Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.

Currently, few pharmacological treatments are available for Alzheimer's disease (AD). However, gut-brain peptides, especially pancreatic polypeptide (PP) analogues, have shown promise. PP analogues have been reported to cross the blood-brain barrier and activate neuropeptide Y4 receptor (NPY4R) in the brain, thereby ameliorating AD-related cognitive deficits. P1642-1 is a novel PP analogue, but its role and mechanism in AD remain unexplored. This study utilized 5 ×FAD mice as a model to assess the effects of P1642-1 on cognitive dysfunction and its underlying mechanisms, while an Aβ25-35-induced cellular model was used to provide complementary mechanistic support. The findings revealed that administration of P1642-1 significantly ameliorated cognitive deficits, alleviated neuronal injury, decreased β-amyloid (Aβ) accumulation, and attenuated mitochondrial damage in the hippocampus of 5 ×FAD mice. These improvements were accompanied by enhanced mitophagy, as evidenced by upregulation of the PINK1/Parkin axis, increased LC3-II, and decreased p62 levels. In the Aβ25-35-induced cellular AD model, P1642-1 also exerted neuroprotective effects and was associated with the regulation of PINK1/Parkin-related mitophagy. Molecular dynamics simulation suggested that P1642-1 may interact with NPY4R, although receptor expression in hippocampal neurons was not directly verified in the present study. In conclusion, our study suggests that the novel PP analogue P1642-1 ameliorates cognitive impairment in 5 ×FAD mice and is associated with enhanced PINK1/Parkin-related mitophagy. These findings provide experimental support for further investigation of P1642-1 as a potential therapeutic candidate for AD.

(Proline3)PP, or (P3)PP, is an enzymatically stable, neuropeptide Y4 receptor (NPY4R)-selective, pancreatic polypeptide (PP) analogue with established weight-lowering and pancreatic islet morphology benefits in obesity-diabetes. In the current study, we now investigate the impact of twice-daily (P3)PP administration (25 nmol/kg) for 11 days on islet cell lineage, using streptozotocin (STZ) diabetic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP transgenic mice with enhanced yellow fluorescent protein (eYFP) labelling of beta-cell and alpha-cells, respectively. (P3)PP had no obvious impact on body weight or blood glucose levels in STZ-diabetic mice at the dose tested, but did return food intake towards control levels in Ins1Cre/+;Rosa26-eYFP mice. Notably, pancreatic insulin content was augmented by (P3)PP treatment in both Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP mice, alongside enhanced beta-cell area and reduced alpha-cell area. Beneficial (P3)PP-induced changes on islet morphology were consistently associated with decreased beta-cell apoptosis, while (P3)PP also augmented beta-cell proliferation in Ins1Cre/+;Rosa26-eYFP mice. Alpha-cell turnover rates were returned towards healthy control levels by (P3)PP intervention in both mouse models. In terms of islet cell lineage, increased transition of alpha- to beta-cells as well as decreased beta- to alpha-cell differentiation were shown to contribute towards the enhancement of beta-cell area in (P3)PP-treated mice. Together these data reveal, for the first time, sustained NPY4R activation positively modulates beta-cell turnover, as well as islet cell plasticity, to help preserve pancreatic islet architecture following STZ-induced metabolic stress.

