Seventy patients aged 15-40 yr with recent-onset insulin-dependent diabetes mellitus (IDDM) were entered into a double-blind trial, in which they were randomly assigned to either cyclosporin (7.5 mg.kg-1.day-1) or to placebo and were monitored for 1 yr for various phenotypic and functional parameters of T-lymphocyte-mediated immunity. Before treatment, the proportions of total T-lymphocytes (CD3+) and helper-inducer T-lymphocytes (CD4+) were normal, whereas significantly decreased values of suppressor/cytotoxic T-lymphocytes (CD8+), as compared with normal controls, were found in 31% of the patients. The interleukin 2 (IL-2)-receptor expression was significantly increased in IDDM patients compared with control subjects, although the single values were low: patients, 2.02 +/- 0.41%; controls, 0.88 +/- 0.25% (means +/- SE). Circulating levels of soluble IL-2 receptor were also significantly increased in IDDM patients compared with controls: patients, 372.3 +/- 25.4 U/ml; controls, 235.5 +/- 29.3 U/ml (means +/- SE). However, no major abnormalities were found in mitogen (phytohemagglutinin)-induced IL-2 production, cell proliferation, or IL-2-receptor expression. After 6 mo of cyclosporin treatment, no major modifications of any of the parameters analyzed were noted, even in patients who had cyclosporin blood trough levels greater than 300 ng/ml, i.e., the threshold value associated with clinical efficacy. One explanation for the absence of a major effect of cyclosporin, in contrast with its demonstrated clinical effectiveness, is the reversibility of its activity. Our results preclude the use of the described tests to reliably monitor IDDM patients undergoing immunosuppressive therapy.

Cyclosporin or placebo was administered in a randomized, double-blind fashion to 13 patients with multiple sclerosis for 1 yr to determine whether cyclosporin adversely affects glucose homeostasis or beta-cell function. No significant differences were observed in fasting glucose, fasting insulin, intravenous glucose tolerance, or glucose-induced insulin secretion before treatment or at 3 wk, 6 mo, or 1 yr during treatment. Longer therapeutic trials with larger patient groups will be necessary to decide whether cyclosporin can be safely given for many years without risk of developing diabetes mellitus.

Cyclosporin is an immunosuppressive drug used with increasing frequency in patients with diabetes mellitus both as experimental primary therapy for insulin-dependent diabetes mellitus and as therapy accompanying pancreatic transplantation. However, reports have appeared contending that cyclosporin causes glucose intolerance and inhibits pancreatic islet beta-cell function. Consequently, concern has been raised that the beneficial effects of immunosuppression may be offset by adverse metabolic effects of the drug. To address this issue, we examined intravenous glucose tolerance and pancreatic islet beta-cell function in a group of nondiabetic multiple sclerosis patients before and during a 2-yr course of cyclosporin or placebo therapy. Patients were randomly assigned to one of the two drug groups and followed in a double-blind manner. Basal levels of glucose, insulin, and C-peptide as well as glucose disappearance rates and pancreatic islet beta-cell function after stimulation with intravenous glucose and arginine were determined immediately before therapy and after 3 wk, 6 mo, 1 yr, and 2 yr of therapy. No abnormalities in these parameters were observed in the cyclosporin of the placebo-treated group. It appears that cyclosporin can be give in conventional doses for as long as 2 yr without encountering evidence for impaired glucose homeostasis. However, whether adverse effects will materialize over longer periods of drug use remains a question.

Proteinuria in diabetes is associated with progressive glomerular damage. We studied the effects of 3-wk dietary protein restriction on proteinuria and renal function in 10 insulin-dependent diabetic men with diabetic nephropathy. Patients were randomly assigned by a crossover design to 40-g low-protein diet (LPD) or usual-protein diet (UPD). Glomerular filtration rate and renal plasma flow were measured by inulin and p-aminohippurate clearance at the end of each period under conditions of sustained euglycemia. Total calorie intake, body weight, serum albumin and total protein concentrations, hematocrit, blood pressure, and glucose control were similar during the two diets. Achieved protein intake was 46 +/- 3 g/day during LPD and 81 +/- 4 g/day during UPD (P less than .001). Urinary urea appearance and plasma urea were significantly lower on LPD. Median total urinary protein was reduced from 3.9 g/day (range 0.5-12.3) on UPD to 2.4 (range 0.2-9.0) on LPD (P less than .006), and there was a significant fall in the median fractional clearance of albumin from 2.0 x 10(-4) (range 0.1-90.9) on UPD to 1.0 x 10(-4) (range 0.1-51.4) on LPD and IgG from 2.1 x 10(-5) (range 0.2-238) to 1.5 x 10(-5) (range 0.1-77) (P less than .006 and P less than .02, respectively). The reabsorption rate of beta 2-microglobulin was similar on the two diets and glomerular filtration rate, renal plasma flow, and filtration fraction remained unchanged. Thus, short-term dietary protein restriction reduces diabetic proteinuria independently of blood glucose or systemic blood pressure changes by improving glomerular permselectivity.

