Nam Hoon Kim

Background: Early intensive therapy may preserve β‐cell function in newly diagnosed Type 2 diabetes mellitus (T2DM), but whether different early treatment strategies produce distinct patterns of β‐cell functional recovery remains unclear. Methods: This post hoc analysis of the TRIPLE‐AXEL trial included 75 drug‐naïve participants who completed 104 weeks of treatment and underwent 75‐g oral glucose tolerance tests at baseline and Week 104. Participants were randomized to initial triple combination therapy (TCT; metformin, dapagliflozin and saxagliptin) or stepwise add‐on therapy (SAT; metformin followed by glimepiride and sitagliptin). Insulin secretion, insulin sensitivity and β‐cell compensatory function were assessed using the insulinogenic index (IGI), Matsuda insulin sensitivity index (ISI) and disposition index (DI), respectively. Results: HbA1c decreased by approximately 2.7% over 104 weeks in both groups. DI increased significantly in both TCT and SAT, with no significant between‐group difference in the baseline‐adjusted change (difference, −0.09 [95% CI, −0.44 to 0.27]; p = 0.63). Baseline‐adjusted changes in IGI and ISI also did not differ significantly between groups ( p = 0.35 and p = 0.85, respectively), although the within‐group increase in ISI was significant only in the TCT group. In multivariable models, greater HbA1c reduction was associated with higher DI at Week 104. Hypoglycaemia occurred in none of the participants in the TCT group and in 23.7% of those in the SAT group. Conclusions: In newly diagnosed T2DM, both treatment strategies improved β‐cell function without significant between‐group differences. TCT achieved this without hypoglycaemia; however, given the on‐treatment assessment, physiological equivalence cannot be concluded. Trial Registration: ClinicalTrials.gov identifier: NCT02946632

Aims/Introduction: Although a low body mass index (BMI) is traditionally associated with high mortality in type 1 diabetes (T1D), the increasing prevalence of obesity and its association with mortality warrant further research. Materials and Methods: Using a nationwide Korean database from 2002 to 2018, we classified patients with T1D into six categories based on metabolic health and BMI (≥25, 18.5–25, and 2 ): metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy underweight (MHUW), and metabolically unhealthy underweight (MUUW). Mortality data were collected until 2020. Results: Among 8,838 patients with T1D (mean age 54.7 years, 60.6% male), the prevalence of MUUW, MHUW, MUNW, MHNW, MHO, and MUO was 1.1%, 3.0%, 28.5%, 31.2%, 6.3%, and 29.9%, respectively. Over a median 8.3‐year follow‐up, patients with MHO exhibited the lowest all‐cause mortality risk (adjusted hazard ratio [aHR], 0.70; P = 0.007), and those with MUO also had a lower risk (aHR, 0.77; P < 0.001) compared with the MHNW group. Conversely, the underweight groups had significantly higher all‐cause (MHUW: aHR, 2.08; MUUW: aHR, 3.94) and cardiovascular disease (CVD)‐related mortalities (MHUW: aHR, 2.47; MUUW: aHR, 6.31). Patients with MHO had a lower risk of CVD (aHR, 0.76), whereas those with MUO, MUNW, and MUUW had increased risks (aHRs, 1.18, 1.32, and 2.22). Conclusions: Metabolic unhealthiness was associated with a higher CVD risk, and the risks of mortality and CVD were particularly high in patients with MUUW, underscoring the importance of maintaining metabolic health in T1D.

Incretin-based therapies have transformed the treatment of type 2 diabetes mellitus and obesity by producing a weight-loss magnitude that was previously achievable only through intensive caloric restriction or bariatric surgery. This therapeutic shift has moved the clinical focus from the quantity of weight loss to the quality of weight loss. Lean mass reduction is frequently observed during weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs), dual glucose-dependent insulinotropic polypeptide/GLP-1RAs, or emerging multi-agonists. However, loss of lean body mass does not necessarily indicate equivalent loss of contractile skeletal muscle or sarcopenia. Incretin-based therapy is generally associated with preferential fat mass reduction, relative preservation of lean mass, and potential improvement in muscle quality through reduced myosteatosis. Thus, the clinically relevant question is whether incretin-associated body-composition changes lead to deterioration in muscle strength or physical performance, an increased risk of falls or fractures, or impaired quality of life. Available evidence does not show obvious functional harm; however, long-term data remain limited, especially in people with reduced muscle reserve. A muscle-conscious approach that integrates body-composition assessment, functional monitoring, resistance training, nutritional optimization, and emerging pharmacologic muscle-preserving strategies is needed to achieve high-quality weight loss.

