To investigate systemic inflammation and the effect of dapagliflozin treatment in (type 2 diabetes mellitus) T2DM patients with mild cognitive impairment (MCI).

Between January and December 2023, 200 participants were recruited from the Department of Endocrinology of Hefei First People's Hospital. Baseline data collected included medical history, fasting blood glucose, HbA1c, liver and kidney function, lipid profiles, IL-1β, TNF-α, sVCAM-1 level, and the urinary albumin-creatinine ratio (uACR). Based on their Montreal Cognitive Assessment Scale (MoCA) scores, these participants were categorized into two groups: 127 in the MCI group and 73 in the non-MCI group. MCI group received dapagliflozin (10 mg daily) alongside standard treatment.

The MCI group showed higher age, height, weight, BMI, HbA1c, FBG, disease duration, carotid plaques, stenosis rates, and elevated IL-1β, TNF-α, and sVCAM-1. MoCA scores were significantly lower in the MCI group. Correlation analysis showed a negative correlation of MoCA scores with IL-1β, TNF-α, sVCAM-1, plaques, stenosis, FBG, and HbA1c, and a positive correlation with height. Binary logistic regression identified age, BMI, IL-1β, sVCAM-1, and FBG as predictors of cognitive impairment in T2DM. Dapagliflozin treatment reduced BMI, HbA1c, inflammatory markers, and FBG, improving MoCA scores.

Dapagliflozin treatment may improve cognitive function by reducing inflammation.

Emerging evidence suggests a bidirectional relationship between Alzheimer's disease (AD) and epilepsy. In our previous studies, we identified a partial AD-like phenotype associated with central insulin resistance in the Wistar audiogenic rat (WAR), a genetic model of epilepsy. We also found that intracerebroventricular administration of streptozotocin, a compound used to model diabetes and AD, exacerbates seizure susceptibility. Given the role of insulin signaling in both AD and epilepsy, we hypothesized that metformin (MET), an anti-diabetic drug known for enhancing insulin sensitivity, could be a potential therapeutic agent for both conditions. Our objective was to investigate MET's effects on brain insulin signaling, seizure activity, and AD-like pathology in WARs. Adult male WARs received oral MET (250 mg/kg) for 21 days. Audiogenic seizures were assessed using the Categorized Severity Index and Racine's scale. Spatial memory was tested with the Morris water maze (MWM), followed by Western blot analysis of hippocampal proteins. MET significantly reduced seizure severity and improved MWM performance. Although MET did not affect insulin receptor levels or activation, it increased phosphoinositide 3-kinase (PI3K), activated Akt, and increased glycogen synthase kinase-3α/β (GSK-3α/β) levels. MET also decreased amyloid β precursor protein (AβPP) levels but did not affect Tau phosphorylation. These results suggest that chronic MET treatment alleviates behaviors related to both AD and epilepsy in WARs and modulates insulin signaling independently of insulin receptor activation. Our findings highlight MET's potential as a therapeutic agent for managing comorbid AD and epilepsy, warranting further investigation into its mechanisms of action.

Pre-existing diabetes raises the likelihood of Parkinson's disease (PD), according to epidemiological and animal research. Our study aimed to investigating the likely neuroprotective effect of metformin (Met) and/or semaglutide (Sem) in model of PD in male diabetic rats and the possible underlying mechanism. Type 2 diabetes (T2DM) was induced by giving high-fat diet (HFD) for 3 weeks followed by a single streptozotocin (STZ) injection (40 mg/kg, i.p., once dose) followed by injection of 9 doses of rotenone every 48 ± 2 h for induction of PD. Met and/or Sema were administered to DM+PD via gastric gavage once daily for 4 weeks. In comparison with the DM+PD group, Met and/or Sem significantly lowered blood glucose levels, HOMA-IR, HbA1C, cholesterol, triglycerides, and LDL with significantly increased insulin and HDL levels. In addition, there was enhanced brain antioxidant status with lower oxidative-inflammatory stress biomarkers associated with improved rat cognitive, locomotor, and olfactory functions. A significant downregulation of caspase 3 and GFAP with concomitant upregulation of NRF2 protein expressions were observed in treated groups. Overall, co-treatment with Met and Sem elicited more efficacy than that of the individual regimen. When combined, the results of this study have demonstrated for the first time that Met and Sem work in concert to create neuroprotection in PD model of male diabetic rats compared to when taken separately. The study's findings indicate that Met and/or Sem have a restorative effect on T2DM and PD-induced changes in neurobehavioral and biochemical/molecular indices ascribed to the improvement of endogenous antioxidant systems, decreased lipid peroxidation, suppression of oxidative/inflammatory stress, and-most importantly-regulation of Nrf2 and caspase 3.

One of the most debilitating drawbacks of cisplatin chemotherapy is neurotoxicity which elicits memory impairment and cognitive dysfunction (chemobrain). This is primarily triggered by oxidative stress and inflammation. Captopril, an angiotensin-converting enzyme inhibitor, has been reported as a neuroprotective agent owing to its antioxidant and anti-inflammatory effects.

We examined the possible neuroprotective effect of captopril against cisplatin-induced neurological and behavioral abnormalities in rats.

Chemobrain was induced in rats by cisplatin (5 mg/kg, i.p.) on the 7th and 14th days of the study while captopril was administered orally (25 mg/kg) daily for three weeks. The effects of captopril were assessed by performing behavioral tests, histological examination, and evaluation of oxidative stress and inflammatory markers.

Cisplatin caused learning/memory dysfunction assessed by passive avoidance and Y-maze tests, decline in locomotion, and rotarod motor balance loss which were further verified by neurodegeneration observed in histological examination. Also, cisplatin aggravated oxidative stress by elevating lipid peroxidation (MDA) levels and diminishing catalase activity. Moreover, cisplatin upregulated the neuroinflammatory markers (TNF, IL-6, GFAP, and NF-κB). Captopril successfully ameliorated cisplatin damage on the levels of neurobehavioral and histopathological changes. Mechanistically, captopril significantly diminished MDA production and preserved catalase antioxidant activity. Captopril also counteracted neuroinflammation through inhibiting NF-κB and its downstream proinflammatory cytokines besides repressing astrocyte activity by reducing GFAP expression.

Our findings revealed that captopril could abrogate cisplatin neurotoxicity via reducing oxidative stress and neuroinflammation thus enhancing cognitive and behavioral performance. This could suggest the repurposing of captopril as a neuroprotective agent, especially in hypertensive cancer patients receiving cisplatin.

