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Kelenjar Pankreas

Homeostasis Glukosa

TIPE DIABETES MELLITUS

INSULIN

BIOSINTESIS INSULIN

SEKRESI INSULIN

DEGRADASI INSULIN

Efek Insulin

Efek Insulin pada Kelenjar Target

SEDIAAN INSULIN

Durasi berbagai Sediaan Insulin

Struktur Insulin Lispro, Aspart, dan Gluilisine

Tempat Penyuntikan Insulin

KOMPLIKASI INSULINHypoglycemicHypoglycemic reactions are the most common complication of insulin therapy. They may result from a delay in taking a meal, inadequate carbohydrate consumed, unusual physical exertion, or a dose of insulin that is too large for immediate needs.Rapid development of hypoglycemia in individuals with intact hypoglycemic awareness causes signs of autonomic hyperactivity, both sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger) and may progress to convulsions and coma if untreated.In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may developconfusion, weakness, bizarre behavior, coma, seizures

Treatment HypoglycemiaAll the manifestations of hypoglycemia are relieved by glucose administration.To treat mild hypoglycemia in a patient who is conscious and able to swallow, dextrose tablets, glucose gel, or any sugar-containing beverage or food may be given.If more severe hypoglycemia has produced unconsciousness or stupor, the treatment of choice is to give 2050 mL of 50% glucose solution by intravenous infusion over a period of 23 minutes.

ORAL ANTIDIABETIC AGENT

MK : Merangsang sekresi insulin dari kelenjar pankreasMenurunkan konsentrasi serum glukagonINSULIN SECRETAGOGUE - SULFONILUREA

INSULIN SECRETAGOGUE - SULFONILUREA

INSULIN SECRETAGOGUE - MEGLITINIDE

INSULIN SECRETAGOGUE(D-PHENYLALANINE DERIVATES)Nateglinide, a D-phenylalanine derivative, is the latest insulin secretagogue to become clinically available. Nateglinide stimulates very rapid and transient release of insulin from B cells through closure of the ATP-sensitive K+ channel. It also partially restores initial insulin release in response to an intravenous glucose tolerance test. This may be a significant advantage of the drug because type 2 diabetes is associated with loss of this initial insulin response. Nateglinide is ingested just before meals. It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is hepatically metabolized by CYP2C9 and CYP3A4 with a half-life of 1.5 hours. The overall duration of action is less than 4 hours.

BIGUANIDES (METFORMIN)MK : Bekerja langsung pada hepar, menurunkan produksi glukosa hati. Tidak merangsang sekresi insulin oleh kelenjar pankreas.ES : gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, diarrhea) and occur in up to 20% of patients.Penggunaan : bersama makanSediaan : Diabex, Glucophage, Gludepatic.Fixed Dose Combination : Glucovance (metformin + Glyburid), metaglip (metformin + glipizid), avandamet (metformin + rosiglitazone)

THIAZOLIDINDIONMK : Meningkatkan kepekaan tubuh terhadap insulin, dengan jalan berikatan dg PPARY (peroxisome protiferator activated receptor-gamma) di otot, jaringan lemak, dan hati untuk menurunkan resistensi insulin. TZD juga menurunkan kecepatan glikoneogenesis.

GOLONGAN -Glucosidase InhibitorMK : menghambat enzim -glukosidase (maltase, isomaltase, glukomaltase, sukrose) mengurangi pencernaan karbohidrat kompleks dan absorbsinya mengurangi kadar glukosa post prandial. Diberikan pada suapan pertama setelah makanSediaan : Glucobay

The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Within the islets, at least four hormone-producing cells are present (Table 411). Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal inhibitor of secretory cells; and pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified.Table 411. Pancreatic Islet Cells and Their Secretory Products.Cell TypesApproximate Percent of Islet MassSecretory ProductsA cell (alpha)20Glucagon, proglucagonB cell (beta)75Insulin, C-peptide, proinsulin, amylinD cell (delta)35SomatostatinF cell (PP cell)1 < 2Pancreatic polypeptide (PP)

*Like most of the other hormones, insulin is a proteincomprising of 2 polypeptide chains A (with 21 amino acidresidues) and B (with 30 amino acid residues) [Fig. 1]. ChainsA and B are linked by disulphide bridges.

