Diabetes & Metabolism Journal

Original Article

Genetics
Identification and Potential Clinical Utility of Common Genetic Variants in Gestational Diabetes among Chinese Pregnant Women: Claudia Ha-ting Tam, Ying Wang, Chi Chiu Wang, Lai Yuk Yuen, Cadmon King-poo Lim, Junhong Leng, Ling Wu, Alex Chi-wai Ng, Yong Hou, Kit Ying Tsoi, Hui Wang, Risa Ozaki, Albert Martin Li, Qingqing Wang, Juliana Chung-ngor Chan, Yan Chou Ye, Wing Hung Tam, Xilin Yang, Ronald Ching-wan Ma; Received March 20, 2024 Accepted June 17, 2024 Published online September 20, 2024; DOI: https://doi.org/10.4093/dmj.2024.0139 [Epub ahead of print]

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Abstract PDF: Background
The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications.
Methods
We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants.
Results
Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; P_meta=7.6×10^-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; P_meta=3.1×10^-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals.
Conclusion
Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Reviews

Basic Research
Systems Biology of Human Microbiome for the Prediction of Personal Glycaemic Response: Nikhil Kirtipal, Youngchang Seo, Jangwon Son, Sunjae Lee; Diabetes Metab J. 2024;48(5):821-836. Published online September 12, 2024; DOI: https://doi.org/10.4093/dmj.2024.0382

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Abstract PDF PubReader ePub: The human gut microbiota is increasingly recognized as a pivotal factor in diabetes management, playing a significant role in the body’s response to treatment. However, it is important to understand that long-term usage of medicines like metformin and other diabetic treatments can result in problems, gastrointestinal discomfort, and dysbiosis of the gut flora. Advanced sequencing technologies have improved our understanding of the gut microbiome’s role in diabetes, uncovering complex interactions between microbial composition and metabolic health. We explore how the gut microbiota affects glucose metabolism and insulin sensitivity by examining a variety of -omics data, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, and metagenomics. Machine learning algorithms and genome-scale modeling are now being applied to find microbiological biomarkers associated with diabetes risk, predicted disease progression, and guide customized therapy. This study holds promise for specialized diabetic therapy. Despite significant advances, some concerns remain unanswered, including understanding the complex relationship between diabetes etiology and gut microbiota, as well as developing user-friendly technological innovations. This mini-review explores the relationship between multiomics, precision medicine, and machine learning to improve our understanding of the gut microbiome’s function in diabetes. In the era of precision medicine, the ultimate goal is to improve patient outcomes through personalized treatments.

Drug/Regimen
Benefit and Safety of Sodium-Glucose Co-Transporter 2 Inhibitors in Older Patients with Type 2 Diabetes Mellitus: Ja Young Jeon, Dae Jung Kim; Diabetes Metab J. 2024;48(5):837-846. Published online September 12, 2024; DOI: https://doi.org/10.4093/dmj.2024.0317

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Abstract PDF PubReader ePub: People with type 2 diabetes mellitus (T2DM) are at higher risk of developing cardiovascular disease, heart failure, chronic kidney disease, and premature death than people without diabetes. Therefore, treatment of diabetes aims to reduce these complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown beneficial effects on cardiorenal and metabolic health beyond glucose control, making them a promising class of drugs for achieving the ultimate goals of diabetes treatment. However, despite their proven benefits, the use of SGLT2 inhibitors in eligible patients with T2DM remains suboptimal due to reports of adverse events. The use of SGLT2 inhibitors is particularly limited in older patients with T2DM because of the lack of treatment experience and insufficient long-term safety data. This article comprehensively reviews the risk-benefit profile of SGLT2 inhibitors in older patients with T2DM, drawing on data from prospective randomized controlled trials of cardiorenal outcomes, original studies, subgroup analyses across different age groups, and observational cohort studies.

