Antihyperglycemic Effect Research Articles

Long-Lasting Exendin-4-Coated Gold Nanoparticles: Synthesis and In Vivo Evaluation of Hypoglycemic Activity

Background: Gold nanoparticles (NPs) have drawn great attention in the area of biomedical research with their relatively safe and versatile properties. This study aimed to synthesize long-lasting exendin-4-coated gold NPs (EX-ABD-AFF-GoldNPs) and evaluate their anti-diabetic effects in vivo. Methods: In the present study, EX-ABD-AFF-GoldNPs were synthesized using a simple one-step aqueous reduction method. The physical characterization of the prepared particles verified the successful formation of the EX-ABD-AFF-GoldNPs through dynamic light scattering (DLS), transmission electron microscopy (TEM), ultraviolet–visible (UV-VIS) light spectroscopy, and Fourier transform infrared spectroscopy (FTIR). The anti-hyperglycemic and anti-obesity effects were assessed in high-fat diet (HFD)-fed obese diabetic mice. Additionally, pharmacokinetics (PK) and biodistribution studies were performed to verify the long-lasting properties. Results: The EX-ABD-AFF-GoldNPs were conglomerates of smaller globular-shaped particles, and the average size was 110(±14) nm, based on the TEM images. Safety assessments using Min6, HepG2, and B16F10 cell lines demonstrated low cytotoxicity, with over 80% cell viability up to the highest tested concentration of 150 μg/mL (as EX-ABD-AFF). Notably, the animal studies showed that the EX-ABD-AFF-GoldNPs exhibited significant hypoglycemic activity, comparable to the EX-ABD-AFF, in the HFD-fed mice. A 4-week treatment with EX-ABD-AFF-GoldNPs produced similar reductions in blood glucose and body weight to the EX-ABD-AFF, without any apparent toxicity. Furthermore, the PK and biodistribution study results confirmed the long-lasting properties (plasma half-life: 43.6 h) of the particles. Conclusions: Overall, this study demonstrated that the preparation of therapeutic protein-loaded gold NPs is feasible and, despite their much larger size compared with the protein, EX-ABD-AFF-GoldNPs can be successfully absorbed through the subcutaneous route and show nearly equivalent hypoglycemic activity to the EX-ABD-AFF protein. Finally, this study showed that long-lasting properties could be acquired by only coating EX-ABD-AFF onto gold NPs.

Advances in the biosynthesis of D-allulose.

D-allulose is a rare monosaccharide and a C-3 epimer of D-fructose. It has physiological functions, such as antihyperglycemic, obesity-preventing, neuroprotective, and reactive oxygen species (ROS) scavenging effects, making it an ideal sugar substitute. The synthesis methods for D-allulose include chemical synthesis and biosynthesis. Chemical synthesis requires strict reaction conditions and tends to produce byproducts. Biosynthesis is mainly an enzymatic process. Enzymatic catalysis for the conversion of starch or glycerol to D-allulose is performed mainly by enzymes such as isoamylase (IA), glucose isomerase (GI), D-allulose 3-epimerase (DPE), D-allulose-6-phosphate 3-epimerase (A6PE), D-allulose 6-phosphate phosphatase (A6PP), ribitol 2-dehydrogenase (RDH), glycerophosphate kinase (GK), glycerophosphate oxidase (GPO), and dihydroxyacetone phosphate (DHAP)-dependent aldolase. Biosynthesis is a more energy-efficient process, producing fewer harmful by-products and pollutants, and significantly reducing negative environmental impacts. Furthermore, the specific catalytic activity of enzymes facilitates the production of compounds of higher purity, thereby facilitating the isolation and purification of the products. It has thus become the main method for producing D-allulose. This article reviews the progress in research on the biosynthetic production of D-allulose, focusing on the enzymes involved and their enzymatic properties, and discusses the production prospects for D-allulose.

Anti-diabetic and anti-inflammatory activities of Marrubiin isolated from Marrubium vulgare: Indications of its interaction with PPAR γ

