deoxycholic-acid and Diabetes-Mellitus--Type-2

Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.. Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008].. Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

Topics: Aged; Bile Acids and Salts; Blood Glucose; Chenodeoxycholic Acid; Cholic Acid; Deoxycholic Acid; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Feces; Female; Gallbladder; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Male; Metformin; Middle Aged; Organ Size; Postprandial Period; Sitagliptin Phosphate; Sulfonylurea Compounds; Ultrasonography; Ursodeoxycholic Acid

Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n = 16) and controls (n = 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment.. Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved glycemic control in T2DM.

Topics: Adult; Allylamine; Bile Acids and Salts; Blood Glucose; Cholic Acid; Colesevelam Hydrochloride; Deoxycholic Acid; Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Signal Transduction

Our epidemiological study showed that the intestinal flora of Uygur T2DM patients differed from that of normal glucose-tolerant people. However, whether the Uygur T2DM fecal microbiota transplantation could reproduce the glucose metabolism disorder and the mechanism behind has not been reported. This study was designed to explore whether Uygur T2DM fecal microbiota transplantation could reproduce the glucose metabolism disorder and its mechanism.. The normal diet and high fat diet group consisted of C57BL/6 mice orally administered 0.2 mL sterile normal saline. For the MT (microbiota transplantation) intervention groups, C57BL/6 mice received oral 0.2 mL faecal microorganisms from Uygur T2DM. All mice were treated daily for 8 weeks and Blood glucose levels of mice were detected. Mice faecal DNA samples were sequenced and quantified using 16S rDNA gene sequencing. Then we detected the ability of the intestinal flora to metabolize bile acids (BAs) through co-culture of fecal bacteria and BAs. BA levels in plasma were determined by UPLC-MS. Further BA receptors and glucagon-like peptide-1 (GLP-1) expression levels were determined with RT-q PCR and western blotting.. MT impaired insulin and oral glucose tolerance. Deoxycholic acid increased and tauro-β-muricholic acid and the non-12-OH BA:12-OH BA ratio decreased in plasma. MT improved the ability of intestinal flora to produce deoxycholic acid. Besides, the vitamin D receptor in the liver and ileum and GLP-1 in the ileum decreased significantly.. Uygur T2DM fecal microbiota transplantation disrupts glucose metabolism by changing the ability of intestinal flora to metabolize BAs and the BAs/GLP-1 pathway.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Chromatography, Liquid; Deoxycholic Acid; Diabetes Mellitus, Type 2; DNA, Ribosomal; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Insulin; Mice; Mice, Inbred C57BL; Receptors, Calcitriol; Saline Solution; Tandem Mass Spectrometry

The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings.. Circulating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB.. Positive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells.. Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Deoxycholic Acid; Diabetes Mellitus, Type 2; Gastric Bypass; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Obese; Middle Aged; Obesity; Receptors, G-Protein-Coupled; Signal Transduction

Topics: Amphotericin B; Antifungal Agents; Biopsy; Brain Diseases; Deoxycholic Acid; Diabetes Mellitus, Type 2; Drug Combinations; Eye; Eye Diseases; Fatal Outcome; Female; Humans; Kidney Failure, Chronic; Magnetic Resonance Imaging; Middle Aged; Mucormycosis; Multiple Organ Failure; Paranasal Sinuses; Temporal Lobe

Intracranial fungal masses are uncommon diseases, but their incidence is increasing, most often due to the prolonged survival of patients with different immunodeficiencies. The management of patients with intracranial fungal masses included stereotactic biopsy for diagnosis, partial or radical surgery excision and prolonged antifungal therapy.. We report the case of a 51-year-old diabetic man with a history of psoas abscess due to Candida albicans 1 year before the onset of neurological symptoms, including headache and generalized tonoclonic seizures.. Magnetic resonance imaging showed a single lesion located in the right parietal lobe with mass effect, surrounding edema and enhancement after injection of gadolinium. The material was purulent.. Direct microscopic examination showed hyaline, branched and septate hyphae compatible with fungal elements.. Fungal infections, especially due to Candida species, should be considered in diabetic patients with parenchymal brain abscesses. Radical excision followed by prolonged antifungal therapy based on fluconazole or amphotericin B is necessary to improve the prognosis of this type of patients.