Prescription-event monitoring (PEM) is the current gold standard for determining the risk of rare drug side-effects and comparing the risk between agents; however, spontaneous or prompted reporting schemes have low case-detection rates and exposure may be difficult to estimate. A novel method is described that allows a comparative adverse event rate between two drugs to be estimated—based on patterns of cross-reactivity—requiring only a sample of cases and no direct knowledge of drug exposure rates. Agreement was compared between the novel method and historical estimates of risk using PEM for comparative risk of rocuronium versus vecuronium anaphylaxis. The novel method was applied to a sample of patients investigated by the Western Australian Anaesthetic Drug Reaction Clinic over a 21-year period. Relative population exposure was estimated from the number of patients with either rocuronium or vecuronium anaphylaxis subsequently shown to be reactive on skin testing to both agents. This was used to correct the total number of cases of hypersensitivity triggered by each agent. Measures of spread were by bootstrap sampling. Historical estimates were gathered by literature review. Additional comparisons of agreement between estimates made by the novel method and PEM were made using cross-reactivity data and PEM rates reported in the literature. There was agreement between estimates of comparative anaphylaxis risk between the novel method and PEM. Two-hundred and twenty-eight cases of anaphylaxis were observed, 89% caused by rocuronium. Patients reactive to both agents were more likely to be female, and had a higher acute mast cell tryptase level. Patients with a history of rocuronium anaphylaxis were more likely to be reactive to one agent only (69% vs. 33%, P < 0.01). It was estimated that rocuronium was prescribed 3.9 times more frequently than vecuronium. When the observed proportion of cases was corrected for exposure rate, the risk of rocuronium anaphylaxis was 2.2 times that of vecuronium (95% confidence interval 1.7 to 2.8). The median risk from historical estimates was 4.7 times, while the previous PEM estimate in Western Australian was 3.0 times. Using a subgroup of patients susceptible to the same side-effect of two drugs, the relative exposure rate and corrected comparative risk of an adverse effect can be estimated for a population. Using this technique, which requires assessment only of cases to estimate relative exposure rates, we have estimated that the risk of anaphylaxis from rocuronium to be 2.2 times that of vecuronium in Western Australia.

Background: Artocarpus heterophyllus, familiar as jackfruit, is a tropical fruit highly valued not only for its nutritional content but also for its medicinal properties, including potential antidiabetic effects. Objectives: This study aimed to evaluate the insulinotropic, β-cell proliferative and anti-hyperlipidaemic properties of the ethanol extract of unripe Artocarpus heterophyllus (EEAH) in high-fat-fed (HFF) diet-induced obese mice. Method: We evaluated acute insulin secretion and β-cell proliferation in BRIN-BD11 cells, and assessed in vitro glucose diffusion and starch digestion. In vivo, acute and chronic studies in HFF induced obese mice measured glucose tolerance, body weight, food and fluid intake, and lipid profiles. A preliminary phytochemical screening was also performed. Results: In this study, EEAH exhibited significant antidiabetic activity through multiple mechanisms. EEAH enhanced glucose-stimulated insulin secretion in BRIN-BD11 β-cells via KATP channel modulation and cAMP-mediated pathways, with partial dependence on extracellular calcium, and it also promoted β-cell proliferation. In vitro assays revealed its ability to inhibit starch digestion and glucose diffusion, indicating delayed carbohydrate digestion and absorption. In high-fat-fed (HFF) obese mice, the acute and chronic oral administration of EEAH improved oral glucose tolerance, reduced fasting blood glucose, decreased body weight, and normalized food and fluid intake. Lipid profile analysis showed increased HDL and reduced total cholesterol, LDL, and triglycerides, while higher doses of EEAH also enhanced gut motility. Phytochemical screening revealed the presence of bioactive compounds such as alkaloids, tannins, flavonoids, saponins, steroids, and terpenoids, which are likely responsible for these therapeutic effects. Conclusion: These findings highlight EEAH as a promising natural candidate for adjunctive therapy in managing type 2 diabetes and associated metabolic disorders and emphasize the importance of future multi-omics studies to elucidate its molecular targets and pathways.