This study is aimed at evaluating the neurotoxic effects of chronic exposure of sodium fluoride (NaF) in developmental stages in rat using prenatal models. NaF (100 ppm, orally) dosing via drinking water was given to pregnant rats in disease group. In the treatment groups, Metformin & Dehydrozingerone (DHZ) (200 mg/kg) were administered orally along with NaF, and the dosing was continued throughout the gestation and lactation periods to the pups until the end of experiment. Behavioural studies like Novel Object Recognition Test (NORT), Open Field & Actophotometer test and biochemical estimations like Acetylcholinesterase (AchE), Glutathione (GSH), Malondialdehyde (MDA) were conducted on animals followed by histopathological image analysis. It was observed that NaF exposure significantly decreased learning, memory and locomotor ability (at p < 0.05, p ≤ 0.01) in rat pups and was also able to induce anxiety like behavior. Levels of AchE (p ≤ 0.001) and MDA (p ≤ 0.01, p ≤ 0.001) was found to be significantly elevated and GSH levels were significantly decreased (p ≤ 0.01, p ≤ 0.001) in hippocampus and frontal cortex in the disease group. Histopathological image analysis showed presence of degenerated neurons in hippocampus of disease group. From this study, it was observed that treatment with Metformin and DHZ, was able to significantly ameliorate the cognitive impairments, improve the condition of oxidative stress and decrease neuronal degeneration in NaF fed rat pups. These results established the protective role of Metformin and DHZ in NaF induced neurodevelopmental toxicity with particular emphasis on their antioxidant properties.

The efficacy and safety of metformin for addressing neurocognitive dysfunction in schizophrenia remain inconclusive. This systematic review evaluates the evidence from randomized controlled trials (RCTs) on the effects of metformin on neurocognitive function in patients with schizophrenia.

A comprehensive search of Chinese databases (WanFang, Chinese Journal Net) and English databases (PubMed, EMBASE, PsycINFO, and Cochrane Library) was conducted to identify RCTs assessing metformin's impact on neurocognitive outcomes in schizophrenia.

Four RCTs involving 271 patients with schizophrenia were included. Three RCTs (75%) demonstrated significant improvements in neurocognitive function with metformin compared to controls, as assessed by the MATRICS Consensus Cognitive Battery, Repeatable Battery for the Assessment of Neuropsychological Status, and Mini-Mental State Examination, but not the Brief Assessment of Cognition in Schizophrenia. Two RCTs (50%) evaluated metformin's effects on total psychopathology and found no significant differences between groups. Adverse events were reported in two RCTs, with inconsistent findings on decreased appetite and diarrhea. Other adverse events and discontinuation rates were comparable between groups.

Preliminary evidence suggests that metformin may improve neurocognitive function in schizophrenia. However, further large-scale, double-blind, high quality RCTs are warranted to validate these findings.

To explore the intricate interplay among cytokines, cognitive functioning, and conversion to psychosis in individuals at clinical high-risk (CHR) for psychosis.

We initially enrolled 385 individuals at CHR and 95 healthy controls (HCs). Subsequently, 102 participants at CHR completed the 1-year follow-up assessments, and 47 participants transitioned to psychosis. We assessed the levels of interleukins (IL-1β, IL-2, IL-6, IL-8, IL-10), tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF). We comprehensively evaluated cognitive performance across six domains, including speed of processing (SP), attention/vigilance (AV), working memory (WM), verbal learning (VeL), visual learning (ViL), and reasoning and problem-solving (RPS).

Higher baseline cognitive domain scores were associated with elevated GM-CSF and reduced VEGF levels. In the follow-up analysis, significant time effects were observed for IL-1β and IL-2. We also observed significant interaction effects between specific cognitive domains (AV, WM, VeL, and OCS) and levels of cytokine (GM-CSF, IL-1β, IL-6, and TNF-α). Changes in WM were negatively correlated with changes in TNF-α levels and positively correlated with changes in VEGF levels. Variations in VeL were inversely correlated with changes in GM-CSF and IL-10 levels, whereas changes in RPS were positively associated with changes in GM-CSF and IL-8 levels.

Our results revealed intricate associations among cytokine levels, cognitive performance, and psychosis progression.

It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still the first-line drug for treatment of T2DM unless there are contra-indications. The drug primarily inhibits hepatic gluconeogenesis and increases the sensitivity of target cells (hepatocytes, adipocytes and myocytes) to insulin; however, increasing evidence suggests that it may also influence the gut. As T2DM patients exhibit gut dysbiosis, the intestinal microbiome has gained interest as a key target for metabolic diseases. Interestingly, changes in the gut microbiome were also observed in T2DM patients treated with metformin compared to those who were not. Therefore, the aim of this review is to present the current state of knowledge regarding the association of the gut microbiome with the antihyperglycemic effect of metformin. Numerous studies indicate that the reduction in glucose concentration observed in T2DM patients treated with metformin is due in part to changes in the biodiversity of the gut microbiota. These changes contribute to improved intestinal barrier integrity, increased production of short-chain fatty acids (SCFAs), regulation of bile acid metabolism, and enhanced glucose absorption. Therefore, in addition to the well-recognized reduction of gluconeogenesis, metformin also appears to exert its glucose-lowering effect by influencing gut microbiome biodiversity. However, we are only beginning to understand how metformin acts on specific microorganisms in the intestine, and further research is needed to understand its role in regulating glucose metabolism, including the impact of this remarkable drug on specific microorganisms in the gut.

The possible association between diabetes mellitus and dementia has raised concerns, given the observed coincidental occurrences.

This study aimed to develop a personalized predictive model, using artificial intelligence, to assess the 5-year and 10-year dementia risk among patients with type 2 diabetes mellitus (T2DM) who are prescribed antidiabetic medications.

This retrospective multicenter study used data from the Taipei Medical University Clinical Research Database, which comprises electronic medical records from 3 hospitals in Taiwan. This study applied 8 machine learning algorithms to develop prediction models, including logistic regression, linear discriminant analysis, gradient boosting machine, light gradient boosting machine, AdaBoost, random forest, extreme gradient boosting, and artificial neural network (ANN). These models incorporated a range of variables, encompassing patient characteristics, comorbidities, medication usage, laboratory results, and examination data.

This study involved a cohort of 43,068 patients diagnosed with type 2 diabetes mellitus, which accounted for a total of 1,937,692 visits. For model development and validation, 1,300,829 visits were used, while an additional 636,863 visits were reserved for external testing. The area under the curve of the prediction models range from 0.67 for the logistic regression to 0.98 for the ANNs. Based on the external test results, the model built using the ANN algorithm had the best area under the curve (0.97 for 5-year follow-up period and 0.98 for 10-year follow-up period). Based on the best model (ANN), age, gender, triglyceride, hemoglobin A1c, antidiabetic agents, stroke history, and other long-term medications were the most important predictors.

We have successfully developed a novel, computer-aided, dementia risk prediction model that can facilitate the clinical diagnosis and management of patients prescribed with antidiabetic medications. However, further investigation is required to assess the model's feasibility and external validity.

