Factors involved in catheter obstruction during long-term peritoneal insulin infusion.

OBJECTIVE: To analyze the efficacy of ECPII and the factors responsible for technical problems often encountered. This treatment has been in use with IDDM patients since 1980. RESEARCH DESIGN AND METHODS: Forty-four IDDM patients were treated by ECPII for 42-78 mo (mean, 53 mo). RESULTS: Glycemic equilibrium was improved during treatment (mean plasma glucose level, 7.6 mM; mean GHb level, 8%). Catheter blockage was the main reason for ECPII failure (74%). Mean catheter survival of each catheter, determined by actuarial analysis, was 11.7 mo and significantly decreased with subsequent implantation. SEM of the catheter tips showed deposits composed of fibrin and cells occluding the inner lumen. Factors such as age, sex, local infection, and low insulin basal rate were not found to have any incidence on the catheter survival. Placement of the catheter in the upper part of the peritoneum, however, increased catheter survival. Anti-insulin antibodies did not seem to be directly involved in blockage. CONCLUSIONS: We conclude from this long-term experience that during ECPII, catheter blockage remains the major recurring complication, probably involving a local immune-inflammatory response in the peritoneum.

Effect of Miglitol (Bay m1099), a new alpha-glucosidase inhibitor, on glucose, insulin, C-peptide and GIP responses to an oral sucrose load in patients with post-prandial hypoglycaemic symptoms.

Sixteen patients suffering from symptoms suggestive of idiopathic reactive hypoglycaemia and reproducible during an oral glucose tolerance test when plasma glucose was less than or equal to 2.8 mM, were included in an acute, double-blind and cross-over study to test the efficacy of Miglitol (Bay m1099), a new alpha-glucosidase inhibitor versus placebo. Patients were randomized to ingest 100 mg Miglitol or placebo together with a sucrose solution (45 g/m2 body surface), one week apart. During four hours, plasma glucose levels were continuously monitored and plasma insulin and gastric inhibitory polypeptide (GIP) levels were measured at 30-minute intervals; serum C-peptide concentration was determined at 0, 30, 60 minutes and then every hour. The post-load rise in plasma glucose was significantly blunted by Miglitol, as shown by the reduced plasma glucose peak, the diminished early (0-120 min) area under the glycaemic curve and the decreased rate of plasma glucose rise. Thereafter, plasma glucose nadir was significantly raised and rate of plasma glucose fall was slowed by Miglitol with a concomitant improvement in the hypoglycaemic index. Insulin secretion was dampened as indicated by parallel reduction of plasma insulin and serum C-peptide peaks; morever, early area under the insulin curve and total (0-240 min) area under the C-peptide curve were significantly reduced. Decrease of plasma GIP peak and total area under the GIP curve were also significant. During sucrose tolerance test with Miglitol, hypoglycaemic symptoms were significantly alleviated but intestinal side-effects were common. Blunting the insulin response to glucose directly by delaying glucose absorption and indirectly through reducing GIP secretion, may be a valuable therapeutic approach in reactive hypoglycemia; nevertheless, long-term study with Miglitol are needed, due to the poor intestinal tolerance of this drug in the present acute study.

A preliminary multicentre study of the treatment of recently diagnosed type 1 diabetes by combination nicotinamide-cyclosporin therapy.

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)

Probability of remission in individual in early adult insulin dependent diabetic patients. Results from the Cyclosporine Diabetes French Study Group.

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.

[Pulsatile administration of gonadotropin releasing hormone in the female. Diagnostic and therapeutic indications]. / Administration pulsatile de gonadolibérine chez la femme. Indications diagnostiques et thérapeutiques.

Prolonged pulsatile exogenous GnRH allows differentiation between hypothalamic and pituitary causes of hypogonadotrophic hypogonadism and is able to induce ovulation and pregnancy in most of women with hypothalamic amenorrhea (HA). When compared with human menopausal gonadotropin, GnRH appears to be a more efficient therapy of HA but yields inferior results in chronic anovulatory patients with persistent LH secretion. Pulsatile GnRH following a GnRH-analog suppression represents a new promising treatment of infertile women with polycystic ovarian syndrome. However such a combined therapy is time-consuming and only permits to attempt 3 to 4 stimulated cycles during a year. Therefore the successful preliminary reports need to be confirmed by a further randomized study.

