Search

Objectives: To describe the present status of type 1 diabetes care in France and study the relations between clinical and socio-economic variables on one hand and disease management and prevalence of complications on the other hand., Methods: A random sample of 365 French specialists in diabetes care performed a cross-sectional study and included consecutively 562 children aged 10-16 and 1691 adults aged 16-45, with more than 2 years of type 1 diabetes. The main outcome measures were the prevalence of complications (retinal, renal, lower-limb, cardiovascular, ketoacidosis); disease management parameters (blood pressure, HbA1c, daily number of insulin injections, frequency of visits to a specialist in diabetes, membership of a patient association); socio-economic status as a score, and treatments received., Results: Retinal complications were rare in children (0.7%) and common in adults (28.3%). 10.2% children and 15.2% adults had micro- or macro-albuminuria, 4.7% adults had plasma creatinine >or=150 micromol/L. Only 15% children and 26% adults had HbA1c<7%, 86.2% children and 62.7% adults had blood pressure<130/85 mmHg; 58% children and 80% adults had at least 3 daily insulin injections. In adults, the risk of experiencing at least one complication was linked significantly with diabetes duration, HbA1c, and socio-economic status. Age, sex, type of insulin therapy, tobacco consumption, and blood pressure control were not significant parameters. Ketoacidosis in the preceding year was only linked with HbA1C and socio-economic status., Conclusion: Although this sample of patients had overall a fair socio-economic status and were followed-up by specialists of diabetes care, metabolic and blood pressure control were not optimal. The care of French type 1 diabetics could probably be improved by a stricter control of glycaemia and blood pressure, and an earlier use of intensive insulin treatment, with a particular focus on adolescents and patients with the lowest socio-economic status.

Objective: Insulin resistance may be a risk factor for diabetic microangiopathy, which may have a familial component. We carried out a family-based study to determine which components of the insulin resistance syndrome are associated with diabetic retinopathy and nephropathy in type 1 diabetes., Research Design and Methods: The Genesis France-Belgium Study is a multicenter binational study designed to investigate the genetic factors involved in the microvascular complications of type 1 diabetes using a family-based design. Probands were type 1 diabetic patients with diabetic retinopathy (classified as background, preproliferative, or proliferative) and possibly diabetic nephropathy (absent, incipient, established, or advanced). The insulin resistance score of their first-degree relatives was calculated according to their BMI and history of arterial hypertension, lipid disorders, and type 2 diabetes., Results: The insulin resistance score of relatives was positively correlated with the albumin excretion rate (P = 0.0009) and fasting plasma glucose (P = 0.0003) and HbA(1c) (P < 0.0001) concentrations. This score was higher in the relatives of probands with than in those without diabetic nephropathy (P = 0.0370). Similarly, it was higher in relatives of subjects with proliferative diabetic retinopathy than in those of probands without, even after controlling for subjects with versus without diabetic nephropathy (P = 0.0379). However, the components of the insulin resistance score in relatives differed according to the severity of diabetic retinopathy or nephropathy in the probands. Obesity and history of arterial hypertension were most common in relatives of probands with proliferative diabetic retinopathy, whereas obesity and history of lipid disorders were most common in the relatives of probands with diabetic nephropathy., Conclusions: Familial insulin resistance segregates with diabetic complications: lipid disorders and obesity segregate with diabetic nephropathy, whereas arterial hypertension and obesity segregate with diabetic retinopathy.

Background: Genetic susceptibility contributes to the risk of diabetic nephropathy. Lipid disorders may favour diabetic nephropathy. Thus polymorphisms in lipid metabolism are candidates for the genetic component of risk for diabetic nephropathy., Methods: We searched for a contribution of the genetic polymorphisms of lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and apolipoprotein epsilon (Apo E) to the development of diabetic nephropathy by studying 494 type 1 diabetic patients with proliferative retinopathy and various stages of diabetic nephropathy (GENEDIAB Study). The selection process ensured that all patients had expressed their risk of chronic complications due to uncontrolled diabetes. Thus the nephropathy stages were largely influenced by genetic background. The lipid profile included fasting plasma total cholesterol (TC), triglycerides (TG), apolipoprotein A1 (Apo A1) and B (Apo B), and lipoprotein (a) (Lp(a)). Genetic polymorphisms were determined by PCR-based detection of Apo epsilon (e2/e3/e4), LPL (mutation Asn 291 Ser) and CETP (TAQ:IB B1/B2)., Results: One hundred and fifty-seven patients (32%) had no nephropathy, 104 (21%) incipient nephropathy, 126 (25%) established nephropathy and 107 (22%) advanced nephropathy. There was a significant relationship between the stages of diabetic nephropathy and TC (P=0.002), TG (P<0.0001), Apo B (P=0.0007) or Lp(a) (P=0. 038), but not Apo A1. However the genetic polymorphism distributions of LPL, CETP and Apo epsilon did not differ in terms of renal complications. The study power to reject the null hypothesis was 58% for the Apo epsilon genotypes., Conclusion: These results support no or only marginal effects of a genetic basis for lipid disturbances encountered in diabetic nephropathy.

