Background This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin.
Methods In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135).
Results At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (–0.47%; 95% confidence interval, –0.61 to –0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%).
Conclusion Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.
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Ideal Combination of Oral Hypoglycemic Agents for Patients with Type 2 Diabetes Mellitus Hye Soon Kim Diabetes & Metabolism Journal.2024; 48(5): 882. CrossRef
Background This study investigated the real-world efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in Korean adults with type 2 diabetes mellitus (T2DM), whose insulin treatment was switched to IDegAsp.
Methods This was a multicenter, retrospective, observational study comprising two 26-week treatment periods, before and after switching to IDegAsp, respectively. Korean adults with uncontrolled T2DM treated with basal or premix insulin (±oral antidiabetic drugs) were enrolled. The primary objective was to compare the degree of glycosylated hemoglobin (HbA1c) change in each 26-week observation period. The analyses included changes in HbA1c, fasting plasma glucose (FPG), body weight, proportion of participants achieving HbA1c <7.0%, hypoglycemic events, and total daily insulin dose (ClinicalTrials.gov, number NCT04656106).
Results In total, 196 adults (mean age, 65.95 years; mean T2DM duration, 18.99 years) were analyzed. The change in both HbA1c and FPG were significantly different between the pre-switching and the post-switching period (0.28% vs. –0.51%, P<0.001; 5.21 mg/dL vs. –23.10 mg/dL, P=0.005), respectively. After switching, the rate of achieving HbA1c <7.0% was significantly improved (5.10% at baseline vs. 11.22% with IDegAsp, P=0.012). No significant differences (before vs. after switching) were observed in body weight change, and total daily insulin dose. The rates of overall and severe hypoglycemia were similar in the two periods.
Conclusion In real-world clinical practice in Korea, the change of insulin regimen to IDegAsp was associated with an improvement in glycemic control without increase of hypoglycemia, supporting the use of IDegAsp for patients with T2DM uncontrolled with basal or premix insulin.
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Background To investigate the association of glycemic control and retinal microvascular changes in patients with type 2 diabetes mellitus (T2DM) without diabetic retinopathy (DR).
Methods This retrospective, observational, cohort study included patients with T2DM without DR. The patients were categorized into intensive control (IC; mean glycosylated hemoglobin [HbA1c] ≤7.0%) and moderate control (MC; mean HbA1c >7.0%) groups. Optical coherence tomography (OCT) and swept-source OCT angiography (OCTA) image parameters were compared between three groups, including healthy controls.
Results In total, 259 eyes of 259 participants (88 IC, 81 MC, and 90 controls) were included. The foveal avascular zone area was significantly larger in the MC group than IC and control groups (all P<0.05). The IC group had lower vessel density in the superficial retinal layer and deep retinal layer than the controls (all P<0.05). The choriocapillaris (CC) flow deficit (FD) was significantly greater in the MC group than in the IC and control groups (18.2%, 16.7%, and 14.2%, respectively; all P<0.01). In multivariate regression analysis, CC-FD was associated with the mean HbA1c level (P=0.008). There were no significant differences in OCT parameters among the groups.
Conclusion OCTA revealed that early CC impairment is associated with HbA1c levels; the CC changes precede clinically apparent DR. The OCTA parameters differed among the groups according to the degree of glycemic control. Our results suggest that microvascular changes precede DR and are closely related to glycemic control.
Background The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD.
Methods A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors.
Results The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle.
Conclusion Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.
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Diagnostic indicators and lifestyle interventions of metabolic-associated fatty liver disease Tianzhu Chen, Xiang Qin, Jianping Jiang, Beihui He Frontiers in Nutrition.2024;[Epub] CrossRef
Sex differences in pathogenesis and treatment of dyslipidemia in patients with type 2 diabetes and steatotic liver disease Tatjana Ábel, Béla Benczúr, Éva Csajbókné Csobod Frontiers in Medicine.2024;[Epub] CrossRef
Associations of traditional healthy lifestyle and sleep quality with metabolic dysfunction-associated fatty liver disease: two population-based studies Jialu Yang, Qi Zhang, Wanying Zhao, Bingqi Ye, Siqi Li, Zhuoyu Zhang, Jingmeng Ju, Jialin He, Min Xia, Tiantian Xiong, Yan Liu Nutrition & Diabetes.2024;[Epub] CrossRef
Background Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort.
