-cell function within 10 years of the onset of type 1 diabetes is associated as well as the acute onset of diabetes, were associated with early …
J Clin Endocrin Metab First published ahead of print September 30, 2008 as doi:101210/jc2008-1209
Rate of -cell Destruction in Type 1 Diabetes Influences the Development of Diabetic Retinopathy: Protective Effect of Residual -cell Function for More Than 10 Years Koji Nakanishi and Chizuru Watanabe From the Department of General Internal Medicine and Metabolism, Toranomon Hospital, Kawasaki, Japan and the Okinaka Memorial Institute for Medical Research, Tokyo, Japan Short title: -cell destruction and diabetic retinopathy Address correspondence and reprint requests to: Koji Nakanishi, Department of General Internal Medicine and Metabolism, Toranomon Hospital, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki, Kanagawa 213-8587, Japan TEL: 81-44-877-5111; FAX: 81-44-877-5333, e-mail: koji01@toranomongrjp Disclosure statement: The authors have nothing to disclose Key words: -cell function, C-peptide, Human leukocyte antigen, Retinopathy, Type 1 diabetes Word count: text; 3,585, abstract: 247, Number of tables: 2, Number of figures: 3 This work was partly supported by the Japanese Ministry of Education, Science, and Culture Grant no 14571117 Précis: Undetectable -cell function within 10 years of
the onset of type 1 diabetes is associated with the earlier occurrence of diabetic retinopathy
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Copyright C 2008 by The Endocrine Society
Abstract Context: Although residual -cell function delays the onset and progression of diabetic retinopathy in patients with type 1 diabetes, the rate of -cell destruction is variable Objective: To clarify the influence of the rate of -cell destruction on the development and progression of diabetic retinopathy in type 1 diabetes Design: Historical cohort study regarding residual -cell function and retinopathy Setting: Out patient clinic in general hospital Patients: 254 patients with type 1 diabetes Main Outcome Measures: Serum C-peptide and fundus findings were evaluated longitudinally Results: The cumulative incidence of mild nonproliferative diabetic retinopathy was higher in the patients without detectable -cell function than in those with residual -cell function at 20, 15, and 10 years after the onset of diabetes p0013, p0006 and p0048; respectively, but not at 5 years after the onset p084 There were higher mean HbA1c values during the entire follow-up period in the patients without detectable -cell function at 20 and 15 years after the
onset of diabetes p0030 and p0042, respectively Positivity for HLA-A24 and -DQA103, as well as the acute onset of diabetes, were associated with early -cell loss and also with early development of diabetic retinopathy Cox proportional hazards analysis showed that undetectable -cell function at 20, 15, or 10 years after the onset of diabetes was an independent risk factor for the development of diabetic retinopathy Conclusions: Undetectable -cell function within 10 years of the onset of type 1 diabetes is associated with the earlier occurrence of diabetic retinopathy
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Introduction Several studies have shown that the existence of residual -cell function delays the onset and progression of diabetic retinopathy in patients with type 1 diabetes through better glycemic control 1-4 However, residual -cell function changes over time in type 1 diabetes, and the rate of -cell destruction is variable both before 5, 6 and after the onset of clinical diabetes 6 Some patients eventually show complete loss of -cell function, whereas residual -cell function is maintained in others over a long period 6 In previous studies that examined the relationship between residual -cell function and
diabetic complications, -cell function was assessed in a cross-sectional manner 2 or over a short follow-up period 3, 4, so the longitudinal changes of -cell function were not addressed Recently, we documented the longitudinal changes of residual -cell function in a cohort of patients with type 1 diabetes 6 In the present study, we retrospectively investigated the time course of retinopathy in relation to longitudinal changes of residual -cell function in the same patient cohort, and evaluated how many years of residual -cell function were required to protect patients with type 1 diabetes from the early onset and progression of diabetic retinopathy Materials and Methods Subjects A total of 254 patients