BackgroundThe aerial parts of Marrubium vulgare L. were used for many ailments like catarrh to diabetes in many parts of Latin America and Asia. PurposeIdentifying the active principle responsible for anti-diabetic activity of methanol extract of M. vulgare leaves and to predict the possible targets. Study designAll the activity investigations were conducted simultaneously for the extract, fraction, and isolated compounds to decipher the activity profile in comparison to each other which allowed the identification of an active principle followed by use of in silico methods to identify the possible target/s. MethodsThe aerial parts of M. vulgare were extracted using methanol. A chloroform fraction was prepared. Marrubiin and marrubinone B were isolated from this fraction. The anti-hyperglycemic, hypoglycemic, and postprandial blood glucose lowering activities were investigated using streptozotocin-induced diabetic and non-diabetic rat models. Pro-inflammatory cytokine inhibitory potential was investigated using LPS induced acute-inflammatory mouse model and RAW 264.7 cells. Further, antioxidant activity was investigated using a DPPH assay. The in silico analysis, using the Swiss-target prediction tool, was carried out to predict the probable targets of the isolated molecules. ResultsMarrubiin exhibited anti-hyperglycemic effect in diabetic rats followed by hypoglycemia, and postprandial blood glucose lowering in non-diabetic rats. Methanol extract (Mv extract) and chloroform fraction (Mv fraction) showed anti-hyperglycemic and hypoglycemic effects. Moderate inhibition of IL-1β, TNF-α, and IL-6 was observed for marrubiin, marrubinone B, Mv extract, and Mv fraction, in vitro and in vivo. Neither marrubiin nor marrubinone B could quench the DPPH free radicals while Mv extract and Mv fraction could show 80 % suppression. In silico analysis has predicted that marrubiin can interact with PPAR γ but not marrubinone B. ConclusionsMarrubiin and marrubinone B were responsible for the anti-inflammatory effect of Mv extract and Mv fraction while not contributing to the antioxidant effect. Marrubiin was found to be responsible for the anti-diabetic activity of Mv extract. The predicted interaction propensity of marrubiin with PPAR γ could explain its dual activity observed in the experimental setup.

Synergistic Antihyperglycemic Effects of Soursop Leaves and Garlic in Alloxan-Induced Rats

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by elevated blood glucose levels due to impaired insulin production. Natural remedies, such as soursop leaves (Annona muricata) (SL) and garlic (Allium sativum) (GAR), are known for their antihyperglycemic properties. This study aimed to investigate the effects of SL and GAR extracts, individually and in combination, on reducing blood glucose levels in alloxan-induced diabetic rats. A total of 24 male Wistar rats were divided into six groups, receiving treatments of either metformin, SL, GAR, or their combination for seven days following alloxan administration to induce hyperglycemia. Blood glucose levels were measured before and after induction, and post-treatment on day 15. The results showed that the combined extracts exhibited better antihyperglycemic activity compared to individual treatments, with the most effective dose being 26.3 mg/kg BW SL + 31.5 mg/kg BW GAR.

Ranolazine therapy is associated with a reduced new diagnosis of diabetes mellitus in chronic coronary syndrome patients: the results of a real-world analysis of an Italian population

Abstract Background Ranolazine (Ran) is an anti-anginal drug acting as a late sodium current inhibitor at a cell membrane level. Some experimental and clinical studies showed an antihyperglycemic effect of the drug, possibly mediated by the increase of insulin secretion, the inhibition of glucagon release, and the protective action on beta-cell function. These effects, additive to the anti-anginal properties of Ran in patients with chronic coronary syndrome (CCS), could modulate and improve glucose metabolic balance. Indeed, data exploring at a population level the association of the drug with diabetes mellitus (DM) incidence are effectively lacking. Aims Aim of this study was to evaluate in CCS patients if the use of Ran, compared with other treatments (No-Ran), was associated with a lower incidence of DM in an Italian real-world clinical setting. Methods Patients included in the database of the National Health System were evaluated (N=6.1 million; about 10% of the Italian population); the recorded information concerned hospitalizations with the related diseases, clinical events, outpatient visits and drug therapy. Patients hospitalized for any cause and discharged with a diagnosis of angina between 2011 and 2020 (ICD-9-CM codes: 413-414) were included in the study after having proved the absence of DM in their medical history. Study population was divided into the Ran (at least one drug prescription) and in the No-Ran cohorts. The mean follow up was 4.3 years for the Ran and 5.0 years for the No-Ran cohorts, respectively. Results The study population included N=171,015 patients (mean age: 72 years, men: 66%). Among them, N=148,808 (No-Ran cohort) were treated with other therapies while N=22,207 (Ran cohort) received Ran. After propensity score matching, Ran (N=6,384) and No-Ran (N=25,536) cohorts did not differ for age, Charlson comorbidity index, use of aspirin and other antithrombotic agents, statins, beta-blockers, Ca-antagonists and nitrates. The incidence of a new diagnosis of DM during the follow-up period was 10.5 and 15.8% in the Ran and in the No-Ran cohorts, respectively (p<0.001). The Cox-regression analysis showed that Ran therapy was associated with a 30% risk reduction to present a new diagnosis of DM (HR=0.70, 95%CI: 0.64-0.76, p<0.001), independently of age, Charlson comorbidity index, heart failure, previous stroke, use of ivabradine, Ca-antagonists and nitrates. Conclusions This real-world study, performed in a whole subset of the Italian population, showed that, in the long-term, the incidence of a new DM diagnosis was lower in Ran users. This association could contribute to explain the benefits of the drug in patients with CCS.

