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)

Sixty-five patients with mild to moderate nonproliferative diabetic retinopathy who enrolled in a prospective controlled clinical trial had stereofundus photographs assessed for change over an 8-mo period. The entire study group showed a worsening of retinopathy with time (P less than 0.001). The worsening was greater in the pump-treated group (15/32) than in the conventionally treated group (9/33). The significance of this difference ranged from P = 0.67, if changes in mean retinopathy level for each patient were compared, to P = 0.177 if a grading system keyed to the worse eye was compared. The difference in rates of change between treatment groups was found to be related to the baseline mean retinopathy level (P = 0.031), but less significantly so if baseline retinopathy keyed to the worse eye was used as a covariate (P = 0.08). Worsening occurred more frequently in those patients starting with the lower retinopathy levels. Progression was associated with the appearance of retinal infarcts (cotton-wool spots, soft exudates) and/or intraretinal microvascular abnormalities, with the pump patients showing a significant increase in these individual retinal lesions compared with the conventionally treated patients over 8 mo (P less than 0.025).

As part of a randomized, prospective trial in subjects with insulin-dependent diabetes assigned to either continuous subcutaneous insulin infusion (CSII) or to their unchanged conventional insulin treatment (CIT) for 8 mo, patients completed questionnaires dealing with general responses and clinical and technological problems. Although there was no significant difference between treatment groups with respect to the number of patients experiencing severe hypoglycemia (i.e., requiring intravenous glucose or intramuscular glucagon injection), there were nine episodes in six patients during CSII compared with one episode during CIT. Diabetic ketoacidosis occurred significantly more often in the CSII group (nine episodes in eight patients) than in the CIT group (no episodes). A number of CSII-related failures occurred, including omission of premeal bolus, needle dislodgement, pump accidentally turned off, and leakage at the infusion site. At 8 mo, 85% of CSII-treated patients wished to continue indefinitely on the pump, and almost all would continue with self-monitoring of blood glucose even if they stopped CSII.

Determination of glycemic differences between groups treated with continuous subcutaneous insulin infusion (CSII) or conventional insulin therapy (CIT) was central to the major objective of the study. Assessment of glycemia was based on 24-h inhospital profiles of plasma glucose; pre- and postprandial and bedtime (seven time points) diurnal profiles performed monthly on outpatient samples; and glycosylated hemoglobin (HbA1) measured bimonthly at each center. The correlation between plasma glucose determinations in the central laboratory and in local laboratories was 0.988. Significance of differences between treatments was by analysis of variance and least-squares regression. At baseline, mean inhospital plasma glucose and HbA1 concentrations and insulin dosages were identical in the groups randomized to CSII or CIT. A prompt decrement of indices of glycemic control during CSII was observed such that mean decrements sustained over the 8-mo treatment period in home and in hospital plasma glucose profiles and HbA1 relative to values obtained during CIT (P less than 0.0001). The likelihood of CSII-treated patients achieving glycemic indices within the normal range was increased. The standardization of the mean and the M-value calculated from inhospital glucose profiles during CSII and CIT at 4 and 8 mo indicated that there was less plasma glucose fluctuation during CSII. The method of pooling standardized local HbA1 measurements from the six centers appeared to be an adequate substitute for centrally performed HbA1 determinations. Advantages of inhospital plasma glucose measurements in terms of accuracy and ability to obtain nocturnal samples contrasted with the likelihood of increased realism and superior correlation with HbA1 in home-obtained samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Newly presenting maturity-onset diabetic subjects were put on diet and if, after 3-4 mo, their fasting plasma glucose continued greater than 6 mmol/L, they were randomized to three therapies: (1) continuing diet alone, (2) with additional sulfonylurea, or (3) with additional basal insulin supplement provided by ultralente insulin. Obese patients were also randomized to metformin therapy. The aim was to lower the fasting plasma glucose to less than 6 mmol/L and the degree to which this reduced the hemoglobin A1C (HbA1C) concentration was studied in 195 patients over 1 yr. Sulfonylurea and insulin similarly reduced (P less than 0.001) the fasting plasma glucose from 8.3 +/- 1.9 to 6.7 +/- 1.3 mmol/L (mean +/- 1 SD) and 8.6 +/- 2.2 to 6.8 +/- 1.4 mmol/L, respectively. This was accompanied by a significant reduction (P less than 0.001) of the HbA1C to the high normal range, from 9.1 +/- 2.1% to 7.8 +/- 1.2%, and from 9.1 +/- 1.9% to 8.1 +/- 1.3%, respectively, both values at 1 yr being significantly (P less than 0.05) lower than in patients randomized to diet alone. Patients randomized to diet alone had little change in fasting plasma glucose (8.6 +/- 1.8 to 9.3 +/- 2.3 mmol/L) or HbA1C (8.8 +/- 1.7% to 9.1 +/- 1.6%, respectively). Thus, the simple therapeutic aim of trying to reduce the fasting plasma glucose to less than 6 mmol/L is an effective means of reducing the HbA1C to a high-normal level. The HbA1C and fasting plasma glucose concentrations were similarly related for all three therapies (HbA1C [%] = 0.47 X fasting plasma glucose [mmol/L] + 4.7).(ABSTRACT TRUNCATED AT 250 WORDS)

