SGLT-2 inhibitors and high-dose acarbose as potential high-risk combinations for ketosis and ketoacidosis in Asian patients with T2DM: A case series.

Key Clinical Message: High-dose acarbose may increase the risk of diabetic ketosis/diabetic ketoacidosis in Asian patients on sodium-glucose cotransporter-2 inhibitors. Healthcare providers and patients should be cautious to avoid this combination. Abstract: Low-calorie diets should be avoided in patients receiving sodium-glucose cotransporter-2 (SGLT-2) inhibitors to decrease the risk of diabetic ketoacidosis (DKA). High-dose acarbose can decelerate carbohydrate absorption. We detail three cases of diabetic ketosis (DK) following concurrent SGLT-2 inhibitor and high-dose acarbose therapy (acarbose 300 mg/day and dapagliflozin 10 mg/day). Patients, aged 38-63 years with 3-10 years of type 2 diabetes mellitus (T2DM), developed DK, indicated by moderate urinary ketones and high glucose (urine ketone 2+ to 3+ and glucose 3+ to 4+) without acidosis, within 4 days to 1 month post-therapy initiation. Serum glucose was 172.8-253.8 mg/dL; HbA1c was 9.97%-10.80%. The combination therapy was halted, and DK was managed with low-dose intravenous insulin and fluids, followed by intensive insulin therapy. High-dose acarbose with SGLT-2 inhibitors may increase the risk of DK/DKA in Asian patients.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.

Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition in females, suggesting that the benefits of acarbose on AD may be largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a WD.

Acarbose might be associated with reduced risk of gastric cancer in patients with diabetes mellitus: A nationwide population-based cohort study.

BACKGROUND: Several epidemiologic studies have revealed a higher risk of cancer in patients with diabetes mellitus (DM) relative to the general population. To investigate whether the use of acarbose was associated with higher/lower risk of new-onset cancers. METHOD: We conducted a retrospective cohort study, using a population-based National Health Insurance Research Database of Taiwan. Both inpatients and outpatients with newly onset DM diagnosed between 2000 and 2012 were collected. The Adapted Diabetes Complications Severity Index (aDCSI) was used to adjust the severity of DM. The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) of disease. RESULTS: A total of 22 502 patients with newly diagnosed DM were enrolled. The Cox proportional hazards regression model indicating acarbose was neutral for risk for gastroenterological malignancies, when compared to the acarbose non-acarbose users group. However, when gastric cancer was focused, acarbose-user group had significantly lowered HR than non-acarbose users group (p = 0.003). After adjusted for age, sex, cancer-related comorbidity, severity of DM, and co-administered drugs, the HR of gastric cancer risk was 0.43 (95% CI = 0.25-0.74) for acarbose-user patients. CONCLUSION: This long-term population-based study demonstrated that acarbose might be associated with lowered risk of new-onset gastric cancer in diabetic patients after adjusting the severity of DM.

Manipulation of Post-Prandial Hyperglycaemia in Type 2 Diabetes: An Update for Practitioners.

This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose "excursions" being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins - prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.

Acarbose Unveiled: A Breakthrough in Postprandial Hypotension Treatment.

Postprandial hypotension (PPH) is characterized by a drop in blood pressure (BP) of at least 20 mmHg within 15 minutes to two hours after any meal. This phenomenon is observed in approximately half of patients with type 2 diabetes mellitus and can also affect otherwise healthy elderly patients. Prolonged instances of PPH can cause serious complications, including but not limited to dizziness, frequent falls, weakness, and even loss of consciousness. Nonpharmacologic interventions can help, such as discontinuing any exacerbating medications, increasing salt and water intake, adopting lifestyle modifications, and engaging in muscle tension-reducing exercises. When these strategies fail, pharmacological treatments may become necessary. Medications like midodrine (an alpha-adrenergic agonist) or droxidopa (a norepinephrine precursor) are commonly prescribed to help maintain BP. However, should BP persistently remain low despite these interventions, alternative therapies are explored. Acarbose, an antidiabetic medication, is an alpha-glucosidase inhibitor that targets pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase. The inhibition slows glucose absorption, further reducing postprandial glucose blood concentrations. This case report presents the management of a 67-year-old woman with persistent PPH that is unresponsive to midodrine, atomoxetine, and sodium chloride tablets. The addition of acarbose to her regimen yields appropriate maintenance of BP after meals. The patient was able to be safely discharged home after.