A randomized double-blind placebo-controlled trial was undertaken to determine whether cyclosporin enhances remission of insulin-dependent diabetes mellitus (IDDM) through the 1st yr after diagnosis. Dosage with insulin was minimized with target control of blood glucose levels less than or equal to 7.8 mM (140 mg/dl) before meals. Metabolic control was evaluated by serial determinations of glycosylated hemoglobin levels, and endogenous secretion of insulin was evaluated by determination of the levels of glucagon-stimulated insulin-connecting peptide (CP) in the plasma at 3-mo intervals. A compound definition of remission required a glucagon-stimulated CP level in plasma greater than or equal to 0.6 nM or a non-insulin-receiving state (NIR) in which target control of glycemia was maintained without administration of insulin. A clinical definition of remission required only the NIR state as defined. One hundred eighty-eight patients aged 10-35 yr entered the study within 6 wk of initiation of insulin therapy and within 14 wk of onset of symptoms and were studied for 1 yr. There were no significant differences in metabolic control between the two treatment groups during the study. The anticipated adverse effects of cyclosporin were not more frequent or severe than in other experience with the drug, but histological changes attributable to cyclosporin were present in some kidney biopsies obtained from selected patients after 1 yr. At 1 yr, by the compound definition, 33% of the cyclosporin-group and 21% of the placebo-group patients were in remission, when the corresponding rates for NIR remissions were 24 and 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-beta-cell-specific cell-mediated immunity was studied over a 12-mo period in 65 recently diagnosed diabetic patients randomly receiving either cyclosporin or placebo. Anti-beta-cell cellular immunity was assessed by an in vitro test based on the inhibition of insulin release from cultured rat islet cells by patients' mononuclear cells. This beta-cell-suppressive effect disappeared in cyclosporin A-treated patients within 1 mo and did not reappear during 12 mo of follow-up. Conversely, the suppressive effect persisted unchanged in placebo-treated patients during 12 mo of follow-up. These changes were predictive neither of cyclosporin A-induced remission nor of relapses. Results of the insulin-release inhibition test were not correlated to islet cell autoantibodies or HLA phenotype.

Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects (aged 29 +/- 7 yrs, diabetes duration 8 +/- 4 yr) randomly allocated to either continuous subcutaneous insulin infusion (CSII; n = 12) or unchanged conventional insulin therapy (CIT; n = 12). Measures of glycemic control and somatosensory and autonomic nerve function were comparable in the two groups at the start. Glycemic control was significantly improved in the CSII group throughout study, whereas it remained unchanged in the CIT group. In the CIT group, vibratory perception threshold (VPT) of the great toe and the medial malleolus deteriorated, as did heart rate variation (HRV) at rest, at deep breathing (.05 less than P less than .06), and at standing. In contrast, CSII patients retained their VPT and HRV. Comparison of nerve function alterations during the 2-yr trial showed better preservation in CSII than in CIT patients of VPT in the great toe (0.8 +/- 1.7 vs. -1.4 +/- 1.9 V, P less than .01) and the medial malleolus (1.5 +/- 2.9 vs. -1.4 +/- 1.8 V, P less than .05) and of HRV at rest (10 +/- 24 vs. -13 +/- 22 ms, P less than .05) and at standing (-0.01 +/- 0.13 vs. -0.15 +/- 0.16 ms, P less than .05). We conclude that intensified glycemic control can favorably influence parasympathetic and somatosensory nerve function in insulin-dependent diabetes mellitus.

The Diabetes Control and Complications Trial (DCCT) is a multicenter randomized clinical trial studying the effect of intensive insulin therapy on the early vascular and neurological complications of insulin-dependent diabetes mellitus (IDDM). During the feasibility phase of the DCCT, baseline neurological histories, physical examinations, and laboratory measurements of somatic and autonomic nerve function were obtained in 278 well-characterized IDDM subjects. Subjects were free of advanced complications, including the presence of peripheral or autonomic neuropathy sufficiently severe to require treatment. Analyses of the cross-sectional data reveal that clinically detectable peripheral neuropathy was present in 39% of the subjects. The presence of clinical neuropathy correlated with greater age, longer duration of IDDM, and male gender. The somatic and autonomic test results confirm the relationship between age, diabetes duration, and male gender and diabetic neuropathy. These results support an effect of age and gender on the development of diabetic complications.