Two-hundred and two pregnant women with impaired glucose tolerance were randomized to treatment with diet or diet and insulin by stratified selection. Self-monitoring of blood glucose was performed six times a day, 3 days/wk. Dietary treatment was considered inappropriate if fasting and postprandial blood glucose values exceeded 7 and 9 mmol/L, respectively, in which case insulin therapy was instituted. Insulin doses were adjusted according to blood glucose values, aiming at fasting and postprandial values below 5 and 6.5 mmol/L, respectively. There were no perinatal deaths. The two treatment regimens disclosed no differences regarding achieved degree of maternal blood glucose control, hemoglobin A1c at delivery, obstetric or neonatal complications, infant's size at birth including skin-fold thickness, or C-peptide concentration in cord serum. Routine treatment of pregnant women with mild carbohydrate intolerance with insulin seems unnecessary. However, 15 patients (14%) in the diet group needed insulin to achieve acceptable blood glucose control, underlining the importance of monitoring blood glucose to detect those who are at risk of developing overt diabetes.

In the present study, 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) consumed eucaloric, mixed food diets on three consecutive days. Diets provided 50% of the calories as carbohydrate, 35% as fat, and 15% as protein. The percent of carbohydrate fed as complex (starches) and simple (mono- and disaccharides) varied among the 3 days. On day 1, the diet contained 80% of the carbohydrate as complex and 20% as simple (80/20); another contained 50% complex and 50% simple (50/50); and the final diet contained 20% of the carbohydrate as complex and 80% as simple (20/80). All simple carbohydrates represent naturally occurring sugars in fruits, vegetables, and dairy products. No refined sugars were added to any of the diets. The three experimental diets were randomly assigned using a 3 X 3 Latin square design. Blood was obtained hourly from 0800 to 1700 h for day-long glucose and insulin concentrations, and 24-h urine collections were made for the measurement of urine glucose. Mean (+/- SEM) day-long glucose concentrations were significantly greater for the 80/20 diet (2245 +/- 199 mg/dl X h, P less than 0.05) than for either the 50/50 (2030 +/- 157 mg/dl X h) or the 20/80 diets (2008 +/- 160 mg/dl X h). No significant differences were noted between the 50/50 and the 20/80 diets. In contrast, day-long insulin concentrations were not significantly different with 401 +/- 62, 370 +/- 50, and 369 +/- 60 mu U/ml X h on the 80/20, 50/50, and 20/80 diets, respectively. Twenty-four-hour urinary glucose excretion paralleled plasma glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven normal volunteers were studied on two different occasions during which 4-h pulsatile (PULS: 0.8 mU X kg-1 X min-1, 7.5 min of 15) and continuous (CONT: 0.4 mU X kg-1 X min-1) intravenous (i.v.) infusions of human insulin (Actrapid HM, Novo) were randomly compared. A euglycemic glucose clamp was performed and a 3-3H-glucose infusion was used for determination of endogenous glucose production (EGP) and metabolic clearance rate (MCR) of glucose. Plasma glucose was similar in both conditions; plasma insulin was stable at about 29 mU/L (CONT) and fluctuated between 10 and 45 mU/L (mean: 28, PULS). Exogenous glucose infused was 1.137 +/- 0.058 and 1.088 +/- 0.099 g X kg-1 X 4 h-1 in CONT and PULS, respectively (NS). EGP was totally suppressed in both conditions. Glucose MCR increased similarly to a maximum of 6.71 +/- 0.19 (CONT) and 6.79 +/- 0.59 (PULS) ml X kg-1 X min-1 during the fourth hour. C-peptide plasma levels remained stable, whereas plasma glucagon, free fatty acids, and 3-hydroxybutyrate were similarly suppressed in both tests. Thus, under these conditions, pulsatile and continuous insulin infusions have similar metabolic effects. These data contrast with those of Matthews et al. (1983) who reported that, at lower plasma concentrations (5-19 mU/L), pulsatile insulin had greater hypoglycemic effect than did continuous delivery. It is concluded that pulsatile insulin shows no greater activity under normoglycemic, moderately hyperinsulinemic conditions in man.

