OBJECTIVE -To assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS-In a 52-week, double-blind, placebocontrolled, multicenter study, 480 patients with type 1 diabetes were randomized to receive preprandial injections of placebo or 30 g pramlintide q.i.d., in addition to existing insulin regimens. At week 20, pramlintide-treated patients were re-randomized to 30 or 60 g pramlintide q.i.d. if decreases from baseline in HbA 1c were Ͻ1% at week 13. Of the 342 patients who completed the 52-week study, 236 individuals (ϳ70%) elected to participate in a 1-year openlabel extension in which all patients received 30 or 60 g pramlintide q.i.d..RESULTS -Treatment with pramlintide led to a mean reduction in HbA 1c of 0.67% from baseline to week 13 that was significantly (P Ͻ 0.0001) greater than the placebo reduction (0.16%), and a significant placebo-corrected treatment difference was sustained through week 52 (P ϭ 0.0071). The greater HbA 1c reduction was associated with an average weight loss, rather than weight gain, and was not accompanied by an increased overall event rate of severe hypoglycemia. In the open-label extension, mean HbA 1c levels decreased rapidly in patients receiving pramlintide for the first time and remained at reduced levels in patients who continued pramlintide treatment. The most common adverse events reported by the pramlintide group were mild nausea and anorexia, which both occurred during the initial weeks of treatment and dissipated over time.CONCLUSIONS -Mealtime pramlintide treatment as an adjunct to insulin improved longterm glycemic control without inducing weight gain or increasing the overall risk of severe hypoglycemia in patients with type 1 diabetes. Diabetes Care 25:724 -730, 2002

There have been conflicting reports about the effect of diabetes on bone density. In 1978, we studied 109 patients, 46 with type I and 63 with type II diabetes; approximately 12 years later we restudied 35 of the 66 surviving patients. In the original study, radial bone density did not differ significantly between patients with either type of diabetes but was significantly lower than in nondiabetic control subjects. In eight osteopenic patients, bone formation rate and other histological indexes of osteoblast recruitment and function were markedly depressed compared with those in nondiabetic control subjects. In patients remeasured approximately 2.5 years (41 patients) and approximately 12.5 years (35 patients) after baseline, bone loss had continued at the expected rate in patients with type I diabetes, with maintenance of the same deficit, but was slower than expected in patients with type II diabetes, such that the initial deficit had been completely corrected. In six of the eight patients who had undergone bone biopsy, one with type I and five with type II diabetes, the mean bone mineral density z-score of the spine and femoral neck approximately 12 years later was > 0 and in one subject was significantly higher than normal at both sites. Based on these data and on previous studies, we propose that in patients with diabetes, low bone formation retards bone accumulation during growth, metabolic effects of poor glycemic control lead to increased bone resorption and bone loss in young adults, and low bone turnover retards age-related bone loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.

OBJECTIVEThe Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODSDPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.RESULTSResults are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01).CONCLUSIONSAmong patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.

Background and Aims After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to demonstrate persistent benefit of prior intensive therapy on neuropathy, retinopathy, and nephropathy in type 1 diabetes mellitus (DM)., The relationship between control of glycemia and gastric emptying (GE) is unclear. Methods We assessed GE with a 13C-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and HbA1c, complications of DM, and gastrointestinal symptoms were evaluated. Results GE was normal (37 participants, 50%), delayed (35 participants, 47%), or rapid (2 participants, 3%). The latest mean HbA1c was 7.7%. In univariate analyses, delayed GE was associated with greater DCCT baseline HbA1c and duration of DM prior to DCCT (P ≤ 0.04), greater mean HbA1c over an average of 27 years of follow up (during DCCT-EDIC, P = 0.01), lower R-R variability during deep breathing (P=0.03) and severe nephropathy (P=0.05) and a greater composite upper gastrointestinal symptom score (P<0.05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (OR 1.6, 95% CI 1.1–2.3) and duration of DM (OR 1.2, 95%CI 1.01–1.3) prior to DCCT entry and mean HbA1c during DCCT-EDIC (OR 2.2, 95%CI 1.04–4.5) were independently associated with delayed GE. Conclusions In the DCCT/EDIC study, delayed GE was remarkably common and associated with gastrointestinal symptoms and with measures of early and long-term hyperglycemia. ClinicalTrials.gov numbers NCT00360815 and NCT00360893.