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Keywords:

  • diabetic retinopathy;
  • glycaemic control;
  • insulin-dependent diabetes mellitus;
  • islet cell antibodies;
  • noninsulin-dependent diabetes mellitus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Henricsson M, Gottsäter A, Jeppsson J-O, Fernlund P, Sundkvist G (Lund University, Malmö University Hospital, Malmö, Sweden). The frequency and severity of retinopathy are related to HbA1c values after, but not at, the diagnosis of NIDDM. J Intern Med 1998; 244: 149–54.

Objectives

To examine the relationship between previous glycaemic exposure and prevalence of retinopathy 8 years after diagnosis of diabetes in 58 islet cell antibodies (ICA)-negative noninsulin-dependent diabetes mellitus (NIDDM) patients and in a group of 14 ICA-positive ‘NIDDM’ and insulin-dependent diabetes mellitus (IDDM) patients.

Design and methods

The Wisconsin retinopathy scale was used to assess the retinopathy which was graded into mild, moderate and severe nonproliferative diabetic retinopathy (NPDR), or proliferative retinopathy (PDR). The frequency and severity of retinopathy was related to HbA1c levels at diagnosis, and 3 and 5 years later.

Results

Thirty of the 58 ICA-negative NIDDM patients (52%) but only 2 of the 14 ICA-positive ‘NIDDM’ or IDDM patients (14%) had mild–moderate–severe NPDR 8 years after diagnosis (P= 0.02). None had PDR. Retinopathy 8 years after diagnosis in NIDDM (= 58 ICA-negative patients) was correlated with the degree of glycaemic control (HbA1c levels) at 3 and 5 years after diagnosis, but not to HbA1c levels at diagnosis. The relative risk for a higher average HbA1c (per percentage) at 3 and 5 years was 1.56 for any retinopathy vs. no retinopathy (95% confidence interval 1.1–2.2; P= 0.01) and 1.68 for moderate to severe NPDR in comparison with no DR and mild NPDR (95% confidence interval 1.0–2.8; P= 0.04).

Conclusions

Retinopathy after 8 years of diabetes in NIDDM patients was associated with impaired glycaemic control during previous years but not with glycaemic control at baseline. Good glycaemic control may prevent retinopathy in patients with NIDDM.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

In insulin-dependent diabetes mellitus (IDDM), good glycaemic control reduces the risk of development and progression of retinopathy [ 1, 2]. An association between poor glycaemic control and retinopathy has been found in patients with maturity-onset type diabetes [ 3] and in diabetic patients diagnosed at or after the age of 30 years [ 4, 5], i.e. patients suspected for noninsulin-dependent diabetes (NIDDM). However, the true impact of poor glycaemic control on retinopathy in NIDDM has not been established. When studying patients with NIDDM, it is essential that islet cell antibodies (ICA) are considered [ 6, 7]. About 10% of patients with clinical NIDDM have ICA at the time of diagnosis of diabetes and thus a slow-onset form of IDDM [ 8]. Therefore a study of ICA-negative NIDDM patients is needed to clarify whether there is a relationship between glycaemic control and retinopathy in NIDDM.

In the current cross-sectional study, retinopathy 8 years after diagnosis of diabetes was related to HbA1c levels at diagnosis as well as 3 and 5 years thereafter in adult-onset diabetic patients with and without ICA. The aim of our study was to evaluate whether the frequency and severity of retinopathy were related to HbA1c levels at or after the diagnosis in ICA-negative NIDDM patients.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

For two years newly diagnosed diabetic patients between 15 and 60 years of age (n= 128) in Malmö, Sweden, were classified as IDDM or NIDDM. The classification of IDDM was based on clinical need for insulin treatment 1 week after diagnosis [ 6]. The patients were tested for ICA and fasting C-peptide [ 6]. The study primarily aimed to investigate the pathogenesis of diabetes, and therefore diabetic complications were not assessed at the diagnosis of diabetes. The patients were re-examined three [ 9] and five [ 10] years after diagnosis. The 5-year examination included blood pressure, HbA1c, plasma lipids, fasting plasma C-peptide, autonomic nerve function, urinary albumin excretion and glomerular filtration rate (GFR). Of the 120 surviving patients, 9/20 (45%) IDDM patients, 7/11 (64%) NIDDM patients with ICA, and 62/89 (70%) NIDDM patients without ICA at diagnosis completed the entire examinations at 3 and 5 years, and were invited to fundus photography 7–9 years after diagnosis of diabetes mellitus.