The impact on remission of normalizing blood glucose levels immediately after diagnosis of type I diabetes was studied in 14 adolescents. Accordingly, in this randomized prospective primary intervention study, 7 of the subjects (i.v. group) received insulin by continuous intravenous (i.v.) infusion via a portable preprogrammed system for 28-62 days and 7 (s.c. group) received conventional subcutaneous (s.c.) therapy. Before therapy, the two groups did not differ significantly with respect to glycosylated hemoglobin, fasting plasma C-peptide, or 24-h urinary C-peptide excretion. During the infusion period, the overall mean fasting plasma glucose (FPG) concentration for the i.v. group was 84 mg/dl with a mean coefficient of variation of 18 +/- 4% (mean +/- SD). During the comparable period for the s.c. group, the mean FPG was 253 mg/dl with a coefficient of variation of 30 +/- 20%. Twenty-four-hour urinary glucose excretions for the two groups were 0.29 +/- 0.06 (mean +/- SEM) and 59 +/- 11 g/day, respectively. Daily insulin requirements in the i.v. group decreased from 1.47 +/- 0.19 U/kg body wt/day at the start to 0.47 +/- 0.10 U/kg/day at the end of the infusion period. Notably, 10-25 days after the infusion period, 5 of 7 subjects experienced a further decrease to a low of 0.27 +/- 0.01 U/kg/day. The mean peak and low requirements in the s.c. group were 0.71 +/- 0.15 and 0.33 +/- 0.13 U/kg/day, respectively, with the only peak requirements being significantly different (P less than 0.01). No patient was able to discontinue insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The final results of a randomized controlled clinical trial of photocoagulation for diabetic maculopathy are reported, when all patients have been followed for at least 5 yr and some for as long as 7 yr. Ninety-nine patients with two similarly affected eyes had one eye chosen by a random procedure, treated with the xenon-arc photocoagulator; the untreated eyes remained as control. The mean visual acuity deteriorated by less than one line in treated eyes but by more than 2 lines in the controls (P less than 0.01). The difference in deterioration was greatest in patients whose initial vision was 6/6-6/9, and was not significant in those whose visual acuity was 6/36 or worse. Thirteen patients became blind in both eyes (visual acuity of 6/60 or less for 2 consecutive yearly assessments), 6 in the treated eye only, and 26 in the control eye only (P less than 0.01). Again the divergence between treated and control eyes was most marked in those whose initial vision was 6/6-6/9, (only one treated but 10 control eyes became blind). Hard exudates, microaneurysms, and hemorrhages improved more in the treated eyes (0.05 less than P less than 0.001) and more control eyes developed new vessels during the follow-up period. Twenty-three patients died during follow-up and another 16 failed to complete the study. Though the blood pressure of those who died was higher than those who survived (P less than 0.05 for both systolic and diastolic) no other medical abnormalities at entry had any clear effect on visual outcome or 5-yr survival. It is concluded that photocoagulation is of benefit in maintaining vision in diabetic maculopathy if the disease is not too far advanced.

A double-blind, randomized, placebo-controlled cross-over trial of the aldose reductase inhibitor sorbinil was undertaken in 15 patients (age 35-68 yr) with chronic painful diabetic neuropathy. Treatment was evaluated by subjective pain responses, clinical examination, vibration perception threshold, motor and sensory nerve electrophysiology, and cardiovascular reflex tests of autonomic nerve function. Among the many measurements, only pain, tendon reflex scores, and sural sensory potential amplitude improved significantly during sorbinil administration, while scores of clinical sensory examination deteriorated. Four patients experienced an idiosyncratic reaction that rapidly recovered on discontinuing the drug. This study suggests that aldose reductase inhibitor treatment with suggests that aldose reductase inhibitor treatment with sorbinil may have an effect on symptomatic diabetic neuropathy in man.

Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.

Twenty insulin-dependent diabetic patients participated in a 1-yr prospective randomized cross-over study comparing multiple subcutaneous injections (MSI) and continuous subcutaneous insulin infusion (CSII) complemented by home blood glucose monitoring. While 4 patients dropped out early, 16 patients completed the study. Patients had severe insulin deficiency documented by absent C-peptide response to glucagon stimulation. A marked improvement in control was observed when mean blood glucose and glycosylated hemoglobin A1 were compared with conventional therapy. No significant differences in the degree of metabolic control achieved, as measured by mean fasting, preprandial, and postprandial capillary blood glucose (CBG), M values, glycosylated hemoglobin A1 concentration, cholesterol and triglyceride levels were seen between MSI and CSII in the sixteen patients who completed the study. However, individual comparisons showed that fasting CBG and M-values were lower under CSII than MSI in seven patients (P less than 0.05). In contrast, two patients exhibited lower M values under MSI than under CSII (P less than 0.01), while for the remaining seven patients the results were similar. After completion of the study, two patients went back to conventional insulin therapy, seven patients remained on the pump, and seven patients chose to stay on MSI. In conclusion, on a long-term basis, the two methods can produce comparable levels of blood glucose and glycosylated hemoglobin in ambulatory insulin-dependent diabetics.

