Most patients with proteinuria are considered to have typical diabetic nephropathy (DN). However, when proteinuria occurs without diabetic retinopathy, with hematuria, or persists despite strict glycemic and blood pressure control, it is considered atypical for DN and warrants further evaluation for non-DN via kidney biopsy. Nevertheless, comprehensive information on renal histopathology and prognosis following kidney biopsy remains limited. This study aimed to clarify these issues through a retrospective analysis. Among 490 patients who underwent kidney biopsy at Shiga University of Medical Science Hospital between 2013 and 2024, 51 Japanese patients with type 2 diabetes who met at least one criterion for proteinuria atypical for DN were included. Pre- and post-biopsy changes in proteinuria levels and eGFR decline rate, as well as renal histology, were analyzed. Among the 51 patients, 17 (33.3%) were histologically diagnosed with typical DN, whereas 34 (66.7%) were diagnosed with non-DN, including membranous nephropathy, immunoglobulin A (IgA) nephropathy, renal sclerosis, interstitial nephritis, vasculitis, and others. Compared with the DN group, patients with non-DN were significantly older and had a lower prevalence of diabetic retinopathy. Additionally, the non-DN group showed significant improvements in both proteinuria levels and in the eGFR decline following biopsy and appropriate disease-specific therapy. A kidney biopsy identified a wide range of kidney diseases as the underlying causes of atypical proteinuria in DN, particularly in elderly patients, thereby improving renal outcomes. These findings underscore the clinical importance of heightened awareness of atypical proteinuria in diabetes management, particularly in aging populations.

The optimal blood pressure (BP) targets for patients with type 2 diabetes (T2D) remain debated among international guidelines. This retrospective cohort analysis evaluated the associations of specific systolic and diastolic BP (SBP and DBP) categories with long-term mortality in patients with T2D. We analyzed 2,198 adults with T2D from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Participants were stratified by baseline SBP (<130, 130-140, ≥140 mmHg) and DBP (<80, 80-89, ≥90 mmHg). Multivariable Cox proportional hazards models were constructed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular, cerebrovascular, and diabetes-related mortality, adjusting for comprehensive baseline covariates. Over a median follow-up of 97.0 months, an SBP ≥140 mmHg was significantly associated with elevated risks for all-cause (HR = 1.66, 95% CI: 1.28-2.16), cardiovascular (HR = 1.53, 95% CI: 1.10-2.13), cerebrovascular (HR = 3.98, 95% CI: 1.71-9.27), and diabetes-related mortality (HR = 1.84, 95% CI: 1.06-3.16) compared to an SBP <130 mmHg. Conversely, a DBP of 80-89 mmHg was associated with significantly lower all-cause (HR = 0.67, 95% CI: 0.46-0.98) and cardiovascular mortality (HR = 0.57, 95% CI: 0.35-0.93) than a DBP <80 mmHg, indicating a distinct J-curve phenomenon. In this observational study, baseline SBP <140 mmHg and DBP 80-89 mmHg were associated with favorable survival outcomes in patients with T2D. These findings suggest that individualized blood pressure management warrants further investigation, taking into account the limitations of observational data and single baseline measurements.

