scholarly journals Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Paul J. McMurdie ◽  
Magdalena K. Stoeva ◽  
Nicholas Justice ◽  
Madeleine Nemchek ◽  
Christian M. K. Sieber ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gut Microbiota ◽  
Critical Role ◽  
Acid Oxidation ◽  
Double Blind ◽  
Inhibitory Interaction ◽  
Probiotic Intervention ◽  
Sulfonylurea Drugs

Abstract Background An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation (‘WBF-011’) in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. Results Here we report targeted and untargeted metabolomic measurements on fasting plasma (n = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation’s C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. Conclusion To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies.

scholarly journals SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, But Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes– a Randomized Double-Blind, Placebo-Controlled Crossover Trial

2020 ◽  
Author(s):  
Katrine M. Lauritsen ◽  
Bent R.R. Nielsen ◽  
Lars P. Tolbod ◽  
Mogens Johannsen ◽  
Jakob Hansen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Glucose Uptake ◽  
Acid Oxidation ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Myocardial Glucose Uptake ◽  
Pet Ct ◽  
Sglt2 Inhibition

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. <p>13 individuals with type 2 diabetes were studied after four weeks treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with <sup>11</sup>C-palmitate and <sup>18</sup>F-FDG PET/CT. Oxygen consumption and myocardial external efficiency (MEE) were measured with <sup>11</sup>C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using <sup>15</sup>O-H<sub>2</sub>O PET/CT. </p> <p>Empagliflozin did not affect myocardial FFA uptake but reduced myocardial glucose uptake by 57% (p<0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (p<0.01), but did not significantly affect stress MBF or MFR.</p> <p>In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose towards other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition. </p>

scholarly journals Metformin Increases Cortisol Regeneration by 11βHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus

2016 ◽  
Vol 101 (10) ◽  
pp. 3787-3793 ◽  
Author(s):  
Anna J. Anderson ◽  
Ruth Andrew ◽  
Natalie Z. Homer ◽  
Gregory C. Jones ◽  
Kenneth Smith ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Random Order ◽  
Whole Body ◽  
Double Blind ◽  
Clinical Research Facility

Context: The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11βhydroxysteroid dehydrogenase 1 (11βHSD1) by insulin and the limited efficacy of selective 11βHSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11βHSD1 activity. Objective: To determine whether metformin regulates 11βHSD1 activity in vivo in obese men with and without type 2 diabetes mellitus. Design: Double-blind, randomized, placebo-controlled, crossover study. Setting: A hospital clinical research facility. Participants: Eight obese nondiabetic (OND) men and eight obese men with type 2 diabetes (ODM). Intervention: Participants received 28 days of metformin (1 g twice daily), placebo, or (in the ODM group) gliclazide (80 mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11βHSD1. Oral cortisone was given to measure hepatic 11βHSD1 activity in the ODM group. The effect of metformin on 11βHSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes. Main Outcome Measures: The effect of metformin on whole-body and hepatic 11βHSD1 activity. Results: Whole-body 11βHSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11βHSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11βHSD1 activity. In vitro, metformin did not increase 11βHSD1 activity in hepatocytes or adipocytes. Conclusions: Metformin increases whole-body cortisol generation by 11βHSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11βHSD1 inhibitors.

scholarly journals 16S rRNA Sequencing and Metagenomics Study of Gut Microbiota: Implications of BDB on Type 2 Diabetes Mellitus

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 469
Author(s):  
Liang Zhang ◽  
Jiao Luo ◽  
Xiangqian Li ◽  
Shuju Guo ◽  
Dayong Shi
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
16S Rrna ◽  
Gut Microbiota ◽  
Critical Role ◽  
Fasting Blood Glucose ◽  
Rrna Gene ◽  
Diabetic Mice

