Microvascular disease: what does the UKPDS tell us about diabetic retinopathy?

Background The UK Prospective Diabetes Study (UKPDS) was a randomised controlled clinical study which looked at the effect of improved blood glucose and blood pressure control on macro- and microvascular complications in Type 2 diabetes. Retinopathy was the commonest microvascular outcome and this paper looks at this complication. Methods Newly diagnosed diabetic patients were randomised to intensive or conventional glycaemic control and a subset of hypertensive patients to tight or less tight blood pressure control. Patients were seen every 3 months in study clinics and retinopathy was assessed by adjudicated grading of triennial colour retinal photographs. Photocoagulation treatment, vitreous haemorrhage and cataract extraction were predefined UKPDS endpoints. Observational analyses of the data were used to examine the relationship of updated mean glycated haemoglobin (HbA(1c)) and mean blood pressure levels to retinopathy outcomes. Results The UKPDS showed that both improved glucose control and improved blood pressure control reduced the risk of retinopathy, with a linear relationship between the log hazard ratio for retinopathy and both updated mean HbA(1c) and updated mean blood pressure. A 1% decrement in HbA(1c) equated to a 31% reduction in retinopathy and a 10 mmHg decrement in systolic blood pressure equated to an 11% reduction in photocoagulation or vitreous haemorrhage. Evidence of retinopathy at diagnosis, including the presence of microaneurysms only, increased significantly the risk of progression to photocoagulation. Conclusions The UKPDS stands out as a landmark study in Type 2 diabetes, emphasising the crucial importance of controlling both blood glucose and blood pressure in order to minimise the risk of developing sight-threatening retinopathy.

Clinical validation of a link between TNF-alpha and the glycosylation enzyme core 2 GlcNAc-T and the relationship of this link to diabetic retinopathy.

AIMS/HYPOTHESIS: Increasing evidence suggests that chronic, subclinical inflammation plays an important role in the pathogenesis of diabetic retinopathy. We recently reported that a glycosylating enzyme, core 2 beta-1,6-N-acetylglucosaminyltransferase (core 2 GlcNAc-T), is implicated in increased leucocyte-endothelial cell adhesion in diabetic retinopathy via an upregulation mechanism controlled by TNF-alpha. SUBJECTS, MATERIALS AND METHODS: We examined the functional link between circulating TNF-alpha and the activity and phosphorylation of core 2 GlcNAc-T in polymorphonuclear leucocytes of patients with type 1 and type 2 diabetes. RESULTS: Plasma levels of TNF-alpha, although similar in patients with type 1 and type 2 diabetes, were significantly higher than in age-matched healthy controls, and correlated well with the severity of retinopathy. Core 2 GlcNAc-T activity followed the same trend and was associated with phosphorylation of the enzyme. Finally, the observation that TNF-alpha levels are also linked to glycaemic values suggests that in patients, as well as in vitro, the glycosylation-mediated cell adhesion process that plays a role in diabetic retinopathy may involve glucose- and TNF-alpha-induced protein kinase beta2 activation, and subsequently raise activity of core 2 GlcNAc-T through increased enzyme phosphorylation. CONCLUSIONS/INTERPRETATION: Our results reveal a novel rationale towards a specific treatment of diabetic retinopathy, based on the inhibition of core 2 GlcNAc-T activity and/or the blockage of cognate glycans.

Quality assurance for diabetic retinopathy telescreening.

AIMS: TOSCA was an EU-Commission supported international research project designed to develop telescreening services in diabetic retinopathy and glaucoma. This paper describes the quality assurance methods developed for the diabetic retinopathy telescreening service within the TOSCA project. SETTING: The study was performed in 1895 patients with diabetes between 2000 and 2002 at diabetic retinopathy screening sites in five European countries. Data were analysed centrally. METHODS: Patients attending each clinic's diabetic retinopathy screening service received standardized retinal photography. The images and associated data were transferred electronically to a remote location for grading. Each photographer uploading images and each grader downloading images for assessment was controlled by a systematic quality management approach. The quality assurance measures defined were image quality, intragrader reliability. A cockpit chart was developed for the management and presentation of relevant results and quality measures. For the intragrader reliability tests, 10% of the images were processed for a second grading. An algorithm for calculating differences between repeated gradings was developed. RESULTS: The assessment of image quality for the different sites showed that only 0-0.7% were unassessable. One hundred per cent agreement for both gradings was achieved in 50-85% of graded cases, depending on site and grader, and an agreement better than 95% in 71-100% of cases. CONCLUSIONS: A telemedicine-supported quality assurance process is practical and advantageous. The cockpit charts have proven to be useful tools when monitoring the performance of a telescreening service. Grader feedback showed high satisfaction with the quality assurance process.