Methods We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion.
Results The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies.
Conclusion We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.
Jannica S. Selenius, Patricia P. Silveira, Mikaela von Bonsdorff, Jari Lahti, Hannu Koistinen, Riitta Koistinen, Markku Seppälä, Johan G. Eriksson, Niko S. Wasenius
Diabetes Metab J. 2024;48(5):960-970. Published online March 25, 2024
Funded: Finnish Foundation for Cardiovascular Research, Finnish Foundation for Diabetes Research, Juho Vainio Foundation, Academy of Finland, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation, Samfundet Folkhälsan, Finska Läkaresällskapet, Liv och Hälsa , European Commission FP7, Canadian Institutes of Health Research, EU Horizon 2020 Award, EU H2020-PHC-2014-DynaHealth, Sigrid Jusélius Foundation
Background To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus.
Methods This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Cardiometabolic markers included body composition, waist circumference, circulating lipids, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 1 and 3 (IGFBP-1 and -3). Glucose and insulin levels were measured during a standardized 2-hour 75 g oral glucose tolerance test and impaired glucose regulation status was defined by the World Health Organization 2019 criteria. Analyzes were adjusted for population stratification, age, smoking, alcohol consumption, socioeconomic status, chronic diseases, birth weight, and leisure-time physical activity.
Results Multinomial logistic regression indicated that one standard deviation increase in hePRS-IR was associated with increased risk of diabetes mellitus in all participants (adjusted relative risk ratio, 1.17; 95% confidence interval, 1.01 to 1.35). In women, higher hePRS-IR was associated with greater waist circumference and higher body fat percentage, levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, insulin, and IGFBP-1 (all P≤0.02). The mePRS-IR was associated with decreased IGF-1 level in women (P=0.02). No associations were detected in men and studied outcomes.
Conclusion hePRS-IR is associated with sex-specific differences in cardiometabolic risk factor profiles including impaired glucose regulation, abnormal metabolic markers, and unfavorable body composition in women.
Funded: National Research Foundation of Korea, Ministry of Science and ICT, Korea Health Industry Development Institute, Ministry of Health and Welfare
Background Diacylglycerol O-acyltransferase 2 (DGAT2) synthesizes triacylglycerol (TG) from diacylglycerol; therefore, DGAT2 is considered as a therapeutic target for steatosis. However, the consequence of inhibiting DGAT2 is not fully investigated due to side effects including lethality and lipotoxicity. In this article, we observed the role of DGAT2 in hepatocarcinoma.
Methods The role of DGAT2 is analyzed via loss-of-function assay. DGAT2 knockdown (KD) and inhibitor treatment on HepG2 cell line was analyzed. Cumulative analysis of cell metabolism with bioinformatic data were assessed, and further compared with different cohorts of liver cancer patients and non-alcoholic fatty liver disease (NAFLD) patients to elucidate how DGAT2 is regulating cancer metabolism.
Results Mitochondrial function is suppressed in DGAT2 KD HepG2 cell along with the decreased lipid droplets. In the aspect of the cancer, DGAT2 KD upregulates cell proliferation. Analyzing transcriptome of NAFLD and hepatocellular carcinoma (HCC) patients highlights negatively correlating expression patterns of 73 lipid-associated genes including DGAT2. Cancer patients with the lower DGAT2 expression face lower survival rate. DGAT2 KD cell and patients’ transcriptome show downregulation in estrogen- related receptor alpha (ESRRA) via integrated system for motif activity response analysis (ISMARA), with increased dimerization with corepressor prospero homeobox 1 (PROX1).
Conclusion DGAT2 sustains the stability of mitochondria in hepatoma via suppressing ESRRA-PROX1 transcriptional network and hinders HCC from shifting towards glycolytic metabolism, which lowers cell proliferation.
Background Metabolic dysregulation is a hallmark of type 2 diabetes mellitus (T2DM), in which the abnormalities in brown adipose tissue (BAT) play important roles. However, the cellular composition and function of BAT as well as its pathological significance in diabetes remain incompletely understood. Our objective is to delineate the single-cell landscape of BAT-derived stromal vascular fraction (SVF) and their characteristic alterations in T2DM rats.
