Improved Glucose Tolerance Research Articles

Beta cell specific ZnT8 gene deficiency and resulting loss in zinc content significantly improve insulin secretion

Zinc transporter 8 (ZnT8) is highly expressed in pancreatic beta cells, localizes to insulin secretory granules (ISG), and regulates zinc content. ZnT8 gene polymorphisms have revealed a relationship between ZnT8 activity and type 2 diabetes (T2D) risk, however, the role of beta-cell ZnT8 is not well understood.A beta cell specific ZnT8 knockout (ZnT8 BKO) mouse model was investigated. ZnT8 BKO islets showed significantly reduced ZnT8 gene expression and reduced zinc content. Compared to controls, ZnT8 BKO mice displayed significantly elevated plasma insulin levels and improved glucose tolerance following acute insulin resistance induced via S961. Glucose stimulated insulin secretion from isolated ZnT8 BKO pancreatic islets revealed enhanced insulin secretion capacity. The difference in insulin secretion between ZnT8 BKO and control islets was negated upon zinc supplementation, and the inhibitory effect of zinc on insulin secretion was confirmed in human islets.These results indicate that the loss of ZnT8 activity and accompanying reduced cellular zinc are associated with increased insulin secretion capacity. The reduction in secreted insulin content upon zinc supplementation in ZnT8 BKO islets suggests that ISG-released zinc normally tempers insulin secretion.

Wnt7b overexpression in osteoblasts stimulates bone formation and reduces obesity in mice on a high-fat diet.

Previous studies have shown that Wnt7b potently stimulates bone formation by promoting osteoblast differentiation and activity. As high-fat feeding leads to obesity and systemic metabolic dysregulation, here we investigate the potential benefit of Wnt7b overexpression in osteoblasts on both bone and whole-body metabolism in mice fed with a high-fat diet (HFD). Wnt7b overexpression elicited massive overgrowth of trabecular and cortical bone but seemed to ameliorate body fat accumulation in mice with prolonged HFD feeding. In addition, Wnt7b overexpression modestly improved glucose tolerance in male mice on HFD. Collectively, the results indicate that targeted overexpression of Wnt7b in osteoblasts not only stimulates bone formation but also improves certain aspects of global metabolism in overnourished mice.

An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice.

Protein folding in the endoplasmic reticulum (ER) requires a high ratio of oxidized to reduced glutathione (GSSG/rGSH). Since the GSSG/rGSH depends on total glutathione (tGSH = GSSG + rGSH) levels, we hypothesized that limiting GSH biosynthesis will ameliorate protein misfolding by enhancing the ER oxidative milieu. As a proof-of-concept, we used DL-buthionine-(S,R)-sulfoximine (BSO) to inhibit GSH biosynthesis in Akita mice, which are prone to proinsulin misfolding. We conducted a 2-week intervention to investigate if BSO was safe and a 6-week intervention to find its effect on glucose intolerance. In both cohorts, male heterozygous Akita (AK) and wild-type (WT) mice were continuously administered 15mM BSO. No adverse effects were observed on body weight, food intake, and water intake in either cohort. Unaltered levels of plasma aspartate and alanine aminotransferases, and cystatin-C, indicate that BSO was safe. BSO-induced decreases in tGSH were tissue-dependent with maximal effects in the kidneys, where it altered the expression of genes associated with GSH biosynthesis, redox status, and proteostasis. BSO treatment decreased random blood glucose levels to 80% and 67%of levels in untreated mice in short-term and long-term cohorts, respectively, and 6-h fasting blood glucose to 82% and 74%of levels in untreated mice, respectively. BSO also improved glucose tolerance by 37% in AK mice in the long-term cohort, without affecting insulin tolerance. Neither glucose tolerance nor insulin tolerance were affected in WT. Data indicate that BSO might treat misfolded proinsulin-induced glucose intolerance. Future studies should investigate the effect of BSO on proinsulin misfolding and if it improves glucose intolerance in individuals with Mutant Insulin Diabetes of Youth.

