Diabetic Retinopathy in Relation with eGDR Value in Patients with Type 1 Diabetes Mellitus

DIANA CLENCIU1#, TIBERIU STEFANITA TENEA COJAN2*, ANDA LORENA DIJMARESCU3#, CRISTINA GABRIELA ENE4, DRAGOS VIRGIL DAVITOIU5#, VLAD DUMITRU BALEANU6#, COSMIN ALEXANDRU CIORA7, BOGDAN SOCEA8, DANIEL-IULIAN VOICULESCU9#, RAMONA-MIHAELA NEDELCUTA10#, VERONICA CALBOREAN11#, VICTOR GHEORMAN12#, IONELA MIHAELA VLADU13 1University of Medicine and Pharmacy of Craiova, Department of Metabolism and Nutrition Diseases, Filantropia Clinical Hospital of Craiova, 1 Filantropiei Str., 200143, Craiova, Romania 2University of Medicine and Pharmacy of Craiova, Department of Surgery, CFR Hospital of Craiova, Stirbei-Voda Str., 200374,Craiova, Romania 3University of Medicine and Pharmacy of Craiova, Obstretics-Gynecology Department, Filantropia Clinical Hospital of Craiova , 1 Filantropiei Str., 200143, Craiova, Romania 4University of Medicine and Pharmacy of Craiova, Pharmacology Department, County Hospital of Craiova, 2-4 Petru Rares Str., 200349, Craiova, Romania 5University of Medicine and Pharmacy of Bucharest, Surgery Department, Clinical Emergency Hospital Sf. Pantelimon Bucharest, 340-343 Pantelimon Road, 021659, Bucharest, Romania 6University of Medicine and Pharmacy of Craiova, Surgery Department, Clinical Emergency Hospital Sf. Pantelimon Bucharest, 340-343 Pantelimon Road, 021659, Bucharest, Romania 7Carol Davila University of Medicine and Pharmacy, Discipline of Gastroenterology and Hepatology, 8 Eroii Revolutiei Blvd., 050474, Bucharest, Romania 8General Surgery Clinic, Emergency Clinical Hospital Sfantul Pantelimon, 340-342 Pantelimon Road, 021659, Bucharest, Romania 9University of Medicine and Pharmacy Carol Davila Bucharest, Department ofSurgery Universitary Emergency Hospital Bucharest, 169 Splaiul Indepenei, 050098, Bucharest, Romania 10University of Medicine and Pharmacy of Craiova, Pediatrics Department, 2 Petru Rares Str., 200349, Craiova, Romania 11University of Medicine and Pharmacy of Craiova, Cardiology Department, 2 Petru Rares Str., 200349, Craiova, Romania 12University of Medicine and Pharmacy of Craiova, Psychiatry Department, Neuropsychiatry Hospital of Craiova, 24 Aleea Potelu Str., 200473, Craiova, Romania 13University of Medicine and Pharmacy of Craiova, Department of Metabolism and Nutrition Diseases, Filantropia Clinical Hospital of Craiova, 1 Filantropiei Str., 200143, Craiova, Romania

Type 1 diabetes mellitus (T1DM) is a chronic disease which represents a major issue for public health. Type 1 diabetes is occurred most frequently in childhood and adolescence, although in recent years due to the increase in the prevalence of obesity in this category of population has been registered a growing number of cases of type 2 diabetes among children and adolescents (1,2).
Keywords: Type 1 diabetes mellitus, diabetic retinopathy, insulin resistance Type 1 diabetes mellitus (T1DM) is a chronic disease which represents a major issue for public health. Type 1 diabetes is occurred most frequently in childhood and adolescence, although in recent years due to the increase in the prevalence of obesity in this category of population has been registered a growing number of cases of type 2 diabetes among children and adolescents [1,2].
As a result of the vascular complications, diabetes is the main cause of blindness, being responsible for up to 40% of the cases of kidney failure and is a determinant key of staff morbidity and mortality by cardiovascular cause [3][4][5].
Insulin resistance has been linked to the pathophysiology of type 2 diabetes mellitus (T2DM) and it has been proved to have an important role in the increase of the risk of cardiovascular complications [6][7][8][9][10][11][12]. It has been recently shown that insulin resistance plays an important role in the natural history of type 1 diabetes, although it is generally known that it is mainly due to immune destruction of the β-pancreatic cells [13][14][15].
Ginsberg has studied the association of insulin resistance with T1DM [16][17]. Subsequent studies [18][19][20][21] showed a significant decrease in glucose disposal mediated by insulin among patients with T1DM suggesting the presence of insulin resistance. After a decade this combination has aroused the interest of many research studies [22-30] to investigate the possible mechanisms of insulin resistance in T1DM.

