Potential risk factors for mild cognitive impairment among patients with type 2 diabetes experiencing hypoglycemia.

AIMS: This study examined the association between hypoglycemia and mild cognitive impairment (MCI) among patients with type 2 diabetes mellitus (T2DM) and identified risk factors for MCI in patients with hypoglycemia. METHODS: In this retrospective study, 328 patients with T2DM were screened in 2019 and followed up in 2022. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). The diagnosis of MCI was based on established criteria. Risk ratio (RR) with 95 % confidence intervals (CI) was calculated to estimate the risk of MCI. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for MCI in those with hypoglycemia. RESULTS: Patients with hypoglycemia had lower cognitive performance 3 years later. The RR of MCI was 2.221 (95 % CI 1.269-3.885). Multivariate logistic analysis showed that low grip strength, existing diabetic retinopathy (DR), and multiple hypoglycemia episodes were associated with higher odds of MCI in patients with hypoglycemia (adjusted odds ratio [OR] 0.909 [95 % CI 0.859-0.963]), 3.078 [95 % CI 1.158-12.358], and 4.642 [95 % CI 1.284-16.776], respectively, all P < 0.05). CONCLUSIONS: Hypoglycemia increased MCI risk among patients with T2DM. Low grip strength, DR, and multiple hypoglycemia episodes may be potential risk factors for hypoglycemia-associated MCI.

Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage.

Hypoglycemia is associated with cognitive dysfunction, but the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia could lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier (BBB) leakage. A streptozotocin T1D model (150 mg/kg, one-time intraperitoneal injection), using male C57BL/6J mice, was used to induce hypoglycemia. Brain tissue was extracted to examine for neuronal damage, permeability of BBB was investigated through Evans blue staining and electron microscopy, reactive oxygen species and adenosine triphosphate in brain tissue were assayed, and the functional changes of pericytes were determined. Cognitive function was tested using Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results showed that BBB leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function.

Thyroid hormone receptor alpha sumoylation modulates white adipose tissue stores.

Thyroid hormone (TH) and thyroid hormone receptor (THR) regulate stem cell proliferation and differentiation during development, as well as during tissue renewal and repair in the adult. THR undergoes posttranslational modification by small ubiquitin-like modifier (SUMO). We generated the THRA (K283Q/K288R)-/- mouse model for in vivo studies and used human primary preadipocytes expressing the THRA sumoylation mutant (K283R/K288R) and isolated preadipocytes from mutant mice for in vitro studies. THRA mutant mice had reduced white adipose stores and reduced adipocyte cell diameter on a chow diet, compared to wild-type, and these differences were further enhanced after a high fat diet. Reduced preadipocyte proliferation in mutant mice, compared to wt, was shown after in vivo labeling of preadipocytes with EdU and in preadipocytes isolated from mice fat stores and studied in vitro. Mice with the desumoylated THRA had disruptions in cell cycle G1/S transition and this was associated with a reduction in the availability of cyclin D2 and cyclin-dependent kinase 2. The genes coding for cyclin D1, cyclin D2, cyclin-dependent kinase 2 and Culin3 are stimulated by cAMP Response Element Binding Protein (CREB) and contain CREB Response Elements (CREs) in their regulatory regions. We demonstrate, by Chromatin Immunoprecipitation (ChIP) assay, that in mice with the THRA K283Q/K288R mutant there was reduced CREB binding to the CRE. Mice with a THRA sumoylation mutant had reduced fat stores on chow and high fat diets and reduced adipocyte diameter.

Thyroid hormone receptor ß sumoylation is required for thyrotropin regulation and thyroid hormone production.

Thyroid hormone receptor ß (THRB) is posttranslationally modified by small ubiquitin-like modifier (SUMO). We generated a mouse model with a mutation that disrupted sumoylation at lysine 146 (K146Q) and resulted in desumoylated THRB as the predominant form in tissues. The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin-stimulating hormone (TSH; 81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4, indicated blunted feedback regulation of TSH. The THRB K146Q mutation altered the recruitment of transcription factors to the TSHß gene promoter, compared with WT, in hyperthyroidism and hypothyroidism. Thyroid hormone content (T4, T3, and rT3) in the thyroid gland of the THRB K146Q mice was 10-fold lower (per gram tissue) than control, despite normal TSH bioactivity. The expression of thyroglobulin and dual oxidase 2 genes in the thyroid was reduced and associated with modifications of cAMP response element-binding protein DNA binding and cofactor interactions in the presence of the desumoylated THRB. Therefore, thyroid hormone production had both TSH-dependent and TSH-independent components. We conclude that THRB sumoylation at K146 was required for normal TSH feedback regulation and TH synthesis in the thyroid gland, by a TSH-independent pathway.

