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.

OBJECTIVE—To evaluate the safety and efficacy of treatment with insulin alone, insulin plus metformin, or insulin plus troglitazone in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 88 type 2 diabetic subjects using insulin monotherapy (baseline HbAlc 8.7%) were randomly assigned to insulin alone (n = 31), insulin plus metformin (n = 27), or insulin plus troglitazone (n = 30) for 4 months. The insulin dose was increased only in the insulin group. Metformin was titrated to a maximum dose of 2,000 mg and troglitazone to 600 mg. RESULTS—HbAlc levels decreased in all groups, the lowest level occurring in the insulin plus troglitazone group (insulin alone to 7.0%, insulin plus metformin to 7.1%, and insulin plus troglitazone to 6.4%, P < 0.0001). The dose of insulin increased by 55 units/day in the insulin alone group (P < 0.0001) and decreased by 1.4 units/day in the insulin plus metformin group and 12.8 units/day in the insulin plus troglitazone group (insulin plus metformin versus insulin plus troglitazone, P = 0.004). Body weight increased by 0.5 kg in the insulin plus metformin group, whereas the other two groups gained 4.4 kg (P < 0.0001 vs. baseline). Triglyceride and VLDL triglyceride levels significantly improved only in the insulin plus troglitazone group. Subjects taking metformin experienced significantly more gastrointestinal side effects and less hypoglycemia. CONCLUSIONS—Aggressive insulin therapy significantly improved glycemic control in type 2 diabetic subjects to levels comparable with those achieved by adding metformin to insulin therapy. Troglitazone was the most effective in lowering HbAlc, total daily insulin dose, and triglyceride levels. However, treatment with insulin plus metformin was advantageous in avoiding weight gain and hypoglycemia.

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Background: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

OBJECTIVE -To evaluate the safety and effectiveness of triple therapy using insulin, metformin, and a thiazolidinedione following a course of dual therapy using insulin and metformin or insulin and a thiazolidinedione in type 2 diabetes.RESEARCH DESIGN AND METHODS -Twenty-eight type 2 diabetic subjects using insulin monotherapy (baseline HbA lc level 8.5%) who had been randomly assigned to insulin (INS) and metformin (MET) (INS ϩ MET, n ϭ 14) or INS and the thiazolidinedione troglitazone (TGZ) (INS ϩ TGZ, n ϭ 14) (dual therapy) for 4 months were given INS, MET, and TGZ (triple therapy: INS ϩ MET, add TGZ; or INS ϩ TGZ, add MET) for another 4 months. The INS dose was not increased. CONCLUSIONS -Triple therapy using INS, MET, and TGZ resulted in lower HbA lc levels and total daily insulin dose than during dual therapy. The use of triple therapy resulted in 100% of subjects achieving an HbA lc Ͻ7.0%, while decreasing the dose of INS. Weight gain was avoided when MET therapy preceded the addition of TGZ therapy. The addition of TGZ resulted in the greatest reductions in HbA lc levels and insulin dose. Triple therapy using INS, MET, and a thiazolidinedione (such as TGZ) can be a safe and effective treatment in type 2 diabetes. RESULTS Diabetes Care 27:1577-1583, 2004R esearch in the previous decade has conclusively demonstrated the benefit of improved blood glucose control in the prevention of diabetes complications (1,2). Efforts to advance our ability to achieve near normal glycemic control have resulted in an array of pharmaceutical interventions that not only lower blood glucose levels, but also have beneficial effects on comorbid conditions such as hypertension and hyperlipidemia. In the treatment of type 2 diabetes, health care providers have the option of using insulin (INS), sulfonylureas, thiazolidinediones, biguanides such as metformin (MET), and other oral agents to achieve treatment goals (3,4).MET has been shown to lower blood glucose levels by sensitizing the liver to the effects of insulin, thus suppressing hepatic glucose output. It also has mild effects on promoting glucose utilization (5,6). Thiazolidinediones, like troglitazone (TGZ), improve insulin sensitivity by enhancing insulin-mediated glucose disposal, resulting in reduced plasma insulin concentrations. Thiazolidinediones may also have modest effects on lowering hepatic glucose production (7-9). In addition, studies have shown that thiazolidinediones enhance ␤-cell responsiveness and may prolong ␤-cell survival (10,11). Several randomized, placebocontrolled studies have demonstrated the effectiveness of dual therapy using oral sulfonylureas or INS in combination with either MET or TGZ in lowering blood glucose levels in type 2 diabetic subjects (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Studies of the combined use of MET plus a thiazolidinedione have also shown improved glycemic control when compared with MET alone (23-26). Thiazolidinediones added to treatment with sulfonylureas and MET resulted in significant improvements in HbA 1c leve...

