- Email: [email protected]
Stigma and its Impact on Glucose Control among Youth with Diabetes, Feasibility Trial (STIGMA)
S72
Abstracts / Can J Diabetes 40 (2016) S27–S74
Table 1 Real-life treatment outcomes in patients initiating dapagliflozin
HbA1c (%) Weight (kg) SBP (mm Hg)
N
Baseline
3-month change
N
Baseline
6-month change
1226 1331 1331
8.6 (1.4) 90.6 (21.5) 127.0 (14.5)
‒0.9 (1.3)* ‒1.8 (2.7)* ‒3.2 (13.8)*
960 1027 1032
8.71 (1.3) 90.6 (21.0) 127.7 (14.0)
‒0.9 (1.3)* ‒2.0 (3.2)* ‒3.2 (14.8)*
Data is presented as mean (standard deviation). * Significantly different from baseline (p<0.05).
204 Stigma and its Impact on Glucose Control among Youth with Diabetes, Feasibility Trial (STIGMA) ANNE-SOPHIE BRAZEAU*, MICHAEL WRIGHT, MERANDA NAKHLA, DANIELE PACAUD, MELANIE HENDERSON, CONSTADINA PANAGIOTOPOULOS, ELHAM RAHME, DEBORAH DA COSTA, KABERI DASGUPTA Montreal, QC Aim: Stigma related to chronic disease is rejection, judgement or exclusion related to the chronic disease itself. We aimed to develop and validate an online questionnaire to address the issue of stigma and type 1 diabetes in adolescent and young adults. Methods: The questionnaire was developed and reviewed by a group of experts and a patient representative. The survey includes 60 close-ended questions on perceptions of stigma, glycemic control, well-being and sociodemographic information, as well as 4 openended questions addressing perceived causes and solutions for stigma. Thirty participants completed the questionnaire on 2 occasions. Test-retest reliability was assessed. Results: Participants (20% male) were 20.5 (SD 2.8) years of age (diabetes duration 9.2 [SD 5.1] years). First language was either French (37%) or English (63%) and participants were from 5 provinces (AB, SK, ON, QC, NB). Scales demonstrated high level intra-class correlation (barriers to diabetes adherence ICC=0.97 95% CI 0.93 to 0.98, stigma sub-scale ICC=0.94 95% CI 0.87 to 0.97, self-efficacy ICC 0.95 95%CI 0.90 to 0.98). Preliminary analyses of open-ended questions demonstrate a consistent concern (over half of respondents) about others lack of awareness regarding the differences between type 1 and type 2 diabetes. Conclusion: The questionnaire showed high test-retest reliability. We are using it in a Canadian Diabetes Association-funded study to evaluate the nation-wide prevalence of stigma in youth and young adults with type 1 diabetes. 205 Dapagliflozin is Associated with Improved Glycemia, Weight and Blood Pressure in a Real-World Clinical Setting NIKHIL GUPTA, RUTH E. BROWN, RONNIE ARONSON Markham, ON Aim: To investigate real-world clinical outcomes of dapagliflozin (Forxiga) in patients with type 2 diabetes (T2D). Methods: A retrospective registry analysis of T2D patients who initiated dapagliflozin in 2015. Results: 2114 patients were eligible for analysis (57.2±9.9 years; 56% male). Hemoglobin A1c (HbA1c), body weight and systolic blood pressure (SBP) were each significantly lower at 3 and 6 months (Table 1, above) (p<0.05). At follow up, 25% of patients were able to achieve HbA1c ≤7.0% vs. 6% at baseline. Higher HbA1c at baseline, shorter duration of T2D and male gender were each associated with greater HbA1c reduction (p<0.05). Concomitant insulin use was associated with a smaller reduction in HbA1c (p<0.01). Diastolic blood pressure, body mass index, fasting plasma glucose, total cholesterol, LDL cholesterol, triglycerides, non-HDL cholesterol and ALT were each also significantly lower (p<0.05).