Intestinal-level anti-inflammatory bioactivities of whole wheat: Rationale, design, and methods of a randomized, controlled, crossover dietary trial in adults with prediabetes

Randomized controlled trials (RCT) demonstrate that whole wheat consumption improves glycemia. However, substantial inter-individual variation is often observed, highlighting that dietary whole grain recommendations may not support the health of all persons. The objective of this report is to describe the rationale and design of a planned RCT aimed at establishing the gut microbiota and metabolome signatures that predict whole wheat-mediated improvements in glucose tolerance in adults with prediabetes. It is hypothesized that a controlled diet containing wheat bread (WHEAT; 160 g/day) compared with refined bread (WHITE) will improve glucose tolerance in a gut microbiota-mediated manner. Biospecimens will be collected before and after each 2-week study arm. Testing for oral glucose tolerance and gastrointestinal permeability will be performed post-intervention. Assessments will include oral glucose tolerance (primary outcome) and secondary outcomes including gut microbiota, targeted and untargeted metabolomics of fecal and plasma samples, intestinal and host inflammatory responses, and intestinal permeability. WHEAT is predicted to alleviate glucose intolerance by shifting microbiota composition to increase short-chain fatty acid-producing bacteria while reducing populations implicated in intestinal inflammation, barrier dysfunction, and systemic endotoxemia. Further, benefits from WHEAT are anticipated to correlate with gut-level and systemic metabolomic responses that can help to explain the expected inter-individual variability in glucose tolerance. Thus, knowledge gained from integrating multi-omic responses associating with glucose tolerance could help to establish a precision nutrition-based framework that can alleviate cardiometabolic risk. This framework could inform novel dietary whole grain recommendations by enhancing our understanding of inter-individual responsiveness to whole grain consumption.

The total tannins of Geum japonicum Thunb. var. chinense extracted by green and natural deep eutectic solvent: Extraction optimization, component identification and hypoglycemic activity

Geum japonicum Thunb. var. chinense (G. japonicum) is a cultivated medicinal plant and used as folk medicine, among which tannins are the main active ingredients. In this work, L-proline-lactic acid (Pro:La) as natural deep eutectic solvents (NADESs) was tailored for the total tannins extraction from G. japonicum with the optimal conditions as follows: water content of 29 %, solid-liquid ratio of 27:1 (mg/mL), extraction time of 48 min, and extraction temperature of 48°C. In high fat diet-induced obese mice, the total tannin extract of G. japonicum can significantly reduce the body weight and serum lipid levels, improve glucose tolerance impairment and insulin resistance, reduce islet hypertrophy and protect the liver. Targeted fractionation of the total tannin extract of G. japonicum led to the isolation of sixteen tannins. Notably, the isolated tannins, except for ellagic acid and 3,3′-di-O-methylellagic acid, possessed strong α-glucosidase inhibitory activities (IC50: 1.401–4.801 μg/mL) and dose-dependently inhibited glucose consumption of Caco-2 model system in vitro. These results indicate that the NADES (Pro:La) can effectively extract total tannins from G. japonicum and provide a reference for further applications in medicine and healthcare products.

Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis

Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.

Effects of Bifidobacterium-Fermented Milk on Obesity: Improved Lipid Metabolism through Suppression of Lipogenesis and Enhanced Muscle Metabolism.

Obesity is a major global health concern. Studies suggest that the gut microflora may play a role in protecting against obesity. Probiotics, including lactic acid bacteria and Bifidobacterium, have garnered attention for their potential in obesity prevention. However, the effects of Bifidobacterium-fermented products on obesity have not been thoroughly elucidated. Bifidobacterium, which exists in the gut of animals, is known to enhance lipid metabolism. During fermentation, it produces acetic acid, which has been reported to improve glucose tolerance and insulin resistance, and exhibit anti-obesity and anti-diabetic effects. Functional foods have been very popular around the world, and fermented milk is a good candidate for enrichment with probiotics. In this study, we aim to evaluate the beneficial effects of milks fermented with Bifidobacterium strains on energy metabolism and obesity prevention. Three Bifidobacterium strains (Bif-15, Bif-30, and Bif-39), isolated from newborn human feces, were assessed for their acetic acid production and viability in milk. These strains were used to ferment milk. Otsuka-Long-Evans Tokushima Fatty (OLETF) rats administered Bif-15-fermented milk showed significantly lower weight gain compared to those in the water group. The phosphorylation of AMPK was increased and the expression of lipogenic genes was suppressed in the liver of rats given Bif-15-fermented milk. Additionally, gene expression related to respiratory metabolism was significantly increased in the soleus muscle of rats given Bif-15-fermented milk. These findings suggest that milk fermented with the Bifidobacterium strain Bif-15 can improve lipid metabolism and suppress obesity.