Correlation between Thyroid Homeostasis and Obesity in Subclinical Hypothyroidism: Community-Based Cross-Sectional Research.

OBJECTIVE: It remains unknown whether obesity has an effect on the pituitary-thyroid feedback control axis in subclinical hypothyroidism (SCH). We aimed to investigate the association of thyroid homeostasis with obesity in a SCH population. METHODS: Our study consisted of a community-based and cross-sectional study from the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 193 subjects with SCH (90 males and 103 females) without a history of treatment of thyroid disease, such as surgery, radiation, and thyroid hormone or antithyroid medication, were included in the present study. Indices of obesity, including body mass index (BMI), waist circumference (WC), and waist-height ratio (WHtR) were measured. RESULTS: Our results showed that the secretory capacity of the thyroid gland (SPINA-GT) and Jostel's thyrotropin index (TSHI) were negatively correlated with BMI, WC, and WHtR, whereas the reciprocal of the thyrotroph thyroid hormone resistance index (TTSI-1) was positively correlated with BMI (all p < 0.05). After adjustment for age, sex, smoking, iodine status, and glucolipid metabolism, the associations between TSHI, TTSI (reciprocal transformation), and BMI still persisted (all p < 0.05). CONCLUSIONS: These results suggest that low levels of thyroid homeostasis indexes may be associated with overall obesity in SCH, rather than central adiposity.

Lifestyle is associated with thyroid function in subclinical hypothyroidism: a cross-sectional study.

BACKGROUND: Few studies have focused on the association between lifestyle and subclinical hypothyroidism (SCH). The purpose of this study was to investigate the association between lifestyle and thyroid function in SCH. METHODS: This study was a part of a community-based and cross-sectional study, the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 159 participants with SCH (81 males and 78 females) and 159 euthyroid (87 males and 72 females) participants without any missing data were included in the analysis. General information and lifestyle information including sleep, exercise, diet and smoking habits of the participants was collected by questionnaire and Pittsburgh sleep quality index scale (PSQI) was collected. Thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TgAb) and urine iodine concentration (UIC) were tested. Thyroid homeostasis parameter thyroid' s secretory capacity (SPINA-GT), Jostel's TSH index (TSHI), thyrotroph T4 sensitivity index (TTSI) were calculated. Logistic regression and multiple linear regression were performed to assess associations. RESULTS: Compared with euthyroid subjects, patients with SCH were more likely to have poor overall sleep quality (15.1 vs.25.8 %, P = 0.018) and l less likely to stay up late on weekdays (54.7 vs. 23.9 % P < 0.001). In SCH group, exercise was the influencing factor of TSH (ß= -0.224, P = 0.004), thyroid secretory capacity (ß = 0.244, P = 0.006) and thyrotropin resistance (ß = 0.206, P = 0.009). Iodine excess was the influencing factor of thyroid secretory capacity (ß = 0.209, P = 0.001) and pituitary thyroid stimulating function (ß = 0.167, P = 0.034). Smoking was the influencing factor of pituitary thyroid stimulating function (ß = 0.161, P = 0.040). Staying up late on weekends was the influencing factor of thyroid secretory capacity (ß = 0.151, P = 0.047). After adjusting for possible confounders, logistic regression showed that those with poor overall sleep quality assessed by PSQI and iodine excess had an increased risk of SCH (OR 2.159, 95 %CI 1.186-3.928, P = 0.012 and OR 2.119, 95 %CI 1.008-4.456, P = 0.048, respectively). CONCLUSIONS: Lifestyle including sleep, smoking, diet and exercise was closely related to thyroid function especially thyroid homeostasis in SCH.

Recurrent non-severe hypoglycemia aggravates cognitive decline in diabetes and induces mitochondrial dysfunction in cultured astrocytes.

The present study aimed to determine the relationship between astrocytes and recurrent non-severe hypoglycemia (RH)2 -associated cognitive decline in diabetes. RH induced cognitive impairment and neuronal cell death in the cerebral cortex of diabetic mice, accompanied by excessive activation of astrocytes. Levels of the neurotrophins BDNF and GDNF, together with BDNF and GDNF- related signaling, were downregulated by RH. In vitro, recurrent low glucose (RLG)3 impaired cell viability and induced apoptosis of high-glucose cultured astrocytes. Accumulating mitochondrial ROS and dysregulated mitochondrial functions, including abnormal morphology, decreased membrane potential, downregulated ATP levels, and disrupted bioenergetic status, were observed in these cells. SS-31 mediated protection of mitochondrial functions reversed RLG-induced cell viability defects and neurotrophin production. These findings demonstrate that RH induced astrocyte overactivation and mitochondrial dysfunction, leading to astrocyte-derived neurotrophin disturbance, which might contribute to diabetic cognitive decline. Targeting astrocyte mitochondria might represent a neuroprotective therapy for hypoglycemia-associated neurodegeneration in diabetes.

