diabetic complications have become a serious issue in japan , and the dramatic rise in the number of patients with diabetes has exacerbated this problem
. however , awareness of one serious health condition , namely , diabetic foot disease , is inadequate among patients and healthcare providers [ 1 , 2 ] . in 2008 , the japanese government introduced a management fee for diabetic complications to facilitate the prevention of diabetic foot ulcers .
consequently , the number of foot care outpatient clinics that specialize in preventing diabetic foot ulcers has risen along with the increase in the number of patients with diabetes in japan . however , only a few japanese reports are available that describe investigations into the long - term occurrence of diabetic foot ulcer and its risk factors .
although diabetic neuropathy and angiopathy have been reported as classical risk factors for diabetic foot ulcer [ 1 , 4 ] , few studies ' findings demonstrate the association between the occurrence of diabetic foot ulcer and microangiopathy complications , including albuminuria ( alb ) and diabetic retinopathy ( dr ) .
indeed , patients with advanced dr or alb are very likely to develop diabetic neuropathy or angiopathy .
moreover , dr reduces visual acuity in adults , and the findings from previous studies have shown that a reduction in visual acuity is a risk factor for diabetic foot ulcer [ 4 , 5 ] .
in addition , alb and elevated serum creatinine ( scr ) levels have been reported as risk factors for diabetic foot ulcer [ 6 , 7 ] . to determine the diabetic foot ulcer incidence and examine the association between diabetic foot ulcer and microangiopathy complications , namely , dr and alb , we conducted a retrospective study of 1,305 patients with type 2 diabetes who had received in - hospital foot care education .
all subjects who had undergone a 2-week education program for diabetic patients between january 1999 and may 2005 were considered for inclusion in the study . during hospitalization ,
the following exclusion criteria were applied : ( 1 ) the presence of an active diabetic foot ulcer at the time of inclusion , ( 2 ) an estimated glomerular filtration rate ( egfr ) < 30  ml / min/1.73  m or a strong suspicion of renal disease other than diabetic nephropathy , for example , glomerulonephritis , and ( 3 ) a follow - up period < 1 year . of the 1,958 study candidates , 648
were transferred to other facilities for medical or personal reasons , or they withdrew from the study for unknown reasons within 1 year , 3 subjects had egfrs < 30  ml / min/1.73  m , and 2 subjects had active diabetic foot ulcers .
data relating to the patients ' ages , sexes , body mass indexes , diabetes durations , and smoking statuses were collected from the medical records at the time of hospitalization .
past histories of cardiovascular disease , including the occurrences of myocardial infarctions , coronary interventions , and ischemic strokes , and the presence of diabetic neuropathy and angiopathy were determined from the patients ' medical records .
blood samples were collected in the early morning of day 2 of hospitalization following an overnight fast . the glycosylated hemoglobin ( hba1c )
( % ; ngsp ) levels on admission were determined using high - performance liquid chromatography .
the presence of diabetic neuropathy was evaluated using the semmes - weinstein monofilament test and the vibratory sensation test .
the semmes - weinstein monofilament test involved assessing a foot 's sensation using a 10  g monofilament at five sites on the plantar aspect of each foot , namely , the hallux , and the first , second , third , and fifth metatarsal heads .
the results from the vibratory sensation test were considered abnormal if the perception of vibration ceased within 10  s after a 128-hz tuning fork was applied to the medial malleolus .
if the sensations from the 10-g monofilament or the vibration sensation tests were reduced , the patient was diagnosed as having sensory neuropathy . when the patients had histories of intermittent claudication and rest pain , peripheral arterial disease , or absent or reduced pedal pulses , ankle brachial index ( abi ) measurements were performed .
every patient rested in a supine position for at least 5  min in a quiet room before the abi was measured .
if either or both abi values were 0.9 , the patient was diagnosed with angiopathy .
in addition , 24-hour urine samples were collected from the patients from day 2 until day 3 of hospitalization .
