Visual electrophysiological responses in persons with type 1 diabetes

Persons with type 1 diabetes show electrophysiological abnormalities of the visual system which are revealed by methods such as flash electroretinogram (FERG), oscillatory potentials (OPs), pattern electroretinogram (PERG), focal electroretinogram (focal ERG), visual evoked potentials (VEP) in basal condition and after photostress. This review reports the changes in electrophysiological responses of the different structures composing the visual system observed in persons with type 1 diabetes before the development of the overt clinical retinopathy. In persons with type 1 diabetes without retinopathy (IDD), the earlier abnormal electrophysiological responses are recorded from the innermost retinal layers and postretinal visual pathways, as suggested by impaired PERGs and delayed retinocortical time (RCT). These are observed in IDD persons with a disease duration shorter than 6 months. Further electrophysiological changes are recorded from the macula (abnormal focal ERG and VEP after photostress) in IDD persons with disease duration greater than 1 year. Additional electrophysiological changes are recorded from the middle and outer retinal layers (impaired FERG and OPs) in IDD persons with a disease duration greater than 10 years. All the electrophysiological tests show a greater degree of abnormal responses in persons with type 1 diabetes when a background retinopathy is present.     

Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria

Summary In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p=0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1–83.6%], p=0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1–26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [–18.6–0.4%] per year in the captopril-treated group (p=0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (–6.4 [–10.2––2.5] vs –1.4 [–5.3–2.6] ml · min^–1 · 1.73 m^–2, p=0.07). Baseline albumin excretion rate (p<0.0001) and glycated haemoglobin (p=0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p=0.02) and serum cholesterol level (p=0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.Abbreviations ACE Angiotensin converting enzyme - IDDM insulin-dependent diabetes mellitus - GFR glomerular filtration rate - C captopril - P placebo - AER albumin excretion rate - MAP mean arterial pressure Corresponding author: Professor G.C. Viberti, Unit for Metabolic Medicine, United Medical and Dental Schools of Guy's and St. Thomas' Hospitals, Guy's Hospital, London SE1 9RT, UKMembership of the Study Group is listed in the Acknowledgement section     

HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM

Summary Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1^*0301, DQA1*0501 and DQB1^*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p > 0.05) and DQB1^*0201/0302 (p < 0.01). The findings of the present study suggest that DQB1^*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1^*0301-DQA1*0501-DQB1^*0201/DRB1*0401 -DQA1^*03-DQB1*0302) are at greater risk of developing severe retinopathy. [Diabetologia (1996) 39: 1313–1317] Received: 15 February 1996 and in revised form: 24 April 1996     

Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM

Summary For the past 10–15 years all the children at our unit with insulin-dependent diabetes mellitus have been repeatedly followed-up with renal function tests. Renal biopsy, examined by light and electron microscopy, was included in the follow-up of 36 adolescents and young adults, aged 13–25 years, with a disease duration of 7–19 years. All subjects had undergone at least three renal function tests before biopsy and none had persistent microalbuminuria. Renal function was evaluated as glomerular filtration rate and effective renal plasma flow determined by clearances of inulin and para-amino hippuric acid. Glomerular filtration rate and filtration fraction were increased before and at the time of the biopsy. Glomerular basement membrane thickness (331–858 nm) and mesangial matrix volume fraction (7.4–17.1 %) were increased. Long-term hyperfiltration and hyperperfusion before biopsy correlated inversely with mean glomerular volume. Increased filtration fraction before the biopsy correlated directly with mean of all HbA_1c (r = 0.485, p < 0.01) and both variables correlated directly with mesangial matrix volume fraction, basement membrane thickness and structural index (r = 0.433, p < 0.01 and r = 0.626, p < 0.001, respectively). Urinary albumin excretion rate correlated directly with foot process width (r = 0.645, p < 0.001). By multiple regression analysis the most important variable for the increase in basal membrane thickness was the metabolic control while the mean of previous filtration fraction was most important for the increase in mesangial matrix volume. In conclusion, although none of the patients showed constant microalbuminuria, early diabetic structural changes were evident with basal membrane thickening and increased mesangial matrix volume. The structural changes related to long-standing hyperfiltration and poor metabolic control. [Diabetologia (1998) 41: 1047–1056] Received: 11 August 1997 and in final revised form: 8 March 1998     

Changes in the diabetic retinopathy epidemiology after 14 years in a population of Type 1 and 2 diabetic patients after the new diabetes mellitus diagnosis criteria and a more strict control of the patients

ObjectiveTo determine the differences observed between two transversal studies separated 14 years.MethodsThe sample was obtained by randomized hazard selection of 1157 Type 2 and 93 Type 1 diabetic patients in the 2006 study, and 741 Type 2 and 76 Type 1 diabetic patients in the 1993 study. We evaluate the prevalence of diabetic retinopathy (DR), microalbuminuria, overt nephropathy, and its risk factors.ResultsIn Type 2 diabetic patients, we observed a decrease of the prevalence of DR from 39.41% in the 1993 study to 27.48% in the 2006 study, but we did not observe it in Type 1 diabetic patients—35.52% in 1993 to 36.55% in 2006. The diabetic macular edema prevalence is similar in both studies—7.15% in 1993 and 7.86% in 2006 in Type 2 patients, and 11.84–12.90% in Type 1; microalbuminuria decreased in Type 2 but not in Type 1 patients (from 22.13% to 17.02% in Type 2, and 28.33–27.95% in Type 1); overt nephropathy decreased in both types of diabetic patients (in Type 1, decreased from 11.84% to 8.60% and, in Type 2, from 8.63% to 6.74%). We may observe a decrease in the number of patients with blindness, from 11.20% to 4.90% in Type 2, and from 9.21% to 7.52% in Type 1 patients.ConclusionsWe may observe a decrease in the prevalence of DR, overt nephropathy, and blindness in Type 1 and 2 patients and a decrease in the prevalence of microalbuminuria only in Type 2 patients.     

Visual evoked potentials in NIDDM: a longitudinal study

Summary In order to assess the possible progression of neurological abnormalities over time and the value of visual evoked potential alterations in predicting stability and severity of diabetes-related optic pathway disease, a longitudinal study in non-insulin-dependent diabetic patients was performed. Neurological examination, visual evoked potentials with pattern reversal, motor and sensory nerve conduction velocities and metabolic control were studied in 18 non-insulin-dependent diabetic patients and in 35 normal control subjects at baseline and again after 4.6±0.8 years (range 4–6). At the first recording the peak P100 wave latencies were significantly delayed in the diabetic patients compared with the control subjects; signs of peripheral neuropathy were detected in five patients, clinical in three and in two there was only neurophysiological alteration without clinical signs. The second recording revealed no significant alterations of P100 latencies in patients compared with baseline, but the number with clinical signs and/or neurophysiological alterations with no clinical signs of peripheral neurological disease was increased to seven. In conclusion, we observed that visual evoked potential alterations were stable over time whereas peripheral neurological disease progressed and correlated positively with metabolic control.Abbreviations VEP-PR Visual evoked potentials with pattern reversal - NCV nerve conduction velocities - LP100 peak latencies of P100 wave - ILD interocular latencies difference - NIDDM non-insulin-dependent diabetes mellitus - ARI aldose reductase inhibitor     

Elevated long-term glycated haemoglobin precedes proliferative retinopathy and nephropathy in Type 1 (insulin-dependent) diabetic patients

Summary The importance of glycaemic control for the development of proliferative retinopathy and nephropathy was assessed by monitoring glycated haemoglobin for 5 years or more before the diagnosis of these complications. The study comprised Type 1 (insulin-dependent) diabetic patients diagnosed at an age less than 31 years, and with diabetes duration 25 years or less. They were followed for an average of 7.9 years with 3.3 measurements per year. Of 172 patients screened for retinopathy 60 had no retinopathy, 104 had background retinopathy, and 8 had proliferative retinopathy. The mean HbA_1c (95% confidence intervals) of the groups was 6.4% (6.2–6.7%), 7.3% (7.1–7.5%) and 8.9% (8.1–9.6%), respectively (p<0.0001); the mean duration of diabetes was 12, 18, and 17 years. Of 186 patients 7 had nephropathy (albuminuria>200 mg/l). Mean HbA_1c in patients without nephropathy was 7.0% (6.8–7.1%) and in patients with nephropathy 8.8% (7.8–9.9%,p<0.001). Mean diabetes duration was 16 years in both groups. Multiple logistic regression including mean HbA₁₀, age at onset, duration, sex, and hypertension, was for both proliferative retinopathy and nephropathy significant only for mean HbA_1c. In all cases, proliferative retinopathy and nephropathy were preceded by poor glycaemic control over several years, suggesting that these complications are caused by poor glycaemic control.     

Monitoring kidney function in diabetic nephropathy

We investigated the validity of a one plasma sample method (I) compared with a multiple plasma sample method (II) for routine clinical determination of glomerular filtration rate (GFR) in 35 insulin-dependent diabetic patients suffering from nephropathy. GFR was measured after an intravenous bolus injection of 100 microCi 51Cr-EDTA by determination of plasma radioactivity in venous blood samples taken from the other arm 180, 200, 220 and 240 min after the injection (II). The plasma radioactivity in the sample drawn 240 min after injection was used in method I. During the mean investigation period of 32 months (12-62 months) a total of 184 GFR determinations were performed. The average interval between the GFR measurements was 6 months (1-21 months). In 127/184 of the study intervals method I indicated a decrease in GFR. The corresponding figure for method II was almost identical, 130/184. The mean decline in GFR was 8.1 +/- 7.2 and 7.8 +/- 6.9 ml year-1 1.73 m-2 using methods I and II, respectively (NS). The methods essentially provided the same GFR values in absolute terms (r = 0.98, P less than 0.001). We conclude that the one plasma sample method can be used as a valid routine technique in non-uraemic patients with nephropathy.     

Insertion/deletion polymorphism in the angiotensin-l-converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy

Summary Insulin-dependent diabetic (IDDM) patients with diabetic nephropathy have a highly increased morbidity and mortality from coronary heart disease. An insertion (I) /deletion (D) polymorphism in the angiotensin-I-converting enzyme (ACE) gene has been shown to be associated with coronary heart disease. Therefore, we have investigated the role of this ACE/ID polymorphism in 198 IDDM patients with diabetic nephropathy and 190 normoalbuminuric IDDM patients. The prevalence of myocardial infarction and other coronary heart disease was significantly elevated in patients with nephropathy, 19 % (38/198) vs 8 % (15/190), p < 0.001. In the nephropathic group 12 of 63 (19 %), 23 of 95 (24 %), and 3 of 40 (7.5 %) patients with the DD, ID and II genotypes, respectively had a history of coronary heart disease, II vs DD and ID, p < 0.05 when compared to nephropathic patients without coronary heart disease. Multiple logistic regression analysis of the risk factors associated with coronary heart disease in univariate analysis revealed that the II genotype acts as an independent protective factor against coronary heart disease, odds ratio II/DD + ID 0.27 (95 % confidence interval 0.07–0.97, p < 0.05). There was no difference in genotype or allele frequency (D/I) between patients with and without nephropathy, 0.56/0.44 in both groups, but plasma ACE concentration was elevated in patients with nephropathy 609 (151–1504) ng/ml as compared to patients with normoalbuminuria, 428 (55–1630) ng/ml, p < 0.001. We suggest that ACE/ID polymorphism may influence the frequency of life-threatening cardiac complications in IDDM patients suffering from diabetic nephropathy, a condition characterized by increased plasma ACE concentration. [Diabetologia (1995) 38: 798–803] Received: 10 October 1994 and in revised form: 20 December 1994     

Cytokine overproduction in healthy first degree relatives of patients with IDDM

Summary Healthy family members of patients with insulin-dependent diabetes mellitus (IDDM) are known to share a number of immunological abnormalities with their affected relatives. Since monocyte and type 1 T-cell-derived cytokines contribute to the pathogenesis of IDDM, we studied the production of these cytokines in the healthy first degree relatives of 29 children with IDDM. We report that circulating tumour necrosis factor-α (TNF-α) and soluble interleukin-2 (sIL-2) receptor were present in increased amounts in non-diabetic family members at levels similar to those found in the diabetic children (duration of disease 3 months–5 years). Furthermore, marked hypersecretion of IL-1α and TNF-α by mitogen-stimulated peripheral blood mononuclear cells was found in both diabetic and healthy family members. Abnormalities of cytokine production in healthy relatives did not correlate with the presence of islet cell antibodies or with HLA DR type. These data indicate that healthy family members of patients with IDDM exhibit overproduction of a number of cytokines that have been implicated in diabetogenesis. [Diabetologia (1998) 41: 343–349] Received: 26 August 1997 and in revised form: 24 October 1997     