Background: A genetic susceptibility for diabetic kidney disease is suspected since diabetic nephropathy occurs in only 30 to 40% of type I diabetic patients. As elevated von Willebrand factor (vWF) plasma concentrations have been reported to precede the development of microalbuminuria in type I diabetes, we addressed a possible implication of vWF as a genetic determinant for diabetic nephropathy., Methods: Three known vWF gene polymorphisms were genotyped in a group of 493 type I diabetic subjects, all showing proliferative retinopathy, but with various stages of renal involvement, which ranged from no microalbuminuria, despite a mean duration of diabetes of 31 years, to advanced nephropathy (GENEDIAB Study): Thr789Ala (Rsa I), M-/M+ (Msp I) (intron 19), and Ala1381Thr (Hph I). Plasma vWF and factor VIII (F VIII) levels were also measured in this population., Results: Plasma vWF and F VIII levels were increased in diabetic subjects with nephropathy (P < 0.001) or with coronary heart disease (CHD; P < 0.001), but there was no interaction of both conditions on plasma levels. The Msp I polymorphism (M-/M+) was weakly associated with nephropathy (P = 0. 04), but this association was not more significant when other risk factors were used in a logistic regression analysis. The vWF Thr789Ala polymorphism was associated with CHD (P = 0.002) and with plasma vWF levels. Logistic regression analysis indicated an independent and codominant effect of the Thr789Ala polymorphism on CHD, but not on nephropathy, with a maximal risk for Ala/Ala homozygotes (OR = 4.2, 95% CI, 1.8 to 9.9, P = 0.0008)., Conclusion: It is unlikely that polymorphisms in the vWF gene contribute to the risk for nephropathy in type I diabetic patients. However, the Thr789Ala polymorphism might affect the risk for CHD in this population through modulation of plasma vWF levels.

The recommended method for assessing long-term blood glucose control in diabetic patients is the measurement of glycated haemoglobin (Hb). The Ames DCA 2000 system for assaying glycated Hb uses an immunoassay with a monoclonal antibody specific for an aminoacid sequence within the HblAc molecule. This study compared the performance of the DCA 2000 system for HblAc measurement with that of high-performance liquid chromatography (HPLC). A total of 1.016 insulin-dependent and non-insulin-dependent diabetic patients from 5 outpatient clinics took part. The correlation coefficients between DCA 2000 and HPLC data ranged between 0.94 and 0.98, depending on site. The mean variations and 95% confidence intervals for the differences between the results for each sample were: site A 0.172 (-1.186 to 1.53), site B -0.275 (-1.317 to 0.767), site C -0.146 (-0.868 to 0.576), site D -0.088 (-0.864 to 0.688), and site E -0.251 (-1.099 to 0.597). The sensitivity of the DCA 2000 assay ranged between 80 and 94%, and the specificity between 88 and 100%, depending on site. For pooled results, the correlation coefficient assayed by the two methods was 0.95. The mean variation was -0.116 and the 95% confidence interval -1.23 to 0.998. The sensitivity of DCA 2000 was 91%, and the specificity 94%. DCA tended to underestimate HbAlc slightly as compared to HPLC. This study confirms the reliability of DCA 2000 for measuring glycated Hb. The system is easy to use and provides valuable information for the care of the diabetic patients.

Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients.

The Diabetes Control and Complications Trial was conducted in heavily-equipped centres on a selected and motivated patient cohort. The aim of the present study was to evaluate at one-year follow-up the results of intensive insulin therapy in patients with insulin-dependent diabetes mellitus attending a department of diabetology. From October 1, 1993, to December 31, 1994, all our hospitalised patients under 55 years of age with HbA1c levels above 8% and receiving 2 daily insulin injections were offered the opportunity to shift to 3 daily injections (short-acting insulin in the morning and at midday, and a mixture of short-acting and intermediate insulin in the evening). Patients were instructed to increase blood glucose self-monitoring and to see their diabetologist more often (once every two months). Five patients refused and 45 accepted this proposal: 22 women and 23 men (mean age 31.8 +/- 10.9 yr), BMI 23.5 +/- 2.9 kg/m2, duration of diabetes 12.8 +/- 10.1 yr, HbA1c 10.0 +/- 2.0%. Five patients were lost to follow-up, 2 asked to have their medical file transferred, 3 returned to 2 daily injections, and 5 consulted only once during the year of follow-up. For the 29 patients seen after one-year follow-up, the decrease in HbA1c levels from 10.0 +/- 1.9% to 9.5 +/- 1.8% was not statistically significant. Sixteen patients complained of increased occurrence of hypoglycaemia (3 comas). In routine clinical practice, the prescription of intensive insulin therapy to non-selected insulin-dependent diabetic patients can be associated with a high number of patients lost to follow-up (17% in our study). An increase in the number of daily insulin injections will improve glycaemic control only if self-monitoring and medical surveillance are also intensified. However, many long-term poorly-controlled insulin-dependent diabetic patients are reluctant to comply with these recommendations.