the clinical staging of diabetic nephropathy was based mainly on the urinary albumin excretion rate ( aer ) and , at the advanced stage , it was based on reductions in the egfr .
alb was defined as a urinary aer > 20  g / min that was determined during the 24-hour urine sample collection .
the egfr , which was used as an index of nephropathy , was obtained using the following formula : ( 1)egfr=194scr1.094age0.287woman0.739 . all of the subjects underwent funduscopic examinations that were carried out by a qualified ophthalmologist during or just before hospital admission .
the subjects were categorized into four groups based on their diabetic microangiopathy complications at baseline , as follows : category 1 , normoalbuminuria without dr ( n = 712 ) ; category 2 , alb without dr ( n = 195 ) ; category 3 , normoalbuminuria with dr ( n = 185 ) ; and category 4 , alb with dr ( n = 213 ) .
the subjects were treated for diabetes mellitus and , when necessary , for coexisting diseases at our outpatient clinics at intervals of between 1 and 4 months , depending on the status of each disease .
the follow - up histories for incident diabetic foot ulcers were obtained from the medical records .
the study 's protocol abided by the japanese government 's ethical guidelines for epidemiological research , and it was reviewed and approved by the ethics committee of saiseikai central hospital ( protocol number 311 ) .
all of the procedures were undertaken in accordance with the ethical standards established by the institutional and national committees on human experimentation and in accordance with the declaration of helsinki .
the patients ' baseline characteristics were determined after they had been stratified into the four categories .
the differences among the categories were evaluated using a one - way analysis of variance .
the 5-year and 10-year cumulative diabetic foot ulcer incidence rates were estimated using the kaplan - meier method .
the log - rank test was used to examine the differences among the four patient categories in relation to the diabetic foot ulcer incidence .
we constructed cox proportional hazard models to estimate the associations between diabetic complications and the diabetic foot ulcer incidence , using the follow - up time as a dependent variable .
age- , sex- , and multivariable - adjusted hazard ratios ( hrs ) were calculated using cox proportional hazards regression models .
the multivariable - adjusted models were adjusted for the presence of diabetic neuropathy alone ( model 2 ) and for the presence of diabetic neuropathy and angiopathy ( model 3 ) .
the multivariable - adjusted hrs were used to calculate the relative risks of diabetic foot ulcer occurrence in each diabetic microangiopathy complications category . a p value < 0.05 was considered to indicate statistical significance .
stata version 10 ( statacorp lp , college station , tx , usa ) was used for the statistical calculations .

 table 1 shows the baseline characteristics of the study participants who were grouped according to their diabetic microangiopathy complications .
the mean age of the study cohort was approximately 60 years , approximately 70% of the patients were men , and the mean diabetes duration was approximately 10 years .
of the 1,305 study participants , 54.6% ( n = 712 ) were assigned to category 1 , 14.9% ( n = 195 ) were assigned to category 2 , 14.2% ( n = 185 ) were assigned to category 3 , and 16.3% ( n = 213 ) were assigned to category 4 .
for example , the subjects in category 4 were older , were predominantly male , and they had longer disease durations compared with the subjects in the other categories .
of the 1,305 subjects evaluated , 93 died , 28 were transferred to other facilities for medical or personal reasons , and 201 withdrew for unknown reasons during the 10-year follow - up period .
the follow - up rate at 10 years was 75.3% . during the median follow - up period of 11.8 years
, 50 cases were diagnosed with new - onset diabetic foot ulcers , yielding 14,291 person - years ( table 2 ) .
the annual diabetic foot ulcer incidence rates were 1.6 , 1.5 , 3.4 , and 12.5 per 1,000 person - years in categories 1 , 2 , 3 , and 4 , respectively .
the kaplan - meier curves showed that the individuals in category 4 had a significantly higher diabetic foot ulcer incidence ( log - rank test , p < 0.001 ) ( figure 1 ) .
