Endocrinology and Metabolism

Articles in E-pub version are posted online ahead of regular printed publication.

Review Article

Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia: Sang Ouk Chin, Constance Chik, Toru Tateno; Received June 28, 2024 Accepted August 2, 2024 Published online August 30, 2024; DOI: https://doi.org/10.3803/EnM.2024.2074 [Epub ahead of print]

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Abstract PDF PubReader ePub: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterized by tumors of the pituitary, parathyroid, and endocrine-gastrointestinal tract. Pituitary neuroendocrine tumors (PitNETs) occur in about 40% of MEN1 cases, with 10% being the first manifestation. Recent studies show a slight female predominance, with microPitNETs (<1 cm) being more common than macroPitNETs (>1 cm). Functional PitNETs (FPitNETs) are more frequent than non-functional ones (36% to 48%), with prolactinomas being the most common FPitNETs. MEN1-associated PitNETs are often plurihormonal, larger, and more invasive compared to sporadic types, though patient age and FPitNET proportions are similar. MEN1 mutation-negative patients tend to have larger, symptomatic PitNETs at diagnosis. Six patients with MEN1 have been reported to have pituitary carcinomas, including a mutation- negative patient. Treatment approach between PitNETs in MEN1 and sporadic types appears to be similar. PitNETs also occur in MEN4, but their epidemiology is less understood. In patients with a MEN1-like phenotype and negative genetic testing, MEN4 should be considered.

Original Articles

Impact of Chronic Kidney Disease and Gout on End-Stage Renal Disease in Type 2 Diabetes: Population-Based Cohort Study: Inha Jung, Da Young Lee, Seung Min Chung, So Young Park, Ji Hee Yu, Jun Sung Moon, Ji A Seo, Kyungdo Han, Nan Hee Kim; Received April 23, 2024 Accepted July 2, 2024 Published online August 30, 2024; DOI: https://doi.org/10.3803/EnM.2024.2020 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
We examined the impact of gout on the end-stage renal disease (ESRD) risk in patients with type 2 diabetes mellitus (T2DM) and determined whether this association differs according to chronic kidney disease (CKD) status.
Methods
Using the Korean National Health Insurance Service, this nationwide cohort study enrolled 847,884 patients with T2DM who underwent health checkups in 2009. Based on the presence of CKD (estimated glomerular filtration rate <60 mL/min/1.73 m²) and gout (two outpatient visits or one hospitalization within 5 years), patients were classified into four groups: CKD⁻Gout⁻, CKD⁻ Gout⁺, CKD⁺Gout⁻, and CKD⁺Gout⁺. Patients with incident ESRD were followed up until December 2018.
Results
Among 847,884 patients, 11,825 (1.4%) experienced progression to ESRD. ESRD incidence increased in the following order: 0.77 per 1,000 person-years (PY) in the CKD⁻Gout⁻ group, 1.34/1,000 PY in the CKD⁻Gout⁺ group, 8.20/1,000 PY in the CKD⁺Gout⁻ group, and 23.06/1,000 PY in the CKD⁺Gout⁺ group. The presence of gout modified the ESRD risk in a status-dependent manner. Hazard ratios (HR) were 1.49 (95% confidence interval [CI], 1.32 to 1.69) and 2.24 (95% CI, 2.09 to 2.40) in patients without and with CKD, respectively, indicating a significant interaction (P<0.0001). The CKD⁺Gout⁺ group had a markedly higher risk of developing ESRD (HR, 18.9; 95% CI, 17.58 to 20.32) than the reference group (CKD⁻Gout⁻).
Conclusion
Gout substantially enhances the risk of ESRD, even in the absence of CKD. Concurrent CKD and gout synergistically increase the risk of ESRD. Therefore, physicians should carefully screen for hyperuricemia to prevent progression to ESRD.