Investigating Taste Perception of Maltodextrins Using Lactisole and Acarbose.

Previous research has demonstrated that complex carbohydrates (maltodextrins) can be perceived in the oral cavity. However, little research has been conducted to thoroughly investigate complex carbohydrate taste perception and contributing factors. This study explored the effects of the degree of polymerization and the concentration of complex carbohydrates on taste perception. Additionally, the impact of lactisole and acarbose on carbohydrate taste perception was investigated. Using a blinded, Latin Square design, participants (n = 40) received samples (control) or samples with acarbose (5 mM) or lactisole (1.4 mM). Per visit, participants received solutions: (1) short chain maltodextrin (average DP 6) (SCM), (2) long chain maltodextrin (average DP 24) (LCM), (3) maltose, and (4) glucose. Samples were evaluated in duplicate, both at low concentration and high concentration. Participants tasted the samples and rated sweetness, starchiness, and viscosity (mouthfeel) perceived on a 10 cm continuous line scale and perceived intensity on a Labelled Magnitude Scale. There was a significant effect of degree of polymerisation on sweetness (p = 0.001) and intensity (p = 0.001). For low concentration samples, no significant differences were found between LCM and acarbose LCM or SCM and acarbose SCM for sweetness, starchiness, or mouthfeel (all p > 0.05). Significant differences were observed between LCM and lactisole LCM for sweetness (1.1 ± 0.1 vs. 2.5 ± 0.3, p = 0.001), starchiness (1.4 ± 0.2 vs. 2.3 ± 0.3, p = 0.005), and mouthfeel (1.4 ± 0.2 vs. 2.3 ± 0.3, p = 0.013). In conclusion, the taste perception of maltodextrins is influenced by the degree of polymerisation. Furthermore, for this study, the sweet taste receptor was not involved in maltodextrin taste perception. While salivary α-amylase did not appear to influence taste perception with low concentration maltodextrins, further investigation is necessary.

Effectiveness of dual combination therapy of acarbose plus metformin and acarbose plus myo-inositol in ameliorating the metabolic and endocrinologic complications of polycystic ovary syndrome - A randomized controlled trial.

INTRODUCTION: PCOS, beyond being characterized by reproductive disturbances, is a complicated rapid expanding metabolic and endocrinologic disorder of the recent times. Nearly 70% PCOS women show resistance to insulin. AIM: The aim of the study is to determine and compare the effectiveness of acarbose plus metformin and acarbose plus myo-inositol combination therapy in alleviating the metabolic and endocrinologic complications of PCOS. MATERIALS AND METHODS: An open labelled RCT was conducted on 168 PCOS women attending the gynaecology clinic at SRM MCH & RC, Chengalpattu and the trial was registered in CTRI (No. CTRI/2022/04/041877). Group A (n = 56) received metformin 500 mg/TID alone; group B (n = 54) received (acarbose 25 mg/TID for 4 weeks then 50 mg/TID for other 20 weeks) along with metformin 500 mg/TID and group C (n = 54) received (acarbose 25 mg/TID for 4 weeks then 50 mg/TID for other 20 weeks) along with myoinositol 1000 mg/BD. All parameters were measured at baseline and at the end of 6 months. RESULTS: Significant reduction of LH, LH: FSH, TT, HOMA-IR was observed in all the groups. FSH increased only in metformin group. Increase in serum progesterone and reduction in FI, TGL, LDL were significant only in acarbose plus myo-inositol group. SHBG and HDL increased significantly only in acarbose plus metformin group. No changes in BMI, TC and VLDL were observed in any group. CONCLUSION: Therefore, decrease in FI, HOMA-IR, TGL, LDL seen in acarbose plus myo-inositol group indirectly contributes to cardio-metabolic safety in PCOS. Similarly, a significant increase in SHBG levels with acarbose plus metformin group shows correction of the excess androgen and restoration of ovulation.