Of the 78 patients invited to fundus photography, the 9 IDDM patients (age 35 ± 14), 5 (71%) NIDDM patients with ICA at diagnosis (age 51 ± 14 years), and 58 (93%) NIDDM patients without ICA at diagnosis (age 57 ± 9 years) agreed to the examination and thus participated in the retinopathy study. Out of these patients 48 were treated with diet alone, 15 had antihyperglycaemic agents, and the 9 IDDM patients were treated with insulin. With regard to age and gender these patients were representative of the whole group. Since previous studies have revealed that NIDDM patients with ICA show decreasing β-cell function and subsequently develop insulin dependency [ 6, 8, 9], this group was assessed together with IDDM patients. The study was approved by the Ethics Committee at the University of Lund, Sweden. Informed consent was obtained from all patients.

Fundus photography

Colour fundus photographs were obtained at an angle of 50° with a Topcon TRC-50 VT fundus camera (Tokyo Optical Co. Ltd, Japan). The photographs covered fields 1–3 of the seven standard fields, with stereo pairs of the macula (field 2). We used the alternative classification of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) to obtain the retinopathy level [ 11]. This classification is based on seven 30° stereoscopic fields and provides an overall retinopathy scale. With the 50° field, a large part of the retina is visualized, and, according to Moss et al. [ 12], fewer fields than seven are sufficient for grading.

Level 10 represents no retinopathy, levels 21 through 51 nonproliferative diabetic retinopathy (NPDR) of increasing severity, and level 60 + all forms of proliferative diabetic retinopathy (PDR), with and without laser treatment. The patient's retinopathy level was derived by giving the eye with the higher level a greater weight. This scheme provides an 11-step scale: 10, 21/10, 21/21, 31/< 31, 31/31, 41/< 41, 41/41, 51/< 51, 51/51, 60 +/< 60 + , 60 +/60 + [ 11]. Thereafter, we divided the retinopathy levels into five groups: no diabetic retinopathy (DR) (level 10), mild retinopathy (levels 21/10–31/31), moderate retinopathy (levels 41/< 41–51/< 51), severe NPDR (level 51/51) or PDR (level 60 +/60 +).

Macular oedema was defined as presence of hard exudates and/or retinal thickening within one disc diameter of the centre of the macula and considered as present if at least one eye was affected.

Photographs were viewed against light boards using Donaldson's stereo-viewer (× 5 magnification) and assessed by one of the authors (M.H.) who had extensive previous experience using this classification. The patients' clinical data were not revealed to the grader . No patients were excluded from the study because of media opacities.

Analytical methods

Body mass index (BMI) was calculated as weight in kilograms/(height in m)2. Supine blood pressure was measured once with a mercury sphygmomanometer in the right upper arm; phase V diastolic sound was used for definition of diastolic blood pressure.

Blood samples for C-peptide and HbA1c determination were collected in tubes with EDTA. Fasting C-peptide was assayed by radioimmunoassay [ 13], reference values 0.25–0.75 nmol L−1. HbA1c was determined by ion exchange chromatography, Mono S-HPLC [ 14], reference values 3.70–5.00%.

S-triglycerides and S-total cholesterol were determined on a DAX 48 automatic analyzer (Ames-Bayer AB, Sweden). S-HDL cholesterol was determined after precipitation of LDL and VLDL lipoproteins with dextran sulfate [ 15]. S-LDL cholesterol was calculated from the values for S-triglycerides, S-total cholesterol and S-HDL cholesterol according to the formula D = A – B – C/2.2, where D is S-LDL cholesterol, A is S-total cholesterol, B is S-HDL cholesterol, and C is S-triglycerides.

U-albumin was determined by rate nephelometry on a Beckman Array Protein system instrument (Beckman Instruments, Fullerton, CA, USA). Microalbuminuria was defined as an albumin excretion of 0.03–0.3 g 24 h−1 [ 16]. Urinary bacterial cultures were not conducted prior to measurements of U-albumin. GFR was evaluated by the 51Cr-EDTA plasma clearance method [ 17].

Autonomic neuropathy was assessed by evaluating the heart rate reaction to deep breathing (expiration/inspiration [E/I] ratio) [ 18] and to tilt (acceleration and brake indices) [ 19], and a value more than 1.5 SD below the age-corrected value was considered abnormal [ 20].

ICA had been assayed at diagnosis of diabetes by an indirect two-colour immunofluorescence test [ 21, 22].