Lipid abnormalities frequently accompany hyperglycemia and thus a primary goal in diabetes therapy is the management of dyslipidemia. Asparagus racemosus root has previously been shown to reduce postprandial blood glucose in diabetic rats by delaying carbohydrate absorption and enhancing insulin secretion. In the present study, the chronic effects of A racemosus root on serum glucose, fructosamine, lipids, and platelet aggregation were assessed in rats with type 2 diabetes induced by neonatal streptozotocin injection. The type 2 diabetes model was created by injecting 48-hour-old pups with a single intraperitoneal dose of streptozotocin (STZ). Platelet aggregation was measured by optical aggregometry. Daily oral administration of ethanol extract of A racemosus to diabetic rats (n = 10) lowered serum glucose by 21% (p<0.01) and fructosamine by 11% (p<0.05) after 28 days. Total cholesterol (p<0.05), triglyceride (p<0.05), and NEFA (p<0.01) levels were also lowered by 9%, 16% and 38% respectively. No difference in HDL cholesterol or body weights was observed compared to control rats but platelet aggregation was significantly reduced by 18% (p<0.05). Food and water intake, stool formation, water content of stools, and urine formation were unchanged in extract-treated rats in a 24-hour acute observational study in Nalgene Metabolic Cages. In conclusion, this study reveals that ethanol extract of A racemosus root lowers circulating glucose, and atherogenic blood lipids and decreases platelet aggregation. Thus, A racemosus is the source of glucose-lowering bioactive agents and a useful dietary adjunct in the management of diabetes, dyslipidemia, and related complications.

Background: Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. Scope of Review: In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. Major Conclusions: Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

Ocimum sanctum leaf extracts have been reported to augment insulin secretion in perfused pancreas, isolated islets, and BRIN-BD11 cells, as well as to decrease postprandial blood glucose levels in diabetic rats by retardation of carbohydrate digestion and absorption. In this study, the glycaemic, lipidemic, and platelet aggregation effects of the ethanol extract of the O sanctum leaves were evaluated in streptozotocin-induced type 2 diabetic rats. O sanctum significantly decreased serum glucose (p<0.01) and fructosamine (p<0.01) by 25% and 14%, respectively in 28 days of oral administration, the extract lowered serum cholesterol (p<0.01) and triglyceride (p<0.01) levels by 29% and 26%, respectively, and increased HDL cholesterol by 18% (p<0.05). O sanctum significantly reduced NEFA level by 50% (p<0.01), and platelet aggregation was decreased by 21% (p<0.05). Body weights were unchanged, and, over a 24-hour study period, there were no variations in food intake, water consumption, urination, or defecation. In conclusion, beyond its blood glucose-lowering effects, ethanol extract of O sanctum leaves lowers atherogenic lipids and decreases platelet aggregation. O sanctum is, therefore, a useful addition in controlling diabetes and its complications.

Background: Pregnancy induces a reversible expansion of pancreatic islet and beta-cell mass, but the impact of multiple pregnancies on these processes remains unclear. Methods: To further investigate this phenomenon, the current study employed transgenic models with beta- or alpha-cell lineage tracing capabilities, namely Ins1 Cre/+ ;Rosa26-eYFP and Glu CreERT2 ;Rosa26-eYFP male mice, respectively. Using these models, we explored late-stage morphological islet adaptations and cellular plasticity in response to primi-, bi- and tri-parity. Results: All pregnant mice exhibited augmented islet and beta-cell areas, associated with decreased beta-cell apoptosis and increased proliferation. Notably, beta-cell proliferative capacity decreased as parity increased, but was still elevated in triparous mice when compared to null parous controls. Interestingly, alpha-cells also exhibited augmented growth and survival in all pregnant mice. In terms of cellular transdifferentiation, ductal to beta-cell conversion appeared greater in primiparous Ins1 Cre/+ ;Rosa26-eYFP mice, but was much less obvious in bi- and tri-parous mice. Whilst quantification of beta- to alpha-cell transition events was more pronounced during pregnancy, it was less obvious in multiparity than primiparity. There were also notable reductions in beta-cell dedifferentiation, supporting positive effects of islet cell plasticity towards retention and expansion of beta-cell mass in multiparity. In harmony, alpha- to beta-cell transdifferentiation appeared markedly increased in multiparous Glu CreERT2 ;Rosa26-eYFP mice, coupled with augmented alpha-cell neogenesis and dedifferentiation, suggesting that these cells act as a principal source for beta-cell expansion. Conclusion: Together, these findings indicate that reduced beta-cell proliferation in multiparity is offset by enhanced islet cell plasticity, contributing to sustained islet adaptation across multiple gestations.

