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

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.

Rapid multigram scale end-to-end continuous flow synthesis of sulfonylurea anti-diabetes drugs: Gliclazide, chlorpropamide and tolbutamide

Herein we report multigram scale robust, efficient, and safe end-to-end continuous flow processes for the diabetes sulfonylurea drugs gliclazide, chlorpropamide and tolbutamide. The drugs were prepared via the treatment of an amine with a haloformate affording carbamate which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was afforded in 87 % yield within 2.5 min total residence time with 26 g/h throughput; 0.2 Kg of the drug was produced in 8 h of running the system continuously. Chlorpropamide and tolbutamide were both afforded in 94 % yield within 1 min residence time with 184-188 g/h throughput; 1.4-1.5 Kg of the drugs was produced in 8 h of running the system continuously. N-substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.

Sulfonylureas for Treatment of Periodontitis-Diabetes Comorbidity-Related Complications: Killing Two Birds With One Stone

Periodontitis is one of the most prevalent oral inflammatory diseases leading to teeth loss and oral health problems in adults. Periodontitis mainly affects periodontal tissue by affecting the host immune system and bone homeostasis. Moreover, periodontitis is associated with various systemic diseases. Diabetes is a metabolic disease with systemic effects. Both periodontitis and diabetes are common inflammatory diseases, and comorbidity of two diseases is linked to exacerbation of the pathophysiology of both diseases. Since bacterial dysbiosis is mainly responsible for periodontitis, antibiotics are widely used drugs to treat periodontitis in clinics. However, the outcomes of antibiotic treatments in periodontitis are not satisfactory. Therefore, the application of anti-inflammatory drugs in combination with antibiotics could be a treatment option for periodontitis-diabetes comorbidity. Anti-diabetic drugs usually have anti-inflammatory properties and have shown beneficial effects on periodontitis. Sulfonylureas, insulin secretagogues, are the earliest and most widely used oral hypoglycemic drugs used for type-2 diabetes. Studies have found that sulfonylurea drugs can play a certain role in the mitigation of periodontitis and inflammation. This article reviews the effects of sulfonylurea drugs on the mitigation of periodontitis-diabetes comorbidity-related inflammation, bone loss, and vascular growth as well as the involved molecular mechanisms. We discuss the possibility of a new application of sulfonylureas (old drug) to treat periodontitis-diabetes comorbidity.

Second-Generation Antidiabetic Sulfonylureas Inhibit Candida albicans and Candidalysin-Mediated Activation of the NLRP3 Inflammasome

ABSTRACT Repurposing of currently approved medications is an attractive option for the development of novel treatment strategies against physiological and infectious diseases. The antidiabetic sulfonylurea glyburide has demonstrated off-target capacity to inhibit activation of the NLRP3 inflammasome in a variety of disease models, including vaginal candidiasis, caused primarily by the fungal pathogen Candida albicans. Therefore, we sought to determine which of the currently approved sulfonylurea drugs prevent the release of interleukin 1β (IL-1β), a major inflammasome effector, during C. albicans challenge of the human macrophage-like THP1 cell line. Findings revealed that the second-generation antidiabetics (glyburide, glisoxepide, gliquidone, and glimepiride), which exhibit greater antidiabetic efficacy than prior iterations, demonstrated anti-inflammatory effects with various degrees of potency as determined by calculation of 50% inhibitory concentrations (IC50s). These same compounds were also effective in reducing IL-1β release during noninfectious inflammasome activation (e.g., induced by lipopolysaccharide [LPS] plus ATP), suggesting that their anti-inflammatory activity is not specific to C. albicans challenge. Moreover, treatment with sulfonylurea drugs did not impact C. albicans growth and filamentation or THP1 viability. Finally, the use of ECE1 and Candidalysin deletion mutants, along with isogenic NLRP3−/− cells, demonstrated that both Candidalysin and NLRP3 are required for IL-1β secretion, further confirming that sulfonylureas suppress inflammasome signaling. Moreover, challenge of THP1 cells with synthetic Candidalysin peptide demonstrated that this toxin is sufficient to activate the inflammasome. Treatment with the experimental inflammasome inhibitor MCC950 led to similar blockade of IL-1β release, suggesting that Candidalysin-mediated inflammasome activation can be inhibited independently of potassium efflux. Together, these results demonstrate that the second-generation antidiabetic sulfonylureas retain anti-inflammatory activity and may be considered for repurposing against immunopathological diseases, including vaginal candidiasis.

An Explaining Theory for Diuretic-Induced-Diabetes Incidences

Many patients with hypertension are also suffering from Type II Diabetes Mellitus (TIIDM). Different studies argued the fact if these patients can use Hydrochlorothiazide (HCTZ) group or not to treat hyper-tension as these diuretics are accused with diuretic-induced diabetes especially Chlorthalidone and Bendroflumethiazide. As nothing is definite yet; in this paper, we are jotting down a new theory. In other words, we are seeking to study HCTZ interactions with sulfonylurea receptor Kir 6.2\SUR1 considering the chemical fact that HCTZ are also sulfonamide derivates like sulfonylurea drugs which are hypoglycemic agents used in the treatment of TIIDM. Therefore, we have studied in-silico 12 HCTZ compounds’ interactions with the binding site of sulfonylurea in its receptor Kir6.2\SUR1. Then, we compared the results to the interactions of Glibenclamide (GBM); a sulfonylurea agent, with the named receptor.  As a result, three compounds of this family (Chlorthalidone 1-1, Bendroflumethiazide 4-1, Metholazone 6-1) had bound to Kir6.2\SUR1 receptor in the same binding site of GBM. The rest members were almost close to the GBM binding site. These findings may explain the adverse effect that chlorthalidone and Bendroflumethiazide are accused with. We suggest that they are agonists for Kir6.1\SUR1 receptor, which results in decreasing insulin secretion from pancreas which consequences with hyper-glycemica. On the other hand, our results confirm that developing new anti hyperglycemia agents from HCTZ as a lead compound is also possible and promising.

Hypoglycemic therapy in patients with type 2 diabetes and chronic heart failure

The article presents a literature review of prevalence, prognosis and treatment of overt tactics of chronic heart failure (CHF) in patients with type 2 diabetes mellitus (T2DM). Application of modern pharmacological preparations and instrumental treatment of cardiovascular disease (CVD) increases life expectancy and improves the quality of life of patients with CHF as with normal carbohydrate metabolism (UO), and with type 2 diabetes. However, the risk of cardiovascular mortality (CAS) in patients with type 2 diabetes, compared to having a normal carbohydrate metabolism remains unchanged.Insulin resistance (IR) and compensatory hyperinsulinemia (GI) play a key role in the pathogenesis of type 2 diabetes. Ongoing research in the twentieth century of coronary heart disease (CHD) and heart failure in patients with type 2 diabetes revealed adverse effects of sulfonylurea medications on the metabolic processes in the myocardium and increased risk of death in patients with severe coronary artery disease. In comparison with sulfonylurea drugs, metformin and insulin not only reduces the risk of cardiovascular disease, but also can prevent or delay the development of type 2 diabetes in individuals with impaired glucose tolerance (IGT) and impaired fasting glucose. Metformin acts on the key link of pathogenesis - insulin resistance, affecting the lower incidence of cardiovascular diseases, the development of chronic disease and mortality compared with insulin and sulfonylurea drugs. However, in patients with chronic heart failure is contraindicated the use of thiazolidinediones and metformin is limited tothe severity of CHF I-II FC NYNA. With effective treatment of chronic heart failure by cardiologists in patients with type 2 diabetes, affecting therapy with insulin resistance should be mandatory.