The possible role of autoimmunity in the pathogenesis of diabetes in B-thalassemia major.

OBJECTIVE: To evaluate the possible role of autoimmunity in the pathogenesis of diabetes associated with B-thalassemia, we studied a cohort of 53 B-thalassemic individuals, under long term blood transfusion, that included twelve patients with diabetes (22.6%). MATERIAL AND METHODS: To evaluate the activation of an autoimmune response, individuals were tested for islet cell antibodies (ICA), glutamic acid decarboxylase (GAD) autoantibodies, insulin autoantibodies (IAA) and serum anti-nuclear antibodies (ANA). RESULTS: Nine of the total B-thalassemic population (16.98%) were ICA-positive. The frequency of ICA-positive subjects among thalassemic individuals was higher than in the general population. Five (41.6%) of the ICA-positive individuals were diabetic. Of these, three were serum C-peptide-negative (<0.21 nmol/l). HLA class II typing of our thalassemic population did not reveal significantly different allelic frequencies with respect to the control population. CONCLUSIONS: Our study demonstrates evidence of immune system activation against pancreatic B-cells in B-thalassemia and we propose that iron deposition may, through oxidative damage, act as an environmental factor that triggers the autoimmune response. Therefore, we speculate that pancreatic autoimmunity may contribute to selective B-cells damage in the pathogenesis of diabetes associated with B-thalassemia.

Clinical, immunological, and genetic heterogeneity of diabetes in an Italian population-based cohort of lean newly diagnosed patients aged 30-54 years. Piedmont Study Group for Diabetes Epidemiology.

OBJECTIVE: In lean diabetic patients, the presentation of the disease does not allow one to easily distinguish between type 1 and type 2. Aims of this study were to describe clinical, immunological, and genetic features of lean newly diagnosed diabetic patients. RESEARCH DESIGN AND METHODS: A population-based cohort of 130 lean (BMI < 25 kg/m2) newly diagnosed patients, aged 30-54 years, was identified among residents of the province of Turin. Islet cell antibodies (ICAs), anti-GAD, fasting and glucagon-stimulated C-peptide values, and HLA DQA1-DQB1 susceptibility genotypes were assessed within 2 months of the diagnosis. RESULTS: A total of 45 (34.6%) and 29 (22.3%) patients were, respectively, ICA+ and anti-GAD+, with 15 (11.5%) having both antibodies. In 59 patients, ICAs and/or anti-GAD antibodies were detected, giving a high prevalence of autoimmunity (45.4%, 95% Cl 36.8-54.0); relative to patients without markers (n = 71), they were younger (40.8 +/- 7.5 vs. 45.0 +/- 6.5 years, P < 0.001) and showed lower values of fasting C-peptide (0.56 +/- 0.33 vs. 0.79 +/- 0.41 nmol/l, P < 0.001) and stimulated C-peptide (1.03 +/- 0.56 vs. 1.42 +/- 0.69 nmol/l, P < 0.001). The lowest stimulated C-peptide values were found in patients with both ICA and anti-GAD antibodies. Frequencies of adult-onset type 1 and type 2 diabetes were, respectively, 49.2 and 50.8%. Clinical and genetic features were not useful in the classification of patients. CONCLUSIONS: Almost 50% of lean young and middle-aged patients were ICA+ and/or anti-GAD+, suggesting a high prevalence of a slowly evolving form of type 1 diabetes. The evaluation at diagnosis of both beta-cell secretory capacity and markers of autoimmunity is recommended to provide a pathogenetic classification of the disease.

Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure. The Italian Microalbuminuria Study Group in IDDM.