Pada proses biosintesa insulin, C-peptide dibentuk sebagai produk yang disekresikan bersamaan dengan insulin melalui proses pemecahan proteolitik dari molekul prekursor proinsulin. Insulin dan C-peptide dibentuk dalam jumlah yang sama dan dilepaskan ke dalam sirkulasi darah melalui vena porta. Sebagian dari insulin diekstraksi di dalam hepar. Tapi hampir tidak ada C-peptide yang diekstraksi di hepar, sehingga masa paruh C-peptide lebih panjang dibandingkan insulin. Kadar C-peptide 510 kali lebih tinggi di dalam sirkulasi perifer, dan kadarnya berfluktuasi sedikit dibandingkan insulin. Konsentrasi C-peptide dalam darah memberikan suatu penilaian yang akurat terhadap fungsi cadangan sel beta pankreas manusia dan ini sudah menjadi suatu petanda yang penting dari sekresi insulin pada pasien DM. Penentuan kadar C-peptide puasa dan setelah stimulasi (dengan glukosa atau glukagon) telah digunakan untuk penentuan aktivitas sekresi sel beta pankreas, karena kadar C-peptide di sirkulasi tidak dipengaruhi insulin eksogen.*Biosynthesis of InsulinInsulin is synthesized in the beta cells of pancreas inthe form of preproinsulin which is the ultimate precursorand gene for the same is located on chromosome 11 closeto that for insulin like growth factor-2 (IGF-2) [Fig.2].2Within a minute after synthesis it is discharged intocisternal space of rough endoplasmic reticulum where it iscleaved into proinsulin by proteolytic enzymes. Proinsulinwith a C (connecting) chain linking A and B chains isthen transported by microvesicles to the Golgi apparatus.Proinsulin is released in vesicles. Conversion of proinsulinto insulin continues in maturing granules through the actionof prohormone converatse 2 and 3 and carboxy peptidaseH.4 Maturing granules are translocated with the help ofmicrotubules and microfi laments.*Insulin is released from pancreatic B cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), certain amino acids (eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 and vagal activity are recognized. One mechanism of stimulated insulin release is diagrammed in Figure 412. As shown in the figure, hyperglycemia results in increased intracellular ATP levels, which close the ATP-dependent potassium channels. Decreased outward potassium efflux results in depolarization of the B cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The insulin secretagogue drug group (sulfonylureas, meglitinides, and D-phenylalanine) exploits parts of this mechanism.

One model of control of insulin release from the pancreatic B cell by glucose and by sulfonylurea drugs. In the resting cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases, potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secretagogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism.

Glukosa masuk ke dalam sel beta melewati reseptor Glut-2. Stlh masuk sel beta, glukosa dioksidasi oleh glukokinase (sbg sensor glukosa). Glukosa < 90 mg/dl tdk menyebabkan keluarnya insulin. Pada substimulatory konsentrasi glukosa, K+ keluar melewati channel Katp, yg menjaga membran sel beta dalam potensial negatif, dimana channel Ca2+ tertutup. Jika ada peningkatan kadar glukosa darah, glukosa akan diambil dan dimetabolisme oleh sel beta, sehingga kadar ATP meningkat channel Katp tertutup terjadi depolarisasi membran membuka channel Ca2+ menstimulasi eksositosis insulin

*Once insulin is secreted into the portal venous system, ~50% is degraded by the liver. Unextracted insulin enters the systemic circulation where it binds to receptors in target sites. Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS) (Fig. 2). IRS and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and mitogenic effects of insulin. As an example, activation of the phosphatidylinositol-3'-kinase (PI-3-kinase) pathway stimulates translocation of glucose transporters (e.g., GLUT4) to the cell surface, an event that is crucial for glucose uptake by skeletal muscle and fat. Activation of other insulin receptor signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin-responsive cells.*Sulfonilurea gen 2 100x lbh poten dari gen 1*Metformin mrpkn agen antihiperglikemia, bukan hipoglikemia, shg tdk mnybbkn hipoglikemi mskpn dlm dosiis besarMK : menurunkan produksi glukosa hepatik, mnurunkan glukoneogenesis, mnurunkan absorbsi glukosa dari usus.Fixed-dose combinations containing metformin and glyburide (GLUCOVANCE, others), glipizide (METAGLIP), and rosiglitazone (AVANDAMET) are available.

*Tdk menimbulkan hipoglikemia Bs dikombinasi dg OHO lain atau insulin hati2 hipoglikemiaHanya mempengaruhi kadar glukosa darah post prandial, tdk mempengaruhi kdr glukosa darah stlh itu*