Insufficient nocturnal sleep was associated with a higher risk of fibrosis in patients with diabetes with metabolic associated fatty liver disease.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) refers to metabolic dysfunction associated with fatty liver disease, and liver fibrosis stage is closely connected with liver-related and all-cause mortality. This study aimed to explore the association of sleep duration with liver fibrosis in the diabetic subgroup of the MAFLD population. METHODS: This retrospective study analyzed 342 patients with MAFLD. Anthropometric measurements, clinical and biochemical markers, and lifestyle parameters were collected. Fibrosis was defined as fibrosis-4 ⩾1.3. Propensity score matching (PSM) was performed to match cases. Student's t-test and chi-square tests were applied for group comparisons, and binary regression models were used to explore the independent risk factors of liver fibrosis. RESULTS: Among the 342 subjects, 87 (25.4%) were diagnosed with fibrosis and 255 (74.6%) without. Baseline characteristic comparisons showed differences in age and diabetes duration between the two groups, and adjustment was made by PSM. Ultimately, the fibrosis group and nonfibrosis group each had 87 patients. The fibrosis group had shorter duration of nocturnal sleep (6.77 ± 1.59 h) than the nonfibrosis group (7.77 ± 1.92 h, p < 0.001). More patients in the fibrosis group stayed up late at night (32.2% versus 14.9%, p < 0.01). Visceral adipose tissue (VAT) areas were larger in the fibrosis group than in the nonfibrosis group (p < 0.001). Glycemic profile, lipid profile, gamma-glutamyl transferase level, and serum uric acid level were not significantly different between the two groups. In the multivariate regression analysis, nocturnal sleep and VAT areas were independently associated with liver fibrosis, with odds ratios of 0.694 [95% confidence interval (CI) 0.551-0.875, p < 0.01] for nocturnal sleep and 1.031 (95% CI 1.014-1.048, p < 0.001) for VAT areas. CONCLUSION: Insufficient nocturnal sleep was independently related to a higher risk of fibrosis. Sleep modification might be beneficial in promoting the health of patients with MAFLD.

Exenatide alleviates mitochondrial dysfunction and cognitive impairment in the 5×FAD mouse model of Alzheimer's disease.

The role of mitochondrial dysfunction has been well-documented in Alzheimer's disease (AD). Glucagon-like peptide 1 (GLP-1) receptor agonists are being utilized as neuroprotectants in the treatment of various neurological disorders, including AD. We conducted this study to explore the effects of exenatide (a GLP-1 receptor agonist) on ß-amyloid plaque (Aß)-induced cognitive impairment and mitochondrial dysfunction in 5xFAD transgenic mice. Spatial memory test showed that exenatide administration (100 µg/kg twice per day) prevented cognitive decline after 16 weeks of treatment. Aß1-42 deposition and synapse damage in the hippocampus was significantly alleviated. Furthermore, exenatide treatment can improve mitochondrial morphology, relieve oxidative damage, correct mitochondrial energy crisis, and normalize mitochondrial dynamics. These findings suggest that exenatide, which has already been applied in clinical medicine, may be a promising agent for AD therapy via mitochondrial protection.

Hypertension outcomes of adrenalectomy in patients with primary aldosteronism: a systematic review and meta-analysis.

BACKGROUND: The hypertension cure rate of unilateral adrenalectomy in primary aldosteronism (PA) patients varies widely in existing studies. METHODS: We conducted an observational meta-analysis to summarize the pooled hypertension cure rate of unilateral adrenalectomy in PA patients. Comprehensive electronic searches of PubMed, Embase, Cochrane, China National Knowledge Internet (CNKI), WanFang, SinoMed and Chongqing VIP databases were performed from initial state to May 20, 2016. We manually selected eligible studies from references in accordance with the inclusion criteria. The pooled hypertension cure rate of unilateral adrenalectomy in PA patients was calculated using the DerSimonian-Laird method to produce a random-effects model. RESULTS: Forty-three studies comprising approximately 4000 PA patients were included. The pooled hypertension cure rate was 50.6% (95% CI: 42.9-58.2%) for unilateral adrenalectomy in PA. Subgroup analyses showed that the hypertension cure rate was 61.3% (95% CI: 49.4-73.3%) in Chinese studies and 43.7% (95% CI: 38.0-49.4%) for other countries. Furthermore, the hypertension cure rate at 6-month follow-up was 53.3% (95% CI: 36.0-70.5%) and 49.6% (95% CI: 40.9-58.3%) for follow-up exceeding 6 months. The pooled hypertension cure rate was 50.9% (95% CI: 40.5-61.3%) from 2001 to 2010 and 50.2% (95% CI: 39.0-61.5%) from 2011 to 2016. CONCLUSIONS: The hypertension cure rate for unilateral adrenalectomy in PA is not optimal. Large clinical trials are required to verify the utility of potential preoperative predictors in developing a novel and effective prediction model.

