Being underweight is an underrecognized risk factor for mortality among individuals with type 2 diabetes (T2D). This study aimed to evaluate the associations of underweight status with mortality among individuals with T2D.
This nationwide, retrospective, population-based cohort study used data from the Korean National Health Insurance Service. We included 1 788 996 adults with T2D who underwent baseline screening between 1 January 2015 and 31 December 2016, with follow-up through December 31, 2022. Underweight was defined as body mass index (BMI) < 18.5 kg/m2 and further categorized as mild (17.0–18.4 kg/m2), moderate (16.0–16.9 kg/m2), and severe (< 160 kg/m2). The primary outcome was all-cause mortality analysed using multivariable Cox proportional hazards regression.
During a median follow-up of 6.96 years, 176 056 deaths occurred. Compared with the non-underweight group (BMI ≥ 18.5 kg/m2), all-cause mortality increased stepwise across underweight categories, with adjusted hazard ratios (aHRs) of 2.037 (95% CI, 1.982–2.094) for mild underweight, 2.719 (2.587–2.857) for moderate underweight, and 3.876 (3.646–4.119) for severe underweight. Cause-specific mortality showed similar gradients. For diabetes-related mortality, the aHRs were 2.265 (2.073–2.474), 3.306 (2.845–3.843) and 5.136 (4.300–6.134) across mild, moderate and severe underweight, respectively; for cardiovascular mortality, 1.881 (1.721–2.055), 2.087 (1.751–2.487) and 2.825 (2.267–3.519); and for cerebrovascular mortality, 2.100 (1.881–2.344), 2.300 (1.846–2.866) and 3.501 (2.702–4.537). Notably, the severe underweight group (BMI < 16.0 kg/m2) showed significantly higher all-cause mortality than the severe obesity group (BMI ≥ 35.0 kg/m2) when compared to the BMI 25.0–29.9 kg/m2 reference group (aHR [95% CI]: 5.168 [4.857–5.499] vs. 1.504 [1.418–1.595]).
Among individuals with T2D, underweight status was associated with substantially elevated mortality risks, with severe underweight exhibiting greater risk than severe obesity.
Ventilator-induced diaphragmatic dysfunction (VIDD) is a major complication in critically ill patients. Prolonged mechanical ventilation (MV) triggers diaphragmatic fibrotic remodelling, but the underlying mechanisms remain unclear. This study investigated the role of the mechanosensitive channel Piezo1 in this process.
A rat model of MV was established for 6 or 12 h. Diaphragm structure (atrophy and fibrosis) and function (frequency-contraction curve and fatigue index) were assessed. The roles of Piezo1 were probed using the inhibitor GsMTx4 (a nonspecific mechanosensitive channel inhibitor) and adeno-associated virus (AAV)–mediated knockdown. Downstream signalling was identified by RNA sequencing (RNA-seq) and validated with cytosporone-B (CsnB, a specific agonist of Nr4a1).
Compared with controls, MV for 12 h induced significant diaphragm fibrosis, atrophy and dysfunction, alongside increased Piezo1 expression (mRNA: 2.362 ± 0.429 vs. 0.920 ± 0.363, p = 0.0018; protein: 1.098 ± 0.103 vs. 0.676 ± 0.102, p = 0.0007). Both GsMTx4 and Piezo1 knockdown alleviated these effects. Knockdown reduced the collagen deposition area by approximately 21% and downregulated key fibrotic markers including fibronectin (0.749 ± 0.118 vs. 1.081 ± 0.117, p < 0.0001), collagen 1 (0.703 ± 0.087 vs. 1.155 ± 0.131, p < 0.0001), collagen 3 (0.879 ± 0.074 vs. 1.063 ± 0.068, p = 0.022) and α-SMA (0.872 ± 0.657 vs. 1.108 ± 0.078, p = 0.0031) compared to the MV12 + shCtrl group. RNA-seq identified Nr4a1 as a downstream factor (p value < 0.009). CsnB treatment increased Nr4a1 expression (1.128 ± 0.113 vs. 0.490 ± 0.084, p < 0.0001), mitigating prolonged MV-induced diaphragm fibrosis and dysfunction but not atrophy (938.1 ± 116.2 vs. 754.7 ± 155.5, p = 0.1079).
Piezo1 upregulation is a key mechanism in ventilator-induced diaphragm fibrosis, potentially mediated through the Akt/Nr4a1 signalling pathway. Targeted inhibition of Piezo1 or activation of Nr4a1 presents a promising therapeutic strategy to prevent fibrosis and preserve diaphragm function.
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