OBJECTIVE - To describe the methods used to implement intensive and conventional therapies in the Diabetes Control and Complications Trial (DCCT) and the metabolic results that occurred with the different treatment regimens.RESEARCH DESIGN AND METHODS - The DCCT was a controlled clinical trial that demonstrated the beneficial effect of intensive therapy on the long-term complications of insulin-dependent diabetes mellitus (IDDM). A total of 1,441 volunteers with IDDM, aged 13-39, from 29 centers in the U.S. and Canada, were randomly assigned to conventional or intensive diabetes therapy. Intensive therapy, which used multiple daily injections (MDI) of insulin (greater than or equal to 3 injections/day) or continuous subcutaneous insulin infusion (CSII), was implemented by a team that included diabetes nurses, dietitians, behavioral experts, and diabetologists. Volunteers in the intensive treatment group could use MDI or CSII, based on patient and clinic preference, and could switch between therapies over the course of the study. The volunteers were followed for a mean of 6.5 years (range 3-9 years).RESULTS - A detailed analysis of implementation of the two treatments indicates that intensive and conventional treatment subjects adhered to their respective insulin injection regimens >97% of the time. Adherence to other elements of intensive treatment was similarly high and resulted in median HbA(1c) values between 6.7 and 7.2, compared with 8.7-9.2 with conventional therapy, over the course of the study. Severe hypoglycemia occurred three times more often in intensively treated subjects. Although subjects on intensive treatment were not randomly assigned to MDI or CSII, we compared those subjects who used either of these methods for greater than or equal to 90% of the study time. CSII-treated patients maintained a mean HbA(1c) of 6.8 vs. 7.0 in MDI-treated subjects during the trial (P < 0.05). The frequency of hypoglycemia with coma and seizure and diabetic ketoacidosis was modestly higher with CSII than with MDI.CONCLUSIONS - Intensive therapy was implemented successfully in the DCCT. The detailed description herein will serve to facilitate translation of the DCCT results to the clinical setting.

Objective: To determine the magnitude of the decrease in the risk of retinopathy progression observed with intensive treatment and its relationship to baseline retinopathy severity and duration of follow-up.Design: Randomized clinical trial, with 3 to 9 years of follow-up.Setting and Patients: Between 1983 and 1989, 29 centers enrolled 1441 patients with insulin-dependent diabetes mellitus aged 13 to 39 years, including 726 patients with no retinopathy and a duration of diabetes of 1 to 5 years (primary prevention cohort) and 715 patients with very mild to moderate nonproliferative diabetic retinopathy and a duration of diabetes of 1 to 15 years (secondary intervention cohort). Ninety-five percent of all scheduled examinations were completed.Interventions: Intensive treatment consisted of the administration of insulin at least three times a day by injection or pump, with doses adjusted based on self-blood glucose monitoring and with the goal of normoglycemia. Conventional treatment consisted of one or two daily insulin injections.Outcome Measures: Change between baseline and follow-up visits on the Early Treatment Diabetic Retinopathy Study retinopathy severity scale, assessed with masked gradings of stereoscopic color fundus photographs obtained every 6 months.Results: Cumulative 8.5-year rates of retinopathy progression by three or more steps at two consecutive visits were 54.1% with conventional treatment and 11.5% with intensive treatment in the primary prevention cohort and 49.2% and 17.1% in the secondary intervention cohort. At the 6- and 12-month visits, a small adverse effect of intensive treatment was noted (''early worsening''), followed by a beneficial effect that increased in magnitude with time. Beyond 3.5 years of follow-up, the risk of progression was five or more times lower with intensive treatment than With conventional treatment. Once progression occurred, subsequent recovery was at lease two times more likely with intensive treatment than with conventional treatment. Treatment effects were similar in all baseline retinopathy severity subgroups.Conclusion: The results of the Diabetes Control and Complications Trial strongly support the recommendation that most patients with insulin-dependent diabetes mellitus use intensive treatment, aiming for levels of glycemia as close to the nondiabetic range as is safely possible.

Physiological hyperglycemia has been speculated to alter phosphoinositide (PPI; inositol phospholipid) signal transduction in cells prone to diabetic complications by two separate mass-action mechanisms with antiparallel putative effects on diacylglycerol (DAG): (i) sorbitol-induced depletion of myo-inositol leads to diminished PPI synthesis and turnover and DAG release, and (ii) elevated glucose-derived DAG precursors enhance de novo DAG synthesis. Because the first mechanism is mediated by aldose reductase (AR2), which converts glucose to sorbitol, the effects of glucose on basal and stimulated PPI signaling were explored in lines of cultured human retinal pigment epithelial cells differing widely in their basal AR2 gene expression and enzymatic activity. The results suggest that the effects of glucose on PPI signaling vary inversely with the level of AR2 activity and parallel the extent of AR2-induced myo-inositol depletion.