Subunit-Specific Developmental Roles of PI3K in SF1- Expressing Cells: My Khanh Q. Huynh, Sang Hee Lyoo, Dong Joo Yang, Yun-Hee Choi, Ki Woo Kim; Received April 4, 2024 Accepted June 19, 2024 Published online August 30, 2024; DOI: https://doi.org/10.3803/EnM.2024.1999 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Phosphatidylinositol 3-kinase (PI3K) regulates cellular development and energy homeostasis. However, the roles of its subunits in organ development remain largely unknown.
Methods
We explored the roles of PI3K catalytic subunits in steroidogenic factor 1 (SF1)-expressing cells through knockout (KO) of the p110α and p110β subunits.
Results
We examined mice with a double KO of p110α and p110β in SF1-expressing cells (p110αβ KO^SF1). Although these animals exhibited no significant changes in the development of the ventromedial hypothalamus, we noted pronounced hypotrophy in the adrenal cortex, testis, and ovary. Additionally, corticosterone and aldosterone levels were significantly reduced. The absence of these subunits also resulted in decreased body weight and survival rate, along with impaired glucose homeostasis, in p110αβ KO^SF1 mice.
Conclusion
The data demonstrate the specific roles of PI3K catalytic subunits in the development and function of SF1-expressing organs.

Elevated Fracture Risks in Patients Using Inhaled Corticosteroids: A Korean Nationwide Study: Sung Hye Kong, Ae Jeong Jo, Chan Mi Park, Kyun Ik Park, Ji Eun Yun, Jung Hee Kim; Received March 24, 2024 Accepted June 10, 2024 Published online August 30, 2024; DOI: https://doi.org/10.3803/EnM.2024.1990 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
In this comprehensive retrospective nationwide cohort study, we examined the relationships between various asthma medications and bone health, utilizing data from the National Health Insurance Service database of South Korea.
Methods
From 2015 to 2019, the relevant dataset included 168,611 individuals aged 66 years, among whom 8,747 were diagnosed with asthma. We focused on a subset of 6,173 patients, all 66-year-old women. Participants were categorized into four groups: nonusers of asthma medication (n=2,868), leukotriene antagonist users (n=2,281), inhaled corticosteroid (ICS) users (n=517), and those using a combination of ICS and long-acting beta-agonist (ICS+LABA) medication (n=507). The primary outcomes measured were the incidences of major osteoporotic fractures and hip fractures during the follow-up period.
Results
Over 2.7 years of follow-up, 615 cases of major osteoporotic fractures and 96 cases of hip fractures were recorded. ICS users exhibited a heightened risk of both injuries, with hazard ratios of 1.38 (95% confidence interval [CI], 1.18 to 1.63; P<0.001) for major osteoporotic fractures and 1.56 (95% CI, 1.33 to 1.83; P<0.001) for hip fractures. Similarly elevated risks were observed in the ICS+LABA group. Notably, the risk associated with ICS was particularly pronounced among patients with osteopenia for both fracture types. Overall, the use of ICS, alone or in combination with LABA, in patients with asthma is associated with significantly increased risks of osteoporotic fractures, especially among those with osteopenia.
Conclusion
These findings underscore the importance of considering bone health when managing asthma, especially in older patients and those with existing bone density issues.

