Background: Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system.Methods: To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide.Results: Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors <i>AT1</i> and <i>AT2</i>, proliferation marker of proliferation Ki-67 (<i>Mki-67</i>), proliferating cell nuclear antigen (<i>Pcna</i>), and cyclin D1 (<i>Ccnd1</i>), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of <i>Pcna</i>, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs.Conclusion: These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.
BACKGROUND The prevalence of type 1 diabetes (T1D) is increasing worldwide, with a much higher proportion of adult patients. However, achieving stable glycemic control is difficult in these patients. OBJECTIVE After periodic implementation of structured education for patients with T1D through the Home and Self-Care Program, a pilot home health care project promoted by the Korean government, we evaluated the program’s effects on glycemic control. METHODS This study was conducted from April 2020 to March 2023. We analyzed 119 participants with T1D aged >15 years. Nursing and nutrition education were provided separately up to 4 times per year, with physician consultation up to 6 times per year. A distinguishing feature of this study compared with previous ones was the provision of remote support using a general-purpose smartphone communication app offered up to 12 times annually on an as-needed basis to enhance the continuity of in-person education effects. Patients were followed up on at average intervals of 3 months for up to 24 months. The primary end point was the mean difference in glycated hemoglobin (HbA<sub>1c</sub>) at each follow-up visit from baseline. For continuous glucose monitoring (CGM) users, CGM metrics were also evaluated. RESULTS The mean HbA<sub>1c</sub> level of study participants was 8.6% at baseline (mean duration of T1D 10.02, SD 16.10 y). The HbA<sub>1c</sub> level reduction in participants who received at least 1 structured educational session went from 1.63% (SD 2.03%; <i>P</i><.001; adjustment model=1.69%, 95% CI 1.24%-2.13% at the first follow-up visit) to 1.23% (SD 1.31%; <i>P</i>=.01; adjustment model=1.28%, 95% CI 0.78%-1.79% at the eighth follow-up visit). In the adjustment model, the actual mean HbA<sub>1c</sub> values were maintained between a minimum of 7.33% (95% CI 7.20%-7.46% at the first follow-up visit) and a maximum of 7.62% (95% CI 7.41%-7.82% at the sixth follow-up visit). Among CGM users, after at least 1 session, the mean time in the target range was maintained between 61.59% (adjusted model, 95% CI 58.14%-65.03% at the second follow-up visit) and 54.7% (95% CI 50.92%-58.48% at the eighth follow-up visit), consistently staying above 54.7% (corresponding to an HbA<sub>1c</sub> level of <7.6%). The mean time below the target range (TBR) also gradually improved to the recommended range (≤4% for TBR of <70 mg/dL and ≤1% for TBR of <54 mg/dL). CONCLUSIONS The Home and Self-Care Program protocol for glycemic control in patients with T1D is effective, producing significant improvement immediately and long-term maintenance effects, including on CGM indexes.
Abstract Disclosure: H. Choe: None. Y. Ko: None. S. Moon: None. C.H. Ahn: None. K. Ha: None. H. Lee: None. J. Bae: None. H. Joo: None. H. Lee: None. J. Sohn: None. D. Kim: None. S. Kim: None. K. Kim: None. Y. Cho: None. Objective: To estimate the economic benefit of replacing non-renal dose adjusted (NRDA) dipeptidyl peptidase-4 (DPP4) inhibitors with renal dose adjusted (RDA) DPP4 inhibitors in patients with impaired kidney function and type 2 diabetes. Patients and Methods: This multicenter study analyzed a total of 67,964,996 prescription records of five teaching hospitals in Korea from January 1, 2012 to December 31, 2018 using a common data model. Prescription patterns of NRDA and RDA DPP4 inhibitors were subgrouped based on estimated glomerular filtration rate (eGFR) determined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: NRDA DPP4 inhibitors were more frequently prescribed to patients with impaired kidney function than those with preserved kidney function (25.7%, 51.3%, 64.3%, and 71.6% in patients with eGFR of ≥60, <60, <45, and <30 mL/min/1.73m2, respectively). When applying the prescription pattern of DPP4 inhibitors for patients with preserved kidney function to those with impaired kidney function, cost savings per year were 7.6% for eGFR <60 mL/min/1.73m2 and 30.4% for eGFR <30 mL/min/1.73m2. Assuming patients with impaired kidney function are solely prescribed with RDA DPP4 inhibitors with appropriate dose reduction, 15.4% to 51.2% per year could be saved depending on kidney impairment severity. Conclusion: NRDA DPP4 inhibitors are frequently prescribed in patients with type 2 diabetes and CKD. Prescribing RDA DPP4 inhibitors with doses adjusted to individual kidney function could alleviate the economic burden associated with medical expenditure. Presentation: Friday, June 16, 2023