Palmitic acid promotes miRNA release from adipocyte exosomes by activating NF-κB/ER stress

ObjectiveThe release of adipose tissue-derived miRNAs is increased under conditions of obesity, but the exact molecular mechanisms involved have not been elucidated. This study investigated whether obesity-induced increases in palmitic acid (PA) content could activate the NF-κB/endoplasmic reticulum stress (ER stress) pathway and promote the expression and release of exosomal miRNAs in adipocytes.MethodsAbdominal adipose tissue and serum samples were collected from normal weight individuals and people with obesity to clarify the correlation of serum PA content with NF-κB/ER stress and the release of exosomal miRNAs. NF-κB and ER stress were blocked in obese mice and in vitro cultured adipocytes to demonstrate the molecular mechanisms by which PA promotes the release of exosomal miRNAs.The morphology, particle size and distribution of the exosomes were observed via transmission electron microscopy and NTA.ResultsAccompanied by increased serum PA levels, the NF-κB/ER stress pathway was activated in the adipose tissue of people with obesity and in high-fat diet (HFD)-induced obese mice; moreover, the levels of miRNAs in both adipose tissue and serum were increased. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reduced the levels of miRNAs in abdominal adipose tissue and serum, decreased blood glucose levels, and improved glucose tolerance and insulin sensitivity in obese mice. In 3T3-L1 adipocytes, high concentrations of PA activated the NF-κB/ER stress pathway and increased the expression and release of miRNAs in exosomes. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reversed the increased release exosomal miRNAs cause by PA.ConclusionsObesity-induced increases in PA content increase the expression and release of miRNAs in adipocyte exosomes by activating the NF-κB/ER stress pathway.

In vitro insulinotropic actions of extracts of Gnetum africanum welw and effects on glucose homeostasis in mice with diet-induced obesity-diabetes

IntroductionGnetum africanum leaf is consumed as a vegetable in many parts of Africa. Many ethnobotanical surveys indicate its usage in the management of inflammation-related diseases (such as diabetes). However, mechanisms underlying its antidiabetic actions are poorly understood. MethodsThis study conducted phytochemical analysis and investigated mechanisms underlying anti-diabetic actions of aqueous extracts of G. africanum in cellular and high fat-fed mice models of diabetes. Reversed phase high performance liquid chromatography (HPLC) analysis, qualitative phytochemical screening and the estimation of the total flavonoid and total phenolic content were conducted. Mechanisms underlying insulinotropic actions of the extracts as well as its effects on cytotoxicity, cell viability, intracellular calcium and membrane potential were assessed. In vivo actions were evaluated in mice with diet-induced obesity-diabetes. ResultsG. africanum has total phenolic content of 1.24±0.23GE/g and total flavonoid content of 1.54±0.06QE/g. HPLC analysis revealed the presence of the presence of atropine, vicenin 3, vicenin 2, alpha-chaconine, isoswertisin and solanidine. The extract stimulated non-toxic, concentration-dependent insulin-release from BRIN-BD11 cells (1.3-fold to 3.3-fold, P < 0.05 to P < 0.001). As glucose concentration increased from 1.1 mM to 5.6 mM and 5.6 mM to 16.7 mM, these effects increased by 2.0-fold (P < 0.001) and 1.2-fold (P < 0.05) respectively. Insulinotropic effects increased in cells depolarised with KCl (30 mM, 1.3-fold, P < 0.05). These effects reduced in the presence of diazoxide (300 µM, 67 %, P < 0.001), verapamil (50 nM, 50 %, P < 0.001), and absence of extracellular calcium (55 %, P < 0.001). Membrane potential (48 %, P < 0.05) and intracellular calcium (34 %, P < 0.05) increased in cells incubated with the extract. The extract improved glucose tolerance (22.2 %, P < 0.01 at 150 mg kg-1 bw; 35.1 %, P < 0.001 at 300 mg kg-1 bw) and plasma insulin levels (1.4-fold, P < 0.05 at 150 mg kg-1 bw; 2.9-fold, P < 0.001 at 300 mg kg-1 bw) in high fat fed mice in a dose-dependent manner. ConclusionThese results suggest a role for the KATP-dependent pathway in G. africanum insulinotropic actions and encourage further development of the therapeutic potential of the extract.