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with type 1 diabetes [145 men and 109 women aged 34 14 years mean SD at the onset of diabetes], who presented to Toranomon Hospital for the first time between establishment of the hospital in 1957 and the end of 2002 and were periodically followed thereafter, were evaluated in the present study A diagnosis of type 1 diabetes was made according to the ADA guidelines 5 In addition, urinary C-peptide excretion of 66 nmol/day or an integrated serum C-peptide value during the 100-g
oral glucose tolerance test of 33 nmol/l was used to define type 1 diabetes, as described previously 2, 6 Autoantibodies to glutamic acid decarboxylase 65 were positive at the onset of diabetes in 802 105/131 of the patients tested This study was approved by the Committee for Investigations Involving Human Subjects of Toranomon Hospital All patients gave informed consent for DNA analysis and C-peptide measurement Assessment of the time course of -cell destruction radioimmunoassay A sensitive was used C-peptide to assess
residual -cell function 7 A fasting serum C-peptide level below the detection limit 0017 nmol/l, a level 0033 nmol/l at 2-3 hours postprandially, or a serum C-peptide response of 0033 nmol/l after a 100-g oral glucose load was defined as loss of detectable -cell function 6, 8 This serum C-peptide level was originally selected as a cut-off value for discrimination between complete
-cell destruction and the presence of minimal residual -cell function 6, 8, but a previous cross-sectional study also showed a difference in the incidence of retinopathy between patients stratified by this cut-off value 2 Measurement of serum C-peptide was done in 241 patients The
sera were stored at -80 until the assay, which was performed yearly since our first report on C-peptide assay 7 In 30 patients, the first assessment of residual -cell function revealed loss of detectable -cell function at more than 5 years after the onset of diabetes, so they were excluded from longitudinal observation of residual -cell function to ensure that the error in determing the time of loss of detectable -cell function was less than 5 years 6 Longitudinal observation of residual -cell function was performed in the other 211 patients, as described previously 6 The clinical onset of diabetes was defined as the starting point In 184 patients, serum C-peptide was measured a total of 51 32 times mean 106 years mean SDrange: 2-26 times over a disease duration of 135 SDrange: 008 - 49 years In 19 patients, loss of detectable -cell function was found by their first assessment of -cell function within 5 years after the onset of diabetes In 8 patients, the presence of residual -cell function was only investigated by one test at 4-24 years median: 14 years after the onset of diabetes, so data for these patients were censored at that time The calendar year at the onset of
4
diabetes
was earlier in the patients excluded from the longitudinal study than those included in the longitudinal study 1975 vs 1984 11, mean Mann-Whitney U-test Evaluation of diabetic retinopathy 6 SD, p00001 by
Evaluation of diabetic retinopathy was performed in 236 patients as described previously 2 To evaluate yearly the presence or progression of diabetic retinopathy, patients with type 1 diabetes have been referred to an ophthalmologist in Toranomon Hospital, to whom C-peptide status was unknown Optic fundi were examined using indirect ophthalmoscope after papillary dilatation with 05 tropic amide Seven ophthalmologists participated in fundus examination through the study period They sketched the findings in a medical chart in the consistent manner, in which the author KN was instructed Grading of diabetic retinopathy was performed by the review of medical records by the author KN The grading of retinopathy in our previous study 2, 9, 10 was adapted to that in international clinical diabetic retinopathy scale 11 in this study, and also related to severity scale in Early Treatment Diabetic Retinopathy Study ETDRS 12 Emergence of microaneurysm and/or blot hemorrhage and/or hard exudate
corresponded diabetic to mild nonproliferative and also retinopathy NPDR
corresponded to ETDRS level 20, because first findings were microaneurysm in all but
one patient 2 The laser photocoagulation performed on nonperfused area recognized by fluorescein of angiogram soft after the and/or identification intraretinal exudates
following formula; Y 0918X - 04 r0986, n581 Sixteen patients had no HbA1c data For the other 238 patients, the mean HbA1c value during the entire illness was determined as follows: mean HbA1c values were calculated for each 5-year period after the onset of diabetes, and these values were further averaged to exclude the influence of differences in the density of measurements between the periods The number of HbA1c measurements during each 5-year period ranged from 2 to 88 median: 22 In 137 patients, HbA1c data were available for the entire disease duration range: 2-27 years; median: 12 years In the other 101 patients, some data were missing, among which 73 data points were missing before 1984 The number of patients examined for -cell function, retinopathy findings, and long-term glycemic control, and their relations were illustrated in Figure 1 Both systolic