Prevalence, risk factors, and prognosis of orthostatic hypotension in diabetic patients: A systematic review and meta-analysis.

BACKGROUND: Orthostatic hypotension (OH) is a major clinical sign of cardiovascular autonomic dysfunction in diabetic patients. Our aim was to quantitatively evaluate the prevalence and risk factors of OH in patients with diabetes mellitus (DM) and assess its prognosis. METHODS: A comprehensive search of the PubMed, Embase, China National Knowledge Infrastructure, VIP Chinese Journal, Wanfang, and SINOMED databases was conducted for related published work up to September 25, 2016, and manually searched eligible studies from the references in accordance with the inclusion criteria. RESULTS: We included 21 studies in the analysis, with a total sample size of 13,772. The pooled prevalence of OH in DM was 24% (95% confidence interval [CI]: 19-28%). Potential risk factors, that is, glycosylated hemoglobin A (HbA1c) (odds ratio [OR], 1.13, 95% CI, 1.07-1.20), hypertension (OR, 1.02, 95% CI, 1.01-1.02), and diabetic nephropathy (OR, 2.37, 95% CI, 1.76-3.19), were significantly associated with OH in DM. In addition, the prognosis of OH in DM was associated with higher risk of total mortality and cardiovascular events. CONCLUSION: The pooled prevalence of OH in DM appears high. HbA1c, hypertension, and diabetic nephropathy are risk factors for OH in DM. OH indicates poor prognosis in diabetic patients. Attention should be focused on diabetic patients with the stated risk factors to prevent OH.

Thyroid hormone treatment activates protective pathways in both in vivo and in vitro models of neuronal injury.

Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase (Dio2) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase (Dio3) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin, genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro. Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes (VEGF, Enolase, HIF2α, c-Jun) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless, important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury.

Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3ß pathway in an amyloid ß protein induced alzheimer disease mouse model.

Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). The glucagon-like peptide-1 analog liraglutide, a novel long-lasting incretin hormone, has been used to treat type 2 diabetes mellitus. In addition, liraglutide has been shown to be neurotrophic and neuroprotective. Here, we investigated the effects of liraglutide on amyloid ß protein (Aß)-induced AD in mice and explored its mechanism of action. The results showed that subcutaneous administration of liraglutide (25nmol/day), once daily for 8 weeks, prevented memory impairments in the Y Maze and Morris Water Maze following Aß1-42 intracerebroventricular injection, and alleviated the ultra-structural changes of pyramidal neurons and chemical synapses in the hippocampal CA1 region. Furthermore, liraglutide reduced Aß1-42-induced tau phosphorylation via the protein kinase B and glycogen synthase kinase-3ß pathways. Thus liraglutide may alleviate cognitive impairment in AD by at least decreasing the phosphorylation of tau.

[Exendin-4 ameliorates high glucose- and TNF-α-induced vascular endothelial cell damage by inhibiting p38 MAPK and NF-κB p65 translocation].

OBJECTIVE: To investigate the protective effects of exendin-4 on vascular endothelial cells and explore the possible mechanism. METHODS: Human umbilical vascular endothelial cells (HUVECs) were cultured in the presence of high glucose and tumor necrosis factor-α (TNF-α, 10 ng/ml) with or without exendin-4. The level of nitric oxide (NO) in the cell culture supernatant was measured using a nitrate reductase method. The expression of intercellular adhesion molecule-1 (ICAM-1) mRNA was measured by real-time PCR, and nuclear factor-κB (NF-κB) p65 translocation was detected using immunofluorescence assay. Western blotting was employed to measure the expression of p38 MAPK protein in the treated cells. RESULTS: In the presence of high glucose and TNF-α, treatment of cells with exendin-4 did not obviously affect the cellular synthesis of NO, but significantly down-regulated the expression of ICAM-1 mRNA (P<0.01). The nuclear fluorescence intensity of NF-κB p65 and the expression level of p38 MAPK protein in the cells were significantly lowered by exendin-4 treatment (P<0.01). CONCLUSION: Exendin-4 ameliorates high glucose- and TNF-α-induced HUVEC-12 cell damage by inhibiting the expression of p38 MAPK protein and translocation of NF-κB p65.