A systematic review, meta-analysis, dose-response, and meta-regression of the effects of acarbose intake on glycemic markers in adults.

Purpose: Prior research has yielded mixed results regarding the impact of acarbose intake on glycemic markers. To provide a more comprehensive analysis, a systematic review and meta-analysis was performed to compile data from various randomized controlled trials (RCTs) examining the effects of acarbose intake on fasting blood sugar (FBS), insulin, hemoglobin A1C (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR) in adults. Methods: To identify relevant literature up to April 2023, a comprehensive search was conducted on various scholarly databases, including PubMed, Web of Science, and Scopus databases. The effect size of the studies was evaluated using a random-effects model to calculate the weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity between studies was assessed using Cochran's Q test and I2. Results: This systematic review and meta-analysis included a total of 101 RCTs with a total of 107 effect sizes. The effect sizes for FBS in milligrams per deciliter (mg/dl), insulin in picomoles per liter (pmol/l), hemoglobin A1C (HbA1c) in percentage (%), and homeostasis model assessment of insulin resistance (HOMA-IR) were 92, 46, 80, and 22, respectively. The pooled analysis indicated that acarbose intake resulted in significant decreases in FBS (p = 0.018), insulin (p < 0.001), HbA1c (p < 0.001), and HOMA-IR (p < 0.001). Conclusion: The findings of this systematic review and meta-analysis suggest that acarbose intake can potentially lead to significant improvements in glycemic parameters by decreasing the levels of FBS, HbA1c, and insulin. However, larger and more rigorously designed studies are still needed to further evaluate and strengthen this association.

Acarbose Impairs Gut Bacteroides Growth by Targeting Intracellular GH97 Enzymes.

Acarbose is a type-2 diabetes medicine that inhibits dietary starch breakdown into glucose by inhibiting host amylase and glucosidase enzymes. Numerous gut species in the Bacteroides genus enzymatically break down starch and change in relative abundance within the gut microbiome in acarbose-treated individuals. To mechanistically explain this observation, we used two model starch-degrading Bacteroides, Bacteroides ovatus (Bo) and Bacteroides thetaiotaomicron (Bt). Bt growth is severely impaired by acarbose whereas Bo growth is not. The Bacteroides use a starch utilization system (Sus) to grow on starch. We hypothesized that Bo and Bt Sus enzymes are differentially inhibited by acarbose. Instead, we discovered that although acarbose primarily targets the Sus periplasmic GH97 enzymes in both organisms, the drug affects starch processing at multiple other points. Acarbose competes for transport through the Sus beta-barrel proteins and binds to the Sus transcriptional regulators. Further, Bo expresses a non-Sus GH97 (BoGH97D) when grown in starch with acarbose. The Bt homolog, BtGH97H, is not expressed in the same conditions, nor can overexpression of BoGH97D complement the Bt growth inhibition in the presence of acarbose. This work informs us about unexpected complexities of Sus function and regulation in Bacteroides, including variation between related species. Further, this indicates that the gut microbiome may be a source of variable response to acarbose treatment for diabetes.

Role of MalQ Enzyme in a Reconstructed Maltose/Maltodextrin Pathway in Actinoplanes sp. SE50/110.

