Masashi Shimoda

Background and aims: Predicting short‐term blood glucose changes after initiation of continuous intravenous insulin infusion (CII) in hyperglycemic crises remains challenging because glucose trajectories are influenced by both patient‐specific metabolic severity and dynamically adjusted treatment. This study aimed to develop and externally validate machine learning models for estimating retest glucose levels and glucose‐lowering responses after CII initiation. Methods: We analyzed 574 post‐CII blood glucose measurements from 191 patients with hyperglycemic crises across five Japanese institutions. An independent external validation cohort included 29 patients from another institution. Two complementary models were developed using gradient‐boosted decision tree algorithms: a direct retest glucose prediction model and a ΔGlu treatment‐response model. We evaluated model performance using internal validation, patient‐level fivefold cross‐validation, and external validation. ΔGlu was defined as the decrease in blood glucose between two consecutive reassessment points. Results: The eight‐feature direct retest glucose model showed stable predictive performance in internal validation (R ² = 0.853, MAE = 76.9 mg/dL, RMSE = 106.0 mg/dL), patient‐level fivefold cross‐validation (R ² = 0.803 ± 0.080), and external validation (R ² = 0.802, MAE = 78.0 mg/dL, RMSE = 101.0 mg/dL). Although the eight‐feature ΔGlu treatment‐response model showed moderate internal performance, its external generalizability for ΔGlu prediction was limited. Conclusions: The direct retest glucose model showed stable performance across internal and external validation, whereas ΔGlu itself was more difficult to generalize across institutions. These complementary models may support objective monitoring of short‐term glucose trajectories during CII for hyperglycemic crises, although further prospective validation is warranted.

PDX-1 and MafA are insulin gene transcription factors and maintain mature pancreatic β-cell function. After chronic exposure to hyperglycemia, however, the expression levels of PDX-1 and MafA are substantially suppressed by provoked oxidative stress and the activation of the JNK/c-Jun pathway, which further aggravates β-cell function. In addition, glucocorticoids are often used to treat a variety of diseases, but they often induce hyperglycemia, not only by increasing insulin resistance, but also by directly impairing insulin biosynthesis in β-cells. Glucocorticoids bind and activate the glucocorticoid receptor in β-cells, while PDX-1 and MafA expression levels are substantially suppressed through the activation of the JNK/c-Jun pathway, which could explain the molecular mechanism behind glucocorticoid-induced β-cell dysfunction. There are similarities in the molecular mechanism for β-cell dysfunction induced by chronic hyperglycemia and glucocorticoid administration. On the other hand, a GLP-1 receptor agonist rapidly enhances microvascular flow in pancreatic islets in a NO-dependent manner. Such phenomena show that the islet microenvironment is substantially regulated by GLP-1 receptor signaling. Also, based on these data, it is likely that rapid microvascular adaptation contributes to the maintenance of β-cell function under diabetic conditions.

Aims: To evaluate the long‐term efficacy and safety of imeglimin added to dipeptidyl peptidase‐4 (DPP‐4) inhibitors in Japanese patients with type 2 diabetes, focusing on glycemic durability and safety in elderly patients over 104 weeks. Materials and Methods: This multicenter, randomized, placebo‐controlled trial comprised a 24‐week double‐blind phase (imeglimin 1000 mg or placebo twice daily) followed by an 80‐week open‐label extension in which all patients received imeglimin. Eligible patients had inadequate glycemic control despite DPP‐4 inhibitor monotherapy. The main assessment measured HbA1c changes from baseline to week 104. Secondary assessments included meal tolerance tests (MTT) for evaluating physiological changes in β‐cell function and insulin resistance and safety monitoring. Results: Of 117 randomized patients, 81 completed 104 weeks. In the early‐start group that received imeglimin from week 0, the significant HbA1c reduction observed at week 24 (−0.65%) was maintained through week 104 (−0.55%; p < 0.001 vs. baseline). The delayed‐start group that switched to imeglimin at week 24 achieved similar glycemic control thereafter. Elderly patients (≥ 65 years) in the early‐start group maintained stable HbA1c reduction (−0.58%) without hypoglycemic events over 2 years. MTT analysis in the early‐start group showed sustained improvements in glucose AUC and insulin sensitivity without unnecessary insulin secretion over time. Conclusions: Imeglimin added to DPP‐4 inhibitors appeared to improve glycemic control for 104 weeks, without clear attenuation. The combination was well‐tolerated with a low risk of hypoglycemia even in elderly patients. The long‐term effect may be associated with improvements in insulin sensitivity. Trial Registration: jRCTs061210082.