Cognitive impairment is a prevalent co-morbidity associated with epilepsy. Emerging studies indicate that neuroinflammation could be a possible link between epilepsy and its comorbidities, including cognitive impairment. In this context, the roles of glial activation, proinflammatory mediators, and neuronal death have been well studied and correlated with epilepsy-associated cognitive impairment in animal studies. While recent reports have demonstrated the anti-epileptogenic and anti-convulsant actions of metformin, its effect on epilepsy associated cognitive deficit remains unknown. Therefore, the current study investigated the effect of metformin treatment on neuroinflammation, neurodegeneration, and cognitive deficits after inducing status epilepticus (SE) with lithium-pilocarpine in rats. Metformin treatment improved the hippocampal-dependent spatial and recognition memory in Morris water maze and Novel object recognition tasks, respectively. Further, metformin treatment attenuated microglial and astroglial activation, accompanied by reduced IL-1β, COX-2 and NF-ĸβ gene expression. Additionally, metformin conferred neuroprotection by inhibiting the neuronal death as assessed by Nissl staining and transmission electron microscopy. These findings suggest that metformin holds promise as a therapeutic intervention for cognitive impairment associated with epilepsy, possibly through its modulation of glial activation and neuronal survival. Further research is needed to elucidate the precise mechanisms and to assess the long-term effect of metformin in epilepsy-associated cognitive impairment.

Fibromyalgia (FM) is a chronic and debilitating condition characterized by diffuse pain, often associated with symptoms such as fatigue, cognitive disturbances, and mood disorders. Metformin, an oral hypoglycemic agent, has recently gained attention for its potential benefits beyond glucose regulation. It has shown promise in alleviating neuropathic and inflammatory pain, suggesting that it could offer a novel approach to managing chronic pain conditions like FM. This study aimed to further explore metformin's analgesic potential by evaluating its effects in an experimental FM model induced by reserpine in both male and female mice. After the administration of 200 mg/kg metformin to male and female mice, the FM-related symptoms were assessed, including mechanical allodynia, thermal hyperalgesia, and depressive-like behaviors. A histological examination of the thalamus, hippocampus, and spinal cord was conducted using haematoxylin and eosin staining. The neurotransmitter and proinflammatory cytokines levels were measured in the brains and spinal cords. Our results have shown that metformin treatment for seven days significantly reversed these FM-like symptoms, reducing pain sensitivity and improving mood-related behaviors in both the male and female mice. Additionally, metformin exhibited neuroprotective effects, mitigating reserpine-induced damage in the hippocampus, thalamus, and spinal cord. It also significantly lowered the levels of the proinflammatory cytokine interleukin 1-beta (IL-1β) in the brain and spinal cord. Notably, metformin modulated the neurotransmitter levels differently between the sexes, decreasing glutamate and increasing serotonin and norepinephrine in the male mice, but not in the females. These findings underscore metformin's potential as an alternative therapy for FM, with sex-specific differences suggesting distinct mechanisms of action.

Insulin, a critical hormone in the human body, exerts its effects by binding to insulin receptors and regulating various cellular processes. While nitric oxide (NO) plays an important role in insulin secretion and acts as a mediator in the signal transduction pathway between upstream molecules and downstream effectors, holds a significant position in the downstream signal network of insulin. Researches have shown that the insulin-NO system exhibits a dual regulatory effect within the central nervous system, which is crucial in the regulation of diabetic encephalopathy (DE). Understanding this system holds immense practical importance in comprehending the targets of existing drugs and the development of potential therapeutic interventions. This review extensively examines the characterization of insulin, NO, Nitric oxide synthase (NOS), specific NO pathway, their interconnections, and the mechanisms underlying their regulatory effects in DE, providing a reference for new therapeutic targets of DE.

Chronic pancreatic dysfunction is frequently observed as a consequence of prolonged high-fat diet consumption and is a serious public health concern. This pro-diabetic insult aggravates inflammation-influenced fibrotic lesions and is associated with deregulated autophagy. Metformin, a conventional anti-hyperglycemic drug, might be beneficial for pancreatic health, but the complex molecular regulations are not clarified. Considering the worldwide prevalence of chronic pancreatic dysfunction in obese individuals, we aimed to unwind the molecular intricacies explaining the involvement of oxidative stress, inflammation and fibrosis and to approbate metformin as a plausible intervention in this crossroad.

Age-matched Swiss Albino mice were exposed to high-fat diet (60 kcal%) against control diet (10 kcal%) to establish diet-induced stress model. Metformin treatment was introduced after 4 weeks to metformin-control and HFD-exposed metformin groups. After 8 weeks, metabolic and molecular outcomes were assessed to establish the impact of metformin on chronic consequences of HFD-mediated injury.

High-fat diet administration to healthy mice primes oxidative stress-mediated chronic inflammation through Nrf2/Keap1/NF-κB interplay. Besides, pro-inflammatory cytokine bias leading to fibrotic (increased TGF-β, α-SMA, and MMP9) and pro-EMT (Twist1, Slug, Vimentin, E-cadherin) repercussions in pancreatic lobules were evident. Metformin distinctly rescues high-fat diet-induced remodeling of pancreatic pro-diabetic alterations and cellular survival/death switch. Further, metformin abrogates the p62-Twist1 crosstalk in an autophagy-dependent manner (elevated beclin1, LC3-II/I, Lamp2) to restore pancreatic homeostasis.

Our research validates the therapeutic potential of metformin in the inflammation-fibrosis nexus to ameliorate high-fat diet-induced pancreatic dysfunction and related metabolic alterations.

The risk of developing diabetes and cardiometabolic disorders is associated with increased levels of alpha-aminoadipic acid and disturbances in the metabolism of branched-chain amino acids. The side effects of the widely used antidiabetic drug metformin include impaired degradation of branched-chain amino acids and inhibition of intracellular thiamin transport. These effects may be interconnected, as thiamine deficiency impairs the functioning of thiamine diphosphate (ThDP)-dependent dehydrogenases of 2-oxo acids involved in amino acids degradation, while diabetes is often associated with perturbed thiamine status. In this work, we investigate the action of metformin in rats with impaired thiamine availability. The reduction in the thiamine influx is induced by simultaneous administration of the thiamine transporters inhibitors metformin and amprolium. After 24 days of combined metformin/amprolium administration, no significant changes in the total brain levels of ThDP or activities of ThDP-dependent enzymes of central metabolism are observed, but the affinities of transketolase and 2-oxoglutarate dehydrogenase to ThDP increase. The treatment also significantly elevates the brain levels of free amino acids and ammonia, reduces the antioxidant defense, and alters the sympathetic/parasympathetic regulation, which is evident from changes in the ECG and behavioral parameters. Strong positive correlations between brain ThDP levels and contents of ammonia, glutathione disulfide, alpha-aminoadipate, glycine, citrulline, and ethanolamine are observed in the metformin/amprolium-treated rats, but not in the control animals. Analysis of the obtained data points to a switch in the metabolic impact of ThDP from the antioxidant and nitrogen-sparing in the control rats to the pro-oxidant and hyperammonemic in the metformin/amprolium-treated rats. As a result, metformin administration along with the amprolium-reduced thiamine supply significantly perturb the metabolism of amino acids in the rat brain, altering behavioral and ECG parameters.

