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ORIGINAL ARTICLE
Year : 2015  |  Volume : 3  |  Issue : 2  |  Page : 45-49

Diabetic retinopathy in noninsulin-dependent diabetes mellitus and its relation to serum insulin level


Department of Ophthalmology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication7-Nov-2016

Correspondence Address:
Prateep Phadikar
Department of Ophthalmology, King George's Medical University, Chowk, Lucknow - 220 006, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2347-5617.193469

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  Abstract 

Background: Insulin has been shown to directly influence retinal blood flow, vascular tone, and angiogenesis, all of which are active aspects of the pathogenesis of diabetic retinopathy (DR). Intensive administration of insulin can increase vascular endothelial growth factor, potentially leading to transient worsening of retinopathy. Aims: The aim of the study is to access the role of serum insulin levels in various stages of DR in type 2 diabetes mellitus (DM). Settings and Design: This was a tertiary care center-based, cross-sectional, case-control, observational study conducted from April 2014 to March 2015. Materials and Methods: A total of 79 patients were divided into groups - controls (No DM), No DR, nonproliferative DR (NPDR), and proliferative DR (PDR). Serum insulin level was compared with severity of DR. Statistical Analysis: Data were summarized and presented as mean ΁ standard error. The variables of the study groups were compared by analysis of variance. For pairwise comparison between the groups, Tukey's test for multiple comparison was used. Results: No significant difference was found between insulin levels in No DM and No DR groups. On the other hand, the difference was statistically significant on comparison between No DM and NPDR (P < 0.001) and also between No DM and PDR (P < 0.05). However, no such difference in insulin level was observed on comparing NPDR and PDR groups. Conclusion: Serum insulin level has an association with the development of retinopathy patients of noninsulin-dependent DM. However, prospective interventional studies are required to establish such role of serum insulin in DR.

Keywords: Diabetic retinopathy, noninsulin-dependent diabetes mellitus, serum insulin


How to cite this article:
David PK, Yadav A, Phadikar P, Singh V. Diabetic retinopathy in noninsulin-dependent diabetes mellitus and its relation to serum insulin level. Egypt Retina J 2015;3:45-9

How to cite this URL:
David PK, Yadav A, Phadikar P, Singh V. Diabetic retinopathy in noninsulin-dependent diabetes mellitus and its relation to serum insulin level. Egypt Retina J [serial online] 2015 [cited 2020 Apr 7];3:45-9. Available from: http://www.egyptretinaj.com/text.asp?2015/3/2/45/193469


  Introduction Top


The prevalence of type 2 diabetes mellitus (DM) is rising rapidly, presumably because of increasing obesity and reduced activity levels. Insulin resistance and abnormal insulin secretion are central to the development of type 2 DM. [1] Diabetic individuals are 25 times more likely to become legally blind than individuals without DM. Of all microvascular complications in diabetes, retinopathy has been diagnosed in 23.7% among all diabetics, with nonproliferative diabetic retinopathy (NPDR) in 20% and proliferative diabetic retinopathy (PDR) in 3.7%. Insulin has also been shown to directly influence retinal blood flow, vascular tone, and angiogenesis, all of which are active aspects of the pathogenesis of diabetic retinopathy (DR). [2]

Aims and objective

In vivo rodent models and in vitro studies involving cultured human retinal pigment epithelial cells have demonstrated that intensive administration of insulin can increase retinal gene expression of the potent angiogenic and vascular permeability factor, i.e., vascular endothelial growth factor, potentially leading to transient worsening of retinopathy. [3],[4] Intensive insulin therapy to maximize glycemic control, however, is unequivocally associated with long-term decreased risk of the development and progression of DR in patients with either type 1 or type 2 DM. [5] It is considered the most important advancement in diabetes care, leading to prolonged survival of patients with DM. Therefore, effects of insulin in diabetes are still debated and hence we seek to access the role of serum insulin levels in various stages of DR in type 2 DM.