Experimental part
The aim of the study The study aims are to determine the prevalence of diabetic retinopathy in Type 1 DM and to correlate it with the presence of risk factors (lifestyle, disease evolution status, onset of disease, metabolic control). Also, we tried to assess the degree of insulin resistance and its correlation with the occurrence of diabetic retinopathy.

Material and methods
The observational cross sectional survey was conducted over a three-year period 2010-2013. The timing of exploration of the patients under study consisted of a complete initial assessment of inclusion in the study group. *email: doctortts@yahoo.com; Phone: 0746095969 # The authors contributed equally to the manuscript and share first authorship.
The analysed group consisted of 200 subjects with type 1 DM. Patients with DM were recruited unselected from patients who underwent consultations in the specialized ambulatory, met the inclusion and exclusion criteria and signed informed consent. After the data collection, the database was created with EXCEL program.
Diagnosis of diabetic retinopathy was determined by ophthalmological examination and eye photography.
Recorded data were analyzed using the SPSS software 17:00 (IBM Corporation, Armonk, NY, USA). The methods used were: t-test, Mann-Whitney test, Chi-square test, simple binary logistic regression, multiparrametric logistic regression, multiparametric logistic regression with stepwise covariate selection.

Results and discussions
We conducted a study of 200 subjects with type 1 DM (116 males and 84 females). The age at onset of diabetes was on average 21.49 years. The evolution of DM in the studied population was on average 16.21 years ( fig. 1). A total of 6 patients (3%) had a DM duration of over 40 years.
We have statistically analysed the proliferative stage of diabetic retinopathy and there have been statistically significant differences between patients with proliferative diabetic retinopathy and those without proliferative retinopathy in terms of age, duration of diabetes, eGDR, presence of hypertension, dyslipidemia and of hyperuricemia (table 1).
The mean age of patients with proliferative diabetic retinopathy and the duration of progression of diabetes is higher than those without proliferative diabetic retinopathy, the difference between the two groups being ver y statistically significant (p<0.001).
Hypertension and hyperuricemia are present in more than half of the patients with proliferative diabetic retinopathy (49.1% and 56.7% vs. 48.9% and 43.1%, p  <0.001), while for dyslipidemia the situation is vice versa in the sense that it is higher percentage in patients without diabetic retinopathy. The HbA1c value is higher in patients with proliferative retinopathy consistent with literature data, but in our study the correlation with the occurrence and progression of retinopathy is statistically insignificant (8.69 ± 1.77 vs. 8.27 ± 1.47, p = 0.069). This is not conclusive, however, as a determined value was analysed at a given time, with no more HbA1c values determined over the evolution of DM to perform the HbA1c mean of each patient.
The eGDR value (expressed in mg. kg -1 . min -1 ) is lower in patients with proliferative retinopathy than in those without this complication (6.41 vs. 11.66; p <0.001), indicating that patients with proliferative retinopathy exhibit a greater insulin resistance than those without proliferative retinopathy.
By performing the stepwise logistic regression analysis in which all the statistically significant parameters in table 1 were entered, the final regression model shown in table 2 is obtained.     The analysis of the area under the ROC curve used to assess the usefulness of studying the parameters in table 2 as independent predictors for the occurrence of diabetic retinopathy in subjects with type 1 DM shows that duration of DM evolution, followed by eGDR, age, presence of hypertension and dyslipidemia are the best predictors (table 3 and fig. 6).

Conclusions
The results of this study have shown that insulin resistance, quantified by eGDR, is more common in patients with diabetic retinopathy than in those without this complication. In addition, it showed that a low value of eGDR (insulin resistance) is independent associated with the presence of chronic complications of DM.
Older age and a long evolution of DM are factors known and shown in numerous studies to be associated with the development and progression of chronic complications in diabetes, whereas this new concept of insulin resistance has appeared lately in type 1 DM and it has gained ground worldwide being accepted by doctors and researchers. Its association with the emergence of chronic vascular complications in particular triggered the development of several studies that try to explain the link between insulin resistance and type 1 DM [32]. This result is very interesting because the presence of insulin resistance is not universally accepted, although it can be a good indicator of all chronic complications independent of other risk factors.
The present study has shown that insulin resistance is associated with an increased risk of chronic complications, but due to the cross-sectional design of this study, the causal relationship can not be evaluated. However, the existence of this causal relationship and the benefit of the treatment of insulin resistance in T1DM are issues to be debated in the future.