Severe early-onset polyneuropathy in insulin-dependent diabetes mellitus. A clinical and pathological study.

BACKGROUND AND METHODS: The pathophysiologic features of diabetic neuropathy, a common and disabling long-term complication of diabetes mellitus, are poorly understood. We studied five patients, 22 to 34 years old, in whom an uncommonly severe symmetric polyneuropathy developed soon after the onset of insulin-dependent diabetes. Their autonomic function and nerve conduction were studied, and sural-nerve biopsy specimens were examined by light and electron microscopy. Other causes of neuropathy were carefully excluded. RESULTS: Four patients had autonomic dysfunction with postural hypotension, fainting, diarrhea, and Argyll Robertson pupils and peripheral neuropathy with loss of sensation of pain and changes in temperature that followed a pattern suggestive of a length-dependent degeneration of nerve fibers. In contrast, the fifth patient had muscle weakness and atrophy of limb extremities, with "glove and stocking" sensory loss, but little autonomic dysfunction. In the biopsy specimens of sural nerves, the mean (+/- SD) density of myelinated fibers was reduced to 20 +/- 14 percent of that measured in five control patients, and the density of unmyelinated fibers was reduced to 6 +/- 4 percent of that in the controls. Regenerating fibers accounted for 38 +/- 11 percent of the myelinated axons. Abnormalities of the myelin sheath affected 33 +/- 21 percent of the isolated fibers, and axonal degeneration 11 +/- 8 percent. Dying-back fibers, a characteristic of the centripetal degeneration of peripheral axons, were also identified. The dying-back process progressed at the rate of a few hundred micrometers per day. CONCLUSIONS: Early-onset symptomatic polyneuropathy in patients with diabetes mellitus is characterized by the loss of both myelinated and unmyelinated nerve fibers. Spontaneous axonal regeneration is remarkably frequent, even when neuropathy is severe.

Initiation of insulin treatment after 70 years of age: patient status 2 years later.

The present study assessed 106 diabetic patients 2 years after beginning insulin treatment at or after 70 years of age. Ten patients (9%) had had the therapy discontinued after 2-4 months, 26 (25%) had died of causes unrelated to insulin therapy, 12 (11%) were lost to follow-up, and 58 (55%) were still alive and insulin treated. Fifty-one were at home and seven institutionalized for reasons unrelated to insulin therapy. Of these 58 patients, 50 were available for further study. Except for frequency of travel, which had decreased, lifestyle either improved or did not change. Patients' perceptions of the goals of treatment were more appropriate to a younger population of patients, who are less vulnerable to hypoglycaemic reactions. Mean fasting blood glucose was considered by the medical staff to be too low in 42% of cases. Adding insulin to the treatment of the elderly did not negatively affect their lifestyle, and indeed, insulin therapy appeared to create or strengthen the patients' existing social support network. Educational interventions must attempt to extend the effect of the specialized unit outside the hospital, to families, visiting nurses as well as general practitioners.

[Effects of deprivation and replacement by percutaneous 17 beta estradiol and oral progesterone on blood pressure and metabolic parameters in menopause patients with non-insulin-dependent diabetes]. / Effets de la substitution par 17 beta estradiol percutané et progestérone orale sur la pression artérielle et les paramètres métaboliques chez des patientes ménopausées diabétiques non insulinodépendantes.

The main purpose of this randomized controlled study was to assess the effects of postmenopausal estrogen replacement therapy on blood pressure (BP) and plasma renin substrate (PRS) in non insulin-dependent diabetic patients (DNID). We randomized 32 postmenopausal DNID (mean age: 55.3 +/- 4.2 years) into two groups: 16 women were untreated, and 16 received percutaneous estradiol (E2) 17 beta and natural progesterone for 6 months. Systolic (SBP) and diastolic (DBP) blood pressure were monitored by an automatic device at inclusion and on the 1st, 3rd and 6th months of therapy. Treatment efficacy was proven by significant E2 plasma increase to 92.2 +/- 13.4 pg/ml in the treated group, which is a sufficient level for preventing postmenopausal osteoporosis. No significant inter or or intra-individual variation in SBP or DBP was observed in either group. The same stability was noted for plasma renin substrate. No significant difference was noted between the two groups in terms of body weight, fructosamine and glycosylated hemoglobin A1c after 1, 3 and 6 months. There was also no change in plasma levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apolipoproteins A1 and B. All the patients who received replacement therapy wished to continue treatment. We conclude that the association of percutaneous E2 17 beta and natural progesterone had no deleterious effects, in diabetic patients, on BP, carbohydrate and lipoprotein metabolism. Thus this postmenopausal replacement therapy appears preferable in this vascular high risk population, particularly since estrogens via the parenteral route may have an antiatherogenic effect by direct action on the vessel walls.