Gintonin Stimulates Glucose Uptake in Myocytes: Involvement of Calcium and Extracellular Signal-Regulated Kinase Signaling.

Ginseng has anti-hyperglycemic effects. Gintonin, a glycolipoprotein derived from ginseng, also stimulates insulin release from pancreatic beta cells. However, the role of gintonin in glucose metabolism within skeletal muscle is unknown. Here, we showed the effect of gintonin on glucose uptake, glycogen content, glucose transporter (GLUT) 4 expression, and adenosine triphosphate (ATP) content in C2C12 myotubes. Gintonin (3-30 μg/mL) dose-dependently stimulated glucose uptake in myotubes. The expression of GLUT4 on the cell membrane was increased by gintonin treatment. Treatment with 1-3 μg/mL of gintonin increased glycogen content in myotubes, but the content was decreased at 30 μg/mL of gintonin. The ATP content in myotubes increased following treatment with 10-100 μg/mL gintonin. Gintonin transiently elevated intracellular calcium concentrations and increased the phosphorylation of extracellular signal-regulated kinase (ERK). Gintonin-induced transient calcium increases were inhibited by treatment with the lysophosphatidic acid receptor inhibitor Ki16425, the phospholipase C inhibitor U73122, and the inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenyl borate. Gintonin-stimulated glucose uptake was decreased by treatment with U73122, the intracellular calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester, and the ERK inhibitor PD98059. These results show that gintonin plays a role in glucose metabolism by increasing glucose uptake through transient calcium increases and ERK signaling pathways. Thus, gintonin may be beneficial for glucose metabolism control.

Preparation and Characterization of Berberine-Loaded Bovine Serum Albumin Nanoparticles: Encapsulation Efficiency and Release Rate Determination

Abstract Introduction/Objective Introduction: Berberine (BER) has garnered attention in various studies for its diverse biochemical and pharmacological properties, including anti-inflammatory, antioxidant, antidepressant, anticancer, antihyperglycemic, hypolipidemic, antihypertensive, and hepatoprotective effects. Nanoparticles serve as efficient carriers for drugs, offering increased surface area and enhanced dissolution in the bloodstream, thereby improving drug delivery. Methods/Case Report Methods: Blank Bovine Serum Albumin Nanoparticles (BSA NPs) were synthesized using a desolvation process, followed by the fabrication of Berberine-loaded Bovine Serum Albumin Nanoparticles (BER-NP). Physicochemical characterization, including particle size and zeta potential, was conducted using a Malvern Zetasizer and dynamic light scattering (DLS). Transmission electron microscopy (TEM) was employed to visualize the morphology of both blank BSA NPs and BER-loaded nanocarriers. Results (if a Case Study enter NA) Results: Fourier-transform infrared (FTIR) spectra and Differential Scanning Calorimetry (DSC) thermograms were obtained for free berberine, BSA NPs, and BER-NPs. Encapsulation efficiency (EE) was determined by measuring the concentration of free BER in the supernatant after centrifugation, with EE calculated based on the difference between total added berberine and the measured supernatant concentration. Dialysis membranes were utilized to assess BER release from BER-NPs in vitro, with initial BER content in nanoparticles determining the release profile. Conclusion Conclusion: The prepared nanoparticles have demonstrated the potential to enhance drug permeation across epithelial and endothelial barriers. This approach holds promise for targeted drug delivery to specific sites, facilitating combined therapy with distinct modalities or drugs.

Ethnomedicinal and Phytopharmacological Aspects of Vernonia amygdalina (Bitter Leaf) Utilized as a Traditional Medicinal Herb

Vernonia amygdalina Delile, commonly known as “bitter leaf,” is a shrub in the Asteraceae family, widely seen in tropical regions of Africa. Vernonia amygdalina is found to be traditionally used in African medicine. Various parts of this plant, especially the leaves, are utilized to treat ailments such as fever, diabetes, and gastrointestinal issues. Research from multiple researchers has shown a wide range of phytochemical and bioactive compounds present in Vernonia amygdalina; examples are terpenoids, tannins, alkaloids, saponins, flavonoids, steroids, glycosides, etc., which have contributed to the medicinal properties of Vernonia amygdalina. Vernonia amygdalina has shown its therapeutic and remedial potentials due to the presence of phytochemicals which exhibit effects such as anti-microbial, anti-inflammatory, anti-cancer, anti-oxidant, anti-diabetic, anti-hyperglycemic, anti-diarrheal, anti-helminthic, anti-pyretic, and anti-nociceptive effects. In this article, the authors highlight recent progress in using Vernonia amygdalina and its therapeutic effects. Research, review, and case study articles were used to write this review. The articles were obtained from academic websites such as Research Gate, Google Scholar, the National Library of Medicine, African journals online, and Semantic journals, and some articles were obtained through a simple Google search. Articles that discussed the medicinal, ethanopharmacological, and therapeutic properties of Vernonia amygdalina were selected for the review. Search terms such as “Vernonia amygdalina,” “bitter leaf,” “phytochemical properties,” and “therapeutic effects” were used to search for relevant articles on the academic databases. Boolean operators such as “AND” and “OR” were used to refine the search further and ensure a comprehensive selection of articles.

Hypoglycemic Effect of Rambutan (Nephelium lappaceum L.) Peel Polyphenols on Type 2 Diabetes Mice by Modulating Gut Microbiota and Metabolites.

Type 2 diabetes mellitus (T2DM) is a metabolic disease with a major global public health effect. Rambutan peel polyphenols (RPPs) have been reported to exert hypoglycemic activity. However, few studies have been explored from the viewpoint of gut microbiota and its metabolites. RPPs are administered by gavage to a mice model of T2DM established by using a high-fat diet combined with streptozotocin. It finds that RPPs treatment alleviates hyperglycemia symptoms by improving glucolipid metabolism and liver function. Immunohistochemistry indicates that the antihyperglycemic effect of RPPs is regulated by the IRS-1/PI3K/AKT/GSK3β signaling pathway. RPPs treatment remodels the structure of gut microbiota (Odoribacter, Lachnospiraceae_NK4A136_group, Lactobacillus, Turicibacter, Erysipelatoclostridium, and Tuzzerella) and enriches the metabolites (RPPs-derived urolithins, short-chain fatty acids, dehydrocholic acid, (+)-catechin, dihydroberberine, pterostilbene, and artesunate) associated with diabetes regulation in T2DM mice. The effects of RPPs in ameliorating glycolipid metabolism disorders are correlated with differential gut microbiota and metabolites. The gut microbiota and its metabolites are key targets for the hypoglycemic effects of RPPs.

Suppression of the postprandial hyperglycemia in patients with type 2 diabetes by a raw medicinal herb powder is weakened when consumed in ordinary hard gelatin capsules: A randomized crossover clinical trial.

Contradictory claims about the efficacy of several medicinal plants to promote glycemic control in patients with type 2 diabetes mellitus (T2DM) have been explained by divergences in the administration form and by extrapolation of data obtained from healthy individuals. It is not known whether the antidiabetic effects of traditional herbal medicines are influenced by gelatin capsules. This randomized crossover trial aimed to evaluate the acute effect of a single dose of raw cinnamon consumed orally either dissolved in water as a beverage or as ordinary hard gelatin capsules on postprandial hyperglycemia (>140 mg/dL; >7.8 mmol/L) in T2DM patients elicited by a nutritionally-balanced meal providing 50 g of complex carbohydrates. Fasting T2DM patients (n = 19) randomly ingested a standardized meal in five experimental sessions, one alone (Control) and the other after prior intake of 3 or 6 g of crude cinnamon in the form of hard gelatin capsules or powder dissolved in water. Blood glucose was measured at fasting and at 0.25, 0.5, 0.75, 1, 1.5 and 2 hours postprandially. After each breakfast, its palatability scores for visual appeal, smell and pleasantness of taste were assessed, as well as the taste intensity sweetness, saltiness, bitterness, sourness and creaminess. The intake of raw cinnamon dissolved in water, independently of the dose, decreased the meal-induced large glucose spike (peak-rise of +87 mg/dL and Δ1-hour glycemia of +79 mg/dL) and the hyperglycemic blood glucose peak. When cinnamon was taken as capsules, these anti-hyperglycemic effects were lost or significantly diminished. Raw cinnamon intake did not change time-to-peak or the 2-h post-meal glycaemia, but flattened the glycemic curve (lower iAUC) without changing the shape that is typical of T2DM patients. This cinnamon's antihyperglycemic action confirms its acarbose-like property to inhibit the activities of the carbohydrate-digesting enzymes α-amylases/α-glucosidases, which is in accordance with its exceptionally high content of raw insoluble fiber. The efficacy of using raw cinnamon as a diabetes treatment strategy seems to require its intake at a specific time before/concomitantly the main hyperglycemic daily meals. Trial registration: Registro Brasileiro de Ensaios Clínicos (ReBEC), number RBR-98tx28b.