Conclusions: In a real-world clinical setting, dapagliflozin produced significant improvements in HbA1c, weight and SBP, comparable to that seen in randomized clinical trials. 206 Statins Cause Interleukin-1β-Dependent Adipose Insulin Resistance via Lower Protein Prenylation BRANDYN HENRIKSBO*, JONATHAN SCHERTZER Hamilton, ON Statins cause interleukin (IL)-1β-dependent adipose insulin resistance via lower protein prenylation. Statins are 1 of the most widely prescribed drug classes because they lower cholesterol and reduce the risk of cardiovascular events. Statin-mediated inhibition of HMG-CoA reductase also lowers substrates required for protein prenylation. This cholesterol independent effect of statins can alter immune function. Lower protein prenylation can increase IL-1β. This pro-inflammatory cytokine can promote insulin resistance, which may be a factor in the recent evidence linking statins to increased incidence of diabetes. IL-1β is unique compared to most cytokines because it is regulated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome. We have already shown that statins cause NLRP3-dependent insulin resistance in fat tissue, but it was not known if this is due to cholesterol, prenylation or IL-1β-mediated inflammation. We hypothesized that statin-induced lowering of protein prenylation activates the NLRP3 inflammasome, which would cause IL-1βdependent insulin resistance in fat tissue. Mouse adipose explants were exposed to Atorvastatin (1 uM, 18 hours) with LPS (4 hours) followed by stimulation with insulin and quantification of the phosphorylation status of AKT. We showed that atorvastatin impaired insulin signalling in adipose tissue from WT, but not IL-1β‒/‒ mice. The isoprenoid, Geranylgeranylpyrophosphate (GGPP, 50 μM), prevented atorvastatin-induced defects in insulin signalling. Atorvastatin caused activation of the stress kinase JNK, which has been shown to inhibit insulin signalling. Our data suggests a statin-induced reduction in isoprenoids required for protein prenylation production impairs insulin action via a IL-1β-JNK mechanism in adipose tissue. 207 Conducting Ethically Robust Pediatric Diabetes Clinical Trials: Lessons from a Scoping Review STEPHANIE KOWAL*, LIZ DENNETT, TANIA BUBELA Edmonton, AB Background: Novel interventions, including cell therapies, are currently under investigation in adults with type 1 diabetes. As some clinical trials are beginning to recruit pediatric participants, it is timely to consider pediatric-specific ethical issues. Most pediatric trials require parental consent, which is influenced by disease severity, age of the child, trial risks, potential benefits and logistics. Adding to the complexity, ethics requirements and regulatory standards for design and conduct of pediatric trials are not harmonized internationally. Methods: We conducted a scoping review of ethical issues of pediatric trials using 8 peer-reviewed and grey literature databases. Of the 4962 articles returned, 238 empirical articles met our inclusion
Abstracts / Can J Diabetes 40 (2016) S27–S74
Table 1 Real-life treatment outcomes in patients initiating dapagliflozin
HbA1c (%) Weight (kg) SBP (mm Hg)
N
Baseline
3-month change
N
Baseline
6-month change
1226 1331 1331
8.6 (1.4) 90.6 (21.5) 127.0 (14.5)
‒0.9 (1.3)* ‒1.8 (2.7)* ‒3.2 (13.8)*
960 1027 1032
8.71 (1.3) 90.6 (21.0) 127.7 (14.0)
‒0.9 (1.3)* ‒2.0 (3.2)* ‒3.2 (14.8)*
Data is presented as mean (standard deviation). * Significantly different from baseline (p<0.05).
204 Stigma and its Impact on Glucose Control among Youth with Diabetes, Feasibility Trial (STIGMA) ANNE-SOPHIE BRAZEAU*, MICHAEL WRIGHT, MERANDA NAKHLA, DANIELE PACAUD, MELANIE HENDERSON, CONSTADINA PANAGIOTOPOULOS, ELHAM RAHME, DEBORAH DA COSTA, KABERI DASGUPTA Montreal, QC Aim: Stigma related to chronic disease is rejection, judgement or exclusion related to the chronic disease itself. We aimed to develop and validate an online questionnaire to address the issue of stigma and type 1 diabetes in adolescent and young adults. Methods: The questionnaire was developed and reviewed by a group of experts and a patient representative. The survey includes 60 close-ended questions on perceptions of stigma, glycemic control, well-being and sociodemographic information, as well as 4 openended questions addressing perceived causes and solutions for stigma. Thirty participants completed the questionnaire on 2 occasions. Test-retest reliability was assessed. Results: Participants (20% male) were 20.5 (SD 2.8) years of age (diabetes duration 9.2 [SD 5.1] years). First language was either French (37%) or English (63%) and participants were from 5 provinces (AB, SK, ON, QC, NB). Scales demonstrated high level intra-class correlation (barriers to diabetes adherence ICC=0.97 95% CI 0.93 to 0.98, stigma sub-scale ICC=0.94 95% CI 0.87 to 0.97, self-efficacy ICC 0.95 95%CI 0.90 to 0.98). Preliminary analyses of open-ended questions demonstrate a consistent concern (over half of respondents) about others lack of awareness regarding the differences between type 1 and type 2 diabetes. Conclusion: The questionnaire showed high test-retest reliability. We are using it in a Canadian Diabetes Association-funded study to evaluate the nation-wide prevalence of stigma in youth and young adults with type 1 diabetes. 