Muribaculaceae Genomes Assembled from Metagenomes Suggest Genetic Drivers of Differential Response to Acarbose Treatment in Mice

The drug acarbose is used to treat diabetes by preventing the breakdown of starch in the small intestine, resulting in dramatic changes in the abundance of some members of the gut microbiome and its fermentation products. In mice, several of the bacteria that respond most positively are classified in the family Muribaculaceae , members of which produce propionate as a primary fermentation product.

Flavonoids as Human Intestinal α-Glucosidase Inhibitors

Certain flavonoids can influence glucose metabolism by inhibiting enzymes involved in carbohydrate digestion and suppressing intestinal glucose absorption. In this study, four structurally-related flavonols (quercetin, kaempferol, quercetagetin and galangin) were evaluated individually for their ability to inhibit human α-glucosidases (sucrase, maltase and isomaltase), and were compared with the antidiabetic drug acarbose and the flavan-3-ol(−)-epigallocatechin-3-gallate (EGCG). Cell-free extracts from human intestinal Caco-2/TC7 cells were used as the enzyme source and products were quantified chromatographically with high accuracy, precision and sensitivity. Acarbose inhibited sucrase, maltase and isomaltase with IC50 values of 1.65, 13.9 and 39.1 µM, respectively. A similar inhibition pattern, but with comparatively higher values, was observed with EGCG. Of the flavonols, quercetagetin was the strongest inhibitor of α-glucosidases, with inhibition constants approaching those of acarbose, followed by galangin and kaempferol, while the weakest were quercetin and EGCG. The varied inhibitory effects of flavonols against human α-glucosidases depend on their structures, the enzyme source and substrates employed. The flavonols were more effective than EGCG, but less so than acarbose, and so may be useful in regulating sugar digestion and postprandial glycaemia without the side effects associated with acarbose treatment.

Efficacy and Safety of Mulberry Twig Alkaloids Tablet for the Treatment of Type 2 Diabetes: A Multicenter, Randomized, Double-Blind, Double-Dummy, and Parallel Controlled Clinical Trial

<b>OBJECTIVE </b>This study aimed to evaluate the efficacy and safety of mulberry twig alkaloids (sangzhi alkaloids, SZ-A) in the treatment of type 2 diabetes (T2D).<a></a> <p><b>RESEARCH DESIGN AND METHODS</b><b> </b><a></a>This was a multicenter, randomized, double-blind, double-dummy, and parallel controlled non-inferiority clinical trial that was conducted for 24 weeks. A total of 600 patients were randomly allocated to the SZ-A group (<i>n</i>=360) or acarbose group (<i>n</i>=240). The primary efficacy endpoint was the change of glycosylated hemoglobin (HbA_1c) in comparison to baseline. In addition, adverse events (AEs), severe adverse events (SAEs), <a>treatment-related </a><a>adverse events</a> (TAEs), and gastrointestinal disorders (GDs) were monitored.</p> <p><b>RESULTS</b> After treatment for 24 weeks, the change <a>in HbA1c was −0.93% (95% CI −1.03 to −0.83) (−10.2 mmol/mol, [95% CI −11.3 to −9.1]) and −0.87% (95% CI −0.99 to −0.76) (−9.5 mmol/mol, [95% CI −10.8 to −8.3]) in the SZ-A and acarbose groups, and the least squares mean difference was −0.05% (95% CI −0.18 to 0.07) (−0.5 mmol/mol, [95% CI −2.0 to 0.8]) between the two groups with no significant difference based on covariance analysis (P > 0.05). The incidence of TAEs and GDs was significantly lower in the SZ-A group than the acarbose group (P < 0.01), but no differences were found for AEs or SAEs between two groups were observed (P > 0.05).</a></p> <p><b>CONCLUSION</b> SZ-A exhibited equivalent hypoglycemic effect to acarbose in patients with T2D. Nevertheless, the incidence of TAEs and GDs was lower following SZ-A treatment than that following acarbose treatment, suggesting good safety.</p>

Efficacy and Safety of Mulberry Twig Alkaloids Tablet for the Treatment of Type 2 Diabetes: A Multicenter, Randomized, Double-Blind, Double-Dummy, and Parallel Controlled Clinical Trial