blood pressure persistently 140 mmHg and diastolic pressure persistently 90mmHg at consecutive
microvascular
abnormalities
corresponded to severe NPDR, which also corresponded to ETDRS level 53 The presence of new vessel despite the laser photocoagulation corresponded to proliferative diabetic retinopathy PDR, which also corresponded to ETDRS level 65 Only findings ascertained at two consecutive fundus examinations were judged as positive to lessen potential errors The mean 21 SD number of eye examinations per patient was 17 range: 2-90 In 165 patients, the last fundus observations were performed from 2003 to 2006 Among the other 71 patients, 22 died during follow-up and 49 underwent their last fundus observation at an earlier time 2000-2003 in 11 patients, 1995-1999 in 17 patients, 1990-1994 in 29 patients, and 1983-1989 in 14 patients Assessment of long-term glycemic control Routine measurement of glycosylated hemoglobin HbA1c was started in 1984 in Toranomon Hospital HbA1c was measured by a chromatographic method 13 with a normal range of 48-61 until May 1997, after which it was measured by a high-performance liquid chromatography method with a normal range of 43-58 14 Data
obtained with the former method X were converted to match the data obtained with the latter method Y by using the
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determinations or use of an antihypertensive drug was regarded as the evidence of hypertension, as described previously 2 Human leukocyte antigen HLA typing HLA-DR and -DQ alleles were typed by previously fragment described length PCR-restriction
polymorphism RFLP methods 6 HLA-A alleles were typed by the microcytotoxicity test or the PCR-RFLP method 6
Definitions of type 1 diabetes subtypes According to the time from the diagnosis of diabetes to the start of insulin therapy, the patients were divided into a group with acute-onset 12 months type 1 diabetes n142 and a group with slow-onset 12 months type 1 diabetes n99 6, 15, 16 Patients who developed ketoacidosis within one week of the and onset had of a hyperglycemic symptoms
Results Time course of -cell destruction and stratification of the patients Among 211 patients for whom longitudinal data on residual -cell function were available, -cell function became undetectable in 81 patients and 93 75/81 of these events occurred within 20 years after the onset of diabetes Fig 2A On the other hand, among 130 patients
who had residual -cell function throughout their observation periods, 37 patients still displayed some -cell function even 20 years after the onset of diabetes Fig 2B Including 7 patients in whom loss of detectable -cell function was observed more than 20 years after the onset of diabetes Fig 2A, 20 44/221 of all patients had residual -cell function even 20 years after the onset Accordingly, we first stratified the patients into a group showing loss of detectable -cell function within 20 years of the onset of diabetes and a group with residual -cell function at 20 years Table 1 To examine the influence of the duration of residual -cell function on the onset and progression of diabetic retinopathy, we next stratified the patients by 5-year intervals stepwise from 20 years Table 1 In these analyses, 30 patients who showed undetectable -cell function at more than 5 years after the onset of diabetes by the first assessment were also included as those without detectable -cell function in the appropriate strata if the assessment time was earlier than each designated time point Table 1
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concomitant rise of pancreatic exocrine enzymes were classified as having fulminant type 1 diabetes
n10 6, 17 Statistical analysis The
Kaplan-Meier method was used to estimate the cumulative incidence of each type of diabetic retinopathy and differences between incidence curves were assessed by the log-rank test 18 Incidence rates were expressed as the number of events per 100 patient-years, calculated as the ratio of the observed number of events to the total number of patient-years of exposure Coxs proportional hazards model 18 was used to examine the combined influence of the variables on the risk of the development of diabetic retinopathy The Mann-Whitney U test was used to compare unpaired data Differences of frequency between 2 groups were assessed by Fishers exact probability test Results are expressed as the means SD All analyses were performed with the JMP60 statistical package SAS Institute Japan, Tokyo, Japan
