Diabetes-associated Cognitive Decline Research Articles

Protective effects of berberine against diabetes-associated cognitive decline in mice.

Diabetes associated cognitive decline (DACD) is a common CNS-related consequence of diabetes. The primary clinical manifestation of DACD includes learning and memory impairment. Unfortunately, there is no cure to delay the cognitive symptoms of diabetes. Although berberine (BBR) has shown promising effect in the treating diabetes and cognitive dysfunction, more research is needed to understand the mechanism of its therapeutic effect. For better understanding, we investigated the functions of BBR involved in anti-inflammation, anti-oxidant and neuroprotection in the hippocampus of diabetic mice. Diabetes was induced in mice using STZ. BBR was administered for 4 weeks before (pre-treatment), and after (post-treatment) STZ administration. The effect of BBR on cognitive functions in diabetic mice was determined using neurobehavioural test. Moreover, how BBR affected neuroinflammation, oxidative stress, and acetylcholine levels in the hippocampus and BBB permeability were analyzed using standard biochemical assays. Lastly, we evaluated the mRNA expression of neuroprotective genes in the hippocampus to uncover the mechanism of BBR. Treatment with BBR improved cognition in diabetic mice. It significantly reduced the levels of IL-6, iNOS, TNF-α, IL-1β, ROS and MDA and increased the levels of TAC, GSH, SOD and Catalase. Moreover, levels of acetylcholine and BBB permeability were reduced in the diabetic mice which was reversed by BBR treatment and increased the expression of IGF and BDNF in the hippocampus of diabetic mice. Our results suggest that BBR might be a potential therapeutic candidate for the treatment of DACD. Our study might serve as a basis for developing novel drugs for treating DACD.

Vitamin K2 Ameliorates Diabetes-Associated Cognitive Decline by Reducing Oxidative Stress and Neuroinflammation.

Diabetes, a chronic metabolic disease, affects approximately 422million people and leads to 1.5million deaths every year, It is found that 45% of individuals with diabetes eventually develop cognitive impairment. Here we study effects of Vitamin K2 on diabetes-associated cognitive decline (DACD) and its underlying mechanism. Diabetes was induced in adult Swiss albino mice with high-fat diet and a low dose (35mg/kg) of streptozotocin and measured by fasting glucose and HbA1c levels. After one week of development of diabetes, one group of animals received Vitamin K2 (100µg/kg) via oral gavage for 21 days. Then different behavioural studies, including the elevated plus maze, Morris water maze, passive avoidance test and novel object recognition test were performed followed by biochemical tests including AchE, different oxidative stress parameters (SOD, GSH, MDA, catalase, SIRT1, NRF2), inflammatory markers (TNFα, IL1β, MCP1, NFκB), apoptosis marker (Caspase 3). Hippocampal neuronal density was measured using histopathology. Vitamin K2 treatment in diabetic animals led to reduced fasting glucose and HbA1c, It could partially reverse DACD as shown by behavioural studies. Vitamin K2 adminstration reduced corticohippocampal AchE level and neuroinflammation (TNFα, IL1β, MCP1, NFκB, SIRT1). It reduced oxidative stress by increasing antioxidant enzymes (SOD, GSH, catalase), transcription factor NRF2 while reducing caspase 3. This eventually increased CA1 and CA3 neuronal density in diabetic animals. Vitamin K2 partially reverses DACD by increasing ACh while reducing the oxidative stress via Nrf2/ARE pathway and neuroinflammation, thus protecting the hippocampal neurons from diabetes associated damage.

Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

Abnormal resting-state functional connectivity of hippocampal subregions in type 2 diabetes mellitus-associated cognitive decline.