OBJECTIVE: Intervention trials on renal function in IDDM patients with microalbuminuria (MA) should adopt the rate of decline of glomerular filtration rate (GFR) as an outcome measure. However, normotensive IDDM patients with MA show no change in GFR over a follow-up period of 10 years. Thus, in the present study, we used the cumulative incidence of progression to albuminuria (albumin excretion rate [AER] > 200 micrograms/min) from MA as the primary endpoint and the yearly increase in AER at a rate of 50% above baseline as the secondary end-point of renal function. RESEARCH DESIGN AND METHODS: Ninety-two normotensive IDDM patients underwent double-blind, double-dummy treatment with either lisinopril or slow-release nifedipine in comparison with placebo. Ten patients discontinued the study during the 3-year follow-up period. RESULTS: During the 3-year follow-up period, 7 of 34 placebo-treated (20.6%), 2 of 32 lisinopril-treated (6.3%), and 2 of 26 nifedipine-treated (7.7%) patients progressed to clinical albuminuria (Fisher's exact test, P < 0.03). Time-to-event analysis indicated a reduction in the risk of progression to macroalbuminuria of 58.1% (95% CI 27.8-68.4%) in the 32 patients on lisinopril (P < 0.02) and of 62.5% (95% CI 32.5-73.4%) in the 26 patients on nifedipine (P < 0.02) after adjustment for mean blood pressure, glycated hemoglobin, and baseline AER in comparison with the 34 patients on placebo. Baseline AER was 71 micrograms/min (range: 20.7-187.3) in progressors and 73 micrograms/min (range: 20.2-174.1) in nonprogressors (NS). The percentage of patients who showed a > 50% yearly increase of AER above baseline values was significantly lower in the lisinopril group (13 of 32, 40.6%, P < 0.02), but not in the nifedipine group (15 of 26, 57.7%), than in the placebo group (23 of 34, 67.6%). The lisinopril group had significantly lower blood pressure values during follow-up than either the nifedipine (P < 0.05) or the placebo (P < 0.01) group. CONCLUSIONS: Our data show that both lisinopril and nifedipine are effective in delaying the occurrence of macroalbuminuria in normotensive IDDM patients with MA. As overt proteinuria strongly predicts end-stage renal failure, both treatments appear capable of preventing such a complication in normotensive IDDM patients with MA. However, lisinopril appears more powerful in slowing the course of nephropathy.

Risk factors for lower limb complications in diabetic patients. The Italian Study Group for the Implementation of the St. Vincent Declaration.

Diabetic lower extremity complications may be influenced by a number of factors, including those related to the interaction between patients and the health-care system. Our objective is to identify risk factors for the development of lower limb complications, by looking for classical clinical variables and those related to quality of care. A case-control study was carried out between December 1993 and June 1994 by interviewing 348 patients with lower-limb diabetic complications and 1050 controls enrolled from 35 diabetes outpatient clinics and 49 general practitioner's offices in Italy. Among sociodemographic characteristics associated with increased risk of lower limb complications were male gender [odds ratio (OR) = 2.5, confidence interval (CI) 1.6-3.9], age between 50 and 70 years as opposed to younger than 50 (OR = 3.6, CI 2.1-6.3) and being single as opposed to married (OR = 1.4, CI 1.1-1.8). Among clinical variables, treatment with insulin for IDDM and NIDDM patients was an important predictor of lower extremity complications compared to NIDDM patients not being treated with insulin. Cardio-cerebrovascular disease and presence of diabetic neuropathy were associated with a higher risk of being a case (OR = 1.4, CI 1.2-1.8 and OR = 3.0, CI 2.1-4.2, respectively). Patients who needed help to reach the health facility before the onset of the complications and those who did not attend health facilities regularly were more liable to develop complications (OR = 1.5, CI 1.1-2.2 and OR = 2.0, CI 1.3-3.0, respectively). Patients who had never received educational intervention had a threefold risk of being a case as compared to those who received health information regularly. The study identifies factors most likely to be related to adverse outcome and permits to discriminate between avoidable and unavoidable factors.

Effect of treatment with an aldose-reductase inhibitor on symptomatic carpal tunnel syndrome in type 2 diabetes.

The aim of this study was to test the efficacy of the aldose-reductase inhibitor Tolrestat in the treatment of carpal tunnel syndrome in Type 2 diabetic patients. Seventeen patients were treated with Tolrestat (200 mg daily for 12 months) clinical and neurophysiological evaluations were performed at baseline, 6 and 12 months; symptoms and blood glucose control were assessed at baseline, 2, 6, and 12 months. Thirteen Type 2 diabetic patients suffering from symptomatic carpal tunnel syndrome served as controls. Neurophysiological studies showed improvement in the sensory conduction velocity of the median nerve between forefinger and wrist (baseline 37.5 +/- 4.3 vs 6 months 41.3 +/- 5.7 ms-1, p < 0.0005 and baseline vs 12 months 41.4 +/- 8.2 ms-1, p < 0.005) but not between wrist and elbow. The terminal latency index of the median nerve was unchanged. Paraesthesiae and pain improved in terms of intensity and frequency. Blood glucose control was not significantly changed. We conclude that treatment of this case series with Tolrestat appears to produce beneficial effect on the outcome of carpal tunnel syndrome in diabetic patients.

Celiac disease and insulin-dependent diabetes mellitus. Screening in an adult population.