The effect of growth hormone (GH) replacement therapy in adult patients with type 1 diabetes mellitus and GH deficiency.

OBJECTIVES: Specific problems in patients with insulin-dependent diabetes mellitus (IDDM) and GH deficiency are hypoglycaemic attacks, increased insulin sensitivity and loss of energy. These problems may be related to GH deficiency. PATIENTS: GH replacement was initiated in five patients with type 1 diabetes mellitus and GH deficiency for 6 months [four males and one female, mean age 41.6 +/- 3.8 years, mean +/- standard error of the mean (SEM); body mass index (BMI) 22.3 +/- 1.2 kg/m2]. METHODS: Body composition (bioimpedance), metabolic control [haemoglobin A1C (HbA1C)], insulin requirement and frequency of hypoglycaemia were measured, and quality of life was assessed using validated questionnaires. Monthly eye photographs were taken. RESULTS: IGF-I concentrations were below the age-adjusted range at baseline and increased significantly following GH replacement therapy [analysis of variance (ANOVA), P < 0.05]. Diabetes control as assessed by HbA1C remained stable (8.2 +/- 0.2 vs. 8.0 +/- 0.4), but needed a 1.75-fold increase in insulin dose/day. Lean body mass tended to increase (P = 0.07) and body fat mass decreased significantly (P > 0.01). Number of severe hypoglycaemic (< 3 mmol/l) attacks decreased significantly (P < 0.04) and quality of life assessed by validated questionnaires improved significantly in all patients [Psychological and General Well-Being Schedule (PGWBS), P < 0.04; Nottingham Health Profile (NHP), P < 0.05]. Monthly eye photographs revealed no changes in the retina in any patients. CONCLUSION: GH replacement therapy has a beneficial effect at the dose used. It restores body composition and decreases frequency and severity of hypoglycaemic episodes, thus improving quality of life. Long-term trials are needed to determine the safety of GH replacement therapy in these patients.

UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis.

AIMS/HYPOTHESIS: To determine risk factors related to the incidence and progression of diabetic retinopathy over 6 years from diagnosis of Type II (non-insulin-dependent) diabetes mellitus. METHODS: This report describes 1919 patients from within the United Kingdom Prospective Diabetes Study (UKPDS), with retinal photographs taken at diagnosis and 6 years later and with complete data available. Photographs were centrally graded for lesions of diabetic retinopathy using the modified Early Treatment of Diabetic Retinopathy Study Final scale. Risk factors were assessed after 3 months diet from the time of diagnosis of diabetes. Patients were seen every 3 months in a hospital setting. Biochemical measurements were done by a central laboratory. End points of vitreous haemorrhage and photocagulation were confirmed by independent adjudication of systematically collected clinical data. The main outcome measures were incidence and progression of retinopathy defined as a two-step Early Treatment of Diabetic Retinopathy Study (ETDRS) final scale change. RESULTS: Of the 1919 patients, 1216 (63 %) had no retinopathy at diagnosis. By 6 years, 22 % of these had developed retinopathy, that is microaneurysms in both eyes or worse. In the 703 (37 %) patients with retinopathy at diagnosis, 29 % progressed by two scale steps or more. Development of retinopathy (incidence) was strongly associated with baseline glycaemia, glycaemic exposure over 6 years, higher blood pressure and with not smoking. In those who already had retinopathy, progression was associated with older age, male sex, hyperglycaemia (as evidenced by a higher HbA1c) and with not smoking. CONCLUSION/INTERPRETATION: The findings re-emphasise the need for good glycaemic control and assiduous treatment of hypertension if diabetic retinopathy is to be minimised.

Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes.