Coronary artery disease may be difficult to detect in diabetic patients. This study was designed to determine the specificity and sensitivity of three noninvasive tests. Accordingly, the results of 48-h ambulatory electrocardiogram (ECG) monitoring, maximal ECG exercise test, and intravenous dipyridamole myocardial thallium scintigraphy were compared in 59 middle-aged diabetic patients who were consecutively selected for suspected coronary artery disease. All patients also underwent coronary angiography, which was performed regardless of the results of the non-invasive tests. Twenty patients (34%) had significant coronary lesions, i.e. stenosis equal to or greater than 70%, and 16 of these 20 patients (80%) had double or triple vessel disease. Sensitivity and specificity were, respectively, 25% and 88% for ambulatory ECG monitoring, 75% and 77% for the exercise test and 80% and 87% for thallium myocardial scintigraphy. This observation strongly supports the use of non-invasive tests for the detection of coronary artery disease in those diabetic patients at high risk of such disease. As the exercise test is cheaper and more widely available than thallium myocardial scintigraphy it should be used as a first line examination. Dipyridamole myocardial scintigraphy may provide an alternative solution for those patients who cannot perform maximal exercise, or with atypical clinical presentation.

Insulin-dependent diabetes mellitus (IDDM), cardiovascular morbidity, and vital prognosis are linked to diabetic nephropathy, which is probably determined by renal hemodynamic abnormalities and by a genetic predisposition. Angiotensin I converting enzyme (ACE) regulates systemic and renal circulations through angiotensin II formation and kinins metabolism. Plasma and cellular ACE levels are genetically determined; an insertion/deletion polymorphism of the ACE gene is strongly associated with ACE levels, subjects homozygote for insertion (genotype II) having the lowest plasma values. We studied the relationship between the ACE gene polymorphism or plasma levels and microcirculatory disorders of IDDM through two independent studies: one involved 57 subjects with or without diabetic retinopathy, and the other compared 62 IDDM subjects with diabetic nephropathy to 62 diabetic control subjects with the same characteristics (including retinopathy severity) but with normal kidney function. The ACE genotype distribution was not different in diabetic subjects with or without retinopathy and in a healthy population. Conversely, an imbalance of ACE genotype distribution, with a low proportion of II subjects, was observed in IDDM subjects with diabetic nephropathy compared with their control subjects (P = 0.006). Plasma ACE levels were mildly elevated in all diabetic groups, independently of retinopathy, but they were higher in subjects with nephropathy than in those without nephropathy (P = 0.0022). The II genotype of ACE gene is a marker for reduced risk for diabetic nephropathy.

In insulin-dependent and non insulin-dependent diabetic patients, the treatment of a modest increase in blood pressure values has been proved effective in reducing the incidence and in improving the evolution of various locations of diabetic angiopathy. This beneficial effect is associated with a cost which can be evaluated by the analysis of IMS and DOREMA data. In France, the evolution of the sales of antihypertensive agents in diabetic patients increased from 117 MF in 1980 to 784 MF in 1991. This dramatic increase is mainly related to the prescription of new antihypertensive agents: calcium antagonists and ACE inhibitors. From 1980 to 1991, the evolution of antihypertensive agent's sales was more important in diabetic patients than in the general population. In 1991, the total cost of antidiabetic treatment: insulin, antidiabetic oral agents and strips for capillary blood glucose monitoring was about 1,100 MF, quite similar to the cost of antihypertensive and hypolipidemic agents used in the same patients.

Prospective studies in insulin-dependent diabetic patients have shown that microalbuminuria is a strong predictor of clinical nephropathy. Because this syndrome is associated with a dramatic excess in mortality, different types of intervention have been proposed for insulin-dependent diabetic patients with microalbuminuria to prevent or postpone clinical nephropathy. The effects of antihypertensive treatment are being extensively investigated. Beta-blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors have proved effective in reducing albumin excretion and postponing overt proteinuria in hypertensive and normotensive insulin-dependent diabetic patients with microalbuminuria. However, many problems remain to be solved. A decrease in albumin excretion may not be an adequate endpoint for intervention trials, because it has been shown that patients with normal albumin excretion can develop diabetic nephropathy lesions, whereas patients with microalbuminuria alone may have little or no pathology. The patients included in these trials all had incipient diabetic nephropathy but exhibited different functional, and probably morphological, forms of the disease. For insulin-dependent diabetic patients with microalbuminuria, the real aim of antihypertensive treatment is not to reduce urinary albumin excretion or to prevent its progression but to preserve renal function and to reduce the incidence of premature cardiovascular deaths. To achieve this, we have to improve our knowledge of the natural history of the early pathology of diabetic nephropathy and of the mechanisms of action of antihypertensive treatment. New large-scale intervention trials will have to be designed in which the patients will have to be carefully characterized on the basis of functional and morphological data.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between poor glycemic control and the development of diabetic microangiopathy has long been recognized. However hyperglycemia alone cannot account for the striking heterogeneity of diabetic patients regarding the presence or absence of microangiopathic lesions. This study was therefore designed to determine the prevalence of retinopathy, nephropathy, and neuropathy, and to identify the factors respectively associated with these lesions. In 157 patients with type I (insulin-dependent) diabetes, the following parameters were recorded: sex, age, duration of diabetes, body mass index, fasting plasma glucose, HbA1c, blood pressure, antihypertensive treatment, tobacco consumption, urinary albumin excretion, plasma creatinine, and presence of retinopathy and neuropathy. One-half of these patients had retinopathy, 32% neuropathy, and 29% nephropathy. Patients with nephropathy exhibited concomitantly high prevalences of retinopathy (69%) and neuropathy (49%). Among patients with retinopathy, 39% had nephropathy; 79% of those with neuropathy had concomitant retinopathy. For each microangiopathic localization, patients with the disease had significantly higher values (p less than 0.05) than those without for duration of diabetes, prevalence of hypertension, and systolic blood pressure. Stepwise logistic regression analysis showed that the following were independent predictive factors of each localization: for nephropathy, systolic blood pressure; for retinopathy, duration of diabetes; and for neuropathy, duration of diabetes, age, and HbA1c.

Thirty percent of insulin-dependent diabetics develop a nephropathy which, when left untreated, leads within a few years to terminal renal failure with its considerable human and financial consequences. Antihypertensive drugs constitute the most effective means of slowing down the deterioration of glomerular filtration. Terminal renal failure and its cardiovascular complications can really be prevented provided the patient is treated at the early stage of incipient diabetic nephropathy. During the last few years, various therapeutic measures have been suggested with very promising short- and medium-term results. The dream of a true prevention of diabetic nephropathy will become a reality when the results of well-controlled clinical trials with prolonged follow-up will be available.

In 1985, an assessment of arterial hypertension treatment in insulin-treated diabetic patient gave disappointing results. In 1988, we carried out another study in order to assess the impact of new antihypertensive drugs (angiotensin converting enzyme inhibitors and calcium antagonists) on the management of arterial hypertension and to identify patients in whom strict normal blood pressure control is mandatory. Seven hundred and fifty four patients were selected. The prevalence of arterial hypertension was 38.4 p. 100 (n = 290). Two hundred and thirty five patients (31.2 p. 100) were on antihypertensive treatment: monotherapy: 60.4 p. 100 (n = 142), bitherapy: 30.6 p. 100 (n = 72), tritherapy: 9 p. 100 (n = 21). In descending order of frequency, the following drugs were used: angiotensin converting enzyme inhibitors, calcium antagonists, diuretics, cardio-selective beta-blockers, central acting agents. Blood pressure values significantly decreased (148/83 mmHg, in 1988, vs 157/85 mmHg, in 1985, p less than 0.05). However, 20 p. 100 of the patients still had blood pressure values greater than or equal to 160 and/or 95 mmHg with or without antihypertensive treatment, and on average, blood pressure values remained higher in patients with antihypertensive treatment than in those without (148/83 mmHg vs 131/77 mmHg, p less than 0.001). Patients with urinary albumin excretion above or equal 30 mg/24 h compared to those with normal albuminuria had significant higher values of blood pressure, glycosylated haemoglobin and blood lipids (p less than 0.01). Only 51 p. 100 of these patients, received an antihypertensive treatment. This study emphasizes the difficulty of antihypertensive treatment in insulin-treated diabetic patients and the necessity to improve education in patients with high risk for widespread angiopathy, and particularly those with increased urinary albumin excretion.