the 10-year cumulative diabetic foot ulcer incidence increased according to the microangiopathy complications category , with 1.7% , 1.2% , 4.2% , and 12.7% of subjects developing diabetic foot ulcers in categories 1 , 2 , 3 , and 4 , respectively ( table 2 ) .
associations between the presence of dr , alb , diabetic neuropathy , and angiopathy and the diabetic foot ulcer incidence were identified using cox regression analysis ( table 3 ) . after adjusting for age and sex ( model 1 ) ,
the presence of diabetic microangiopathy complications was positively and significantly associated with the diabetic foot ulcer incidence . in model 3 , which was additionally adjusted for the presence of diabetic neuropathy and angiopathy , the hrs and the 95% confidence intervals ( cis ) for the diabetic foot ulcer incidence were 0.66 ( 95% ci , 0.182.36 ) , 1.72 ( 95% ci , 0.674.42 ) , and 3.17 ( 95% ci 1.526.61 ; p = 0.002 ) for categories 2 , 3 , and 4 , respectively , compared with category 1 .
this study aimed to determine the diabetic foot ulcer incidence in patients with type 2 diabetes and to investigate the association between diabetic foot ulcer and microangiopathy . following in - hospital education ,
the 5-year and 10-year cumulative diabetic foot ulcer incidence rates in patients with type 2 diabetes were 1.9% and 3.7% , respectively .
importantly , the 10-year cumulative diabetic foot ulcer incidence rate in category 4 , which comprised patients with both dr and alb , was 12.7% and was up to threefold higher than the 10-year cumulative diabetic foot ulcer incidence rate in category 1 .
after adjusting for the presence of diabetic neuropathy and angiopathy , the presence of diabetic microangiopathy complications was positively and significantly associated with the occurrence of diabetic foot ulcers .
the findings from this study provide information about the risk of patients developing diabetic foot ulcers , and they enable more realistic risk estimations in relation to the occurrence of diabetic foot ulcers in individuals with dr and alb . although the number of foot care outpatient departments has grown in response to the increase in the number of patients with diabetes in japan , few long - term follow - up studies have investigated the diabetic foot ulcer incidence , and the results from short - term studies only are available in the literature .
reports from asian countries are particularly uncommon , and an association between the diabetic foot ulcer incidence and the presence of dr and/or alb has not been proposed .
diabetic microangiopathy progresses with the duration of a patient 's diabetes , and the diabetic complications observed are interrelated .
the results from this study may enable type 2 diabetes patients with dr and/or alb to understand the actual risk in relation to diabetic foot ulcer development .
moreover , the 10-year cumulative diabetic foot ulcer incidence rates in the patients in categories 3 and 4 , which included those with dr , were higher than the 10-year cumulative diabetic foot ulcer incidence rates in the patients in categories 1 and 2 , which contained patients who did not have dr , indicating that dr is a particularly important factor associated with the occurrence of diabetic foot ulcers . indeed , boyko et al .   and leese et al
.   found that poor vision , which was defined as a corrected visual acuity of 20/40 or lower , is a risk factor for diabetic foot ulcer .
in addition , dr is a risk factor for all causes of death , cardiovascular events , and arteriosclerosis . in their study ,
ohtomo et al .   found that approximately 20% of the patients with dr had coronary artery disease , which may reflect impaired vascular perfusion caused by arteriosclerosis . in another study ,
ogawa et al .   reported that diabetic neuropathy was present in all of the patients with type 2 diabetes who were hospitalized for diabetic foot ulcers and that dr and nephropathy were present in 96.4% and 78.6% of the patients , respectively .
the incidence of dr in japanese patients with type 2 diabetes is 38.3/1,000 person - years , and the dr progression rate has been reported as 21.1/1,000 person - years . since subjective symptoms are often absent , even when dr is at an advanced stage , it is important to encourage patients with definitively diagnosed or suspected diabetes to visit an ophthalmology department . the diabetic foot ulcer incidence has been investigated previously . from their study ,
peters and lavery   reported that during the 3-year follow - up period , foot ulceration occurred in 14.3% , 18.8% , and 55.8% of the patients with diabetic neuropathy , diabetic neuropathy combined with foot deformities or peripheral arterial disease , and previous histories of foot ulceration , respectively .
moss et al .   followed up with 906 patients who were diagnosed with type 2 diabetes before they were 30 years old and 984 patients who were diagnosed with type 2 diabetes after they were 30 years old for 14 years , and they found that amputations caused by diabetic foot ulcers were required in 7.2% and 9.9% of these patients , respectively , and they concluded that severe retinopathy was a risk factor for amputation . in our study cohort ,
the diabetic foot ulcer frequency was lower than the frequencies reported from these aforementioned studies , which could be a consequence of the in - hospital education that our patients received . in a japanese study , oe et al
.   followed up with 578 patients with diabetes who visited a specialized outpatient department for 5 years , and they found diabetic foot ulcers in 6 ( 1.2% ) patients .
however , 70% of the subjects did not have diabetic neuropathy or angiopathy ; therefore , the patients ' backgrounds differed from those in the current study , in which 40% of the patients had diabetic neuropathy .
despite the patients in the current study attending a group lecture about foot care as part of an in - hospital education program , the patients with type 2 diabetes , dr , and alb developed diabetic foot ulcers , and a sharp increase in the cumulative diabetic foot ulcer incidence was observed after 5 years ( figure 1 ) .
therefore , since the complications associated with diabetes tend to progress with its duration , patients with microangiopathy may require recurring outpatient education programs .
first , this was a hospital - based cohort study ; hence , a selection bias can not be excluded .
second , a considerable percentage of the subjects were lost to follow - up during the study period .
in addition , changes in the glucose levels and changes to the therapeutic regimens were not considered during the outpatient treatment period .
furthermore , we did not identify an association between dr and visual acuity . finally , the impacts of the foot care and education programs on the study 's results are unknown
. future investigations into the occurrence of diabetic foot ulcer in japan should account for these limitations .
the findings from this study showed that diabetic individuals with dr and alb were at a significantly increased risk of developing diabetic foot ulcers .
from the perspective of a diabetic patient 's evaluation of risk , the presence of asymptomatic dr and/or alb may not be considered serious ; hence , early intervention and long - term follow - up programs are crucial to prevent diabetic foot ulcers .
 
 aim . to determine the diabetic foot ulcer incidence and examine its association with microangiopathy complications , including diabetic retinopathy ( dr ) and albuminuria ( alb ) , in type 2 diabetes patients 
 . methods . 
 this was a retrospective cohort study of 1,305 patients with type 2 diabetes who were assigned to the following groups : category 1 , normoalbuminuria without dr ( n = 712 ) ; category 2 , alb without dr ( n = 195 ) ; category 3 , normoalbuminuria with dr ( n = 185 ) ; and category 4 , alb with dr ( n = 213 ) . 
 cox proportional hazard models were used to compare the risks of developing diabetic foot ulcers across the categories . 
 results . during 14,249 person - years of follow - up 
 , 50 subjects developed diabetic foot ulcers , with incidence rates of 1.6/1,000 , 1.5/1,000 , 3.4/1,000 , and 12.5/1,000 person - years in categories 1 , 2 , 3 , and 4 , respectively . 
 after adjusting for the presence of diabetic neuropathy and macroangiopathy , the hazard ratios and 95% confidence intervals ( cis ) for the risk of diabetic foot ulcer development were 0.66 ( 95% ci , 0.182.36 ) , 1.72 ( 95% ci , 0.674.42 ) , and 3.17 ( 95% ci , 1.526.61 ) in categories 2 , 3 , and 4 , respectively , compared with category 1 . conclusion . 
 the presence of dr and alb significantly increases the risk of diabetic foot ulcer development . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions