diabetes mellitus ( dm ) is a chronic illness and diabetic retinopathy ( dr ) is a main cause of blindness in working age . large randomized - clinical trials suggest that intensive management of hyperglycemia is associated with decreased rates of development and progression of dr in type 1 dm patients   and that glycemic control in type 2 dm patients resulted in a 25% risk reduction in retinal microvascular events . thus , excess glucose is generally considered to be the primary culprit in the progression of dr , and glycemic control can prevent this . glycemic control may have a negative effect on the retina , even though longitude control works well . not much has been done to clarify what occurs in the retina during glycemic control [ 57 ] , so further studies are needed to elucidate this question . in glaucoma eyes , retinal nerve fiber layer ( rnfl ) decreases as a progression   and many studies also reported rnfl changes in dm patients [ 914 ] , but to our knowledge , only a few studies have evaluated the relationship between rnfl thickness and glycemic control . these days , various instruments have been established for evaluation of rnfl with no invasion . especially , optical coherence tomography ( oct ) has been proposed as a powerful tool for retinal measurement and provides detailed information with a high resolution [ 1618 ] . we hypothesize that rnfl thickness is affected by glycemic control and indicates retinal damage . here , we conducted a study to assess the effect of glycemic control on rnfl thickness using this useful oct and to identify what occurs in the retina during glycemic control . patients with type 2 dm who had been referred to our endocrinology department for blood glucose regulation were assessed for the study . all patients were japanese and one eye of each subject was selected randomly for examination . all subjects were treated in accordance with the declaration of helsinki for clinical research and the study was conducted with the understanding and the consent of the human subject . they were receiving treatment with diet and exercise , oral hypoglycemic agents , or insulin . all subjects were examined as follows : ( 1 ) initial visit , ( 2 ) 1 month , ( 3 ) 2 months , and ( 4 ) 4 months after the initial examination . on each occasion , glycosylated hemoglobin ( hba1c ) levels and general ophthalmic evaluations including oct scanning were examined . fundus examination and oct scanning were done under dilated condition using 1% tropicamide and 2.5% phenylephrine hydrochloride . patients underwent fundus examination using a + 90 diopter lens and were classified by an independent grader according to the criteria of the etdrs protocol . the progression of dr was defined as the examination of retinal signs from this classification . eligible subjects had to meet the following criteria : ( 1 ) subjects whose hba1c on initial examination was over 7.0 , ( 2 ) subjects who could be followed up over 4 months , and ( 3 ) improved glycemic control evaluated using hba1c was satisfactorily achieved . a reduction of hba1c after 4 months by 10% or more was defined as an improvement . hba1c was measured each time at our hospital in order to provide uniformity among laboratory results . eyes with high myopia , neural ophthalmic anomalies , advanced cataract , cloudy media , and intraocular pressure over 21  mmhg as determined by goldmann applanation tonometry were excluded from the evaluation . normal optic disc appearance was defined as a vertical asymmetry of 0.2 or less , a cup - disc ratio of 0.6 or less , and an intact neuroretinal rim without peripapillary hemorrhages , notches , localized pallor , or rnfl defect on clinical examination . those eyes with progression of dr which required photocoagulation or other therapy during follow - up terms oct ( oct 1 , zeiss - humphrey systems , dublin , ca ) scanning was performed using near - infrared , low - coherence illumination ( 840  nm ) with a tissue resolution of approximately 1017  m [ 1518 ] . at each setting , two or three oct scans were acquired for each patient . from the acquired scans , the best quality , properly aligned scan was chosen for analysis . the 360 circular scans with a diameter of 3.4  mm centered on the optic disc were performed as previously described [ 21 , 22 ] . rnfl thickness was defined as the number of pixels between the anterior and posterior edge of the rnfl detected using the attached automatic boundary detection software ( version a5 , humphrey - zeiss ) . each resulting image consists of rnfl thickness measurements at 100 points along a 360 circular ring around the optic disc . rnfl thickness was calculated automatically with existing software : mean ( all 360 measurements ) , temporal quadrant ( 31645 unit circle ) , superior quadrant ( 46135 ) , nasal quadrant ( 136225 ) and inferior quadrant ( 226315 ) thickness ( figure 1 ) . statistical analysis was performed using jmp5.01j ( sas institute inc , cary , nc ) . significant differences were determined by use of a non - repeated measures analysis of variance ( anova ) and snk test as a post hoc test . the student 's t - test for paired group was used for analysis . a p value of < .05 was considered statistically significant . eight patients were placed on only diet and exercise therapy , 20 patients were treated with oral hypoglycemic agents alone , and 10 patients were treated with insulin alone . twenty - four eyes had no retinopathy and 14 eyes had nonproliferative diabetic retinopathy . during the study , a significant decrease of hba1c was seen , which indicates fair glycemic control ( p = .00233 , non - repeated measures of anova , table 1 ) .   