-Actions-of-GLP1-mediated-by-PKA-and-Epac-include-the-recruitment-and-priming-of-secretory-granules-thereby-increasing-the-number-of-granules-available-for-Ca2dependent-exocytosis-s

Simultaneously, GLP-1 promotes Ca(2+) influx and mobilizes an intracellular source of Ca(2+). GLP-1 receptors) to stimulatory effects of Ca(2+), thereby promoting Ca(2+)-induced Ca(2+) release (CICR). In the model presented here, CICR activates mitochondrial dehydrogenases, thereby upregulating glucose-dependent production of ATP. The resultant increase in cytosolic [ATP]/[ADP] concentration ratio leads to closure of ATP-sensitive K(+) channels (K-ATP), membrane depolarization, and influx of Ca(2+) through voltage-dependent Ca(2+) channels (VDCCs). Ca(2+) influx stimulates exocytosis of secretory granules by promoting their fusion with the plasma membrane. Under conditions where Ca(2+) release channels are sensitized by GLP-1, Ca(2+) influx also stimulates CICR, generating an additional round of ATP production and K-ATP channel closure.

In the absence of glucose, no "fuel" is available to support ATP production, and GLP-1 fails to stimulate insulin secretion. This new "feed-forward" hypothesis of beta-cell stimulus-secretion coupling may provide a mechanistic explanation as to how GLP-1 exerts a beneficial blood glucose-lowering effect in type 2 diabetic subjects.Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs.The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are degraded by dipeptidyl peptidase IV (DPP IV), thereby losing insulinotropic activity. DPP IV inhibition reduces exogenous GLP-1 degradation, but the extent of endogenous incretin protection has not been fully assessed, largely because suitable assays which distinguish between intact and degraded peptides have been unavailable. Using newly developed assays for intact GLP-1 and GIP, the effect of DPP IV inhibition on incretin hormone metabolism was examined. Conscious dogs were given NVP-DPP728, a specific DPP IV inhibitor, at a dose that inhibited over 90% of plasma DPP IV for the first 90 min following treatment.

Total and intact incretin concentrations increased (P<0001) following a mixed meal, but on control days (vehicle infusion), intact peptide concentrations were lower (P<01) than total peptide concentrations (22 +/- 1% intact GIP; 10 +/- 0% intact GLP-1). Following inhibitor treatment, the proportion of intact peptide increased (92 +/- 4% intact GIP, P<0001; 99 +/- 22% intact GLP-1, P<02). Active (intact) incretins increased after NVP-DPP728 (from 4797 +/- 364 to 10 649 +/- 106 pM x min for GIP, P<03; from 646 +/- 134 to 2822 +/- 528 pM x m in for GLP-1, P<05). In contrast, total incretins fell (from 21 632 +/- 654 to 12 084 +/- 1723 pM x min for GIP, P<002; from 5145 +/- 677 to 3060 +/- 601 pM x min for GLP-1, P<05). Snag it now , insulin and glucagon concentrations were unaltered by the inhibitor. We have concluded that DPP IV inhibition with NVP-DPP728 prevents N-terminal degradation of endogenous incretins in vivo, resulting in increased plasma concentrations of intact, biologically active GIP and GLP-1. Total incretin secretion was reduced by DPP IV inhibition, suggesting the possibility of a feedback mechanism.

10152/ajpendo0231022. glucagon-like peptide 1 mouse brown adipose tissue mitochondrial proteome and potentiates body mass reduction induced by liraglutide.University of Campinas, Campinas, Brazil.Scientific and Technological Development, São Paulo, Brazil.Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide.

A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids.