Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid‐stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA‐induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA‐induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN.

Aims: Previous studies investigated the associations between sleep traits and cardiac diseases, but the evidence for the causal inferences was unclear. This study aimed to explore the causal relationship between sleep and cardiac diseases by virtue of Mendelian randomization (MR). Methods and results: Summary-level data for exposure variables (sleep duration, chronotype, and insomnia) and outcome variables (ischaemic heart disease, atrial fibrillation, myocardial infarction, and heart failure) were derived from UK Biobank. Data from the FinnGen consortium was used as a robustness check. In MR analysis, the inverse variance weighted (IVW) method was applied to infer causality between exposure and outcome. MR-Egger regression was used to identify pleiotropy, and MR-PRESSO outlier test was used to remove the pleiotropy of the genetic instruments. Based on UK Biobank, MR analysis suggested that sleep duration was weakly associated with atrial fibrillation (OR = 0.9999, 95% CI: 0.9998–0.9999) and ischaemic heart disease (OR = 0.9997, 95% CI: 0.9995–0.9998). Insomnia was associated with ischaemic heart disease (OR = 1.0117, 95% CI: 1.0051–1.0183) and myocardial infarction (OR = 1.0049, 95% CI: 1.0019–1.0079). No associations were found between chronotype and cardiac diseases (P > 0.05). We did not find pleiotropy except for insomnia with ischaemic heart disease and myocardial infarction using MR-Egger regression, and MR-PRESSO analysis consistent with IVW. Finally, we obtained the same direction as with UK Biobank using the FinnGen data. Conclusions: Sleep duration and insomnia might be the potential causal risk factors of cardiac diseases. As the OR was small, these associations are probably not clinically relevant. Further validation studies are needed.

Purposes: Observational studies indicate that birth weight and childhood obesity are associated with essential hypertension, but their causal effect on essential hypertension remains unclear. The aim of our study is to elucidate the causal relationship between birth weight, childhood obesity, and essential hypertension by Mendelian randomization (MR) with genetic variants as instrumental variables (IVs). Methods: We identified IVs based on single nucleotide polymorphisms (SNPs) associated with birth weight (n = 160 295) and childhood obesity (n = 6889, 1509 cases and 5380 controls) from the meta-analysis of a genome-wide association study. Summary level data from the UK Biobank essential hypertension consortium (n = 463 010, 54 358 cases and 408 652 controls) was used to analyze the relationship between IVs and essential hypertension. Two MR analysis methods, two threshold values of selecting IVs, and leave-one-out analysis were used to ensure the robustness of the results. Results: Genetic predisposition to higher birth weight did not increase the risk of essential hypertension. In contrast, per one standard deviation increase in childhood body mass index was significantly associated with an increased risk of essential hypertension (odds ratio = 1.0075, 95% confidence interval: 1.0035–1.0116) when using seven SNPs that achieved genome-wide significance (P < 5 × 10⁻⁸). Sensitivity analysis and MR-Egger regression indicated that the results were robust and not influenced by pleiotropy. Conclusions: No evidence of an association between birth weight and essential hypertension was found. Childhood obesity, however, showed a causal relationship with the risk of essential hypertension, which was helpful to understand the mechanisms of essential hypertension and develop strategies for its prevention.

Aim: Acute ischemic stroke (AIS) patients with diabetes mellitus (DM) have significantly lower brain‐derived neurotrophic factor (BDNF) levels compared to nondiabetic patients. However, the impact of BDNF on thrombus characteristics is unclear. The relationship between the plasma BDNF and fibrin ultrastructure of thrombi was investigated. Methods: This study analyzed 72 AIS patients (35 with T2DM) with first‐ever stroke and 10 healthy controls. All patients were assessed for severity and type of stroke, risk factors, and levels of plasma BDNF in the acute stroke. Retrieved arterial thrombi from AIS patients underwent histopathological (immunohistochemical, Martius scarlet blue staining, and immunofluorescence), ultrastructural (scanning/transmission electron microscopy), and permeability (CT/CTA) analyses. In vitro effects of recombinant BDNF (rHu‐BDNF) on fibrin polymerization (turbidity assay), clot firmness (thromboelastography), and lysis were assessed in plasma pools. Results: AIS/DM patients exhibited significantly lower plasma BDNF versus AIS/non‐DM patients (6.83 ± 0.81 vs. 8.70 ± 0.73 ng/mL, p < 0.001) and controls (9.81 ± 0.59 ng/mL). Meanwhile, AIS/DM patients had higher baseline NIHSS scores than AIS/non‐DM patients (17.09 ± 8.29 vs. 13.22 ± 6.15, p = 0.027). AIS/DM thrombi histopathological showed lower BDNF staining intensity, higher fibrin density, and reduced permeability. Moreover, BDNF levels positively correlated with thrombus permeability ( r = 0.862, p < 0.001). We showed that rHu‐BDNF reduced the density of fibrin fiber ( p < 0.001), turbidity ( p < 0.05), and maximum clot firmness ( p < 0.05), while increasing the diameter of fibrin ( p < 0.05), prolonging thrombin time ( p < 0.001), and accelerating lysis ( p < 0.001) in a concentration‐dependent manner in plasma from AIS/DM patients. Conclusion: This study demonstrates that low BDNF levels in AIS/DM patients promote fibrin‐rich, dense clot formation, partly via altered fibrin fiber structure and fibrin polymerization. BDNF may serve as a novel biomarker for thrombus heterogeneity and a potential target to improve thrombolysis in diabetic stroke.

Objectives Diabetes is closely associated with risk of stroke and its adverse sequelae. Approximately 20%–33% of patients with stroke have diabetes. In China, however, it is unclear how stroke affects healthcare utilisation, medications and complications among people with diabetes. This study aimed to analyse the clinical characteristics, treatment options, medical expenses and complications of hospital outpatient healthcare associated with stroke in patients with diabetes in China. Design A retrospective, multicentre, observational study. Setting Beijing Municipal Medical Insurance Database, with data from 2016 to 2018. Participants The study included patients with diabetes whose data included 2016–2018 outpatient medication records and who had Beijing medical insurance. Patients who did not have continuous prescription records for more than 2 months were excluded from the analysis. In total, 2 853 036 people with diabetes were included, and patients who had and did not have a stroke were compared. Results In our study, 19.75%–22.30% of patients with diabetes suffered from stroke between 2016 and 2018. The average annual medical cost for a patient diagnosed with diabetes is ¥9606.65, and the cost increases to ¥13 428.39 when diabetes was combined with stroke; thus, stroke increases the medical cost for patients with diabetes by 39.78% (p<0.0001). Among patients with diabetes who had a stroke, 4.76 medications were used (1.8 hypoglycaemic drugs and 2.97 non-hypoglycaemic drugs); these numbers were significantly greater than for patients with diabetes who did not have a stroke receiving both hypoglycaemic drugs and non-hypoglycaemic drugs (p<0.0001). Among patients with diabetes who did not have a stroke, 3.58 medications were used (1.66 hypoglycaemic drugs and 1.92 non-hypoglycaemic drugs). Patients with diabetes who had a stroke also had significantly greater incidences of diabetic peripheral neuropathy, diabetic kidney disease, diabetic retinopathy and diabetic angiopathy than those who did not have a stroke (p<0.0001). These drugs and costs increased with the number of complications (p<0.0001). The increased medical costs for each specific complication are also listed. We also analysed the medical costs and medication regimens stratified by sex, age group and complications. Conclusions Stroke is associated with a significant increase in complications and medications for patients with diabetes and greatly adds to the economic burden of these patients. Early identification of stroke risk factors in patients with diabetes, as well as targeted poststroke diabetes management, is crucial from a socioeconomic perspective for a comprehensive management and treatment of stroke in patients with diabetes.