Design, Synthesis, molecular dynamic analysis, and In-Vivo anti-diabetic evaluation of novel hydrazine carboximidamide derivatives

Diabetes is one of the most rapidly growing health problems globally, and researchers working hard to develop novel efficient therapies against it. In this regard, hydrazine carboximidamide has a great deal of attention owing to its diverse biological activities. Herein, a new series of N, N-disubstituted hydrazine carboximidamide derivatives was designed, synthesized, and assessed for their antidiabetic activity. Docking studies were performed to initially evaluate the binding of the designed compounds to the target enzyme. It was found that all of the pivotal ligand-enzyme interactions, including the interactions with Glu205/Glu206 aminoacids were observed in docking studies. The molecular dynamic analysis showed that the antidiabetic activity of the newly developed compounds may be implemented through the inhibition of dipeptidyl peptidase 4 (DPP-4), an important target that involves enhancing insulin release and suppressing glucagon discharge from the pancreas. The target molecules were synthesized practically and all the newly-developed chemical structures were confirmed via spectrophotometric methods, including IR, LC-MS, 1H NMR, and 13C NMR techniques. Finally, the in-vivo studies were carried out to confirm the results obtained from the docking and molecular dynamics studies. Compounds 6b and 6d demonstrated improved glucose tolerance through oral glucose tolerance tests in NMRI mice (at a dose of 10 mg/kg). Furthermore, prolonged administration of compounds 6b and 6d to diabetic Wistar rats for 14 days led to a noteworthy reduction in blood levels of glucose, akin to the effects observed with sitagliptin, a standard diabetes medication.

Serum isthmin-1 is a potential biomarker for metabolic dysfunction associated fatty liver disease in patients with metabolic syndrome and type 2 diabetes mellitus

IntroductionMetabolic dysfunction associated fatty liver disease (MAFLD) is a prevalent condition in patients with type 2 diabetes mellitus (T2DM). Isthmin-1 (ISM1) is an adipokine that promotes glucose uptake and improves...

Asian Low-Carbohydrate Diet with Increased Whole Egg Consumption Improves Metabolic Outcomes in Metabolic Syndrome: A 52-Week Intervention Study

BackgroundThe low-carbohydrate-ketogenic diet, an effective strategy to address metabolic syndrome (MetS) and obesity has raised concerns about high-fat consumption on atherogenic lipoproteins. ObjectiveThe aim of this study was to compare the Asian ketogenic diet (AKD), which incorporates balanced protein and fat intake from Asian foods, with a balanced low-caloric diet (BLC) in individuals diagnosed with MetS. MethodsA 52-wk randomized clinical trial included 3 parallel groups: AKD with increased whole egg intake [egg yolk Asian ketogenic diet (Yolk-AKD, n = 28)], yolk-free ketogenic diet with egg white supplementation [egg white Asian ketogenic diet (White-AKD, n = 26)], and BLC (n = 22). Primary outcomes were anthropometric and metabolic changes. ResultsThe AKD groups achieved significant reductions in weight and waist circumference (P < 0.05). Compared with the BLC group, the AKD groups demonstrated significant improvements in insulin resistance at week 6 and in triglyceride concentrations at weeks 12 (Yolk-AKD) and 35 (White-AKD) (P < 0.05). The AKD groups experienced improvements in hormones associated with insulin sensitivity and appetite, whereas only the Yolk-AKD group had a significant decrease in inflammation-related hormones (P < 0.05). From weeks 35–52, the AKD maintained reductions in anthropometric measurements, blood pressure, improved glucose tolerance, enhanced lipid profiles, and better liver function compared with the BLC. ConclusionsThe AKD proved safe and effective, yielding various metabolic improvements in individuals with MetS compared with the BLC. Emphasizing a low-saturated fat diet while disregarding dietary cholesterol, this approach holds promise for MetS and obesity management. The inclusion of both White-AKD and Yolk-AKD groups allowed for a comprehensive assessment of the AKD's impact, elucidating the differential effects of whole egg consumption on metabolic outcomes. Further studies are warranted.This trial was registered at clinicaltrials.gov as NCT04608136.

