Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However, whether OSA exacerbates cognitive impairment and anxiety in patients with T2DM remains unclear. Moreover, TREM2 upregulation has been suggested to play a protective role in attenuating microglia activation and improving synaptic function in T2DM mice. The aim of this study was to explore the regulatory mechanisms of TREM2 and the cognitive and anxiety-like behavioral changes in mice with OSA combined with T2DM. METHODS: A T2DM with OSA model was developed by treating mice with a 60% kcal high-fat diet (HFD) combined with intermittent hypoxia (IH). Spatial learning memory capacity and anxiety in mice were investigated. Neuronal damage in the brain was determined by the quantity of synapses density, the number and morphology of brain microglia, and pro-inflammatory factors. For mechanism exploration, an in vitro model of T2DM combined with OSA was generated by co-treating microglia with high glucose (HG) and IH. Regulation of TREM2 on IFNAR1-STAT1 pathway was determined by RNA sequencing and qRT-PCR. RESULTS: Our results showed that HFD mice exhibited significant cognitive dysfunction and anxiety-like behavior, accompanied by significant synaptic loss. Furthermore, significant activation of brain microglia and enhanced microglial phagocytosis of synapses were observed. Moreover, IH was found to significantly aggravate anxiety in the HFD mice. The mechanism of HG treatment may potentially involve the promotion of TREM2 upregulation, which in turn attenuates the proinflammatory microglia by inhibiting the IFNAR1-STAT1 pathway. Conversely, a significant reduction in TREM2 in IH-co-treated HFD mice and HG-treated microglia resulted in the further activation of the IFNAR1-STAT1 pathway and consequently increased proinflammatory microglial activation. CONCLUSIONS: HFD upregulated the IFNAR1-STAT1 pathway and induced proinflammatory microglia, leading to synaptic damage and causing anxiety and cognitive deficits. The upregulated TREM2 inT2DM mice brain exerted a negative regulation of the IFNAR1-STAT1 pathway. Mice with T2DM combined with OSA exacerbated anxiety via the downregulation of TREM2, causing heightened IFNAR1-STAT1 pathway activation and consequently increasing proinflammatory microglia.

Anti-saccade as a tool to evaluate cognitive impairment in vestibular migraine.

Background: Vestibular migraine (VM), an intricate subtype of migraine, amalgamates the dual attributes of migraine and vestibular disorders. In clinical settings, individuals with VM frequently articulate concerns regarding the manifestation of subjective cognitive impairment. This cognitive dysfunction is intricately linked with diminished mobility, heightened susceptibility to falls, and increased absenteeism in afflicted patients. Consequently, comprehending the features of cognitive impairment in VM patients holds potential clinical significance. The pursuit of rapid and objective methods for detection and assessment is foundational and prerequisite for efficacious cognitive management of VM patients. Methods: The study encompassed 50 patients diagnosed with vestibular migraine and recruited 50 age-sex matched healthy controls. All participants underwent anti-saccade tasks, and cognitive evaluation was performed using the MMSE and MoCA to assess overall cognitive function. Additionally, RBANS scales were employed to measure specific cognitive domains. Results: The VM patients and normal controls demonstrated statistical parity in terms of age, gender, education, weight, and BMI, with no significant differences observed. Analysis of cognitive scores divulged a marked increase in the incidence of Mild Cognitive Impairment (MCI) in VM patients compared to Healthy Controls (HCs). Both MMSE and MoCA scores were notably lower in VM patients compared to their healthy counterparts. The RBANS cognitive test indicated significant impairment in immediate memory, visuospatial construction, language, attention, and delayed memory among VM patients. Notably, the Trail Making Test and Stroop Color-Word Test revealed compromised processing speed and executive function cognitive domains. The anti-saccadic task highlighted significantly elevated anti-saccadic latency and frequency of direction errors in vestibular migraine patients. Symptom severity, illness duration, and episode frequency in VM patients positively correlated with counter-scanning errors and negatively correlated with cognitive performance across diverse cognitive domains. Conclusion: VM patients exhibit cognitive decline across multiple cognitive domains during the interictal period. This cognitive impairment may not be fully reversible, underscoring its potential clinical significance for cognitive management in VM patients. The sensitivity of anti-saccade tasks to the cognitive status of VM patients positions them as promising objective indicators for diagnosis, intervention, and evaluation of cognitive impairment effects in VM in future applications.

Impact of a high dietary fiber cereal meal intervention on body weight, adipose distribution, and cardiovascular risk among individuals with type 2 diabetes.

Objective: This study sought to examine the impacts of a high dietary fiber cereal meal in comparison to conventional dietary management for diabetes on body weight, distribution of adipose tissue, and cardiovascular risk among individuals diagnosed with type 2 diabetes (T2DM). Methods: A cohort of 120 patients diagnosed with T2DM was enlisted as the study population and divided into two groups using a ratio of 2:1-namely, the W group (n=80) and the U group (n=40). The U group (control) received usual diet, while the W group (intervention) incorporated a high dietary fiber cereal meal in place of their regular staple food in addition to adhering to conventional diabetes dietary recommendations. The high dietary fiber cereal meal was based on whole grains, traditional Chinese medicinal foods, and prebiotics. A subsequent follow-up period of 3 months ensued, during which diverse parameters such as body mass index (BMI),waist-hip ratio (WHR), glycated hemoglobin (HbA1c),fasting blood glucose(FBG),C-peptide levels, blood pressure, blood lipids, high-sensitivity C-reactive protein (hsCRP),10-year cardiovascular disease (CVD) risk, and Lifetime CVD risk were assessed before and after the intervention. Results: Among the participants, a total of 107 successfully completed the intervention and follow-up, including 72 individuals from the W group and 35 from the U group. Following the intervention, both cohorts exhibited decrease in BMI, WHR, HbA1c, FBG, blood pressure, and blood lipid levels in contrast to their initial measurements. Remarkably, the improvements in BMI, WHR, HbA1c, FBG, total cholesterol (TC), triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C), and the ratio of 2-hour C-peptide (2hCP) to fasting C-peptide (FCP) were more marked within the W group, exhibiting statistically significant disparities (P<0.05) in comparison to the U group. Furthermore, the levels of hsCRP declined among individuals in the W group, while the U group experienced an elevation.10-year CVD risk reduction were similar in the two groups. While, Lifetime CVD risk only decreased significantly in the W group. Conclusion: The intervention centred on a cereal-based dietary approach showcased favourable outcomes with regard to body weight, adipose distribution, and cardiovascular risk in overweight individuals grappling with T2DM.

Enhancement of Impaired Olfactory Neural Activation and Cognitive Capacity by Liraglutide, but Not Dapagliflozin or Acarbose, in Patients With Type 2 Diabetes: A 16-Week Randomized Parallel Comparative Study.

OBJECTIVE: The comparative neuroprotective effects of different antidiabetes drugs have not been characterized in randomized controlled trials. Here, we investigated the therapeutic effects of liraglutide, dapagliflozin, or acarbose treatment on brain functional alterations and cognitive changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirty-six patients with type 2 diabetes inadequately controlled with metformin monotherapy were randomized to receive liraglutide, dapagliflozin, or acarbose treatment for 16 weeks. Brain functional MRI (fMRI) scan and a battery of cognitive assessments were evaluated pre- and postintervention in all subjects. RESULTS: The 16-week treatment with liraglutide significantly enhanced the impaired odor-induced left hippocampal activation with Gaussian random field correction and improved cognitive subdomains of delayed memory, attention, and executive function (all P < 0.05), whereas dapagliflozin or acarbose did not. Structural equation modeling analysis demonstrated that such improvements of brain health and cognitive function could be partly ascribed to a direct effect of liraglutide on left hippocampal activation (ß = 0.330, P = 0.022) and delayed memory (ß = 0.410, P = 0.004) as well as to the metabolic ameliorations of reduced waist circumference, decreased body fat ratio, and elevated fasting insulin (all P < 0.05). CONCLUSIONS: Our head-to-head study demonstrated that liraglutide enhanced impaired brain activation and restored impaired cognitive domains in patients with type 2 diabetes, whereas dapagliflozin and acarbose did not. The results expand the clinical application of liraglutide and provide a novel treatment strategy for individuals with diabetes and a high risk of cognitive decline.

Connecting Peripheral to Central Neuropathy: Examination of Nerve Conduction Combined with Olfactory Tests in Patients with Type 2 Diabetes.

AIM: Few studies have investigated the associations between diabetic peripheral neuropathy (DPN) and cognitive decline. Olfactory impairment is related to neurodegenerative diseases and type 2 diabetes mellitus (T2DM); however, the cognitive alterations of patients with DPN and the role of olfactory function in DPN are not known. We explored alterations in cognition with DPN and the associations of neuropathy parameters with cognition and olfaction. METHODS: Healthy controls (HCs) and patients with T2DM underwent nerve-conduction tests, detailed cognitive assessment, olfactory-behavior tests, and odor-induced functional magnetic resonance imaging (fMRI). T2DM patients were divided into two groups (non-DPN [NDPN] and DPN). Olfactory brain regions showing different activation between the two groups were selected for functional connectivity (FC) analyses. A structural equation model (SEM) was also generated to demonstrate the association among cognition, olfactory, and neuropathy parameters. RESULTS: One hundred individuals (36 HCs, 36 NDPN, and 28 DPN) were matched for age, sex, and educational level. Compared with the NDPN group, the DPN group had significantly lower scores for memory and processing speed, as well as lower olfactory identification and memory scores, decreased activation of the left frontal lobe, and reduced seed-based functional connectivity in the right insula. The nerve conduction velocity in patients with T2DM was associated with cognitive functions. The association between nerve conduction and executive function was mediated by olfactory behavior. CONCLUSION: Patients with DPN had worse cognition than the NDPN patients in the domains of memory and processing speed. Cognitive dysfunction could be predicted by olfactory-behavior tests and electrophysiological examination.

Better Islet Function and Cardiovascular Autonomic Function in Chinese Type 2 Diabetic Patients with Pure Small Fiber Neuropathy than with Mixed Neuropathy.

INTRODUCTION: The clinical characteristics and outcomes of small fiber neuropathy (SFN) in Chinese patients with type 2 diabetes mellitus (T2DM) have not been thoroughly described. In this study, we investigated the metabolic and neurological indexes and the prognosis of patients with T2DM based on skin biopsy. METHODS: A total of 34 healthy Chinese volunteers were recruited for skin biopsy to establish the reference range of intra-epidermal nerve fiber density (IENFD), and 89 patients with T2DM attending the Nanjing Drum Tower Hospital were evaluated at baseline. Of these 89 patients, 17 with pure SFN and nine with mixed diabetic polyneuropathy (DPN) were reassessed at the end of the follow-up. RESULTS: Glycated hemoglobin and postprandial blood glucose levels were lower (P = 0.005 and P = 0.041, respectively) and postprandial C-peptide and insulin levels were higher (P = 0.001 and P = 0.019, respectively) in the pure SFN group than in the mixed DPN group. A partial correlation study showed that there was a negative correlation between IENFD of the distal leg and cardiovascular autonomic reflex test (CART) scores (r = - 0.513, P = 0.001) after adjusting for age and duration of diabetes. Only vitamin B12 level (P = 0.028) and motor nerve conduction velocity (MCV) of the common peroneal nerve (P = 0.045) were increased in the patients with pure SFN at the final visit while MCVs of the common peroneal nerve (P = 0.025) and tibial nerve (P = 0.047) were decreased in the mixed DPN group at the final visit. CONCLUSION: Better islet function and cardiovascular autonomic function were observed in patients with pure SFN compared with mixed DPN. The metabolic and neurological indexes remained relatively stable in the patients with pure SFN during the follow-up.