Raoul Rottiers

Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study

Aims/hypothesis: Proliferative diabetic retinopathy (PDR), a leading cause of blindness, cannot be totally prevented by optimizing metabolic and blood pressure control and responds to no specific treatment other than partially destructive retinal photocoagulation. Recognizing risk factors using large-scale epidemiological studies could help identify targets for treatment. The EURODIAB Prospective Complications Study (PCS) includes the largest cohort so far of patients with Type I (insulin-dependent) diabetes mellitus. Methods: Baseline data were collected between 1989 and 1991 on 3250 patients who were recalled for follow-up. Physical examination, biochemical tests and assessment of complications were done on both occasions. In particular, 1249 patients had retinal photographs taken both basally and after an average of 7.3 years. Results: Proliferative retinopathy had developed in 157 patients (cumulative incidence 17.3/1000 patient-years; 95 %-CI: 13.6–21.1). HbA1 c (standardized regression estimate – SRE = 3.03, CI 2.49–3.69), diabetes duration (1.71, 1.42–2.06), age at diagnosis < 12 (1.66, 1.11–2.50), diastolic blood pressure less than or equal to 83 (1.50, 1.03–2.20) and waist-to-hip ratio (1.50, 1.03–2.20) were all independent predictors for progression to PDR when entered simultaneously into a logistic regression model. Including retinopathy at baseline maintained the effects of metabolic control and pre-pubertal onset only. Including the albumin excretion rate maintained the effect of control but reduced SRE for pre-pubertal onset to 1.49 (0.94–2.33). There was no evidence for a threshold effect for HbA1 c concentrations at baseline and progression to proliferative retinopathy. Conclusion/hypothesis: Metabolic control and duration of diabetes are strong indicators of progression to proliferative retinopathy. Onset of diabetes before puberty could be an additional independent risk factor. [Diabetologia (2001) 44: 2203–2209]

Reduced Frequency of Severe Hypoglycemia and Coma in Well-Controlled IDDM Patients Treated With Insulin Lispro

OBJECTIVE Several studies have suggested that use of the short-acting insulin analog, insulin lispro, in multiple injection therapy may reduce the risk of hypoglycemia in comparison with regular insulin. This effect might be more pronounced in well-controlled patients, since intensive treatment of IDDM increases the rate of severe hypoglycemic events. This study evaluated the effects of insulin lispro on glycemic control and hypoglycemia rates in well-controlled IDDM patients. RESEARCH DESIGN AND METHODS This was an open, randomized, 6-month crossover study of 199 IDDM patients. Glycemic control was evaluated by HbA1c, home blood glucose measurements, and rate and timing of hypoglycemic events. At the end of the study, patients completed an evaluation form regarding therapy-related quality of life. RESULTS HbA1c remained constant at ∼ 7.3% throughout the study. Meal-related glucose excursions were significantly lower with insulin lispro compared with regular insulin (mean −0.8 ± 1.7 vs. 1.1 ± 1.6 mmol/l, P < 0.001), as was the within-day variability (M value 27.7 ± 19.7 vs. 30.2 ± 23.1, P = 0.007). The incidence of severe hypoglycemic events (58 vs. 36, P = 0.037) including coma (16 vs. 3, P = 0.004) was significantly lower with insulin lispro than with regular insulin. Patients felt that insulin lispro increased flexibility and freedom of lifestyle. CONCLUSIONS In well-controlled IDDM patients, insulin lispro is associated with a lower risk of severe hypoglycemia and coma.

Androgen plasma levels in male diabetics

Plasma level of androgens were studied in 47 normal male controls (20–50 yr-old; mean age 38 yr) and in a group of forty-one male diabetics (23–55 yr-old; mean age: 37.5 yr). Of these 36 showed type 11 and 5 type I diabetes. The results showed that while the mean basal plasma LH was unchanged, there was a decrease in testosterone levels in the diabetics. Moreover, testosterone binding globulin (TeBG) capacity appeared to be augmented and, as a consequence, the apparent free testosterone concentration (AFTC) was markedly decreased. It is interesting to note that the anomalies in androgen secretion observed are rather similar to those found in elderly man and could play some role (with other factors) in the onset of the frequent sexual disturbances in male diabetics.