OBJECTIVE: To determine the incidence of retinopathy and the relative importance of its risk factors in type 1 diabetes. RESEARCH DESIGN AND METHODS: This is a 7.3-year follow-up of 764 of 1,215 (63%) people with type 1 diabetes across Europe, aged 15-60 years at baseline with no retinopathy (the EURODIAB Prospective Complications Study). Retinal photographs were taken at baseline and follow-up and risk factors were assessed to a standard protocol. RESULTS: Retinopathy incidence was 56% (429/764, 95% CI 52-59%). Key risk factors included diabetes duration and glycemic control. We found no evidence of a threshold effect for HbA1c on retinopathy incidence. Univariate associations were observed between incidence and albumin excretion rate, cholesterol, triglyceride, fibrinogen, von Willebrand factor, gamma-glutamyltransferase, waist-to-hip ratio, and insulin dose. No associations were observed for blood pressure, cardiovascular disease, or smoking. Independent risk factors, as assessed by standardized regression effects, were HbA1C (1.93, P = 0.0001), duration (1.32, P = 0.008), waist-to-hip ratio (1.32, P = 0.01), and fasting triglyceride (1.24, P = 0.04). CONCLUSIONS: Retinopathy incidence in type 1 diabetes remains high. Key risk factors include diabetes duration and glycemic control, with no evidence of a threshold for the latter. Other independent risk factors, such as waist-to-hip ratio and triglyceride levels, both markers of insulin resistance, were strongly related to incidence.

Activity of the glycosylating enzyme, core 2 GlcNAc (beta1,6) transferase, is higher in polymorphonuclear leukocytes from diabetic patients compared with age-matched control subjects: relevance to capillary occlusion in diabetic retinopathy.

The exact mechanism for capillary occlusion in diabetic retinopathy is still unclear, but increased leukocyte-endothelial cell adhesion has been implicated. We examined the possibility that posttranslational modification of surface O-glycans by increased activity of core 2 transferase (UDP-Glc:Galbeta1-3GalNAcalphaRbeta-N-acetylglucoaminyltr ansferase) is responsible for increased adhesion of leukocytes to vascular endothelium in diabetes. The mean activity of core 2 transferase in polymorphonuclear leukocytes isolated from type 1 and type 2 diabetic patients was higher compared with age-matched control subjects (1,638 +/- 91 [n = 42] vs. 249 +/- 35 pmol x h(-1) x mg(-1) protein [n = 24], P = 0.00013; 1,459 +/- 194 [n = 58] vs. 334 +/- 86 [n = 11], P = 0.01). As a group, diabetic patients with retinopathy had significantly higher mean activity of core 2 transferase compared with individuals with no retinopathy. There was a significant association between enzyme activity and severity of retinopathy in type 1 and type 2 diabetic patients. There was a strong correlation between activity of core 2 transferase and extent of leukocyte adhesion to cultured retinal capillary endothelial cells for diabetic patients but not for age-matched control subjects. Results from transfection experiments using human myelocytic cell line (U937) demonstrated a direct relationship between increased activity of core 2 transferase and increased binding to cultured endothelial cells. There was no relationship between activity of core 2 transferase and HbA(1c) (P = 0.8314), serum advanced glycation end product levels (P = 0.4159), age of the patient (P = 0.7896), and duration of diabetes (P = 0.3307). On the basis that branched O-glycans formed by the action of core 2 transferase participate in leukocyte adhesion, the present data suggest the involvement of this enzyme in increased leukocyte-endothelial cell adhesion and the pathogenesis of capillary occlusion in diabetic retinopathy.

Microaneurysms in the development of diabetic retinopathy (UKPDS 42). UK Prospective Diabetes Study Group.

AIMS/HYPOTHESIS: To determine whether microaneurysms, in the absence of other lesions, have a predictive role in the progression of diabetic retinopathy in Type II (non-insulin-dependent) diabetes mellitus. METHODS: Retinal photographs taken at diagnosis in patients participating in the United Kingdom Prospective Diabetes Study, and thereafter at 3 yearly intervals, were assessed using a modified Early Treatment of Diabetic Retinopathy grading system for lesions of diabetic retinopathy and end points of vitreous haemorrhage and photocoagulation. The number of microaneurysms in each eye was recorded. RESULTS: The changes between diagnosis and later photographs were analysed in 2424 patients at 6 years, 1236 at 9 years and 414 at 12 years. Of the 2424 patients studied in the 6 year cohort 1809 had either no retinopathy or microaneurysms only at entry. In these patients the presence of microaneurysms alone and also the number of microaneurysms had a high predictive value for worsening retinopathy at 3, 6, 9, and 12 years after entry into the study (e. g. at 6 years chi(2) for trend = 75 on 1 df, p < 0.001). The predictive value of the presence or absence of microaneurysms and their number at 3 years from diagnosis and subsequent worsening retinopathy was similar to that at entry. CONCLUSION/INTERPRETATION: Microaneurysms are important lesions of diabetic retinopathy and even one or two microaneurysms in an eye should not be regarded as unimportant.

