Background This study aims to identify the status of continuous glucose monitoring (CGM) use among individuals with type 1 diabetes mellitus (T1DM) in South Korea and to investigate whether age-related disparities exist.
Methods Individuals with T1DM receiving intensive insulin therapy were identified from the Korean National Health Insurance Cohort (2019–2022). Characteristics of CGM users and non-users were compared, and the prescription rates of CGM and sensor- augmented pump (SAP) or automated insulin delivery (AID) systems according to age groups (<19, 19–39, 40–59, and ≥60 years) were analyzed using chi-square tests. Glycosylated hemoglobin (HbA1c) levels and coefficients of variation (CV) among CGM users were also examined.
Results Among the 56,908 individuals with T1DM, 10,822 (19.0%) used CGM at least once, and 6,073 (10.7%) used CGM continuously. Only 241 (0.4%) individuals utilized either SAP or AID systems. CGM users were younger than non-users. The continuous prescription rate of CGM was highest among individuals aged <19 years (37.0%), followed by those aged 19–39 years (15.8%), 40–59 years (10.7%), and ≥60 years (3.9%) (P<0.001 for between-group differences). Among CGM users, HbA1c levels decreased from 8.7%±2.4% at baseline to 7.2%±1.2% at 24 months, and CV decreased from 36.6%±11.9% at 3 months to 34.1%±12.7% at 24 months.
Conclusion Despite national reimbursement for CGM devices, the prescription rates of CGM remain low, particularly among older adults. Given the improvements in HbA1c and CV following CGM initiation, more efforts are needed to increase CGM utilization and reduce age-related disparities.
Background The autonomic nervous system plays a crucial role in the brain’s communication with metabolically important peripheral organs, modulating insulin sensitivity and secretion. Increased sympathetic tone is a common feature in prediabetes and diabetes. The parasympathetic nervous system activity might be improvable through resonance frequency breathing (RFB) with heart rate variability biofeedback (HRV-BF) training.
Methods We here investigated the effect of a 4-week mobile RFB-HRV-BF intervention on glucose metabolism and HRV of 30 healthy adults (17 females; mean age 25.77±3.64 years; mean body mass index 22.65±2.95 kg/m2). Before and after the intervention, glucose metabolism was assessed by 75 g oral glucose tolerance tests (with blood sampling every 30 minutes over 2 hours) and HRV was measured through electrocardiography.
Results RFB-HRV-BF training did not influence glucose metabolism in healthy adults but reduced fasting as well as 2-hour-postload glucose in participants categorized as more insulin resistant before the intervention. In addition, RFB-HRV-BF training was associated with an increase in the time and frequency domain HRV parameters standard deviation of all NN-intervals, root mean square successive differences, HRV high-frequency and HRV low-frequency after 4 weeks of intervention.
Conclusion Our findings introduce RFB-HRV-BF training as an effective tool to modulate the autonomic nervous system with a shift towards the parasympathetic tone. Along with the observed decrease in glycemia in those with lower insulin sensitivity, RFB-HRV-BF training emerges as a promising non-pharmacological approach to improve glucose metabolism which has to be further investigated in prediabetes and diabetes.
Background Diabetic retinopathy (DR) is a major cause of vision loss, linked to hyperglycemia, oxidative stress, and inflammation. Despite advancements in DR treatments, approximately 40% of patients do not respond effectively, underscoring the need for novel, noninvasive biomarkers to predict DR risk and progression. This study investigates causal relationships between specific biomarkers, dietary factors, and DR development using Mendelian randomization (MR) and cross-sectional data.
Methods We conducted a two-phase analysis combining MR and cross-sectional methods. First, MR analysis examined causal associations between 35 biomarkers, 226 dietary factors, and DR progression using data from the UK Biobank and Genome-Wide Association Study (GWAS) datasets. Second, a cross-sectional study with National Health and Nutrition Examination Survey (NHANES) and a clinical cohort from Tianjin Medical University Eye Hospital validated findings and explored biomarkers’ predictive capabilities through a nomogram-based prediction model.
Results MR analysis identified eight biomarkers (e.g., glycosylated hemoglobin [HbA1c], high-density lipoprotein cholesterol [HDL-C]) with significant causal links to DR. Inflammatory markers and metabolic factors, such as high glucose and HDL-C levels, were strongly associated with DR risk and progression. Specific dietary factors, like cheese intake, exhibited protective roles, while alcohol intake increased DR risk. Validation within NHANES and Tianjin cohorts supported these causal associations.
Conclusion This study elucidates causal relationships between biomarkers, dietary habits, and DR progression, emphasizing the potential for personalized dietary interventions to prevent or manage DR. Findings support the use of HDL-C, HbA1c, and dietary factors as biomarkers or therapeutics in DR, though further studies are needed for broader applicability.
Background Patients with diabetes are known to be at high risk for end-stage kidney disease (ESKD), but the accurate annual risk data for new-onset ESKD is still limited. In South Korea, the prevalence and incidence of ESKD are increasing more rapidly compared to the global average. This study aimed to determine the incidence rate (IR) of ESKD by diabetes status from 2012 to 2022.
Methods Using data from the Korean National Health Insurance Service, we calculated the IR and hazard ratio (HR) for newonset ESKD in the general population. Individuals were categorized based on diabetes status into nondiabetes, impaired fasting glucose (IFG), diabetes duration <5 and ≥5 years.
Results Among the participants, 67.6% were nondiabetic, 22.3% had IFG, and 10% had diabetes. In Korea, the IRs of ESKD were 139 per million population (pmp) for nondiabetes, 188 pmp for IFG, 632 pmp for diabetes <5 years, and 3,403 pmp for diabetes ≥5 years. An advanced estimated glomerular filtration rate (eGFR) category was the strongest risk factor for ESKD development. However, even in patients with normal renal function, those with long-standing diabetes had a 14-fold higher risk of ESKD compared to nondiabetic individuals. The risk of ESKD associated with diabetes increased exponentially with declining renal function. Notably, IFG showed an increasing tendency for ESKD in younger patients (<65 years) with early-stage chronic kidney disease (CKD; eGFR ≥60 mL/min/1.73 m²).
Conclusion Longer diabetes duration amplifies ESKD risk, particularly as renal function declines. Even in patients with normal renal function, long-standing diabetes significantly increases ESKD risk, while IFG is associated with elevated risk only in younger individuals with early-stage CKD.
Background This study compares the association between real-time continuous glucose monitoring (rtCGM) and intermittently- scanned CGM (isCGM) and glycemic control in individuals with type 1 diabetes mellitus (T1DM) in a real-world setting.
Methods Using data from the Korean National Health Insurance Service Cohort, individuals with T1DM managed by intensive insulin therapy were followed at 3-month intervals for 2 years after the initiation of CGM. The glycosylated hemoglobin (HbA1c) levels and coefficients of variation (CVs) of rtCGM and isCGM users were compared using independent two-sample t-test and a linear mixed model.
Results The analyses considered 7,786 individuals (5,875 adults aged ≥19 years and 1,911 children and adolescents aged <19 years). Overall, a significant reduction in HbA1c level was observed after 3 months of CGM, and the effect was sustained for 2 years. The mean HbA1c level at baseline was higher in rtCGM users than in isCGM users (8.9%±2.7% vs. 8.6%±2.2%, P<0.001). However, from 3 to 24 months, rtCGM users had lower HbA1c levels than isCGM users at every time point (7.1%±1.2% vs. 7.5%±1.3% at 24 months, P<0.001 for all time points). In both adults and children, the greater reduction in HbA1c with rtCGM remained significant after adjusting for the baseline characteristics of the users. The CV also showed greater decrease with rtCGM than with isCGM.
Conclusion In this large nationwide cohort study, the use of rtCGM was associated with a greater improvement in glycemic control, including HbA1c reduction, than the use of isCGM in both adults and children with T1DM.
Background Our previous studies have investigated the role of hepatic insulin resistance (hepatic IR) and islet β-cell function in the pathogenesis of diabetes. This study aimed to explore the contributions of hepatic IR and islet β-cell dysfunction to the blood glucose spectrum in patients with newly diagnosed type 2 diabetes mellitus.
Methods Hepatic IR was assessed by the hepatic insulin resistance index (HIRI). Islet β-cell function was assessed by insulin secretion- sensitivity index-2 (ISSI2). The associations between blood glucose spectrum and hepatic IR and ISSI2 were analyzed.
Results A total of 707 patients with new-onset diabetes were included. The fasting blood glucose (FBG) and 30 minutes postload blood glucose elevated with rising HIRI (both P for trend <0.001). The FBG, 30 minutes, 2 hours, and 3 hours post-load blood glucose elevated with decreasing ISSI2 quartiles (all P for trend <0.001). There was a negative correlation between ISSI2 and HIRI after adjusting blood glucose levels (r=–0.199, P<0.001).
Conclusion Hepatic IR mainly contributed to FBG and early-phase postprandial plasma glucose, whereas β-cell dysfunction contributed to fasting and postprandial plasma glucose at each phase.
Nam Hoon Kim, Soo Lim, In-Kyung Jeong, Eun-Jung Rhee, Jun Sung Moon, Ohk-Hyun Ryu, Hyuk-Sang Kwon, Jong Chul Won, Sang Soo Kim, Sang Yong Kim, Bon Jeong Ku, Heung Yong Jin, Sin Gon Kim, Bong-Soo Cha, on Behalf of Investigators of ENVELOP Study
Diabetes Metab J. 2025;49(2):225-234. Published online January 6, 2025
Background The novel sodium-glucose cotransporter-2 (SGLT2) inhibitor enavogliflozin effectively lowers glycosylated hemoglobin levels and body weights without the increased risk of serious adverse events; however, the long-term clinical benefits of enavogliflozin in terms of cardiovascular and renal outcomes have not been investigated.
Methods This study is an investigator-initiated, multicenter, randomized, pragmatic, open-label, active-controlled, non-inferiority trial. Eligible participants are adults (aged ≥19 years) with type 2 diabetes mellitus (T2DM) who have a history of, or are at risk of, cardiovascular disease. A total of 2,862 participants will be randomly assigned to receive either enavogliflozin or other SGLT2 inhibitors with proven cardiorenal benefits, such as dapagliflozin or empagliflozin. The primary endpoint is the time to the first occurrence of a composite of major adverse cardiovascular or renal events (Clinical Research Information Service registration number: KCT0009243).
Conclusion This trial will determine whether enavogliflozin is non-inferior to dapagliflozin or empagliflozin in terms of cardiorenal outcomes in patients with T2DM and cardiovascular risk factors. This study will elucidate the role of enavogliflozin in preventing vascular complications in patients with T2DM.
Background Both sodium-glucose cotransporters (SGLTs) and Na+/H+ exchangers (NHEs) rely on a favorable Na-electrochemical gradient. Gastrin, through the cholecystokinin B receptor (CCKBR), can induce natriuresis and diuresis by inhibiting renal NHEs activity. The present study aims to unveil the role of renal CCKBR in diabetes through SGLT2-mediated glucose reabsorption.
Methods Renal tubule-specific Cckbr-knockout (CckbrCKO) mice and wild-type (WT) mice were utilized to investigate the effect of renal CCKBR on SGLT2 and systemic glucose homeostasis under normal diet, high-fat diet (HFD), and HFD with a subsequent injection of a low dose of streptozotocin. The regulation of SGLT2 expression by gastrin/CCKBR and the underlying mechanism was explored using human kidney (HK)-2 cells.
Results CCKBR was downregulated in kidneys of diabetic mice. Compared with WT mice, CckbrCKO mice exhibited a greater susceptibility to obesity and diabetes when subjected to HFD. In vitro experiments using HK-2 cells revealed an upregulation of glucose transporters after incubation with high glucose, a response that was significantly attenuated following gastrin intervention. The glucose uptake from the culture medium of cells was altered accordingly. Moreover, gastrin administration effectively mitigated hyperglycemia in WT diabetic mice by inhibition of SGLT2 mediated glucose reabsorption, but this effect was compromised in the absence of CCKBR, as seen in CckbrCKO mice. Mechanistically, gastrin/CCKBR substantially reduced SGLT2 expression in HK-2 cells exposed to high glucose, via modulating Erk/nuclear factor-kappa B (NF-κB) pathway.
Conclusion Our study underscores the crucial role of renal gastrin/CCKBR in SGLT2 regulation and glucose reabsorption, and renal gastrin/CCKBR can be a promising therapeutic target for diabetes.
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
Diabetes Metab J. 2025;49(1):128-143. Published online September 20, 2024
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; Pmeta=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; Pmeta=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.
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Hexokinase Domain Containing 1 (HKDC1) Gene Variants and Their Association With Gestational Diabetes Mellitus: A Mini-Review Sekar Kanthimathi, Polina Popova, Viswanathan Mohan, Wesley Hannah, Ranjit Mohan Anjana, Venkatesan Radha Journal of Diabetology.2024; 15(4): 354. CrossRef
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.
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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.
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.
Background This study investigated the optimal coefficient of variance (%CV) for preventing hypoglycemia based on real-time continuous glucose monitoring (rt-CGM) data in people with type 1 diabetes mellitus (T1DM) already achieving their mean glucose (MG) target.
Methods Data from 172 subjects who underwent rt-CGM for at least 90 days and for whom 439 90-day glycemic profiles were available were analyzed. Receiver operator characteristic analysis was conducted to determine the cut-off value of %CV to achieve time below range (%TBR)<54 mg/dL <1 and =0.
Results Overall mean glycosylated hemoglobin was 6.8% and median %TBR<54 mg/dL was 0.2%. MG was significantly higher and %CV significantly lower in profiles achieving %TBR<54 mg/dL <1 compared to %TBR<54 mg/dL ≥1 (all P<0.001). The cut-off value of %CV for achieving %TBR<54 mg/dL <1 was 37.5%, 37.3%, and 31.0%, in the whole population, MG >135 mg/dL, and ≤135 mg/dL, respectively. The cut-off value for %TBR<54 mg/dL=0% was 29.2% in MG ≤135 mg/dL. In profiles with MG ≤135 mg/dL, 94.2% of profiles with a %CV <31 achieved the target of %TBR<54 mg/dL <1, and 97.3% with a %CV <29.2 achieved the target of %TBR<54 mg/ dL=0%. When MG was >135 mg/dL, 99.4% of profiles with a %CV <37.3 achieved %TBR<54 mg/dL <1.
Conclusion In well-controlled T1DM with MG ≤135 mg/dL, we suggest a %CV <31% to achieve the %TBR<54 mg/dL <1 target. Furthermore, we suggest a %CV <29.2% to achieve the target of %TBR<54 mg/dL =0 for people at high risk of hypoglycemia.
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 The initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) typically leads to a reversible initial dip in estimated glomerular filtration rate (eGFR). The implications of this phenomenon on clinical outcomes are not well-defined.
Methods We searched MEDLINE, Embase, and Cochrane Library from inception to March 23, 2023 to identify randomized controlled trials and cohort studies comparing kidney and cardiovascular outcomes in patients with and without initial eGFR dip after initiating SGLT2i. Pooled estimates were calculated using random-effect meta-analysis.
Results We included seven studies in our analysis, which revealed that an initial eGFR dip following the initiation of SGLT2i was associated with less annual eGFR decline (mean difference, 0.64; 95% confidence interval [CI], 0.437 to 0.843) regardless of baseline eGFR. The risk of major adverse kidney events was similar between the non-dipping and dipping groups but reduced in patients with a ≤10% eGFR dip (hazard ratio [HR], 0.915; 95% CI, 0.865 to 0.967). No significant differences were observed in the composite of hospitalized heart failure and cardiovascular death (HR, 0.824; 95% CI, 0.633 to 1.074), hospitalized heart failure (HR, 1.059; 95% CI, 0.574 to 1.952), or all-cause mortality (HR, 0.83; 95% CI, 0.589 to 1.170). The risk of serious adverse events (AEs), discontinuation of SGLT2i due to AEs, kidney-related AEs, and volume depletion were similar between the two groups. Patients with >10% eGFR dip had increased risk of hyperkalemia compared to the non-dipping group.
Conclusion Initial eGFR dip after initiating SGLT2i might be associated with less annual eGFR decline. There were no significant disparities in the risks of adverse cardiovascular outcomes between the dipping and non-dipping groups.
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Effect of Initial eGFR and Albuminuria Changes on Clinical Outcomes in People With Diabetes Receiving SGLT2 Inhibitors Birdie Huang, Yi-Wei Kao, Kun-Chi Yen, Shao-Wei Chen, Tze-Fan Chao, Yi-Hsin Chan The Journal of Clinical Endocrinology & Metabolism.2025;[Epub] CrossRef