The pseudotetrasaccharide acarbose, produced by Actinoplanes sp. SE50/110, is a relevant secondary metabolite used in diabetes type II medication. Although maltose plays a crucial role in acarbose biosynthesis, the understanding of the maltose/maltodextrin metabolism and its involvement in acarbose production is at an early stage. Here, we reconstructed the predicted maltose-maltodextrin pathway that involves four enzymes AmlE, MalZ, MalP, and MalQ. An investigation of enzyme activities was conducted through in vitro assays, leading to an expansion of previously postulated substrate spectra. The maltose-induced α-glucosidase AmlE is noteworthy for its high hydrolysis rate of linear α-1,4-glucans, and its capability to hydrolyze various glycosidic bonds. The predicted maltodextrin glucosidase MalZ showed slow hydrolysis activity on linear α-glucans, but it was resistant to acarbose and capable of releasing glucose from acarbose. AmlE compensates for the low activity of MalZ to ensure glucose supply. We determined the enzyme activity of MalP and its dual function as maltodextrin and glycogen phosphorylase. The 4-α-glucanotransferase MalQ plays a central role in the maltose/maltodextrin metabolism, alongside MalP. This study confirmed the simultaneous degradation and synthesis of long-chain α-glucans. The product distribution showed that with an increasing number of glycosidic bonds, less glucose is formed. We found that MalQ, like its sequence homolog AcbQ from the acarbose biosynthetic gene cluster, is involved in the formation of elongated acarviosyl metabolites. However, MalQ does not participate in the elongation of acarbose 7-phosphate, which is likely the more readily available acceptor molecule in vivo. Accordingly, MalQ is not involved in the formation of acarviosyl impurities in Actinoplanes sp. SE50/110.

Sigma Factor Engineering in Actinoplanes sp. SE50/110: Expression of the Alternative Sigma Factor Gene ACSP50_0507 (σHAs) Enhances Acarbose Yield and Alters Cell Morphology.

Sigma factors are transcriptional regulators that are part of complex regulatory networks for major cellular processes, as well as for growth phase-dependent regulation and stress response. Actinoplanes sp. SE50/110 is the natural producer of acarbose, an α-glucosidase inhibitor that is used in diabetes type 2 treatment. Acarbose biosynthesis is dependent on growth, making sigma factor engineering a promising tool for metabolic engineering. ACSP50_0507 is a homolog of the developmental and osmotic-stress-regulating Streptomyces coelicolor σHSc. Therefore, the protein encoded by ACSP50_0507 was named σHAs. Here, an Actinoplanes sp. SE50/110 expression strain for the alternative sigma factor gene ACSP50_0507 (sigHAs) achieved a two-fold increased acarbose yield with acarbose production extending into the stationary growth phase. Transcriptome sequencing revealed upregulation of acarbose biosynthesis genes during growth and at the late stationary growth phase. Genes that are transcriptionally activated by σHAs frequently code for secreted or membrane-associated proteins. This is also mirrored by the severely affected cell morphology, with hyperbranching, deformed and compartmentalized hyphae. The dehydrated cell morphology and upregulation of further genes point to a putative involvement in osmotic stress response, similar to its S. coelicolor homolog. The DNA-binding motif of σHAs was determined based on transcriptome sequencing data and shows high motif similarity to that of its homolog. The motif was confirmed by in vitro binding of recombinantly expressed σHAs to the upstream sequence of a strongly upregulated gene. Autoregulation of σHAs was observed, and binding to its own gene promoter region was also confirmed.

Two weeks of acarbose treatment shows no effect on gut microbiome composition in patients with type 2 diabetes: a randomised, placebo-controlled, double-blind, crossover study.

Aim: The alpha-glucosidase inhibitor acarbose is approved for the treatment of type 2 diabetes (T2D). It acts in the lumen of the gut by reducing intestinal hydrolysis and absorption of ingested carbohydrates. This reduces postprandial blood glucose concentration and increases the content of carbohydrates in the distal parts of the intestine potentially influencing gut microbiome (GM) composition and possibly impacting the gut microbiome (GM) dysbiosis associated with T2D. Here, we investigated the effect of acarbose on GM composition in patients with T2D. Methods: Faecal samples were collected in a previously conducted randomised, placebo-controlled, double-blind, crossover study in which 15 individuals with metformin-treated T2D (age 57-85 years, HbA1c 40-74 mmol/mol, BMI 23.6-34.6 kg/m2) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a 6-week wash-out period. Faecal samples were collected before and by the end of each treatment period. The GM profiles were evaluated by 16S rRNA gene amplicon sequencing. Results: The GM profiles after the treatment periods with acarbose or placebo remained unaffected (P > 0.7) when compared with the GM profiles before treatment. This applied to the analysis of within-sample diversity (α-diversity) and between-sample bacterial composition diversity (ß-diversity). Additionally, no dominant bacterial species differentiated the treatment groups, and only minor increases in the relative abundances of Klebsiella spp. and Escherichia coli (P < 0.05) were observed after acarbose treatment. Conclusion: In patients with metformin-treated T2D, 14 days of treatment with acarbose showed only minor effects on GM as seen in increased relative abundances of Klebsiella spp. and Escherichia coli.