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.

The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solutin, or gel for the correction of insulin reactions.

Recommendations for the treatment of insulin reactions are based more on habit than data. We investigated the efficacy in correcting blood glucose levels and alleviating clinical symptoms of hypoglycemia of seven orally administered carbohydrates--glucose in solution, tablets, and gel; sucrose in solution and tablets; a hydrolized polysaccharide solution; and orange juice--each of which provided 15 g of carbohydrate. Forty-one type I diabetic patients recently treated with insulin agreed to submit to artificially induced hypoglycemia by an intravenous injection of insulin. Corrective therapy was given when patients experienced symptoms and asked for treatment. Mean blood glucose levels 10 minutes after ingestion were found to be similar whether correction was dispensed with the tablets and the solutions of glucose, those of sucrose, or the polysaccharide preparation. However, almost no increment was obtained at this time point with the gel or the fruit juice. Fifteen and 20 minutes after carbohydrate intake, blood glucose levels were higher with the tablet forms than with the solutions, although differences only became signifiant for sucrose. Glycemic responses were again consistently lower with the sucrose gel and the orange juice. Clinical symptoms were alleviated in 14.0 +/- 0.8 minutes (mean +/- SEM) with sucrose and glucose in solution or tablets. We conclude that in moderately severe hypoglycemia, ingestion of 15 g of carbohydrate in the form of glucose or sucrose tablets or as a solution provides an effective therapy; both sugars seem equivalent. Even if sucrose lumps are better recommended in terms of cost and availability, they may not be recommendable in terms of palatability. Glucose gel or orange juice cannot be recommended, at least in light of our experimental procedure and at the dosage used therein.

Handedness, immune disorders and information bias.

In order to investigate the relations between handedness and migraine or immune disorders, we performed a case control study comparing the handedness of patients suffering from systemic lupus erythematosus (SLE), type I diabetes, Graves' disease, or migraine to that of a random sample of controls from the general population. A handedness index was measured from a 10-item questionnaire. No significant difference was observed. But when the controls who denied having ever suffered from migraine or any allergic disease were set apart from those who gave at least one positive answer to the same questions, the former were found more right-handed, i.e. with a lower handedness index than the latter (P less than 0.05) and than the SLE patients (P less than 0.05). More generally, the mean observed handedness index of controls giving a positive answer to any question about their health was found repeatedly higher than that of controls giving a negative answer: this was observed for 27 of the 32 questions. These results are highly suggestive of an information bias, the subjects saying they use the right hand for each of the 10 activities considered in the questionnaire being more likely to deny having suffered from a given disease or used, more or less recently, some drug or medical service. Our conviction is that previous observations dealing with the same topic are also more easily explained by the presence of an information bias than by Geschwind's theory. The implications for the design of further epidemiologic studies are discussed.

Relative sweetness of fructose compared with sucrose in healthy and diabetic subjects.

