GLP-1 controls blood glucose following nutrient absorption via stimulation of glucose-dependent insulin secretion, insulin biosynthesis, islet proliferation, and neogenesis and inhibition of glucagon secretion. Glucagon-like peptide-1 (GLP-1 is an insulinotropic hormone, GLP-1 also inhibits glucagon secretion. GLP-1 lowers blood glucose in normal subjects and in patients with type 2 diabetes. The major biological action of GLP-2 appears to be the stimulation of small-bowel hyperplasia, manifested by an increases in both villous height and small-bowel weight. A pilot study of GLP-2 administration in human subjects with short bowel syndrome demonstrated significant improvements in energy absorption, bone density, increased body weight, which correlated with increased crypt plus villus height on intestinal biopsy sections. The biological actions of two of these glucagon-related peptides, suggest that they may have therapeutic relevance for the treatment of human diseases such as diabetes, selective intestinal disorders and cardiac diseases. Role of the prohormone convertase PC3 in the processing of proglucagon to Proglucagon is processed differentially in pancreatic alpha-cells and intestinal endocrine L cells to release either glucagon or glucagon-like peptide-1-(7-36amide) (tGLP-1), two peptide hormones with opposing biological actions. Previous studies have demonstrated that the prohormone convertase PC2 is responsible for the processing of proglucagon to glucagon, and have suggested that the related endoprotease PC3 is involved in the formation of tGLP-1. To understand better the biosynthetic pathway of tGLP-1, proglucagon processing was studied in the mouse pituitary cell line AtT-20, a cell line that mimics the intestinal pathway of proglucagon processing and in the rat insulinoma cell line INS-1. In both of these cell lines, proglucagon was initially cleaved to glicentin and the major proglucagon fragment (MPGF) at the interdomain site Lys70-Arg71. In both cell lines, MPGF was cleaved successively at the monobasic site Arg77 and then at the dibasic site Arg109-Arg110, thus releasing tGLP-1, the cleavages being less extensive in INS-1 cells. Glicentin was completely processed to glucagon in INS-1 cells, but was partially converted to oxyntomodulin and very low levels of glucagon in AtT-20 cells in the face of generation of tGLP-1. Adenovirus-mediated co-expression of PC3 and proglucagon in GH4C1 cells (normally expressing no PC2 or PC3) resulted in the formation of tGLP-1, glicentin, and oxyntomodulin, but no glucagon. When expressed in alphaTC1-6 (transformed pancreatic alpha-cells) or in rat primary pancreatic alpha-cells in culture, PC3 converted MPGF to tGLP-1. Finally, GLP-1-(1-37) was cleaved to tGLP-1 in vitro by purified recombinant PC3. Taken together, these results indicate that PC3 has the same specificity as the convertase that is responsible for the processing of proglucagon to tGLP-1, glicentin and oxyntomodulin in the intestinal L cell, and it is concluded that this enzyme is thus able to act alone in this processing pathway.Stereospecific effects of fatty acids on proglucagon-derived peptide secretion The ingestion of fats is a potent stimulus for the secretion of the proglucagon-derived peptides (PGDPs), including the insulinotropic peptide glucagon-like peptide-1 from the intestinal L cell. The aim of the study was to characterize the structural requirements for fatty acid-induced secretion of the PGDPs and investigate the cellular mechanisms through which fatty acids mediate PGDP secretion. semaglutide injection were incubated with 10-150 microM fatty acids that differed in chain length (14-18 carbons) and degree of unsaturation (0-2). Inhibitors of protein kinase C (PKC) and fatty acid esterification and oxidation were also incubated with the cells in the presence of stimulatory fatty acids. The cultures were assayed for glucagon-like immunoreactivity and glucagon-like peptide-1-(7-36)NH2 secretion. Monounsaturated fatty acids of chain length greater than 14 carbons stimulated PGDP secretion by 1 to 3-fold in a dose-dependent fashion (P < 05 to P < 001). Enhanced PGDP secretion was lost upon full saturation of the stimulatory fatty acids. Furthermore, although blockade of fatty acid esterification with a carboxyl methyl ester group prevented PGDP secretion, inhibition of fatty acid oxidation with methyl palmoxirate did not prevent PGDP secretion. Finally, is semaglutide safe of various inhibitors of PKC (staurosporine, H7, 24-h down-regulation) also did not alter fatty acid-induced PGDP secretion. In conclusion, monounsaturated long-chain fatty acids possessing a free carboxyl group stimulate intestinal PGDP secretion. Neither fatty acid oxidation nor classical isoforms of PKC appear to be directly involved in this response. Therefore, the structure of the fatty acid plays a central role in inducing intestinal PGDP secretion. These findings suggest that fat composition may significantly affect the magnitude of the GLP-1 response to ingested nutrients.The Xenopus proglucagon gene encodes novel GLP-1-like peptides with The proglucagon gene encodes several hormones that have key roles in the regulation of metabolism.
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