1Angela Putri405090139

1 Liver2 Left and right hepatic ducts3 Common hepatic duct4 Cystic duct5 Gall bladder6 Pancreatic duct and head of pancreas7 Pylorus (cut)8 Right gastro-oinental (gastroepiploic) artery9 Minor duodenal papilla (probe)10 Major duodenal papilla (probe)11 Superior mesenteric artery and vein17 12 Inferior vena cava and iliocolic artery19 13 Portal vein, Iig. teres of liver and lig. venosum14 Aorta15 Common hepatic artery, left branch of hepatic arteryproper, and right gastric artery16 Gastroduodenal artery and right branch of hepatic29 artery proper17 Spleen18 Splenic artery and vein19 Tail of pancreas20 Left gastro-omental artery21 Middle colic artery22 Jejunum23 Jejunal arteries24 Aorta and inferior mesenteric artery25 Common bile duct26 Horizontal part of duodenum27 Esophagus28 Stomach29 Pancreatic duct30 Duodenojejunal flexure31 Lumbal vertebrae

1 Left hepatic duct2 Right hepatic duct3 Cystic duct4 Neck of gallbladder5 Body of gallbladder6 Fundus of gallbladder7 Common hepatic duct8 Common bile duct9 Pancreatic duct10 Greater duodenal papilla11 Second lumbar vertebra12 Folds of mucous membrane of gallbladder13 Muscular coat of gallbladder14 eck of gallbladder (opened)15 Cystic duct with spiral fold16 Lesser duodenal papilla17 Accessory pancreatic duct18 Uncinate process19 Plica circularis of duodenum (Kerckrings's fold)20 Head of pancreas21 Body of pancreas22 Tail of pancreas23 Descending part of duodenum24 Incisure of pancreas

Structure of human proinsulin. Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme (open arrows) followed by several cleavages by a carboxypeptidase-like enzyme (solid arrows) results in the production of the heterodimeric (AB) insulin molecule (light color) and the C-peptide. Insulin Is Synthesized as a Preprohormone & Modified Within the CellInsulin has an AB heterodimeric structure with one intrachain (A6A11) and two interchain disulfide bridges (A7B7 and A20B19) (Figure 4112). The A and B chains could be synthesized in the laboratory, but attempts at a biochemical synthesis of the mature insulin molecule yielded very poor results. The reason for this became apparent when it was discovered that insulin is synthesized as a preprohormone (molecular weight approximately 11,500), which is the prototype for peptides that are processed from larger precursor molecules. The hydrophobic 23-amino-acid pre-, or leader, sequence directs the molecule into the cisternae of the endoplasmic reticulum and then is removed. This results in the 9000-MW proinsulin molecule, which provides the conformation necessary for the proper and efficient formation of the disulfide bridges. As shown in Figure 4112, the sequence of proinsulin, starting from the amino terminal, is B chainconnecting (C) peptideA chain. The proinsulin molecule undergoes a series of site-specific peptide cleavages that result in the formation of equimolar amounts of mature insulin and C peptide. These enzymatic cleavages are summarized in Figure 4112.

Some Hormones Act Through a Protein Kinase CascadeSingle protein kinases such as PKA, PKC, and Ca2+-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the ligand EGF was an important breakthrough. The insulin and IGF-I receptors also contain intrinsic ligand-activated tyrosine kinase activity. Several receptorsgenerally those involved in binding ligands involved in growth control, differentiation, and the inflammatory responseeither have intrinsic tyrosine kinase activity or are associated with proteins that are tyrosine kinases. Another distinguishing feature of this class of hormone action is that these kinases preferentially phosphorylate tyrosine residues, and tyrosine phosphorylation is infrequent (< 0.03% of total amino acid phosphorylation) in mammalian cells. A third distinguishing feature is that the ligand-receptor interaction that results in a tyrosine phosphorylation event initiates a cascade that may involve several protein kinases, phosphatases, and other regulatory proteins.