Cardiovascular Risk/Epidemiology
Artificial Light at Night and Type 2 Diabetes Mellitus: Jong-Ha Baek, Yong Zhu, Chandra L. Jackson, Yong-Moon Mark Park; Diabetes Metab J. 2024;48(5):847-863. Published online September 12, 2024; DOI: https://doi.org/10.4093/dmj.2024.0237

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Abstract PDF PubReader ePub: The widespread and pervasive use of artificial light at night (ALAN) in our modern 24-hour society has emerged as a substantial disruptor of natural circadian rhythms, potentially leading to a rise in unhealthy lifestyle-related behaviors (e.g., poor sleep; shift work). This phenomenon has been associated with an increased risk of type 2 diabetes mellitus (T2DM), which is a pressing global public health concern. However, to date, reviews summarizing associations between ALAN and T2DM have primarily focused on the limited characteristics of exposure (e.g., intensity) to ALAN. This literature review extends beyond prior reviews by consolidating recent studies from 2000 to 2024 regarding associations between both indoor and outdoor ALAN exposure and the incidence or prevalence of T2DM. We also described potential biological mechanisms through which ALAN modulates glucose metabolism. Furthermore, we outlined knowledge gaps and investigated how various ALAN characteristics beyond only light intensity (including light type, timing, duration, wavelength, and individual sensitivity) influence T2DM risk. Recognizing the detrimental impact of ALAN on sleep health and the behavioral correlates of physical activity and dietary patterns, we additionally summarized studies investigating the potential mediating role of each component in the relationship between ALAN and glucose metabolism. Lastly, we proposed implications of chronotherapies and chrononutrition for diabetes management in the context of ALAN exposure.

Original Article

Cardiovascular Risk/Epidemiology
Impact of New-Onset Diabetes after Transplantation on Cardiovascular Risk and Mortality in Korea: A Nationwide Population-Based Study: Seung Shin Park, Bo Kyung Koo, Sanghyun Park, Kyungdo Han, Min Kyong Moon; Received February 18, 2024 Accepted June 17, 2024 Published online September 12, 2024; DOI: https://doi.org/10.4093/dmj.2024.0078 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Limited data are available on the adverse effects of new-onset diabetes after transplantation (NODAT) in solid organ transplantation (TPL) other than kidney. This study aimed to identify the risk of complications associated with NODAT in recipients of kidney, liver, or heart TPL.
Methods
Using the Korean National Health Insurance Service database, recipients of kidney, liver, or heart TPL between 2009 and 2015 were identified. The incidence of coronary artery disease (CAD), cerebrovascular accident (CVA), and malignancy was compared across groups with NODAT, pretransplant diabetes mellitus (DM), and without DM using Cox regression analysis.
Results
A total of 9,632 kidney, liver, or heart TPL recipients were included. During the median follow-up of 5.9 years, NODAT independently increased the incidence of CAD (hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.39 to 4.30) and overall mortality (HR, 1.48; 95% CI, 1.14 to 1.95) compared to the reference group even after adjustment for confounders; this was more prominent in kidney TPL than in liver TPL. The risk of CVA was significantly increased by pretransplant DM but not by NODAT in both kidney and liver TPL (HR, 2.47; 95% CI, 1.68 to 3.65; and HR, 3.18; 95% CI, 1.07 to 9.48, respectively). NODAT increased the risk of malignancy in the crude model, which lost its statistical significance after confounder adjustment.
Conclusion
NODAT independently increases the risk of CAD and mortality after TPL, which is more evident in kidney recipients. There was no additional increased risk of CVA or malignancy with NODAT in solid organ TPL.