corresponding periods data not shown Stratified analysis of retinopathy Mild Although the cumulative incidence of PDR was higher in the patients who lost detectable -cell function within 10 years of the onset of diabetes, in whom it reached 50 at 247 years after the onset of diabetes, than in those who retained -cell function after 10 years, in whom it reached
50 at 340 years after the onset of diabetes p001, it did not differ between those showing undetectable -cell function within 20, 15, or 5 years after the onset of diabetes and those who had residual -cell function after the corresponding periods data not shown Stratified analysis of glycemic control and severe NPDR, and PDR were detected in 129, 90, and 46 patients during 2,708, 3,405, and 4,021 patient-years of observation, respectively Incidence rate of each type of retinopathy according to the status of -cell function at each designated time point was shown in Table 1 The cumulative incidence of mild NPDR was higher among the patients who showed undetectable -cell function within 20, 15, and 10 years after the onset of diabetes than among those with residual -cell function after the corresponding periods p0013, p0006 and p0048, respectively, Fig 3D, C and B In contrast, the cumulative incidence of mild NPDR did not differ between those who lost detectable -cell function within 5 years of the onset of diabetes and those with residual -cell function at 5 years after the onset p084, Fig 3A Severe NPDR was found earlier in the patients who showed undetectable -cell function within
20 years of the onset of diabetes than in those with residual -cell function at 20 years p0031 Cumulative incidence of severe NPDR reached 50 at 192 years after onset of diabetes in the former and at 258 years after onset of diabetes in the latter On the other hand, the cumulative incidence of severe NPDR did not differ between the patients who showed undetectable -cell function within 15, 10, and 5 years after the onset of diabetes and those with residual -cell function after the
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The mean HbA1c value was higher in the patients who showed undetectable -cell function within 20 or 15 years from the onset of diabetes than in those with residual -cell function after the corresponding periods, whereas it did not differ between those who lost detectable -cell function within 10 or 5 years from the onset of diabetes and those who retained -cell function after the corresponding periods Table 1 Genetical and clinical characteristics of the patient strata Because -cell status affected the development of mild NPDR most strongly, genetical and clinical characteristics of the patient strata were analyzed in relation to mild NPDR
The frequencies of a 3-HLA allele combination HLA-A24, -DQA103
and -DR9 and a 2-HLA allele combination HLA-A24 and -DQA103, which are known to be associated with the acute onset of type 1 diabetes and early complete -cell destruction 6, were higher in the patients who showed undetectable -cell function at any time point during the study than in the patients who retained -cell function after the corresponding periods, except for the combination of HLA-A24 and -DQA103 at 5 years after the onset of diabetes Table 1 The cumulative incidence of mild NPDR was higher in patients with the 2-allele combination n125, in whom it reached 50 at 147 years after onset of diabetes, than in those without this combination n81, in whom it reached 50 at 185 years after onset of diabetes p0041, though it did not differ between patients with the 3-allele combination n 
55 and those without this combination n147 data not shown Acute-onset type 1 diabetes was more common among the patients who showed undetectable -cell function at any time point during the study than in those who retained -cell function Table after 1 the The corresponding periods
The age at the onset of diabetes were older, frequency of hypertension was lower, and the calendar year of onset was later
in the patients without -cell function than those with residual -cell function at the time points of 20, 10, and 5 years, 15 and 10 years, and every time point after the onset of diabetes, respectively Table 1 Multivariate analysis To examine the influence of loss of detectable -cell function until various designated time points on the development of diabetic retinopathy after adjusting for possible confounders, hazard ratios HRs and the associated 95 confidence intervals CIs were estimated in each data set using Coxs proportional hazards model Table 2 In this model, the response variable was the time until the occurrence of each type of retinopathy or the time until the last eye examination included the The covariates examined and gender, hypertension