Background The prognostic value of coronary computed tomographic angiography ( CCTA ) for evaluating coronary artery disease in asymptomatic older adults is controversial. We investigated the prognostic value of CCTA in community‐dwelling elderly Koreans. Methods and Results Participants (n=470; mean age: 75.1±7.3 years) who underwent CCTA were enrolled from KLoSHA (Korean Longitudinal Study on Health and Aging), a community‐based prospective cohort. Using CCTA , coronary artery disease was classified as normal, nonobstructive , or obstructive according to the presence of 0%, <50%, or ≥50% stenosis, respectively. Coronary artery calcium scores were investigated together with Framingham risk score, atherosclerotic cardiovascular disease score, and individual risk factors. Major adverse cardiac events ( MACE ) were defined as a composite of cardiac event–related death or nonfatal myocardial infarction. During a median follow‐up of 8.2 years (interquartile range: 7.7–10.1 years), MACE occurred in 24 participants (5.1%). Compared with the normal group, participants in the obstructive group showed higher incidence of MACE (hazard ratio: 5.65; 95% CI, 1.22–26.16; P =0.027), whereas there were no significant differences in MACE between the normal and nonobstructive groups. The 8‐year event‐free survival rates were 98.1±1.1%, 94.9±1.6%, and 81.7±4.8% in the normal, nonobstructive, and obstructive groups, respectively. Compared with the Framingham risk score and c oronary artery calcium score model, CCTA improved risk prediction by C‐index (from 0.698 to 0.749) and category‐free net reclassification index (0.478; P =0.022). Conclusions CCTA showed better long‐term prognostic value for MACE than coronary artery calcium score in this asymptomatic older population.
Background: In the Canadian TITRATION study, the INSIGHT algorithm was as effective as the EDITION algorithm for insulin dose titration in patients with type 2 diabetes. However, these algorithms have not been evaluated in Asian patients. Objective: To compare the efficacy and safety of two algorithms, the INSIGHT and EDITION, for insulin glargine 300 units/mL (Gla-300) in patients with uncontrolled type 2 diabetes treated with basal insulin Methods: The Korean TITRATION was a 12-week, single-center, open-label, randomized, treat-to-target, and pragmatic trial. We randomly assigned 130 patients to either the INSIGHT (self-titration by 1 unit/day) or EDITION (self-titration no more than every 3 days) groups to achieve a fasting self-monitored blood glucose (SMBG) in the range of 4.4 to 5.6 mmol/L. The primary endpoint was a proportion of patients reaching fasting SMBG ≤5.6 mmol/L without hypoglycemia. Results: A total of 129 patients were included in the study. At week 12, patients achieving the primary endpoint were 24.6% (INSIGHT) and 23.4% (EDITION) (P = 0.961). Fasting SMBG were 102.0 mg/dL (INSIGHT) and 111.2 mg/dL (EDITION) (P = 0.110). Proportions of patients with HbA1c ≤7% were 23.1% (INSIGHT) and 20.3% (EDITION) (P = 0.867). There was no difference in changes in fasting plasma glucose, HbA1c, and body weight between the two groups. Mean changes in total daily insulin doses were significantly higher in the INSIGHT group than in the EDITION group (12.83 units/day vs. 6.81 units/day, P = 0.030). However, the incidence of hypoglycemia was comparable between the two groups. In addition, adherence to the algorithm tended to be higher in the INSIGHT group than in the EDITION group (45.7% vs. 35.9%, P = 0.109). Conclusion: The self-titration of Gla-300 with the INSIGHT algorithm is effective and safe compared to that with the EDITION algorithm in Korean patients with uncontrolled type 2 diabetes. Disclosure J. Bae: None. C. Ahn: None. Y. Yang: None. S. Moon: None. S. Kwak: None. H. Jung: None. K. Park: None. Y. Cho: None.
