Altered bile acid profiles in duodenal bile and urine in diabetic subjects

Andersen, Eva; Karlaganis, Georg; Sjövall, Jan

doi:10.1111/j.1365-2362.1988.tb02408.x

Cited by 54 publications

(42 citation statements)

References 28 publications

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“…5). This has important implications in diabetes therapy as work in our laboratory has confirmed the distal GIT to be the site of intended drug delivery due to an abundance of efflux transporters, which have been associated with PB absorption after oral administration, such as the transporter ABCA1 (37,38). However, the exact impact of such release patterns in PB oral absorption, efficacy and safety profiles remains difficult to predict (39)(40)(41).…”

Section: Drug Release Studies and In Vitro Dissolutionmentioning

confidence: 94%

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

et al. 2014

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Abstract. In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6±0.25% PB content, and zeta potential of −66±1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p<0.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85±5 and 92±2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules.

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Section: Drug Release Studies and In Vitro Dissolutionmentioning

confidence: 94%

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

et al. 2014

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“…Indeed, Brufau et al showed that patients with type 2 diabetes exhibited increased concentrations of deoxycholic acid and decreased concentrations of chenodeoxycholic acid, which was due to the increased synthesis rate of cholic acid and deoxycholic acid. Other human studies have found similar changes in the bile acid pool in diabetes, but these studies are difficult to interpret in a comparative manner due to different methodologies and study populations (131,136,136,137,138). Recently, Haeusler et al have reported that there might be a plausible, mechanistic explanation for diabetes-related changes in the bile acid pool composition involving Forkhead box protein 01 (FOX01 (FOXP1)), a transcription factor regulating gluconeogenesis, glycogenolysis and liver sensitivity to insulin (140,146).…”

Section: Bile Acid Pool Composition Is Altered In Type 2 Diabetesmentioning

confidence: 99%

“…Subsequently, changes in bile acid pool composition have been demonstrated in both animal models of type 1 diabetes and type 2 diabetes, respectively (132,133,134,135), as well as in early (131,136,137,138,139) and recent human studies (22, 111, 121, 140). Of note, both glucose (141) and insulin have been suggested to modulate bile acid synthesis in preclinical studies (135,142,143) and in some (131,138,144), but not all (137), clinical studies. As noted by Staels & Fonseca, the finding that insulin is able to suppress FXR (NR1H4) gene expression (in contrast to glucose, which produces the opposite effect) suggests that diabetes is associated with the dysregulation of FXR expression (141,145).…”

Section: Bile Acid Pool Composition Is Altered In Type 2 Diabetesmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

Sonne

Hansen

Knop

2014

European Journal of Endocrinology

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Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently -despite elusive mechanisms of action -bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

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“…Bile acids are also signaling molecules that activate bile acid receptors to regulate bile acid synthesis and glucose metabolism (2). In vivo studies show that bile acid pool and excretion increase in diabetic human patients (3,4) and in experimental diabetic animals (5,6). Insulin treatment restores bile acid pool and synthesis to the normal levels.…”

mentioning

confidence: 99%

Insulin Regulation of Cholesterol 7α-Hydroxylase Expression in Human Hepatocytes

Kong

Owsley

et al. 2006

Journal of Biological Chemistry

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Bile acid synthesis and pool size increases in diabetes, whereas insulin inhibits bile acid synthesis. The objective of this study is to elucidate the mechanism of insulin regulation of cholesterol 7␣-hydroxylase gene expression in human hepatocytes. Real-time PCR assays showed that physiological concentrations of insulin rapidly stimulated cholesterol 7␣-hydroxylase (CYP7A1) mRNA expression in primary human hepatocytes but inhibited CYP7A1 expression after extended treatment. The insulin-regulated forkhead box O1 (FoxO1) and steroid regulatory element-binding protein-1c (SREBP-1c) strongly inhibited hepatocyte nuclear factor 4␣ and peroxisome proliferator-activated receptor ␥ coactivator-1␣ trans-activation of the CYP7A1 gene. FoxO1 binds to an insulin response element in the rat CYP7A1 promoter, which is not present in the human CYP7A1 gene. Insulin rapidly phosphorylates and inactivates FoxO1, whereas insulin induces nuclear SREBP-1c expression in human primary hepatocytes. Chromatin immunoprecipitation assay shows that insulin reduced FoxO1 and peroxisome proliferators-activated receptor ␥-coactivator-1␣ but increased SREBP-1c recruitment to CYP7A1 chromatin. We conclude that insulin has dual effects on human CYP7A1 gene transcription; physiological concentrations of insulin rapidly inhibit FoxO1 activity leading to stimulation of the human CYP7A1 gene, whereas prolonged insulin treatment induces SREBP-1c, which inhibits human CYP7A1 gene transcription. Insulin may play a major role in the regulation of bile acid synthesis and dyslipidemia in diabetes.The liver plays a central role in lipid metabolism and maintaining whole body lipid homeostasis, which is dysregulated in metabolic syndrome (syndrome X), obesity, and diabetes (1). Bile acid synthesis in the liver is the predominant pathway for cholesterol catabolism and is regulated by cholesterol 7␣-hydroxylase (CYP7A1) 2 (2). Bile acids are physiological agents that facilitate biliary cholesterol excretion, intestinal absorption of nutrients, and disposal of toxic metabolites. Bile acids are also signaling molecules that activate bile acid receptors to regulate bile acid synthesis and glucose metabolism (2). In vivo studies show that bile acid pool and excretion increase in diabetic human patients (3, 4) and in experimental diabetic animals (5, 6). Insulin treatment restores bile acid pool and synthesis to the normal levels. It has been reported that physiological concentrations of insulin (1.4 -14 nM) inhibit bile acid synthesis by down-regulation of CYP7A1 (7-9), sterol 12␣-hydroxylase (CYP8B1) (10), and sterol 27-hydroxylase (CYP27A1) gene transcription (9). We have previously reported that insulin plays a dominant role in the inhibition of CYP7A1 gene transcription (7,8). How insulin regulates human CYP7A1 and what factors mediate the insulin effects remain unknown.Insulin is known to induce more than 100 genes but inhibit only a few hepatic genes involved in glucose metabolism (11). The consensus sequence of negative insulin response element (IRE), T(G...

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Altered bile acid profiles in duodenal bile and urine in diabetic subjects

Cited by 54 publications

References 28 publications

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

Insulin Regulation of Cholesterol 7α-Hydroxylase Expression in Human Hepatocytes

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