Stage 2 or 3 connected insulin pens (CIPs) refer to tracking insulin pens that are capable of transmitting insulin dose data via cloud connectivity. Stage 4 CIPs feature a bolus calculator that determines appropriate insulin doses based on real-time continuous glucose monitoring (CGM) data, carbohydrate intake, previous dosing history, and preset parameters. Stage 5 CIPs additionally offer advanced decision-support features, such as education modules and coaching. However, the efficacy and safety of Stage 5 CIPs have not yet been established. In this prospective, open-label, parallel-group, multicenter, randomized controlled trial, we will include adults aged ≥19 and <75 years with type 1 or type 2 diabetes receiving multiple daily insulin injections (MDI) and having glycosylated hemoglobin (HbA1c) levels of 7.5% to 12.0%. In total, 152 participants will be randomized in a 1:1 ratio to receive either Stage 5 CIPs with CGM or tracking insulin pens with CGM. Stage 5 CIPs include a Setup Wizard that recommends individualized initial settings and an algorithm that provides advanced insulin dosing guidance based on analyses of each participant's CGM and insulin injection data. The primary outcome will be the change in HbA1c levels from baseline to week 12 (ClinicalTrials.gov, NCT07004153). This trial will determine whether Stage 5 CIPs are superior to tracking insulin pens in improving glycemic control among adults with type 1 or type 2 diabetes treated with MDI. Overall, this study may offer a promising strategy for enhancing the management and outcomes of patients with diabetes.

Aim: Thiazolidinediones (TZDs) are effective insulin sensitisers; however, their use is restricted owing to adverse effects such as fluid retention. Previous research has linked increased vascular permeability in white adipose tissue (WAT) to TZD‐induced fluid retention. We explore the potential of sodium‐glucose cotransporter 2 inhibitors (SGLT2is) to counteract this side effect and elucidate the underlying mechanisms. Materials and Methods: High‐fat‐diet‐induced obese mice (C57BL/6) were assigned to three groups: (1) lobeglitazone 0.5 mg/kg (TZD monotherapy); (2) a combination of lobeglitazone 0.5 mg/kg plus empagliflozin 10 mg/kg with 0.16 mg/mL in drinking water (TZD + SGLT2i combination therapy); and (3) distilled water (control). After 6 weeks of treatment, body composition and water content in multiple tissues were measured. The expression of proteins and mRNA related to vascular permeability, renal sodium and water channels was investigated. Additionally, in vivo and in vitro experiments (the latter in human umbilical vein endothelial cells) using anti‐VEGF agents were conducted. Results: TZD treatment escalated vascular leakage and fluid retention in WAT, which was associated with diminished VE‐cadherin expression and compromised vascular integrity. Co‐treatment with the SGLT2i mitigated these adverse effects, reinstating VE‐cadherin expression, reducing vascular permeability and normalizing tissue water content. Empagliflozin was found to inhibit the VEGF‐A/VEGFR2 signalling pathway, thereby reducing VE‐cadherin internalisation and degradation. In vitro studies reinforced these findings, emphasizing the interplay between VEGF and VE‐cadherin in maintaining endothelial junction stability. Conclusions: Our results suggest that SGLT2is protect against TZD‐induced fluid retention by preserving vascular integrity in WAT, providing a viable therapeutic strategy to minimise TZD‐associated side effects.

Patients with chronic kidney disease (CKD) have a significantly increased risk of developing cardiovascular disease (CVD), making dyslipidemia management a critical component of cardiovascular risk reduction in this population. However, as the estimated glomerular filtration rate declines, distinct pathophysiological mechanisms—unlike those observed in the general population—contribute to the development and progression of CVD. Consequently, dyslipidemia management in patients with CKD requires a tailored approach that considers altered lipid profiles, comorbid conditions, and potential safety concerns associated with pharmacological therapy. This review aimed to summarize key clinical trials evaluating lipid-lowering strategies in CKD and compare current international and regional clinical practice guidelines. We assessed cardiovascular outcomes associated with various lipid-lowering agents, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, fibrates, and omega-3 fatty acids. In addition, we discuss optimal therapeutic strategies across distinct patient subgroups, including those not treated with dialysis or kidney transplantation, those on dialysis, and kidney transplant recipients.