possession of HLA-A24 and -DQA103 as categorical variables, as well as the mean HbA1c value, the period before insulin therapy, and the age at onset as continuous variables Table 2 Loss of detectable -cell function until 20, 15, or 10 years from the onset of diabetes was shown to be an independent risk factor for the development of diabetic retinopathy Table 2 In contrast, loss of detectable -cell function by 5 years after the onset
of diabetes was not an independent risk factor for diabetic retinopathy Table 2 Mean
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cumulative incidence of mild NPDR was higher in the patients with acute-onset diabetes n131, in whom it reached 50 at 122 years after the onset of diabetes, than in those with slow-onset diabetes n86, in whom it reached 50 at 146 years after the onset of diabetes p0044
HbA1c value was a most significant risk factor for the development of diabetic retinopathy in any data set Table 2 In the data set for residual -cell function at 20 years after the onset of diabetes hypertension was an independent risk factor for the development of diabetic retinopathy Table 2 Discussion The simplest way to determine the period of residual -cell function that is sufficient to protect patients with type 1 diabetes against the early occurrence of diabetic retinopathy would be to compare the incidence of retinopathy among patient groups who lost detectable -cell function within various given periods, for example, at 5-year intervals However, it is difficult to achieve this in a follow-up study because there are always censored cases Therefore, we chose to compare the incidence between groups whose -cell status was
judged at designated time points set at 5-year intervals If the difference of the incidence between stratified groups was significantly affected by a stepwise 5-year shift of the assessment time point, then the 5-year period in question could be assumed the to be pivotal in of determining retinopathy This study showed that retaining some -cell function for more than 20, 15, or 10 years after the onset of diabetes delayed the development of mild NPDR and preservation of residual -cell function for more than 20
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or 15 years after the onset of diabetes was associated with lower mean HbA1c values The most significant risk factor for mild NPDR was mean analysis, HbA1c values in multivariate however These
findings suggest that the better glycemic control throughout the entire duration of disease attained by preserved -cell function for at least 10 years protect patients with type 1 diabetes from the early development of diabetic retinopathy Glycemic exposure for long period is established as a primary risk factor for retinopathy in the large cohort with type 1 19 as well as type 2 diabetes 20 On the other hand, after adjusting for possible confounders including the mean HbA1c value,
multivariate analysis showed that loss of detectable -cell function by 20, 15, or 10 years after the onset of diabetes were risk factors for the development of diabetic retinopathy It suggests that, even if the mean HbA1c is the same, better stability of blood glucose achieved by residual -cell function 7 may be protective against diabetic retinopathy, because glycemic spikes are suspected to be a risk factor for microangiopathy 21 The influence of physiological effects of C-peptide 22 on the protection of diabetic retinopathy is uncertain from this study Acceleration of progression to severe NPDR or PDR by loss of detectable beta-cell function was less marked than the influence on the development of mild NPDR in this study This may have been partly due to the lower event rates of severe NPDR and PDR
early
occurrence
compared with mild NPDR, which meant that our study had limited statistical power to detect differences Alternatively, although the extent of -cell destruction obviously influences glycemic control, progression to proliferative retinopathy may also be influenced by other variables such as production of vascular endothelial growth factor 23 The combination of HLA-A24
and -DQA103 is known as a marker for the acute onset of type 1 diabetes and early complete -cell destruction 6, and it was a surrogate marker for early development of diabetic retinopathy in this study In addition, the acute onset of type 1 diabetes, which reflects a higher rate of -cell destruction 5 and is strongly associated with early complete -cell loss 6, was also a surrogate marker for the early development of diabetic retinopathy These surrogate markers are correlated with diabetic retinopathy indirectly through -cell destruction and subsequent worsening of glycemic control An older age of disease onset was also associated with earlier complete -cell loss, which may have been due to including patients with fulminant type 1 diabetes that develops later than acute-onset type 1 diabetes 24 However, an older age of onset was not associated with any type of diabetic retinopathy The higher age of onset in our patients compared with Caucasians may also be due to the inclusion of patients with slow-onset type 1 diabetes, which also develops later than acute-onset type 1 diabetes 16 In the data set for