Type 2 diabetes mellitus (T2DM) over time predisposes to inflammatory responses and abnormalities in functional brain networks that damage learning, memory, or executive function. The hippocampus is a key region often reporting connectivity abnormalities in memory disorders. Here, we investigated peripheral inflammatory responses and resting-state functional connectivity (RSFC) changes characterized of hippocampal subregions in type 2 diabetes-associated cognitive decline (T2DACD). The study included 16 patients with T2DM, 16 patients with T2DACD and 25 healthy controls (HCs). Subjects were assessed for cognitive performance, tested for the expression of inflammatory factors IL-6, IL-10 and TNF-α in peripheral serum, underwent resting-state functional magnetic resonance imaging scans, and analyzed for RSFC using the hippocampal subregions as seeds. We also calculated the correlation between cognitive performance and RSFC of hippocampal subregion, and analyzed the significantly altered RSFC values of T2DACD for Receiver Operating Characteristic (ROC) analysis. T2DACD patients showed a decline in their ability to complete cognitive assessment scales and experimental paradigms, and T2DM did not show abnormal cognitive performance. IL-6 expression was increased in peripheral serum in both T2DACD and T2DM. Compared with HCs, T2DACD showed abnormalities RSFC of the left anterior hippocampus with left precentral gyrus and left angular gyrus. T2DM showed abnormalities RSFC of the left middle hippocampus with right medial frontal gyrus, right anterior and middle hippocampus with left precuneus, left anterior hippocampus with right precuneus and right posterior middle temporal gyrus. Compared with T2DM, T2DACD showed abnormalities RSFC of the left posterior hippocampus and right middle hippocampus with left precuneus. In addition, RSFC in the left posterior hippocampus with left precuneus of T2DACD was positively correlated with Flanker conflict response time (r=0.766, P=0.001). In the ROC analysis, the significantly altered RSFC values of T2DACD achieved significant performance. T2DACD showed a significant decrease in attentional inhibition and working memory, peripheral pro-inflammatory response increased, and abnormalities RSFC of the hippocampal subregions with default mode network and sensory-motor network. T2DM did not show a significant cognitive decline, but peripheral pro-inflammatory response increased and abnormalities RSFC of the hippocampus subregions occurred in the brain. In addition, the left precuneus may be a key brain region in the conversion of T2DM to T2DACD. The results of this study may provide a basis for the preliminary diagnosis of T2DACD.

ZiBu PiYin recipe regulates central and peripheral Aβ metabolism and improves diabetes-associated cognitive decline in ZDF rats

Ethnopharmacological relevanceCognitive impairment caused by central neuropathy in type 2 diabetes mellitus (T2DM), namely diabetes-associated cognitive decline (DACD), is one of the common complications in patients with T2DM. Studies have shown that brain β-amyloid (Aβ) deposition is a typical pathological change in patients with DACD, and that there is a close relationship between intestinal microorganisms and cognitive impairment. However, the specific mechanism(s) of alteration in Aβ metabolism in DACD, and of the correlation between Aβ metabolism and intestinal microorganisms remain unknown. Aim of the studyRevealing the mechanism of ZBPYR regulating Aβ metabolism and providing theoretical basis for clinical evaluation and diagnosis of DACD. Materials and methodsWe characterized Aβ metabolism in the central and peripheral tissues of Zucker diabetic fatty (ZDF) rats with DACD, and then explored the preventive and therapeutic effects of ZiBu PiYin Recipe (ZBPYR). Specifically, we assessed these animals for the formation, transport, and clearance of Aβ; the morphological structure of the blood-brain barrier (BBB); and the potential correlation between Aβ metabolism and intestinal microorganisms. ResultsZBPYR provided improvements in the structure of the BBB, attenuation of Aβ deposition in the central and peripheral tissues, and a delay in the development of DACD by improving the expression of Aβ production, transport, and clearance related protein in ZDF rats. In addition, ZBPYR improved the diversity and composition of intestinal microorganisms, decreased the abundance of Coprococcus, a bacterium closely related to Aβ production, and up regulate the abundance of Streptococcus, a bacterium closely related to Aβ clearance. ConclusionThe mechanism of ZBPYR ability to ameliorate DACD may be closely related to changes in the intestinal microbiome.