Estimates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients

Summary Normal subjects, fasted 60 h, and patients with insulin-dependent diabetes mellitus (IDDM), withdrawn from insulin and fasted overnight, were given phenylacetate orally and intravenously infused with [3-¹⁴C]lactate and ¹³C-bicarbonate. Rates of hepatic gluconeogenesis relative to Krebs cycle rates were estimated from the ¹⁴C distribution in glutamate from urinary phenylacetylglutamine. Assuming the ¹³C enrichment of breath CO₂ was that of the CO₂ fixed by pyruvate, the enrichment to be expected in blood glucose, if all hepatic glucose production had been by gluconeogenesis, was then estimated. That estimate was compared with the actual enrichment in blood glucose, yielding the fraction of glucose production due to gluconeogenesis. Relative rates were similar in the 60-h fasted healthy subjects and the diabetic patients. Conversion of oxaloacetate to phosphoenolpyruvate was two to eight times Krebs cycle flux and decarboxylation of pyruvate to acetyl-CoA, oxidized in the cycle, was less than one-30th the fixation by pyruvate of CO₂. Thus, in estimating the contribution of a gluconeogenic substrate to glucose production by measuring the incorporation of label from the labelled substrate into glucose, dilution of label at the level of oxaloacetate is relatively small. Pyruvate cycling was as much as one-half the rate of conversion of pyruvate to oxaloacetate. Glucose and glutamate carbons were derived from oxaloacetate formed by similar pathways if not from a common pool. In the 60-h fasted subjects, over 80 % of glucose production was via gluconeogenesis. In the diabetic subjects the percentages averaged about 45 %. [Diabetologia (1995) 38: 831–838] Received: 12 October 1994 and in revised form: 13 January 1995     

Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study)

Summary Nicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels (6.7 ± 1.8 % nicotinamide vs 7.1 ± 0.6 % placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty. We conclude that in these patients nicotinamide can be added to insulin at the time of disease diagnosis to maintain and possibly improve residual beta-cell function. However, further studies on patients diagnosed after puberty are needed to confirm whether nicotinamide can be considered an additional tool to insulin in early-onset IDDM. [Diabetologia (1995) 38: 848–852] Received: 20 June 1994 and in final revised form: 20 January 1995     

Autoantibodies to oxidised low density lipoproteins in IDDM are inversely related to metabolic control and microvascular complications

Summary Diabetes mellitus is associated with an increased risk of atherosclerosis. The oxidation of low-density lipoproteins (LDL) is considered a key event in the initiation of atherosclerosis. To investigate LDL oxidation in vivo we measured autoantibodies to oxidised LDL (oxLDL) in 94 patients with insulin-dependent diabetes mellitus (IDDM), compared to 27 age-matched, healthy control subjects. Patients and control subjects were screened for autoantibodies using a solid phase ELISA, comparing the binding to oxLDL with that to native LDL (nLDL). In patients with IDDM the oxLDL/nLDL antibody ratio was significantly higher than in control subjects (means ± SEM: 2.24 ± 0.26 vs 1.17 ± 0.17, p < 0.03). Antibody-negative patients had a longer diabetes duration (13.5 ± 1.3 vs 9.1 ± 1.1 years, p < 0.01) and higher actual and mean HbA_{1 c} levels compared to antibody-positive patients (8.8 ± 0.2 vs 7.9 ± 0.2 %, p < 0.005 and 8.3 ± 0.2 vs 7.7 ± 0.2 %, p < 0.03; respectively). In patients with a high microangiopathy score, the antibody ratio was lower than in patients without complications (1.04 ± 0.10 vs 2.40 ± 0.29, p < 0.01). OxLDL specific immune complexes were found exclusively in antibody-negative as compared to antibody-positive patients (18.3 vs 0 %; p < 0.01). Our data demonstrate an inverse relationship between free oxLDL antibodies and the severity of the disease. This apparent paradox can be explained in part by our demonstration of oxLDL immune complexes, masking free antibodies. [Diabetologia (1998) 41: 350–356] Received: 18 June 1997 and in final revised form: 30 September 1997     

Renal functional reserve in IDDM patients

Summary The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM) patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation by amino acid infusion (4.5 mg · kg⁻¹· min⁻¹). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 ± 3 ml · min⁻¹· 1.73 m⁻²) was higher whereas RFR (10 ± 4 ml · min⁻¹· 1.73 m⁻²) was lower (p < 0.05) than in control subjects (113 ± 4 and 28 ± 2 ml · min⁻¹· 1.73 m⁻², respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR and RFR (109 ± 7 and 24 ± 6 ml · min⁻¹· 1.73 m⁻², respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed macroalbuminuria and hypertension, baseline GFR (78 ± 8 ml · min⁻¹· 1.73 m⁻²) was lower than in control subjects (p < 0.05) and RFR (8 ± 4 ml · min⁻¹· 1.73 m⁻²) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 ± 4 and 11 ± 4 mm Hg · l⁻¹· min⁻¹· 1.73 m⁻², respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy. [Diabetologia (1998) 41: 86–93] Received: 12 February 1997 and in final revised form: 28 August 1997     

The frequency and severity of retinopathy are related to HbA1c values after, but not at, the diagnosis of NIDDM

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.     

Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control

Summary The adhesion of leucocytes to the endothelium, an early step in atherogenesis, is mediated by cell adhesion molecules. In this study we evaluated the concentration of soluble adhesion molecules in patients with insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) and studied its relation to glycaemic control. Soluble adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) were measured in 31 diabetic patients (18 with IDDM and 13 with NIDDM), 20 hyperlipoproteinaemic patients (10 with type IIa and 10 with type IIb) and 20 healthy subjects. Increased E-selectin concentrations were found in the patients with IDDM and NIDDM and in the hyperlipoproteinaemic patients when compared to the control subjects (p<0.01 for all the groups). ICAM-1 was found to be elevated only in the patients with NIDDM (p<0.01). No significant differences in VCAM-1 concentration were found in the different groups of subjects. The concentration of plasma E-selectin was positively correlated with the glycated haemoglobin (r=0.54, p<0.01) in patients with IDDM and NIDDM. In the same patients E-selectin was not related to the concentrations of plasma lipids in spite of the fact that it was found to be elevated in hyperlipoproteinaemic subjects. The results though preliminary suggest that in diabetic patients the concentration of soluble adhesion molecules and especially of E-selectin may be related to metabolic control.Abbreviations IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - ICAM-1 intercellular adhesion molecule-1 - VCAM-1 vascular adhesion molecule-1 - AGE advanced glycation end products     

Physiological response to postural change during mild hypoglycaemia in patients with IDDM

Summary It has been suggested that patients with insulin-dependent diabetes mellitus may be less aware of impending hypoglycaemia when lying than standing. We have studied the effect of posture and duration of hypoglycaemia on symptoms and physiological responses in 10 men with insulin-dependent diabetes. A standard tilting protocol was used (supine, 50, 90 headup, and return to supine, 5 min at each position). At one visit patients were tilted before, 10 min after and 40 min after achieving hypoglycaemia (blood glucose 2.5 mmol/l), and at another visit were tilted after euglycaemia (5.0 mmol/l) using a hyperinsulinaemic clamp. At each position, hormonal and physiological responses and symptoms (using visual analogue scales) were recorded. After 10 min of hypoglycaemia, adrenaline was significantly higher when 90 headup compared with supine (mean [±SEM] 6.26 [±1.88] vs 1.68 [±0.4] nmol/l; p<0.05), and fell significantly (to 2.46 [±0.65] nmol/l; p<0.05) when returned to supine; sweating, symptom score and blood pressure followed a similar pattern. After 40 min of hypoglycaemia a similar effect of standing was seen on sweating, adrenaline and blood pressure but symptoms did not increase. Five patients underwent two further periods of hypoglycaemia, remaining supine or standing throughout. Face skin blood flow (p<0.05) and temperature (p=0.05) decreased when standing was maintained compared with lying. In conclusion, standing increases awareness of early hypoglycaemia and modifies many of the physiological changes. This increase in awareness is lost if hypoglycaemia is prolonged.Abbreviations IDDM Insulin-dependent diabetes mellitus - ANOVA analysis of variance - bpm beats per min     

Presence and further development of retinal dysfunction after 3-year follow up in IDDM patients without angiographically documented vasculopathy

Summary Abnormalities in neuroretinal function may play a role in the development of diabetic retinopathy. The natural course of diabetic retinal dysfunction in a group of subjects with insulin-dependent diabetes mellitus and with no apparent microvascular alterations in the retina was followed-up with fluorescein angiography and a sensitive electrophysiological technique, i.e., steady-state focal electroretinogram at the macula, for 3 years. Before the beginning and throughout our study, strict glycaemic control was maintained by three or four daily insulin injections under careful monitoring. Analysis of macular electroretinogram provided information from different neural layers. At the first examination, functional activities of postreceptoral neurons were significantly decreased with respect to those of age-matched control subjects. Diabetic patients showed a functional loss of both ganglion cell (0.53±0.09 vs 0.42 ±0.11 V; t=5; p=0.0001) and preganglion cell (0.51±0.13 vs 0.42±0.14 V; t=2.8; p=0.007) layers. Diabetes did not alter photoreceptor activity. After 3 years, dysfunction was significantly greater in the preganglion cell layer (0.28±0.11 V; t=6.3; p=0.0001). Although in some patients further impairment of ganglion cell function was shown, no significant difference was found in 3 years. Photoreceptor function remained unaltered. No vascular abnormalities in the retina were noted after 3 years in this group of patients. Metabolic control was not correlated to functional changes. Our findings suggest that the middle retinal layer is the most sensitive physiological locus of progressive diabetes-induced dysfunction in the absence of angiographically documented abnormalities.Abbreviations IDDM insulin-dependent diabetes mellitus - ERG electroretinogram     

Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM Complications Study

Summary We present the methodology for 45 retinal photography and detail the development, application and validation of a new system of 45 field grading standards for the assessment of diabetic retinopathy. The systems were developed for the EURODIAB IDDM Complications Study, part of a European Community funded Concerted Action Programme into the epidemiology and prevention of diabetes (EURODIAB). Assessment of diabetic retinopathy was carried out centrally by a trained reader of colour retinal photographs using the newly-developed system. The system proved to be acceptably accurate, repeatable and relatively simple to apply. It compared well with the recognised gold standard 7-field 30 stereo photography (assessed using a modified Airlie House classification scheme), against which the new system was validated in a series of 48 eyes. Selection was as a stratified random sample based on clinical retinopathy status: 5, no retinopathy; 25, non-proliferative retinopathy; 16, proliferative or photocoagulated; plus 2, eyes with potentially confounding lesions (vein occlusion). Simple presence of retinal lesions was correctly detected by both systems in 43 of the 48 eyes, giving 100% agreement on detection. Both systems correctly identified the two known cases of confounding vein occlusion. In eyes with diabetic retinopathy (n=41), when severity was expressed in three groups: mild background, moderate/severe background and proliferative/ photocoagulated, at least one grader (out of five) using the new system matched the verified results in 38 out of 41 (93%) eyes and three or more graders matched in 31 (76%) eyes. Individually the five graders' 2-field allocations agreed well with the verified levels (median number of agreements 37, range 28–43). Repeatability was assessed by measures of within and between observer variation using randomly selected samples of 10% (n=252 eyes) and 5% (n=123 eyes) of the main study, respectively, expressed as a resultant kappa value for chance-corrected proportional agreement. Within observer assessment yielded a kappa of 0.85 and between observers a value of 0.83; indicating very good agreement for both measures. The method is particularly useful for large epidemiological studies, in which participating centres have a limited experience in retinal photography.Abbreviations HMA Haemorrhages and microaneurysms - ETDRS Early Treatment Diabetic Retinopathy Study     

Raised serum apolipoprotein (a) in active diabetic retinopathy

Summary Progressive capillary occlusion often leads to severe retinopathy within 15–20 years of the onset of Type 1 (insulin-dependent) diabetes mellitus. Lipoprotein (a), a complex formed by apolipoprotein (a), apo B-100 and lipids, is considered an independent, genetically determined, predictor of cardiovascular disease. It may have antifibrinolytic properties in view of its similarity to plasminogen. To test the hypothesis that circulating lipoprotein (a) is associated with the process that leads to clinically active diabetic retinopathy, we measured the circulating levels of apolipoprotein (a) (which are strictly correlated with those of lipoprotein (a)) in two groups of patients with Type 1 diabetes of at least 15 years duration: 25 with active retinopathy and 27 without clinically detectable retinal lesions. Thirty-eight healthy subjects of the same age and sex served as controls. Serum apolipoprotein (a) was higher in the patients with active retinopathy (36(2-193) U/dl, geometric mean and range) than in those without clinically detectable retinal lesion (17(1–160)) and the control subjects (14(0–115)), p < 0.01 in both cases. The distribution of apolipoprotein (a) levels was skewed to the left, as expected, in the patients without clinically evident retinal lesions and the control groups, but there was a bimodal trend of distribution among those with active retinopathy. The levels of glycated haemoglobin were similar in the two groups of diabetic patients, and no significant differences were found for total and HDL cholesterol, triglycerides or apolipoproteins A1 and B between them and the control subjects. These preliminary results suggest that serum apolipoprotein (a) is elevated in patients with active retinopathy. The role of this lipoprotein as a predictor or a pathogenic effector of diabetic retinopathy, or both deserves further investigation.