  Materials and Methods Top


A tertiary care center-based, cross-sectional, case-control, observational study was done for the duration of 1 year from April 2014 to March 2015. The study was conducted on patients with noninsulin-dependent DM with or without DR attending the retinal clinic of the department of ophthalmology and diabetic clinic of the department of medicine and nondiabetic, nonhypertensive controls attending the ophthalmology inpatient department (IPD) for cataract surgery from April 2014 to March 2015. Patients attending the retinal clinic and medicine outpatient department having type 2 DM, aged between 30 and 80 years, with a fair glycemic control as decided by glycosylated hemoglobin levels (≤8) and having blood urea and serum creatinine within normal limits with no albuminuria and normal blood pressure (with treatment or otherwise) were included in the study. In bilateral cases, the eye with more severe form of the disease was considered.

Patient with any other ocular disease such as glaucoma, optic nerve disease, intraocular inflammation, or any media opacity obscuring visualization of fundus and systemic disease affecting the retinal vascular pathology such as anemia, pregnancy, nondiabetic renal disease, obstructive uropathy, severe heart failure, liver disease, cancer, or autoimmune disease were excluded from the study.

Every eligible patient was enrolled into the study after taking an informed consent.

Protocol followed for the patient included detailed history, age, sex, duration of symptoms, duration since diagnosed as a case of diabetic neuropathy (if already diagnosed), current medications for DM (insulin, oral hypoglycemic agents, diet control, or exercise), history of previous or concomitant ocular disease, if any, history of any other systemic disease (hypertension, renal disease). Detailed general and systemic evaluation with special emphasis was laid on cardiovascular, respiratory, and excretory system of the patient with regard to diabetic status. Diabetic status was evaluated with glycosylated hemoglobin.

Ocular examination included best-corrected visual acuity, intraocular pressure (Goldman's applanation tonometer), slit-lamp examination, and fundus evaluation.

Cases were divided into patients of DM with No DR, NPDR, PDR. Further stratification was done on the basis of duration of DM: <5 years, 5-10 years, >10 years controls included age-, sex-, and body mass index (BMI)-matched nondiabetic, nonhypertensive patients admitted in ophthalmology IPD for cataract surgery.

For diagnosis of DM, the American Diabetes Association guidelines for diagnosis of DM was followed: fasting plasma glucose level ≥126 mg/dl, 2-h plasma glucose level ≥140 mg/dl during an oral glucose tolerance test, and random plasma glucose level ≥200 mg/dl with symptoms (polyuria, polydipsia, etc.). Patients were grouped under nonproliferative and proliferative retinopathy based on the Early Treatment of Diabetic Retinopathy Study classification and guidelines. Fundus examination was done with slit-lamp biomicroscopy with ninety diopter lens by a retina specialist with 10-year experience in this field. A total of 79 patients were recruited under the above-mentioned groups and subgroups.

Assay of serum insulin was carried out using the Accubind Lilac Insulin Microplate ELISA test procured from Monobind Inc., Lake Forest, CA, USA. Hematological examination for the estimation of hemoglobin, blood sugar level, glycosylated hemoglobin, serum urea, serum creatinine, serum cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein was measured on an autoanalyzer following the standard protocol.

All experiments pertaining to human subjects were performed according to approval from the Institutional Ethics Committee and in accordance with the Declaration of Helsinki.

Data were summarized and presented as mean ± standard error. The variables of the study groups - controls, No DR, NPDR, and PDR - were compared by one-factor analysis of variance. For pairwise comparison between the groups, Tukey's test for multiple comparison was used. Pearson correlation analysis was used to assess association between the variables. P < 0.05 was considered statistically significant.


  Observations and Results Top


A total of 79 patients were included in this study conducted from April 2014 to March 2015. The enrolled patients were then divided into cases: diabetes mellitus with No DR (n = 20), NPDR (n = 20), PDR (n = 18). Controls included nondiabetic, nonhypertensive patients aged 30-80 years admitted to the department of ophthalmology for cataract surgery (n = 21) [Table 1],[Table 2],[Table 3],[Table 4],[Table 5],[Table 6],[Table 7],[Table 8] and [Table 9].
Table 1: Age distribution of patients

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Table 2: Sex distribution of the patients

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Table 3: Distribution of the patients according to treatment

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Table 4: Comparison of duration of disease

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Table 5: Distribution of patients according to body mass index

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Table 6: Comparison of blood sugar

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Table 7: Comparison of glycated hemoglobin among the different diagnoses

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Table 8: Tukey's post hoc multiple comparison test of glycated hemoglobin among the diagnosis groups

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Table 9: Comparison of insulin level

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On further analysis by Tukey's post hoc multiple comparison test, no significant difference was found between insulin levels in No DM and No DR groups. On the other hand, the difference was statistically significant on comparison between control group (No DM) and NPDR (P < 0.001) and also between No DM and PDR (P < 0.05). However, no such difference in insulin level was observed on comparing NPDR and PDR groups.