Insulin Transmits Signals by Several Kinase CascadesThe insulin, epidermal growth factor (EGF), and IGF-I receptors have intrinsic protein tyrosine kinase activities located in their cytoplasmic domains. These activities are stimulated when the receptor binds ligand. The receptors are then autophosphorylated on tyrosine residues, and this initiates a complex series of events (summarized in simplified fashion in Figure 428). The phosphorylated insulin receptor next phosphorylates insulin receptor substrates (there are at least four of these molecules, called IRS 14) on tyrosine residues. Phosphorylated IRS binds to the Src homology 2 (SH2) domains of a variety of proteins that are directly involved in mediating different effects of insulin. One of these proteins, PI-3 kinase, links insulin receptor activation to insulin action through activation of a number of molecules, including the kinase PDK1 (phosphoinositide-dependent kinase-1). This enzyme propagates the signal through several other kinases, including PKB (akt), SKG, and aPKC (see legend to Figure 428 for definitions and expanded abbreviations). An alternative pathway downstream from PKD1 involves p70S6K and perhaps other as yet unidentified kinases. A second major pathway involves mTOR. This enzyme is directly regulated by amino acids and insulin and is essential for p70S6K activity. This pathway provides a distinction between the PKB and p70S6K branches downstream from PKD1. These pathways are involved in protein translocation, enzyme activity, and the regulation, by insulin, of genes involved in metabolism (Figure 428). Another SH2 domain-containing protein is GRB2, which binds to IRS-1 and links tyrosine phosphorylation to several proteins, the result of which is activation of a cascade of threonine and serine kinases. A pathway showing how this insulin-receptor interaction activates the mitogen-activated protein (MAP) kinase pathway and the anabolic effects of insulin is illustrated in Figure 428. The exact roles of many of these docking proteins, kinases, and phosphatases remain to be established.

Insulin signaling pathways. The insulin signaling pathways provide an excellent example of the "recognition hormone release signal generation effects" paradigm outlined in Figure 421. Insulin is released in response to hyperglycemia. Binding of insulin to a target cell-specific plasma membrane receptor results in a cascade of intracellular events. Stimulation of the intrinsic tyrosine kinase activity of the insulin receptor marks the initial event, resulting in increased tyrosine (Y) phosphorylation (Y Y-P) of the receptor and then one or more of the insulin receptor substrate molecules (IRS 14). This increase in phosphotyrosine stimulates the activity of many intracellular molecules such as GTPases, protein kinases, and lipid kinases, all of which play a role in certain metabolic actions of insulin. The two best-described pathways are shown. First, phosphorylation of an IRS molecule (probably IRS-2) results in docking and activation of the lipid kinase, PI-3 kinase, which generates novel inositol lipids that may act as "second messenger" molecules. These, in turn, activate PDK1 and then a variety of downstream signaling molecules, including protein kinase B (PKB or akt), SGK, and aPKC. An alternative pathway involves the activation of p70S6K and perhaps other as yet unidentified kinases. Second, phosphorylation of IRS (probably IRS-1) results in docking of GRB2/mSOS and activation of the small GTPase, p21RAS, which initiates a protein kinase cascade that activates Raf-1, MEK, and the p42/p44 MAP kinase isoforms. These protein kinases are important in the regulation of proliferation and differentiation of several cell types. The mTOR pathway provides an alternative way of activating p70S6K and appears to be involved in nutrient signaling as well as insulin action. Each of these cascades may influence different physiologic processes, as shown. Each of the phosphorylation events is reversible through the action of specific phosphatases. For example, the lipid phosphatase PTEN dephosphorylates the product of the PI-3 kinase reaction, thereby antagonizing the pathway and terminating the signal. Representative effects of major actions of insulin are shown in each of the boxes. The asterisk after phosphodiesterase indicates that insulin indirectly affects the activity of many enzymes by activating phosphodiesterases and reducing intracellular cAMP levels. (IGFBP, insulin-like growth factor binding protein; IRS 14, insulin receptor substrate isoforms 14; PI-3 kinase, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PKD1, phosphoinositide-dependent kinase; PKB, protein kinase B; SGK, serum and glucocorticoid-regulated kinase; aPKC, atypical protein kinase C; p70S6K, p70 ribosomal protein S6 kinase; mTOR, mammalian target of rapamycin; GRB2, growth factor receptor binding protein 2; mSOS, mammalian son of sevenless; MEK, MAP kinase kinase and ERK kinase; MAP kinase, mitogen-activated protein kinase.)

Hormones Regulate Fat MobilizationInsulin Reduces the Output of Free Fatty AcidsThe rate of release of free fatty acids from adipose tissue is affected by many hormones that influence either the rate of esterification or the rate of lipolysis. Insulin inhibits the release of free fatty acids from adipose tissue, which is followed by a fall in circulating plasma free fatty acids. It enhances lipogenesis and the synthesis of acylglycerol and increases the oxidation of glucose to CO2 via the pentose phosphate pathway. All of these effects are dependent on the presence of glucose and can be explained, to a large extent, on the basis of the ability of insulin to enhance the uptake of glucose into adipose cells via the GLUT 4 transporter. Insulin also increases the activity of pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase, reinforcing the effects of increased glucose uptake on the enhancement of fatty acid and acylglycerol synthesis. These three enzymes are regulated in a coordinate manner by phosphorylation-dephosphorylation mechanisms.A principal action of insulin in adipose tissue is to inhibit the activity of hormone-sensitive lipase, reducing the release not only of free fatty acids but of glycerol as well. Adipose tissue is much more sensitive to insulin than are many other tissues, which points to adipose tissue as a major site of insulin action in vivo.

