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.

We investigated the immunogenicity of human proinsulin (HPI) when used as the sole or principal insulin agonist in insulin-naive patients with insulin-dependent (type I) and non-insulin-dependent (type II) diabetes mellitus. Sixty-one patients (13 type I, 48 type II) were treated with rDNA human insulin (NPH HI with or without regular HI) and 53 were treated with HPI (8 type I, 45 type II). At 6 mo, virtually identical levels of HbA1c (5.2 vs. 5.3%, P = NS) were achieved. However, regular HI was added less often to the treatment regimen in HPI-treated patients (16 vs. 32 patients, P less than .001). Overall, there was no significant increase in proinsulin-specific antibodies in either treatment group. However, 8 of 51 (1 transiently) patients in the HPI group developed low levels of binding of HPI (highest percentage bound was 5%). Two patients in the HI group developed very low levels of HPI binding (1.2 and 1.9%). Binding of HI (greater than 2.4%) was seen in both treatment groups; however, the prevalence of HI binding was less in the HPI group at 6 mo (39 of 60 in HI group vs. 20 of 51 in HPI group, P = .008). Concomitant treatment with regular HI did not affect the prevalence or level of binding of HPI or HI. We conclude that human proinsulin is a weak immunogen when used as the principal insulin agonist and may reduce both the formation of anti-HI antibodies and the need for concomitant therapy with regular HI.

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.

The effect of long-term treatment with the aldose reductase inhibitor sorbinil (125 mg daily for 6 mo) was examined in 22 diabetic patients with subclinical abnormalities of nerve function. This was a placebo-controlled, double-blind crossover trial in which each of the two treatment periods lasted 6 mo. Peripheral nerve function was assessed electrophysiologically and by quantitative sensory testing; autonomic function was assessed by measurement of five cardiovascular reflexes and of mean heart rate from a 24-h ECG recording. Measurement of erythrocyte sorbitol concentrations demonstrated very significant inhibition of aldose reductase activity with sorbinil treatment, but no concomitant improvement in either peripheral or autonomic nerve function was observed.

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 investigated the hormonal and metabolic response to a 100-g sucrose load given 15 min after adaptation to moderate-intensity (50% VmaxO2) long-duration (4-h) exercise in healthy volunteers. The effect of a 100-mg dose of the alpha-glucosidase inhibitor Acarbose ingested with the sucrose load was also investigated. "Naturally labeled [13C] sucrose" was used to follow the conversion to expired-air CO2 of the sugar ingested by isotope-ratio mass spectrometry. Circulating hormone and metabolite data were obtained in nine subjects, and indirect calorimetry and stable isotope methodology were applied to six of them. Under placebo, 93 +/- 4 g sucrose were entirely oxidized during the 4 h of exercise, total carbohydrate utilization was 235 +/- 14 g, endogenous carbohydrate utilization was 142 +/- 13 g, and total lipid oxidation was 121 +/- 7 g. A single oral dose of 100 mg Acarbose ingested with the sucrose load did not significantly modify total carbohydrate (239 +/- 2 g/4 h) or lipid (122 +/- 6 g/4 h) oxidation. In contrast, sucrose oxidation was reduced to 53 +/- 6 g/4 h and endogenous carbohydrate utilization increased to 186 +/- 7 g/4 h. Reduction of the rises in blood glucose and fructose and of the increases in plasma insulin and C peptide under Acarbose confirmed these effects, whereas lower circulating levels of alanine suggested a higher rate of gluconeogenesis. These data show that a 100-g glucose load ingested soon after initiation of exercise is a perfect available metabolic substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Azathioprine (2 mg/kg) was given, in addition to routine insulin treatment, to alternate patients presenting with recent-onset type I diabetes. Treated (N = 13) and untreated (N = 11) patients did not differ significantly at diagnosis with respect to age, duration of symptoms, body weight, blood glucose, hemoglobin A1c, or presence of ketosis. Eight patients were treated for 12 mo, three elected to stop treatment at 6 mo, and treatment was stopped in two because of side effects. Seven treated patients had a remission compared with one untreated patient. At 12 mo these seven patients were distinguished by significantly higher basal and glucagon-stimulated levels of C-peptide (1.98 +/- 0.52 and 3.88 +/- 0.34 micrograms/L, respectively) compared with the other six treated patients (0.93 +/- 0.52 and 1.32 +/- 0.85 microgram/L, respectively), and by the persistence of islet cell cytoplasmic antibodies. Remissions were not sustained in the 1-2 yr after treatment, although relapsed patients required less insulin for control. These results corroborate those from nonrandomized trials using cyclosporine and suggest that protracted treatment with nonspecific immunosuppressive drugs may be necessary to avert insulin dependence.