Variation in the Phenolic Profile and Antioxidant, Antihyperglycemic, and Anti-Inflammatory Activity in Leaves of Cotoneaster zabelii during Growing Season

Cotoneaster zabelii is a medicinal plant that is beneficial due to its polyphenol-rich leaves. In the course of optimizing the harvest time for C. zabelii cultivated in Poland, the leaf samples were collected monthly during the annual plant vegetation season, and the hydromethanolic leaf extracts were evaluated for their phenolic composition and model biological activities, including antioxidant, antihyperglycemic, and anti-inflammatory effects in vitro. The phenolic profiles were analyzed using UHPLC-PDA-ESI-MS3, HPLC-PDA, and spectrophotometric methods (total phenolic content, TPC) to understand their seasonal variability and its correlation with bioactive properties. The identified phenolic compounds included caffeic acid derivatives, flavan-3-ols (especially (−)-epicatechin and procyanidins B-type), and flavonoids like quercetin mono- and diglycosides. Leaves harvested in July and October contained the highest polyphenolic levels and demonstrated significant antioxidant activity in most tests. The leaves harvested in July, September, and October showed optimal anti-inflammatory effects, whereas the highest antihyperglycemic activity was observed in the leaves collected from June to July. Regarding polyphenolic levels and bioactivity, the summer and autumn months appear to be the most advantageous for harvesting leaf material of optimal quality for phytotherapy.

GC-MS SCRUTINY OF PHYTOCONSTITUENTS, IN VITRO EVALUATION OF ANTIHYPERGLYCEMIC, ANTIADIPOGENIC ACTIVITIES, AND CYTOTOXIC EFFECT USING 3T3 L1 ADIPOCYTE CELL LINE AND MOLECULAR DOCKING STUDIES OF PREMNA CORYMBOSA

Objective: The present study was intended to list out the phytochemical multiples and to investigate the antihyperglycemic effect of Premna corymbosa using in vitro assays and in silico molecular docking methods. Methods: The phytochemical multiples of methanol proportion of P. corymbosa leaves were appraised by Gas Chromatography-Mass Spectrometry (GC-MS) scrutiny to illustrate the attendance of phytochemical composites. Moreover, the in vitro antihyperglycemic, antiadipogenic activities, and cytotoxic effects of the extract were elucidated using a 3T3 L1 adipocyte cell line. Mode of action of phytochemical composites in methanol leaf extract of P. corymbosa was probed by Western blotting with IRS1, IRS2, mTOR, and glucose transporter type 4 (GLUT 4) receptors. At present, to probe the consequence of the aboriginal drugs, it is necessary to perform in silico docking on the diabetic receptor which could be useful for the progress of enhanced formulation for the psychoanalysis of diabetes. Results: The GC-MS scrutiny depicted the being there of thirty-five phytochemical multipart. Amid the thirty-five multipart’s recognized, focal composites were Phytol, acetate (RT-16.78), n-Hexadecanoic acid (RT-18.16), Phytol (RT-19.51), 9,12,15-octadecatrienoic acid (Z,Z,Z) (RT-19.85), octadecanoic acid (RT-20.04), and Bis (2-ethylhexyl) phthalate (RT-23.09). The results of the glucose conception assay, adipocyte differentiation assay, and MTT assay showed potent in vitro antihyperglycemic activity with methanol leaf extract of P. corymbosa in 3T3l1Cell line. The results attained from western blotting revealed good antihyperglycemic activity of P. corymbosa. The in silico molecular docking results illustrated that the selected herbal lead compound is an effective target against the receptors. The compound showed favorable interactions with the amino acid residues thereby substantiating their proven efficacy as an antihyperglycemic compound. Conclusion: The outcome of the current study substantiates the antihyperglycemic prospective of the methanol leaf extract of P. corymbosa on the hyperglycemic causal agents and its activity against diabetes by a molecular approach.