The Impact of Cholecystectomy in Patients with Post-Bariatric Surgery Hypoglycemia.

BACKGROUND: Metabolic surgery is the foremost treatment for obesity and its associated medical conditions. Nonetheless, post-bariatric hypoglycemia (PBH) emerges as a prevalent complication. PBH pathophysiology implicates heightened insulin and glucagon-like peptide 1 (GLP-1) levels, with bile acids (BA) contributing to GLP-1 release. A plausible association exists between cholecystectomy and PBH, which is attributed to alterations in BA metabolism and ensuing hormonal responses. The objective of this retrospective cohort study was to evaluate the impact of cholecystectomy on PBH pharmacological treatment, diagnostic timelines and metabolic parameters. MATERIALS AND METHODS: Patients diagnosed with PBH after bariatric surgery were evaluated based on their history of cholecystectomy. Demographic, anthropometric and clinical data were collected. Mixed meal tolerance tests (MMTT) results were compiled to assess metabolic responses. RESULTS: Of the 131 patients with PBH included in the study, 29 had prior cholecystectomy. The time to PBH diagnosis was similar across groups. Patients with prior cholecystectomy required higher doses of acarbose (p = 0.046), compared to those without prior cholecystectomy. Additionally, MMTT revealed higher insulin (t = 60 min: p = 0.010 and t = 90 min: p = 0.034) and c-peptide levels (t = 60 min: p = 0.008) and greater glycemic variability in patients with prior cholecystectomy (p = 0.049), highlighting the impact of cholecystectomy on glucose metabolism. CONCLUSION: Our study offers novel insights into PBH pharmacotherapy, indicating that PBH patients with a history of cholecystectomy require elevated doses of acarbose for symptom control than PBH patients without such surgical history. Furthermore, our findings underscore the pivotal role of hyperinsulinism in PBH aetiology, emphasizing the significance of the BA-GLP-1-insulin axis.

Therapeutic potential of acarbose in ameliorating the metabolic and endocrinological complications of polycystic ovarian syndrome: a review.

Polycystic ovarian syndrome is a perplexed condition addressing endocrinal, cardiometabolic and gynaecological issues. It affects women of adolescent age and is drastically increasing in the Indo-Asian ethnicity over the recent years. According to Rotterdam criteria, PCOS is characterized by clinical or biochemical excess androgen and polycystic ovarian morphology; however, it has been established in the recent years that PCOS exacerbates to further serious metabolic conditions on the long term. This is a narrative literature review and not systematic review and is based on PubMed searches with relevant keywords "Polycystic ovarian syndrome AND acarbose OR metformin OR myoinositol; PCOS AND metabolic syndrome OR cardiovascular disease OR menstrual irregularity OR infertility OR chronic anovulation OR clinical hyperandrogenism" used in the title and are limited to articles published in English language with no time limits. A prominent aspect of PCOS is hyperandrogenaemia and hyperinsulinemia. About 50-70% of afflicted women have compensatory hyperinsulinemia and close to one tierce suffer from anovulation and infertility. Insulin resistance leads to metabolic complications and works with luteinizing hormone in increasing the ovarian androgen production. This excess androgen leads to clinical manifestations, irregular menstrual cycles and infertility. There isn't an entire cure, only the symptomatic clinical factors are considered rather than focusing on the underlying long-term complications. Therefore, the article focuses on a potent alpha glucosidase inhibitor, acarbose which suppresses the post meal glucose and insulin by delaying the absorption of complex carbs. It exhibits cardio-metabolic and hormonal benefits and is well tolerable in the south asian population. This review highlights the safety, effectiveness of acarbose in ameliorating the long-term complications of PCOS.