10
assessing -cell function at 20 years after the onset of diabetes,
hypertension was a independent risk factor for mild NPDR as described 25 The calendar year of the onset of diabetes was later in the patients without residual -cell function at any time point, which was thought to be due to exclusion of the patients who had no C-peptide data during first 5 years and showed undetectable -cell function thereafter from the longitudinal study, because such patients were prevalent in earlier years in this study This study was performed retrospectively and the observations were not standardized These are limitations with respect to delineating longitudinal changes of residual -cell function 6 and retinopathy findings Missing HbA1c data including those before 1984 is also limitation for assessment of long-term glycemic control Limitations also exist in the method of grading retinopathy in this study Indirect ophthalmoscopy by one person may be less reliable and more prone to bias than stereoscopic fundus photographs assessed Prospective retinopathy by independent on using observers and stereoscopic study findings C-peptide
fundus photographs will be needed to confirm our study Acknowledgements We thank Fumie Takano for her secretarial work
References 1
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complete -cell destruction in type 1 diabetes: longitudinal study of residual -cell function Diabetes 55: 1862-1868 7 Nakanishi K, Kobayashi T, Miyashita H, Ohkubo M, Sugimoto T, Murase T, Kosaka K, Inouye K, Kono M 1990 Relationships among islet cell antibodies, residual -cell function, and metabolic control in patients with insulin-dependent diabetes mellitus of long duration: Use of a sensitive C-peptide radioimmunoassay Metabolism 39: 925-930 8 Nakanishi K, Kobayashi T, Murase T, Nakatsuji T, Inoko H, Tsuji K, Kosaka K 1993 Association of HLA-A24 with complete -cell destruction in IDDM Diabetes 42: 1086-1093 9 Aiello LM, Rand LI, Sebestyen JG, Weiss JN, Bradbury MJ, Wafari MZ, Briones JC 1985 The eyes and diabetes In: Marble A, Krall LP, Bradley RF, Christlieb AR, Soeldner JS, eds Joslins Diabetes Mellitus 12th ed Philadelphia: Lea and Febiger; 600-634 10 11 Matsui M, Sato Y 1989 Classification of diabetic retinopathy and application standard of photocoagulation Ophthalmol Jpn 93: 803-808 Wilkinson CP, Ferris, III, FL, Klein RE, Lee PP, Agardh CD, Davis M, Dills D, Kampik A, Pararajasegaram R, Verdaguer JT 2003 Proposed international clinical diabetic retinopathy and diabetic
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Nakanishi K, Kobayashi T, Miyashita H, Okubo M, Sugimoto T, Murase T, Hashimoto M, Fukuchi S, Kosaka K 1994 Exocrine pancreatic ductograms in insulin-dependent diabetes mellitus Am J Gastroenterol 89: 762-766
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Kobayashi T, Tamemoto K, Nakanishi K, Kato N, Okubo M, Kajio H, Sugimoto T, Murase T, Kosaka K 1993 Immunogenetic and clinical characterization of slowly progressive IDDM Diabetes Care 16: 780-788
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Matsuzawa Y 2000 A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies N Engl J Med 342: 301-307
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Cox DR, Oakes D 1984 Analysis of Survival Data London: Chapman and Hall; 91-111 Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN 2008 Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial -revisited Diabetes 57: 995-1001
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Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE, Matthews DR UKPDS 50: risk factors for incidence and progression of retinopathy in type II diabetes over 6 years from diagnosis Diabetologia 44: 156-163
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Ceriello A 2003 The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications Diabetologia 46 Suppl 1 : M9-M16 Wahren J, Ekberg K, Jörnvall H 2007 C-peptide is a bioactive peptide Diabetologia 50: 503-509 Al-Kateb H, Mirea L, Xie X, Sun L, Liu M, Chen H, Bull SB, Boright AP, Paterson A 2007 Multiple variants in vascular endothelial growth factor VEGFA are risk factors for time to severe retinopathy in type 1 diabetes The DCCT/EDIC genetics study Diabetes 56:
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diabetes: a nationwide survey in Japan Diabetes Care 26: 2345-2352 25 Krolewski AS, Warram J 2005 Epidemiology of late complications of diabetes: A basis for the development and evaluation of preventive program In: Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ eds Joslins Diabetes Mellitus 14th ed Philadelphia: Lippincott Williams Wilkins; 795-808