IA-2 autoantibodies predict impending Type I diabetes in siblings of patients

Abstract Aims/hypothesis. Multiple islet autoantibody positivity is currently believed to best predict progression to Type I (insulin-dependent) diabetes mellitus. We compared its predictive value with that of positivity for a particular type of islet autoantibody, directed against the IA-2 antigen. Methods. Autoantibodies against islet cell cytoplasm (ICA), insulin (IAA), GAD (GADA) and IA-2 (IA-2A) were measured at initial sampling in 1724 non-diabetic siblings (median age [range]:16 [0–39] years) of Type I diabetic patients with a median follow-up of 50 months. Results. On initial sampling 11% of siblings were positive for one antibody type or more and 2.1% for three of more types. During follow-up, 27 antibody-positive siblings developed diabetes. Using survival analysis, the risk for clinical onset within 5 years was 34% in subjects positive for three or more types compared with 13% in those with one type or more. Progression to diabetes amounted to 12% within 5 years among siblings positive for IAA, 20% for ICA, 19% for GADA but 59% for IA-2A (p<0.001 vs absence of the respective antibody). IA-2A were detected in 1.7% of all siblings and in 56% of the prediabetic subjects on first sampling. Initial positivity for two or three antibody markers was associated with a higher progression rate in IA-2A positive as compared to IA-2A negative siblings (p=0.001). In absence of IA-2A initial positivity for another antibody (IAA, ICA or GADA) conferred a low (<10% within 5 years) risk of diabetes compared to subjects lacking this antibody. Conclusions/interpretation. In siblings of Type I diabetic patients, IA-2A positivity is a more direct predictor of impending clinical onset than multiple antibody positivity per se. Assessment of IA-2A status allows us to select subjects with homogeneously high risk of diabetes for participation in prevention trials.

Circulating plasma vascular endothelial growth factor and microvascular complications of Type 1 diabetes mellitus: the influence of ACE inhibition

SUMMARY

Different risk factors of microangiopathy in patients with Type I diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study

Aims/hypothesis. To identify factors associated with early development of and late protection from microvascular complications in subjects with Type I (insulin-dependent) diabetes mellitus.¶Methods. The frequency of microvascular complications and their relation to risk factors were studied in 300 Type I diabetic subjects with short duration of disease ( ≤ 5 years) compared with 1062 subjects with long duration ( ≥ 14 years). Microvascular disease was defined as the presence of either retinopathy (assessed from centrally-graded retinal photographs) or urinary albumin excretion rate of more than 20 μg/min.¶Resu1ts. The prevalence of microvascular disease was 25 % in the short duration group. In the long duration group 18 % had no evidence of microvascular complications. In the short duration group factors associated with early development of complications were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of long duration of diabetes had better glycaemic control, lower blood pressure, better lipid profile and lower von Willebrand factor levels.¶Conclusion/interpretation. At the early stages of Type I diabetes, cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications. At a later stage, additional risk factors are poorer glycaemic control, higher blood pressure, and an unfavourable lipid profile possibly associated with endothelial dysfunction. Many of these factors are amenable to long-term intervention which should be started as soon as possible in the course of the disease. [Diabetologia (2000) 43: 348–355]

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Aims/hypothesisPrevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset.MethodsAntibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40.ResultsOn first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan–Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status.Conclusions/interpretationThese observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.

CLINICAL-STUDY OF TICLOPIDINE IN DIABETIC-RETINOPATHY.

In this multicentre double-blind study, 100 insulin-treated diabetics with background retinopathy were randomly assigned to treatment with either 250 mg ticlopidine b.i.d. (49 patients) or placebo (51