bluuebunny/crossref_metadata_2025_split huggingface dataset:
461-P: Treatment with Mild Electrical Stimulation + Heat Shock (MET) Suppresses the Progression of Atherosclerosis in ApoE-Deficient Mice
Authors: YOSHIZUMI RINTARO , KONDO TATSUYA , WATANABE TAKURO , MIYAKAWA NOBUKAZU 
Published: June 2023

[Purpose] We have previously reported that mild electrical stimulation + heat shock (MET) treatment promotes the expression of heat shock protein 72 (HSP72), which works as molecular chaperone to suppresses oxidative stress, JNK activity and mitochondrial dysfunction, and thus ameliorates insulin resistance and hyperglycemia. Macrophage polarity and atherogensis with MET were investigated.[Methods] RAW264.7 and mouse bone marrow-derived macrophages (BMM) were treated with MET (42°C, 55 pulses/sec, 0.1 ms duration) and LPS 1 ng/mL. Six-week-old HSP+/+/ApoE-/- and HSP-/-/ApoE-/- mice were given a high-fat diet (HFD) for 14 weeks, and Sham/MET treatment was started from 10 weeks of age onwards. Glucose tolerance, biochemical parameters were examined, and the degree of arteriosclerosis (AS) formation and oxidative stress were evaluated histologically in aorta. [Results] After MET treatment in RAW264.7, HSP72 mRNA was increased, and LPS-stimulated MCP-1 and iNOS expression and JNK phosphorylation were all decreased. Experiment using BMM showed similar results with RAW264.7. There were no significant differences in physiologocal and metabolic parameters between Sham and MET groups after HFD. Compared with the MET group of HSP-/-/ApoE-/- mice, the degree of AS formation, necrotic core and fibrous capsule thickness were all significantly decreased in the MET group of HSP+/+/ApoE-/- mice. However, no beneficial effects were observed either in Sham or MET in HSP-/-/ApoE-/- mice. Immunostaining of the plaque showed significant suppression of 4-HNE and F4/80 in the HSP+/+/ApoE-/- mice treated with MET compared to those with Sham. Neither Sham nor MET had an inhibitory effect of 4-HNE and F4/80 in HSP-/-/ApoE-/- mice.[Conclusion] The enhancement of HSP72 expression by MET showed anti-inflammatory effect by polarity changes in macrophages and suppression of oxidative stress, which may lead to the suppression of atherosclerosis.

Disclosure
R.Yoshizumi: None. T.Kondo: None. T.Watanabe: None. N.Miyakawa: None.
462-P: DPP-4 Deficiency Suppresses the Progression of Atherosclerosis via Inducing M2 Macrophage Polarization
Authors: ZHOU YUQI , MATSUMURA TAKESHI , YAGI YOSHITAKA , YOSHINAGA TOMOAKI , SENOKUCHI TAKAFUMI , ISHII NORIO , KONDO TATSUYA , ARAKI EIICHI 
Published: June 2023

Background: Dipeptidyl peptidase-4 (DPP4) inhibitors suppressed progression of atherosclerosis in atherosclerotic mouse models. However, the role of DPP4 on the progression of atherosclerosis is not clear. We investigated the effect of DPP4 deficiency on the progression of atherosclerosis in DPP4 and apolipoprotein-E double knockout (DPP4/ApoE-DKO) mice.
Methods: Both ApoE-KO mice and DPP4/ApoE-DKO mice were fed with normal chow until 20 weeks of age. Whole aorta and aortic sinus were stained with Oil red O. Bone marrow-derived macrophages (mφ) from wildtype or DPP4-KO mice were used in in vitro study. Expression of iNOS, MCP-1, TNF-α and IL-1β (M1 markers), and arginase-1, Mgl2 and Ym1 (M2 markers) mRNA were evaluated by real-time RT-PCR, and mφ polarization was evaluated by flowcytometry.
Results: There were no differences on food intake, body weight, lipid profiles and the blood glucose levels by insulin tolerance test between each group, but the blood glucose levels by glucose tolerance test were significantly decreased in DPP4/ApoE-DKO mice. Oil-Red-O staining demonstrated that the size of atherosclerotic lesions was significantly smaller in DPP4/ApoE-DKO mice. In in vitro assay, LPS+IFNγ induced the mRNA expression of M1 markers and there was no difference between wildtype mφ and DPP4-KO mφ. On the other hand, the mRNA expression of M2 markers were significantly increased in DPP4-KO mφ. Flowcytometry revealed that the number of iNOS (M1 marker)-positive cells were increased by LPS+IFNγ, which was comparable between wildtype mφ and DPP4-KO mφ. On the other hand, the number of CD206 (M2 marker)-positive cells was higher in DPP4-KO mφ than that in wildtype mφ.
Conclusion: This study suggests that DPP4 deficiency suppresses the progression of atherosclerosis in apoE-KO mice. Moreover, DPP4 deficiency increases the polarization of M2 mφ. These findings may indicate the involvement of DPP4 at least in part on the development of diabetic macrovascular complications.

