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To follow‐up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log‐rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%–11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2‐(2‐hydroxyphenyl) benzothiazole (HBX), and INT‐767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose‐control drugs in humans.

Computer aided toxicity and pharmacokinetic prediction studies attracted the attention of pharmaceutical industries as an alternative means to predict potential drug candidates. In the present study, in-silico pharmacokinetic properties (ADME), drug-likeness, toxicity profiles of sixteen antidiabetic flavonoids that have ideal bidentate chelating sites for metal ion coordination were examined using SwissADME, Pro Tox II, vNN and ADMETlab web tools. Density functional theory (DFT) calculations were also employed to calculate quantum chemical descriptors of the compounds. Molecular docking studies against human alpha amylase were also conducted. The results were compared with the control drugs, metformin and acarbose. The drug-likeness prediction results showed that all flavonoids, except myricetin, were found to obey Lipinski’s rule of five for their drug like molecular nature. Pharmacokinetically, chrysin, wogonin, genistein, baicalein, and apigenin showed best absorption profile with human intestinal absorption (HIA) value of ≥ 30%, compared to the other flavonoids. Baicalein, butein, ellagic acid, eriodyctiol, Fisetin and quercetin were predicted to show carcinogenicity. The flavonoid derivatives considered in this study are predicted to be suitable molecules for CYP3A probes, except eriodyctiol which interacts with P-glycoprotein (p-gp). The toxicological endpoints prediction analysis showed that the median lethal dose (LD 50 ) values range from 159–3919 mg/Kg, of which baicalein and quercetin are found to be mutagenic whereas butein is found to be the only immunotoxin. Molecular docking studies showed that the significant interaction (-7.5 to -8.3 kcal/mol) of the studied molecules in the binding pocket of the α-amylase protein relative to the control metformin with the crucial amino acids Asp 197, Glu 233, Asp 197, Glu 233, Trp 59, Tyr 62, His 101, Leu 162, Arg 195, His 299 and Leu 165. Chrysin was predicted to be a ligand with high absorption and lipophilicity with 84.6% absorption compared to metformin (78.3%). Moreover, quantum chemical, ADMET, drug-likeness and molecular docking profiles predicted that chrysin is a good bidentate ligand.

The comparative neuroprotective effects of different hypoglycemic drugs have not been characterized in randomized controlled trials. Here, we investigated the effects of dapagliflozin, liraglutide, or acarbose treatment on the directed functional connectivity of primary olfactory cortex (POC) circuit and local activation under odor stimulation in patients with type 2 diabetes (T2D). In the 16-week randomized parallel-group open-label trial, 36 patients with T2D, inadequately controlled with metformin, were randomized 1:1:1 to receive dapagliflozin, liraglutide or acarbose. Simultaneously, 36 normal controls were recruited. Olfactory task functional MRI and a battery of olfactory and cognitive tests were conducted in all subjects and postintervention. Generalized psychophysiological interaction analysis was used to identify directed functional connectivity of POC circuit under odor stimulation. The 16-week treatment with dapagliflozin restored odor-induced functional integration of POC-sensorimotor cortex-middle temporal cortex circuit with Gaussian random field correction, but liraglutide and acarbose did not, and dapagliflozin tended to improve attention (P = 0.071). Liraglutide enhanced odor-induced activation in the left hippocampus, but dapagliflozin and acarbose did not. The decreased odor-induced directed functional connectivity was associated with improvements in lipid levels and changes in olfactory threshold, executive function, and memory performance (all P < 0.05). These results suggest that dapagliflozin and liraglutide have unique neuroprotective effects, respectively. Liraglutide may act on the activation of local olfactory-related regions, while dapagliflozin acts on the functional integration of neural circuits. These findings highlight the importance of targeting both metabolic and neural pathways in the management of T2D-related cognitive decline.

α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

The clinical efficacy of the antidiabetic drug acarbose is hampered by degradation by the acarbose-preferred glucosidase (Apg) from K. grimontii TD1. Understanding the catalytic mechanism of Apg can aid the design of next-generation hypoglycemic pharmaceuticals acarbose analogs. Here, we determine several crystal structures of Apg to identify the catalytic residues and the ligand-binding pocket of Apg. Structural analyses and computational modeling reveal D448 as the active nucleophile, contrasting with prior studies that assumed D336 to be the nucleophile. In addition to E373 proposed as the proton donor in previous reports, we find that R334 might be an alternative proton donor. Our experimental and computational analyses indicate the two-ring product acarviosine is the two-step hydrolyzed product, where the second hydrolysis is the rate-limiting step. Additionally, further investigation of the acarbose analogs acarstatins A and B that are resistant to Apg is conducted by computational analysis. Overall, our studies provide perspectives into the intricacies of Apg’s catalytic mechanism, contributing to the design of next-generation hypoglycemic pharmaceuticals. The clinical efficacy of the antidiabetic drug acarbose is hampered by degradation by acarbose-preferred glucosidase (Apg) from the intestinal bacterium K. grimontii . Here the authors decipher the mechanism of Apg-mediated acarbose degradation and provide avenues towards the design of next-generation diabetes drugs.