The use of electrophysiological (EP) tests as the primary basis for determining outcome in clinical trials of therapy for symptomatic diabetic polyneuropathy, and the frequently short duration of such trials, is based on assumptions at variance with the pathology and natural history of this disorder and with the evidence that the commonly employed EP tests predominantly reflect the status of the large myelinated nerve fibers. The course of painful, distal symmetrical, primarily sensory polyneuropathy was studied in nine chronic diabetics, aged 21--59 yr, selected for the absence of other forms of diabetic neuropathy, other causes of neuropathy, and other significant illness. All were treated with modifications of diet, insulin, and a daily multivitamin tablet, and, on a randomized basis, also received either placebo or myo-inositol tablets. Initially, and after 2, 4, and 6 mo, a standardized questionnaire was used to assess symptoms, and a standardized neurological examination and battery of EP tests were performed. A minimum of 6 mo was found necessary to assess the clinical course of this syndrome. Clinical improvement occurred in both legs and arms in four patients, as judged by improvement both in symptoms and in the extent of deficits in pinprick and temperature perception; abnormalities in sensory modalities mediated by large myelinated fibers, however, were generally unaltered after 6 mo. A nonuniform distribution of abnormal EP tests of sensory components of the commonly studied nerves of the leg and arm was demonstrated in the study group at the outset, and clinical improvement was not accompanied by evidence of any consistent pattern of improvement in the initially abnormal EP tests. A significant fraction of chronic diabetics with painful, distal symmetrical, primarily sensory polyneuropathy selected by standard criteria appear to have potential for clinical improvement over 6 mo, but primarily in sensory modalities that make it inappropriate to use the common EP tests as the primary basis of judging outcome.

Twenty-four volunteers, mean age 78, including eight mildly non-insulin-dependent diabetics, were randomly allocated to one of two groups and were fed (daily for 8 wk) 9 g of either chromium-rich brewers' yeast (experimental) or chromium-poor torula yeast (control). Before and after yeast supplementation, the serum glucose and insulin response to 100 g oral glucose was measured at 30 min intervals for 2 h. Fasting serum cholesterol, total lipids, and triglycerides were also determined. In the total experimental group (normals + diabetics) and in both the diabetic and nondiabetic experimental subgroups, glucose tolerance improved significantly and insulin output decreased after supplementation. Cholesterol and total lipids fell significantly after supplementation in the total experimental group. The cholesterol decrease was particularly marked in hypercholesterolemic subjects (cholesterol > 300 mg/dl). In the control group, no significant change in glucose tolerance, insulin, triglycerides, or total lipids was found. Cholesterol was significantly lowered in the nondiabetic but not in the diabetic group. Thus, chromium-rich brewers' yeast improved glucose tolerance and total lipids in elderly subjects, while chromium-poor torula yeast did not. An improvement in insulin sensitivity also occurred with brewers' yeast supplementation. This supports the thesis that elderly people may have a low level of chromium and that an effective source for chromium repletion, such as brewers' yeast, may improve their carbohydrate tolerance and total lipids. The improvement in serum cholesterol in some control subjects, as well as in the total experimental group, also suggests the presence of a hypocholesterolemic factor other than chromium in both brewers' and torula yeast.

Forty-two diabetic patients on insulin once a day in the early stage of diabetic retinopathy were randomly assigned to one of two kinds of insulin regimen, i.e., single or multiple daily injections. Retinal changes were quantitatively estimated by counting the microaneurysms (MAs) observed on fluorescein angiograms at the posterior pole of the more diseased eye. Baseline characteristics of the two groups were not significantly different. These included duration of diabetes, age at diagnosis, daily dose of insulin, amount of urinary sugar excreted in 24 hours, fasting blood sugar (FBS), and number of MAs. During the follow-up (mean duration of three years) the mean yearly progression in the number of MAs was significantly less in the multiple- than in the single-injection groups: 1.8 +/- 0.7 versus 7.2 +/- 1.9 (p less than 0.01; nonparametric test: p less than 0.02). Final values were, respectively, MAs: 15.2 +/- 4.9; 33.0 +/- 7.9; glycosuria (gm./24 hrs): 20.6 +/- 2.5; 27.5 +/- 4.3; FBS (mg./100 ml.): 154 +/- 15; 195 +/- 11. P values comparing the two groups were less than 0.02, less than 0.02, and less than 0.05. Thus, in this clinical trial, made under routine treatment conditions, the use of divided daily insulin injections was effective in improving diabetic control and delaying retinal changes.