Wednesday, 3 August 2011

Bile acid signalling, how important is it?

Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes?

"it has become clear that bile acids not only act as simple fat solubilizers, but additionally represent complex hormonal metabolic integrators."

"bile acids are ligands for the nuclear receptor FXR controlling transcription of genes involved in, for example, bile acid, cholesterol, and glucose metabolism"

"Bile acid activation of TGR5 results in increased intracellular cAMP levels, which in brown adipose tissue and muscle cells modulates energy expenditure by activating type 2 iodothyronine deiodinase, which in turn deiodinates thyroxine to the active thyroid hormone triiodothyronine"

"The reason for these limitations may be due to the fact that current GLP-1-based drugs exert their effects via elevated plasma levels of “GLP-1 receptor agonists”, and therefore, allegedly, may not elicit the local effects that endogenous secreted GLP-1 might have."

"Roux-en-Y gastric bypass (RYGB) surgery incurs remission of type 2 diabetes in the majority of patients (4), a “cure” of type 2 diabetes that has been linked to increased endogenous GLP-1 secretion"

"recent studies provide evidence for L cell expression of several G protein-coupled receptors (for example GPR120), which can be activated by long-chain fatty acids and, hence, result in GLP-1 secretion"

"Recently, the G protein-coupled receptor TGR5 was found in the enteroendocrine GLP-1-secreting cell line STC-1 (17) and in primary L cells from mice"

"These findings suggest that postprandial gall bladder contraction and increased flow of bile acids to the intestine potentiate nutrient-induced GLP-1 secretion from the L cells via TGR5 activation. "

"The newly described role of bile-induced TGR5 activation in L cell secretion combined with findings of reduced postprandial gall bladder emptying in type 2 diabetes (38, 39) [worsened by diabetic neuropathy typical for patients with long-standing disease (39)] suggests that reduced postprandial GLP-1 responses in patients with type 2 diabetes may, hypothetically, arise as a consequence of diabetic gall bladder dysmotility, which in turn might reduce postprandial bile flow to the intestine and, thereby, TGR5 activation in the L cells."

"Last, serum bile acids have been found to increase following RYGB (positively correlated with GLP-1 and negatively correlated with thyrotropic hormone) (33). As direct access of bile acids to L cell-rich parts of the small intestine is established following RYGB"

The Changes of Pro-opiomelanocortin Neurons in Type 2 Diabetes Mellitus Rats After Ileal Transposition: The Role of POMC Neurons.

"The Ileal transposition group demonstrated significantly improved plasma glucose homeostasis with increased glucagon-like peptide 1 secretion.

"associated with increased central neuronal activity with increased pro-opiomelanocortin and derivative gene expression in the hypothalamus and increased protein expression in the pituitary gland."

"More pro-opiomelanocortin neurons in the hypothalamus of diabetes rats were activated after ileal transposition. "

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