The aim of the present study, a pilot trial, was to find out if nicotinamide (50 mg kg-1 day-1) in combination with cyclosporin A favours remission in recently diagnosed Type 1 diabetic patients, and if it postpones relapse even when cyclosporin A is administered in decreasing doses (trough blood level 300-500 micrograms l-1 until month 4, and 100-300 micrograms l-1 until month 9) and then discontinued. The criteria for inclusion in the study and the follow-up protocol were the same as those used in the Cyclosporin Diabetes France (CDF) programme in which all five of the centres involved in this study participated. The data of the present preliminary open study were therefore compared retrospectively with those of the placebo (CDF-placebo) and cyclosporin (CDF-active) group of the CDF programme. Clinical remission (fasting plasma glucose less than 7.8 mmol l-1, postprandial plasma glucose less than 11.1 mmol l-1, HbA1c less than 7.5% with neither insulin nor oral hypoglycaemic agents) was achieved within 6 months in 12 out of 35 patients (34%) vs 16 out of 63 (25%) in CDF-active and 11 out of 59 (19%) in CDF-placebo. Remission was achieved by month 9 in 6 out of 35 patients (17%) vs 13 out of 54 (24%) in CDF-active and 3 out of 52 (6%) in CDF-placebo. By 12 months remission persisted in 3 out of 35 patients (9%) vs 11 out of 63 (17%) in CDF-active and 0 out of 52 (0%) in CDF-placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to determine which candidates were suitable for immunotherapy among adult insulin dependent diabetic patients of recent onset. A statistical analysis was performed using the results of a multicentre randomized trial of cyclosporine versus placebo after nine months of treatment. When the baseline characteristics of the patients in remission were compared with those not in remission, there was no difference observed either in initial residual beta-cell function (glucagon stimulated C-peptide level), or in immunological markers (T4 and T8 lymphocytes counts, Interleukin 2). The parameters showing the most difference were, in addition to treatment group, the duration of diabetes symptoms and body mass index at inclusion, and the HLA-DR phenotype. This was confirmed using a logistic regression analysis, in which these variables were found to be significantly related to remission. The probability of remission in each individual patient was then calculated using these variables in the mathematical function provided by the logistic model. Ninety eight out of 110 patients were correctly classified using this method. In addition, it must be noted that only subjects adequately treated by cyclosporine were still in complete remission after a one year follow-up. Conversely, it appeared that immunosuppression in subjects having a predicted probability of remission lower than 0.35 using the mathematical function, and being non-DR3, non-DR4 has to be avoided. These results will be useful in optimizing the recruitment of patients in on-going or future trials of immunotherapy in early diabetes.

To assess the effect of Glipizide on glycaemic control and peripheral insulin sensitivity, 9 type 1 (insulin dependent) diabetic patients with normal BMI, mean age 42.1 +/- 11.0 years, diabetes duration 16.3 +/- 9.2 years were studied. They were treated by continuous subcutaneous insulin infusion for a mean duration of 32.2 +/- 11.0 months, they were in good glycaemic control (mean HbA1 7.9 +/- 1.2%, upper limit of normal value 7.5%). In a double blind randomized control study they were successively allocated for a three month period to 15 mg of Glipizide daily or a Placebo. At the end of each period the following parameters were recorded: HbA1, mean plasma glucose levels, daily insulin dosage: basal rate and pre prandial bolus, peripheral insulin sensitivity assessed by euglycaemic hyperinsulinic clamp technique, the addition of Glipizide did not induce any statistically significant modification of HbA1, glycaemic values, and daily insulin dosage: basal rate 18.2 +/- 8.7 vs. 17.9 +/- 7.3 IU/24 hours and pre prandial bolus 18.6 +/- 7.0 vs 17.6 +/- 6.3 IU/24 hours. During the glucose clamp, glucose uptake was similar under Glipizide or Placebo with the 3 levels of insulin infused. These results suggest that in type 1 diabetic patients the addition of Glipizide to insulin therapy does not alter glycaemic control and peripheral insulin sensitivity.

To study the relationship between retinal and renal microangiopathy, the albumin excretion rate (AER) was measured by radioimmunoassay in 111 insulin-dependent diabetics and compared to their stages of retinopathy, as assessed by ophthalmoscopic examination and fluorescein angiography. The prevalence of pathological AER differed from that of diabetic retinopathy. The stage of retinopathy was related to the duration of diabetes (r = 0.59; P = 0.001), which was not the case for AER (r = 0.06; ns). Half of patients with proliferative retinopathy (11/22) had a normal AER, while 12% of those without retinopathy had a pathological AER (microalbuminuria). No relationship was found between glycaemic control and AER. The highest prevalence of hypertension was found in patients with macroalbuminuria (greater than 500 mg/24 h) and/or severe retinopathy. The mean AER was higher in hypertensive diabetics than in non-hypertensive diabetics (P less than 0.005). These results suggest that the risk of retinopathy is dissociated from the risk of glomerulopathy in diabetics, and that hypertension associates with diabetes mellitus in a greater risk of pathological AER.