Background: This study demonstrates the difference between glucose management indicator (GMI) and glycated hemoglobin (HbA 1c ) according to sensor mean glucose and HbA 1c status using 2 continuous glucose monitoring (CGM) sensors in people with type 1 diabetes. Methods: A total of 275 subjects (117 Dexcom G6 [G6] and 158 FreeStyle Libre 1 [FL]) with type 1 diabetes was included. The G6 and FL sensors were used, respectively, over 90 days to analyze 682 and 515 glycemic profiles that coincide with HbA 1c . Results: The mean HbA 1c was 6.6% in Dexcom G6 and 7.2% in FL profiles. In G6 profiles, GMI was significantly higher than HbA 1c irrespective of mean glucose (all P < .001, mean difference: 0.58% ± 0.49%). The GMI was significantly higher than the given HbA 1c when HbA 1c was below 8.0% (all P < .001). The discordance was the highest at 0.9% for lower HbA 1c values (5.0%-5.9%). The proportion of discordance >0.5% improved from 60.1% to 30.9% when using the revised GMI equation in G6 profiles. In FL profile, the overall mean difference between GMI and HbA 1c was 0 ( P = .966). The GMI was significantly lower by 0.9% than HbA 1c of 9.0% to 9.9% and higher by 0.5% in HbA 1c of 5.0% to 5.9% (all P < .001). Conclusions: The GMI is overestimated in G6 users, particularly those with well-controlled diabetes, but the GMI and HbA 1c discordance improved with a revised equation from the observed data. The FL profile showed greater discordance for lower HbA 1c levels or higher HbA 1c levels.
Background: To compare risk of diabetic retinopathy (DR) between patients taking sodium-glucose cotransporter-2 inhibitors (SGLT2is) and those taking glucagon-like peptide-1 receptor agonists (GLP1-RAs) in routine care.Methods: This retrospective cohort study emulating a target trial included patient data from the multi-institutional Chang Gung Research Database in Taiwan.Totally, 33,021 patients with type 2 diabetes mellitus using SGLT2is and GLP1-RAs between 2016 and 2019 were identified.3,249 patients were excluded due to missing demographics, age <40 years, prior use of any study drug, a diagnosis of retinal disorders, a history of receiving vitreoretinal procedure, no baseline glycosylated hemoglobin, or no follow-up data.Baseline characteristics were balanced using inverse probability of treatment weighting with propensity scores.DR diagnoses and vitreoretinal interventions served as the primary outcomes.Occurrence of proliferative DR and DR receiving vitreoretinal interventions were regarded as vision-threatening DR.Results: There were 21,491 SGLT2i and 1,887 GLP1-RA users included for the analysis.Patients receiving SGLT2is and GLP-1 RAs exhibited comparable rate of any DR (subdistribution hazard ratio [SHR], 0.90; 95% confidence interval [CI], 0.79 to 1.03), whereas the rate of proliferative DR (SHR, 0.53; 95% CI, 0.42 to 0.68) was significantly lower in the SGLT2i group.Also, SGLT2i users showed significantly reduced risk of composite surgical outcome (SHR, 0.58; 95% CI, 0.48 to 0.70).Conclusion: Compared to those taking GLP1-RAs, patients receiving SGLT2is had a lower risk of proliferative DR and vitreoretinal interventions, although the rate of any DR was comparable between the SGLT2i and GLP1-RA groups.Thus, SGLT2is may be associated with a lower risk of vision-threatening DR but not DR development.
There is a great need to discover factors that could protect pancreatic β-cells from apoptosis and thus prevent diabetes mellitus. Clusterin (CLU), a chaperone protein, plays an important role in cell protection in numerous cells and is involved in various cellular mechanisms, including autophagy. In the present study, we investigated the protective role of CLU through autophagy regulation in pancreatic β-cells.To identify the protective role of CLU, mouse insulinoma 6 (MIN6) cells were incubated with CLU and/or free fatty acid (FFA) palmitate, and cellular apoptosis and autophagy were examined.Treatment with CLU remarkably upregulated microtubule-associated protein 1-light chain 3 (LC3)-II conversion in a doseand time-dependent manner with a significant increase in the autophagy-related 3 (Atg3) gene expression level, which is a mediator of LC3-II conversion. Moreover, co-immunoprecipitation and fluorescence microscopy experiments showed that the molecular interaction of LC3 with Atg3 and p62 was markedly increased by CLU. Stimulation of LC3-II conversion by CLU persisted in lipotoxic conditions, and FFA-induced apoptosis and dysfunction were simultaneously improved by CLU treatment. Finally, inhibition of LC3-II conversion by Atg3 gene knockdown markedly attenuated the cytoprotective effect of CLU.Taken together, these findings suggest that CLU protects pancreatic β-cells against lipotoxicity-induced apoptosis via autophagy stimulation mediated by facilitating LC3-II conversion. Thus, CLU has therapeutic effects on FFA-induced pancreatic β-cell dysfunction.
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