Statistics

The statistical significance of group differences was determined by the Mann–Whitney U-test and the Fisher's exact test. Correlations were tested with the Spearman Rank correlation test. The relationships between retinopathy and different variables were assessed with multiple logistic regression analysis. For each patient, the HbA1c values at 3 and 5 years were put together, and the mean of this value was employed in the analysis together with HbA1c at diagnosis and systolic and diastolic blood pressures. Significance was considered for P≤ 0.05. Data are presented as mean ± SD.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Thirty out of 58 (52%) NIDDM patients without ICA had retinopathy in comparison with only 2 out of 14 (14%) IDDM and NIDDM patients with ICA (P= 0.02). Amongst NIDDM patients without ICA, 24/58 (41%) had mild DR, 5/58 (9%) moderate NPDR, and one patient severe NPDR. Four NIDDM patients had macular oedema; two of them had mild and two of them had moderate NPDR. Table 1 demonstrates that there was no significant difference in mean HbA1c at diagnosis between NIDDM patients with and without retinopathy 8 years later. After diagnosis, however, there was an increase in HbA1c in patients who had retinopathy 8 years later ( Fig. 1); HbA1c was significantly higher in patients with retinopathy than in those without 5 years after diagnosis ( Table 1).

Table 1.  Clinical characteristics in NIDDM patients without ICA Thumbnail image of
image

Figure 1. Average HbA1c (± SEM) at diagnosis, after 3 and 5 years in patients with (filled circles) and without (open circles) retinopathy.

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Five years after diagnosis, fasting blood glucose, HbA1c, tU-albumin, and supine systolic and diastolic blood pressures were significantly higher in NIDDM patients with retinopathy later than in patients without ( Table 1). However, there was no significant difference in the frequency of autonomic neuropathy between patients with and without retinopathy. Table 2 shows that retinopathy 8 years after diagnosis was correlated with the HbA1c levels at 3 and 5 years after diagnosis, blood pressures and the degree of albuminuria 5 years after diagnosis, but not with lipids, C-peptide, BMI or autonomic neuropathy. In a multiple logistic regression analysis with any retinopathy as a dependent variable, the average HbA1c value at 3 and 5 years after diagnosis was associated with any retinopathy (Table 3a) as well as with moderate– severe NPDR (Table 3b).

Table 2.  Spearman correlations between any retinopathy and associated variables Thumbnail image of

Amongst the 58 ICA-negative NIDDM patients, four patients required insulin treatment 5 years after diagnosis, 26 patients were treated with oral agents, and 28 patients were treated with diet alone. There were no significant differences in the prevalence of retinopathy between the three treatment groups.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study demonstrates that 8 years after diagnosis of diabetes, ICA-negative NIDDM patients have a much higher prevalence of retinopathy (52%) than ICA-positive ‘NIDDM’ and IDDM patients (14%). This finding must be interpreted with caution; the latter group was small. Owing to the design of the study, no baseline retinopathy data are available in the material. Onset of NIDDM is supposed to occur several years before the clinical diagnosis [ 23], but this could only partially explain the high frequency of retinopathy after 8 years in this group of patients. The frequency of retinopathy within 2 years of diagnosis is only 12.5% in Swedish patients aged > 30 years at onset of the diabetes [ 24]. In keeping with the DCCT [ 1] and the Stockholm Study [ 2] in IDDM, our study demonstrated that disturbed glycaemic control favours development of retinopathy in NIDDM [ 3]. Although glycaemic control at diagnosis was not associated with the prevalence of retinopathy 8 years later, our study confirms the importance of hyperglycaemia for the development of retinopathy in NIDDM. In addition, glycaemic control in itself and not endogenous insulin production seems to be of relevance. In agreement with Klein et al. [ 25], we could not find any relationship between C-peptide levels and retinopathy.

Some previous studies have suggested an association between elevated blood pressure and the development and progression of diabetic retinopathy in IDDM and NIDDM [ [26][27]26–28]. In the current study there was a correlation between retinopathy and elevation in systolic and diastolic blood pressures ( Table 2). However, this association did not remain in the multiple logistic regression analysis (Tables 3a and 3b), and therefore noted blood pressure changes might be considered as parallel phenomena (a feature of diabetic nephropathy?) to retinopathy. In agreement with this, patients with retinopathy had a higher degree of albuminuria 5 years after diagnosis of diabetes than patients without retinopathy.

In conclusion, retinopathy in patients with NIDDM was associated with a previous deterioration of glycaemic control. Improvement of glycaemic control may prevent retinopathy in NIDDM.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was supported by grants from the Swedish Medical Research Council (7507), the Swedish Diabetes Association, the Malmö Diabetes Association, the Swedish Heart Lung Foundation, the Lundström Foundation, the Novo Nordic Foundation, the Child Diabetes Fund, Research Funds at Malmö University Hospital and the Lund Medical Faculty.

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  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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