Hypoglycemic Effects of Extracts Obtained from Endemic Betonica bulgarica Degen and Neic.

The increasing prevalence of diabetes mellitus, together with the limited access of many patients to conventional antidiabetic drugs and the side effects resulting from their use, are the reason for the ever-increasing need for new agents. One of the most important strategies used in the therapy of this disease is to reduce the postprandial blood glucose level by inhibiting the carbohydrate-degrading enzymes α-amylase and α-glucosidase. The purpose of the present study was to provide in vitro evidence for the potential hypoglycemic effect of leaf and inflorescence aqueous extracts of Bulgarian endemic species Betonica bulgarica Degen and Neic. Total phenolic and flavonoid contents and antioxidant activities were determined by spectrophotometric methods. Qualitative and quantitative determinations of principal phenolic acids and flavonoids were performed using HPLC with a dual absorbance detector. The plant extracts were able to retard the enzymatic breakdown of starch to glucose with 50% inhibiting concentrations of 1.86 mg/mL and 1.54 mg/mL respectively for leaf and flower extract. Some of the plant constituents are proven inhibitors of α-amylase and/or α-glucosidase, but their adsorption on starch seems to be one additional mechanism for the inhibition of glucose release. Combination index analysis carried out with binary mixtures of acarbose and plant extracts showed a tendency toward synergism with an increase in concentrations and level of inhibition.

Mitigating candidiasis with acarbose by targeting Candida albicans α-glucosidase: in-silico, in-vitro and transcriptomic approaches.

Biofilm-associated candidiasis poses a significant challenge in clinical settings due to the limited effectiveness of existing antifungal treatments. The challenges include increased pathogen virulence, multi-drug resistance, and inadequate penetration of antimicrobials into biofilm structures. One potential solution to this problem involves the development of novel drugs that can modulate fungal virulence and biofilm formation, which is essential for pathogenesis. Resistance in Candida albicans is initiated by morphological changes from yeast to hyphal form. This transition triggers a series of events such as cell wall elongation, increased adhesion, invasion of host tissues, pathogenicity, biofilm formation, and the initiation of an immune response. The cell wall is a critical interface for interactions with host cells, primarily through various cell wall proteins, particularly mannoproteins. Thus, cell wall proteins and enzymes are considered potential antifungal targets. In this regard, we explored α-glucosidase as our potential target which plays a crucial role in processing mannoproteins. Previous studies have shown that inhibition of α-glucosidase leads to defects in cell wall integrity, reduced adhesion, diminished secretion of hydrolytic enzymes, alterations in immune recognition, and reduced pathogenicity. Since α-glucosidase, primarily converts carbohydrates, our study focuses on FDA-approved carbohydrate mimic drugs (Glycomimetics) with well-documented applications in various biological contexts. Through virtual screening of 114 FDA-approved carbohydrate-based drugs, a pseudo-sugar Acarbose, emerged as a top hit. Acarbose is known for its pharmacological potential in managing type 2 diabetes mellitus by targeting α-glucosidase. Our preliminary investigations indicate that Acarbose effectively inhibits C. albicans biofilm formation, reduces virulence, impairs morphological switching, and hinders the adhesion and invasion of host cells, all at very low concentrations in the nanomolar range. Furthermore, transcriptomic analysis reveals the mechanism of action of Acarbose, highlighting its role in targeting α-glucosidase.

A cocktail of rapamycin, acarbose, and phenylbutyrate prevents age-related cognitive decline in mice by targeting multiple aging pathways.

Aging is a primary risk factor for cognitive impairment and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing, insulin signaling, and histone deacetylation activity. Therefore, a pharmaceutical intervention of aging that targets distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. Our previous study showed that middle-aged mice treated with a cocktail of rapamycin, acarbose, and phenylbutyrate for 3 months had increased resilience to age-related cognitive decline. This finding provided the rationale to investigate the transcriptomic and molecular changes within the brains of mice that received this cocktail treatment or control treatment. Transcriptomic profiles were generated through ribonucleic acid (RNA) sequencing, and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured using immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or control. Results showed that biological processes that enhance aging were suppressed, with an increased trend of autophagy in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.

