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Association of Uterine Leiomyoma with Type 2 Diabetes Mellitus in Young Women: A Population-Based Cohort Study (Diabetes Metab J 2024;48:1105-13)
Ji-Hee Sung, Kyung-Soo Kim, Kyungdo Han, Cheol-Young Park
Diabetes Metab J. 2024;48(6):1183-1184.   Published online November 21, 2024
DOI: https://doi.org/10.4093/dmj.2024.0681
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Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway (Diabetes Metab J 2024;48:716-29)
Shan-Shan Li, Lu Pan, Shipeng Dang, Ru-Xing Wang
Diabetes Metab J. 2024;48(6):1181-1182.   Published online November 21, 2024
DOI: https://doi.org/10.4093/dmj.2024.0675
  • 147 View
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Letters
Association of Uterine Leiomyoma with Type 2 Diabetes Mellitus in Young Women: A Population-Based Cohort Study (Diabetes Metab J 2024;48:1105-13)
Zhenzhi Qin, Yan Xu
Diabetes Metab J. 2024;48(6):1179-1180.   Published online November 21, 2024
DOI: https://doi.org/10.4093/dmj.2024.0552
  • 141 View
  • 7 Download
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Targeting Cardiac Fibrosis in Diabetic Heart Failure: The Role of the EZH2, AMPK, and PPAR-γ Pathways (Diabetes Metab J 2024;48:716-29)
Jooyeop Lee, Joon Ho Moon
Diabetes Metab J. 2024;48(6):1176-1178.   Published online November 21, 2024
DOI: https://doi.org/10.4093/dmj.2024.0551
  • 162 View
  • 11 Download
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Brief Report
Complications
Article image
Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights
Han-Sang Baek, Chaiho Jeong, Yeoree Yang, Joonyub Lee, Jeongmin Lee, Seung-Hwan Lee, Jae Hyoung Cho, Tae-Seo Sohn, Hyun-Shik Son, Kun-Ho Yoon, Eun Young Lee
Diabetes Metab J. 2024;48(6):1169-1175.   Published online June 10, 2024
DOI: https://doi.org/10.4093/dmj.2024.0036
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  • 137 Download
  • 1 Crossref
AbstractAbstract PDFPubReader   ePub   
One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

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  • Diabetes mellitus im Alter
    Andrej Zeyfang, Jürgen Wernecke, Anke Bahrmann
    Diabetologie und Stoffwechsel.2024; 19(S 02): S226.     CrossRef
Original Articles
Others
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Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea
Byung-Joon Kim, Jun-Seop Shin, Byoung-Hoon Min, Jong-Min Kim, Chung-Gyu Park, Hee-Jung Kang, Eung Soo Hwang, Won-Woo Lee, Jung-Sik Kim, Hyun Je Kim, Iov Kwon, Jae Sung Kim, Geun Soo Kim, Joonho Moon, Du Yeon Shin, Bumrae Cho, Heung-Mo Yang, Sung Joo Kim, Kwang-Won Kim
Diabetes Metab J. 2024;48(6):1160-1168.   Published online May 21, 2024
DOI: https://doi.org/10.4093/dmj.2023.0260
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans.
Methods
A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness.
Conclusion
A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.
Others
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Serum Magnesium Levels Are Negatively Associated with Obesity and Abdominal Obesity in Type 2 Diabetes Mellitus: A Real-World Study
Man-Rong Xu, Ai-Ping Wang, Yu-Jie Wang, Jun-Xi Lu, Li Shen, Lian-Xi Li
Diabetes Metab J. 2024;48(6):1147-1159.   Published online May 29, 2024
DOI: https://doi.org/10.4093/dmj.2023.0401
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  • 1 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
There remains controversy over the relationship between serum magnesium levels and obesity in type 2 diabetes mellitus (T2DM). Therefore, the aim of this study was to assess whether there is any association of serum magnesium levels with obesity and abdominal obesity in T2DM.
Methods
This cross-sectional, real-world study was conducted in 8,010 patients with T2DM, which were stratified into quintiles according to serum magnesium levels. The clinical characteristics and the prevalence of obesity and abdominal obesity were compared across serum magnesium quintiles in T2DM. Regression analyses were used to evaluate the relationship of serum magnesium with obesity and abdominal obesity in T2DM (clinical trial registration number: ChiCTR1800015893).