The dawn phenomenon was evaluated in eight C-peptide-negative type I (insulin-dependent) diabetic patients on two occasions by measuring glucose concentrations every 30 min from 2400 to 0800 h while the subjects were receiving an insulin infusion (0.12 mU.kg-1.min-1). In random order at 2230 h, they orally received either a sleeping medication alone or with 5.0 mg methscopolamine bromide, an anticholinergic agent. The peak growth hormone (GH) concentrations (ng/ml +/- SE) after sleep were markedly inhibited by methscopolamine (4.7 +/- 2.6 vs. 23.0 +/- 9.2). During the control night, the late (0400-0800 h) glucose response (area under curve but above 0400 h value) was significantly higher (P less than .02) than the early (2400-0400 h) glucose response (area under curve but above 2400 h value). After methscopolamine, the early and late glucose responses were virtually identical. The anticholinergic agent did not affect glucagon levels, overnight urinary catecholamine excretion, or the diurnal cortisol concentrations. The total area under the free fatty acid (FFA) curves was significantly (P less than .05) reduced by methscopolamine. We conclude that sleep-induced GH secretion may cause the dawn phenomenon by increasing FFA levels. Oral administration of methscopolamine at bedtime is a simple pharmacological approach that could test the clinical importance of the dawn phenomenon.

To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 +/- 0.7 to 7.6 +/- 0.5 and 7.1 +/- 0.2%, respectively, P less than .01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P less than .001). Both agents comparably increased (P less than .01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P less than .05). Tolazamide (P less than .05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P less than .05) lowered postabsorptive hepatic glucose release (from 2.8 +/- 0.3 to 2.3 +/- 0.2 mg . kg-1 . min-1), but not to normal rates (1.8 +/- 0.1 mg . kg-1 . min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Fresh whole-blood buffy coats from American Red Cross volunteers were used to treat early type I diabetes. Attempts were made to adapt to human diabetic patients a protocol successfully used in prediabetic BB rats. Twenty-two type I diabetic patients (duration of disease less than 4 wk) were randomized to treatment or control groups; the treatment patients were given one buffy coat (approximately 0.6 X 10(9) T-lymphocytes) weekly for 5 wk. Plasma C-peptide (stimulated and unstimulated), insulin dose, and hemoglobin A1c were measured before and periodically after the treatment for 24 wk. The control group underwent the same studies. Although there were no significant differences for the parameters studied between the two groups, 2 of 12 patients in the treatment group underwent three complete (normal glycemia without insulin) temporary remissions. One of these patients was given a second course of transfusions after relapse from the first remission and developed a second complete remission that lasted 2 mo. No control patient had remissions during the 24-wk study. Although the future of adoptive immunotherapy in the treatment or prevention of diabetes is not known, several probable limitations of the current protocol, as discussed here, can explain the differences in results between this trial and the rodent studies.

This study addressed the controversial question of whether a negative-insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 +/- 1.4 mU/min during the control study to 4.0 +/- 1.2 and 3.2 +/- 0.9 mU/min during plasma insulin levels of 34 +/- 4 and 61 +/- 6 microU/ml, respectively (P less than .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

The aim of this study was to investigate the role of plasma glucagon levels on the blood glucose response to intravenous insulin administered continuously or in a pulsatile manner. Six type I diabetic patients proven to have no residual insulin secretion were investigated. Endogenous glucagon secretion was inhibited by a continuous intravenous infusion of somatostatin (100 micrograms/h) and replaced by exogenous infusions of the hormone at three different rates (7.5, 4.5, and 2.5 micrograms/h), resulting in three different plasma glucagon steady-state levels (i.e., approximately equal to 200, approximately equal to 130, and approximately equal to 75 pg/ml, respectively). Each subject, in random order and on different days, was infused intravenously with regular human insulin either continuously (0.17 mU X kg-1 X min-1) or with the same amount of insulin infused in a pulsatile manner (0.85 mU X kg-1 X min-1 during 2 min followed by 8 min during which no insulin was infused). At plasma glucagon levels approximately equal to 200 pg/ml, blood glucose rose from approximately 10 to approximately 13 mM without any difference between the two modalities of insulin infusion. For plasma glucagon levels approximately equal to 130 pg/ml, plasma glucose remained steady throughout the experiments, but during the last 40 min, plasma glucose levels were significantly lower when insulin was administered intermittently. This greater blood glucose-lowering effect of pulsatile insulin occurred earlier and was more pronounced for plasma glucagon levels averaging 75 pg/ml. We conclude that the greater hypoglycemic effect of insulin administered intravenously in a pulsatile manner in type I diabetics critically depends on plasma glucagon circulating levels.