Disclosure
Y.Zhou: None. T.Matsumura: Research Support; Shimadzu Corporation, Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc. Y.Yagi: None. T.Yoshinaga: None. T.Senokuchi: None. N.Ishii: None. T.Kondo: None. E.Araki: Research Support; Eli Lilly Japan K.K., Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Speaker's Bureau; AstraZeneca, Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Sumitomo Pharma Co., Ltd., Daiichi Sankyo, Novo Nordisk Pharma Ltd.
466-P: Appendicular Skeletal Muscle Mass and Grip Strength in Relation to the Progression of Carotid Plaque Score in Patients with Type 2 Diabetes
Authors: YEL SHIN JANG 
Published: June 2023

Sarcopenia is suggested to be associated with increased cardiovascular (CV) risk and mortality in old adults. We investigated longitudinal associations of appendicular skeletal muscle mass (ASM) and hand grip strength (GS) with carotid plaque score progression (PSP) in patients with type 2 diabetes (T2D). A total of 1507 patients with T2D were recruited from January 2018 to June 2020 in the out-patients clinic. Finally, 1187 patients (Mean age = 62.6 ± 9.7 years, BMI=25.1 ± 3.4 kg/m2) completed the follow-up (fu) study. Mean fu duration (fuD) was 3.5±0.9 years. ASM and GS were measured at baseline using dual-energy X-ray absorptiometry and digital dynamometer. Carotid PS (0 to 12) was measured at baseline and fu (after≥2 years). PSP was defined as PS at fu≥1 point increase compared with one at baseline. Out of 1187 patients, 389 patients (32.8%) had PSP. Mean PS were 2.9 ± 2.8 and 3.4 ± 3.2 at baseline and fu. Patients with PSP were more likely to be old, male, and hypertensive and had higher systolic BP, diabetes duration, intima-medial thickness, and PS, but lower diastolic BP, HDL cholesterol, eGFR, ASM/BMI, and GS than those without PSP. Prevalence of PSP increased progressively with decreasing ASM/BMI and GS terile (Highest vs. Middle vs. Lowest=18.5% vs. 30.8% vs. 49.0% and 18.0% vs. 30.9% vs. 50.1%, p &lt; 0.001). The hazard ratios and 95% CI for PSP after adjusting for age and sex were 1.53 (1.08 - 2.16) and 2.90 (2.06 - 4.08) in the middle and the lowest ASM/BMI tertile groups and 1.50 (1.06 - 2.14) and 2.66 (1.85 - 3.84) in the middle and the lowest GS tertile groups. The association of ASM/BMI and GS with PSP remained significant after further adjusting for multiple potential confounders. This study showed that low baseline ASM/BMI and low GS were longitudinally associated with PSP in patients with T2D regardless of variable metabolic and CV risk factors. Our findings suggest that low muscle mass and strength may be predicting factors for PSP.

