Research advances in the anti-inflammatory effects of SGLT inhibitors in type 2 diabetes mellitus.

Diabetes mellitus is one of the most significant global burden diseases. It is well established that a chronic, systemic, low-grade inflammatory condition is strongly correlated with type 2 diabetes mellitus (T2D) and the development of target-organ damage (TOD). Sodium-glucose cotransporter inhibitors (SGLTis), novel oral drugs for the treatment of diabetes, act mainly by reducing glucose reabsorption in proximal renal tubules and/or the intestine. Several high-quality clinical trials and large observational studies have revealed that SGLTis significantly improve cardiovascular and renal outcomes in T2D patients. Increasing evidence suggests that this is closely related to their anti-inflammatory properties, which are mainly manifested by a reduction in plasma concentrations of inflammatory biomarkers. This review analyses the potential mechanisms behind the anti-inflammatory effects of SGLTis in diabetes and presents recent evidence of their therapeutic efficacy in treating diabetes and related TOD.

Importance of Bmal1 in Alzheimer's disease and associated aging-related diseases: Mechanisms and interventions.

With the aging world population, the prevalence of aging-related disorders is on the rise. Diseases such as Alzheimer's, type 2 diabetes mellitus (T2DM), Parkinson's, atherosclerosis, hypertension, and osteoarthritis are age-related, and most of these diseases are comorbidities or risk factors for AD; however, our understandings of molecular events that regulate the occurrence of these diseases are still not fully understood. Brain and muscle Arnt-like protein-1 (Bmal1) is an irreplaceable clock gene that governs multiple important physiological processes. Continuous research of Bmal1 in AD and associated aging-related diseases is ongoing, and this review picks relevant studies on a detailed account of its role and mechanisms in these diseases. Oxidative stress and inflammation turned out to be common mechanisms by which Bmal1 deficiency promotes AD and associated aging-related diseases, and other Bmal1-dependent mechanisms remain to be identified. Promising therapeutic strategies involved in the regulation of Bmal1 are provided, including melatonin, natural compounds, metformin, d-Ser2-oxyntomodulin, and other interventions, such as exercise, time-restricted feeding, and adiponectin. The establishment of the signaling pathway network for Bmal1 in aging-related diseases will lead to advances in the comprehension of the molecular and cellular mechanisms, shedding light on novel treatments for aging-related diseases and promoting aging-associated brain health.

Preadmission Insulin-Treated Type 2 Diabetes Mellitus Patients Had Increased Mortality in Intensive Care Units.

Aim: To explore the clinical outcomes among preadmission insulin-treated type 2 diabetes mellitus (T2DM) in intensive care units (ICU). Patients and Methods: In this retrospective observational study, 578 T2DM patients admitted to ICU were recruited from March 2011 to February 2021, which were composed of 528 patients treated with insulin after ICU admission (including 300 preadmission non-insulin-treated and 228 preadmission insulin-treated patients) and 50 patients treated without insulin before and after ICU admission. Clinical outcomes were compared between the groups. Variables of age (± 10 years), gender, blood glucose >10 mmol/l on ICU admission, and original comorbidities were used for matching to get the 1:1 matched cohort. The Kaplan-Meier survival curves were graphed to describe the survival trend and Cox regression analysis was performed to get adjusted hazard ratio (HR). Results: Compared with the preadmission non-insulin-treated T2DM patients, preadmission insulin-treated T2DM patients had higher incidence of hypoglycemia [14.5% (33/228) vs 8.7% (26/300); p = 0.036]. In the 1:1 matched cohort, the preadmission insulin-treated T2DM patients had significantly increased mortality rate [30.0% (45/150) vs (16.0% (24/150)); adjusted HR, 1.68 (1.01-2.80)] than preadmission non-insulin-treated T2DM patients. Compared with T2DM patients treated without insulin before and after ICU admission, preadmission insulin-treated T2DM patients had higher mortality and longer length of ICU stay (all p < 0.05). Conclusion: Preadmission insulin treatment was associated with increased mortality rate and longer length of ICU stay among T2DM patients in ICU. Preadmission insulin-treated T2DM patients might have worse clinical outcomes when they are critically ill.

Time-restricted feeding rescues circadian disruption-aggravated progression of Alzheimer's disease in diabetic mice.

Circadian rhythms, type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are closely related and interacted with each other. We have previously showed circadian disruption aggravated progression of AD in T2DM mice. Time-restricted feeding (TRF) is shown to be a potential synchronizer. This study aims to determine whether TRF has a protective effect against the circadian disruption-aggravated progression of AD in T2DM. 6-week-old male diabetic (db/db) mice and wildtype (wt/wt) mice were kept under normal 12:12 light/dark cycles or altered 6:18 light/dark cycles (dark extended to 18 h) with or without TRF (food restricted to 8 h during the active (dark) period). After 8 weeks, three behavioral tests (open field test, novel object recognition test, barnes maze test) were performed and the circadian gene expression, body weight, lipid levels and AD-associated tau phosphorylation were evaluated. We found altered light/dark cycles contributed to disruptive circadian rhythms in the hippocampus of db/db mice, while TRF prevented this effect. TRF also ameliorated circadian disruption-aggravated increased body weight and lipid accumulation in db/db mice. Importantly, the db/db mice under circadian disruption showed impaired cognition accompanied by increased tau phosphorylation, whereas TRF reversed these changes. The altered light/dark cycles only affected circadian rhythms but not other indicators like plasma/liver lipids, cognition and tau phosphorylation in the wt/wt mice. Collectively, TRF has a protective effect against altered light/dark cycles-aggravated AD progression in diabetic mice.