Forty-five insulin-dependent diabetics were randomized to 1 yr treatment with either continuous subcutaneous insulin infusion (CSII), multiple insulin injections (MI), or continued conventional treatment. The CSII group used regular insulin only, the MI group used 4-6 premeal injections of regular insulin and intermediate insulin at night, and the conventional group used two daily injections of combined regular and intermediate insulin. Only highly purified porcine insulin was used. Near normoglycemia was obtained during CSII and MI but not during conventional treatment. Antibodies against insulin were measured in serum samples by measuring the binding of iodinated porcine insulin to serum after removal of free and antibody-bound insulin from the samples by acid charcoal. The percent binding of 125I-labeled insulin increased significantly during MI and CSII, in contrast to conventional treatment. Nineteen patients had sufficient binding capacity for Scatchard analysis. In the CSII and MI groups, high- or low-affinity antibodies or both were induced. When insulin was administered subcutaneously during MI or CSII for 1 yr, the insulin antibody production increased, in contrast with conventional treatment.

We studied the renal effects of nicardipine, a calcium entry blocker, in eight patients with essential hypertension (group A, WHO I or II), six hypertensive type II diabetics with mild-to-moderate nephropathy (group B, urinary albumin 200-789 mg/day), and six hypertensive type II diabetics with severe or advanced nephropathy (group C, urinary albumin 1,596-4,300 mg/day). The patients received an intravenous dose of nicardipine hydrochloride (0.5 mg) or saline placebo in a random order. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by means of thiosulfate sodium and p-aminohippurate, respectively, during the 30 min after the nicardipine or saline injection. Blood pressures were serially monitored during the study. Nicardipine reduced both systolic and diastolic blood pressures significantly (P less than .05 to .01) at all measurement periods in all study groups compared with the respective placebo. Nicardipine increased RBF (P less than .01), GFR (P less than .05), and urinary Na+ excretion (P less than .01) and decreased total renal vascular resistance (P less than .01) in groups A and B, but these parameters remain unchanged in group C. The filtration fraction remained unaltered in all groups. The results indicate that nicardipine has several favorable renal effects with a concomitant hypotensive action in hypertensive type II diabetics with mild-to-moderate nephropathy, as observed in patients with uncomplicated essential hypertension, and the renal pharmacological responsiveness appears to be related to the severity of nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

To study the effect of sorbinil on the alteration of the blood-retinal barrier, 32 adult-onset, non-insulin-dependent diabetic patients with minimal or no retinopathy were randomly assigned to receive either oral sorbinil (250 mg once a day) or a placebo for 6 mo. All patients underwent fundus photography, fluorescein angiography, and vitreous fluorophotometry before treatment and at 3 and 6 mo after treatment. Vitreous fluorophotometry data showed that the alteration of the blood-retinal barrier increased significantly less in the sorbinil-treated group compared with the placebo group during the 6-mo study period. Side effects were limited to hypersensitivity reactions, with skin rash and fever, in only 2 of the 16 patients who received the drug. These hypersensitivity reactions disappeared with discontinuation of the medication. Aldose-reductase inhibition may play an important role in stabilization of the blood-retinal barrier in early diabetic retinopathy.

The Diabetes Control and Complications Trial (DCCT) is a randomized, controlled clinical trial designed to assess the relationship between glycemic control and the development, progression, or amelioration of early vascular complications in persons with insulin-dependent diabetes mellitus (IDDM). The DCCT consists of two parallel studies: a primary prevention study and a secondary intervention study. The principal outcome in the primary prevention study is the initial appearance and subsequent progression of background retinopathy. In the secondary intervention study, the principal outcome is the progression or amelioration of preexistent minimal retinopathy. Subjects are randomly assigned to receive either experimental or standard therapy. Experimental therapy involves the use of an intensive insulin regimen designed to maintain near-normal glycemic levels in the absence of severe hypoglycemia. Standard treatment is designed to maintain near-normal glycemic levels in the absence of severe hypoglycemia. Standard treatment is designed to maintain subjects free of clinical symptoms related to hyper- or hypoglycemia while receiving up to two insulin injections daily. Two hundred seventy-eight volunteers have been enrolled in 21 centers in the United States and Canada in a preliminary study to assess the feasibility of conducting a full-scale, long-term clinical trial. Based on an external review of the feasibility study results, the DCCT will be expanded to include over 1400 subjects treated for a period of up to 10 yr. This article describes the DCCT and the considerations that led to the choice of specific design features for the feasibility phase.