205 Dapagliflozin is Associated with Improved Glycemia, Weight and Blood Pressure in a Real-World Clinical Setting NIKHIL GUPTA, RUTH E. BROWN, RONNIE ARONSON Markham, ON Aim: To investigate real-world clinical outcomes of dapagliflozin (Forxiga) in patients with type 2 diabetes (T2D). Methods: A retrospective registry analysis of T2D patients who initiated dapagliflozin in 2015. Results: 2114 patients were eligible for analysis (57.2±9.9 years; 56% male). Hemoglobin A1c (HbA1c), body weight and systolic blood pressure (SBP) were each significantly lower at 3 and 6 months (Table 1, above) (p<0.05). At follow up, 25% of patients were able to achieve HbA1c ≤7.0% vs. 6% at baseline. Higher HbA1c at baseline, shorter duration of T2D and male gender were each associated with greater HbA1c reduction (p<0.05). Concomitant insulin use was associated with a smaller reduction in HbA1c (p<0.01). Diastolic blood pressure, body mass index, fasting plasma glucose, total cholesterol, LDL cholesterol, triglycerides, non-HDL cholesterol and ALT were each also significantly lower (p<0.05).
Conclusions: In a real-world clinical setting, dapagliflozin produced significant improvements in HbA1c, weight and SBP, comparable to that seen in randomized clinical trials. 206 Statins Cause Interleukin-1β-Dependent Adipose Insulin Resistance via Lower Protein Prenylation BRANDYN HENRIKSBO*, JONATHAN SCHERTZER Hamilton, ON Statins cause interleukin (IL)-1β-dependent adipose insulin resistance via lower protein prenylation. Statins are 1 of the most widely prescribed drug classes because they lower cholesterol and reduce the risk of cardiovascular events. Statin-mediated inhibition of HMG-CoA reductase also lowers substrates required for protein prenylation. This cholesterol independent effect of statins can alter immune function. Lower protein prenylation can increase IL-1β. This pro-inflammatory cytokine can promote insulin resistance, which may be a factor in the recent evidence linking statins to increased incidence of diabetes. IL-1β is unique compared to most cytokines because it is regulated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome. We have already shown that statins cause NLRP3-dependent insulin resistance in fat tissue, but it was not known if this is due to cholesterol, prenylation or IL-1β-mediated inflammation. We hypothesized that statin-induced lowering of protein prenylation activates the NLRP3 inflammasome, which would cause IL-1βdependent insulin resistance in fat tissue. Mouse adipose explants were exposed to Atorvastatin (1 uM, 18 hours) with LPS (4 hours) followed by stimulation with insulin and quantification of the phosphorylation status of AKT. We showed that atorvastatin impaired insulin signalling in adipose tissue from WT, but not IL-1β‒/‒ mice. The isoprenoid, Geranylgeranylpyrophosphate (GGPP, 50 μM), prevented atorvastatin-induced defects in insulin signalling. Atorvastatin caused activation of the stress kinase JNK, which has been shown to inhibit insulin signalling. Our data suggests a statin-induced reduction in isoprenoids required for protein prenylation production impairs insulin action via a IL-1β-JNK mechanism in adipose tissue. 207 Conducting Ethically Robust Pediatric Diabetes Clinical Trials: Lessons from a Scoping Review STEPHANIE KOWAL*, LIZ DENNETT, TANIA BUBELA Edmonton, AB Background: Novel interventions, including cell therapies, are currently under investigation in adults with type 1 diabetes. As some clinical trials are beginning to recruit pediatric participants, it is timely to consider pediatric-specific ethical issues. Most pediatric trials require parental consent, which is influenced by disease severity, age of the child, trial risks, potential benefits and logistics. Adding to the complexity, ethics requirements and regulatory standards for design and conduct of pediatric trials are not harmonized internationally. Methods: We conducted a scoping review of ethical issues of pediatric trials using 8 peer-reviewed and grey literature databases. Of the 4962 articles returned, 238 empirical articles met our inclusion