<b>OBJECTIVE </b>This study aimed to evaluate the efficacy and safety of mulberry twig alkaloids (sangzhi alkaloids, SZ-A) in the treatment of type 2 diabetes (T2D).<a></a> <p><b>RESEARCH DESIGN AND METHODS</b><b> </b><a></a>This was a multicenter, randomized, double-blind, double-dummy, and parallel controlled non-inferiority clinical trial that was conducted for 24 weeks. A total of 600 patients were randomly allocated to the SZ-A group (<i>n</i>=360) or acarbose group (<i>n</i>=240). The primary efficacy endpoint was the change of glycosylated hemoglobin (HbA_1c) in comparison to baseline. In addition, adverse events (AEs), severe adverse events (SAEs), <a>treatment-related </a><a>adverse events</a> (TAEs), and gastrointestinal disorders (GDs) were monitored.</p> <p><b>RESULTS</b> After treatment for 24 weeks, the change <a>in HbA1c was −0.93% (95% CI −1.03 to −0.83) (−10.2 mmol/mol, [95% CI −11.3 to −9.1]) and −0.87% (95% CI −0.99 to −0.76) (−9.5 mmol/mol, [95% CI −10.8 to −8.3]) in the SZ-A and acarbose groups, and the least squares mean difference was −0.05% (95% CI −0.18 to 0.07) (−0.5 mmol/mol, [95% CI −2.0 to 0.8]) between the two groups with no significant difference based on covariance analysis (P > 0.05). The incidence of TAEs and GDs was significantly lower in the SZ-A group than the acarbose group (P < 0.01), but no differences were found for AEs or SAEs between two groups were observed (P > 0.05).</a></p> <p><b>CONCLUSION</b> SZ-A exhibited equivalent hypoglycemic effect to acarbose in patients with T2D. Nevertheless, the incidence of TAEs and GDs was lower following SZ-A treatment than that following acarbose treatment, suggesting good safety.</p>

The role of GLP-1 in the postprandial effects of acarbose in type 2 diabetes

Aims The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9–39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes. Methods In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57–85 years, HbA1c: 40–74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9–39)NH2 and saline, respectively, were performed. Results Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9–39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9–39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163). Conclusions We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9–39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9–39)NH2 was most pronounced during acarbose treatment.

Muribaculaceae genomes assembled from metagenomes suggest genetic drivers of differential response to acarbose treatment in mice

The drug acarbose (ACA) is used to treat diabetes, and, by inhibiting α-amylase in the small intestine, increases the amount of starch entering the lower digestive tract. This results in changes to the composition of the microbiota and their fermentation products. Acarbose also increases longevity in mice, an effect that has been correlated with increased production of the short-chain fatty acids propionate and butyrate. In experiments replicated across three study sites, two distantly related species in the bacterial family Muribaculaceae were dramatically more abundant in ACA-treated mice, distinguishing these responders from other members of the family. Bacteria in the family Muribaculaceae are predicted to produce propionate as a fermentation end product and are abundant and diverse in the guts of mice, although few isolates are available. We reconstructed genomes from metagenomes (MAGs) for nine populations of Muribaculaceae to examine factors that distinguish species that respond positively to acarbose. We found two closely related MAGs (B1A and B1B) from one responsive species that both contain a polysaccharide utilization locus with a predicted extracellular α-amylase. These genomes also shared a periplasmic neopullulanase with another, distantly related MAG (B2) representative of the only other responsive species. This gene differentiated these three MAGs from MAGs representative of non-responding species. Differential gene content in B1A and B1B may be associated with the inconsistent response of this species to acarbose across study sites. This work demonstrates the utility of culture-free genomics for inferring the ecological roles of gut bacteria including their response to pharmaceutical perturbations.ImportanceThe drug acarbose is used to treat diabetes by preventing the breakdown of starch in the small intestine, resulting in dramatic changes in the abundance of some members of the gut microbiome and its fermentation products. In mice, several of the bacteria that respond most positively are classified in the family Muribaculaceae, members of which produce propionate as a primary fermentation product. Propionate has been associated with gut health and increased longevity in mice. We found that genomes of the most responsive Muribaculaceae showed signs of specialization for starch fermentation, presumably providing them a competitive advantage in the large intestine of animals consuming acarbose. Comparisons among genomes enhance existing models for the ecological niches occupied by members of this family. In addition, genes encoding one type of enzyme known to participate in starch breakdown were found in all three genomes from responding species, but none of the other genomes.