6989 Novel Use of Dual GIP/GLP-1 Receptor Agonist in HNF4A-MODY

Abstract Disclosure: A. Mehdi: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Pharmaceuticals. Other; Self; Scientific presenter in a symposium funded by Amryt Pharmaceuticals. C.L. Martin: None. B.E. Gregg: None. N. Nachawi: None. E. Frontera: None. E.A. Oral: Consulting Fee; Self; Amryt Pharmaceuticals, Akcea Therapeutics, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals. Grant Recipient; Self; Amryt Pharmaceuticals (now part of Cheisi, manufacturer of metreleptin), Akcea Therapeutics, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl Laboratories, GI Dynamics (now Morfic Medical. Other; Self; Royalty rights from the use of Metreleptin in lipodystrophy. W.H. Herman: Advisory Board Member; Self; Member of the Data Safety and Monitoring Board for Merck Sharp & Dohme, LLC, Memer of the Data Safety and Monitoring Board for Rivus Pharmaceuticals. Other; Self; Chair for the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS) Workgroup. D.T. Broome: Consulting Fee; Self; Tayco, Inc. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals, Inc. HNF4A-MODY (formerly MODY-1) is an autosomal dominant form of diabetes caused by a mutation in the transcription factor HNF4A[1],2. Affected patients are initially very sensitive to the anti-hyperglycemic effect of sulfonylureas, but become unresponsive to sulfonylureas at a rate of 1-4% per year3. Recently, the efficacy of glucagon-like peptide-1 receptor agonists has been demonstrated in HNF4A-MODY2, but there have been no reports on the use of dual gastric inhibitory polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1 RA) in HNF4A-MODY. This report describes a patient with HNF4A-MODY who was treated with a dual GIP/GLP-1 RA. A 42-year-old White male with a pathogenic heterozygous mutation in Q268X was diagnosed with HNF4A-MODY at the age of 10 years (part of the RW pedigree)3. He was diagnosed with diabetes at age 20, treated with metformin from age 20 to age 30, and had glipizide extended release added at age 30. His dose of glipizide was titrated over 9-years to the maximum therapeutic dose. At the age of 40, when his HbA1c was no longer controlled, dulaglutide 1.5 mg once weekly was added. Thereafter, his HbA1c was well controlled between 5.5-7.0%, until it increased to 7.7%. He was then transitioned from dulaglutide to tirzepatide 5 mg once weekly for 4 weeks, 7.5 mg once weekly for 4 weeks, then 10 mg once weekly. He has been maintained on tirzepatide 10 mg once weekly, glipizide extended release 10 mg once daily, and metformin 1,000 mg twice daily without significant side effects. His HbA1c improved from 7.7% to 5.8% and he lost 7 lbs since transitioning from dulaglutide to tirzepatide (while on tirzepatide for 4 months in total). During his recent visit, he was without significant hyper- or hypoglycemia and his BMI was 31.2 kg/m2. (down from 32.32 kg/m2). To our knowledge, this is the first case report demonstrating preliminary efficacy of dual GIP/GLP-1 receptor agonist in HNF4A-MODY. While it is known that GIP and GLP-1 can cause glucose stimulated insulin secretion, and the mechanism of GLP-1 was previously described in MODY4, the differential effects and/or predominance of GIP or GLP-1 in MODY requires further investigation.

The Anti-Hyperglycemic and Antioxidative Effects of Aqueous Extracts from Sphenocentrum jollyanum: Evidence from In Vitro and In Vivo Studies

The Anti-Hyperglycemic and Antioxidative Effects of Aqueous Extracts from Sphenocentrum jollyanum: Evidence from In Vitro and In Vivo Studies

A narrative review on the role of naturopathy in the management of diabetes mellitus

Abstract: Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Alternative therapies with antihyperglycemic effects are increasingly sought after by patients with diabetes. Some potential alternative treatments for diabetes include yoga and naturopathy, which encompass hydrotherapy, massage therapy, mud therapy, acupuncture, and more. While there are review articles on various alternative therapies for diabetes individually, no known reviews have reported the collective effect of naturopathy therapies, including acupuncture, on diabetes. This comprehensive review was conducted using PubMed/Medline and Google Scholar electronic databases, aiming to provide evidence-based effects of naturopathy therapies such as hydrotherapy, mud therapy, fasting therapy, diet therapy, massage therapy, magnetotherapy, acupuncture, and reflexology, commonly practiced in India, on the management of diabetes. The literature suggests that these treatment modalities significantly improve type 2 diabetes mellitus (T2DM). However, more studies are needed to understand the comprehensive effects of administering these treatments, either individually or in combination, in effectively treating T2DM.