The hormones that act rapidly in promoting lipolysis, ie, catecholamines, do so by stimulating the activity of adenylyl cyclase, the enzyme that converts ATP to cAMP. The mechanism is analogous to that responsible for hormonal stimulation of glycogenolysis (Chapter 19). cAMP, by stimulating cAMP-dependent protein kinase, activates hormone-sensitive lipase. Thus, processes which destroy or preserve cAMP influence lipolysis. cAMP is degraded to 5'-AMP by the enzyme cyclic 3',5'-nucleotide phosphodiesterase. This enzyme is inhibited by methylxanthines such as caffeine and theophylline. Insulin antagonizes the effect of the lipolytic hormones. Lipolysis appears to be more sensitive to changes in concentration of insulin than are glucose utilization and esterification. The antilipolytic effects of insulin, nicotinic acid, and prostaglandin E1 are accounted for by inhibition of the synthesis of cAMP at the adenylyl cyclase site, acting through a Gi protein. Insulin also stimulates phosphodiesterase and the lipase phosphatase that inactivates hormone-sensitive lipase. The effect of growth hormone in promoting lipolysis is dependent on synthesis of proteins involved in the formation of cAMP. Glucocorticoids promote lipolysis via synthesis of new lipase protein by a cAMP-independent pathway, which may be inhibited by insulin, and also by promoting transcription of genes involved in the cAMP signal cascade. These findings help to explain the role of the pituitary gland and the adrenal cortex in enhancing fat mobilization. Adipose tissue secretes the hormone leptin, which regulates energy homeostasis. Although it was initally thought to protect against obesity, current evidence suggests that the main role of leptin is to act as a signal of energy sufficiency rather than energy excess.The sympathetic nervous system, through liberation of norepinephrine in adipose tissue, plays a central role in the mobilization of free fatty acids. Thus, the increased lipolysis caused by many of the factors described above can be reduced or abolished by denervation of adipose tissue or by ganglionic blockade.

Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone; FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone; the action of lipase phosphatase; the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA; the inhibition of adenylyl cyclase by adenosine; and the removal of cAMP by the action of phosphodiesterase. ACTH, TSH, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

Glucose Transporters

Glucose enters cells by facilitated diffusion (see Chapter 1: The General & Cellular Basis of Medical Physiology) or, in the intestine and kidneys, by secondary active transport with Na+. In muscle, fat, and some other tissues, insulin facilitates glucose entry into cells by increasing the number of glucose transporters in the cell membranes.The glucose transporters that are responsible for facilitated diffusion of glucose across cell membranes are a family of closely related proteins that cross the cell membrane 12 times and have their amino and carboxyl terminals inside the cell. They differ from and have no homology with the sodium-dependent glucose transporters, SGLT 1 and SGLT 2, responsible for the secondary active transport of glucose out of the intestine (see Chapter 25: Digestion & Absorption) and renal tubules (see Chapter 38: Renal Function & Micturition), although the SGLTs also have 12 transmembrane domains. Particularly in transmembrane helical segments 3, 5, 7, and 11, the amino acids of the facilitative transporters appear to surround channels that glucose can enter. Presumably, conformation then changes and glucose is released inside the cell.Seven different glucose transporters, called in order of discovery GLUT 17, have been characterized (Table 195). They contain 492524 amino acid residues, and their affinity for glucose varies. Each transporter appears to have evolved for special tasks. GLUT 4 is the transporter in muscle and adipose tissue that is stimulated by insulin. A pool of GLUT 4 molecules is maintained in vesicles in the cytoplasm of insulin-sensitive cells. When the insulin receptors of these cells are activated, the vesicles move rapidly to the cell membrane and fuse with it, inserting the transporters into the cell membrane (Figure 195). When insulin action ceases, the transporter-containing patches of membrane are endocytosed, and the vesicles are ready for the next exposure to insulin. Activation of the insulin receptor brings about the movement of the vesicles to the cell membrane by activating phosphoinositol-3 kinase (Figure 195), but how this activation triggers vesicle movement is still unsettled. Most of the other GLUT transporters that are not insulin-sensitive appear to stay in the cell membrane.