Intracellular protein glycation in cultured retinal capillary pericytes and endothelial cells exposed to high-glucose concentration.

There is now increasing evidence suggesting that non-enzymatic glycation (NEG) of proteins is involved in the pathogenesis of chronic diabetic complication. In this study we demonstrate that chronic exposure to high-glucose concentration leads to intracellular protein glycation in cultured bovine retinal capillary pericytes and endothelial cells. The level of intracellular protein glycation, as measured using a competitive enzyme-linked immunoabsorbant assay (ELISA), was found to increase in both pericytes and endothelial cells as function of time. As expected products of NEG were only detected when the Schiff base and the Amadori products were chemically reduced to glucitollysine by sodium borohydride. Despite the accumulation of early glycation products on cellular proteins there was no further rearrangement reaction into advanced glycation endproducts (AGEs), even after 12 days of incubation in high-glucose medium. Immunofluorescence microscopy demonstrated that the monoclonal antibody reacting with glucitollysine stains the cytoplasm of both pericytes and endothelial cells in a finely punctate pattern. Further studies using Western blot analysis suggested that a number of cellular proteins, including smooth muscle actin in pericytes, become rapidly glycated. The results from this in vitro study suggest that excessive accumulation of early products of non-enzymatic glycation in pericytes and endothelial cells may play an important role in the pathogenesis of diabetic retinopathy.

Effect of angiotensin-converting enzyme inhibition with perindopril and beta-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects.

The effect of angiotensin-converting enzyme (ACE) inhibitors on the diabetic retinal circulation has not been studied previously. The aim of this study was to evaluate the effect of ACE inhibition and beta-blockade on retinal blood flow (RBF) in a group of 45 hypertensive diabetic subjects using a randomized double-blind trial over a period of 12 months. Laser Doppler velocimetry and computed image analysis were used to measure RBF. The changes in blood pressure over 12 months were comparable (perindopril [PE]: systolic [SBP] 152.1 +/- 3.3 and diastolic [DBP] 97.2 +/- 1.7 mm Hg to SBP 136.8 +/- 3.4 and DBP 85.8 +/- 2.1; atenolol: SBP 158.9 +/- 5.1 and DBP 97.5 +/- 1.6 mm Hg to SBP 137.9 +/- 3.4 and DBP 85.1 +/- 1.6; P = .607, mean +/- SEM). RBF decreased from 17.19 +/- 2.21 microL x min(-1) to 14.18 +/- 1.50 microL x min(-1) in the PE group (n = 15, P = .208) while it increased with atenolol from 15.80 +/- 1.24 microL x min(-1) to 16.99 +/- 1.18 microL x min(-1) (n = 17, P = .399). The comparison of percentage changes in RBF (PE -7.16% +/- 11.49%; atenolol, +15.31% +/- 9.51%) reached statistical significance (P < .05). There was an increase in RBF in 33.3% of subjects receiving PE and in 70.6% of those receiving atenolol. Similar trends were found for retinal conductance. There were no significant changes in the parameters of retinal vascular permeability. Albuminuria decreased to a greater degree with PE, but did not reach significance (PE, 112.1 +/- 39.5 mg/24 h to 88.6 +/- 30.5 mg/24 h; atenolol, 87.3 +/- 51.7 mg/24 h to 82.1 +/- 47.7 mg/24 h). This suggests that ACE inhibition therapy may promote a hemodynamic milieu in the hypertensive diabetic retinal circulation that serves to protect against the progression of diabetic retinopathy, whereas beta-blockade has the opposite effect.

Effect of isovolaemic haemodilution on visual outcome in branch retinal vein occlusion.