during oct analysis in all quadrant areas , no significant rnfl change was seen between the initial and 1 or 2 month examination . but a significant decrease was seen in the superior area between the initial and 4 month examination ( p = .043 , non - repeated measures of anova , table 2 ) . no significant change was found in other areas .   next , to clarify the relationship between the change in hba1c ( dhba1c ) and the changes in rnfl thickness ( drnflt ) after 4 months of control , we compare them using pearson correlation analysis . the drnflt was related to the dhba1c in the superior , temporal , and inferior quadrants ( p < .05 in each area , student 's t - test , figure 2 ) . in this study , rnfl thickness decreased in all quadrants area after 4 months of glycemic control . generally , in glaucomatous eyes , the rnfl is initially damaged in superior area [ 2326 ] and previously we reported that superior rnfl thickness is already decreased in the early stage of dr . additionally , in vivo study using diabetic animal so this area is more susceptible to damage than other areas and may have a tendency for higher rates of cell death , which results in rnfl thinning . there remains a question that thinning of the rnfl does not necessarily mean a loss of retinal nerve fibers and the rnfl may have been swollen due to a partial blockade of the axoplasmic flow in the hyperglycemic state . but our data indicates some kind of change , including thinning , occuring in retina components . thus , superior rnfl thickness is an indicator for retinal damage under the glycemic control .   according to clinical evidence , there is no doubt that glycemic control is most important for stability of dm and dr . but intensive glycemic control sometimes induces worsening of dr , known as an early worsening ( ew ) . as the worsening results , hard exudates and macular edema occur . intensive glycemic control may lead to a transient deterioration of dr and patients who already have background dr are at higher risk for ew changes . on this point , funatsu et al . it should be noted that several reports also have shown interaction between glycemic control and retina change including blood - retina barrier ( brb ) or macula edema progression [ 57 ] . such vascular breakdown may change the tissue construction and it is reasonable to propose that rnfl damage is followed by this change as an aspect of neurodegeneric change . some molecular mechanism may participate in this change and some experimental studies have shown that insulin stimulates a cascade of neovascularization . vascular endothelial growth factor ( vegf ) [ 31 , 32 ] is one of the major mediators of neovascularization or ischemia . insulin up - regulates vegf in vitro and enhances vascular permeability or proliferative effects [ 33 , 34 ] which results in proliferative retinal changes . thus , insulin itself plays an important role in neovascularization or brb breakdown and may be one of the causes of several complications during glycemic control , including ew . patients in this study were treated variably ; some were given insulin , some were given oral agent , and some were treated without medication . because of the small number of patients , there was no significant rnfl thickness change for our ten of insulin - treated patients and other patients in each area between the initial visit and each subsequent visit ( p > .05 in each area , data not shown ) . and there is a report that progression of dr differs by insulin type , so further clarification is needed to examine the relation between rnfl damage and insulin . having had more sample number would have been helpful in truly allowing the hypothesis that the correlation between hba1c levels and rnfl thinning is due to insulin or other factors . and first , the patients are poorly characterized in aspects of several factors such as age , sex , duration of diabetes , coexistent renal disease and blood pressure ( bp ) . as several studies mentioned about importance of bp control for prevention of dr , there is a possibility that increased bp and secondary increase in cerebrospinal fluid pressure may relate with rnfl change . second , we did not use updated technology of oct which can detect much detailed change than oct 1 , which we used here . and third , there is a possibility that visual fields evaluation may support our results much precisely . on these points , in summary , this study suggests that the glycemic control affects rnfl within 4 months and superior rnfl thickness can be used as an indicator for this change .
purpose . to assess an effect of glycemic control on retinal nerve fiber layer ( rnfl ) in type 2 diabetes mellitus . 
 methods . 
 thirty - eight eyes of 38 patients with type 2 diabetes undergoing blood glucose regulation were enrolled . 
 all patients were examined at ( 1 ) initial visit , ( 2 ) 1 month , ( 3 ) 2 months , and ( 4 ) 4-month after the initial examination . on each occasion , glycosylated hemoglobin ( hba1c ) levels and optical coherence tomography ( oct ) scanning for rnfl thickness were evaluated . 
 360 degree circular oct scans with a diameter of 3.4  mm centered on the optic disc were performed . 
 results . 
 significant rnfl decrease was seen in the superior area between initial and 4 months examination ( p = .043 ) . 
 the relationship between the changes in hba1c and the changes in rnfl thickness was observed in superior , temporal , and inferior area ( p < 
 .05 ) at 4 months . conclusions . 
 this study suggests that the glycemic control affects rnfl within 4 months .