Antihyperglycemic activity of a novel polyherbal formula (HF344), a mixture of fifteen herb extracts, for the management of type 2 diabetes: Evidence from in vitro, ex vivo, and in vivo studies

Antihyperglycemic effects of a novel polyherbal formula (HF344), comprising fifteen Thai herbal extracts, were elucidated for pharmacological mechanisms and potential for managing type 2 diabetes mellitus, by employing in vitro, ex vivo, and in vivo approaches. LC/MS analysis of HF344 extract revealed several phytoconstituents, with piperine identified as the major active compound. HF344 extract significantly enhanced insulin secretion in RINm5F cells in vitro and inhibited glucose uptake into the everted sacs of the mouse small intestine ex vivo in a concentration-dependent manner compared to the control (p < 0.05). It exhibited potent α-glucosidase inhibition in vitro, with an IC50 of 96.74 μg/mL. Moreover, HF344 extract upregulated mRNA levels of GLUT1 in L6 skeletal myoblasts, suggesting increased glucose uptake into skeletal muscle. In addition, in vivo antihyperglycemic effects were assessed in streptozotocin (STZ)-nicotinamide (NA)-induced diabetic mice. Acute oral toxicity testing confirmed the HF344 extract's safety, with an LD50 exceeding 2000 mg/kg. Oral administration of HF344 extract (500 and 1000 mg/kg) in STZ-NA-induced diabetic mice significantly reduced the area under the fasting blood glucose (FBG)-time curve (AUC) in the oral glucose tolerance test (OGTT) model and treatment for 28-day reduced the FBG levels as compared with control (p < 0.05). This was accompanied by increased serum insulin levels and improved insulin resistance. HF344 extract also demonstrated a concentration-dependent inhibitory effect on malondialdehyde (MDA) production in vitro, with an IC50 of 7.24 μg/mL. Oral treatment with HF344 extract decreased MDA production in the homogenized muscle ex vivo collected from STZ-NA-induced mice. Furthermore, pretreatment with HF344 extract effectively restored the survival of RINm5F cells from STZ-induced damage. These findings suggest that HF344 is a promising polyherbal formula for managing blood glucose levels, enhancing insulin production, and providing antioxidant benefits in T2DM. Further research is required to evaluate the clinical efficacy and safety profiles of HF344.

Injectable Gelled Multiple Emulsion for Glucose-Responsive Insulin Delivery.

A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W1/O/W2) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC)and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin.

Herbs for the Therapy of Diabetes Mellitus: A Thorough Analysis with Particular Emphasis on Preclinical, Clinical Trials, and their Hypothesised Mechanisms

Background: In recent times, herbal medicines have experienced an expansion in both developing and developed countries due to their natural origin and low incidence of adverse effects. A systematic review was performed to gather information regarding herbal plants used to treat diabetes mellitus. Objective: The aim of this article was to review evidence from preclinical and clinical trials and the proposed mechanism of herbal drugs in diabetes mellitus. Methods: A literature survey was carried out mainly focused on scientific papers published in recent years. The search strategy involved interrelated keywords, like “Diabetes mellitus,” “Herbs,” “Hyperglycaemia,” and other uniterms. Electronic databases used were Scopus, Web of Science, PubMed, and Elsevier. Results: Twenty studies, including preclinical and clinical trials, were selected for evaluating the mechanism of the anti-hyperglycaemic effect of herbal drugs in diabetes mellitus. Conclusion: Through clinical and preclinical research as well as an analysis of the mechanism of action of herbs, the current review provides preliminary evidence for possible anti-diabetic benefits of herbal medicines.

Hypoglycemic and antihyperglycemic effects of Abelmoschus esculentus and Alchornea cordifolia in normal and alloxan-induced diabetic rats