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Figure legends Figure 1 Number of patients examined for -cell function C-peptide measurement, retinopathy findings, and long-term glycemic control HbA1c data, and their relations Plus or minus - means presence or absence of the data, respectively Figure 2 Histograms of patients who showed undetectable -cell function A and detectable -cell function B at final assessment of C-peptide during follow-up of 211 patients The patients with residual -cell function at the designated time point consisted of those who showed detectable -cell function after that time and those who showed undetectable -cell function after that time in the longitudinal observation The
patients without detectable -cell function at the designated tome point consisted of those who showed undetectable -cell function until that time in the longitudinal observation, and those who showed undetectable -cell function at more than 5 years after the onset of diabetes by the first assessment of -cell function if the assessment time was earlier than the designated time point, the number of whom was shown in parenthesis in table 1 Figure 3 Cumulative incidence of mild nonproliferative diabetic retinopathy in the patients who lost detectable -cell function solid lines and those with residual -cell function broken lines at 5 years A, 10 years B, 15 years C, and 20 years D after the onset of diabetes The Kaplan-Meier data were drawn using 10 patients as the maximum follow-up number
14
Table 1 Clinical characteristics and incidence rate of each type of retinopathy in the patients without detectable -cell function or with residual -cell function at each designated time point Time points of judgment regarding the status of residual -cell function 5 years Residual -cell function No of patients Men/Women Age at onset years Calendar year of onset Mean HbA1c Frequency of
hypertension Frequency of 3-allele combination HLA-A24, -DQA103, and -DR9 Frequency of 2-allele combination HLA-A24 and DQA103 Frequency of acute-onset type 1 diabetes Incidence rate per 100 patient-years Mild NPDR Severe NPDR PDR 344 196 077 412 236 099 477 224 108 415 239 100 522 214 076 418 241 102 541 261 101 425 260 116 70326/37 43665/149 00054 63338/60 45647/103 0035 65555/84 47335/74 0025 63566/104 41517/41 0016 68624/35 50372/143 0060 66137/56 46546/99 0038 69753/76 47234/72 00074 68465/95 43617/39 00089 40014/35 18025/139 0011 38221/55 14614/96 00013 41331/75 14510/69 00004 36234/94 1084/37 00049 829109 81 3/37 819110 179 27/151 076 021 842100 67 4/60 818109 221 23/104 026 0015 854103 83 7/84 810102 227 17/75 0042 0015 846100 144 15/104 787073 268 11/41 0030 009 37 23/13 4013 19916 152 84/68 3414 198111 036 0027 00001 P 606 40/20 3814 19887 10 years Residual -cell function 105 63/42 3313 197810 041 0014 00001 P 8418 53/31 3615 19878 15 years Residual -cell function 76 42/34 3314 197510 034 013 00001 P 10429 65/39 3615 19859 20 years Residual -cell function 42 22/20 3012 197010 027 00499 00001 P
Times judging residual -cell function are expressed from the onset of
diabetes Residual -cell function-or means loss of detectable -cell function at the designated time point or residual -cell function at the designated point Number in parenthesis means the number of the patients who showed undetectable -cell function at more than 5 years after the onset of diabetes by the first assessment of residual -cell function NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy
Table 2 Relative hazard of the development of diabetic retinopathy according to Coxs proportional hazards model in the patients with type 1 diabetes
Time points of judgment of residual -cell function 5 years HR 95 CI Mean HbA1c Detectable -cell function 0present, 1absent Hypertension 0no, 1yes Possession of HLA-A24 and -DQA103 0no, 1yes Sex 0women, 1man Age at onset years Period before insulin therapy months Time point of judgment of residual -cell function is expressed as the duration from the onset of diabetes HR, hazard ratio; CI, confidence interval 081 062-105 101 099-103 100 099-100 012 027 060 089 068-116 100 098-102 100 099-101 037 087 074 085 065-112 100 098-101 100 099-100 025 062 073 089 065-122 098 096-101 100 099-101 047 014 069 103
079-135 084 107 082-142 061 111 084-150 046 116 084-163 037 119 081-167 037 114 076-163 049 147 095-213 0079 175 114-257 0012 188 142-251 119 077-173 p 00001 040 10 years HR 95 CI 196 148-260 143 107-190 p 00001 0016 15 years HR 95 CI 175 133-233 154 114-210 p 00001 00048 20 years HR 95 CI 194 136-281 163 104-272 p 00002 0034
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