AIMS: To assess the efficacy of isovolaemic haemodilution therapy (IHT) in the treatment of patients with branch retinal vein occlusion (BRVO). METHODS: Patients presenting with BRVO between 1 July 1991 and 31 August 1993 were eligible for inclusion and randomised into treatment and control groups. Patients randomised to receive IHT were treated for 6 weeks with venesection and volume replacement using hydroxyethylstarch, a plasma expander. The target haematocrit was 35%. Follow up was for 1 year. RESULTS: The baseline visual acuity of the two groups was similar at 0.74 and 0.75 logMAR units (Snellen 6/36), for the IHT and control groups, respectively. At 6 weeks, visual acuity in the IHT group had improved by 0.20 logMAR units (2 lines on the Bailey-Lovie chart) (p = 0.0001). Vision was unchanged in the control group. At 1 year, the IHT group exhibited an improvement of 0.43 logMAR units. By comparison, the improvement in the control group at 1 year was significantly less at 0.17 logMAR units (p = 0.03). The final visual acuity in the IHT and control groups was 0.30 (Snellen 6/12) and 0.60 (Snellen 6/24) logMAR units, respectively. CONCLUSIONS: The results support the theory that IHT has a positive effect on the visual outcome in patients with BRVO.

Retinal blood flow in nonischemic central retinal vein occlusion.

OBJECTIVE: The authors studied the changes in retinal blood flow (RBF) and oxygen reactivity in a major temporal vein in patients with central retinal vein occlusion (CRVO). PARTICIPANTS: Eleven patients with nonischemic CRVO approximately 7 weeks from onset of disease. INTERVENTION: Laser Doppler velocimetric measurement of RBF and vessel reactivity to inhaling 60% oxygen. Measurements were performed at baseline and 3 months. RESULTS: Flow velocity in the affected eye had increased significantly by 3 months, from 1.6 +/- 0.4 cm/second to 2.0 +/- 0.4 cm/second (P = 0.02). Retinal blood flow, however, remained unchanged (13.7 +/- 5.8 microl/minute versus 15.0 +/- 6.5 microl/minute). The two comparable RBF values, despite differing velocity values, suggest that the relatively normal baseline value was achieved through higher intravascular pressure at baseline (Bernoulli's principle). This is supported by the fact that oxygen reactivity had improved from 2.1% +/- 3.6% at baseline to 3.8% +/- 3.1% (P = 0.001) at 3 months, which suggests an improved ability to respond to hyperoxia from reduced intravascular pressure. CONCLUSION: Intravascular pressure in CRVO appears to continue to decrease during the first 5 months after the onset of CRVO, indicating continuing reduction in the degree of outflow obstruction during this time.

United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors.

OBJECTIVES: To report on the prevalence of retinopathy in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) and to evaluate the relationship of retinopathy to clinical and biochemical variables. DESIGN: A multicenter, randomized, controlled clinical study of therapy in patients with NIDDM. SETTING AND PATIENTS: Patients were part of the United Kingdom Prospective Diabetes Study, a 23-center study of 2964 white patients who had both eyes photographed and assessed. OUTCOME MEASURES: The presence and severity of diabetic retinopathy were evaluated by sex, and the relationship of retinopathy to medical and biochemical parameters was assessed. RESULTS: Retinopathy, defined as microaneurysms or worse lesions in at least 1 eye, was present in 39% of men and 35% of women. Marked retinopathy with cotton wool spots or intraretinal microvascular abnormalities was present in 8% of men and 4% of women. The severity of retinopathy was related in both sexes to higher fasting plasma glucose levels, higher systolic and diastolic blood pressure, lower serum insulin levels, and reduced beta-cell function. In addition, in men, increased alcohol consumption was related to increased severity of retinopathy, while leaner women had more severe eye lesions. Visual acuity was normal in most patients, but in men there was a trend for those with more severe retinal lesions to have worse visual acuity. CONCLUSIONS: Diabetic retinopathy is common in patients with newly diagnosed NIDDM. Careful ophthalmic assessment at diagnosis is important.

Toxic action of advanced glycation end products on cultured retinal capillary pericytes and endothelial cells: relevance to diabetic retinopathy.