We screened for celiac disease, by means of IgA class anti-endomysium antibodies (EmA), 383 consecutive adults with insulin-dependent diabetes mellitus (IDDM). Two control populations entered the study as well: 151 adults with biopsy proven celiac disease, as true positives; and 520 controls (healthy and diseased) as true negatives. IgA-EmA positivity was found in 145 of 151 (96%) celiac disease patients but in none of the controls (100% specificity). EmA were positive in 12 of 383 (3.13%) IDDM patients: 10 of these positives underwent intestinal biopsy, which showed either partial or total villous atrophy. Only one patient presented with gastrointestinal complaints, but severe iron deficiency was found in all. The IDDM celiac patients were started on a gluten-free diet: four refused both the diet and the follow-up protocol. Approximately one year after gluten withdrawal no significant change in the degree of diabetes control was observed, while an increased requirement for insulin was observed in three of four patients who strictly complied with the diet. The prevalence of biopsy-proven celiac disease among adult IDDM patients (1:38), eight times higher than that recently estimated for the general Italian population and the absence, except in one case, of gastrointestinal symptoms emphasizes the benefit of screening programs on populations at risk.

Pudendal neuropathy in diabetic patients with faecal incontinence.

To investigate the pathophysiology of faecal incontinence in diabetes mellitus, two groups of diabetic patients were studied: 14 subjects (7 females and 7 males, mean age 57 +/- 9 years) with faecal incontinence (Group A) and 15 subjects (6 females and 9 males, mean age 54.7 +/- 8 years) without faecal incontinence but affected by somatic peripheral neuropathy. A third group (C) of 10 healthy volunteers was used as controls. All subjects underwent electroneurographic evaluation of peripheral neuropathy, pudendal nerve terminal motor latency, anorectal manometry and rectal sensitivity tests. All the patients of group A had somatic peripheral neuropathy. Maximum squeeze pressure was lower in A compared to C (P < 0.025) and sustained for a shorter period in A compared with B (P < 0.0005) and C (P < 0.0005). All rectal sensitivity thresholds were higher in A compared with B and C. Pudendal Nerve Terminal Motor Latency was prolonged in 93% of patients studied in group A and in 73% of patients in group B (A vs B P < 0.005), with a significant difference in comparison with C: A vs C P < 0.0005, B vs C P < 0.005. Our findings suggest that somatic neuropathy plays an important role in faecal incontinence in diabetic patients, combined with sensation threshold impairment as a feature of an autonomic involvement.

[Prevalence of urinary infections caused by GBS in diabetic patients]. / Studio della prevalenza delle infezioni urinarie da Gbs in pazienti diabetici.

On a randomized sample of 305 diabetic patients and of 479 controls was studied for an epidemiological research about the colonization of urinary tract by Group B-Streptococci (GBS). The detection rate was 16.44% in the diabetics, and 8.77% in the controls. and it was higher in diabetic women than diabetic men (R.P. 1.96, p < 0.05). The age, the model of diabetes treatment, and the metabolic control of diabetic people didn't be significatively correlated with GBS presence. Most of GBS that have been identified in diabetic patients were belonged to the sierotype I, whereas in the controls were belonged to the sierotype III.

An open prospective study on the effects on carbohydrate metabolism of an oral monophasic contraceptive containing gestodene (WL-70).

The effects of a monophasic oral contraceptive (gestodene 75mcg + ethinylestradiol 30 mcg) on plasma glucose (PG) and insulin (IRI) responses to an oral glucose load (OGTT) and on glycosylated haemoglobin Alc (HbAlc), fructosamine (Fr), total cortisol (FT) and transcortin (CBG) were studied in 30 healthy women. Blood samples were taken before treatment and after 6 and 12 cycles. After 6 and 12 months, OGTT-PG and IRI levels showed substantially unchanged values; for HbAlc and Fr the same behaviour was seen with the exception of the latter between 6 and 12 months; FT and CBG showed significant rises. All recorded values were in the normal range. The basal and dynamic PG and IRI behaviour failed to show any significant variations between pre-treatment values and those after 6 and 12 months of OC administration. Other data showed a substantial neutrality for this oral contraceptive containing gestodene.

The hyperlactatemic effect of biguanides: a comparison between phenformin and metformin during a 6-month treatment.