Elevated serum preptin concentrations in patients with diabetic nephropathy

Preptin is a peptide synthesized and secreted accompanied with insulin from pancreatic β cells. Here, we tested the hypothesis that serum preptin concentrations are correlated with diabetic nephropathy (DN). Our study was performed in a population of 234 patients with type 2 diabetes mellitus (T2DM) and 78 healthy subjects. Patients with T2DM were divided into three groups: normoalbuminuria group (DN0, n=106), microalbuminuria group (DN1, n=90), and macroalbuminuria group (DN2, n=38) according to urine albumin to creatinine ratio (ACR). Serum preptin concentrations were significantly increased in the three T2DM subgroups than those in the controls. DN2 group showed significantly higher serum preptin concentrations compared with DN0 and DN1 groups. Moreover, DN1 group had higher serum preptin concentrations than DN0 group. Serum preptin was correlated with a higher risk of T2DM and DN after logistic regression analysis. Simply linear regression analysis demonstrated a positive correlation between serum preptin and gender, body mass index (BMI), blood urea nitrogen, creatinine, ACR, and a negative correlation between serum preptin and glomerular filtration rate, metformin, acarbose treatment. Gender, BMI, and ACR were still positively correlated with serum preptin after multiple linear regression analysis. Our findings indicate that serum preptin concentrations are associated with renal function and DN.

The Glucoamylase Inhibitor Acarbose Has a Diet-Dependent and Reversible Effect on the Murine Gut Microbiome

ABSTRACTAcarbose is a safe and effective medication for type 2 diabetes that inhibits host glucoamylases to prevent starch digestion in the small intestines and thus decrease postprandial blood glucose levels. This results in an increase in dietary starch in the distal intestine, where it becomes food for the gut bacterial community. Here, we examined the effect of acarbose therapy on the gut community structure in mice fed either a high-starch (HS) or high-fiber diet rich in plant polysaccharides (PP). The fecal microbiota of animals consuming a low dose of acarbose (25 ppm) was not significantly different from that of control animals that did not receive acarbose. However, a high dose of acarbose (400 ppm) with the HS diet resulted in a substantial change to the microbiota structure. Most notably, the HS diet with a high dose of acarbose lead to an expansion of theBacteroidaceaeandBifidobacteriaceaeand a decrease in theVerrucomicrobiaceae(such asAkkermansia muciniphila) and theBacteroidalesS24-7. Once acarbose treatment ceased, the community composition quickly reverted to mirror that of the control group, suggesting that acarbose does not irreversibly alter the gut community. The high dose of acarbose in the PP diet resulted in a distinct community structure with increased representation ofBifidobacteriaceaeandLachnospiraceae. Short-chain fatty acids (SCFAs) measured from stool samples were increased, especially butyrate, as a result of acarbose treatment in both diets. These data demonstrate the potential of acarbose to change the gut community structure and increase beneficial SCFA output in a diet-dependent manner.IMPORTANCEThe gut microbial community has a profound influence on host physiology in both health and disease. In diabetic individuals, the gut microbiota can affect the course of disease, and some medications for diabetes, including metformin, seem to elicit some of their benefits via an interaction with the microbiota. Here, we report that acarbose, a glucoamylase inhibitor for type 2 diabetes, changes the murine gut bacterial community structure in a reversible and diet-dependent manner. In both high-starch and high-fiber diet backgrounds, acarbose treatment results in increased short-chain fatty acids, particularly butyrate, as measured in stool samples. As we learn more about how human disease is affected by the intestinal bacterial community, the interplay between medications such as acarbose and the diet will become increasingly important to evaluate.

Changes in the gut microbiota and fermentation products associated with enhanced longevity in acarbose-treated mice

BackgroundTreatment with theα-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to increased longevity in mice. To explore this hypothesis, we compared the fecal microbiome of mice treated with acarbose to control mice at three independent study sites.ResultsMicrobial communities and the concentrations of SCFAs in the feces of mice treated with acarbose were notably different from those of control mice. At all three study sites, the bloom of a single bacterial taxon was the most obvious response to acarbose treatment. The blooming populations were classified to the largely unculturedBacteroidalesfamilyMuribaculaceaeand were the same taxonomic unit at two of the three sites. Total SCFA concentrations in feces were increased in treated mice, with increased butyrate and propionate in particular. Across all samples,Muribaculaceaeabundance was strongly correlated with propionate and community composition was an important predictor of SCFA concentrations. Cox proportional hazards regression showed that the fecal concentrations of acetate, butyrate, and propionate were, together, predictive of mouse longevity even while controlling for sex, site, and acarbose.ConclusionWe have demonstrated a correlation between fecal SCFAs and lifespan in mice, suggesting a role of the gut microbiota in the longevity-enhancing properties of acarbose. Treatment modulated the taxonomic composition and fermentation products of the gut microbiome, while the site-dependence of the microbiota illustrates the challenges facing reproducibility and interpretation in microbiome studies. These results motivate future studies exploring manipulation of the gut microbial community and its fermentation products for increased longevity, and to test a causal role of SCFAs in the observed effects of acarbose.