Conditions like diabetes mellitus (DM), cancer, infections, inflammation, cardiovascular diseases (CVDs), and gastrointestinal (GI) disorders continue to have a major global impact on mortality and morbidity. Medicinal plants have been used since ancient times in ethnomedicine (e.g., Ayurveda, Unani, Traditional Chinese Medicine, and European Traditional Medicine) for the treatment of a wide range of disorders. Plants are a rich source of diverse phytoconstituents with antidiabetic, anticancer, antimicrobial, antihypertensive, antioxidant, antihyperlipidemic, cardioprotective, immunomodulatory, and/or anti-inflammatory activities. This review focuses on the 35 plants most commonly reported for the treatment of these major disorders, with a particular emphasis on their traditional uses, phytoconstituent contents, pharmacological properties, and modes of action. Active phytomolecules with therapeutic potential include cucurbitane triterpenoids, diosgenin, and limonoids (azadiradione and gedunin), which exhibit antidiabetic properties, with cucurbitane triterpenoids specifically activating Glucose Transporter Type 4 (GLUT4) translocation. Capsaicin and curcumin demonstrate anticancer activity by deactivating NF-κB and arresting the cell cycle in the G2 phase. Antimicrobial activities have been observed for piperine, reserpine, berberine, dictamnine, chelerythrine, and allitridin, with the latter two triggering bacterial cell lysis. Quercetin, catechin, and genistein exhibit anti-inflammatory properties, with genistein specifically suppressing CD8+ cytotoxic T cell function. Ginsenoside Rg1 and ginsenoside Rg3 demonstrate potential for treating cardiovascular diseases, with ginsenoside Rg1 activating PPARα promoter, and the PI3K/Akt pathway. In contrast, ternatin, tannins, and quercitrin exhibit potential in gastrointestinal disorders, with quercitrin regulating arachidonic acid metabolism by suppressing cyclooxygenase (COX) and lipoxygenase activity. Further studies are warranted to fully investigate the clinical therapeutic benefits of these plants and their phytoconstituents, as well as to elucidate their underlying molecular mechanisms of action.

Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.

Diabetes mellitus (DM) is currently regarded as a global public health crisis for which lifelong treatment with conventional drugs presents limitations in terms of side effects, accessibility, and cost. Type 2 diabetes (T2DM), usually associated with obesity, is characterized by elevated blood glucose levels, hyperlipidemia, chronic inflammation, impaired β-cell function, and insulin resistance. If left untreated or when poorly controlled, DM increases the risk of vascular complications such as hypertension, nephropathy, neuropathy, and retinopathy, which can be severely debilitating or life-threatening. Plant-based foods represent a promising natural approach for the management of T2DM due to the vast array of phytochemicals they contain. Numerous epidemiological studies have highlighted the importance of a diet rich in plant-based foods (vegetables, fruits, spices, and condiments) in the prevention and management of DM. Unlike conventional medications, such natural products are widely accessible, affordable, and generally free from adverse effects. Integrating plant-derived foods into the daily diet not only helps control the hyperglycemia observed in DM but also supports weight management in obese individuals and has broad health benefits. In this review, we provide an overview of the pathogenesis and current therapeutic management of DM, with a particular focus on the promising potential of plant-based foods.

Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase-4 (DPP-4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N-Pal]PP, and [N-Pal,P3]PP, and their impact on pancreatic beta-cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP-4 degradation. In addition, all peptides inhibited alanine-induced insulin secretion from BRIN-BD11 beta cells. Native PP and related analogs (10-8 and 10-6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokine-induced beta-cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N-Pal,P3]PP. In mice, all peptides, except [N-Pal]PP and [N-Pal,P3]PP, evoked a dose-dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose-regulatory actions of GLP-1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with mid-chain acylation, creates PP analogs with benefits on beta-cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.