ACE2 Knockout Mice Are Resistant to High-Fat Diet-Induced Obesity in an Age-Dependent Manner.

Angiotensin converting enzyme 2 (ACE2) presents pleiotropic actions. It hydrolyzes angiotensin I (AngI) and angiotensin II (AngII) into angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), respectively, as well as participates in tryptophan uptake in the gut and in COVID-19 infection. Our aim was to investigate the metabolic effect of ACE2 deletion in young adults and elderly mice under conditions of high calorie intake. Male C57Bl/6 (WT) and ACE2-deficient (ACE2-/y) mice were analyzed at the age of 6 and 12 months under standard diet (StD) and high-fat diet (HFD). Under StD, ACE2-/y showed lower body weight and fat depots, improved glucose tolerance, enhanced insulin sensitivity, higher adiponectin, and lower leptin levels compared to WT. This difference was even more pronounced after HFD in 6-month-old mice, but, interestingly, it was blunted at the age of 12 months. ACE2-/y presented a decrease in adipocyte diameter and lipolysis, which reflected in the upregulation of lipid metabolism in white adipose tissue through the increased expression of genes involved in lipid regulation. Under HFD, both food intake and total energy expenditure were decreased in 6-month-old ACE2-/y mice, accompanied by an increase in liquid intake, compared to WT mice, fed either StD or HFD. Thus, ACE2-/y mice are less susceptible to HFD-induced obesity in an age-dependent manner, as well as represent an excellent animal model of human lipodystrophy and a tool to investigate new treatments.

Effects of a xylitol-casein complex on insulin resistance and gut microbiota composition in high-fat-diet + streptozotocin-induced type 2 diabetes mellitus mice

This study investigated the effects of a xylitol-casein non-covalent complex (XC) on parameters related to type 2 diabetes mellitus (T2DM), in addition to related changes in gut microbiome composition and functions. High-fat-diet (HFD) + streptozotocin (STZ)-induced T2DM mice were treated with xylitol (XY), casein (CN), and XC, after which fecal samples were collected for gut microbiota composition and diversity analyses based on 16S rRNA high-throughput sequencing and multivariate statistics. XC decreased body weight and improved glucose tolerance, insulin sensitivity, pancreas impairment, blood lipid levels, and liver function in T2DM mice compared to XY- and CN-treated mice. Furthermore, XC modulated the α-diversity, β-diversity and gut microbiota composition. Based on Spearman’s correlation analysis, the relative abundances of Alistipes, Bacteroides, and Faecalibaculum were positively correlated and those of Akkermansia, Lactobacillus, Bifidobacterium, and Turicibacter were negatively correlated with the phenotypes related to the improvement of T2DM. In conclusion, we found that XC alleviated insulin resistance by restoring the gut microbiota of T2DM mice. Our results provide strong evidence for the beneficial effects of XC on T2DM and motivation for further investigation in animal models and, eventually, human trials.

Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice

ObjectiveGlucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. MethodsWe investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. ResultsDietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. ConclusionGlucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

Multi-omics analysis of Au@Pt nanozyme for the modulation of glucose and lipid metabolism

Au@Pt nanozyme, a bimetallic core–shell structure Au and Pt nanoparticle, has attracted significant attention due to its excellent catalytic activity and stability. Here, we propose that Au@Pt improves glucose tolerance and reduces TG after four weeks administration. The transcriptomic analysis of mouse liver tissues treated with Au@Pt nanozyme showed changes in genes related to glucose and lipid metabolism signaling pathways, including glycolysis/gluconeogenesis, pyruvate metabolism, PPAR signaling, and insulin signaling. Moreover, analysis of fecal samples from mice treated with Au@Pt nanozyme showed significant changes in the abundance of beneficial gut microbiota such as Dubosiella, Parvibacter, Enterorhabdus, Monoglobus, Lachnospiraceae_UCG-008, Lachnospiraceae_UCG-006, Lachnospiraceae_UCG-001, and Christensenellaceae_R-7_group. Combined multi-omics correlation analyses revealed that the modulation of glucose and lipid metabolism by Au@Pt was strongly correlated with changes in hepatic gene expression profiles as well as changes in gut microbial profiles. Overall, our integrated multi-omics analysis demonstrated that Au@Pt nanozyme could modulate glucose and lipid metabolism by regulating the expression of key genes in the liver and altering the composition of gut microbiota, providing new insights into the potential applications of Au@Pt nanozyme in the treatment of metabolic disorder.Graphical

The Intake of Dietary Lipids Improves Glucose Tolerance via Modulating Gut Microbiota.

The composition of gut microbiota is determined not only by genetic factors but also by environmental factors, such as diet, exercise, and disease conditions. Among these factors, diet is crucial in changing the gut microbial composition. Dietary lipids composed of different fatty acids not only alter host metabolism but also have a significant impact on the composition of gut microbiota. However, the molecular mechanisms underlying the relationship between these host effects and their impact on gut microbiota remain unclear. Here, we demonstrated that intake of different dietary lipids improved glucose tolerance by modulating gut microbiota. The results of our analysis show that the taxa of bacteria that increase in number as a result of dietary lipid intake play an important role in glucose metabolism. Thus, we have identified a new mechanism underlying the function of dietary lipids in regulating glucose homeostasis. Our findings contribute to possible new methods to prevent and treat metabolic disorders by modifying the composition of gut microbiota.

The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice

ObjectiveThe development of glucagon-like peptide-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has been accompanied by evidence for anti-inflammatory and cytoprotective actions in the heart, blood vessels, kidney, and brain. Whether GLP-1R agonists might be useful clinically for attenuating deterioration of cognitive dysfunction and reducing the progression of Alzheimer's disease remains uncertain. MethodsHere we evaluated the actions of semaglutide and tirzepatide, clinically distinct GLP-1 medicines, in two mouse models of neurodegeneration. ResultsSemaglutide reduced body weight and improved glucose tolerance in 12-month-old male and female 5XFAD and APP/PS1 mice, consistent with pharmacological engagement of the GLP-1R. Nevertheless, amyloid plaque density was not different in the cerebral cortex, hippocampus, or subiculum of semaglutide-treated 12-month-old 5XFAD and APP/PS1 mice. IBA1 and GFAP expression were increased in the hippocampus of 5XFAD and APP/PS1 mice but were not reduced by semaglutide. Moreover, parameters of neurobehavioral and cognitive function evaluated using Open Field testing or the Morris water maze were not improved following treatment with semaglutide. To explore whether incretin therapies might be more effective in younger mice, we studied semaglutide and tirzepatide action in 6-month-old male and female 5XFAD mice. Neither semaglutide nor tirzepatide modified the extent of plaque accumulation, hippocampal IBA1+ or GFAP+ cells, or parameters of neurobehavioral testing, despite improving glucose tolerance and reducing body weight. mRNA biomarkers of inflammation and neurodegeneration were increased in the hippocampus of male and female 5XFAD mice but were not reduced after treatment with semaglutide or tirzepatide. ConclusionsCollectively, these findings reveal preservation of the metabolic actions of two GLP-1 medicines, semaglutide and tirzepatide, yet inability to detect improvement in structural and functional parameters of neurodegeneration in two mouse models of Alzheimer's disease.

Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson's disease.