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1β, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.

Diabetic encephalopathy (DE) is a severe complication that occurs in the central nervous system (CNS) and leads to cognitive impairment. DE involves various pathophysiological processes, and its pathogenesis is still unclear. This review summarised current research on the pathogenesis of diabetic encephalopathy, which involves neuroinflammation, oxidative stress, iron homoeostasis, blood-brain barrier disruption, altered gut microbiota, insulin resistance, etc. Among these pathological mechanisms, neuroinflammation has been focused on. This paper summarises some of the molecular mechanisms involved in neuroinflammation, including the Mammalian Target of Rapamycin (mTOR), Lipocalin-2 (LCN-2), Pyroptosis, Advanced Glycosylation End Products (AGEs), and some common pro-inflammatory factors. In addition, we discuss recent advances in the study of potential therapeutic targets for the treatment of DE against neuroinflammation. The current research on the pathogenesis of DE is progressing slowly, and more research is needed in the future. Further study of neuroinflammation as a mechanism is conducive to the discovery of more effective treatments for DE in the future.

Alzheimer's disease (AD) constitutes a major public-health issue of our time. Regrettably, despite our considerable understanding of the pathophysiological aspects of this disease, current interventions lead to poor outcomes. Furthermore, experimentally promising compounds have continuously failed when translated to clinical trials. Along with increased population ageing, Type 2 Diabetes Mellitus (T2DM) has become an extremely common condition, mainly due to unbalanced dietary habits. Substantial epidemiological evidence correlates T2DM with cognitive impairment as well. Considering that brain insulin resistance, mitochondrial dysfunction, oxidative stress, and amyloidogenesis are common phenomena, further approaching the common features among these pathological conditions. Metformin constitutes the first-choice drug to preclude insulin resistance in T2DM clinical management. Experimental evidence suggests that its functions might include neuroprotective effects, in addition to its hypoglycemic activity. This review aims to summarize and discuss current knowledge of experimental data on metformin on this path towards translational medicine. Finally, we discuss the controversial data of responses to metformin in vitro, and in vivo, animal models and human studies.

Astrocytes are glial cells that play key roles in neuroinflammation, which is a common feature in diabetic encephalopathy and aging process. Metformin is an antidiabetic compound that shows neuroprotective properties, including in inflammatory models, but astroglial signaling pathways involved are still poorly known. Interferons α/β are cytokines that participate in antiviral responses and the lack of their signaling increases susceptible to viral infections. Here, we investigated the effects of metformin on astrocytes from hypothalamus, a crucial brain region related to inflammatory processes. Astrocyte cultures were derived from interferon α/β receptor knockout (IFNα/βR-/-) and wild-type (WT) mice. Metformin did not change the expression of glial fibrillary acidic protein but caused an anti-inflammatory effect by decreasing pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β), as well as increasing gene expression of anti-inflammatory proteins interleukin-10 and Nrf2 (nuclear factor erythroid derived 2 like 2). However, nuclear factor κB p65 and cyclooxygenase 2 were downregulated in WT astrocytes and upregulated in IFNα/βR-/- astrocytes. AMP-activated protein kinase (AMPK), a molecular target of metformin, was upregulated only in WT astrocytes, while sirtuin 1 increased in both mice models. The expression of inducible nitric oxide synthase was decreased in WT astrocytes and heme oxygenase 1 was increased in IFNα/βR-/- astrocytes. Although loss of IFNα/βR-mediated signaling affects some effects of metformin, our results support beneficial roles of this drug in hypothalamic astrocytes. Moreover, paradoxical response of metformin may involve AMPK. Thus, metformin can mediate glioprotection due its effects on age-related disorders in non-diabetic and diabetic encephalopathy individuals.

Metformin, a biguanide compound (N-1,1-dimethylbiguanide), is widely prescribed for diabetes mellitus type 2 (T2D) treatment. It also presents a plethora of properties, such as anti-oxidant, anti-inflammatory, anti-apoptosis, anti-tumorigenic, and anti-AGE formation activity. However, the precise mechanism of action of metformin in the central nervous system (CNS) needs to be clarified. Herein, we investigated the neuroprotective role of metformin in acute hippocampal slices exposed to methylglyoxal (MG), a highly reactive dicarbonyl compound and a key molecule in T2D developmental pathophysiology. Metformin protected acute hippocampal slices from MG-induced glutamatergic neurotoxicity and neuroinflammation by reducing IL-1β synthesis and secretion and RAGE protein expression. The drug also improved astrocyte function, particularly with regard to the glutamatergic system, increasing glutamate uptake. Moreover, we observed a direct effect of metformin on glutamate transporters, where the compound prevented glycation, by facilitating enzymatic phosphorylation close to Lys residues, suggesting a new neuroprotective role of metformin via PKC ζ in preventing dysfunction in glutamatergic system induced by MG.

Memory issues are a prevalent symptom in different neurodegenerative diseases and can also manifest in certain psychiatric conditions. Despite limited medications approved for treating memory problems, research suggests a lack of sufficient options in the market. Studies indicate that a significant percentage of elderly individuals experience various forms of memory disorders. Metformin, commonly prescribed for type 2 diabetes, has shown neuroprotective properties through diverse mechanisms. This study explores the potential of metformin in addressing memory impairments. The current research gathered its data by conducting an extensive search across electronic databases including PubMed, Web of Science, Scopus, and Google Scholar. Previous research suggests that metformin enhances brain cell survival and memory function in both animal and clinical models by reducing oxidative stress, inflammation, and cell death while increasing beneficial neurotrophic factors. The findings of the research revealed that metformin is an effective medication for enhancing various types of memory problems in numerous studies. Given the rising incidence of memory disorders, it is plausible to utilize metformin, which is an affordable and accessible drug. It is often recommended as a treatment to boost memory.

Majhool date (Phoenix dactylifera), renowned for its premium taste and texture, is extensively consumed in the Islamic world, particularly during Ramadan. Despite its popularity, concerns persist regarding its potential to induce diabetes in non-patients. This study aims to explore the diabetogenic effects of prolonged Majhool date (Phoenix dactylifera) consumption, the widely used fruit in the Islamic world, through animal experiments and human clinical data.