As excessive monocyte adhesion to blood vessel wall could produce endothelial cell injury, we undertook comparative studies on the monocyte adhesiveness in insulin-dependent diabetics with vascular complications (n = 26) and healthy, normal subjects (n = 36). In the diabetic group, the extent of monocyte adhesion on fibronectin- and autologous plasma-coated surfaces was significantly increased compared with that in the control group (p less than 0.01 on both types of surfaces). Monocytes adhesion to the plasma-coated surface, but not to the fibronectin-coated surface, could be inhibited by monoclonal anti-Mo-1 antibody in a dose-dependent manner. For diabetic monocyte adhesion, a higher amount of anti-Mo-1 antibody was required to produce a similar extent of inhibition as observed with control monocytes. This indication of increased Mo-1 expression on diabetic monocytes was further confirmed by analyzing the fluorescence intensity of monocytes labeled with the antibody anti-Mo-1. The results of the present study suggest that diabetic monocytes have increased adhesiveness as the result of increased expression of fibronectin and Mo-1 receptors.

The relation between blood glucose control and erythrocyte adhesion to cultured human vascular endothelial cells was studied in 12 Type 1 (insulin-dependent) diabetic patients. Erythrocyte adhesion was measured before, 8 days and 6 weeks after continuous subcutaneous insulin infusion (CSII). Compared to controls, erythrocyte adhesion expressed as an adhesion ratio was increased in 10 diabetic patients at the first examination (adhesion ratio greater than 1.52). After 8 days, adhesion ratio was normalized in 5 patients. After 6 weeks, adhesion ratio was normal in 7 patients and significantly lower in the group of 12 patients (p less than 0.01). The adhesion ratio was significantly correlated with glycosylated haemoglobin values (p less than 0.001). Insulin did not directly affect erythrocyte adhesion. Adequate insulin treatment modifies erythrocyte adhesion through a metabolic effect which needs longer than 1 week to be effective.

In order to investigate the endocrine pancreatic dysfunction resulting from iron overload, plasma pancreatic polypeptide (PP) response to a protein-rich meal was studied in 10 healthy controls and 30 insulin-dependent (type I) diabetic patients: ten with idiopathic haemochromatosis (IH), ten with chronic pancreatitis and ten with idiopathic type I diabetes. While fasting plasma PP levels were slightly higher in diabetic with IH (40,8 +/- 7 pmol/l) than those in controls (27,1 +/- 3) on in type I diabetics (31,3 +/- 3) they were similar after the meal (peak level 95 +/- 18, 139 +/- 23, 100 +/- 36 respectively). In contrast the mean PP level was low in diabetics with chronic pancreatitis in the fasting state (15.9 +/- 3.6 pmol/l) and did not rise following the meal. These findings suggest that there is no PP cell injury in diabetics with IH.

Opinions diverge as to the frequency of hypoglycaemia in patients under continuous subcutaneous insulin infusion (CSII). In this prospective study the incidence and severity of hypoglycaemia were evaluated in 10 type I brittle diabetic patients under conventional treatment (period A), then under chronic treatment with CSII for at least 1 year (period B: the first 3 months; period C: the last 3 months). Metabolic control (as assessed from mean blood glucose, glycaemia lability indices and glycosylated haemoglobin A1) significantly improved between periods A and B (p less than 0.01). The occurrence of biochemical hypoglycaemia (less than 3 mmol/l) was reduced by 52% and that of clinical hypoglycaemia by 60%. The results observed in period C were not different from those observed in period B. One hypoglycaemic coma occurred under CSII (as opposed to 4 during period A); it was secondary to reduction in food intake and had no sequelae. Thus, in this study, the improvement in metabolic control was associated with a reduction in the frequency and severity of hypoglycaemia. We consider that patients presenting with frequent and severe attacks of hypoglycaemia under conventional insulin treatment can and should benefit from CSII.