Unintentional weight loss, primarily due to the loss of fat mass rather than muscle mass, is common among patients with Parkinson's disease (PD) and is associated with poor quality of life and accelerated disease progression. Since transgenic mice overexpressing human wild-type α-synuclein (α-Syn mice) are modestly leaner than control mice, and since diabetes, a metabolic disorder, is a major risk factor for PD, we reasoned that high-fat diet-induced diabetes/metabolic dysregulation in α-Syn mice may serve as a robust tool for exploring how early α-synuclein pathology contributes to metabolic dysregulation, leading to weight loss in PD. Thus, α-Syn and age-matched controls were fed a high-fat diet (HFD) chow (60% fat calories) ad libitum for four months. Compared with controls on HFD (control-HFD), α-Syn mice on HFD (α-Syn-HFD) were dramatically leaner. The resistance to gaining weight in α-Syn-HFD mice was accompanied by improved glucose tolerance, a dramatic decrease in fat mass, and an increase in energy expenditure. Despite this leaner phenotype and better glucose tolerance, the mortality was much higher in male α-Syn-HFD mice than in all controls, but was unaffected in females, suggesting protective effects of female sex hormones, as well as lower α-synuclein levels. Immunoblot analysis of insulin signaling in the olfactory bulb, the proposed initial seeding site of α-synuclein pathology, revealed a decrease of IGF-IRβ, p GSK, and p mTOR in α-Syn-HFD mice. Since GSK-3β and mTOR regulate synaptic plasticity, we assessed levels of PSD-95 and synaptophysin in the olfactory bulb. As anticipated, we observed a significant decrease in the levels of PSD-95, along with a potentially compensatory increase in synaptophysin levels. Our results show that α-Syn mice, when challenged with diet-induced diabetes/metabolic dysregulation, clearly reveal a profile of robust metabolic dysfunction, thus providing a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. We propose a role for olfactory dysfunction in PD-related unintentional weight loss and suggest that strategies aimed at increasing body weight/BMI will improve the quality of life and prognosis for people living with PD.

Role of the peripheral chemoreceptors in cardiovascular and metabolic control in type 2 diabetes.

Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes (T2D) and the contribution of the peripheral chemoreceptors to resting cardiovascular and metabolic control. We hypothesized that: (1) adults with T2D exhibit exaggerated peripheral chemoreflex sensitivity; (2) the peripheral chemoreceptors contribute to cardiovascular dysfunction in T2D; and (3) attenuation of peripheral chemoreceptor activity improves glucose tolerance in T2D. Seventeen adults with diagnosed T2D [six males/11 females; aged 54±11years; glycated haemoglobin (HbA1c) 7.6±1.5%] and 20 controls without T2D (9 males/11 females; aged 49±13years, HbA1c 5.2±0.4%) participated in the study. The hypoxic ventilatory response (HVR) was assessed as an index of peripheral chemosensitivity. Resting heart rate, blood pressure and minute ventilation were measured when breathing normoxic followed by hyperoxic air (1.0 ) to acutely attenuate peripheral chemoreceptor activity. A subset of participants (n=9 per group) completed two additional visits [normoxia (0.21 ), hyperoxia (1.0 )] where glucose and insulin were measured for 2h following an oral glucose challenge. HVR was augmented in adults with T2D (-0.84±0.49Lmin-1/%) vs. control (-0.48±0.40Lmin-1/%, P=0.021). Attenuation of peripheral chemoreceptor activity decreased heart rate (P<0.001), mean blood pressure (P=0.009) and minute ventilation (P=0.002); any effect of hyperoxia did not differ between groups. There was no effect of hyperoxia on the glucose (control, P=0.864; T2D, P=0.982), nor insulin (control, P=0.763; T2D, P=0.189) response to the oral glucose challenge. Peripheral chemoreflex sensitivity is elevated in adults with T2D; however, acute attenuation of peripheral chemoreflex activity with hyperoxia does not restore cardiometabolic function. KEY POINTS: Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes and the contribution of the peripheral chemoreceptors to resting cardiovascular control and glucose tolerance. We observed elevated peripheral chemoreflex sensitivity in adults with diabetes which was associated with glycaemic control (i.e. glycated haemoglobin). Notably, acute attenuation of peripheral chemoreflex activity with hyperoxia did not restore cardiometabolic function in the individuals studied.