Topics: Amphotericin B; Antifungal Agents; Brain Abscess; Candida albicans; Candidiasis; Combined Modality Therapy; Craniotomy; Deoxycholic Acid; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Fluconazole; Humans; Hyphae; Magnetic Resonance Imaging; Male; Mannitol; Middle Aged; Parietal Lobe; Psoas Abscess

The stable isotope dilution measurement of bile acid pool sizes and turnover rates in humans has involved the collection of nine blood samples over four days. This precludes widespread application to larger population studies. This study describes a two time-point approach for blood sampling without loss of statistical power. Isotopic decay curves of cholic acid, chenodeoxycholic acid and deoxycholic acid acquired in three recent human studies were analysed. The optimal combination of two time-points was determined. Time-points around 12 and 72 h after administration allowed for the most accurate description of the decay curves and prediction of kinetic parameters. Analyses of 39 statistical comparisons of kinetic parameters based upon the two time-points and all time-points approaches exhibited only one slightly discrepant result. In conclusion, for group comparison of bile acid kinetics in humans, a two time-point blood collection approach at time-points near 12 and 72 h provides statistically reliable data.

Topics: Bile Acids and Salts; Carbon Isotopes; Chenodeoxycholic Acid; Cholic Acid; Deoxycholic Acid; Deuterium; Diabetes Mellitus, Type 2; Female; Humans; Hypertriglyceridemia; Isotope Labeling; Kinetics; Male; Obesity; Radioisotope Dilution Technique; Reference Values; Time Factors

To develop an effective long-acting antidiabetic, the GLP-1 analogue of exendin-4 was modified with three different bile acids (BAs; cholic, deoxycholic, or lithocholic acid), at its two lysine residues. The biological, pharmaceutical, and physicochemical characteristics of these exendin-4 analogues were carefully investigated. Biological activity tests demonstrated that the monobile acid substitutions of exendin-4 showed well preserved receptor binding efficacy without noticeable insulinotropic or antidiabetic activity loss. However, physicochemical and pharmacokinetic studies revealed that the albumin-binding properties and in vivo elimination half-lives of BAM1-Ex4s (Lys(27)-BA-Ex4s) were significantly enhanced by increasing the hydrophobicities of the conjugated BAs. Furthermore, the protracted antidiabetic effects of the BAM1-Ex4s were also verified by the prolonged restoration of normoglycemia in type 2 diabetic mice. Accordingly, the present study suggests that the derivatization of exendin-4 with BAs offers a means of producing long-acting GLP-1 receptor agonists for type 2 diabetic therapy.

Topics: Animals; Cell Line, Tumor; Cholic Acids; Deoxycholic Acid; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents; In Vitro Techniques; Islets of Langerhans; Lithocholic Acid; Male; Mice; Peptides; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Serum Albumin; Structure-Activity Relationship; Venoms

Efficacy and reproducibility of insulin administered intranasally as an insulin-deoxycholate 1% (w/v) aerosol to normal and diabetic subjects were assessed by measurements of blood glucose and serum insulin levels. Following administration of 0.5 U insulin/kg with the unconjugated bile salt to fasting volunteers (N = 29), peak serum insulin levels of 103 +/- 49 microU/ml above baseline were observed at 10 min. Blood glucose concentration began to fall by 10 min, reaching 54 +/- 14% of control levels by 30 min, and returning to baseline by 60-80 min. Blood glucose response and peak serum insulin levels were reproducible when the same aerosol dose was repeatedly administered to the same subjects; however, intersubject variations were noted. By comparing serum insulin levels after i.v. and nasal routes of administration, nasal insulin absorption was approximately 10% as efficient as intravenous insulin. Dose response studies revealed that peak serum insulin concentrations were a linear function of the administered dose. In subjects with type I and type II diabetes mellitus, serum insulin levels increased in a manner similar to controls, and resulted in a prompt reduction of blood glucose concentration. However, in contrast to normal subjects, the duration of the glucose response was more prolonged, lasting as long as 5 h. Nasal administration of insulin as an aerosol with bile salts or bile salt analogs should be further evaluated as a possible nonparenteral approach to insulin therapy.

Topics: Absorption; Administration, Intranasal; Adult; Aerosols; Blood Glucose; Deoxycholic Acid; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Middle Aged; Nasal Mucosa