In the tissues in which insulin increases the number of glucose transporters in the cell membranes, the rate of phosphorylation of the glucose, once it has entered the cells, is regulated by other hormones. Growth hormone and cortisol both inhibit phosphorylation in certain tissues. The process is normally so rapid that it is not a rate-limiting step in glucose metabolism. However, it is rate-limiting in the B cells (see below).Insulin also increases the entry of glucose into liver cells, but it does not exert this effect by increasing the number of GLUT 4 transporters (see below) in the cell membranes. Instead, it induces glucokinase, and this increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell.Insulin-sensitive tissues also contain a population of GLUT 4 vesicles that move into the cell membrane in response to exercise and are independent of the action of insulin. This is why exercise lowers blood sugar (see below). A 5'-AMP-activated kinase may be responsible for the insertion of these vesicles in the cell membrane.

Insulin Preparations

The maximal decline in plasma glucose occurs 30 minutes after intravenous injection of crystalline insulin. After subcutaneous administration, the maximal fall occurs in 23 hours. A wide variety of insulin preparations are now available commercially. These include insulins that have been complexed with protamine and other polypeptides to delay absorption and synthetic insulins in which there have been changes in amino acid residues. In general, they fall into three categories: rapid, intermediate-acting, and long-acting (2436 hours).

Relation to Potassium

Insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration. Infusions of insulin and glucose significantly lower the plasma K+ level in normal individuals and are very effective for the temporary relief of hyperkalemia in patients with renal failure. Hypokalemia often develops when patients with diabetic acidosis are treated with insulin. The reason for the intracellular migration of K+ is still uncertain. However, insulin increases the activity of Na+K+ ATPase in cell membranes, so that more K+ is pumped into cells.

Other Actions

The hypoglycemic and other effects of insulin are summarized in temporal terms in Table 193, and the net effects on various tissues are summarized in Table 194. The action on glycogen synthase fosters glycogen storage, and the actions on glycolytic enzymes favor glucose metabolism to two carbon fragments (see Figure 178), with resulting promotion of lipogenesis. Stimulation of protein synthesis from amino acids entering the cells and inhibition of protein degradation foster growth.The anabolic effect of insulin is aided by the protein-sparing action of adequate intracellular glucose supplies. Failure to grow is a symptom of diabetes in children, and insulin stimulates the growth of immature hypophysectomized rats to almost the same degree as growth hormone.

CONSEQUENCES OF INSULIN DEFICIENCY

Pancreatic islets.

Diabetes and abnormalities in glucose-stimulated insulin secretion. Glucose and other nutrients regulate insulin secretion by the pancreatic beta cell. Glucose is transported by the GLUT2 glucose transporter; subsequent glucose metabolism by the beta cell alters ion channel activity, leading to insulin secretion. The SUR receptor is the binding site for drugs that act as insulin secretagogues. Mutations in the events or proteins underlined are a cause of maturity onset diabetes of the young (MODY) or other forms of diabetes. SUR, sulfonylurea receptor; ATP, adenosine triphosphate; ADP, adenosine diphosphate, cAMP, cyclic adenosine monophosphate.

Insulin signal transduction pathway in skeletal muscle. The insulin receptor has intrinsic tyrosine kinase activity and interacts with insulin receptor substrates (IRS and Shc) proteins. A number of "docking" proteins bind to these cellular proteins and initiate the metabolic actions of insulin [GrB-2, SOS, SHP-2, p65, p110, and phosphatidylinositol-3'-kinase (PI-3-kinase)]. Insulin increases glucose transport through PI-3-kinase and the Cbl pathway, which promotes the translocation of intracellular vesicles containing GLUT4 glucose transporter to the plasma membrane.

Temporal model for development of type 1 diabetes. Individuals with a genetic predisposition are exposed to an immunologic trigger that initiates an autoimmune process, resulting in a gradual decline in beta cell mass. The downward slope of the beta cell mass varies among individuals and may not be continuous. This progressive impairment in insulin release results in diabetes when ~80% of the beta cell mass is destroyed. A "honeymoon" phase may be seen in the first 1 or 2 years after the onset of diabetes and is associated with reduced insulin requirements

Metabolic changes during the development of type 2 diabetes mellitus (DM). Insulin secretion and insulin sensitivity are related, and as an individual becomes more insulin resistant (by moving from point A to point B), insulin secretion increases. A failure to compensate by increasing the insulin secretion results initially in impaired glucose tolerance (IGT; point C) and ultimately in type 2 DM (point D).

Diabetic Retinopathy

cause of blindness in the United States. The retinopathy of diabetes takes years to develop but eventually appears in nearly all cases. Regular surveillance of the dilated fundus is crucial for any patient with diabetes. In advanced diabetic retinopathy, the proliferation of neovascular vessels leads to blindness from vitreous hemorrhage, retinal detachment, and glaucoma These complications can be avoided in most patients by administration of panretinal laser photocoagulation at the appropriate point in the evolution of the disease.