Review

Others
T-Cell Senescence in Human Metabolic Diseases: Ha Thi Nga, Thi Linh Nguyen, Hyon-Seung Yi; Diabetes Metab J. 2024;48(5):864-881. Published online August 28, 2024; DOI: https://doi.org/10.4093/dmj.2024.0140

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Abstract PDF PubReader ePub: Immunosenescence denotes a state of dysregulated immune cell function characterized by a confluence of factors, including arrested cell cycle, telomere shortening, markers of cellular stress, mitochondrial dysfunction, loss of proteostasis, epigenetic reprogramming, and secretion of proinflammatory mediators. This state primarily manifests during the aging process but can also be induced in various pathological conditions, encompassing chronic viral infections, autoimmune diseases, and metabolic disorders. Age-associated immune system alterations extend to innate and adaptive immune cells, with T-cells exhibiting heightened susceptibility to immunosenescence. In particular, senescent T-cells have been identified in the context of metabolic disorders such as obesity, diabetes, and cardiovascular diseases. Recent investigations suggest a direct link between T-cell senescence, inflammation, and insulin resistance. The perturbation of biological homeostasis by senescent T-cells appears intricately linked to the initiation and progression of metabolic diseases, particularly through inflammation-mediated insulin resistance. Consequently, senescent T-cells are emerging as a noteworthy therapeutic target. This review aims to elucidate the intricate relationship between metabolic diseases and T-cell senescence, providing insights into the potential roles of senescent T-cells in the pathogenesis of metabolic disorders. Through a comprehensive examination of current research findings, this review seeks to contribute to a deeper understanding of the complex interplay between immunosenescence and metabolic health.

Original Article

Cardiovascular Risk/Epidemiology
Different Associations between Lipid Levels and Risk for Heart Failure according to Diabetes Progression: Seung-Hwan Lee, Kyu Na Lee, Jong-Chan Youn, Hun Sung Kim, Kyungdo Han, Mee Kyoung Kim; Received February 10, 2024 Accepted May 13, 2024 Published online August 28, 2024; DOI: https://doi.org/10.4093/dmj.2024.0066 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The relationship between circulating lipid levels and the risk for heart failure (HF) is controversial. We aimed to examine this association, and whether it is modified by the duration of diabetes or treatment regimens in people with type 2 diabetes mellitus.
Methods
Individuals (n=2,439,978) who underwent health examinations in 2015 to 2016 were identified from the Korean National Health Information Database. Subjects were categorized according to the duration of diabetes (new-onset, <5, 5–10, or ≥10 years) and number of antidiabetic medications. Incident HF was defined according to the International Classification of Diseases, 10th Revision (ICD-10) code I50 as the primary diagnosis during hospitalization. The risk for HF was estimated using multivariate Cox proportional hazard analysis.
Results
During a median follow-up of 4.0 years, 151,624 cases of HF occurred. An inverse association between low-density lipoprotein cholesterol (LDL-C) levels and incident HF was observed in the new-onset diabetes group, with an approximately 25% lower risk in those with LDL-C levels of 100–129, 130–159, and ≥160 mg/dL, compared to those with levels <70 mg/dL. However, J-shaped associations were noted in the long-standing diabetes group, with a 16% higher risk in those with LDL-C level ≥160 mg/dL, compared to those with levels <70 mg/dL. Similar patterns were observed in the relationship between total cholesterol or non-high-density lipoprotein cholesterol and the risk for HF, and when subjects were grouped according to the number of antidiabetic medications instead of diabetes duration.
Conclusion
Different associations between lipid levels and the risk for HF were noted according to disease progression status among individuals with diabetes.

Brief Report

Technology/Device
Effectiveness of Predicted Low-Glucose Suspend Pump Technology in the Prevention of Hypoglycemia in People with Type 1 Diabetes Mellitus: Real-World Data Using DIA:CONN G8: Jee Hee Yoo, Ji Yoon Kim, Jae Hyeon Kim; Received January 24, 2024 Accepted March 29, 2024 Published online August 28, 2024; DOI: https://doi.org/10.4093/dmj.2024.0039 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: We evaluated the effectiveness of the predictive low-glucose suspend (PLGS) algorithm in the DIA:CONN G8. Forty people with type 1 diabetes mellitus (T1DM) who used a DIA:CONN G8 for at least 2 months with prior experience using pumps without and with PLGS were retrospectively analyzed. The objective was to assess the changes in time spent in hypoglycemia (percent of time below range [%TBR]) before and after using PLGS. The mean age, sensor glucose levels, glucose threshold for suspension, and suspension time were 31.1±22.8 years, 159.7±23.2 mg/dL, 81.1±9.1 mg/dL, and 111.9±79.8 min/day, respectively. Overnight %TBR <70 mg/dL was significantly reduced after using the algorithm (differences=0.3%, from 1.4%±1.5% to 1.1%±1.2%, P=0.045). The glycemia risk index (GRI) improved significantly by 4.2 (from 38.8±20.9 to 34.6±19.0, P=0.002). Using the PLGS did not result in a change in the hyperglycemia metric (all P>0.05). Our findings support the PLGS in DIA:CONN G8 as an effective algorithm to improve night-time hypoglycemia and GRI in people with T1DM.

Original Articles

Cardiovascular Risk/Epidemiology
Prognostic Value of Plasma Endothelin-1 in Predicting Worse Outcomes in Patients with Prediabetes and Diabetes and Stable Coronary Artery Diseases: Cheng Yang, Cheng-Gang Zhu, Yuan-Lin Guo, Na-Qiong Wu, Qian Dong, Rui-Xia Xu, Yong-Jian Wu, Jie Qian, Jian-Jun Li; Diabetes Metab J. 2024;48(5):993-1002. Published online August 21, 2024; DOI: https://doi.org/10.4093/dmj.2023.0410

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Abstract PDF Supplementary Material PubReader ePub: Background
Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in coronary artery disease (CAD) and diabetes. This study aimed to determine the prognostic value of ET-1 in the patients with stable CAD under different glucose metabolism states.
Methods
In this prospective, large-cohort study, we consecutively enrolled 7,947 participants with angiography-diagnosed stable CAD from April 2011 to April 2017. Patients were categorized by baseline glycemic status into three groups (normoglycemia, prediabetes, and diabetes) and further divided into nine groups by circulating ET-1 levels. Patients were followed for the occurrence of cardiovascular events (CVEs), including nonfatal myocardial infarction, stroke, and cardiovascular mortality.
Results
Of the 7,947 subjects, 3,352, 1,653, and 2,942 had normoglycemia, prediabetes, and diabetes, respectively. Over a median follow-up of 37.5 months, 381 (5.1%) CVEs occurred. The risk for CVEs was significantly higher in patients with elevated ET-1 levels after adjustment for potential confounders. When patients were categorized by both status of glucose metabolism and plasma ET-1 levels, the high ET-1 levels were associated with higher risk of CVEs in prediabetes (adjusted hazard ratio [HR], 2.089; 95% confidence interval [CI], 1.151 to 3.793) and diabetes (adjusted HR, 2.729; 95% CI, 1.623 to 4.588; both P<0.05).
Conclusion
The present study indicated that baseline plasma ET-1 levels were associated with the prognosis in prediabetic and diabetic patients with stable CAD, suggesting that ET-1 may be a valuable predictor in CAD patients with impaired glucose metabolism.

Metabolic Risk/Epidemiology
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; Received December 8, 2023 Accepted June 17, 2024 Published online August 19, 2024; DOI: https://doi.org/10.4093/dmj.2023.0444 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader 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.

Basic Research
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; Received August 12, 2023 Accepted March 26, 2024 Published online July 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0275 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader 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.

Reviews

Others
Holistic and Personalized Strategies for Managing in Elderly Type 2 Diabetes Patients: Jae-Seung Yun, Kyuho Kim, Yu-Bae Ahn, Kyungdo Han, Seung-Hyun Ko; Diabetes Metab J. 2024;48(4):531-545. Published online July 26, 2024; DOI: https://doi.org/10.4093/dmj.2024.0310

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Abstract PDF PubReader ePub: Due to increased life expectancy and lifestyle changes, the prevalence of diabetes among the elderly in Korea is continuously rising, as is the associated public health burden. Diabetes management in elderly patients is complicated by age-related physiological changes, sarcopenia characterized by loss of muscle mass and function, comorbidities, and varying levels of functional, cognitive, and mobility abilities that lead to frailty. Moreover, elderly patients with diabetes frequently face multiple chronic conditions that elevate their risk of cardiovascular diseases, cancer, and mortality; they are also prone to complications such as hyperglycemic hyperosmolar state, diabetic ketoacidosis, and severe hypoglycemia. This review examines the characteristics of and management approaches for diabetes in the elderly, and advocates for a comprehensive yet personalized strategy.

