Type 2 diabetes mellitus (T2DM) is one of the most pressing global public health challenges. Exercise intervention, as a cost-effective and safe non-pharmacological strategy, exerts its metabolic benefits through coordinated multi-organ and multi-target regulation. Metabolomics technologies provide powerful tools for dissecting the molecular mechanisms underlying exercise intervention in T2DM. This narrative review summarizes current evidence on metabolic dysregulation in T2DM and the metabolic mechanisms underlying exercise intervention, with particular emphasis on insights provided by metabolomics. Furthermore, it elaborates the mechanisms by which exercise intervention systemically reverses T2DM-associated metabolic abnormalities: restoring tricarboxylic acid cycle flux to alleviate glycolytic stress; accelerating branched-chain amino acid oxidative catabolism to rectify aromatic amino acid metabolic disturbances; and promoting fatty acid oxidation while clearing lipotoxic products. In addition, this review highlights the clinical potential of metabolomics for predicting exercise responsiveness, dynamically evaluating intervention outcomes and safety, thereby providing a potential basis for more individualized exercise intervention strategies in T2DM.
SGLT-2 inhibitors are now used beyond type 2 diabetes (T2DM) in heart failure (HF) and chronic kidney disease (CKD), where glucose is monitored less routinely. Whether their established ketoacidosis signal-particularly euglycaemic diabetic ketoacidosis (euDKA)-is maintained as the indications expand, and whether it reproduces across independent reporting systems, is untested. We analysed the US FAERS (2020Q1-2026Q1) and Japanese JADER using one pipeline. Signals required consensus across four methods (ROR, PRR, IC, EBGM/EB05). Analyses were run overall, within report-level indication strata [T2DM, HF, CKD, off-label type 1 diabetes (T1DM)] and against an active comparator (DPP-4 inhibitors), with two pre-specified negative controls, time-to-onset modelling and sensitivity analyses. The DKA signal met four-method consensus within every indication stratum, including HF and CKD, and was highest in off-label T1DM; it was therefore maintained, not diluted, as indications expanded. Overall RORs were 67.4 (95% CI 65.7-69.2) in FAERS and 112.3 (104.8-120.3) in JADER. SGLT-2 inhibitors accounted for 85.8% (FAERS) and 91.7% (JADER) of all euDKA reports, though euDKA was only 4.1% and 7.8% of SGLT-2 inhibitor reports. Both negative controls were null in both databases. Median time-to-onset was 60 days (Weibull β=0.48, 95% CI 0.46-0.50). Across two independent reporting systems, the SGLT-2 inhibitor ketoacidosis signal was maintained across the expanding cardiorenal indications, with euDKA concentrated within this class and early onset. Ketone-based assessment is warranted when ketoacidosis is suspected, particularly soon after initiation. As a disproportionality analysis, these are hypothesis-generating signals that cannot establish incidence, relative risk, or causality.
Background:Prediabetes (Pre-DM) confers an elevated risk of peripheral neuropathy and subsequent diabetic foot complications, yet there is a lack of sufficient research on the biomechanical alterations of plantar pressure distribution associated with glycemic abnormalities. Objective:To investigate the relationship between blood glucose and plantar pressure distributions of 11 zones in Pre-DM patients. Methods:Fifty-five Pre-DM patients were enrolled. Fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and two-hour postprandial plasma glucose (2hPG) levels were measured. Pressure-time integral (PTI), peak force (PF), and mean plantar pressure (MPP) during walking were recorded using the FreeStep plantar pressure measurement system. Spearman's rank correlation analysis was used to assess the associations between three glycemic indicators and plantar pressure parameters. A hierarchical linear regression analysis was conducted to examine the association between blood glucose and the related plantar pressure. Results:Hierarchical linear regression analysis showed that in the first block, BMI was associated with on PF in left HL-L, MPP in left MH2, MPP in left HL-M/L (p < 0.01) and MPP in left MF-M (p< 0.05). Age was also associated with MPP in left MH2 (p< 0.01) and HL-M (p < 0.05). In the second block, 2hPG and HbA1c were independently associated with PTI and PF in left MH1, and 2hPG was associated with PF in left HL-L (p < 0.05); higher blood glucose levels were associated with increased plantar pressure. In contrast, 2hPG and HbA1c were associated with PF in left T2-5 and in both MH5 (p < 0.05); higher blood glucose levels were associated with decreased plantar pressure. FBG had no effect on plantar pressure (p>0.05). Conclusion:Our exploratory study provides the first evidence that 2hPG and HbA1c are independently associated with dynamic plantar pressure in Pre-DM patients. Higher glucose levels are associated with increased loading on left MH1 and heel; conversely, with decreased loading on bilateral MH5 and left T2-5. BMI and age are also the independently associated with dynamic plantar pressure in the left foot.