Fingolimod alleviates type 2 diabetes associated cognitive decline by regulating autophagy and neuronal apoptosis via AMPK/mTOR pathway

This study aimed to reveal the role of fingolimod (FTY720) in mice with type 2 diabetes-associated cognitive decline and explore its potential neuroprotective mechanism. Mice were divided into five groups: normal control, normal control + FTY720 (1.0 mg/kg/day), type 2 diabetes mellitus, type 2 diabetes mellitus + low-dose FTY720 (0.5 mg/kg/day), and type 2 diabetes mellitus + high-dose FTY720 (1.0 mg/kg/day). Different doses of FTY720 were administered daily for 8 weeks after the induction of type 2 diabetes using a four-week high-fat diet feeding combined with continuous low-dose intraperitoneal injections of streptozotocin. After 8 weeks of treatment, the body weights and fasting blood glucose levels of mice from the five groups were compared. Morris water maze and new object recognition tests were used to evaluate cognitive function. Pathological changes in the hippocampal CA1 region were observed using haematoxylin-eosin and Nissl staining, and the ultrastructure of the hippocampal neurones was assessed using transmission electron microscopy. The expression levels of autophagy- and apoptosis-related proteins, such as LC3, Beclin-1, P62, Bax, and Bcl-2, in the mice hippocampus were detected by western blotting. Simultaneously, AMPK/mTOR signaling pathway proteins were detected to understand the potential mechanism. FTY720 had no significant effect on the body weight or fasting blood glucose levels in mice with type 2 diabetes. However, both FTY720 doses improved the cognitive function and hippocampal damage. In addition, the results suggested that FTY720 dramatically decreased P62 and Bax levels and increased LC3 II/LC3 I ratio, Beclin-1, and Bcl-2 expression in the hippocampus of type 2 diabetic mice. FTY720 also affected the expression of the AMPK/mTOR signaling pathway. Thus, FTY720 improved cognitive function and hippocampal pathological changes in type 2 diabetic mice without affecting fasting blood glucose levels. Our results show that FTY720 may exert neuroprotective effects in vivo by enhancing hippocampal autophagy and inhibiting apoptosis via the AMPK/mTOR signaling pathway.

Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

Efficacy and safety of the integration of traditional Chinese medicine and western medicine in the treatment of diabetes-associated cognitive decline: a systematic review and meta-analysis

Objective: In order to offer possible therapeutic treatment evidence for diabetes-associated cognitive decline (DACD), we thoroughly evaluated the effectiveness and safety of combining Traditional Chinese Medicine (TCM) and Western Medicine (WM) in the current study.Methods: The present study employed a comprehensive search strategy across multiple databases, namely, PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, Chinese Scientific Journals Database (VIP), and Chinese Biomedical Literature Database (CBM), to identify relevant articles published until July 2023. Subsequently, a systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted to assess the efficacy and safety of integrating TCM with WM for the treatment of DACD. The literature included in this study was assessed using the GRADE criteria and the Cochrane Handbook for Systematic Reviews of Interventions. Statistical analysis was conducted using RevMan 5.4 software.Results: A total of 20 RCTs involving 1,570 patients were ultimately included in this meta-analysis. The pooled results demonstrated that the integration of TCM and WM therapy significantly enhanced the overall effectiveness rate compared to WM therapy alone [OR = 4.94, 95% CI (3.56, 6.85), p < 0.00001]. Additionally, the combination therapy resulted in reductions in fasting blood glucose [MD = −0.30, 95% CI (−0.49, −0.10), p = 0.003], HbA1c [MD = −0.71, 95%CI (−1.03, −0.40), p < 0.00001], TNF-α levels [MD = −8.28, 95%CI (−13.12, −3.44), p = 0.0008], and TCM Syndrome Score [MD = −5.97, 95%CI (−9.06, −2.88), p = 0.0002]. Meanwhile, the combination therapy had a positive effect on MoCA Score [MD = 2.52, 95% CI (1.75, 3.30), p < 0.00001], and MMSE Score [MD = 2.31, 95% CI (1.33, 3.29), p < 0.00001]. In addition, the safety of the combination therapy was comparable to that of the WM alone [OR = 0.40, 95% CI (0.12, 1.31), p = 0.13].Conclusion: The integration of TCM and WM therapy outperformed WM alone in DACD treatment. Simultaneously, the combination therapy could improve the therapeutic effect on blood glucose, cognitive function, and inflammation to a certain extent with few adverse effects. However, given the constraints imposed by the quality limitations of the incorporated studies, as well as the potential presence of reporting bias, it is imperative that our findings be substantiated through rigorous, large-scale, randomized controlled trials of superior quality in the future.