[Drug pumps]. / Pompes à drogue.

The aim of therapeutic research is to find out an effective medication against the disease without any dangerous toxic action. The delicate problem is that very often the dose of drug confines with toxicity. The solutions are numerous: transformation of supports, change of the introduction route, adaptation of the concentration. It has been realised that, in certain disease, continuous infusion of medication was much more effective than repeated intermittent injections. The general technic of drug contribution by a pump supposed a drug reservoir with sufficient volume to prevent the frequent manipulations, a source of energy assuring the circulation of the drug and a control of the speed of the drug delivery. These attempts are not exceptional in our practice, being very often utilized in the treatment of difficult diabetes by insulin infusion, the thrombosing diseases be heparin infusion, some forms of diffused cancers by specific chemotherapeutic agents, acute polyhormonal insufficiencies... It is also possible to use infusion pumps in intensive cares with administration of antibiotics, of antalgic drugs, in cardiology for the management of atrial fibrillation, atrial and/or ventricular tachycardias, etc. The most common are the portable pumps and the implantable.

Effects of ACE-inhibition on glucose metabolism.

ACE inhibition is widely used for treatment of arterial hypertension or congestive heart failure. No change occurs in glucose metabolism either in diabetic or non diabetic subjects. No change occurs in glucose metabolism in patients with chronic renal failure. Glucose intolerance induced by diuretics is attenuated when ACE inhibitor is associated with thiazides. In some very rare circumstances (with high plasmatic levels of norepinephrine), insulin sensitivity seems to be enhanced by captopril. Then, in clinical use, no adverse effect occurs with ACE inhibition in non diabetic or diabetic subjects. Under thiazide treatment, ACE inhibitors protect against glucose intolerance.

[Diabetic cheiroarthropathy. Microcirculatory aspects]. / Cheiroarthropathie diabétique. Aspects microcirculatoires.

Diabetic cheiroarthropathy (DCA) or pseudosclerodermatous hand of the diabetic is characterized by nonpainful limited extension of the proximal metacarpophalangeal and/or interphalangeal joints with spontaneous flexum of the fingers. The mechanism of lesion formation is poorly known but apparently associates neurogenic, vascular and cutaneous phenomena. Fifteen patients with DCA (9 men, 6 women; range 20-74 years) were studied by capillaroscopy, photoplethysmography and skin biopsy. Eleven had type 1 diabetes and 4 type 2 over periods ranging from 1 to 42 years (mean 19.9 years). Diabetic retinopathy was noted 10/15 times, nephropathy 5/15 times and neuropathy of the lower limbs 13/15 times. All patients had at least one of these abnormalities. In capillaroscopy, "Shoal of fish" features of diabetic microangiopathy were found only 4 times, but minor dystrophy was noted in 12 cases. In digital photoplethysmography, a drop in digital systolic pressure or an increase in pulse time was noted in 5 cases. The Hillestad test was less than or equal to 2 in 8 patients. Histological study showed constant dermal collagenous fibrosis in diseased skin, which was also found in normal skin in 6/13 patients. PAS staining showed a thickening of vascular basal membrane 14/15 times in diseased skin and 11/13 times in normal skin. The relation between DCA and microangiopathy is discussed in terms of collagen metabolism abnormalities observed during diabetes.

[Methods of analysis of hormonal pulsatility]. / Méthodes d'analyse de la pulsatilité hormonale.

Methods for detection and characterization of episodic fluctuations in circulating hormone levels are frequently used for endocrine investigations, related to the physiological importance of the pulsatile nature of hormone secretion in modulating target-cells response. Several sophisticated methods of pulse analysis have been recently developed and validated, aiming to minimize the false-positive and false-negative error rates. The present report mainly devoted to the clinician aims to analyze and discuss the main features of the most widely used methods for pulse detection.