In 16 insulin-dependent diabetic patients, 36 +/- 8 years old with no microangiopathy, hypertension or coronary artery disease, and 16 healthy control subjects matched for sex, age and body surface area, the following parameters were obtained by Doppler-echocardiography: (1) end-diastolic left ventricular thickness and radius; (2) aortic pulse wave velocity; (3) mitral flow with measurement of early and late (atrial) peak velocities (E and A), pressure half-time and the velocity time integrals of the entire mitral curve and of the atrial wave; and (4) isovolumic relaxation time (i.e., the time between aortic closure and the mitral opening signals recorded simultaneously by continuous-wave Doppler). Heart rate and systolic blood pressure were not different in the 2 groups. Aortic pulse wave velocity and the wall thickness to radius ratio were significantly increased in the diabetic patients compared to the controls. E was significantly reduced whereas A/E, pressure half-time, the atrial contribution to the left ventricular filling (i.e., the ratio of the atrial velocity time integral to the mitral velocity time integral) and the isovolumic relaxation time were significantly increased in the diabetic group versus the control subjects. Lastly, 11 of 16 diabetic patients (69%) had at least 2 of the following abnormalities: A/E greater than 0.71, an atrial contribution to the left ventricular filling greater than 0.25, a pressure half-time greater than 50 ms and an isovolumic relaxation time greater than 88 ms. No correlations were found between the wall thickness to radius ratio, aortic pulse wave velocity and the filling indexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Home blood glucose monitoring (HBGM) may be useful to achieve better metabolic control in type I diabetes. The aim of this study was to evaluate longterm results in a large population. A questionnaire was given to 282 routinely insulin-treated diabetics regularly attending our clinic. Home blood glucose testing was performed by 64.5% of the patients. Seventy nine percent of them continued to test urines. Mean HbA1 at the time of the visit was not statistically different in patients performing home blood glucose testing only (9.3 +/- 2.1%), in patients monitoring both blood and urines (9.2 +/- 2%), or urines only (9.3 +/- 1.7%) and in patients who did not practice self-monitoring (9.5 +/- 1.8%). The influence of HBGM on metabolic control as currently performed by diabetic patients in everyday life may be overemphasized. These disappointing results are mainly due to the fact that patients carry out passive home glucose testing and not home blood glucose monitoring which implies day-to-day adaptation of insulin dosage. Such an attitude seems to be due to incorrect selection of the patients, insufficient education and care and, for some patients, poor compliance with medical advice.

In diabetic patients, it has been suggested that angiotensin converting enzyme inhibitors may be associated with unexplained hypoglycaemic episodes. Such a side effect may limit the use of these drugs in diabetic hypertensive patients. Ten insulin-dependent diabetic patients mean age 38.4 +/- 13.1 years, mean diabetes duration 10.3 +/- 6.6 years (m +/- SD) were selected on the basis of good glycaemic control: HbA1: 7.6 +/- 0.9 per cent (upper limit of normal value less than 7.5 per cent) on continuous subcutaneous insulin infusion. In a double blind study, they were randomly and successively allocated for a 3 months period to enalapril 20 mg daily or placebo. Before treatment, after enalapril and placebo, mean blood glucose values, HbA1, daily insulin dosage were recorded as well as the number of clinical and biological (less than 3 mmol/l) hypoglycaemic episodes. Peripheral insulin sensitivity was assessed by euglycaemic insulin clamp technique. Compared to placebo, enalapril did not induce any modification of daily insulin dosage, glycaemic control. The incidence of hypoglycaemic episodes was similar. Neither peripheral insulin sensitivity was modified by enalapril. In the conditions of this study, enalapril did not interfere with glycaemic control in insulin-dependent diabetics in good metabolic control.

Combined continuous subcutaneous insulin infusion (CSII) and metformin (M) was tested in 10 overweighted insulin requiring diabetic patients (body mass index 27.9 +/- 4.9 kg/m2). They were still poorly controlled (HbA1 9.6 +/- 0.8%) despite large doses of lente insulin (Novo) (51.7 +/- 19.6 IU/24 h) injected once daily. With CSII after two weeks on placebo (P) they were enrolled in a randomized double blind cross-over trial with two successive one month periods of M (2550 mg/day) or P. At the end of the two-weeks period CSII--initial P, the daily regular insulin requirement decreased significantly (40.1 +/- 18.1). During M and P body weight and HbA1 were unchanged (respectively 28.6 +/- 6.0 vs 29.0 +/- 59 kg/m2 and 7.7 +/- 1.1 vs 7.7 +/- 0.8%). With M daily insulin requirements decreased significantly (32.0 +/- 16.8 vs 38.4 +/- 18.2 IU, p less than 0.05). During test-meals, M compared to placebo also reduced peripheral free insulin concentrations (-24.9 +/- 26.0%) while plasma glucose and C peptide remained comparable. In the conditions of this study, combined CSII and M reduced the insulin resistance observed in overweighted insulin requiring diabetic patients.