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline

Aims/hypothesisType 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets.MethodsSingle-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes.ResultsCompared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density.Conclusions/interpretationTaken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes.Data availabilityThe single-cell sequencing data that supports this study are available at GEO accession GSE217665 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217665).Graphical

Molecular mechanisms underlying hyperglycemia associated cognitive decline.

Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia. DM can lead to a number of secondary complications affecting multiple organs in the body including the eyes, kidney, heart, and brain. The most common effect of hyperglycemia on the brain is cognitive decline. It has been estimated that 20-70% of people with DM have cognitive deficits. High blood sugar affects key brain areas involved in learning, memory, and spatial navigation, and the structural complexity of the brain has made it prone to a variety of pathological disorders, including T2DM. Studies have reported that cognitive decline can occur in people with diabetes, which could go undetected for several years. Moreover, studies on brain imaging suggest extensive effects on different brain regions in patients with T2D. It remains unclear whether diabetes-associated cognitive decline is a consequence of hyperglycemia or a complication that co-occurs with T2D. The exact mechanism underlying cognitive impairment in diabetes is complex; however, impaired glucose metabolism and abnormal insulin function are thought to play important roles. In this review, we have tried to summarize the effect of hyperglycemia on the brain structure and functions, along with the potential mechanisms underlying T2DM-associated cognitive decline.

Impaired lipophagy induced-microglial lipid droplets accumulation contributes to the buildup of TREM1 in diabetes-associated cognitive impairment

ABSTRACT Neuroinflammation caused by microglial activation and consequent neurological impairment are prominent features of diabetes-associated cognitive impairment (DACI). Microglial lipophagy, a significant fraction of autophagy contributing to lipid homeostasis and inflammation, had mostly been ignored in DACI. Microglial lipid droplets (LDs) accumulation is a characteristic of aging, however, little is known about the pathological role of microglial lipophagy and LDs in DACI. Therefore, we hypothesized that microglial lipophagy could be an Achilles’s heel exploitable to develop effective strategies for DACI therapy. Here, starting with characterization of microglial accumulation of LDs in leptin receptor-deficient (db/db) mice and in high-fat diet and STZ (HFD/STZ) induced T2DM mice, as well as in high-glucose (HG)-treated mice BV2, human HMC3 and primary mice microglia, we revealed that HG-dampened lipophagy was responsible for LDs accumulation in microglia. Mechanistically, accumulated LDs colocalized with the microglial specific inflammatory amplifier TREM1 (triggering receptor expressed on myeloid cells 1), resulting in the buildup of microglial TREM1, which in turn aggravates HG-induced lipophagy damage and subsequently promoted HG-induced neuroinflammatory cascades via NLRP3 (NLR family pyrin domain containing 3) inflammasome. Moreover, pharmacological blockade of TREM1 with LP17 in db/db mice and HFD/STZ mice inhibited accumulation of LDs and TREM1, reduced hippocampal neuronal inflammatory damage, and consequently improved cognitive functions. Taken together, these findings uncover a previously unappreciated mechanism of impaired lipophagy-induced TREM1 accumulation in microglia and neuroinflammation in DACI, suggesting its translational potential as an attractive therapeutic target for delaying diabetes-associated cognitive decline. Abbreviations: ACTB: beta actin; AIF1/IBA1: allograft inflammatory factor 1; ALB: albumin; ARG1: arginase 1; ATG3: autophagy related 3; Baf: bafilomycin A1; BECN1: beclin 1, autophagy related; BW: body weight; CNS: central nervous system; Co-IP: co-immunoprecipitation; DACI: diabetes-associated cognitive impairment; DAPI: 4’,6-diamidino-2-phenylindole; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; DMEM: Dulbecco’s modified Eagle’s medium; DSST: digit symbol substitution test; EDTA: ethylenedinitrilotetraacetic acid; ELISA: enzyme linked immunosorbent assay; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; HG: high glucose; IFNG/IFN-γ: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL4: interleukin 4; IL6: interleukin 6; IL10: interleukin 10; LDs: lipid droplets; LPS: lipopolysaccharide; MAP2: microtubule associated protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MWM: morris water maze; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family pyrin domain containing 3; NOS2/iNOS: nitric oxide synthase 2, inducible; NOR: novel object recognition; OA: oleic acid; PA: palmitic acid; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PLIN2: perilipin 2; PLIN3: perilipin 3; PS: penicillin-streptomycin solution; RAPA: rapamycin; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RELA/p65: RELA proto-oncogene, NF-kB subunit; ROS: reactive oxygen species; RT: room temperature; RT-qPCR: Reverse transcription quantitative real-time polymerase chain reaction; STZ: streptozotocin; SQSTM1/p62: sequestosome 1; SYK: spleen asociated tyrosine kinase; SYP: synaptophysin; T2DM: type 2 diabetes mellitus; TNF/TNF-α: tumor necrosis factor; TREM1: triggering receptor expressed on myeloid cells 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling;

Diabetes mellitus type 2 as an underlying, comorbid or consequent state of mental disorders

Somatic disturbances that occur in parallel with psychiatric diseases are a major challenge in clinical practice. Various factors contribute to the development of mental and somatic disorders. Type 2 diabetes mellitus (T2DM) is a significant health burden worldwide, and the prevalence of diabetes in adults is increasing. The comorbidity of diabetes and mental disorders is very common. By sharing a bidirectional link, both T2DM and mental disorders influence each other in various manners, but the exact mechanisms underlying this link are not yet elucidated. The potential mechanisms of both mental disorders and T2DM are related to immune and inflammatory system dysfunction, oxidative stress, endothelial dysfunction, and metabolic disturbances. Moreover, diabetes is also a risk factor for cognitive dysfunction that can range from subtle diabetes-associated cognitive decline to pre-dementia and dementia. A complex re-lationship between the gut and the brain also represents a new therapeutic approach since gut-brain signalling pathways regulate food intake and hepatic glucose production. The aim of this minireview is to summarize and present the latest data on mutual pathogenic pathways in these disorders, emphasizing their complexity and interweaving. We also focused on the cognitive performances and changes in neurodegenerative disorders. The importance of implementing integrated approaches in treating both of these states is highlighted, along with the need for individual therapeutic strategies.

Carnosine-Based Reversal of Diabetes-Associated Cognitive Decline via Activation of the Akt/mTOR Pathway and Modulation of Autophagy in a Rat Model of Type 2 Diabetes Mellitus

Introduction: Carnosine can suppress secondary complications in diabetes and show robust neuroprotective activity against neurodegenerative diseases. Here, we report that carnosine ameliorates diabetes-associated cognitive decline in vivo through the modulation of autophagy. Methods: A high-fat diet (HFD) and one intraperitoneal injection of 30 mg/kg streptozotocin (STZ) were used to induce type 2 diabetes mellitus in Sprague-Dawley rats. The rats were randomly divided into five groups: control (CON), HFD/STZ, and three intragastric carnosine treatment groups receiving low (100 mg/kg), medium (300 mg/kg), and high (900 mg/kg) doses over 12 weeks. Body weight, blood glucose levels, and cognitive function were continuously monitored. From excised rat hippocampi, we determined superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels; carnosine concentration; protein expressions of Akt, mTOR and the autophagy markers LC3B and P62 and performed histopathological evaluations of the cornu ammonis 1 region. Results: The HFD/STZ group showed increased blood glucose levels and decreased body weight compared to the CON group. However, there were no significant differences in body weight and blood glucose levels between carnosine-treated and -untreated HFD-STZ-induced diabetic rats. Diabetic animals showed obvious learning and memory impairments in the Morris water maze test compared to the CON group. Compared to those in the HFD/STZ group, carnosine increased SOD activity and decreased MDA levels, increased hippocampal carnosine concentration, increased p-Akt and p-mTOR expression, decreased LC3B and P62 expression, alleviated neuronal injuries, and improved cognitive performance in a dose-dependent manner. Conclusion: Independent of any hyperglycemic effect, carnosine may improve mild cognitive impairments by mitigating oxidative stress, activating the Akt/mTOR pathway, and modulating autophagy in the hippocampus of type 2 diabetic rats.