Background: In this study, we aimed to determine the metabolic characteristics and changes in the early stages of young-onset type 2 diabetes mellitus (YOD) in Koreans.Methods: From the Anam Diabetes Observational Study cohort (2017–2023), the characteristics of newly diagnosed YOD (<40 years of age, n=39) and later-onset (≥40 years of age) type 2 diabetes mellitus (LOD, n=178) were compared at diagnosis and 1 year later. All participants underwent an oral glucose tolerance test at diagnosis and annually thereafter. β-Cell function was determined using the disposition index (DI), calculated as the insulinogenic index×Matsuda insulin sensitivity index (ISI). Insulin sensitivity was determined using ISI and homeostasis model assessment of insulin resistance (HOMA2-IR).Results: Mean (±standard deviation) age of individuals with YOD was 29.8±6.4 years, and 76.9% were male. YOD patients had higher body mass index (29.8 kg/m2 vs. 27.2 kg/m2, P=0.020), fat mass (30.5 kg vs. 24.1 kg, P=0.011), fatty liver index (65.4 vs. 49.2, P=0.005), and glycosylated hemoglobin (HbA1c) level at diagnosis (9.3% vs. 7.7%, P<0.001) compared with LOD patients. YOD patients exhibited lower insulin sensitivity (ISI: 2.79 vs. 3.26, P=0.008; HOMA2-IR: 2.72 vs. 1.83, P<0.001) and β-cell function (DI) at diagnosis (0.41 vs. 0.72, P=0.003) than LOD patients. Following 1 year of treatment, DI improved by 94% in YOD along with improvement in HbA1c; however, it was still significantly lower than that of LOD (0.64 vs. 0.90, P=0.017).Conclusion: Individuals with YOD have unfavorable metabolic characteristics, substantially reduced insulin sensitivity, and decompensated β-cell function at disease onset, which persist even after treatment.

Background: We aimed to assess the therapeutic inertia associated with injectable therapies and the factors influencing glycemic control following these therapies in patients with type 2 diabetes mellitus (T2DM) in South Korea.Methods: This multicenter, retrospective cohort study included 2,598 T2DM patients aged 20 to 75 years from 10 referral medical centers in South Korea. These patients had been treated with three or four oral antidiabetic drugs (OADs) and were subsequently initiated on insulin (n=1,942) or glucagon-like peptide-1 receptor agonists (GLP-1RAs, n=656) between January 2015 and December 2021. We analyzed the time to initiation of injectable therapy, changes in glycated hemoglobin (HbA1c), and associations between clinical factors and glycemic control.Results: At the time of injectable therapy initiation, the mean HbA1c was 9.54%, with insulin users having a higher HbA1c level (9.79%) than GLP-1RA users (8.70%). The mean time from starting 3 or 4 OADs to initiating injectable therapy was 3.19 years: 53.5% of patients had started injectable therapy after 2 years, and 24.2% started after 5 years. Among insulin users, older age (P= 0.004), higher body mass index (P=0.035), and lower HbA1c levels at insulin initiation (P<0.001) were associated with better glycemic control. Among GLP-1RA users, only the HbA1c level at therapy initiation (P<0.001) was a significant factor.Conclusion: This study highlighted significant delays in initiating injectable therapies, particularly insulin, in T2DM patients in South Korea. Early initiation of injectable therapy may improve long-term glycemic control in these patients.

Background/Objectives: Fat-free mass (FFM) loss after metabolic and bariatric surgery (MBS) is associated with adverse long-term outcomes, including osteoporosis. Identifying biomarkers that predict excessive FFM loss can improve perioperative patient management and postoperative risk stratification. This study investigated whether preoperative amino acid metabolite (AAM) levels could predict excessive FFM loss after laparoscopic sleeve gastrectomy (LSG). Methods: Forty patients with morbid obesity who underwent LSG between 2019 and 2020 were retrospectively analyzed. Based on the FFM loss to body weight loss ratio (%FFML/BWL) at 3 months postoperatively, patients were categorized into excessive (>25%) and non-excessive (≤25%) FFM loss groups. Anthropometric measurements and serum sampling were performed preoperatively and at 3, 6, and 12 months postoperatively. AAM profiles were collected before surgery. Statistical analyses, including logistic regression and receiver operating characteristic curves, were performed. Results: Twenty-five patients showed excessive FFM loss 3 months after surgery. They had significantly lower preoperative tyrosine (Tyr) levels (p = 0.025). Logistic regression revealed that higher Tyr levels were significantly associated with lower odds of being male, suggesting a potential protective effect (odds ratio (OR) =0.019, p = 0.010). Tyr profiling demonstrated acceptable predictive performance (area under the curve =0.715, p = 0.025). Despite nonsignificant p-values, trends showed lower FFM and muscle mass and higher fat mass in the excessive FFM loss group throughout follow-up. Conclusions: Preoperative Tyr profiling may help identify patients at risk for excessive FFM loss. These findings support prioritizing metabolic health alongside total weight loss in the evaluation of MBS outcomes.