Methods T2DM was induced in rats by intraperitoneal injection of low-dose streptozotocin and high-fat diet feeding. Single-cell mRNA sequencing was then performed on BAT samples and compared to normal rats to characterize changes in T2DM rats. Subsequently, the importance of key cell subsets in T2DM was elucidated using various functional studies.
Results Almost all cell types in the BAT-derived SVF of T2DM rats exhibited enhanced inflammatory responses, increased angiogenesis, and disordered glucose and lipid metabolism. The multidirectional differentiation potential of adipose tissue-derived stem cells was also reduced. Moreover, macrophages played a pivotal role in intercellular crosstalk of BAT-derived SVF. A novel Rarres2+macrophage subset promoted the differentiation and metabolic function of brown adipocytes via adipose-immune crosstalk.
Conclusion BAT SVF exhibited strong heterogeneity in cellular composition and function and contributed to T2DM as a significant inflammation source, in which a novel macrophage subset was identified that can promote brown adipocyte function.
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.
Funded: Chungnam National University, National Research Foundation of Korea, Ministry of Science, ICT and Future Planning, Chungnam National University Hospital, Korea Health Industry Development Institute, Ministry of Health and Welfare
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.
Funded: Ministry of Science ICT , National Research Foundation of Korea, Korea Health Industry Development Institute, Ministry of Health and Welfare, Korea National Institute of Health, GIST Research Institute
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.
Funded: National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, National Institutes of Health, Gyeongsang National University
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.
Funded: National Key R&D Program of China, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Basic and Applied Research Foundation, Guangzhou Science and technology planning project, Guangzhou Science and Technology Program, Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Background Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods The constructed ASGR1 knockout mice and ASGR1-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.
Background This study examines integrating physical and mental healthcare for disadvantaged persons with type 2 diabetes mellitus and mild-to-moderate depression in the community, using a mobile application within a public-private-academic partnership.
Methods The Korean Diabetes Association has developed a mobile application combining behavioral activation for psychological well-being and diabetes self-management, with conventional medical therapy. Participants were randomly assigned to receive the application with usual care or only usual care. Primary outcomes measured changes in psychological status and diabetes selfmanagement through questionnaires at week 12 from the baseline. Secondary outcomes assessed glycemic and lipid control, with psychological assessments at week 16.
Results Thirty-nine of 73 participants completed the study (20 and 19 in the intervention and control groups, respectively) and were included in the analysis. At week 12, the intervention group showed significant reductions in depression severity and perceived stress compared to the control group. Additionally, they reported increased perceived social support and demonstrated improved diabetes self-care behavior. These positive effects persisted through week 16, with the added benefit of reduced anxiety. While fasting glucose levels in the intervention group tended to improve, no other significant differences were observed in laboratory assessments between the groups.
Conclusion This study provides compelling evidence for the potential efficacy of a mobile application that integrates physical and mental health components to address depressive symptoms and enhance diabetes self-management in disadvantaged individuals with type 2 diabetes mellitus and depression. Further research involving larger and more diverse populations is warranted to validate these findings and solidify their implications.
Background To investigate the association between the time-varying resting heart rate (RHR) and change in RHR (∆RHR) over time and the risk of diabetes mellitus (DM) by sex.
Methods We assessed 8,392 participants without DM or atrial fibrillation/flutter from the Korean Genome and Epidemiology Study, a community-based prospective cohort study that was initiated in 2001 to 2002. The participants were followed up until December 31, 2018. Updating RHR with biennial in-study re-examinations, the time-varying ∆RHR was calculated by assessing the ∆RHR at the next follow-up visit.
Results Over a median follow-up of 12.3 years, 1,345 participants (16.2%) had DM. As compared with RHR of 60 to 69 bpm, for RHR of ≥80 bpm, the incidence of DM was significantly increased for both male and female. A drop of ≥5 bpm in ∆RHR when compared with the stable ∆RHR group (–5< ∆RHR <5 bpm) was associated significantly with lower risk of DM in both male and female. However, an increase of ≥5 bpm in ∆RHR was significantly associated with higher risk of DM only in female, not in male (hazard ratio for male, 1.057 [95% confidence interval, 0.869 to 1.285]; and for female, 1.218 [95% confidence interval, 1.008 to 1.471]).
Conclusion In this community-based longitudinal cohort study, a reduction in ∆RHR was associated with a decreased risk of DM, while an increase in ∆RHR was associated with an increased risk of DM only in female.