Disclosure
J.Shin: None.
468-P: Use of New Glucose-Lowering Drugs and the Risk of Major Adverse Cardiovascular Events in People with Type 2 Diabetes and Prior Stroke
Authors: HYUN BAE JAE , CHOI JIMI , HOON KIM NAM , GON KIM SIN 
Published: June 2023

Background: It remains uncertain whether the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and incretin-based drugs is associated with a reduced risk of major adverse cardiovascular events (MACE) compared with that of thiazolidinediones (TZDs) in people with type 2 diabetes and stroke.
Objectives: To compare the effectiveness of SGLT2is, incretin-based drugs, and TZDs on MACE in people with type 2 diabetes and prior stroke.
Methods: We did a population-based cohort study involving 117,355 individuals who underwent health checkups under the Korean National Health Insurance Service from 2014 to June 2021 and followed up until December 2021. The primary outcome was MACE, defined as a composite of myocardial infarction, ischemic stroke, and all-cause death. We used propensity score weighting for balancing baseline covariates between treatment groups. Weighted cox proportional regression analyses were used to estimate the association of treatments with MACE after adjusting confounders.
Results: In a new-user cohort, the incidence rate of MACE was 547, 679, and 625 per 1,000 person-years in the SGLT2i, incretin-based drug, and TZD groups, respectively. Compared with the TZD group, the risk of MACE was significantly reduced in the SGLT2i group (adjusted hazard ratio [HR] 0.87; 95% CI 0.79-0.96) but increased in the incretin-based drug group (adjusted HR 1.11; 95% CI 1.03-1.19). No significant differences were observed in the risk of myocardial infarction and ischemic stroke between the groups. The risk of all-cause death was significantly increased in the incretin-based drug group (adjusted HR 1.14; 95% CI 1.03-1.25) compared with the TZD group.
Conclusion: In this population-based study of people with type 2 diabetes and stroke, SGLT2is were associated with a reduced risk of MACE compared with incretin-based drugs and TZDs. Incretin-based drugs were associated with an increased risk of MACE compared with TZDs.

Disclosure
J.Bae: None. J.Choi: None. N.Kim: None. S.Kim: None.
476-P: Analysis of Upstream Signaling Pathway of Erk2 following Transient High-Glucose Exposure in Coronary Artery Endothelial Cells
Authors: OKADA JUNICHI , YAMADA EIJIRO , SAITO TSUGUMICHI , OKADA SHUICHI 
Published: June 2023

Using an experimental approach, we investigated the mechanisms by which brief high-glucose exposure activates extracellular signal-regulated kinase 2 (Erk2) in cultured human coronary artery endothelial cells. The cells were cultured in standard medium for 14 days (5.5 mM D-glucose). Thereafter, transient glucose elevation was achieved by adding either 183 mg/dL L-glucose or 183 mg/dL D-glucose to the culture medium for 1 h. The Erk2 activation status was measured by western blot analysis of phospho-Erk2. As part of the analysis of the upstream signaling pathway of Erk2, Rap1 and Ras activation status were examined. Furthermore, guanine nucleotide-binding protein G (i) α2 (Giα2) protein and microRNA-138 (miR-138) levels were measured. Ras and Erk2 were activated, whereas Rap1 was deactivated following addition of 183 mg/dL D-glucose to the culture medium and incubation for 1 h. Furthermore, Giα2 protein levels increased and miR-138 levels decreased. The addition of 183 mg/dL L-glucose did not affect the results. In general, our findings suggest that transient exposure to high amounts of D-glucose decreased miR-138 levels, resulting in an increase in Giα2 protein levels, Rap1 deactivation, Ras activation, and Erk2 activation. Here we report a novel mechanism that links transient high-glucose levels to Erk2 activation in cultured human coronary artery endothelial cells.

