Glucagon Synthesis and Metabolism Glucagon, a 29-amino-acid peptide, is produced in cells of the pancreas by the

proteolytic processing of proglucagon, a larger precursor protein. In addition to the pancreas, proglucagon is also expressed in the intestine and brain. While glucagon is the major bioactive metabolite produced in the pancreatic cell, differential processing in the intestine results in the production of glucagon-like peptide (GLP)-1 and GLP-2 in response to a meal (Figure 185). This tissue-specific processing results in peptides with opposing effects on carbohydrate metabolism; pancreatic glucagon opposes the effects of insulin, whereas GLPs acts as incretins, gut-derived peptides that enhance glucose-stimulated insulin secretion. Long-acting analogues of GLP-1, which also stimulates cell proliferation and increases cell mass, are currently being studied for the treatment of Type 2 diabetes. The circulatory half-life of glucagon is 36 minutes. Like insulin, glucagon is metabolized in the liver and kidneys. However, the liver accounts for only 25% of glucagon clearance.

Glukagon, sebuah peptida 29-asam amino, diproduksi dalam sel-sel pankreas oleh pengolahan proteolitik proglucagon, protein prekursor yang lebih besar. Selainpankreas, proglucagon juga dinyatakan dalam usus dan otak. Sementara glukagonadalah metabolit bioaktif utama yang dihasilkan dalam sel pankreas, diferensialpengolahan dalam hasil usus dalam produksi glukagon-like peptide (GLP) -1 dan GLP-2dalam menanggapi makan (Gambar 18-5). Hal ini mengakibatkan pengolahan spesifik jaringan di peptida dengan menentang efek pada metabolisme karbohidrat; glukagonpankreas menentang efek insulin, sedangkan tindakan GLPs sebagai incretins, ususyang diturunkan dari peptida yang meningkatkan glukosa dirangsang sekresi insulin.Longacting analog, GLP-1 yang juga merangsang proliferasi sel dan massa selmeningkat, saat ini sedang dipelajari untuk pengobatan diabetes tipe 2. Peredaran darah paruh glukagon adalah 3-6 menit. Seperti insulin, glukagon dimetabolisme di hati dan ginjal. Namun, hati menyumbang hanya 25% dari izin glukagon.

Mechanism of Action The liver is the major target organ for glucagon action. Glucagon binds to a glucagon receptor present on the cell surface of hepatocytes. Binding of glucagon promotes interaction of the receptor with a stimulatory G protein, which in turn activates adenylyl cyclase. Cyclic adenosine monophosphate, generated by adenylyl cyclase, activates protein kinase A, which then phosphorylates enzymes responsible for the biologic activity of glucagon in the liver. There is also some evidence that the glucagon receptor may act via an adenylyl cyclase-independent mechanism by stimulation of phospholipase C.

Hati adalah organ target utama untuk tindakan glukagon. Glukagon mengikat ke reseptorglukagon hadir pada permukaan sel hepatosit. Pengikatan glukagon mempromosikaninteraksi re septor dengan protein stimulasi G, yang pada gilirannya mengaktifkanadenilat adenylyl. Monofosfat siklik adenosin, yang dihasilkan oleh adenylyl adenilat, mengaktifkan protein kinase A, yang kemudian phosphorylates enzim bertanggung jawab atas aktivitas biologis glukagon dalam hati. Ada juga beberapa bukti bahwa reseptor glukagon dapat bertindak melalui mekanisme adenilatindependen adenylyloleh stimulasi fosfolipase C.

Effects The actions of glucagon were first demonstrated in 1921 by Banting and Best when they observed a mild transient hyperglycemia preceding insulin-induced hypoglycemia when testing pancreatic extracts in vivo. Glucagon is a counter-regulatory hormone, acting in a catabolic fashion to oppose the effects of insulin. Indeed, glucagon injections are used clinically to treat severe hypoglycemia. Hepatic effects of glucagon (Table 18 3) include: (1) stimulation of both hepatic glucose synthesis (gluconeogenesis) and the release of glycogen stores (glycogenolysis) to increase hepatic glucose output; (2) stimulation of fatty acid oxidation and ketogenesis, thus providing an alternative fuel

(ketone bodies) that can be used by the brain when glucose is not available; and (3) increased hepatic uptake of amino acids, which fuels gluconeogenesis.

Tindakan glukagon pertama kali ditunjukkan pada tahun 1921 oleh Banting dan Best ketika mereka mengamati hiperglikemia transien ringan sebeluminsulin diinduksi hipoglike mia ketika mengujiekstrak pankreas in vivo. Glukagon adalah hormon kontra-regulasi, bertindak dengan carakatabolik untuk melawan efek insulin. Memang, suntikan glukagon yang digunakan secara klinisuntuk mengobati hipoglikemia berat. Hati efekglukagon (Tabel 183) meliputi: (1) stimulasi baiksintesis glukosa hati (glukoneogenesis) dan pelepasan toko glikogen (glikogenolisis) untuk meningkatkan produksi glukosa hepatik, (2)stimulasi oksidasi asam lemak dan ketogenesis,sehingga memberikan bahan bakar alternatif (badan keton) sehingga dapat digunakan olehotak ketika glukosa tidak tersedia, dan (3)serapan hati peningkatan asam amino, yangbahan bakar glukoneogenesis.