Lawsonia inermis flower aqueous extract expressed better anti-alpha-glucosidase and anti-acetylcholinesterase activity and their molecular dynamics

Lawsonia inermis (henna) has been used in traditional medicine throughout the world and biological property of its flower has been least explored. In the present study, the phytochemical characterization and biological activity (in vitro radical scavenging activity, anti-alpha glucosidase and anti-acetylcholinesterase) of aqueous extract prepared from henna flower (HFAE) was carried out by both Qualitative and quantitative phytochemical analysis and Fourier-transform infrared spectroscopy revealed the functional group of the phytoconstituents such as phenolics, flavonoids, saponin, tannins and glycosides. The phytochemicals present in HFAE was preliminary identified by liquid chromatography/electrospray ionization tandem mass spectrometry. The HFAE showed potent in vitro antioxidant activity and the HFAE inhibited mammalian α-glucosidase (IC50 = 129.1 ± 5.3 µg/ml; Ki = 38.92 µg/ml) and acetylcholinesterase (AChE; IC50 = 137.77 ± 3.5 µg/ml; Ki = 35.71 µg/ml) activity by competitive manner. In silico molecular docking analysis revealed the interaction of active constituents identified in HFAE with human α-glucosidase and AChE. Molecular dynamics simulation for 100 ns showed the stable binding of top two ligand/enzyme complexes with lowest binding energy such as 1,2,3,6-Tetrakis-O-galloyl-beta-D-glucose (TGBG)/human α-glucosidase, Kaempferol 3-glucoside-7-rhamnoside (KGR)/α-glucosidase, agrimonolide 6-O-β-D-glucopyranoside (AMLG)/human AChE and KGR/AChE. Through MM/GBSA analysis, the binding energy for TGBG/human α-glucosidase, KGR/α-glucosidase, AMLG/human AChE and KGR/AChE was found to be −46.3216, −28.5772, −45.0077 and −47.0956 kcal/mol, respectively. Altogether, HFAE showed an excellent antioxidant, anti-alpha glucosidase and anti-AChE activity under in vitro. This study suggest HFAE with remarkable biological activities could be further explored for therapeutics against type 2 diabetes and diabetes-associated cognitive decline.Communicated by Ramaswamy H. Sarma

Type 2 diabetes mellitus-associated cognitive impairment and management

Diabetes mellitus (DM) is a complex metabolic condition characterized by persistent hyperglycemia and poor metabolism due to insulin production irregularities and/or insulin resistance type 2 DM (T2DM) and dementia are linked through a variety of methods. Thus, in terms of the long-term repercussions of diabetes, the current idea focuses on cognitive damage, the exact pathophysiology of which is unknown. A new term, “diabetes-associated cognitive decline,” has recently been proposed to aid study in this field. This review discusses how different variables contribute to the development of T2DM. Furthermore, we investigated an expanding body of literature on insulin signaling in diabetics, as well as various factors such as insulin resistance, hyperglycemia, neuroinflammation, and Aβ (amyloid beta) plaques that may act alone or in combination to link T2DM with cognitive impairments. Finally, we looked at how physical activity and a balanced diet might help fight the condition.

Structural Alteration of Gut Microbiota During the Amelioration of Chronic Psychological Stress-Aggravated Diabetes-Associated Cognitive Decline by a Traditional Chinese Herbal Formula, ZiBu PiYin Recipe.

Chronic psychological stress (PS) hinders the treatment of diabetes-associated cognitive decline (DACD). However, the impact of chronic PS on the risk of developing DACD remains unclear. There is growing evidence that gut flora interventions are promising targets for treating stress-related diseases. We examined whether chronic PS triggers or exacerbates the onset of DACD in rats and aimed to elucidate whether ZiBuPiYin recipe (ZBPYR) prevents and treats chronic PS-aggravated DACD by dynamically maintaining the components of the gut microbiota. We performed chronic PS (restraint, rotation, and congestion) on ZDF rats to establish a model. Cognitive function was evaluated by behavioral experiments, and activation of the hypothalamic-pituitary-adrenal axis was detected by ELISA. Weekly feces from rats were collected for 16 S RNA sequencing. We found that chronic PS promoted cognitive abnormalities and exacerbated DACD phenotypes. Additionally, chronic PS altered intestinal flora diversity, dynamically elevating the abundance of Alistipes and Coprococcus; enriching Module 1 (Dorea, Blautia, Ruminococcus) and Module 48 (Blautia); and inhibiting Module 20 (Lactobacillus, SMB53), and Module 42 (Akkermansia). ZBPYR significantly alleviated hyperglycemia and cognitive impairment in chronic PS-aggravated DACD rats and dynamically reduced the abundance of Alistipes and Coprococcus; significantly enriched Module 3 (Ruminococcus) and Module 45 (Lactobacillus, Coprococcus, SMB53); and suppressed Module 2 (Lactobacillus), Module 16 (Turicibacter, Trichococcus, Lactobacillus, 02d06, Clostridium), Module 23 (Bifidobacterium), and Module 43 (Clostridium). ZBPYR might prevent and treat chronic PS-aggravated DACD by dynamically regulating Lactobacillus, Alistipes, and Coprococcus.

