patients without retinopathy	Patients with retinopathy	p
Number of individuals (n)	70	55
Males (n, %)	25 (35.7)	20 (36.4)	NS
Age (years)	29 (23-36)	36 (30-43)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p = 0.001
BMI (kg/m²)	23.6 ± 3.2	23.3 ± 3.4	NS
Diabetes duration (years)	15 ± 6	23 ± 5^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p < 0.001
Glucose (mg/dl)	158 (112-246)	134 (80-243)	NS
HbA1c (%)	8.2 ± 1.1	8.5 ± 1.4	NS
AST (U/l)	23 (19-30)	23 (18-27)	NS
ALT (U/l)	29 ± 10	30 ± 9	NS
Albumin (g/dl)	4 ± 0.4	4 ± 0.5	NS
Urea (mg/dl)	29 (26-34)	39 (30-57)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p < 0.001
Creatinine (mg/dl)	0.8 (0.68-0.92)	1 (0.73-1.51)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p = 0.001
Glomerular filtration rate (ml/min/1.73 m²)	104 (82-116)	69 (42-106)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p < 0.001
Albuminuria (mg/g)	4 (3-5)	17 (7-57)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p < 0.001
Cystatin C (mg/l)	0.76 (0.64-0.87)	1.08 (0.78-2.04)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p < 0.001
Family history of diabetes (n, %)	41 (58.6)	39 (70.9)	NS
Tobacco smoking (n, %)	6 (8.6)	5 (9.1)	NS
Physical activity (n, %)	29 (41.4)	22 (40)	NS
Neuropathy (n, %)	6 (8.6)	14 (25.5)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p = 0.010
Use of statins (n, %)	14 (20)	26 (47.3)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p = 0.001
Use of anti-hypertensive drug (n, %)	34 (48.6)	46 (83.6)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p < 0.001
Use of ASA (n, %)	5 (7.1)	16 (29.1)^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid.	^* * p < 0.05 for patients with retinopathy compared with patients without retinopathy. NS: not significant; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine transaminase; ASA: acetylsalicylic acid. p = 0.001
Use of thyroxine (n, %)	9 (12.9)	9 (16.4)	NS

	IFN-γ (pg/ml)	IL-6 (pg/ml)	IL-10 (pg/ml)	TNF-α (pg/ml)
IFN-γ (pg/ml)	-	-	-	-
IL-6 (pg/ml)	0.757^ p < 0.01.	-	-	-
IL-10 (pg/ml)	0.826^ p < 0.01.	0.602^ p < 0.01.	-	-
TNF-α (pg/ml)	0.54^ p < 0.01.	0.461^ p < 0.01.	0.686^ p < 0.01.	-

	IFN-γ (pg/ml)	IL-6 (pg/ml)	IL-10 (pg/ml)	TNF-α (pg/ml)
IFN-γ (pg/ml)	-	-	-	-
IL-6 (pg/ml)	0.256	-	-	-
IL-10 (pg/ml)	0.956^ p < 0.01.	0.373^ p < 0.01.	-	-
TNF-α (pg/ml)	0.393^ p < 0.01.	0.477^ p < 0.01.	0.51^ p < 0.01.	-

	IFN-γ (pg/ml)	IL-6 (pg/ml)	IL-10 (pg/ml)	TNF-α (pg/ml)
IFN-γ (pg/ml)	-	-	-	-
IL-6 (pg/ml)	0.41	-	-	-
IL-10 (pg/ml)	0.811^ p < 0.01.	0.732^ p < 0.01.	-	-
TNF-α (pg/ml)	0.744^ p < 0.01.	0.713^ p < 0.01.	0.885^ p < 0.01.	-

	IFN-γ (pg/ml)	IL-6 (pg/ml)	IL-10 (pg/ml)	TNF-α (pg/ml)
IFN-γ (pg/ml)	-	-	-	-
IL-6 (pg/ml)	0.312^* * p < 0.05;	-	-	-
IL-10 (pg/ml)	0.939^ p < 0.01.	0.406^ p < 0.01.	-	-
TNF-α (pg/ml)	0.412^ p < 0.01.	0.492^ p < 0.01.	0.535^ p < 0.01.	-

	Patients without retinopathy	Patients with retinopathy	p
IFN-γ (pg/ml)	98.4 ± 23.2	104.8 ± 29.8	NS
IL-6 (pg/ml)	16.4 ± 2.6	16.3 ± 2	NS
IL-10 (pg/ml)	1,166 ± 215.6	1,154.5 ± 214.5	NS
TNF-α (pg/ml)	169.1 ± 101.9	175.8 ± 94.9	NS

Sociedade Brasileira de Patologia Clínica, Rua Dois de Dezembro,78/909 - Catete, CEP: 22220-040v - Rio de Janeiro - RJ, Tel.: +55 21 - 3077-1400 / 3077-1408, Fax.: +55 21 - 2205-3386 - Rio de Janeiro - RJ - Brazil
E-mail: jbpml@sbpc.org.br

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[1] CORRESPONDING AUTHOR: Caroline Pereira Domingueti Universidade Federal de São João del-Rei; campus Centro-Oeste, Dona Lindu; Rua Sebastião Gonçalves Coelho, 400; Chanadour; CEP: 35501-296; Divinópolis-MG, Brasil; Phone: +55 (37) 99957-2442; e-mail: caroldomingueti@ufsj.edu.br