BackgroundAbelmoschus esculentus and Alchornea cordifolia are commonly used in Traditional Chinese Medicine (TCM) to treat several diseases. Abelmoschus esculentus is used to treat infertility and menorrhagia, while Alchornea cordifolia is used for the treatment of venereal diseases, cough, and diarrhoea. However, very few studies assessed the antidiabetic effects of these plants. Therefore, this study aimed to investigate the hypoglycemic and antihyperglycemic effects of aqueous extract of A. esculentus fruits and A. cordifolia leaves. Material and MethodsFresh Abelmoschus esculentus fruits and the powder from the dried leaves of Alchornea cordifolia leaves were prepared by maceration in the aqueous phase (200g/100mL and 50g/100mL respectively) for 24 hours, then filtered and concentrated in an oven at 45°C. Diabete was induced to male Wistar rats by a single intraperitoneal injection of alloxan (150 mg/kg, b.w). Rats with a blood glucose level greater than or equal to 200 mg/dL were selected, divided into groups and were daily administered orally with either aqueous extracts of A. esculentus at 30 mg/kg (AEAE30) or A. cordifolia at 400 mg/kg (AEAC400) for 14 consecutive days. For comparison, acarbose (100 mg/kg), glibenclamide (5 mg/kg), and metformin (500 mg/kg) were administered orally as reference drugs. Moreover, insuline was also used as a positive control and administered intraperitoneally at a dose of 5 IU/kg. Then, blood glucose levels, oral glucose tolerance test, oral maltose tolerance club, body weight and hemoglobin were assessed. For evaluation of the aqueous extracts in the intestinal transit, imodium (2 mg/kg, p.o) and fructine (5 mg/kg, p.o) were used as a positive control to determine the spasmolytic and laxative activities, respectively. The histopathological study of the liver, kidney, pancreas, testis, epididymis, and seminal vesicle was also carried out using the hematoxyline & eosin (H&E) technique. ResultsAEAE30 and AEAC400 significantly reduced (P<0.001) fasting blood glucose (FBG) levels and significantly prevented (P<0.001) postprandial glycemia in AI-db rats following oral glucose tolerance test (OGTT) and oral maltose tolerance test (OMTT) in alloxan-induced diabetic rats (AI-db). In normoglycemic and insulin-resistant (IR) rats, AEAE30 significantly prevented the post-prandial blood glucose level during the OGTT (P<0.01) only in normoglycemic rats. At the end of treatment, AEAE30 significantly reduced the relative weight of the liver (P<0.01) and significantly increased (P<0.001) the relative weight of the testes and pancreas while AEAC400 significantly increased the relative weight of the testes compared to untreated AI-db rats. The histopathological study revealed a restoration of alloxan-induced tissue damage close to the normal control group in AI-db animals treated with plant extracts, as well as an increase in sperm density in the epididymis unlike in the untreated AI-db group. ConclusionThese findings suggested that AEAE and AEAC exhibited hypoglycemic and antihyperglycemic activities and could be therefore a useful source of antidiabetic agent.

Synergistic modulation of endoplasmic reticulum stress pathway, oxidative DNA damage and apoptosis by β-amyrin and metformin in mitigating hyperglycemia-induced renal damage using adult zebrafish model

Diabetic nephropathy (DN) can be prevented with early therapeutic intervention in diabetic patients. Recent investigations suggest that β-amyrin, a pentacyclic triterpenoid, could offer significant benefits with its potential antihyperglycemic and nephroprotective effects. We investigated the protective effects of β-amyrin alone and combined it with metformin, the cornerstone therapy for diabetes, using a hyperglycemic adult Zebrafish (ZF) model. The ZF were subjected to hyperglycemia by immersing them in 111 mM glucose solutions. Treatment efficacy was assessed by measuring serum glucose and insulin levels and antioxidant, ER stress, apoptosis, and proinflammatory markers. ZF kidneys were also studied for immunohistochemistry and histopathology. Results revealed that the combined treatment of β-amyrin and metformin resulted in a significant decrease (p ≤ 0.05) in blood glucose levels to 104.54 ± 1.63 mg/dL, in comparison to 388.75 ± 4.32 mg/dL in the untreated diseased control group. The reduction in hyperglycemia was more pronounced than treatment with either compound alone. Moreover, treatment with the combination restored renal function in diseased ZF, leading to significantly lower (p ≤ 0.05) serum urea (SU: 19.57 ± 1.61 mg/dL) and serum creatinine (SC: 0.56 ± 0.02 mg/dL) values compared to treatment with β-amyrin (SU:27.02 ± 0.96 mg/dL; SC: 0.7 ± 0.01 mg/dL) or metformin (SU: 24.53 ± 1.29 mg/dL; SC: 0.6 ± 0.02 mg/dL) alone. The treatment also reduced oxidative stress markers, apoptosis and ER stress markers, and proinflammatory cytokines. Histopathological analysis showed improved renal architecture with significantly lower (p ≤ 0.05) renal tubular injury scores with the combination than with individual treatment. This study provides novel insights into the combined therapeutic effects of β-amyrin and metformin in mitigating hyperglycemia-induced renal damage through key molecular pathways, highlighting a potentially effective therapeutic strategy for diabetic nephropathy. The findings hold promising translational relevance for developing combination therapies aimed at improving clinical outcomes in diabetic nephropathy patients.