ZiBuPiYin recipe ameliorates diabetes-associated cognitive decline by improving neuronal mitochondrial function in chronic psychologically stressed zucker diabetic fatty rats

Ethnopharmacological relevanceZibu Piyin Recipe (ZBPYR) is a traditional Chinese medicine compound composed of 12 kinds of Chinese herbal medicines including red ginseng and yam. Long-term basic and clinical applications have proved that ZBPYR can prevent and treat cognitive dysfunction. Previous studies showed that chronic psychological stress can increase the risk of type 2 diabetes mellitus (T2DM), and lead to cognitive decline. Mitochondrial dysfunction plays a key role in chronic psychological stress-induced diabetes mellitus. While the mechanism of mitochondrial dysfunction and insulin resistance in diabetes-associated cognitive decline (DACD) is unclear. Aim of the studyOur previous research found that a ZiBuPiYin recipe (ZBPYR) has significant pharmacological effects against DACD. The present study investigated changes in mitochondrial dysfunction in the brain and the mechanism of insulin resistance and mitochondrial damage to explore the relationship between neuronal mitochondrial dysfunction and insulin resistance in chronic psychologically stressed DACD rats. Materials and methodsZucker diabetic fatty (ZDF) rats with spontaneous T2DM and rats with diabetic cognitive impairment that was induced by chronic psychological stress were used in in vivo experiments. PC12 cells that were damaged by rotenone were used for the in vitro experiment. ResultsThe findings indicated that the number of mitochondria decreased, morphology and membrane potential were damaged, and reactive oxygen species increased in the cortex and hippocampus in psychologically stressed DACD rats. Protein kinase Cβ2 (PKCβ2) activation and insulin resistance were markedly induced by chronic psychological stress, together with decreases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial fusion protein 2 (Mfn2). Furthermore, ZBPYR exerted protective effects both in in vivo and in vitro. ConclusionMitochondrial damage and insulin resistance were observed in the brain in chronic psychologically stressed DACD rats. The ZBPYR significantly improved brain mitochondrial damage and insulin resistance in chronic psychologically stressed DACD rats. These results provide novel insights for the development of ZBPYR as a traditional Chinese medicine for the treatment of chronic psychological stress and DACD.

HECTD3 promotes NLRP3 inflammasome and pyroptosis to exacerbate diabetes-related cognitive impairment by stabilising MALT1 to regulate JNK pathway

Background HECTD3 (HECT domain E3 ubiquitin protein ligase 3) exerts biological activities in neuroinflammation of distinct diseases, such as autoimmune encephalomyelitis and donations after heart death. However, the effect of HECTD3 on diabetes-associated cognitive decline (DACD) remains unclear. Methods Wild-type or HECTD3-knockout rats were administered with streptozotocin to establish diabetic model. Pathological changes in the hippocampus were assessed by NISSL and haematoxylin and eosin staining. Morris water maze test was used to assess cognitive function. Neuronal survival and inflammation were investigated by immunofluorescence staining and ELISA assay. NLRP3 inflammasome and pyroptosis were assessed by western blot, immunofluorescence and flow cytometry assays. Results HECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12 cells. Knockout of HECTD3 increased the number of neurons and improved the learning and memory function. Moreover, knockout of HECTD3 promoted in vivo neuronal survival, and reduced levels of IL-1β, TNF-α, and IL-6 in the hippocampus. Silencing of HECTD3 increased cell viability, and reduced IL-1β, TNF-α, and IL-6 in high glucose-induced PC12 cells. Fluorescence intensities of NLRP3, GSDMD-N and caspase-1 were reduced in HECTD3-knockout diabetic rats, and knockdown of HECTD3 down-regulated protein expression of NLRP3, GSDMD-N, caspase-1, IL-1β, and IL-18 in high glucose-induced PC12 cells to suppress the pyroptosis. HECTD3 promoted the stability of mucosa-associated lymphoid tissue 1 (MALT1) through up-regulation of c-JUN and phospho (p)-JNK in high glucose-induced PC12 cells. Over-expression of MALT1 attenuated neuroprotective effects of HECTD3 silencing on high glucose-induced PC12 cells. Conclusion HECTD3 silencing exerted neuroprotective effect against DACD through MALT1-mediated JNK signalling. Highlights HECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12. Knockout of HECTD3 promoted in vivo neuronal survival, reduced inflammation and pyroptosis, and improved the learning and memory function in diabetic rats. Knockout of HECTD3 suppressed the activation of NLRP3 inflammasome in diabetic rats. Silencing of HECTD3 exerted neuroprotective effects through MALT1-mediated JNK signalling.