Medjool dates were processed into an ethanolic extract for the animal experiment. Then, 21 Balb/c mice received varying doses of the extract for one month. The fasting blood glucose levels were analyzed at the beginning and after one month of consumption of the Majhool date extract. For the clinical study, 387 healthy participants were recruited, with fasting blood glucose levels assessed before and after Ramadan, a period of heightened Majhool date consumption.

all groups of the experimental animals exhibited a significant (p<0.05) weight increase after Majhool date consumption, while no significant (p>0.05) alteration in fasting blood glucose levels among groups. In addition, it was found that fasting blood glucose levels remained statistically unchanged (p>0.05) after heightened Majhool date consumption among humans.

The study challenges the belief that Majhool date induces diabetes, supported by both animal and human data. Findings suggest that Majhool date consumption, even at higher doses, does not induce diabetes. Further investigations could explore the impact of other date varieties on the fasting blood glucose levels.

Alcohol, a widely consumed drug, exerts significant toxic effects on the human organism. This review focuses on its impact during fetal development, when it leads to a spectrum of disorders collectively termed Fetal Alcohol Spectrum Disorders (FASD). Children afflicted by FASD exhibit distinct clinical manifestations, including facial dysmorphism, delayed growth, and neurological and behavioral disorders. These behavioral issues encompass diminished intellectual capacity, memory impairment, and heightened impulsiveness. While the precise mechanisms underlying alcohol-induced fetal damage remain incompletely understood, research indicates a pivotal role for reactive oxygen species (ROS) that are released during alcohol metabolism, inciting inflammation at the cerebral level. Ethanol metabolism amplifies the generation of oxidant molecules, inducing through alterations in enzymatic and non-enzymatic systems responsible for cellular homeostasis. Alcohol consumption disrupts endogenous enzyme activity and fosters lipid peroxidation in consumers, potentially affecting the developing fetus. Addressing this concern, administration of metformin during the prenatal period, corresponding to the third trimester of human pregnancy, emerges as a potential therapeutic intervention for mitigating FASD. This proposed approach holds promise for ameliorating the adverse effects of alcohol exposure on fetal development and warrants further investigation.

The entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin-converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin-L (CTSL). COVID-19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality.

The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse Ace2, Tmprss2, and Ctsl and correlate it with the pathological alterations in the lungs and the heart of DM mice.

Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of Ace2, Tmprss2, Ctsl, Cyp4a11, and Adrb1 genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real-time polymerase chain reaction (RT-PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination.

After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (P < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of Ace2 gene expression (P < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of Ctsl gene expression in their hearts (P < 0.05). Notably, Cyp4a12 gene expression was significantly downregulated (P < 0.05) in UDM mice but returned to normal levels in CDM mice.

We conclude from this study that T1DM downregulates Ace2 receptor and Cyp4a12 gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the lungs. Insulin administration for controlling T1DM ameliorated these pathological alterations. These results can help increase our understanding of the impact of controlled and uncontrolled T1DM on the lungs and may explain, at least in part, why DM patients with COVID-19 experience exacerbation of symptoms.

Transketolase (TKT) is an essential thiamine diphosphate (ThDP)-dependent enzyme of the non-oxidative branch of the pentose phosphate pathway, with the glucose-6P flux through the pathway regulated in various medically important conditions. Here, we characterize the brain TKT regulation by acylation in rats with perturbed thiamine-dependent metabolism, known to occur in neurodegenerative diseases. The perturbations are modeled by the administration of oxythiamine inhibiting ThDP-dependent enzymes in vivo or by reduced thiamine availability in the presence of metformin and amprolium, inhibiting intracellular thiamine transporters. Compared to control rats, chronic administration of oxythiamine does not significantly change the modification level of the two detected TKT acetylation sites (K6 and K102) but doubles malonylation of TKT K499, concomitantly decreasing 1.7-fold the level of demalonylase sirtuin 5. The inhibitors of thiamine transporters do not change average levels of TKT acylation or sirtuin 5. TKT structures indicate that the acylated residues are distant from the active sites. The acylations-perturbed electrostatic interactions may be involved in conformational shifts and/or the formation of TKT complexes with other proteins or nucleic acids. Acetylation of K102 may affect the active site entrance/exit and subunit interactions. Correlation analysis reveals that the action of oxythiamine is characterized by significant negative correlations of K499 malonylation or K6 acetylation with TKT activity, not observed upon the action of the inhibitors of thiamine transport. However, the transport inhibitors induce significant negative correlations between the TKT activity and K102 acetylation or TKT expression, absent in the oxythiamine group. Thus, perturbations in the ThDP-dependent catalysis or thiamine transport manifest in the insult-specific patterns of the brain TKT malonylation and acetylations.

The combination of Astragulus embranaceus (Fisch.) Bge (Huangqi) and Dioscorea opposita Thunb (Shanyao) are one of the most widely accepted herb pairs in traditional Chinese medicine prescriptions for treating sarcopenia. However, the mechanisms underlying the combination of these herbs for anti-sarcopenia treatment are not yet fully understood.

To investigate the potential effect of the Astragulus embranaceus (Fisch.) Bge and Dioscorea opposita Thunb herb pair (Ast-Dio) on sarcopenia in mice that have been induced with senile type 2 diabetes mellitus, as well as to explore the underlying mechanisms related to the Rab5a/mTOR signaling pathway and mitochondrial quality control.

Network pharmacology was utilized to identify the main active ingredients of Ast-Dio and potential therapeutic targets for sarcopenia. Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to explore the underlying mechanisms of Ast-Dio in treating sarcopenia. The high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry was developed to quantify the major constituents of Ast-Dio. Male C57/BL6 mice, aged 12 months, induced with type 2 diabetes mellitus via streptozotocin were divided into three groups for 8 weeks: the model group, Ast-Dio treatment group (7.8 g/kg), and metformin treatment group (100 mg/kg). Normal control groups included mice aged 3 and 12 months, respectively. The study monitored changes in fasting blood glucose levels, grip strength, and body weight during 8 weeks of intragastric administration. Liver and kidney function in mice was evaluated by measuring the levels of serum creatinine, alanine transaminase, and aspartate transaminase. Skeletal muscle mass condition was evaluated by muscle weight, and hematoxylin and eosin staining. Protein and mRNA expressions related to muscle atrophy, mitochondrial quality control, and the Rab5a/mTOR signaling pathway were detected using immunofluorescence staining, immunohistochemical staining, Western blotting, and quantitative real-time polymerase chain reaction. In addition, transmission electron microscopy was employed to investigate the condition of mitochondria in the groups.