Gut microbiota has a critical role in metabolic diseases, including type 2 diabetes mellitus (T2DM). 3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol (BDB) is a natural bromophenol isolated from marine red alga Rhodomela confervoides. Our latest research showed that BDB could alleviate T2DM in diabetic BKS db mice. To find out whether BDB modulates the composition of the gut microbiota during T2DM treatment, 24 BKS db diabetic mice were randomly grouped to receive BDB (n = 6), metformin (n = 6), or the vehicle (n = 6) for 7 weeks in a blinded manner. Non-diabetic BKS mice (n = 6) were used as normal control. Diabetic mice treated with BDB or metformin demonstrated significant reductions in fasting blood glucose (FBG) levels compared with the vehicle-treated mice in the 7th week. Pyrosequencing of the V3–V4 regions of the 16S rRNA gene revealed the changes of gut microbiota in response to BDB treatment. The result demonstrated short-chain acid (SCFA) producing bacteria Lachnospiraceae and Bacteroides were found to be significantly more abundant in the BDB and metformin treated group than the vehicle-treatment diabetic group. Remarkably, at the genus levels, Akkermansia elevated significantly in the BDB-treatment group. Metagenomic results indicated that BDB may alleviate the metabolic disorder of diabetic mice by promoting propanoate metabolism and inhibiting starch and sucrose metabolism, amino sugar and nucleotide sugar metabolism. In conclusion, our study suggests that the anti-diabetic effect of BDB is closely related to the modulating structure of gut microbiota and the improvement of functional metabolism genes of intestinal microorganisms.

scholarly journals 1-Kestose supplementation mitigates the progressive deterioration of glucose metabolism in type 2 diabetes OLETF rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ayako Watanabe ◽  
Yoshihiro Kadota ◽  
Rina Kamio ◽  
Takumi Tochio ◽  
Akihito Endo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Gut Microbiota ◽  
Control Diet ◽  
Oletf Rats ◽  
Preventative Strategy ◽  
Metabolic Conditions ◽  
Gastrointestinal Enzymes

Abstract The fructooligosaccharide 1-kestose cannot be hydrolyzed by gastrointestinal enzymes, and is instead fermented by the gut microbiota. Previous studies suggest that 1-kestose promotes increases in butyrate concentrations in vitro and in the ceca of rats. Low levels of butyrate-producing microbiota are frequently observed in the gut of patients and experimental animals with type 2 diabetes (T2D). However, little is known about the role of 1-kestose in increasing the butyrate-producing microbiota and improving the metabolic conditions in type 2 diabetic animals. Here, we demonstrate that supplementation with 1-kestose suppressed the development of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, possibly through improved glucose tolerance. We showed that the cecal contents of rats fed 1-kestose were high in butyrate and harbored a higher proportion of the butyrate-producing genus Anaerostipes compared to rats fed a control diet. These findings illustrate how 1-kestose modifications to the gut microbiota impact glucose metabolism of T2D, and provide a potential preventative strategy to control glucose metabolism associated with dysregulated insulin secretion.

scholarly journals SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, But Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes– a Randomized Double-Blind, Placebo-Controlled Crossover Trial

2020 ◽  
Author(s):  
Katrine M. Lauritsen ◽  
Bent R.R. Nielsen ◽  
Lars P. Tolbod ◽  
Mogens Johannsen ◽  
Jakob Hansen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Glucose Uptake ◽  
Acid Oxidation ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Myocardial Glucose Uptake ◽  
Pet Ct ◽  
Sglt2 Inhibition

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. <p>13 individuals with type 2 diabetes were studied after four weeks treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with <sup>11</sup>C-palmitate and <sup>18</sup>F-FDG PET/CT. Oxygen consumption and myocardial external efficiency (MEE) were measured with <sup>11</sup>C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using <sup>15</sup>O-H<sub>2</sub>O PET/CT. </p> <p>Empagliflozin did not affect myocardial FFA uptake but reduced myocardial glucose uptake by 57% (p<0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (p<0.01), but did not significantly affect stress MBF or MFR.</p> <p>In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose towards other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition. </p>

scholarly journals SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, But Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes– a Randomized Double-Blind, Placebo-Controlled Crossover Trial

2021 ◽  
Author(s):  
Katrine M. Lauritsen ◽  
Bent R.R. Nielsen ◽  
Lars P. Tolbod ◽  
Mogens Johannsen ◽  
Jakob Hansen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxygen Consumption ◽  
Glucose Uptake ◽  
Acid Oxidation ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Myocardial Glucose Uptake ◽  
Pet Ct ◽  
Sglt2 Inhibition

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. <p>13 individuals with type 2 diabetes were studied after four weeks treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with <sup>11</sup>C-palmitate and <sup>18</sup>F-FDG PET/CT. Oxygen consumption and myocardial external efficiency (MEE) were measured with <sup>11</sup>C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using <sup>15</sup>O-H<sub>2</sub>O PET/CT. </p> <p>Empagliflozin did not affect myocardial FFA uptake but reduced myocardial glucose uptake by 57% (p<0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (p<0.01), but did not significantly affect stress MBF or MFR.</p> <p>In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose towards other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition. </p>

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