A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) patients are at a higher risk of developing Alzheimer's disease (AD). Mounting evidence suggests the emerging important role of circadian rhythms in many diseases. Circadian rhythm disruption is considered to contribute to both T2DM and AD. Here, we review the relationship among circadian rhythm disruption, T2DM and AD, and suggest that the occurrence and progression of T2DM and AD may in part be associated with circadian disruption. Then, we summarize the promising therapeutic strategies targeting circadian dysfunction for T2DM and AD, including pharmacological treatment such as melatonin, orexin, and circadian molecules, as well as non-pharmacological treatments like light therapy, feeding behavior, and exercise.

Catestatin enhances ATP-induced activation of glial cells mediated by purinergic receptor P2X4.

The activation of glial cells and its possible mechanism play an extremely important role in understanding the pathophysiological process of some clinical diseases, and catestatin (CST) is involved in regulating this activation. In this project, we found that CST could enhance the activation of satellite glial cells (SGCs) and microglial cells and that the expression of P2X4 was increased; the co-expression of the P2X4 receptor with glial fibrillary acidic protein (GFAP) and the P2X4 receptor with CD11b was also increased significantly in glial cells of the ATP + CST group, and TNF-α and IL-1ß also showed a rising trend; the expression of phosphorylated ERK1/2 was also increased in the ATP + CST group. In summary, we conclude that CST could enhance ATP-induced activation of SGCs and microglial cells mediated by the P2X4 receptor and that the ERK1/2 signaling pathway may be involved in this activation process.

Association of ANGPTL8 and Resistin With Diabetic Nephropathy in Type 2 Diabetes Mellitus.

Background: Previous studies showed altered angiopoietin-like protein-8 (ANGPTL-8) and resistin circulating levels in type 2 diabetes mellitus (T2DM). Whether or not the alteration in ANGPTL-8 and resistin level can be a predictive maker for increased diabetic nephropathy risk remains unclear. Aim: To Investigate the possible association of ANGPTL-8 and resistin with DN, and whether this association is affected by NAFLD status. Methods: A total of 278 T2DM patients were enrolled. Serum levels of ANGPTL8, resistin, BMI, blood pressure, duration of diabetes, glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), hypersensitive C-reactive protein (hs-CRP), lipid profile, liver, and kidney function tests were assessed. The relationship between DN with ANGPTL8 and resistin was analyzed in the unadjusted and multiple-adjusted regression models. Results: Serum levels of ANGPTL8 and resistin were significantly higher in DN compared with T2DM subjects without DN (respectively; P <0.001), especially in non-NAFLD populations. ANGPTL8 and resistin showed positive correlation with hs-CRP (respectively; P<0.01), and negative correlation with estimated GFR (eGFR) (respectively; P=<0.001) but no significant correlation to HOMA-IR(respectively; P>0.05). Analysis showed ANGPTL8 levels were positively associated with resistin but only in T2DM patients with DN(r=0.1867; P<0.05), and this significant correlation disappeared in T2DM patients without DN. After adjusting for confounding factors, both ANGPTL8(OR=2.095, 95%CI 1.253-3.502 P=0.005) and resistin (OR=2.499, 95%CI 1.484-4.208 P=0.001) were risk factors for DN. Data in non-NAFLD population increased the relationship between ANGPTL8 (OR=2.713, 95% CI 1.494-4.926 P=0.001), resistin (OR=4.248, 95% CI 2.260-7.987 P<0.001)and DN. The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and resistin was 0.703, and the specificity was 70.4%. These data were also increased in non-NAFLD population, as the AUC (95%CI) was 0.756, and the specificity was 91.2%. Conclusion: This study highlights a close association between ANGPTL8, resistin and DN, especially in non-NAFLD populations. These results suggest that ANGPTL-8 and resistin may be risk predictors of DN.

Disruption of Circadian Clocks Promotes Progression of Alzheimer's Disease in Diabetic Mice.

The circadian clock is an endogenous system designed to anticipate and adapt to daily changes in the environment. Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is more prevalent in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disruption on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (a 6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability, and AD-related pathophysiology. Our results indicated that housing in these conditions led to disrupted diurnal circadian rhythms in the hippocampus of db/db mice and contributed to their weight gain. In the brain, the circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in amyloid protein (Aß) plaque deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under the 6:18 light/dark cycle. Circadian alterations could promote the development of AD in T2DM.

Regulatory mechanisms and therapeutic potential of microglial inhibitors in neuropathic pain and morphine tolerance.

Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.

Modeling, analysis, and validation of an active T-shaped noise barrier.

With ever-increasing land traffic, abatement of traffic noise using noise barriers remains significant, yet it is a challenging task due to spatial competition with other infrastructure. In this study, a deep insight into the diffraction characteristics of acoustic fields near noise barriers of various geometries and surface conditions was achieved using numerical simulations. A T-shaped passive noise barrier with acoustically soft upper surfaces was demonstrated to outperform other candidates in a middle- or high-frequency range. Based on attributes of the acoustic field diffracted by T-shaped barriers, an active control strategy was developed to revamp the T-shaped barrier, in which a filtered minimax algorithm was established to drive the secondary sound sources. This algorithm resulted in more uniformly distributed residual sound fields than a filtered-X least mean square algorithm. Performance of the actively controlled barrier was evaluated at different positions and spacings of secondary sound sources and error sensors, leading to a series of optimal criteria for the design of active noise barriers. A prototype was fabricated and validated experimentally, manifesting particular effectiveness in insulating low-frequency noise, supplementing well the capacity of a passive T-shaped barrier which is effective in the middle- or high-frequency range.