To compare the chronic hyperlactatemic effect of phenformin and metformin, we performed a double-blind study in 10 non insulin-dependent diabetics without any other known hyperlactatemic condition. After a pre-study period, each patient was allocated to a 6-month treatment with phenformin (50 mg bid) or metformin (850 mg bid) in random sequence. Body weight values were not significantly different between phenformin and metformin. Diabetic control was significantly (p less than 0.001) improved by both biguanides versus pre-study, but was the same during metformin and phenformin: HbAI = 13.8 +/- 0.3 SEM% during pre-study 9.7 +/- 0.2% during phenformin, 10.2 +/- 0.2% during metformin. Mean values of plasma lactate during metformin were significantly lower versus phenformin (1.30 +/- 0.05 vs 1.64 +/- 0.05 mmol/l, p less than 0.001). Mean values of plasma lactate/pyruvate ratio during metformin were significantly lower versus phenformin (16.92 +/- 0.59 vs 22.65 +/- 0.87, p less than 0.001), but not versus pre-study (16.19 +/- 0.51). These results indicate that: 1) during a 6-month treatment with a diabetic control of similar degree phenformin produces a significantly higher hyperlactatemic effect vs metformin; 2) metformin treatment is associated with less impairment of intracellular redox state versus phenformin, and therefore should be considered advantageous in the long-term treatment of non insulin-dependent diabetics.

Univariate and multivariate analysis of associated factors of retinopathy in 894 Italian adult diabetics.

The prevalence of diabetic retinopathy and the evaluation of its risk factors is poorly known in Italian population. Therefore, we have studied 894 diabetic outpatients (420 males, 474 females, 27.6% IDDs, 38.1% insulin-treated) in order to investigate the effect of clinical and metabolic characteristics on the frequency of diabetic retinopathy, classified into six different classes. In univariate analyses age, duration of disease, systolic and diastolic blood pressure, blood urea nitrogen, 24 hr proteinuria and fasting glycemia significantly correlated (p less than 0.001) with severity of retinopathy. The significance was confirmed in multivariate analysis for duration, age and systolic blood pressure (p less than 0.001). Stratification by type of diabetes showed that undefined onset of diabetes probably reduced in NID patients the power of duration as an associated factor of retinopathy. Worsening of this complication in three clinical classes of therapy (diet, oral and insulin-treatment) is evident too. Finally, our 11 variables in the step-wise multiple-regression analysis explain only 16.8% of diabetic retinopathy in all patients, but 36.6% in selected ID subjects.

Capillary glucose determination in the screening of gestational diabetes.

Paired capillary-venous blood samples were obtained from 418 pregnant women undergoing an oral glucose challenge test (GCT) for the screening of gestational diabetes (GD). The relationship between capillary and plasma glucose concentrations was investigated in order to establish a capillary GCT threshold. Plasma glucose was assayed by the glucose oxidase method and capillary glucose using Reflocheck Glucose strips and a Reflocheck reflectance meter. During GCT the capillary values exceeded plasma glucose values by a mean difference of 10-12 mg/dl fasting and 22-24 mg/dl after 1 h. A high correlation between the glucose values of the two techniques was found, particularly for those at 1 h, with corresponding capillary determinations being 20 mg/dl above plasma values. The sensitivity, specificity and predictive value of the various capillary thresholds investigated in detecting GD corresponded substantially to the accuracy of plasma thresholds 20 mg/dl lower. The receiver operator characteristic curves of the plasma and capillary thresholds were similar in shape and the optimal cut-off point for performing a diagnostic test was set at 135 and 155 mg/dl, respectively. These cut-off values should be reconsidered in the light of the costs and perinatal outcome.

Postprandial exercise in type I diabetic patients on multiple daily insulin injection regimen.

This study shows the influence on plasma glucose concentrations of 45 min of mild exercise (48 +/- 4% of maximum aerobic capacity) performed 180 min after breakfast and 195 min after a subcutaneous injection of regular insulin by six type I (insulin-dependent) diabetic patients on a three-daily insulin injection regimen (regular insulin before breakfast and lunch, regular + intermediate insulin before supper). It has been observed that such exercise does not induce a large plasma glucose decrease. Actually, plasma glucose concentrations were 99 +/- 18 mg/dl before exercise, reached a nadir of 78 +/- 17 mg/dl at 35 min, and were 81 +/- 15 mg/dl at the end of exercise. During the control study at rest, in the same 45-min time interval, plasma glucose decreased from 146 +/- 31 to 128 +/- 31 mg/dl. In the exercise study, one patient began exercising while hypoglycemic, and another patient developed asymptomatic hypoglycemia during exercise. In the control study at rest, one patient showed hypoglycemic glucose concentrations. Throughout the exercise study, plasma free-insulin concentrations decreased (from 32 +/- 5 to 20 +/- 4 microU/ml) as a result of the pharmacokinetics of subcutaneously injected insulin.

Comparison between monocomponent human insulin U-40 and U-100 in CSII treatment of type 1 diabetics.

