ABSTRACT Objective Circadian rhythm disruption is associated with metabolic disorders, yet the role of clock genes in glucose metabolism remains unclear. D‐box binding protein (DBP) is a clock output gene that activates the D‐box, and we used systemic Dbp knockout (KO) mice to investigate DBP's role in glucose metabolism. Methods We generated two independent KO mouse lines. Intraperitoneal insulin tolerance tests (IPITTs) were performed in 13‐week‐old male mice at zeitgeber time (ZT) 1 and ZT 13. To assess hepatic and muscle insulin sensitivity, we examined 2‐deoxy‐D‐glucose (2DG) content and AKT phosphorylation followed by transcriptome analysis using muscle. Results In the KO mice, enhanced insulin sensitivity was observed in ZT1 following IPITT compared to wild‐type (WT) mice, but not in ZT13. These findings indicate that while systemic insulin sensitivity fluctuates throughout the day in WT mice, it does not fluctuate in KO mice. Increased glucose uptake and AKT phosphorylation in gastrocnemius muscle (GM), but not the liver, were observed in KO mice at ZT1. Plasma nonesterified fatty acid (NEFA) levels were reduced during the inactive phase in KO mice. Muscle transcriptome analysis identified chemokine and cytokine–related pathways as the most enriched, including C–C motif chemokine ligand 5 (CCL5) and its receptor C–C chemokine receptor type 5 (CCR5). Conclusion Muscle insulin sensitivity oscillates, with a reduction during the inactive phase. This study demonstrates that DBP deficiency suppresses circadian fluctuations of muscle insulin sensitivity, likely via plasma NEFA and CCL5‐CCR5 signaling. DBP plays a role in circadian regulation of muscle insulin sensitivity.
ABSTRACT Aims/Introduction The association between the fasting serum C‐peptide levels and diabetic polyneuropathy (DPN) in patients with type 2 diabetes remains controversial. Furthermore, the association with the electrophysiological parameters of nerve conduction studies (NCS) has not been elucidated. Therefore, we investigated whether the fasting serum C‐peptide levels are associated with nerve conduction velocity (CV) and action potential amplitude (Amp) in patients with type 2 diabetes. Materials and Methods This retrospective cross‐sectional study enrolled outpatients with type 2 diabetes who underwent the DPNCheck® at the Higashikurume Ekimae Clinic in Tokyo, Japan, between March 1, 2016, and June 30, 2025. Participants were categorized into tertiles according to their fasting serum C‐peptide levels. Abnormal values of CV and Amp were defined as CV <46.5 m/s and Amp <10.5 μV. A logistic regression analysis was used to evaluate whether the fasting serum C‐peptide levels were associated with CV and Amp abnormalities. Results One‐hundred thirty‐one participants were included and stratified into tertiles based on fasting serum C‐peptide levels: Tertile 1, ≤1.9 ng/mL; Tertile 2, 2.0–2.8 ng/mL; and Tertile 3, ≥2.9 ng/mL. Tertile 1 was independently associated with an abnormal Amp (odds ratio: 5.08, 95% confidence interval: 1.41–18.4), whereas no independent association was observed with an abnormal CV. Tertile 2 was not associated with an abnormal CV or Amp. Additionally, a nonlinear relationship was observed between the fasting serum C‐peptide levels and an abnormal Amp. Conclusions Low fasting serum C‐peptide levels were independently associated with abnormal Amp in patients with type 2 diabetes.
ABSTRACT Aims/Introduction To evaluate the real‐world effectiveness and safety of enavogliflozin as a single‐pill formulation (Enavo group; enavogliflozin 0.3 mg) or fixed‐dose combination with metformin (EnavoMet group; enavogliflozin 0.3 mg/metformin 1000 mg) in patients with type 2 diabetes (T2DM) in Korean primary care. Materials and Methods This prospective, multicenter, non‐interventional observational study enrolled 8796 adults with type 2 diabetes mellitus from 273 primary care clinics across Korea (Safety Set). The full analysis set comprised 8704 participants (Enavo: 7046; EnavoMet: 1658) with baseline and at least one post‐baseline glycated hemoglobin (HbA1c) measurement. The primary endpoint was HbA1c change at 24 weeks. Results At 24 weeks, mean HbA1c decreased by −0.69 percentage points (95% CI: −0.71, −0.67) in Enavo ( n = 7003) and −0.86 (−0.90, −0.82) in EnavoMet ( n = 1648). In these paired cohorts, 1728 (24.7%) and 371 (22.5%), respectively, already had HbA1c <7.0% at baseline. Overall 24‐week HbA1c <7.0% rates were 61.6% and 63.6%, combining maintenance and new attainment; <6.5% rates were 30.0% and 37.2%. Weight and systolic blood pressure decreased (−2.43/−2.73 kg; −3.05/−3.77 mmHg). Adverse events were recorded in 39 participants (0.44%); no serious events were recorded. Conclusions Enavogliflozin use was associated with decreases in HbA1c, body weight, and blood pressure over 24 weeks. Overall target rates include participants already below target at baseline and do not establish causal treatment effects.