Tyrosine-kinase defect of the insulin receptor in cultured fibroblasts from patients with lipoatropic diabetes.

Postbinding defects in insulin action were described previously in cultured fibroblasts from six patients with lipoatropic diabetes. To define the contribution of the insulin receptor tyrosine kinase in these defects, we studied autophosphorylation and kinase activity of lectin purified receptors from these six patients and six normal cell lines. The patients' insulin receptors, prepared by precipitation with polyethylene glycol, had normal insulin binding characteristics and autophosphorylation properties, but a 56% decrease in the tyrosine kinase activity toward an exogenous substrate. To identify more subtle qualitative defects in autophosphorylation, insulin receptors were sequentially immunoprecipitated and analyzed for their phosphoaminoacid content. The phosphorylated receptors precipitated with an antiphosphotyrosine antibody contained labeled phosphotyrosine, whereas those in the supernatant, when further precipitated with an antireceptor antibody, contained only phosphoserine. Under these conditions, the insulin-stimulated autophosphorylation of tyrosine was significantly decreased by 54% in the patient receptors compared to normal subjects' receptors. In addition, insulin-like growth factor-I stimulation of autophosphorylation of its receptor was reduced by 59% in the patients' cells compared to those from normal subjects. We conclude that fibroblasts from patients with lipoatropic diabetes have defects in the tyrosine kinase activity of their insulin and their insulin-like growth factor-I receptors that might give rise to the in vitro hormone resistance and be related to the in vivo hormone resistance that occurs in these patients.

[Diabetic cheiroarthropathy]. / La cheiroarthropathie diabétique.

Cheiroarthropathy is quite frequent in diabetics, but is only really specific at stage III, which is the most characteristic form. It is all the more frequent as the diabetes is old, but remains unrelated to sex, age and type of diabetes. The stiffening of the joint readily extends to other joints. The patients are moderately alerted in the absence of other associated pathologies: trigger finger, Dupuytren's disease, carpal tunnel syndrome. All these manifestations form the "diabetic hand", of which cheiroarthropathy is only one component. The need for an accurate analysis with the purpose of appropriate treatments, should be emphasized. The angiologic and histopathological study of patients with stage III cheiroarthropathy, enables us to demonstrate moderate abnormalities of the microcirculation, which are quite different from those encountered in sclerodermia. The etiopathogenesis of cheiroarthropathy remains mysterious and is probably related to an alteration of the collagen metabolism. One of the most interesting component is the association between cheiroarthropathy and the micro-angiopathic complications of diabetes mellitus: cheiroarthropathy being the indicator of such diabetes.

Failure to achieve tight control of plasma cholesterol and apolipoprotein B with intraperitoneal insulin infusion in type 1 diabetes.

The best route of insulin administration by infusion pumps remains a subject of controversy. For that reason plasma lipids and apolipoproteins were compared in three groups of nine patients who had been treated for several months or years with conventional treatment (group I), continuous subcutaneous insulin infusion (CSII, group II) or continuous intraperitoneal insulin infusion (CPII, group III). Plasma cholesterol and apolipoprotein B remained increased on CPII compared with CSII even when similar satisfactory or even tight diabetic control was achieved with both techniques. This study suggests that cholesterol and perhaps apolipoprotein B biosynthesis by the liver is increased in patients treated with CPII compared to those treated with CSII.

[Surveillance using vitreo-fluoro-photometry of diabetics treated with an insulin pump, without or with minimal retinopathy. Results after 3 years]. / Surveillance par vitréofluorophotométrie de diabétiques traités par pompe à insuline, avec rétinopathie absente ou minime. Résultats à 3 ans.