Inhibition and kinetic studies of phytochemical constituents of Goniothalamus wynaadensis and their isoxazoline derivatives on α-glucosidase.

α-Glucosidase, an enzyme involved in post-prandial hyperglycaemia, was used as a target to study the effect of compound(s) isolated from Goniothalamus wynaadensis and its isoxazoline derivatives. Among thirteen compounds screened, compounds 1, 3a and 3j exhibited significant inhibition with IC50 values of 63.42, 61.36 and 58.89 µg/mL, respectively, outperforming acarbose (71.72 µg/mL). Kinetic studies revealed competitive binding for compound 1 and uncompetitive/non-competitive binding for 3a and 3j. Fluorescence quenching showed a linear relationship between I0/I at different inhibitor concentrations. The binding sites in α-glucosidase were ≤ 1. The binding constants 3a (0.7307) > 3j (0.6563) > 1 (0.5415) displayed strong interactions. Docking study revealed binding affinities; 3j (-8.9) > 3a (-7.7) > 1 (-7), and acarbose, 1, 3a and 3j had ARG-312, PHE-157 interactions in common to α-glucosidase. The toxicity profile showed compounds fell in classes IV and V. Overall, the results indicate that compounds 1, 3a and 3j are effective against α-glucosidase.

Medicinal plants of Southeast Asia with anti-α-glucosidase activity as potential source for type-2 diabetes mellitus treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus, a widespread chronic illness, affects millions worldwide, and its incidence is increasing alarmingly, especially in developing nations. Current pharmacological treatments can be costly and have undesirable side effects. To address this, medicinal plants with antidiabetic effects, particularly targeting α-glucosidase for controlling hyperglycaemia in type-2 diabetes mellitus (T2DM), hold promise for drug development with reduced toxicity and adverse reactions. AIM OF THIS REVIEW: This review aims to succinctly collect information about medicinal plant extracts that exhibit antidiabetic potential through α-glucosidase inhibition using acarbose as a standard reference in Southeast Asia. The characteristics of this inhibition are based on in vitro studies. MATERIALS AND METHODS: Relevant information on medicinal plants in Southeast Asia, along with α-glucosidase inhibition studies using acarbose as a positive control, was gathered from various scientific databases, including Scopus, PubMed, Web of Science, and Google Scholar. RESULTS: About 49 papers were found from specific counties in Southeast Asia demonstrated notable α-glucosidase inhibitory potential of their medicinal plants, with several plant extracts showcasing activity comparable to or surpassing that of acarbose. Notably, 19 active constituents were identified for their α-glucosidase inhibitory effects. CONCLUSIONS: The findings underscore the antidiabetic potential of the tested medicinal plant extracts, indicating their promise as alternative treatments for T2DM. This review can aid in the development of potent therapeutic medicines with increased effectiveness and safety for the treatment of T2DM.

Acarbose glycosylation by AcbE for the production of acarstatins with enhanced α-amylase inhibitory activity.

Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). Various acarbose analogs have been identified while exploring compounds with improved pharmacological properties. In this study, we found that AcbE from Actinoplanes sp. SE50/110 catalyzes the production of acarbose analogs that exhibit significantly improved inhibitory activity towards α-amylase than acarbose. Recombinant AcbE mainly catalyzed the formation of two new compounds, namely acarstatins A and B, using acarbose as substrate. Using high-resolution mass spectrometry, nuclear magnetic resonance, and glycosidase hydrolysis, we elucidated their chemical structures as O-α-d-maltosyl-(1 â†’ 4)-acarbose and O-α-d-maltotriosyl-(1 â†’ 4)-acarbose, respectively. Acarstatins A and B exhibited 1584- and 1478-fold greater inhibitory activity towards human salivary α-amylase than acarbose. Furthermore, both acarstatins A and B exhibited complete resistance to microbiome-derived acarbose kinase 1-mediated phosphorylation and partial resistance to acarbose-preferred glucosidase-mediated hydrolysis. Therefore, acarstatins A and B have great potential as candidate therapeutic agents for T2DM.