Correlation of tight glycemic control by antidiabetic medications with serum levels of monocyte chemoattractant protein(MCP-1) and cathepsin-D in type 2 diabetes with and without retinopathy.

INTRODUCTION Diabetes mellitus or simply diabetes, is a group of metabolic diseases in which a person has high blood

sugar, either because the body does not produce enough insulin and / or because cells do not respond

to the insulin that is produced. There are two main types of diabetes mellitus(DM). Globally, as of 2015,

an estimated 415 million people had diabetes worldwide, with T2DM making up about 90% of cases

with the other 10% due to  type 1 DM. Type 1 DM results from the body’s failure to produce

insulin. Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly,

sometimes combined with an relative insulin deficiency. Prevention involve maintaining a healthy diet,

regular physical exercise, a normal body weight and avoiding use of tobacco. If blood glucose levels are

not adequately lowered by these measures, antidiabetic medications may be needed(1)

 Type 1 DM can only be treated with insulin injections. Type 2 DM patients treated with oral

hypoglycemics included sulfonylureas and meglitinides and oral antihyperglycemics included biguanides,

thiazolidinediones, alpha glucosidase inhibitors, DPP (dipeptidyl peptidase) 4 inhibitors and other newer

antidiabetic drugs.

 Diabetic retinopathy is one of the late complications of diabetes and usually it affects people who have

had diabetes for considerably longer duration. The incidence of the disease is approximately 60% after

10 years with type 1 diabetes and after 20 yrs with type 2 diabetes(2). The main initiating factor for

changes in course of diabetic retinopathy is hyperglycemia. Chronic or non physiological high blood

glucose levels in diabetic patients causes pericyte damage in retina, these cells are the ones most

quickly reacting to glucose overflow. Recent trials show that the primary cause of diabetic retinopathy is

retinal neovascularisation caused by disequilibrium between pro and angiogenic factors(3).  The disease

begins to damage the small vessels in the retina, the light sensing layer of tissue in the back of eye,

causing them to leak fluid and blood. As the disease progresses, blood vessels become blocked and

rupture or new vessels grow on the retina, leading to permanent and sometimes profound vision

loss(4).

 The two biomarkers MCP 1 and cathepsin D were progressively increased in diabetic patients with both

non proliferative and proliferative retinal disease. Higher levels of MCP 1 and cathepsin D in young onset

T2DM patients represent an accelerated ageing phenotype, a driving force for faster development of

diabetic retinopathy. It is expected that targeting the pathways related to these biomarkers could be a

future strategy for preventing the heightened risk of developing diabetic retinopathy in young onset

T2DM(4).

 MCP-1 ( monocyte chemoattratant protein-1) is a chemokine, showed insulin resistance by decreasing

insulin stimulated glucose uptake. Reportedly myofibroblasts and vascular endothelial cells are the

major cell types expressing MCP-1 in epiretinal membranes, caused by changes in the vitreous humour

in diabetic eyes(2).

 Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes. The main

function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre

lysosomal compartments. Cathepsin D disrupts endothelial juctional barrier via increased rho

dependent cell contractility. Cathepsin D is increased in retina of diabetic patients.

  LACUNAE IN EXISTING KNOWLEDGE  Association of increased levels of MCP 1 and cathepsin D in young onset type 2 DM predicting

development of retinopathy have been studied recently (4). There is no data in literature showing the

correlation of tight glycemic control by antidiabetic medications with serum levels of MCP 1 and

cathepsin D in type 2 diabetes with and without retinopathy.

 RESEARCH HYPOTHESIS

| | | --- | | Tight glycemic control with antidiabetic medications normalizes serum MCP-1 and cathepsin-D  levels.

PRIMARY OBJECTIVES

To study the correlation of tight glycaemic control by antidiabetic medications with serum levels of MCP-1 and cathepsin-D in type 2 diabetes with and without retinopathy.

SECONDARY OBJECTIVES

1.  To correlate levels of serum MCP-1 and cathepsin-D with diabetic retinopathy .

1.    2. To assess the quality of lifein diabetic patients with and without retinopathy by using questionnaire (WHOQOL-BREF).

STUDY METHODOLOGYDiabetes patients with and without retinopathy coming to hospital for treatment will be enrolled in the study based on inclusion and exclusion criteria. A written informed consent shall be taken from all patients. Patients’ demographic profile and medical history will be recorded. Blood samples would be collected and the following parameters would be done in all patients, serum MCP 1 and cathepsin D, serum HbA1c levels , serum lipid levels and serum C peptide levels. Also, routine investigations will be included.

All subjects will be divided into 2 groups-

GROUP A ( diabetic  patients without retinopathy) n=60

GROUP B ( diabetic patients with retinopathy) n=60

Good glycaemic control group – HbA1c ≤ 7 %

Poor glycaemic control group – HbA1c ≥ 7 %

Blood samples (3-5 ml) will be taken from each subject to determine serum MCP 1 and cathepsin D levels. All samples will be stored at 4°C till their analysis. These samples will be analysed for MCP 1 and cathepsin D levels using ELISA ASSAY KITs.

Patients will also be asked to complete a questionnaire to assess their quality of life (WHOQOL-BREF).

Subgroup analysis will be attempted on the basis of tight glycaemic control by antidiabetic medications (oral hypoglycemic agents or insulin).

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Tight glycemic control with antidiabetic medications normalizes serum MCP-1 and cathepsin-D  levels.