Carbohydrate responsive element-binding protein (ChREBP) is a glucose-activated transcription factor implicated in metabolic regulation and β-cell proliferation. Although in vitro studies have suggested that ChREBP promotes glucose-stimulated β-cell proliferation, its in vivo role under physiological and pathophysiological conditions remains unclear. We generated β-cell-specific ChREBP knockout (βChrebp cKO) mice and examined β-cell proliferation and glucose metabolism under three conditions known to induce β-cell expansion: pharmacologically induced insulin resistance using the insulin receptor antagonist S961, high-fat diet (HFD) feeding, and pregnancy. β-cell proliferation was assessed by 5-Bromo-2'-deoxyuridineincorporation; islet gene expression was evaluated by quantitative PCR and RNA sequencing. βChrebp cKO mice displayed significantly impaired β-cell proliferation under both S961 treatment and HFD feeding, accompanied by decreased expression of the ChREBP target gene Rgs16. These mice also exhibited a mild defect in early-phase insulin secretion at 1 year of age and developed age-associated glucose intolerance. In contrast, pregnancy-induced β-cell proliferation and the expression of mitogenic genes (e.g., Tph2, Ccnb1, Ccnb2) were preserved in βChrebp cKO mice, and Rgs16 expression was unaffected. These findings suggest that ChREBP is critical for β-cell adaptation under hyperglycemia and insulin-resistant states, but not during normoglycemic pregnancy. ChREBP plays a context-dependent role in regulating β-cell proliferation, particularly under metabolic stress. The ChREBP-RGS16 axis may mediate adaptive β-cell proliferation in diabetes-related conditions, and this axis represents a potential therapeutic target to preserve or restore β-cell mass in type 2 diabetes.

During the coronavirus disease 2019 (COVID-19) pandemic, Japan imposed voluntary-based restrictions under a state of emergency (SOE) from 2020 to 2021, and nationwide behavioral restrictions ended with its category 5 status in May 2023. The long-term metabolic impact and their behavioral adaptations of these restrictions and relaxation remain unclear in individuals with glucose intolerance (GI). This single-center observational study assessed changes in glycemic control, body composition, and lifestyle changes across the pre-SOE (2019), SOE (2020-2021), and post-SOE (2023) periods in outpatients. We included 221 outpatients with GI who had complete data for glycated hemoglobin (HbA1c) and body composition in all three periods. Lifestyle changes were evaluated using a questionnaire at post-SOE period. HbA1c levels gradually increased, with a significant elevation post-SOE compared to pre-SOE. While body weight and BMI remained stable during the SOE, both decreased post-SOE. Fat mass increased during the SOE and thereafter decreased, whereas skeletal muscle mass decreased progressively. Among 68 individuals whose HbA1c worsened during the SOE, 25 experienced further deterioration post-SOE, whereas 43 showed improvements in both glycemic control and body composition. Clustering analysis of questionnaire responses in this subgroup identified two behavioral patterns. One cluster, marked by the combination of persistent reductions in physical activity and increased snacking, showed greater post-SOE HbA1c increases. This study clarified long-term metabolic effects of COVID-19 restrictions with glycemic deterioration in individuals with GI. In exploratory analysis of those with HbA1c worsening during SOE, behavioral patterns were associated with post-SOE HbA1c changes.

Future directions in incretin research: Three major directions currently shape therapeutic innovation in incretin research: multi-receptor agonism, oral drug development, and mechanistic reappraisal of glucose-dependent insulinotropic polypeptide (GIP) physiology. These advances indicate that incretin-based therapies should be understood within an integrated enteroinsular network rather than through isolated hormone actions. DPP-4, dipeptidyl peptidase-4; GCGR, glucagon receptor; GIPR, GIP receptor; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; T2D, type 2 diabetes.

To evaluate whether a coronary artery disease (CAD) polygenic risk score (PRS) can improve atherosclerotic cardiovascular disease (ASCVD) risk stratification in individuals with type 2 diabetes (T2D), particularly those at borderline or intermediate 10-year risk. In the UK Biobank (n = 340,299), we integrated CAD PRS into the Pooled Cohort Equations (PCE) to evaluate whether it improved the prediction of incident ASCVD in individuals with T2D at borderline and intermediate 10-year risk. CAD PRS was associated with ASCVD in T2D (1.18-fold). Among those at borderline and intermediate risk, PRS was strongly predictive (1.47-fold and 1.11-fold), and individuals in the top 10% had 1.86-fold and 1.32-fold higher risk. Integration of PRS into PCE modestly improved AUROC (0.050, P = 0.024) and significantly improved net reclassification (0.343, P = 2.62 × 10-4). CAD PRS enhances ASCVD risk prediction in individuals with T2D, supporting utilizing genetic information in tailored risk stratification and preventive care.