Results
After adjustment for age, sex, and duration of diabetes, the prevalence of obesity and abdominal obesity was significantly declined across magnesium quintiles (obesity: 51.3%, 50.8%, 48.9%, 45.3%, and 43.8%, respectively, P<0.001 for trend; abdominal obesity: 71.5%, 70.5%, 68.2%, 66.4%, and 64.5%, respectively, P=0.001 for trend). After controlling for confounders, there were clearly negative associations of serum magnesium levels and quintiles with obesity and abdominal obesity in T2DM. Moreover, C-reactive protein partly mediates the effect of serum magnesium on obesity and abdominal obesity (P=0.016 and P=0.004, respectively).
Conclusion
The significantly negative relationship between serum magnesium and the risk of obesity and abdominal obesity was observed in T2DM. Furthermore, the independently negative association of serum magnesium with obesity may be explained by its anti-inflammatory functions. Serum magnesium levels may be applied to assess the risk of obesity and abdominal obesity in T2DM.

Citations

Citations to this article as recorded by  
  • Magnesium Matters: A Comprehensive Review of Its Vital Role in Health and Diseases
    Ghizal Fatima, Andrej Dzupina, Hekmat B Alhmadi, Aminat Magomedova, Zainab Siddiqui, Ammar Mehdi, Najah Hadi
    Cureus.2024;[Epub]     CrossRef
Pathophysiology
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Recent Glycemia Is a Major Determinant of β-Cell Function in Type 2 Diabetes Mellitus
Ji Yoon Kim, Jiyoon Lee, Sin Gon Kim, Nam Hoon Kim
Diabetes Metab J. 2024;48(6):1135-1146.   Published online June 17, 2024
DOI: https://doi.org/10.4093/dmj.2023.0359
  • 1,717 View
  • 80 Download
  • 1 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Progressive deterioration of β-cell function is a characteristic of type 2 diabetes mellitus (T2DM). We aimed to investigate the relative contributions of clinical factors to β-cell function in T2DM.
Methods
In a T2DM cohort of 470 adults (disease duration 0 to 41 years), β-cell function was estimated using insulinogenic index (IGI), disposition index (DI), oral disposition index (DIO), and homeostasis model assessment of β-cell function (HOMA-B) derived from a 75 g oral glucose tolerance test (OGTT). The relative contributions of age, sex, disease duration, body mass index, glycosylated hemoglobin (HbA1c) levels (at the time of the OGTT), area under the curve of HbA1c over time (HbA1c AUC), coefficient of variation in HbA1c (HbA1c CV), and antidiabetic agents use were compared by standardized regression coefficients. Longitudinal analyses of these indices were also performed.
Results
IGI, DI, DIO, and HOMA-B declined over time (P<0.001 for all). Notably, HbA1c was the most significant factor affecting IGI, DI, DIO, and HOMA-B in the multivariable regression analysis. Compared with HbA1c ≥9%, DI was 1.9-, 2.5-, 3.7-, and 5.5-fold higher in HbA1c of 8%–<9%, 7%–<8%, 6%–<7%, and <6%, respectively, after adjusting for confounding factors (P<0.001). Conversely, β-cell function was not affected by the type or duration of antidiabetic agents, HbA1c AUC, or HbA1c CV. The trajectories of the IGI, DI, DIO, and HOMA-B mirrored those of HbA1c.
Conclusion
β-Cell function declines over time; however, it is flexible, being largely affected by recent glycemia in T2DM.

Citations

Citations to this article as recorded by  
  • The Importance of Treating Hyperglycemia in β-Cell Dysfunction of Type 2 Diabetes Mellitus
    Arim Choi, Kyung-Soo Kim
    Diabetes & Metabolism Journal.2024; 48(6): 1056.     CrossRef
Complications
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Association of Succinate and Adenosine Nucleotide Metabolic Pathways with Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus
Inha Jung, Seungyoon Nam, Da Young Lee, So Young Park, Ji Hee Yu, Ji A Seo, Dae Ho Lee, Nan Hee Kim
Diabetes Metab J. 2024;48(6):1126-1134.   Published online July 1, 2024
DOI: https://doi.org/10.4093/dmj.2023.0377
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Although the prevalence of diabetic kidney disease (DKD) is increasing, reliable biomarkers for its early detection are scarce. This study aimed to evaluate the association of adenosine and succinate levels and their related pathways, including hyaluronic acid (HA) synthesis, with DKD.