Effects of Fibroblast Growth Factor 21 on Lactate Uptake and Usage in Mice with Diabetes-Associated Cognitive Decline

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exerts beneficial effects on glucose and lipid metabolic homeostasis. However, the impact of FGF21 on type 1 diabetes-associated cognitive decline (DACD) and its mechanisms of action remain unclear. In this study, we aimed to evaluate the effects of FGF21 on lactate uptake and usage in a mouse model of streptozotocin-induced DACD. Six-week-old male C57BL/6 mice were divided into the control, diabetic, and FGF21 (which received 2mg/kg recombinant human FGF21) groups. At the end of the treatment period, learning and memory performance, nuclear magnetic resonance-based metabonomics, and expressions of various hippocampal protein were analyzed to determine the efficacy of FGF21. The results showed that compared to the control mice, the diabetic mice had reduced long-term memory performance after the hyperglycemic insult; decreased hippocampal levels of lactate dehydrogenase-B (LDH-B) activity, bioenergy metabolites, and monocarboxylate transporter 2 (MCT2); and increased lactate levels. Impaired phosphoinositide 3-kinase (PI3K) signaling was also observed in the diabetic mice. However, FGF21 treatment improved LDH-B activity, β-nicotinamide adenine dinucleotide, and ATP levels, and increased MCT2 expression and PI3K signaling pathway, which in turn improved the learning and memory defects. These findings demonstrated that the effects of FGF21 on DACD were associated with its ability to improve LDH-B-mediated lactate usage and MCT2-dependent lactate uptake. Further, these beneficial effects of FGF21 in the hippocampus were mediated by the PI3K signaling pathways.

Integrated Analyses of Microbiomics and Metabolomics Explore the Effect of Gut Microbiota Transplantation on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats.

Diabetes-associated cognitive decline (DACD), one of the complications of type 2 diabetes (T2DM), correlates significantly with the disorder in glycolipid metabolism, insulin/leptin resistance, and accumulation of β-amyloid (Aβ). Although gut microbiota transplantation (GMT), a novel non-invasive physiotherapy strategy, has been a promising intervention to alleviate the symptoms of T2DM, its protective effect on progressive cognitive decline remains elusive. Here, we transplanted the gut microbiota of healthy or cognitive decline donor rats into ZDF or LZ rats, and integrated microbiomics and metabolomics to evaluate the directional effect of the gut microbiota on the recipient rats. The basal metabolism phenotype changed in ZDF rats instead of in LZ rats. One possible mechanism is that the microbiota and metabolites alter the structure of the intestinal tract, stimulate the brain insulin and leptin signaling pathways, and regulate the deposition of Aβ in the brain. It is worth noting that 10 species of genera, such as Parabacteroides, Blautia, and Lactobacillus, can regulate 20 kinds of metabolites, such as propanoic acid, acetic acid, and citramalic acid, and having a significant improvement on the cognitive behavior of ZDF rats. In addition, the correlation analysis indicated the gut microbiota and metabolites are highly associated with host phenotypes affected by GMT. In summary, our study indicates that altering the microbiota-gut-brain axis by reshaping the composition of gut microbiota is a viable strategy that has great potential for improving cognitive function and combatting DACD.