The antihypertensive efficacy of enalapril and its effects on the metabolism and kidney function were investigated in 11 insulin-dependent diabetic subjects with uncomplicated mild to moderate hypertension. During a short-term single-blind controlled trial, one daily dose of 20 or 40 mg enalapril significantly reduced both systolic and diastolic blood pressure. In the supine position, mean systolic blood pressure declined from 169 +/- 6 to 142 +/- 6 mmHg (P less than .01) and mean diastolic blood pressure from 101 +/- 1.5 to 85 +/- 2 mmHg (P less than .001). No changes in heart rate or postural hypotension were observed. During 1 yr of treatment, the antihypertensive efficacy of enalapril did not decline, and no clinical side effects were observed. Inhibition by enalapril of angiotensin-converting enzyme did not modify daily insulin requirements, glycemic control, uricemia, or lipid metabolism; kalemia and the markers of diabetic nephropathy were not significantly altered. These results suggest that enalapril once daily should be used as the first step in the treatment of diabetic patients with mild to moderate hypertension.

In insulin-dependent diabetics the course of the renal disease can be followed by measuring arterial blood pressure and urinary albumin excretion. Already at the stage of incipient nephropathy (microalbuminuria) a moderate but gradually increasing rise in blood pressure is noticeable. At the stage of patent nephropathy (macroalbuminuria) nothing but an effective antihypertensive treatment can slow down the deterioration of renal function and delay by a few years the occurrence of end-stage renal failure. When macroproteinuria or obvious arterial hypertension are present, it is much too late to institute an antihypertensive treatment. To really prevent diabetic nephropathy, this treatment must be given earlier, as soon as microalbuminuria is detected and irrespective of blood pressure values. Prescribing antihypertensive drugs, and especially angiotensin-converting enzyme inhibitors, seems to be the most effective way of reducing urinary albumin excretion. 6

Unlabelled: We studied 16 normotensive insulin-dependent diabetic patients (D) (11 males + 5 females) aged of 25-51 years old (mean = 35 +/- 6) with a good glycemic control, without microangiopathy and previous heart disease and 16 healthy control of 25 subjects (C) matched for sex age and body area. We measured: Systolic blood pressure (SBP) with a mercury sphygmomanometer, aortic diameter (AD), end diastolic left ventricular radius (r) and wall thickness (Th) by Echocardiography TM with 2 D echo control, the pulse wave delay (PWD) by measurement of time between the feet of aortic velocity tracings, recorded in the isthmus and near the diaphragm, Sternal length (L). Parameters calculated were: the ratio th/r. The pulse wave velocity PWV = L/PWD and the ratio PWV/AD which represents an indirect index of aortic characteristic impedance. (table; see text) PWV and the radio Th/r are significantly increased in diabetic patients as compared to the control group. Th/r is not significantly correlated with PWV in the 2 groups. This lack of correlation could be explained in the control group by the small rang of values of PWV (5-7.3 ms-1) and Th/r (0.26-0.38). It is not the case in the diabetic group where values are widespread (PWD 5-10 ms-1 and Th/r 0.23-0.53)., In Conclusion: in normotensive young insulin-dependent diabetic patients studied by doppler echocardiography: aortic rigidity measured by the pulse wave velocity is increased. Th/r ratio is also increased but this change of left ventricular geometry is not related to aortic rigidity in this group of patients.

Renal Kallikrein, an enzyme of the distal tubule acting through kinin liberation, may participate to the control of renal circulation and blood pressure. To study if an impairment of its secretion may exist in diabetics, a cross-sectional study was carried out on 40 non-hypertensive and 29 hypertensive diabetics, compared to 30-age related controls. Urinary Kallikrein Activity (UKA) was measured by its kininogenase activity with and without trypsin preincubation. Compared to UKA in controls (86 +/- 9 micrograms lysyl-bradykinin [LBK] produced per minute of incubation), UKA was significantly reduced either in non-hypertensive diabetics (59 +/- 8 micrograms LBK. min.-1; p less than 0.05) and in hypertensive diabetics (26 +/- 6 micrograms LBK. min.-1; p less than 0.001). The ratio of total/active urinary kallikrein was similar in diabetics and in controls. The decline of UKA in diabetics was related to the duration of their disease (r = -0.38; p less than 0.05) and to their stage of retinopathy (r = -0.46; p less than 0.001). UKA values were proportional to creatinine clearance in diabetics (r = 0.58; p less than 0.001). The lowest UKA values were found in patients with a high urinary excretion of albumin (above 500 mg/day): 8 +/- 2 micrograms LBK. min-1 (p less than 0.001) and beta-2-microglobulin (above 382 micrograms/day): 12 +/- 4 micrograms LBK. min-1 (p less than 0.001). These findings support that an impaired secretion of renal kallikrein in diabetics can be related to the duration of diabetes and to the severity of microangiopathy.