Methods
We examined 235 participants and categorized them into three groups: healthy controls; those with diabetes but without DKD; and those with DKD, which was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. We compared the concentrations of urinary adenosine, succinate, and HA and the serum levels of cluster of differentiation 39 (CD39) and CD73, which are involved in adenosine generation, among the groups with DKD or albuminuria. In addition, we performed multiple logistic regression analysis to evaluate the independent association of DKD or albuminuria with the metabolites after adjusting for risk factors. We also showed the association of these metabolites with eGFR measured several years before enrollment. This study was registered with the Clinical Research Information Service (https://cris.nih.go.kr; Registration number: KCT0003573).
Results
Urinary succinate and serum CD39 levels were higher in the DKD group than in the control and non-DKD groups. Correlation analysis consistently linked urinary succinate and serum CD39 concentrations with eGFR, albuminuria, and ΔeGFR, which was calculated retrospectively. However, among the various metabolites studied, only urinary succinate was identified as an independent indicator of DKD and albuminuria.
Conclusion
Among several potential metabolites, only urinary succinate was independently associated with DKD. These findings hold promise for clinical application in the management of DKD.
Complications
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Does the Relationship of the Autonomic Symptoms Questionnaire COMPASS 31 with Cardiovascular Autonomic Tests Differ between Type 1 and Type 2 Diabetes Mellitus?
Ilenia D’Ippolito, Marika Menduni, Cinzia D’Amato, Aikaterini Andreadi, Davide Lauro, Vincenza Spallone
Diabetes Metab J. 2024;48(6):1114-1125.   Published online February 26, 2024
DOI: https://doi.org/10.4093/dmj.2023.0301
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic neuropathy (CAN) and diagnostic performance between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).
Methods
Seventy-nine participants with T1DM and 140 with T2DM completed COMPASS 31 before cardiovascular reflex tests (CARTs) for CAN, and assessment of symptoms, signs, vibration, and thermal perception thresholds for diabetic polyneuropathy (DPN) diagnosis.
Results
COMPASS 31 total weighted score (TWS) was similar in the two groups, but significantly associated with confirmed CAN only in T1DM (P=0.0056) and not T2DM group (P=0.1768) and correlated with CARTs score more strongly in T1DM (rho=0.356, P=0.0016) than in T2DM group (rho=0.084, P=0.3218) (P=0.016). Only in T1DM and not T2DM group, the area under the receiver operating characteristic curve (AUC) reached a fair diagnostic accuracy (>0.7) for confirmed CAN (0.73±0.07 vs. 0.61±0.08) and DPN (0.75±0.06 vs. 0.68±0.05), although without a significant difference. COMPASS 31 TWS (cut-off 16.44) reached acceptable diagnostic performance in T1DM, with sensitivity for confirmed CAN 81.2% and sensitivity and specificity for DPN 76.3% and 78%, compared to T2DM group (all <70%). AUC for DPN of orthostatic intolerance domain was higher in T1DM compared to T2DM group (0.73±0.05 vs. 0.58±0.04, P=0.027).
Conclusion
COMPASS 31 is more weakly related to CAN in T2DM than in T1DM, with a fair diagnostic accuracy for confirmed CAN only in T1DM. This difference supports a multifactorial origin of symptoms and should be considered when using COMPASS 31.

Citations

Citations to this article as recorded by  
  • Frequency and severity of autonomic dysfunction assessed by objective hemodynamic responses and patient-reported symptoms in individuals with myasthenia gravis
    Monika Zawadka-Kunikowska, Mirosława Cieślicka, Jacek J. Klawe, Małgorzata Tafil-Klawe, Wojciech Kaźmierczak, Łukasz Rzepiński
    Frontiers in Neuroscience.2024;[Epub]     CrossRef
Metabolic Risk/Epidemiology
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Association of Uterine Leiomyoma with Type 2 Diabetes Mellitus in Young Women: A Population-Based Cohort Study
Ji-Hee Sung, Kyung-Soo Kim, Kyungdo Han, Cheol-Young Park
Diabetes Metab J. 2024;48(6):1105-1113.   Published online August 19, 2024
DOI: https://doi.org/10.4093/dmj.2023.0444
  • 889 View
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
We investigated the association between uterine leiomyoma (UL) and incident type 2 diabetes mellitus (T2DM) in young women.