A multicentric study has been carried out to compare the efficacy and the safety of monocomponent human insulins of different concentration (Novo Actrapid HM U-40 and U-100) in CSII-treated Type 1 diabetics. 15 males, all of whom had been diabetic for at least 2 yr, had been treated by CSII and were skillful in the self-monitoring of diabetes were selected for observation at 3 different clinical centres (Bologna, Chieti and Torino). After a 1-week period of insulin dose optimization, the patients were asked not to modify either basal or pre-prandial insulin infusion during the following 2 weeks in which they were treated alternately by U-40 or by U-100 insulin (7 days for each treatment in random sequence). Each day or at least every other day, patients recorded at home a 9-point blood glucose profile by means of glucose-sensitive strips and photometric reading (Reflocheck System-BOEHRINGER MANNHEIM, FRG). The patients used the microinfuser Miles Microjet Bolus 2 for the U-40 infusion and the same model with appropriate modifications for the U-100 infusion. On the last day of each study period, blood samples were drawn after the pre-breakfast insulin bolus. Paired Student's t-test analyses between blood glucose values obtained with different regimens did not show a significant difference in metabolic control. Similarly no difference could be observed in insulin absorption after an identical bolus of U-40 or U-100 insulin. In conclusion human U-100 insulin seems to be as effective and safe as U-40 and is recommended in order to reduce the size of microinfusers.

Continuous subcutaneous insulin infusion versus intensive conventional insulin therapy in type I and type II diabetic pregnancy.

Two groups of pregnant diabetic women, fifteen with type I and fourteen with type II diabetes, were randomly assigned either to CSII or to ICT and the subgroups compared with respect to glycaemic control, insulin requirement and perinatal out-come. Ten non-diabetic pregnant women served as controls for the variations in the metabolic parameters considered (24-hour mean blood glucose and glycosylated hemoglobin). Strict glycaemic control was achieved and maintained by both regimens before week 13 in all patients with type I and in 57.1% of patients with type II diabetes. The mean insulin requirements in the type I group increased up to week 34-36 and then stabilized to term in patients receiving CSII and rose progressively to term in those receiving ICT. In the type II group insulin requirements rose up to week 36 in patients receiving CSII and up to week 32 in those receiving ICT, stabilizing thereafter on both regimens. No significant differences in mean insulin requirement at the different stages of gestation were found between the patients receiving CSII and those receiving ICT of either group. Perinatal outcome was satisfactory in both groups, although control of foetal growth was better with ICT than with CSII. CSII is a practical, safe and effective method of maintaining maternal normoglycemia in pregnancy but for the present we cannot consider it superior to ICT in the treatment of pregnant diabetic women.

VEP pattern reversal in the assessment of optic nerve function in diabetics.

The visual evoked potentials (VEP pattern) were studied in a group of 18 type I diabetic subjects. Age of patients, duration of disease, glicosilated hemoglobin, blood sugar were correlated with the modifications in latency and amplitude of visual evoked responses.

Interference on metabolism induced by muzolimine and chlorthalidone in type II hypertensive diabetics.

There is a very high prevalence of hypertension in diabetic subjects, which makes it necessary to use an antihypertensive drug with the least possible metabolic interference. For example, in the early phase of hypertension, diuretics usually worsen the metabolic equilibrium. According to recent reports, a new diuretic, muzolimine (MZ), which acts on the loop of Henle, seems to present a minor effect on carbohydrate metabolic balance. In order to determine whether this assumption was correct or not, we carried out a clinical trial on 26 type II (non-insulin-dependent) diabetics, in fairly good metabolic control and with moderate hypertension (orthostatic diastolic pressure from 100 to 115 mmHg), comparing the effect of MZ with those of chlorthalidone (CL). According to a randomized, single-blind cross-over design, the patients were treated with MZ (20 mg/day) or CL (50 mg/day) for the duration of 4 weeks. After the treatment period with the first drug, there was a 2 week wash-out period on placebo (PL) before the second drug was given. During the study, a set of metabolic and non-metabolic parameters was monitored, as were the clinostatic and orthostatic blood pressure values. The results show that the antihypertensive effect of the two drugs was the same (both caused a more than 10% decrease in systolic and diastolic blood pressure). No significant changes in plasma electrolyte levels occurred. There was a significant (p less than 0.05) increase in urinary aldosterone excretion after CL (20.7 +/- 11 micrograms/24 hours vs. 13.3 +/- 8.5 after PL, and 14.5 +/- 7.2 after MZ) (mean values +/- standard deviations).(ABSTRACT TRUNCATED AT 250 WORDS)