Thirty patients with insulin-dependent diabetes mellitus (IDDM) who had advanced background retinopathy were randomized to unchanged conventional treatment (UCT) or to continuous subcutaneous insulin infusion (CSII). They were followed prospectively for 2 yr. The mean blood glucose and hemoglobin A1C (HbA1C) were significantly lower in the CSII group than in the UCT group. The mean blood glucose and HbA1C did not change from the first to the second year in either of the treatment groups in spite of less frequent home-monitoring of blood glucose and less frequent outpatient visits during the second year. Four patients in the CSII group and five in the UCT group developed proliferative retinopathy. However, a marginally significant trend was found toward more frequent improvement of retinal morphology in the CSII group (47%) than in the UCT group (13%). Beat-to-beat variation was found to deteriorate significantly with UCT compared with a nonsignificant improvement with CSII therapy. Vibration sense was unchanged in both treatment groups. It is concluded that near-normal blood glucose levels can be maintained with CSII therapy in spite of less frequent home-monitoring of blood glucose and outpatient visits. Furthermore, established background retinopathy may progress to proliferative retinopathy in spite of 2 yr of near-normal blood glucose levels. However, a marginally significant trend toward more frequent improvement of retinal morphology was found among CSII-treated patients compared with conventionally treated patients. Large-scale, prospective, randomized studies are needed to confirm these results.

As part of a multicenter trial, 70 individuals with insulin-dependent diabetes were randomized to either conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII). In order to standardize patient selection in the six participating centers, one of the eligibility criteria was the demonstration that each patient had no residual endogenous insulin secretion as assessed by plasma C-peptide determinations. The patients were of average (+/- SEM) age of 33.0 +/- 1.6 yr, had had diabetes for a mean (+/- SEM) duration of 17.4 +/- 1.1 yr, and had both fasting and postglucagon stimulation C-peptide values of less than 0.1 pmol/ml, consistent with clinically insignificant endogenous insulin secretion. There was no change in C-peptide response at 4 or 8 mo compared with baseline values, whether or not the patient's glucose control remained unchanged (CIT group) or significantly improved to near-normoglycemia (CSII group). In a subgroup of 34 patients at three centers, the 24-h mean glucose concentration was significantly lower in the CSII group compared with the CIT group at 4 mo (126 +/- 10 versus 176 +/- 14 mg/dl) and at 8 mo (121 +/- 5 versus 183 +/- 15 mg/dl) (P less than 0.005). Although the 24-h mean serum free immunoreactive insulin levels were shown to be no different at baseline (27.4 +/- 3.8 versus 26.2 +/- 3.1 microU/ml) or after 4 mo (22.5 +/- 3.2 versus 25.6 +/- 3.2) or 8 mo (26.5 +/- 3.4 versus 28.8 +/- 3.4) of CIT or CSII therapy, respectively, the mean increase of free insulin concentrations in relation to the main meals was greater in the CSII group (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The general and ophthalmologic eligibility criteria were applied in the course of formal screening of selected members of clinic populations at the six treatment centers between August 1980 and November 1981. Patients eligible on the grounds of the history and general physical examination underwent a detailed ophthalmologic examination and determination of C-peptide status. Initial rates of recruitment were slow, which occasioned modifications of the eligibility criteria and a prolongation of the recruitment phase. All six clinics approached their goal of at least six patients in each of the continuous subcutaneous insulin infusion (CSII) and conventional insulin treatment (CIT) groups, with a final total of 70 randomized subjects. The method of paired randomization was acceptable, but led to some delay during periods of slow recruitment activity. Data from two patients who chose to drop out of the study shortly after randomization are included in the baseline characteristics. There was no difference between treatment groups with respect to age or duration of known diabetes, body weight, systolic blood pressure, proportion of cigarette smokers, retinopathy level as assigned by analysis of stereofundus photographs, or microaneurysm counts performed on fluorescein angiograms. A trend toward milder retinopathy in the CIT group proved to be statistically insignificant. Subsequent assessment of stereofundus photographs at the Fundus Photograph Reading Center indicated that six patients were misclassified by treatment center ophthalmologists with respect to ophthalmologic eligibility. We conclude that recruitment goals were met and randomization was successful.