In order to appreciate quantitatively the effect of strict metabolic control obtained with continuous insulin infusion, we have carried out a clinical, angiographical and vitreofluorophotometrical follow-up during a mean period of 36 months, on 21 eyes of 11 patients treated with intraperitoneal insulin pump for brittle diabetes. Patients had no (5 patients) or minimal retinopathy (less than 10 microanevrysms, no exsudate or ischemic areas) (6 patients). At the same time, vitreous fluorophotometry was performed on one eye of 15 volunteer patients without any ocular or general pathology. Vitreous fluorophotometry measurements were made with the Fluorotron Master; after substraction of background autofluorescence, and spread function, results are expressed by the level of posterior vitreous penetration by fluorescein. Good metabolic control was achieved during the study (mean +/- S.D. glycemia = 1.47 g/l +/- 0.21, mean +/- S.D. HbA1 = 7.99% +/- 0.84). Final visual acuities were identical to initial ones, there was no angiographical evolution of the retinopathy, and final vitreous fluorophotometry data (OD = 4.19 10(-6)/mn +/- 0.44 S.E.M., OS = 3.28 10(-6)/mn +/- 0.51 S.E.M.) did not statistically differ from the initial data (OD = 3.88 10(-6)/mn +/- 0.49 S.E.M., OS = 4.08 10(-6)/mn +/- 0.64 S.E.M.). On the contrary, volunteers' measurements (2.15 10(-6)/mn +/- 0.26 S.E.M.) were significantly lower than initial (p less than 0.01) and final (p less than 0.05) diabetics' measurements. These results confirm the early breakdown of the blood-retinal barrier during diabetic disease, and would support the notion of a favorable effect of strict metabolic control on early stages of diabetic retinopathy.

Effect of different insulin administration modalities on vitamin D metabolism of insulin-dependent diabetic patients.

The vitamin D status of IDDs was studied in 3 groups of patients who were treated for several months with (i) conventional insulin therapy (group I, n = 17, HbA1 = 10.1 +/- 0.5%); (ii) continuous subcutaneous insulin infusion (CSII, group II, n = 11, HbA1 = 8.9 +/- 0.6%); and (iii) continuous intraperitoneal insulin infusion (CPII, group III, n = 13, HbA1 = 8.0 +/- 0.4%). In all patient groups the plasma concentration of vitamin D metabolites were within normal range. However plasma 25 OH D (ng/ml) was significantly lower in groups I (13.0 +/- 0.8, P less than 0.01) and II (12.5 +/- 1.5, P less than 0.02) than in group III: 22.1 +/- 2.3 (normal range 7-27). Plasma 24,25-(OH)2D (ng/ml) was positively correlated to plasma 25 OH D and was significantly decreased in groups I (1.5 +/- 0.2, P less than 0.05) and II (1.4 +/- 0.2, P less than 0.05) compared with group III: 2.3 +/- 0.3. No significant differences were found in plasma 1,25-(OH)2D between the three groups of diabetics. Plasma PTH was similar in the three groups. The same differences in plasma 25 OH D were observed between the patients treated with CPII and 15 subcutaneously treated patients matched for diabetic control (HbA1 less than 10 per cent). The present results seem to indicate that insulin might have a stimulatory effect on the hepatic 25 hydroxylase activity.

Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy.

Microalbuminuria is a reliable predictor of the eventual development of overt diabetic nephropathy and blood pressure is known to accelerate the course of this nephropathy. In the present studies, the effect of a 6-week treatment by placebo (n = 7), nifedipine (n = 7) and captopril (n = 8) on renal function and urinary excretion of albumin (UAE) was investigated in normotensive, insulin-dependent, diabetic patients with incipient nephropathy (UAE greater than 15 micrograms/min). No change in arterial pressure, renal function or UAE was observed in the placebo group. In response to captopril and nifedipine, mean arterial pressure decreased slightly and similarly in both groups. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased to a similar extent in the nifedipine group, thus resulting in no change in filtration fraction (FF). In response to captopril, GFR was unchanged whilst ERPF increased; as a consequence FF decreased. Opposite changes in UAE were observed in response to the two treatments; UAE decreased by 40% in the captopril group and by 40% in nifedipine-treated patients. These results indicate that intrarenal changes may be crucial with respect to the effect of therapy on UAE. It is suggested that only agents which reduce FF and probably intraglomerular capillary pressure, such as converting enzyme inhibitors, alter UAE and may possibly interfere with the course of incipient diabetic nephropathy in normotensive patients.