Methods
A nationwide population-based cohort study of 2,541,550 women aged between 20 and 40 years was performed using the National Health Information Database. Cox proportional hazards models were used to analyze the risk of incident T2DM according to the presence of UL and myomectomy.
Results
The mean age was 29.70 years, and mean body mass index was 21.31 kg/m2. Among 2,541,550 participants, 18,375 (0.72%) women had UL. During a median 7.45 years of follow-up, 23,829 women (0.94%) were diagnosed with T2DM. The incidence of T2DM in women with UL (1.805/1,000 person-years) was higher than in those without UL (1.289/1,000 person-years). Compared with women without UL, women with UL had a higher risk of incident T2DM (hazard ratio, 1.216; 95% confidence interval [CI], 1.071 to 1.382). Women with UL who did not undergo myomectomy had a 1.505 times (95% CI, 1.297 to 1.748) higher risk for incident T2DM than women without UL. However, women with UL who underwent myomectomy did not have increased risk for incident T2DM.
Conclusion
Young women with UL were associated with a high risk of incident T2DM. In addition, myomectomy seemed to attenuate the risk for incident T2DM in young women with UL.
Metabolic Risk/Epidemiology
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Association of Body Composition Changes with the Development of Diabetes Mellitus: A Nation-Wide Population Study
Hyung Jun Kim, Hyung-Woo Lee, Min-Kyoung Kang, Gwang Hyun Leem, Min-Ho Kim, Tae-Jin Song
Diabetes Metab J. 2024;48(6):1093-1104.   Published online May 21, 2024
DOI: https://doi.org/10.4093/dmj.2023.0243
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
We investigated the association between body composition changes and new-onset diabetes mellitus (DM) development according to the body mass index (BMI) in a longitudinal setting in the general Korean population.
Methods
From 2010 to 2011 (1st) and 2012 to 2013 (2nd), we included 1,607,508 stratified random sample participants without DM from the National Health Insurance Service-Health Screening dataset of Korean. The predicted appendicular skeletal muscle mass index (pASMMI), body fat mass index (pBFMI), and lean body mass index (pLBMI) were calculated using pre-validated anthropometric prediction equations. A prediction equation was constructed by combining age, weight, height, waist circumference, serum creatinine levels, alcohol consumption status, physical activity, and smoking history as variables affecting body composition.
Results
Decreased pASMMI (men: hazard ratio [HR], 0.866; 95% confidence interval [CI], 0.830 to 0.903; P<0.001; women: HR, 0.748; 95% CI, 0.635 to 0.881; P<0.001), decreased pLBMI (men: HR, 0.931; 95% CI, 0.912 to 0.952; P<0.001; women: HR, 0.906; 95% CI, 0.856 to 0.959; P=0.007), and increased pBFMI (men: HR, 1.073; 95% CI, 1.050 to 1.096; P<0.001; women: HR, 1.114; 95% CI, 1.047 to 1.186; P=0.007) correlated with the development of new-onset DM. Notably, only in the overweight and obese BMI categories, decreases in pASMMI and pLBMI and increases in pBFMI associated with new-onset DM, regardless of gender.
Conclusion
Decreased pASMMI and pLBMI, and increased pBFMI with excess fat accumulation may enhance the risk of newonset DM. Therefore, appropriate changes in body composition can help prevent new-onset DM.
Cardiovascular Risk/Epidemiology
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Cardiovascular Disease & Diabetes Statistics in Korea: Nationwide Data 2010 to 2019
Jin Hwa Kim, Junyeop Lee, Kyungdo Han, Jae-Taek Kim, Hyuk-Sang Kwon, on Behalf of the Diabetic Vascular Disease Research Group of the Korean Diabetes Association
Diabetes Metab J. 2024;48(6):1084-1092.   Published online November 21, 2024
DOI: https://doi.org/10.4093/dmj.2024.0275
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
This study aimed to provide updated insights into the incidence and management of cardiovascular disease (CVD) in Korean adults with diabetes.