While preserving skeletal muscle mass (SMM) is advocated in type 2 diabetes mellitus (T2DM), mass-based assessments often overlook muscle quality. This study aimed to investigate whether the balance between cellular integrity (phase angle [PhA]) and metabolic load (body fat mass [BFM]) is more clinically relevant to glycemic control than SMM-based profiling in patients with T2DM. In this cross-sectional study of 622 patients, participants were stratified into four groups based on sex-specific medians of PhA and BFM, and similarly for SMM and BFM. Multivariate logistic regression evaluated associations with glycemic targets (HbA1c <8.0% and <7.0%), adjusting for confounders. Sensitivity analyses utilized continuous Z-scores and interaction terms. High-PhA/High-BFM and High-PhA/Low-BFM groups showed significantly higher odds of HbA1c <8.0% compared with the Low-PhA/High-BFM reference group (adjusted odds ratio [OR] 2.05, 95% confidence interval [CI] 1.22–3.44; OR 2.10, 95% CI 1.21–3.64, respectively). Conversely, SMM/BFM combinations showed no significant associations. Neither profile was significantly associated with the stricter HbA1c <7.0% target. In continuous models, the PhA × BFM interaction was significantly associated with achievement of HbA1c <8.0% (p = 0.025), whereas SMM × BFM interaction was not. In conclusion, the PhA/BFM interplay shows a clearer association with glycemic control than SMM/BFM profiling in T2DM. Higher PhA may reflect a more favorable metabolic phenotype against adiposity and is associated with a lower likelihood of severe hyperglycemia (HbA1c ≥8.0%). PhA/BFM profiling offers a novel approach to identify high-risk patients overlooked by conventional mass-based assessments.

Hypokalemia is a common and potentially life-threatening complication of continuous intravenous insulin infusion (CII) in patients with hyperglycemic crises. However, no simple quantitative indicator can estimate the risk of hypokalemia at treatment initiation. This multicenter retrospective cohort study enrolled patients hospitalized for hyperglycemic crises who received CII. Clinical data available at CII initiation were collected. Machine-learning techniques were primarily employed for feature selection and model comparison to develop a simple, clinically interpretable prediction model. A logistic regression–based indicator was constructed using the most contributory variables and validated internally and externally. Hypokalemia was defined as a serum potassium level <3.5 mmol/L. The model-building and external validation cohorts included 99 and 55 patients, respectively. Among multiple candidate models, a lightweight logistic regression model using only two variables, serum potassium level and insulin infusion rate per body weight, was selected for clinical applicability. In internal validation, the model demonstrated good discriminative performance (receiver operating characteristic-area under the curve [ROC-AUC] 0.821). When applied to the external validation cohort, the ROC-AUC was 0.655, and accuracy decreased slightly. A lower threshold may increase sensitivity in screening, whereas a higher threshold may improve specificity. In conclusion, this study presents a simple and clinically applicable indicator for predicting CII-related hypokalemia using only two routinely available variables at treatment initiation. This model supports individualized electrolyte monitoring during the acute management of hyperglycemic crises. Additionally, it may facilitate safer and more efficient clinical decision-making without reliance on complex algorithms.

Sarcoidosis is a granulomatous disease that affects multiple organs; however, pituitary involvement is extremely rare. Although autoimmune diseases, such as Sjögren's disease (SjD), may coexist, overlapping cases presenting with hypopituitarism are exceedingly rare. A 76-year-old man was admitted with hyponatremia and altered consciousness as chief complaints. Endocrine testing revealed panhypopituitarism, and magnetic resonance imaging showed pituitary gland and pituitary stalk enlargement with homogeneous enhancement. Whole-body imaging revealed extensive lymphadenopathy. Histological examination of lymph node and lung biopsy specimens revealed non-necrotizing granulomas, indicative of sarcoidosis. Salivary gland biopsy and autoantibody testing confirmed the presence of concomitant SjD. Hormone replacement therapy markedly improved pituitary enlargement and pituitary hormone secretion, allowing the discontinuation of replacement therapy after 137 days. However, despite the improvement in pituitary and lymph node lesions, interstitial pneumonia subsequently developed due to SjD, necessitating systemic immunosuppressive therapy. In conclusion, this case demonstrates a rare overlap between sarcoidosis presenting with hypopituitarism and SjD, in which pituitary lesions improved, but immune activity progressed in other organs. Thus, immune-mediated disease activity may differ between organs in overlapping syndromes, and pituitary lesions in sarcoidosis do not necessarily parallel systemic disease activity.