Insulin Resistance and Impaired Insulin Secretion Predict Incident Diabetes: A Statistical Matching Application to the Two Korean Nationwide, Population-Representative Cohorts: Hyemin Jo, Soyeon Ahn, Jung Hun Ohn, Cheol Min Shin, Eunjeong Ji, Donggil Kim, Sung Jae Jung, Joongyub Lee; Received March 20, 2024 Accepted June 11, 2024 Published online August 30, 2024; DOI: https://doi.org/10.3803/EnM.2024.1986 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
To evaluate whether insulin resistance and impaired insulin secretion are useful predictors of incident diabetes in Koreans using nationwide population-representative data to enhance data privacy.
Methods
This study analyzed the data of individuals without diabetes aged >40 years from the Korea National Health and Nutrition Examination Survey (KNHANES) 2007–2010 and 2015 and the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). Owing to privacy concerns, these databases cannot be linked using direct identifiers. Therefore, we generated 10 synthetic datasets, followed by statistical matching with the NHIS-HEALS. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were used as indicators of insulin resistance and insulin secretory function, respectively, and diabetes onset was captured in NHIS-HEALS.
Results
A median of 4,580 (range, 4,463 to 4,761) adults were included in the analyses after statistical matching of 10 synthetic KNHANES and NHIS-HEALS datasets. During a mean follow-up duration of 5.8 years, a median of 4.7% (range, 4.3% to 5.0%) of the participants developed diabetes. Compared to the reference low–HOMA-IR/high–HOMA-β group, the high–HOMA-IR/low– HOMA-β group had the highest risk of diabetes, followed by high–HOMA-IR/high–HOMA-β group and low–HOMA-IR/low– HOMA-β group (median adjusted hazard ratio [ranges]: 3.36 [1.86 to 6.05], 1.81 [1.01 to 3.22], and 1.68 [0.93 to 3.04], respectively).
Conclusion
Insulin resistance and impaired insulin secretion are robust predictors of diabetes in the Korean population. A retrospective cohort constructed by combining cross-sectional synthetic and longitudinal claims-based cohort data through statistical matching may be a reliable resource for studying the natural history of diabetes.

Brief Report

Impact of Diabetes on COVID-19 Susceptibility: A Nationwide Propensity Score Matching Study: Han Na Jang, Sun Joon Moon, Jin Hyung Jung, Kyung-Do Han, Eun-Jung Rhee, Won-Young Lee; Received April 17, 2024 Accepted June 13, 2024 Published online August 28, 2024; DOI: https://doi.org/10.3803/EnM.2024.2014 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Prior research has highlighted poor clinical outcomes in coronavirus disease 2019 (COVID-19)-infected patients with diabetes; however, susceptibility to COVID-19 infection in patients with diabetes has not been extensively studied. Participants aged ≥30 years who underwent COVID-19 testing from December 2019 to April 2020 were analyzed using the National Health Insurance Service data in South Korea. In a cohort comprising 29,433 1:1 propensity score-matched participants, COVID-19 positivity was significantly higher in participants with diabetes than in those without diabetes (512 [3.5%] vs. 395 [2.7%], P<0.001). Logistic regression analysis indicated that diabetes significantly increased the risk of COVID-19 test positivity (odds ratio, 1.307; 95% confidence interval, 1.144 to 1.493; P<0.001). Patients with diabetes exhibited heightened COVID-19 infection rates compared to individuals without diabetes, and diabetes increased the susceptibility to COVID-19, reinforcing the need for heightened preventive measures, particularly considering the poor clinical outcomes in this group.

Original Article

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE): Nam Hoon Kim, Juneyoung Lee, Suk Chon, Jae Myung Yu, In-Kyung Jeong, Soo Lim, Won Jun Kim, Keeho Song, Ho Chan Cho, Hea Min Yu, Kyoung-Ah Kim, Sang Soo Kim, Soon Hee Lee, Chong Hwa Kim, Soo Heon Kwak, Yong‐ho Lee, Choon Hee Chung, Sihoon Lee, Heung Yong Jin, Jae Hyuk Lee, Gwanpyo Koh, Sang-Yong Kim, Jaetaek Kim, Ju Hee Lee, Tae Nyun Kim, Hyun Jeong Jeon, Ji Hyun Lee, Jae-Han Jeon, Hye Jin Yoo, Hee Kyung Kim, Hyeong-Kyu Park, Il Seong Nam-Goong, Seongbin Hong, Chul Woo Ahn, Ji Hee Yu, Jong Heon Park, Keun-Gyu Park, Chan Ho Park, Kyong Hye Joung, Ohk-Hyun Ryu, Keun Yong Park, Eun-Gyoung Hong, Bong-Soo Cha, Kyu Chang Won, Yoon-Sok Chung, Sin Gon Kim; Received April 1, 2024 Accepted June 12, 2024 Published online August 22, 2024; DOI: https://doi.org/10.3803/EnM.2024.1995 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined.
Methods
This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months.
Conclusion
This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Editorial