Disclosure
J.Okada: None. E.Yamada: None. T.Saito: None. S.Okada: None.
478-P: Brain Volume Changes after Long-Term Opioid Treatment in Painful Diabetic Peripheral Neuropathy
Authors: SLOAN GORDON P. , TEH KEVIN , RAPPAI SHILLO PALLAI , TESFAYE SOLOMON , SELVARAJAH DINESH , WILKINSON IAIN D. 
Published: June 2023

Aim: Opioid medications are commonly used to treat Painful-Diabetic Peripheral Neuropathy (Painful-DPN). However, opioids are associated with significant adverse effects, including prescription opioid use disorder which has reached epidemic proportions in the United States. There is an urgent need to determine the effect of long-term opioid treatment (&gt;6-months) on cerebral structure in Painful-DPN.
Methods: A total of 56 participants with Painful-DPN were recruited (17 on long-term opioid treatment [O+] and 39 not on opioid treatment [O-]). Participants underwent detailed clinical and neurophysiological assessments and cerebral imaging (3T, Phillips Medical Systems, Holland). Brain morphometric analysis was performed using Freesurfer.
Results: O+ participants were prescribed: codeine (n=3, 18%), tramadol (n=5, 29%), morphine modified release (n=1, 6%), buprenorphine (n=1, 6%), and combination treatment (n=5, 29%). O+ participants had a longer duration of diabetes, greater HbA1c, higher pain severity and higher scores on Hospital Anxiety and Depression scales compared to the O- group. Participants in the O+ group had a greater mean caudate volume (O+ 3.5mL ± 0.4; O- 3.2 ± 0.4mL, p=0.034); mean insula volume (O+ 6.3 ± 0.8; O- 5.9 ± 0.6, p=0.049) and mean insular vertices (O+ 3,286 ± 411; O- 3055 ± 282, p=0.018).
Conclusion: This is the first study to examine the impact of long-term opioid use on cerebral structure in Painful-DPN. Our findings suggest that chronic opioid use may alter affective/attentional pain processing (insular cortex) and brain regions associated with binge/intoxication (caudate nucleus). These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure in Painful-DPN. Clearer clinical utility will come from future longitudinal modelling of the prognostic characteristics of opioid use disorder from the neuroimaging features identified in this study.

Disclosure
G.P.Sloan: None. K.Teh: None. P.Shillo: None. S.Tesfaye: Advisory Panel; Bayer Inc., Wörwag Pharma GmbH & Co. KG, Angelini, Speaker's Bureau; Viatris Inc., Nevro Corp., Procter & Gamble, Novo Nordisk, Berlin-Chemie AG. D.Selvarajah: None. I.D.Wilkinson: None.

Funding
European Foundation for the Study of Diabetes; Novartis Knowledge Exchange Support Fund (X/162218); Efficacy and Mechanism Evaluation Programme (NIHR129921); Medical Research Council/National Institute for Health Research Partnership
479-P: Natural Course of Declining Nerve Function during the First 10 Years of Well-Controlled Type 2 Diabetes
Authors: STROM ALEXANDER , STRASSBURGER KLAUS , SIPOLA GUNDEGA , ZIEGLER DAN , WAGNER ROBERT , RODEN MICHAEL , BÖNHOF GIDON J. ,   GDS GROUP
Published: June 2023

There is a lack of evidence on the long-term changes of nerve function in individuals with type 2 diabetes (T2D) compared to those with normal glucose tolerance (NGT). Therefore, we assessed motor and sensory nerve conduction velocities (MNCV, SNCV), sensory nerve action potentials, vibration perception threshold (VPT) and thermal detection threshold of lower extremities in 45 individuals with T2D (known diabetes duration [mean±SD]: 164±95 days) and NGT from the German Diabetes Study (GDS) at baseline (BL) and 5-year follow-up. Individuals were matched pairwise for age (T2D/NGT: 52.9±10.4/52.9±10.3 years) and sex (64/64% male). In addition, 103 individuals with T2D were followed over 10 years. At BL, 1/6 indices was lower in T2D vs NGT (peroneal MNCV: 45.6±4.0 vs 47.2±2.8 m/s; P&lt;0.05). After five years, one index deteriorated in T2D (peroneal MNCV: 45.3±4.1 vs 43.5±3.8 m/s) and one in NGT (malleolar VPT: 1.29±1.88 vs 2.25±3.06 µm) (all P&lt;0.05). After adjustment for BL values and pairwise matching, nerve function similarly declined over the first five years in T2D and NGT (e.g. Δperoneal MNCV; figure). A comparable deterioration was observed in individuals with T2D over 10 years (figure). Parallel decline in small and large fiber function in both NGT and well controlled T2D indicates that the main events leading to impaired nerve function in well controlled T2D might occur earlier than previously assumed.