Through the prediction analysis of network pharmacology, we identified mTOR as one of the primary targets for Ast-Dio therapy of sarcopenia. Gene Ontology functional enrichment analysis revealed that mitochondrial control quality is crucial in the treatment of sarcopenia with Ast-Dio. Our findings showed that senile type 2 diabetes mellitus induced muscle mass loss and a reduction in grip strength, both of which were dramatically restored by Ast-Dio treatment. Notably, Ast-Dio increased Myogenin expression while decreasing Atrogin-1 and MuRF-1 expression. Additionally, Ast-Dio activated Rab5a/mTOR and its downstream effector AMPK. Moreover, Ast-Dio modulated mitochondrial quality control by decreasing Mitofusin-2 expression while increasing the expression of TFAM, PGC-1α, and MFF.

Our results suggest that Ast-Dio treatment may alleviate sarcopenia in mice with senile type 2 diabetes mellitus through its effects on the Rab5a/mTOR pathway and mitochondrial quality control.

Introduction:There is a variation in drug response among patients who practice intermittent fasting. Alteration in the expression of drug-metabolizing enzymes (DMEs) can affect the pharmacokinetics and drug response.Aims: This research aimed to determine the effect of intermittent fasting on the mRNA expression of major drug-metabolizing cyp450s in the liver of diabetic mice.Methods: Thirty-two male Balb/c mice were divided into four groups; control, nonfasting diabetic, non-diabetic fasting, and diabetic fasting mice. Insulin-dependent diabetes was induced in mice by a single high-dose (250 mg/kg) streptozocin. Mice of non-diabetic and diabetic fasting groups were subjected to 10-day intermittent fasting for 17 hours daily. Then, the mRNA expression of mouse phase I DMEs cyp1a1, cyp2c29, cyp2d9, and cyp3a11 was analyzed using real-time polymerase chain reaction. In addition, the liver of mice in all groups was examined for pathohistological alterations.Results: Diabetes downregulated the mRNA expression of hepatic drug-metabolizing cyp450s in diabetic mice, while intermittent fasting significantly (P < 0.05) increased it. Also, cyp2d9 and cyp3a11 were upregulated in the liver of diabetic fasting mice. These alterations in the gene expression were correlated with the pathohistological alterations, where livers of diabetic mice showed dilatation in the blood sinusoids and inflammatory cells leukocyte infiltrations. Whereas livers of diabetic fasting mice showed almost comparable histological findings to control mice.Conclusions: Intermittent fasting can protect the liver against diabetes-induced hepatotoxicity and the down-regulation of DME genes in the diabetic liver. These results can explain, at least partly, the inter-individual variation in the drug response during practicing fasting.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

Alzheimer Associated Diabetes Mellitus, commonly known as Type 3 Diabetes Mellitus (T3DM) is a distinct subtype of diabetes with a pronounced association with Alzheimer's disease (AD). Insulin resistance serves as a pivotal link between these two conditions, leading to diminished insulin sensitivity, hyperglycemia, and impaired glucose uptake. The brain, a vital organ in AD context, is also significantly impacted by insulin resistance, resulting in energy deficits and neuronal damage, which are hallmark features of the neurodegenerative disorder. To pave the way for potential therapeutic interventions targeting the insulin resistance pathway, it is crucial to comprehend the intricate pathophysiology of T3DM and identify the overlapped features between diabetes and AD. This comprehensive review article aims to explore various pathway such as AMPK, PPARγ, cAMP and P13K/Akt pathway as potential target for management of T3DM. Through the analysis of these complex mechanisms, our goal is to reveal their interdependencies and support the discovery of innovative therapeutic strategies. The review extensively discusses several promising pharmaceutical candidates that have demonstrated dual drug action mechanisms, addressing both peripheral and cerebral insulin resistance observed in T3DM. These candidates hold significant promise for restoring insulin function and mitigating the detrimental effects of insulin resistance on the brain. The exploration of these therapeutic options contributes to the development of innovative interventions that alleviate the burden of T3DM and enhance patient care.

Diabetic cognitive impairment (DCI) is a complex complication of diabetes in the central nervous system, and its pathological mechanism is still being explored. Astrocytes are abundant glial cells in central nervous system that perform diverse functions in health and disease. Accumulating excellent research has identified astrocyte dysfunction in many neurodegenerative diseases (such as Alzheimer's disease, aging and Parkinson's disease), and summarized and discussed its pathological mechanisms and potential therapeutic value. However, the contribution of astrocytes to DCI has been largely overlooked. In this review, we first systematically summarized the effects and mechanisms of diabetes on brain astrocytes, and found that the diabetic environment (such as hyperglycemia, advanced glycation end products and cerebral insulin resistance) mediated brain reactive astrogliosis, which was specifically reflected in the changes of cell morphology and the remodeling of signature molecules. Secondly, we emphasized the contribution and potential targets of reactive astrogliosis to DCI, and found that reactive astrogliosis-induced increased blood-brain barrier permeability, glymphatic system dysfunction, neuroinflammation, abnormal cell communication and cholesterol metabolism dysregulation worsened cognitive function. In addition, we summarized effective strategies for treating DCI by targeting astrocytes. Finally, we discuss the application of new techniques in astrocytes, including single-cell transcriptome, in situ sequencing, and prospected new functions, new subsets and new targets of astrocytes in DCI.

In addition to the anti-diabetic effect of metformin, a growing number of studies have shown that metformin has some exciting properties, such as anti-oxidative capabilities, anticancer, genomic stability, anti-inflammation, and anti-fibrosis, which have potent, that can treat other disorders other than diabetes mellitus. We aimed to describe and review the protective and antidotal efficacy of metformin against biologicals, chemicals, natural, medications, pesticides, and radiation-induced toxicities. A comprehensive search has been performed from Scopus, Web of Science, PubMed, and Google Scholar databases from inception to March 8, 2023. All in vitro, in vivo, and clinical studies were considered. Many studies suggest that metformin affects diseases other than diabetes. It is a radioprotective and chemoprotective drug that also affects viral and bacterial diseases. It can be used against inflammation-related and apoptosis-related abnormalities and against toxins to lower their effects. Besides lowering blood sugar, metformin can attenuate the effects of toxins on body weight, inflammation, apoptosis, necrosis, caspase-3 activation, cell viability and survival rate, reactive oxygen species (ROS), NF-κB, TNF-α, many interleukins, lipid profile, and many enzymes activity such as catalase and superoxide dismutase. It also can reduce the histopathological damages induced by many toxins on the kidneys, liver, and colon. However, clinical trials and human studies are needed before using metformin as a therapeutic agent against other diseases.