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.

Although the benefits of metabolic intervention on the microvascular complications of diabetes mellitus remain unproven, it is generally assumed though not proven that prognosis in terms of blindness and renal failure will reflect the long-term glycemic response to therapy. Treatment goals however remain poorly defined. Costs and hazards of achieving near-normoglycemia in insulin-dependent diabetes mellitus (IDDM) are major. A multicenter trial was proposed to test the hypothesis that in IDDM two levels of mean glycemia, sufficiently separated to examine the control/complications relationship, could be maintained by the six collaborating centers, using randomized patient allocation to conventional insulin therapy (CIT) and continuous subcutaneous insulin infusion (CSII) as the alternative treatment modalities. Methods of maintaining and monitoring metabolic control and of assessing renal and retinal responses were to be applied, evaluated, and possibly improved. All clinics shared a common experimental protocol, which received ethical approval at each treatment center. Retinal assessment facilities were provided by the Fundus Photograph Reading Center at the University of Wisconsin in Madison, and at the Diabetic Retinopathy Department, Royal Postgraduate Medical School, Hammersmith, United Kingdom. The Central Biochemistry Laboratory was at the University of Newcastle, United Kingdom. Collaborators agreed on policy for recruitment, baseline assessment, and randomization of patients with IDDM, complicated by early microvascular disease. CIT took the form of the unchanged prestudy regimen; glycemic goals were set for CSII and their achievement based on inpatient and outpatient sampling of plasma glucose. Glycosylated hemoglobin was measured, retinal abnormalities recorded photographically, and urinary albumin excretion quantitated at baseline, 4, and 8 mo in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Data from 70 type I diabetic patients with nonproliferative retinopathy participating in a multicenter clinical trial of control and complications were analyzed to test for associations of clinical variables with baseline levels and 8-mo changes in retinopathy. Predictor variables included age, duration of diabetes, systolic blood pressure, inpatient and outpatient plasma glucose levels, glycosylated hemoglobin (HbA1), M-values, serum cholesterol, serum triglycerides, and creatinine clearance. Retinopathy was assessed by fundus photography and graded at the Fundus Photograph Reading Center according to a detailed protocol. For the entire group, baseline retinopathy was positively correlated (P less than 0.05) with baseline systolic blood pressure, plasma glucose, HbA1, serum cholesterol, and duration of disease and negatively correlated with creatinine clearance. Conversely, during treatment, progression of retinopathy was negatively correlated (P less than 0.05) with mean levels during treatment of plasma glucose, HbA1, M-values, serum cholesterol, and with changes during treatment in plasma glucose and serum triglycerides. Two-group and three-group multivariate classification analysis of progression of retinopathy (improved or unchanged versus worsening--mild or moderate) indicated lower plasma glucose as the single best predictor of worsening of retinopathy (P less than 0.05), correctly classifying 71% of patients with positive progression. Decreased creatinine clearance during therapy was found to be the best discriminator between mild and moderate progression. Other multivariate models yielded specificity values of up to 71% and sensitivity values of up to 92%. We conclude that associations among clinical predictors and retinopathy during short-term glycemic control differ strikingly from those at baseline.(ABSTRACT TRUNCATED AT 250 WORDS)