Steve Edelman

Effects of Vitamin E on Susceptibility of Low-Density Lipoprotein and Low-Density Lipoprotein Subfractions to Oxidation and on Protein Glycation in NIDDM

OBJECTIVE To evaluate the effect of vitamin E supplementation on the susceptibility of low-density lipoprotein (LDL) and LDL subfractions to oxidation and on protein glycation in non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Twenty-one men with NIDDM (HbA1c = 6-10%), ages 50–70, were randomly assigned to either 1,600 IU/day of vitamin E or placebo for 10 weeks after a 4-week placebo period. LDL and LDL subfractions were isolated after 4 weeks of placebo and after 6 and 10 weeks of therapy. Susceptibility of LDL to copper-mediated oxidation was measured by conjugated diene formation (lag time) and formation of thiobarbituric acid-reactive substances (TBARS). Fasting serum glucose, mean weekly blood glucose, HbA1c, and glycated plasma protein concentrations were also determined at these time points. RESULTS Vitamin E content in plasma and LDL increased 4.0- and 3.7-fold, respectively, in the vitamin E-treated group. Vitamin E decreased the susceptibility of LDL to oxidation in comparison with placebo (lag time, 243 ± 46 vs. 151 ± 22 min, P < 0.01; 3 h TBARS, 24 ± 12 vs. 66 ± 18 nmol malondialdehyde/mg LDL, P < 0.05). Vitamin E content also increased significantly in both buoyant and dense LDL subfractions, and their oxidation was dramatically reduced. The lag time of LDL oxidation correlated well with the content of vitamin E in both LDL and its subfractions (r = 0.69–0.92). Glycemic indexes did not change significantly in either group during the study. Protein glycation, including glycated hemoglobin, glycated albumin, glycated total plasma proteins, and glycated LDL were unchanged in the vitamin E group. CONCLUSIONS Supplementation of vitamin E in NIDDM leads to enrichment of LDL and LDL subfractions and reduced susceptibility to oxidation. Despite a greater percentage increase in vitamin E content in small dense LDL, it remained substantially more susceptible to oxidation than was buoyant LDL. This suggests that dense, LDL may gain less protection against oxidation from antioxidant supplementation than does larger, more buoyant LDL. In contrast to previous reports, vitamin E supplementation did not reduce glycation of intracellular or plasma proteins.

CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes.

Previous cross-sectional analyses demonstrated that CD8(+) and CD4(+) T-cell reactivity to islet-specific antigens was more prevalent in T1D subjects than in healthy donors (HD). Here, we examined T1D-associated epitope-specific CD4(+) T-cell cytokine production and autoreactive CD8(+) T-cell frequency on a monthly basis for one year in 10 HD, 33 subjects with T1D, and 15 subjects with T2D. Autoreactive CD4(+) T-cells from both T1D and T2D subjects produced more IFN-γ when stimulated than cells from HD. In contrast, higher frequencies of islet antigen-specific CD8(+) T-cells were detected only in T1D. These observations support the hypothesis that general beta-cell stress drives autoreactive CD4(+) T-cell activity while islet over-expression of MHC class I commonly seen in T1D mediates amplification of CD8(+) T-cells and more rapid beta-cell loss. In conclusion, CD4(+) T-cell autoreactivity appears to be present in both T1D and T2D while autoreactive CD8(+) T-cells are unique to T1D. Thus, autoreactive CD8(+) cells may serve as a more T1D-specific biomarker.

AUTONOMY: The first randomized trial comparing two patient-driven approaches to initiate and titrate prandial insulin lispro in type 2 diabetes

OBJECTIVE To compare two self-titration algorithms for initiating and escalating prandial insulin lispro in patients with type 2 diabetes inadequately controlled on basal insulin. RESEARCH DESIGN AND METHODS The trial was designed as two independent, multinational, parallel, open-label studies (A and B), identical in design, to provide substantial evidence of efficacy and safety in endocrine and generalist settings. Subjects were 18–85 years old (study A: N = 528; study B: N = 578), on basal insulin plus oral antidiabetic drugs for ≥3 months, and had an HbA1c 7.0% to ≤12.0% (>53.0 to ≤107.7 mmol/mol). Once optimized on insulin glargine, subjects were randomized to one of two self-titration algorithm groups adjusting lispro either every day (Q1D) or every 3 days (Q3D) for 24 weeks. The primary outcome was the change in HbA1c from baseline. The primary and secondary objectives were evaluated for the overall population and subjects ≥65 years old. RESULTS Baseline HbA1c was similar (study A: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.453; study B: Q1D 8.3% [67.2 mmol/mol] vs. Q3D 8.4% [68.3 mmol/mol], P = 0.162). Both algorithms had significant and equivalent reductions in HbA1c from baseline (study A: Q3D –0.96% [–10.49 mmol/mol], Q1D –1.00% [–10.93 mmol/mol], Q3D–Q1D 0.04% [0.44 mmol/mol] [95% CI –0.15 to 0.22 (–1.64 to 2.40)]; study B: Q3D –0.92% [–10.06 mmol/mol], Q1D –0.98% [–10.71 mmol/mol], Q3D–Q1D 0.06% [0.66 mmol/mol] [95% CI –0.12 to 0.24 (–1.31 to 2.62)]). The incidence and rate of hypoglycemia were similar for Q3D and Q1D in both studies. In general, no clinically relevant differences were found between the two algorithms in subjects ≥65 years old in either study. CONCLUSIONS Prandial insulin lispro can effectively and safely be initiated, by either of two self-titrated algorithms, in a variety of practice settings.

Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus

To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM).

Comparative Assessment of Lixisenatide, Exenatide, and Liraglutide Pen Devices A Pilot User-Based Study

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively recent addition to the treatment options for type 2 diabetes mellitus (T2DM) and are administered using prefilled pen devices. Method: In this open-label task and interview-based pilot study, 3 GLP-1 receptor agonist pen devices—exenatide (Byetta®, Bristol-Myers Squibb/AstraZeneca), liraglutide (Victoza®, Novo Nordisk), and lixisenatide (Lyxumia®, Sanofi-Aventis)—were comparatively assessed in a randomized order in 30 participants with T2DM for ease of use, using a series of key performance measures (time taken to complete a series of tasks, number of user errors [successful performance], and user satisfaction rating). Linear and logistic regression analysis was conducted for the lixisenatide and liraglutide pens versus the exenatide pen. Participants’ mean age was 60 years; 27% and 20% of the participants had visual impairments and reduced manual dexterity, respectively. Results: Tasks were completed faster (P < .001) and with higher successful performance (P = .001) with the lixisenatide pen than with the exenatide pen, whereas the liraglutide pen was not statistically significant versus the exenatide pen on these parameters. Overall, user satisfaction was statistically higher for the lixisenatide and liraglutide pens versus the exenatide pen (P < .001 for both). Conclusions: Lixisenatide and liraglutide pens are associated with higher user satisfaction compared with the exenatide pen. In addition, the lixisenatide pen is faster and results in fewer errors than its comparator (exenatide). The lixisenatide pen may therefore be a suitable choice for patients with T2DM, including older and pen device-naïve patients, and those with visual impairments and reduced manual dexterity.

Control of type 2 diabetes after 1 year of laparoscopic adjustable gastric banding in the helping evaluate reduction in obesity (HERO) study

The 5‐year, open‐label, prospective, observational helping evaluate reduction in obesity (HERO) study (N = 1106) examines efficacy and safety of the LAP‐BAND AP® laparoscopic adjustable gastric band (LAGB) in obese patients. This interim analysis assessed the control of type 2 diabetes (T2D), 1 year after the implantation of the LAGB.

Insights into optimal basal insulin titration in type 2 diabetes: results of a quantitative survey

Basal insulin (BI) treatment initiation and dose titration in type 2 diabetes (T2DM) are often delayed. Such “clinical inertia” results in poor glycaemic control and high risk of long‐term complications. This survey aimed to determine healthcare professional (HCP) and patient attitudes to BI initiation and titration.

Temporal Intra-Individual Variation of Immunological Biomarkers in Type 1 Diabetes Patients: Implications for Future Use in Cross-Sectional Assessment

Multiple immune parameters such as frequencies of autoreactive CD4+, CD8+ T-cells and CD4+CD25+Foxp3+ T-cells have been explored as biomarkers in human T1D. However, intra-individual temporal variation of these parameters has not been assessed systematically over time. We determined the variation in each of these parameters in a cohort of T1D and healthy donors (HDs), at monthly intervals for one year. Despite low intra- and inter-assay co-efficient of variation (CV), mean CVs for each of the immune parameters were 119.1% for CD4+ T-cell-derived IFN-γ, 50.44% for autoreactive CD8+ T-cells, and 31.24% for CD4+CD25+Foxp3+ T-cells. Further, both HDs and T1D donors had similar CVs. The variation neither correlated with BMI, age, disease duration or insulin usage, nor were there detectable cyclical patterns of variation. However, averaging results from multiple visits for an individual provided a better estimate of the CV between visits. Based on our data we predict that by averaging values from three visits a treatment effect on these parameters with a 50% effect size could be detected with the same power using 1.8–4-fold fewer patients within a trial compared to using values from a single visit. Thus, our present data contribute to a more robust, accurate endpoint design for future clinical trials in T1D and aid in the identification of truly efficacious therapies.

Response to Comment on Edelman et al. AUTONOMY: The First Randomized Trial Comparing Two Patient-Driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes. Diabetes Care 2014;37:2132–2140

We thank Drs. Rodbard and Karolicki for their commentary (1) to clarify key points related to the FullSTEP study discussed in our article (2), in particular, the use of self-titration algorithms to adjust prandial insulin dose. The FullSTEP (3) study and AUTONOMY (Study of Insulin Lispro in Participants With Inadequately Controlled Type 2 Diabetes) (2) trial highlight the importance of patient involvement in care and the effectiveness of self-titration of prandial insulin doses. In this regard, the two studies complement each other, supporting patient-centric approaches to insulin therapy intensification. We appreciate that the authors of FullSTEP have taken this opportunity to reinforce how a patient-centric approach to insulin therapy …