Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

Figure 5 Mechanisms of glucagon-like peptide 1 release from enteroendocrine L cell. Glucagon-like peptide 1 (GLP-1) release from L-cells is regulated by direct nutrient sensing via receptors and channels on apical processes or indirectly via neuro-hormonal mechanisms[70,71,86,87]. A: Nutrient signals. Carbohydrates: Glucose derived from carbohydrate metabolism is the most potent stimuli for GLP-1 secretion. Glucose can trigger GLP-1 release by two mechanisms: (1) the sodium-glucose cotransporter-1 (SGLT-1) couples the transport of glucose with Na ions. Na = influx leads to membrane depolarization (ΔΨ) (red arrows); and (2) glucose metabolism generates adenosine triphosphate (ATP). Elevated intracellular ATP concentrations [ATP]ⁱ close KATP channels and leads to membrane depolarization (ΔΨ) (green arrows). Both routes to membrane depolarisation increase intracellular Ca levels ([Ca²⁺]ⁱ) by opening L-type Ca channels. Elevated [Ca²⁺]ⁱ triggers the exocytosis of GLP-1 secretory granules located at the basolateral surface of the enteroendocrine L cell (dashed lines). Fats: Fats are potent stimuli for GLP-1 secretion. Free fatty acids (FFA) (blue arrows) interact with G-protein coupled receptors (GPCRs) that trigger Ca²⁺ release from internal stores and also activate protein kinase C (PKC). FFA derivates (purple arrows) interact with GPCRs that activate second messenger systems involving adenylate cyclase (AC) and cyclic AMP (cAMP) which increases [Ca²⁺]ⁱ. Bile acids (orange arrows) and short chained fatty acids (not shown) also increase [Ca²⁺]ⁱ by GPCR interactions. Proteins: Protein is a weak stimulator of GLP-1 release when compared with sugars and lipids. Amino acids (AA) derived from protein breakdown are transported intracelluarly with Na⁺via Na⁺ dependent AA transporters. Na⁺ influx causes membrane depolarization and elevated [Ca²⁺]ⁱ with resultant GLP-1 exocytosis (pink arrows); B: Hormonal signals. Somatostatin inhibits GLP-1 release by blocking AC activation (light blue arrows). The peripheral adiposity signals leptin (yellow arrows) and insulin (brown arrows) are thought to stimulate GLP-1 release via activation of mitogen-activated protein kinase (MAPK) signalling pathway; C: Neural signals. Acetylcholine binding to muscarinic receptors (M1R, M2R) elevates [Ca²⁺]^I stimulating GLP-1 release (grey arrows). GRP is though to stimulate GLP-1 release in association with the activation of mitogen activated protein kinase kinase (MAPKK) and subsequent phosphorylation and activation of MAPK (not shown).