Insulin-Like Growth Factor 1 as a Pillar in Acromegaly: From Diagnosis to Long-Term Management: Mi Kyung Kim; Received July 14, 2024 Accepted July 22, 2024 Published online August 21, 2024; DOI: https://doi.org/10.3803/EnM.2024.2096 [Epub ahead of print]

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Original Article

Amelioration of Insulin Resistance after Delivery Is Associated with Reduced Risk of Postpartum Diabetes in Women with Gestational Diabetes Mellitus: Heejun Son, Joon Ho Moon, Sung Hee Choi, Nam H. Cho, Soo Heon Kwak, Hak Chul Jang; Received March 4, 2024 Accepted May 7, 2024 Published online August 21, 2024; DOI: https://doi.org/10.3803/EnM.2024.1974 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Identifying risk factors for postpartum type 2 diabetes in women with gestational diabetes mellitus (GDM) is crucial for effective interventions. We examined whether changes in insulin sensitivity after delivery affects the risk of type 2 diabetes in women with GDM.
Methods
This prospective cohort study included 347 women with GDM or gestational impaired glucose tolerance, who attended the follow-up visits at 2 months postpartum and annually thereafter. Changes in insulin sensitivity were calculated using the Matsuda index at GDM diagnosis and at 2 months postpartum (ΔMatsuda index). After excluding women with pregestational diabetes or those followed up only once, we analyzed the risk of postpartum type 2 diabetes based on the ΔMatsuda index tertiles.
Results
The incidence of type 2 diabetes at the two-month postpartum visit decreased with increasing ΔMatsuda index tertiles (16.4%, 9.5%, and 1.8%, P=0.001). During a 4.1-year follow-up, 26 out of 230 women who attended more than two follow-up visits (11.3%) developed type 2 diabetes. Compared to the lowest tertile, subjects in the highest ΔMatsuda index tertile showed a significantly reduced risk of type 2 diabetes (hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.93; P=0.036) after adjusting for confounders.
Conclusion
Improvement in insulin sensitivity after delivery is associated with a reduced risk of postpartum type 2 diabetes in women with GDM. Postpartum changes in insulin sensitivity could be a useful prediction for future type 2 diabetes development in women with GDM.

Review Article

Epidemiology and Trends of Obesity and Bariatric Surgery in Korea: Kyungdo Han, Jin-Hyung Jung, Su-Min Jeong, Mee Kyoung Kim; Received June 5, 2024 Accepted June 19, 2024 Published online August 2, 2024; DOI: https://doi.org/10.3803/EnM.2024.2056 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: The prevalence of obesity in Korea has steadily increased over the past decade, reaching 38.4% in 2021. Notably, the rate of class II– III obesity, defined as a body mass index (BMI) of 30 kg/m² or higher, exceeded 7% in the same year. Since January 2019, the National Health Insurance Service (NHIS) has provided coverage for bariatric surgery (BS) for eligible patients. Coverage is available for individuals with a BMI of 35 kg/m² or higher, or those with a BMI of 30 kg/m² or higher who also have obesity-related comorbidities. Additionally, partial reimbursement is offered for BS in patients with type 2 diabetes mellitus who have BMI values between 27.5 and 30 kg/m². From 2019 to 2022, the NHIS recorded 9,080 BS procedures, with sleeve gastrectomy being the most commonly performed. The average percentage of weight loss 198±99.7 days post-surgery was 17.9%, with 80.0% of patients losing more than 10% of their body weight. This article presents the trends in obesity and BS in Korea.

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