The toxic effects of advanced glycation end products (AGEs) on bovine retinal capillary pericytes (BRP) and endothelial cells (BREC) were studied. AGE-modified bovine serum albumin (AGE-BSA) was toxic to BRP. At a concentration of 500 micrograms/ml it reduced the BRP number to 48 +/- 3% (p < 0.05) of untreated controls, as determined by cell counting with haemocytometer. AGE-BSA was also toxic to bovine aortic endothelial cells (BAEC) reducing cell number to 84 +/- 3.1% of untreated controls. Under similar conditions, low concentrations (62.5 micrograms/ml) of AGE-BSA were mitogenic to BREC increasing the cell proliferation to 156 +/- 11% (p < 0.05) above that of untreated controls. At a higher dose of 500 micrograms/ml AGE-BSA decreased the proliferation of BREC to 85 +/- 6% of untreated controls. Immunoblot analysis demonstrated that BRP and BREC express the p60 AGE-receptor. Retinal capillary bed from the human also stained positively for the p60 AGE-receptor. Addition of 0.25 micrograms/ml of p60 AGE-receptor antibody was able to block the effects of AGE-BSA on BRP and BREC. The level of binding of [125I]-labelled AGE-BSA to the cell surface was small but significant among the three cell types. There was also an increase in the internalized pool of radioligand in BRP and BREC but this was very much lower than in BAEC. In all the cell types the internalized pool of [125I]-labelled AGE-BSA was much larger than the amount associated with the cell surface. Degradation products were not detected in the media over the 24-h incubation of the cells with [125I]AGE-BSA. The binding of [125I]-labelled AGE-BSA to the cell surface was prevented by the addition of p60 AGE-receptor. These results suggest that the interaction of AGE-modified proteins with the membrane-bound AGE-receptor may play an important role in the pathogenesis of diabetic retinopathy.

The accurate assessment of changes in retinal vessel diameter using multiple frame electrocardiograph synchronised fundus photography.

PURPOSE: Detection and precise quantification of changes in retinal vessel diameter by image analysis techniques is important in a number of fields of research. The retinal vessels have been shown to exhibit pulse related changes in diameter. These may need to be taken into account when studying diameter changes due to other causes. This study examined the effect of using multiple fundus photographs with and without electrocardiographic synchronisation on the size and statistical significance of changes in mean retinal vessel diameter. METHODS: Twelve fundus photographs spaced throughout the cardiac cycle by electrocardiographic synchronisation were taken in 10 normal volunteers: (a) at rest, (b) during isometric exercise, and (c) during oxygen inhalation. Vessel diameters were measured using a computer assisted image analysis system. Subsequently smaller sample sizes, with and without electrocardiograph synchronisation were modeled from the available data. RESULTS: With a group of ten subjects six or more electrocardiograph synchronised photographs enable reliable detection of small diameter changes (1.4%) induced by isometric exercises while other methods either failed to detect change or were unreliable at doing so. With six subjects twelve synchronised photographs were required to reliably detect a change of the same magnitude. Larger diameter changes (5.4%) were detected by any method including a single unsynchronised photograph. CONCLUSIONS: Multiple frame electrocardiograph synchronized fundus photography permits more accurate detection of small changes in retinal vessel diameter.

Causes of death and risk factors in young and old diabetic patients referred to a retinopathy clinic.

The causes of death and associated risk factors are compared in young and old diabetic patients attending a retinopathy clinic. Mortality in those diagnosed under and over the age of 30 years is also examined in order to compare insulin-dependent with non-insulin-dependent patients. A defined cohort attending the Hammersmith Hospital Retinopathy Clinic was followed for an average of 11 years. Main outcome measures were standardized mortality ratios (SMRs) in different age/sex groups and relative hazard rates (RHRs) for possible risk factors related to mortality. The patients were divided into those aged under and over the age of 60 years at attendance at the clinic. The RHRs were smaller in the elderly for plasma urea [1.015 versus 1.107 (p < 0.01)]. Attenuation of risk was also suggested for systolic blood pressure (RHR of 1.005 in the elderly versus 1.015 in the younger patients) and for the effects of smoking [RHR of 1.17 (elderly patients) and 1.35 (younger patients)]. In those diagnosed under the age of 30 years, there were very high SMRs for renal disease, cerebrovascular disease (men only), ischemic heart disease, other heart disease, and respiratory disease (men only), but increased SMRs were also demonstrated in those diagnosed over the age of 30 years. The risk factors associated with poor survival were similar for those diagnosed over and under the age of 30 years: poor diabetic control, high systolic and diastolic blood pressure, and increased plasma urea. In conclusion, there was no evidence that blood sugar control or diastolic blood pressure were less important in older age groups. Plasma urea, systolic pressure, and being on insulin were less useful as predictors of mortality in the elderly, but were still important in patients diagnosed over the age of 30 years.