Disclosure
A.Strom: None. K.Strassburger: None. G.Sipola: None. D.Ziegler: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a.

Funding
German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research
48-LB: Changes in Plasma Levels of Nonnutritive Sweetener Erythritol Are Related to Two-Year Changes of Insulin Sensitivity in Response to Weight-Loss Diets—The POUNDS Lost trial
Authors: HEIANZA YORIKO , XUE QIAOCHU , ROOD JENNIFER , BRAY GEORGE , SACKS FRANK , QI LU 
Published: June 2023

Evidence on the benefits of non-nutritive sweeteners for weight management and improving insulin sensitivity and glucose metabolism is inconsistent. Recently, high levels of circulating erythritol, a sugar alcohol used as one of the non-nutritive sweeteners, have been linked to increased risks of type 2 diabetes and its vascular complications. Whether changes in circulating erythritol levels are related to insulin sensitivity and glucose metabolism remains unknown. Here, we investigated whether changes in plasma erythritol induced by weight-loss diet interventions were related to improved insulin sensitivity and glucose metabolism. This study included overweight or obese participants without diabetes or unstable cardiovascular disease from the POUNDS Lost trial with available data on circulating erythritol at baseline (n=805) and its changes from baseline to 6 months (n=670) and 2 years (n=533) during weight-loss diet interventions. At baseline, higher plasma levels of erythritol were related to hyperinsulinemia and greater degrees of insulin resistance assessed by HOMA-IR, even after adjusting for covariates, including BMI (P &lt;0.05 for all). In response to weight-loss dietary interventions, a greater decrease in plasma erythritol was significantly associated with larger reductions of fasting insulin (p= 0.0001) and HOMA-IR (p=0.039) at 6 months, regardless of the initial levels of BMI, erythritol, and the respective outcome. Similarly, we found a significant association between long-term changes in erythritol and a 2-year reduction of fasting insulin (p=0.0027).
In conclusion, circulating plasma erythritol, a marker of non-nutritive sweetener consumption, was significantly associated with hyperinsulinemia and insulin sensitivity among adults with overweight or obesity. Weight-loss diet-induced decreases in plasma erythritol were related to improved insulin sensitivity.

Disclosure
Y. Heianza: None. Q. Xue: None. J. Rood: None. G. Bray: Advisory Panel; Medifast, Inc., Herbalife International of America, Inc. F. Sacks: None. L. Qi: None.

Funding
National Institutes of Health (DK091718, DK100383, DK115679, 2P20GM109036-06A1-7233)
483-P: Heterogeneous Treatment Effects of Metformin on the Risk of Dementia in People with Type 2 Diabetes—A Longitudinal Observational Study
Authors: TANG HUILIN , GUO JINGCHUAN , ELIZABETH SHAABAN C. , FENG ZHENG , WU YONGHUI , MAGOC TANJA , DONAHOO WILLIAM T. , DEKOSKY STEVEN T. , BIAN JIANG 
Published: June 2023

Background: Previous studies have reported conflicting results on the association between metformin and risk of dementia which might be caused by varied drug responses of metformin in different population subgroups. We aimed to examine the heterogeneous treatment effects (HTEs) of metformin on dementia risk in the population with type 2 diabetes (T2D).
Method: Using 2005-2021 data from the National Alzheimer’s Coordinating Center (NACC), we identified individuals with diabetes (≥50 years old, ≥2 clinic visits) and normal cognition at baseline. The primay outcome was incident dementia. We applied a causal machine learning approach - doubly robust learning - to estimate the conditional average treatment effects (CATEs) in the overall cohort and then the HTE subgroups based on the identified important features using a summary decision tree model.
Results: Of 1,505 individuals with T2D, 822 (55%) were taking metformin at baseline and 683 (45%) were not. 109 participants (7.2%) developed dementia over a median follow-up of 4.0 years. In the estimation of CATEs in the overall cohort, metformin was associated with a lower risk of dementia (Risk difference [RD], -2.9%; 95% confidence interval [CI], -5.9% to -0.002%). We identified four subgroups with varied risks for dementia in those on metformin therapy, defined by neuropsychiatric disorders, alcohol abuse, and antidepressant use. Metformin was significantly associated with a lower risk of dementia in the subgroup with no neuropsychiatric disorders and no alcohol abuse (-5.9%; -9.6% to -2.3%); however, it was associated with a greater risk in those with neuropsychiatric disorders and no antidepressant use (7.4%; 0.8% to 14.0%).
Conclusion: Metformin use was significantly associated with lower risk of dementia in individuals with T2D, with significant variability among subgroups. Data-driven subgroup analyses may guide personalized treatment for diabetes care.

Disclosure
H.Tang: None. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health. C.Shaaban: None. Z.Feng: None. Y.Wu: None. T.Magoc: None. W.T.Donahoo: None. S.T.Dekosky: Advisory Panel; Acumen Pharmaceuticals, Cognition Therapeutics, Other Relationship; Biogen, Prevail Pharmaceuticals, UpToDate, Up-To-Date. J.Bian: None.

Funding
National Institute on Aging (1R01AG076234-01); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)
49-LB: A Low Biologically Available Glucose Diet Reduces Hemoglobin A1c in Type 2 Diabetes Mellitus—A Randomized Controlled Trial
Authors: ANDERSON JULIE D. , HANSON MICHELLE A. , LYSNE LESIA F. , EBERLY LYNN E. , SEAQUIST ELIZABETH R. , KNIGHTS DAN , CHOW LISA S. , WANG QI , BANTLE ANNE 
Published: June 2023

Introduction: The Low Biologically Available Glucose (LoBAG) diet was designed to improve glycemic control of type 2 diabetes mellitus (T2D). This study tested the effectiveness of the diet in free-living participants with T2D.
Methods: A 12-week randomized controlled trial in participants with T2D compared the LoBAG30 diet (30% low starch carbohydrate, 30% protein, 40% fat) to a control diet (55% carbohydrate, 15% protein, 30% fat). Participants were taking metformin at a stable dose or no glucose-lowering medication. Diets were prescribed to be weight neutral and participants were asked to keep physical activity level constant. Diet instruction and dietitian support were provided to both study groups; food was not provided. The primary outcome was hemoglobin A1c (HbA1c) at the end of the intervention, compared between groups.
Results: Forty-eight participants were enrolled (30 female/18 male; 77% white, 15% Black/African American, 2% Asian, 2% American Indian, 4% not reported; 15% Hispanic/Latino). The majority (88%) took metformin. Baseline characteristics were mean (SD) age 57.4 (10.4) years, HbA1c 7.7 (0.6) %, weight 101.5 (19.7) kg, and BMI 35.4 (5.9) kg/m2 with no significant differences between groups. Thirty-eight participants completed the entire intervention; 4/10 non-completers were withdrawn due to the COVID-19 pandemic. HbA1c decreased in both groups over 12 weeks: mean (SD) -1.0 (0.8) % for the LoBAG diet (p&lt;0.01) and -0.6 (0.7) % for control (p&lt;0.01). The final HbA1c was 6.6 (0.6) % in the LoBAG diet group versus 7.2 (0.8) % for control (p=0.01 for comparison between groups). Both groups lost weight: -6.0 (6.9) kg with the LoBAG diet versus -4.3 (3.5) kg for control (p=0.34 for comparison between groups).
Conclusion: Participants with T2D consuming the LoBAG diet had greater reduction in HbA1c over 12 weeks than those consuming a control diet. The LoBAG diet is an effective option for dietary management of blood glucose in patients with T2D.

Disclosure
J. D. Anderson: None. M. A. Hanson: None. L. F. Lysne: None. L. E. Eberly: None. E. R. Seaquist: Consultant; Zucara Therapeutics. D. Knights: None. L. S. Chow: Research Support; Dexcom, Inc. Q. Wang: None. A. Bantle: None.

Funding
University of Minnesota Department of Medicine; National Center for Advancing Translational Sciences (UL1TR002494, KL2TR002492); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK115906)