N-nitrosodiethylamine (NDEA) is a potential carcinogen known to cause liver tumors and chronic inflammation, diabetes, cognitive problems, and signs like Alzheimer's disease (AD) in animals. This compound is classified as probably carcinogenic to humans. Usual sources of exposure include food, beer, tobacco, personal care products, water, and medications. AD is characterized by cognitive decline, amyloid-β (Aβ) deposit, tau hyperphosphorylation, and cell loss. This is accompanied by neuroinflammation, which involves release of microglial cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β), by nuclear factor kappa B (NF-κB) upregulation; each are linked to AD progression. Weak PI3K/Akt insulin-signaling inhibits IRS-1 phosphorylation, activates GSK3β and promotes tau hyperphosphorylation. Metformin, an antihyperglycemic agent, has potent anti-inflammatory efficacy. It reduces proinflammatory cytokines such as IL-6, IL-1β, and TNF-α via NF-κB inhibition. Metformin also reduces reactive oxidative species (ROS) and modulates cognitive disorders reported due to brain insulin resistance links. Our study examined how NDEA affects spatial memory in Wistar rats. We found that all NDEA doses tested impaired memory. The 80 µg/kg dose of NDEA increased levels of Aβ1-42, TNF-α, and IL-6 in the hippocampus, which correlated with memory loss. Nonetheless, treatment with 100 mg/kg of metformin attenuated the levels of pro-inflammatory cytokines and Aβ1-42, and enhanced memory. It suggests that metformin may protect against NDEA-triggered memory issues and brain inflammation.

Metformin has shown good efficacy in the management of antipsychotic-induced metabolic syndrome (MetS) in patients with schizophrenia or schizoaffective disorders. Its ability to induce antidepressant behavioural effects and improve cognitive functions has also been investigated: yet information has not been systematized. The aim of this study was therefore to investigate the effects of metformin on cognitive and other symptom dimension in schizophrenic patients treated with antipsychotics through a systematic review and meta-analysis.

We searched PubMed, ClinicalTrials.Gov, Embase, PsycINFO, and WHO ICTRP database up to February 2022, Randomised Controlled Trials (RCT) evaluating patients diagnosed with schizophrenia and related disorders, who were treated with metformin as add-on therapy to antipsychotics for the treatment of weight gain and in which changes in psychiatric symptoms and cognitive functions were evaluated.

A total of 19 RCTs met the inclusion criteria. Meta-analysis was performed on 12 eligible studies. We found a positive trend after 24 weeks of treatment in schizophrenic patients with stable conditions [SMD (95%CI) = -0.40 (-0.82;0.01), OR (95%CI) = 0.5 (-2.4;3.4)]. Better performance was detected in the Brief Assessment of Cognition in Schizophrenia and Positive and Negative Syndrome Scale (PANSS) with low heterogeneity among studies. One study reported changes in BACS-verbal memory subdomain in favour of placebo [MD (95%CI) = -16.03 (-23.65;8.42)]. Gastrointestinal disorders, xerostomia, and extrapyramidal syndrome were the most reported adverse effects. Psychiatric adverse events were also described: in particular, symptoms attributable to a relapse of schizophrenia.

Some degree of efficacy was found for Metformin in improving cognitive and other symptom dimensions in patients with Schizophrenia. Given the clinical relevance of this potential pharmacological effect, longer specific studies using adequate psychometric scales are strongly recommended. Likewise, how metformin acts in this context needs to be evaluated in order to enhance its efficacy or find more efficacious drugs.

Metformin has been introduced as a neuroprotective agent in recent years. Here we evaluate the therapeutic effects of metformin in sporadic mouse model of Alzheimer's disease (SAD).

AD was induced by streptozotocin (STZ, 0.5 mg/kg) on days 1 and 3. Metformin (MET, 200 mg/kg per day) was used for two weeks. Novel objective recognition (NOR) and Barnes Maze test were used to test the learning and memory. Nissl staining was used as s histological method for counting the dying neurons in different regions of hippocampus. Immunofluorescence staining against glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and NeuN were used to visualize reactive astrocytes, microglia and neurons, respectively.

In NOR test, the discrimination indices in the STZ group were significantly lower than the control and treatment groups. Goal sector/non-goal sector (GS/NGS) ratio index in Barnes maze was increased in metformin group compared to other groups. The number of dying neurons was increased by SAD and metformin reduced it. GFAP level was increased in CA1, CA3 and cortex of STZ group and reversed following the treatment. Iba1 level was significantly higher in STZ group in CA3 and cortex regions compared to Control and decreased by metformin in CA3 and cortex. Counting NeuN⁺ cells demonstrated significant reduction of neurons in DG+CA1 and CA3 after SAD induction.

Metformin decreased inflammatory cells and reactive astrocytes as well as the dying neurons in the hippocampus region and the cortex in SAD, and improved the cognitive performance.

Great body of evidence links cognitive decline to diabetes/insulin resistance. In this study the effect of Portulaca oleracea (PUR) (100 mg/kg), Metformin (MET) (200 mg/kg), a first line diabetes mellitus type 2 therapy, and their combination on cognitive function and hippocampal markers in diabetic rats were assessed. Male rats were injected with streptozotocin (30 mg/kg on two successive weeks) followed by 4 weeks of treatment. Possible antioxidant, anti-inflammatory, and autophagy enhancing mechanisms of these drugs were investigated in the hippocampal tissue using spectrophotometry, ELISA, and western blotting. Diabetic rats suffered significant cognitive impairment in Morris's water maze, hippocampal TBARS elevation, GSH depletion, and SOD upregulation. In addition, diabetes promoted the secretion of hippocampal inflammatory cytokines, TNF-α and IL-1β, and depleted anti-inflammatory cytokines as IL-10. Such detrimental changes were reversed by MET and/or PUR. Notably, AMPK was upregulated by diabetes, then restored to normal by MET and/or PUR. The pattern of change in AMPK expression was concomitant with changes in oxidative and inflammatory burden. Hence, AMPK is believed to be a key mediator in most of the measured pre-AD markers in this study. However, from our results, PUR is believed to have non-AMPK dependent actions as well. In conclusion, antidiabetic agents as metformin and purslane extract proved to be invaluable in addressing the cognitive decline and hippocampal changes that arise as a complication of diabetes. They mainly acted through AMPK pathway; however, their usefulness was not limited to AMPK pathways since their combination was suggested to have a different mechanism.