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)‐1,3‐butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2‐activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short‐lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti‐aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding. The C2017 ITP dataset shows that combinations of anti‐aging drugs may have effects that surpass the benefits produced by either drug used alone. The data further show that males benefit more than females from the combination of RAPA and acarbose.

The human microbiome encodes a large repertoire of biochemical enzymes and pathways, most of which remain uncharacterized. Here, using a metagenomics-based search strategy, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose 1 , 2 , resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases 3 , limiting the ability of the target organism to metabolize complex carbohydrates. Using biochemical assays, X-ray crystallography and metagenomic analyses, we show that microbiome-derived acarbose kinases are specific for acarbose, provide their harbouring organism with a protective advantage against the activity of acarbose, and are widespread in the microbiomes of western and non-western human populations. These results provide an example of widespread microbiome resistance to a non-antibiotic drug, and suggest that acarbose resistance has disseminated in the human microbiome as a defensive strategy against a potential endogenous producer of a closely related molecule. Bacteria in the human gut and oral microbiome encode enzymes that selectively phosphorylate the antidiabetic drug acarbose—an inhibitor of both human and bacterial α-glucosidases—resulting in its inactivation and limiting the drug's effects on the ability of the host to metabolize complex carbohydrates.

Purpose While metformin is known to regulate thyroid stimulating hormone (TSH) levels, the effects of acarbose on thyroid function remain unreported. Our study was designed to evaluate the impact of acarbose and metformin on thyroid function and thyroid hormone sensitivity in type 2 diabetic patients. Methods In the MARCH study, 788 patients with type 2 diabetes were randomly assigned to treat with acarbose (300 mg) or metformin (1,500 mg) for 48 weeks. Thyroid function was assessed at baseline, 24 weeks, and 48 weeks, and the thyroid feedback quantile index (TFQI) and parameterized thyroid feedback quantile index (PTFQI) were calculated. Generalized estimating equations adjusted for confounders were used to analyze changes over time. Results Eighty-four patients with subclinical hypothyroidism (SCH) exhibited a decrease in TSH levels ( p  = 0.001) with no significant differences between the two treatment groups ( p  = 0.460). Both TFQI ( p  = 0.029) and PTFQI ( p  < 0.001) also decreased over time. Mediation analysis revealed that these change over time were not mediated by BMI (all p  < 0.05). Among the 489 euthyroid subjects, no significant changes in TSH levels were observed ( p  > 0.05). Stratification by baseline TSH levels revealed significant increases in TSH, TFQI, and PTFQI (all p  < 0.05) in the normal-low TSH group and significant decreases in PTFQI (all p  < 0.05) in the normal-high TSH group after treatment with acarbose and metformin. Conclusions Acarbose and metformin have similar buffering effects on TSH levels, the TFQI and the PTFQI. In patients with lower TSH levels, acarbose and metformin do not further decrease TSH levels. Clinical Trial Registry number ChiCTR-TRC-08000231.

The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0·75 [95% CI 0·63–0·90]; p=0·0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0·0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.

This study aimed to investigate the changes in inflammatory biomarkers between newly diagnosed type 2 diabetes (T2DM) patients under one-year acarbose treatments and those under metformin managements. Seventy patients with newly diagnosed T2DM and 32 volunteers with normal glucose tolerance (normal controls, NCs) were enrolled. Seventy patients with T2DM were randomly assigned to two subgroups and treated with acarbose (n=34) or metformin (n=36) for 1 year. Blood glucose, insulin, glycosylated hemoglobin (A1C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and inflammatory biomarker levels (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and ferritin) were detected at 0, 6 and 12 months. After adjusting for sex, the waist-to-hip ratio (WHR) and body mass index (BMI), higher fasting plasma glucose (FPG), standard meal test 1/2 hr and 2 hr glucose, TG, TC, LDL-C, IL-6, TNF-α, IL-2 and ferritin levels were observed in T2DM group than in NCs ( <0.05). After 6 months of treatment, TNF-α levels were significantly decreased in both subgroups, and IL-6 and ferritin levels were significantly decreased after 12 months ( <0.05). However, no significant differences in the IL-6, TNF-α and ferritin levels were observed between the two subgroups. Moreover, significantly higher IL-6 and TNF-α levels were detected in the T2DM group than in NCs after 12 months of treatment ( <0.05). Patients with newly diagnosed T2DM exhibited a marked chronic inflammatory state characterized by increased IL-6, TNF-α, IL-1β, IL-2 and ferritin levels. After 1 year of treatment with acarbose or metformin, IL-6, TNF-α, IL-1β and ferritin levels were significantly decreased compared with the baseline. The anti-inflammatory effects of acarbose and metformin were comparable and required a long-term treatment (1 year), but the characteristics were different. Further investigations are needed to determine whether this effect was independent of the hypoglycemic effects.