  Discussion Top


The role of levels of serum insulin as a predictor of risk of development of diabetes and its progression has been estimated. [6] It is also well established in cases of macrovascular complications such as atherosclerosis. [7] Role of serum insulin in pathogenesis of diabetic microvascular complication, DR is still debated. Therefore, in our cross-sectional study, we aimed to evaluate the status of serum insulin levels and its association with severity of diabetic neuropathy.

The chances of DR increased with age in a study performed by Agrawal et al. [8] No significant difference was found in the age of different groups in the present study. The mean age of patients attending our clinic ranged from 51 to 55 ± 8, and the increase in age did not correspond to severity of disease. Varma et al. [9] found that men had 50% greater risk of developing any retinopathy compared to women. The male to female ratio in our study was 1.13:1. However, this difference was not statistically significant.

Most of the patients in this study were found to be taking oral hypoglycemic agents as part of their treatment for diabetes (40/79; 50.6%). It was found to be used mostly in "No DR" group followed closely by NPDR and then by PDR. The use of insulin was highest in PDR cases. This suggests use of oral hypoglycemic agents as a preferred modality of treatment in earlier stages of retinopathy.

Rema and Pradeepa [10] concluded that one of the major systemic risk factors for onset and progression of DR was duration of diabetes. In the present study, mean duration of diabetes was more in patients of PDR compared to diabetics without retinopathy and NPDR, thus agreeing to the findings of the aforementioned study.

The BMI of all study groups was comparable, and no significant difference was observed in any group regardless of the presence or absence of disease or its severity. On the other hand, in a population-based cross-sectional study by Van Leiden et al., [11] the prevalence of DR was positively associated with BMI. No such association was found in our study.

Higher values of glycosylated hemoglobin were found in PDR than other retinopathy groups, and it differed significantly between diabetics and nondiabetics. This was in accordance to general consensus by various studies of a positive correlation of hemoglobin A1c levels and severity of retinopathy. [12],[13]

In the present study, a significant difference was observed in serum insulin levels among study groups (P = 0.001). No significant difference was found between insulin levels in nondiabetics and patients of DM without retinopathy. On the other hand, the difference was significant on comparison between control group (No DR) and NPDR (P < 0.001) and also between No DM and PDR (P < 0.05), indicating a definite association between the presence of retinopathy and serum insulin levels. However, no such difference was observed on comparing NPDR and PDR groups signifying the absence of correlation with severity of disease. The Rotterdam study [14] conducted on 6191 patients concluded that there was no association of serum insulin levels with severity of retinopathy. On other hand, the UKPDS, a 23-center study of 2964 patients found severity of retinopathy related to lower serum insulin levels.

These findings may be explained by variation in levels of insulin secretion with severity of diabetes. Insulin secretion is initially higher as insulin resistance progressively increases in the body with worsening of diabetic status. However, as resistance becomes very high, beta cells of the pancreas go into decompensation and are unable to keep insulin secretion in tune with resistance. This leads to decreased insulin levels in worse form of disease. Thus, patients with worse stage of retinopathy, i.e., PDR may have insulin levels anywhere from very low to very high and hence cannot be used to definitely predict severity in these cases. These findings nevertheless may have clinical implications in predicting diabetic patients at risk of developing retinopathy. Serum insulin levels may thus indicate propensity for development of complications in diabetic individuals without retinopathy and with higher insulin levels, i.e., having higher insulin resistance. This association may help physicians decide a more effective management of such patients with drugs targeting insulin resistance rather than those increasing its secretion. Serum insulin levels were found to be higher in NPDR cases indicating increased resistance and increased compensatory insulin secretion in this group. On the other hand, levels in the PDR were variable, ranging from low to very high, indicating different phases of pancreatic response to increased insulin resistance. Measuring insulin levels in diabetic individuals routinely may give an insight into their pancreatic secretory capacity and help detect pancreatic decompensation early on. Such patients can be managed much more effectively and in a timely manner by insulin supplementation rather than use of secretagogues, thus bringing about a better control of disease.

To summarize, serum insulin level was found to be higher in patients of noninsulin-dependent diabetes mellitus as compared to reference population. Serum insulin level is higher in patients of DR than reference population. Level of serum insulin is significantly associated with the presence of retinopathy in patient population.

The major limitation in our study is the sample size which limits its predictive value for general population. This being a cross-sectional study of a small duration cannot comment on progression of disease and its association with serum insulin levels. We can only predict a trend toward correlation, but more prospective interventional studies are required to assess the role of serum insulin level as a useful marker of the risk of complications in diabetic individuals and to advocate therapy based on those findings.


  Conclusion Top


Serum insulin level has an association with the development of retinopathy patients of noninsulin-dependent DM. This may help in deciding future therapeutic modalities based on insulin levels. However, prospective interventional studies are required to establish such role of serum insulin in the management of DR.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Fauci A, Braunwald E, Isselbacher K, Wilson J, Kasper D. Diabetes mellitus. In: Harrison′s Textbook of Internal Medicine. 18 th ed. New York: McGraw-Hill Medical Publishing Division; 2012. p. 2167-98.  Back to cited text no. 1
    
2.
Anfossi G, Russo I, Doronzo G, Trovati M. Relevance of the vascular effects of insulin in the rationale of its therapeutical use. Cardiovasc Hematol Disord Drug Targets 2007;7:228-49.  Back to cited text no. 2
    
3.
Lu M, Amano S, Miyamoto K, Garland R, Keough K, Qin W, et al. Insulin-induced vascular endothelial growth factor expression in retina. Invest Ophthalmol Vis Sci 1999;40:3281-6.  Back to cited text no. 3
    
4.
Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, et al. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. J Clin Invest 2002;109:805-15.  Back to cited text no. 4
    
5.
Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol 2008;126:1707.  Back to cited text no. 5
    
6.
Brancati FL, Kao WH, Folsom AR, Watson RL, Szklo M. Incident type 2 diabetes mellitus in African American and white adults: The Atherosclerosis Risk in Communities Study. JAMA 2000;283:2253-9.  Back to cited text no. 6
    
7.
Carnethon MR, Palaniappan LP, Burchfiel CM, Brancati FL, Fortmann SP. Serum insulin, obesity, and the incidence of type 2 diabetes in black and white adults: The atherosclerosis risk in communities study: 1987-1998. Diabetes Care 2002;25:1358-64.  Back to cited text no. 7
    
8.
Agrawal RP, Ranka M, Beniwal R, Gothwal SR, Jain GC, Kochar DK, et al. Prevalence of diabetic retinopathy in type 2 diabetes in relation to risk factors: Hospital based study. Int J Diabetes Dev Ctries 2003;23:16-9.  Back to cited text no. 8
    
9.
Varma R, Macias GL, Torres M, Klein R, Peña FY, Azen SP. Los Angeles Latino Eye Study Group. Biologic risk factors associated with diabetic retinopathy: The Los Angeles Latino Eye Study. Ophthalmology 2007;114:1332-40.  Back to cited text no. 9
    
10.
Rema M, Pradeepa R. Diabetic retinopathy: An Indian perspective. Indian J Med Res 2007;125:297-310.  Back to cited text no. 10
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11.
van Leiden HA, Dekker JM, Moll AC, Nijpels G, Heine RJ, Bouter LM, et al Blood pressure, lipids, and obesity are associated with retinopathy: The hoorn study. Diabetes Care 2002;25:1320-5.  Back to cited text no. 11
    
12.
Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527-32.  Back to cited text no. 12
    
13.
Raman R, Verma A, Pal SS, Gupta A, Vaitheeswaran K, Sharma T. Influence of glycosylated hemoglobin on sight-threatening diabetic retinopathy: A population-based study. Diabetes Res Clin Pract 2011;92:168-73.  Back to cited text no. 13
    
14.
Stolk RP, Vingerling JR, de Jong PT, Dielemans I, Hofman A, Lamberts SW, et al. Retinopathy, glucose, and insulin in an elderly population. The Rotterdam Study. Diabetes 1995;44:11-5.  Back to cited text no. 14
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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