Fructose is credited with some advantages over sucrose: it causes less of an increment in plasma glucose and insulin response, and the taste is sweeter. We reevaluated the latter property with a new methodology (the "up and down" method adapted from Dixon) in 33 healthy subjects, 17 insulin-dependent diabetes mellitus (IDDM) patients, and 12 non-insulin-dependent diabetes mellitus (NIDDM) patients. Sweetening potency was determined over 2-3 test sessions in each subject. Results are expressed in percent as the relative sweetness (R) of fructose (F) over sucrose (S), taken as reference. In the first set of experiments, with a 30-g/L sucrose-water solution at pH 7, we found that R values were similar for healthy subjects (102 +/- 8%) and diabetic subjects (106 +/- 7%) (P less than .05). No significant difference between IDDM and NIDDM patients was observed. In a second set of experiments, performed in healthy subjects only, R was increased in acid water (114%; P less than .01), in lemon juice (136%; P less than .001), in water at 2 degrees C (130%; P less than .001), and in coffee at 2 degrees C (120%; P less than .02); mean values were decreased in grapefruit juice (77%; P less than .001), in water at 43 degrees C (88%; P less than .01), and in coffee at 53 degrees C (87%; P less than .001). We found that the test methodology had a very satisfactory intrasubject reproducibility (coefficient of variation [C.V.] less than 8%) but a very wide intersubject variability (C.V. congruent to 32%).(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of detectable deleterious effects on metabolic control of daily fructose ingestion for 2 mo in NIDDM patients.

The effects of a daily intake of 30 g fructose on blood glucose regulation, erythrocyte insulin receptors, and lipid metabolism have been studied in type II (non-insulin-dependent) diabetic subjects. Eight well-controlled patients received, in a randomly assigned crossover design over two 2-mo study periods, 30 g of fructose in exchange for an isocaloric amount of starch. Fructose could be taken at any time during the day as part of the 1400-1600 kcal allowed diet (50% carbohydrate, 30% fat, 20% protein). No significant difference was observed concerning body weight, HbA1c, fasting plasma glucose, fasting plasma insulin, uric acid, total cholesterol, high-density lipoprotein cholesterol, and triglycerides, nor was there any change in insulin binding to erythrocytes between the fructose and the control starch period. However, the mean plasma triglyceride levels after the fructose period, although still in the normal range, were significantly higher than baseline values (P less than .05). We conclude that moderate amounts of fructose incorporated into the diet of well-controlled type II diabetic subjects have no significant deleterious effect on glycemic control, insulin receptors of erythrocytes, or lipid metabolism.

[Auto-immune hypoglycemic syndrome induced by pyritinol]. / Syndrome hypoglycémique auto-immun induit par le pyritinol.

The auto-immune hypoglycemic syndrome is characterized by the association of hypoglycemia (clinical and/or biological) and anti-insulin antibodies in patients who have never received exogenous insulin. Initially this syndrome was most often described in Japanese patients some of whom were treated with drugs containing a sulfydril group. We now recall the case of a female caucasian patient treated with Pyritinol for rhumatoid polyarthritis and who presented severe spontaneous hypoglycemia linked with the presence of anti-insulin antibodies in her serum. The level of her antibodies decreased abruptly on suspension of the drug. The recent and more developed characterization techniques of the different forms of circulating insulin and of their antibodies may help to differenciate an auto-immune hypoglycemia from hypoglycemia due to the secret auto-administration of bovine and porcine insuline, and permit us to suggest that an abnormality in the structure of the molecule of insulin might be a cause of this syndrome. However, the exact mechanism of hypoglycemia linked with the presence of anti-insulin auto-antibodies is not yet clear as is the predisposition of a drug with a sulfydril group to induce such an auto-immune phenomenon.

Effect of intranasal glucagon on blood glucose levels in healthy subjects and hypoglycaemic patients with insulin-dependent diabetes.

Glucagon in solution with a surfactant (deoxycholic acid 1% w/v) was administered by intranasal spray to 6 healthy fasting subjects and 6 insulin-dependent diabetics with insulin-induced hypoglycaemia. In the normal subjects, intranasal glucagon increased plasma glucose levels, with a dose-response effect. In the diabetic patients, plasma glucose levels showed a mean increase of 100% above nadir values in approximately 26 min in response to 7.5 mg intranasal glucagon; hypoglycaemic symptoms were relieved within about 7 min. These results suggest that intranasal glucagon is effective and may represent an alternative to parenteral glucagon or glucose or to oral sugar as the first-line treatment of hypoglycaemic episodes in insulin-dependent diabetics.