Methods
Using data from the Korean National Health Insurance Service and Korea National Health and Nutrition Examination Survey, we analyzed the representative national estimates of CVD in adults with diabetes.
Results
The age- and sex-standardized incidence rate of ischemic heart disease (IHD), ischemic stroke, and peripheral artery disease (PAD) decreased from 2010 to 2019 in individuals with type 2 diabetes mellitus (T2DM). However, an increase in the incidence of heart failure (HF) was observed during the same period. Only 4.96% of adults with diabetes and CVD achieved optimal control of all three risk factors (glycemic levels, blood pressure, and lipid control). Additionally, high-intensity statin treatment rates were 8.84% and 9.15% in individuals with IHD and ischemic stroke, respectively. Treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) or a glucagon-like peptide-1 receptor agonist (GLP-1RA) was relatively low in 2019, with only 11.87%, 7.10%, and 11.05% of individuals with IHD, ischemic stroke, and HF, respectively, receiving SGLT2i treatment. Furthermore, only 1.08%, 0.79%, and 1.06% of patients with IHD, ischemic stroke, and HF, respectively, were treated with GLP-1RA.
Conclusion
The incidence of most CVD (IHD, ischemic stroke, and PAD) decreased between 2010 and 2019, whereas the incidence of HF increased. The overall use of high-intensity statins, SGLT2i, and GLP-1RA remained low among individuals with T2DM and CVD.
Cardiovascular Risk/Epidemiology
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Social Determinants of Health and Cardiovascular Risk among Adults with Diabetes: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Lisa Zhang, Evgeniya Reshetnyak, Joanna B. Ringel, Laura C. Pinheiro, April Carson, Doyle M. Cummings, Raegan W. Durant, Gargya Malla, Monika M. Safford
Diabetes Metab J. 2024;48(6):1073-1083.   Published online July 22, 2024
DOI: https://doi.org/10.4093/dmj.2023.0380
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Social determinants of health (SDOH) have been associated with diabetes risk; however, their association with cardiovascular disease (CVD) events in individuals with diabetes is poorly described. We hypothesized that a greater number of SDOH among individuals with diabetes would be associated with a higher risk of CVD events.
Methods
The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is a national, biracial cohort of 30,239 individuals ≥45 years old recruited in 2003–2007. We included 6,322 participants with diabetes at baseline, defined as healthcare professional diagnosis, diabetes medication use, or blood glucose values. Seven SDOH that were individually associated with CVD events were included (P<0.20). The outcome was CVD events, a composite of expert-adjudicated myocardial infarction, stroke, or cardiovascular death. We estimated Cox proportional hazard models to examine associations between number of SDOH (0, 1, 2, ≥3) and CVD events.
Results
In an age and sex adjusted model, the presence of multiple SDOH significantly increased the risk of any CVD event (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.26 to 1.74 for two SDOH; HR, 1.68; 95% CI, 1.43 to 1.96 for ≥3 SDOH). This finding was attenuated but remained statistically significant in a fully adjusted model (HR, 1.19; 95% CI, 1.01 to 1.40 for two SDOH; HR, 1.27; 95% CI, 1.07 to 1.50 for ≥3 SDOH).
Conclusion
Having multiple SDOH was independently associated with an increased risk of CVD events, a finding driven by cardiovascular death. Identifying individuals with diabetes who have multiple SDOH may be helpful for detecting those at higher risk of experiencing or dying from CVD events.
Basic Research
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PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca2+ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes
Yongxin Liu, Yongqing Wei, Xiaolong Jin, Hongyu Cai, Qianqian Chen, Xiujuan Zhang
Diabetes Metab J. 2024;48(6):1058-1072.   Published online July 29, 2024
DOI: https://doi.org/10.4093/dmj.2023.0275
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action.
Methods
High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic β-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca2+ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit.
Results
PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic β-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic β-cells. Additionally, PDZD8 knockdown alleviated Ca2+ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of β-cells.
Conclusion
PDZD8 knockdown inhibited pancreatic β-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca2+ into the mitochondria.

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