OBJECTIVE -To evaluate the safety and effectiveness of rosiglitazone in the treatment of overweight subjects with type 1 diabetes.RESEARCH DESIGN AND METHODS -A total of 50 adult type 1 diabetic subjects with a baseline BMI Ն27 kg/m 2 were randomly assigned in a double-blind fashion to take insulin and placebo (n ϭ 25) or insulin and rosiglitazone 4 mg twice daily (n ϭ 25) for a period of 8 months. Insulin regimen and dosage were modified in all subjects to achieve near-normal glycemic control.RESULTS -Both groups experienced a significant reduction in HbA 1c (A1C) level (rosiglitazone: 7.9 Ϯ 1.3 to 6.9 Ϯ 0.7%, P Ͻ 0.0001; placebo: 7.7 Ϯ 0.8 to 7.0 Ϯ 0.9%, P ϭ 0.002) and a significant increase in weight (rosiglitazone: 97.2 Ϯ 11.8 to 100.6 Ϯ 16.0 kg, P ϭ 0.008; placebo: 96.4 Ϯ 12.2 to 99.1 Ϯ 15.0, P ϭ 0.016). Baseline measures of BMI (P ϭ 0.001), total daily insulin dose (P ϭ 0.002), total cholesterol (P ϭ 0.005), HDL cholesterol (P ϭ 0.00l), and LDL cholesterol (P ϭ 0.02) were predictors of improvement in A1C level only in the group treated with rosiglitazone. Total daily insulin dose increased in subjects taking placebo (74.0 Ϯ 33.8 to 82.0 Ϯ 48.9 units, P Ͻ 0.05 baseline vs. week 32), but it decreased slightly in subjects taking rosiglitazone (77.5 Ϯ 28.6 to 75.3 Ϯ 33.1 units). Both systolic blood pressure (137.4 Ϯ 15.6 vs. 128.8 Ϯ 14.8 mmHg, baseline vs. week 32, P Ͻ 0.02) and diastolic blood pressure (87.2 Ϯ 9.4 vs. 79.4 Ϯ 7.2 mmHg, P Ͻ 0.0001) improved in the group treated with rosiglitazone. The total incidence of hypoglycemia did not differ between groups.CONCLUSIONS -Rosiglitazone in combination with insulin resulted in improved glycemic control and blood pressure without an increase in insulin requirements, compared with insulin-and placebo-treated subjects, whose improved glycemic control required an 11% increase in insulin dose. Weight gain and hypoglycemia were similar in both groups at the end of the study. The greatest effect of rosiglitazone occurred in subjects with more pronounced markers of insulin resistance. Diabetes Care 28:1562-1567, 2005R esearch in the past decade has conclusively demonstrated that improved blood glucose control is of benefit in preventing the microvascular complications of diabetes (1,2). Although new insulin analogs and intensive insulin treatment regimens are effective in improving glycemic control, these treatments involve considerable effort and cost (3) and can result in weight gain and increased risk for severe and asymptomatic hypoglycemia (4). Faced with the challenge of balancing aggressive insulin replacement therapy against the risk for the potentially serious consequences of excessive weight gain and insulininduced hypoglycemia, investigators continue to search for treatments that address both the treatment of insulin deficiency as well as other metabolic abnormalities that are associated with diabetes (5).Insulin resistance, a metabolic abnormality common in type 2 diabetes, appears to be present in individuals with type 1 diabetes, as well. Although insuli...

Use of a meter with memory in conjunction with computer-generated analyses of stored blood glucose test results can lead to improved glycemic control when used by a group of intensively treated adult diabetic patients. Improvement in glycemic control was related to frequency of blood glucose testing.