Neuroinflammation plays a crucial role in the occurrence and development of cognitive impairment in type 2 diabetes mellitus (T2DM), but the specific injury mechanism is not fully understood. Astrocyte polarization has attracted new attention and has been shown to be directly and indirectly involved in neuroinflammation. Liraglutide has been shown to have beneficial effects on neurons and astrocytes. However, the specific protection mechanism still needs to be clarified. In this study, we assessed the levels of neuroinflammation and A1/A2-responsive astrocytes in the hippocampus of db/db mice and examined their relationships with iron overload and oxidative stress. First, in db/db mice, liraglutide alleviated the disturbance of glucose and lipid metabolism, increased the postsynaptic density, regulated the expression of NeuN and BDNF, and partially restored impaired cognitive function. Second, liraglutide upregulated the expression of S100A10 and downregulated the expression of GFAP and C3, and decreased the secretion of IL-1β, IL-18, and TNF-α, which may confirm that it regulates the proliferation of reactive astrocytes and A1/A2 phenotypes polarize and attenuate neuroinflammation. In addition, liraglutide reduced iron deposition in the hippocampus by reducing the expression of TfR1 and DMT1 and increasing the expression of FPN1; at the same time, liraglutide by up-regulating the levels of SOD, GSH, and SOD2 expression, as well as downregulation of MDA levels and NOX2 and NOX4 expression to reduce oxidative stress and lipid peroxidation. The above may attenuate A1 astrocyte activation. This study preliminarily explored the effect of liraglutide on the activation of different astrocyte phenotypes and neuroinflammation in the hippocampus of a T2DM model and further revealed its intervention effect on cognitive impairment in diabetes. Focusing on the pathological consequences of astrocytes may have important implications for the treatment of diabetic cognitive impairment.

Elderly people over the age of 65 are those most likely to experience Alzheimer's disease (AD), and aging and AD are associated with apparent metabolic alterations. Currently, there is no curative medication against AD and only several drugs have been approved by the FDA, but these drugs can only improve the symptoms of AD. Many preclinical and clinical trials have explored the impact of adjusting the whole-body and intracellular metabolism on the pathogenesis of AD. The most recent evidence suggests that mitochondria initiate an integrated stress response to environmental stress, which is beneficial for healthy aging and neuroprotection. There is also an increasing awareness of the differential risk and potential targeting strategies related to the metabolic level and microbiome. As the main participants in intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been regarded as potential therapeutic targets for AD. This review summarizes and highlights these advances.

The evidence of metformin's effect on dementia is conflicting. This study investigates the association between metformin use and the risk of dementia among patients with diabetes mellitus (DM). This study included patients with new-onset DM between 2002 and 2013. We divided the patients into patients who used metformin and patients who did not. Two models were used to assess metformin use: the cumulative defined daily dose (cDDD) of metformin use and the intensity of metformin use. This study with 3-year and 5-year follow-ups investigated the risk of dementia among patients with DM who used metformin. At the 3-year follow-up, patients who received cDDD < 300 had an odds ratio (OR) of developing dementia of 0.92 (95% confidence interval [CI] = 0.89-0.96); patients who used metformin at intensities <10 and 10-25 DDD/month had ORs of 0.92 (95% CI: 0.87-0.97) and 0.92 (95% CI: 0.85-1.00), respectively. Metformin use at cDDD 300-500 (OR = 0.80, 95% CI = 0.56-1.15) or >500 (OR = 1.48, 95% CI = 0.48-4.60) or at an intensity >25 DDD/month (OR = 0.84, 95% CI = 0.60-1.18) were not associated with an incident of dementia. There were similar results at the 5-year follow-up. Patients with a low intensity of metformin use had a lower risk of dementia. However, higher doses of metformin with higher intensity exhibited no protective role in dementia. Prospective clinical trials are warranted to evaluate the actual underlying mechanisms between metformin dosage and the risk of dementia.

Diabetes mellitus (DM) is a metabolic disease that activates several molecular pathways involved in neurodegenerative disorders. Metformin, an anti-hyperglycemic drug used for treating DM, has the potential to exert a significant neuroprotective role against the detrimental effects of DM. This review discusses recent clinical and laboratory studies investigating the neuroprotective properties of metformin against DM-induced neurodegeneration and the roles of various molecular pathways, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and its related cascades. A literature search was conducted from January 2000 to December 2022 using multiple databases including Web of Science, Wiley, Springer, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, Scopus, and the Cochrane Library to collect and evaluate peer-reviewed literature regarding the neuroprotective role of metformin against DM-induced neurodegenerative events. The literature search supports the conclusion that metformin is neuroprotective against DM-induced neuronal cell degeneration in both peripheral and central nervous systems, and this effect is likely mediated via modulation of oxidative stress, inflammation, and cell death pathways.

Recent studies claim that Type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) overlap in several common pathological pathways which from neuronal damage to impaired memory performance. It is known that the use of Rosa canina L. (R. canina) as medicine in folk medicine dates back to ancient times and is used in the treatment of nervous diseases in Persian medicine. However, the effect of R. canina on diabetes-related cognitive decline and memory impairment has not yet been studied.

We evaluated the impact of T2DM on AD-like alterations and examined the molecular mechanism of a possible effect of R. canina on cognitive alterations in diabetic rats.

R. canina ethanol extract was obtained by maceration method. This study was performed with male Spraque-Dawley rats fed with a high-fat diet (HFD) for 8 weeks, low-dose streptozotocin (STZ; 35 mg/kg IP) injection for 4 weeks, and R. canina (250 mg/kg; per oral) and metformin (400 mg/kg; per oral) administration for 4 weeks. The weight and blood glucose of rats were measured weekly. To evaluate glucose tolerance area under the curve (AUC) was calculated by performing an oral glucose tolerance test. Then the rats were subjected to behavioural tests, and their hippocampus and cortex tissues were obtained for biochemical and morphological analyses.

R. canina could manage glucose responsiveness by reducing post-prandial blood glucose levels, preventing weight loss, and raising serum insulin levels in T2DM-induced rats. Behavioural tests showed that R. canina significantly improves diabetes-related cognitive decline in recall and long-term memory. Treatment with R. canina significantly reversed HFD/STZ-induced increases in insulin, amyloid-β, amyloid precursor protein levels, and acetylcholinesterase activity in the prefrontal cortex and hippocampus. Furthermore, histological analyzes revealed the protection of R. canina against neuronal disruption in the cortical and hippocampal CA3 region caused by chronic hyperglycemia.

Analyzed collectively, these results suggest that R. canina can correct T2DM-related cognitive decline may be attributed to insulin pathway modulation, prevention of amyloid deposition, and increased cholinergic transmission.

Diabetic encephalopathy is a central nervous complication of diabetes mellitus which is characterized by cognitive impairment and structural and neurochemical abnormalities, which is easily neglected. Lipocalin-2 (LCN2) is a 25 kDa transporter in the lipocalin family that can transport small molecules, including fatty acids, iron, steroids, and lipopolysaccharides in the circulation. Recently, LCN2 has been found to be a significant regulator of insulin resistance and glucose homeostasis. Numerous studies have shown that LCN2 is connected to central nervous system abnormalities, including neuroinflammation and neurodegeneration, while the latest researches have found that LCN2 is closely related to the development of diabetic encephalopathy. Nevertheless, its precise role in the pathogenesis of diabetic encephalopathy remains to be determined. In this paper, we review recent evidence on the role of LCN2 in diabetic encephalopathy from multiple perspectives in order to decipher the impact of LCN2 in both the aetiology and treatment of diabetic encephalopathy.