Others
Korean National Burden of Disease: The Importance of Diabetes Management: Chung-Nyun Kim, Yoon-Sun Jung, Young-Eun Kim, Minsu Ock, Seok-Jun Yoon; Diabetes Metab J. 2024;48(4):518-530. Published online July 26, 2024; DOI: https://doi.org/10.4093/dmj.2024.0087

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Abstract PDF PubReader ePub: Diagnosing the current health status and disease burden in a population is crucial for public health interventions. The ability to compare the burden of different diseases through a single measure, such as disability-adjusted life years has become feasible and continues to be produced and updated through the Global Burden of Diseases (GBD) study. However, the disease burden values of the GBD study do not accurately reflect the unique situation in a specific country with various circumstances. In response, the Korean National Burden of Disease (KNBD) study was conducted to estimate the disease burden in Koreans by considering Korea’s cultural context and utilizing the available data sources at the national level. Both studies identified non-communicable diseases, such as diabetes mellitus (DM), as the primary cause of disease burden among Koreans. However, the extent of public health interventions currently being conducted by the central and local governments does not align with the severity of the disease burden. This review suggests that despite the high burden of DM in South Korea, the current policies may not fully address its impact, underscoring the need for expanded chronic disease management programs and a shift towards prevention-focused healthcare paradigms.

Original Articles

Basic Research
NG2-Glia Cause Diabetic Blood-Brain Barrier Disruption by Secreting MMP-9: Xiaolong Li, Yan Cai, Zhu Zhong, Maolin Li, Dong Huang, Zhifei Qiao, Hongli Zhou, Zuo Zhang, Jiyin Zhou; Received September 25, 2023 Accepted February 22, 2024 Published online July 23, 2024; DOI: https://doi.org/10.4093/dmj.2023.0342 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Disorders of the blood-brain barrier (BBB) arising from diabetes mellitus are closely related to diabetic encephalopathy. Previous research has suggested that neuron-glia antigen 2 (NG2)-glia plays a key role in maintaining the integrity of the BBB. However, the mechanism by which NG2-glia regulates the diabetic BBB remains unclear.
Methods
Type 2 diabetes mellitus (T2DM) db/db mice and db/m mice were used. Evans-Blue BBB permeability tests and transmission electron microscopy techniques were applied. Tight junction proteins were assessed by immunofluorescence and transmission electron microscopy. NG2-glia number and signaling pathways were evaluated by immunofluorescence. Detection of matrix metalloproteinase-9 (MMP-9) in serum was performed using enzyme-linked immunosorbent assay (ELISA).
Results
In T2DM db/db mice, BBB permeability in the hippocampus significantly increased from 16 weeks of age, and the structure of tight junction proteins changed. The number of NG2-glia in the hippocampus of db/db mice increased around microvessels from 12 weeks of age. Concurrently, the expression of MMP-9 increased in the hippocampus with no change in serum. Sixteen- week-old db/db mice showed activation of the Wnt/β-catenin signaling in hippocampal NG2-glia. Treatment with XAV-939 improved structural and functional changes in the hippocampal BBB and reduced MMP-9 secretion by hippocampal NG2-glia in db/db mice. It was also found that the upregulation of β-catenin protein in NG2-glia in the hippocampus of 16-week-old db/db mice was significantly alleviated by treatment with XAV-939.
Conclusion
The results indicate that NG2-glia can lead to structural and functional disruption of the diabetic BBB by activating Wnt/β-catenin signaling, upregulating MMP-9, and degrading tight junction proteins.

Cardiovascular Risk/Epidemiology
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; Received October 24, 2023 Accepted March 26, 2024 Published online July 22, 2024; DOI: https://doi.org/10.4093/dmj.2023.0380 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader 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.

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