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Insulin26242332Phe 1NH2Figure 29.2 Insulin Structure A illustrates the proinsulin molecule, which is composed of an A (blue)and B (red) chain of insulin, connected by two disulfide bridges (yellow). In the endoplasmic reticulum, theinsulin chains are attached to the connecting “C”-peptide, which is cleaved in the Golgi apparatus to yieldthe insulin and C-peptide and then packaged in secretory granules; the three-dimensional structure of activeinsulin is illustrated in B.acetylcholine also promote insulin secretion (Fig. 29.3B).
Acommon theme is that all of these elements reflect the fed stateas a stimulus for elevating insulin. Lastly, glucagon can alsostimulate insulin secretion by increasing intracellular Ca2+ (viaphospholipase C). This modulates the hyperglycemic effectsof glucagon.Insulin secretion is suppressed when blood glucose is low,when the sympathetic nervous system is stimulated (elevatednorepinephrine and epinephrine), and when local somatostatin is elevated.GlucagonGlucagon is a 29 amino acid peptide hormone produced as aprohormone in the α-cells of the islets of Langerhans.
As withinsulin, intracellular processing results in packaging of activeglucagon molecules in dense core granules.Glucagon acts to mobilize glucose into blood (actions opposite of insulin); the secretion of glucagon is stimulated primarily by low blood glucose. Insulin inhibits glucagon secretionin a paracrine manner. Thus, modulation of glucagon isobserved with ingestion of amino acids, which increases bothinsulin and glucagon. Glucagon secretion is also inhibited byhigh glucose and fatty acids in the blood.SomatostatinAlthough not well understood, somatostatin plays a lesser rolein control of blood glucose. It is a 14 amino acid peptideproduced in the δ-cells of the islets and acts in a paracrinemanner to suppress both insulin and glucagon. This adds onemore level of control in modulating blood glucose levels.
Thesomatostatin produced in the pancreas is the same hormonethat is produced in the brain and gut, and as in these othertissues, it acts locally on adjacent cells.Pancreatic polypeptide is another endocrine hormonesecreted from F-cells in the pancreatic islets. Althoughthe function is not clear, it is released in response to meals highin protein, and it appears to decrease secretion of gastric andintestinal enzymes, modulating the effects of cholecystokinin(see Chapter 23).342Endocrine PhysiologyAK+GlucoseGLUT2transporterCa2+GlucoseVmGlucokinaseGlucose-6-phosphateATPNADPH-H+Ca2+PyruvateGranulesCO2H2OInsulinBCholecystokininAcetylcholinePhospholipase CγβαGqGlucagonGLP-1Adenylyl cyclaseSomatostatinγβαGiαγβαGSαDiacylglycerolERIP3Proteinkinase CATPProteinkinase ACa2+InsulincAMPInsulinInsulinFigure 29.3 Insulin Synthesis and Release Glucose is the most important factor regulating insulinsynthesis and secretion, although gastrointestinal peptides and local glucagon and somatostatin also contribute to modulation of release.
A depicts the action of glucose to increase Ca2+ influx, which stimulatesinsulin secretion. B illustrates the receptor-mediated stimulation of insulin secretion by local glucagon, gutpeptides (CCK and GLP-1), and ACh, and inhibition of insulin by local somatostatin. ACh, acetylcholine;CCK, cholecystokinin; GLP, glucagon-like peptide.ACTIONS OF PANCREATIC HORMONESInsulinThe primary role of the pancreatic hormones is to maintainan appropriate basal level of glucose in the blood, which inhumans is 70 to 90 mg%. To accomplish this, the hormonessequester glucose into cells when there is an influx duringfeeding—the hypoglycemic effect of insulin—and mobilizeglucose out of cells during fasting—the hyperglycemic effectof glucagon. This overall balance is accomplished by the integration of glucose metabolic activity primarily within liver,muscle, and adipose tissues, all orchestrated by the pancreatichormones.As discussed earlier, elevation of blood glucose level will stimulate insulin secretion.
Overall, insulin promotes entry ofglucose into cells, synthesis of glycogen stores, and reducedlipolysis (Fig. 29.4). These anabolic functions ensure thatnutrients are stored and thus available to tissues betweenmeals (fasting).Whereas the insulin receptor is expressed on most tissues,the receptor concentration is high in liver, muscle, and adiposetissue. The insulin receptor consists of two extracellularThe Endocrine Pancreas343AminoacidsMuscleGlycogenGlucoseLiverGlucose-PGlucosePyruvateCO2Free fatty acidsKeto acidsInsulinStimulatesAdiposetissueInhibitsFigure 29.4 Actions of Insulin Insulin is considered a “fuel storage” hormone, and therefore insulinpromotes the storage of glucose (as glycogen) and fatty acids (as triglycerides [TG] in adipose tissue). Insulinstimulates the uptake of glucose into cells via GLUT4 transporters, and the glucose is used or stored asglycogen.
The major glycogen stores are in muscle and liver. Insulin also stimulates fat synthesis and inhibition of lipolysis in adipose tissue, which maintains stores of TGs and reduces keto acid production. Lastly,insulin stimulates uptake of amino acids into skeletal muscle and storage as protein. The overall result isthat insulin decreases plasma glucose, fatty acids, and keto acids.α-subunits and two β-subunits (transmembrane).
Insulinbinds to the α-subunits and stimulates phosphorylation of theβ-subunits, as well as phosphorylation of other intracellularproteins. Thus, the ability of insulin to phosphorylate variousintracellular proteins causes its hypoglycemic effect by:■■■Increasing GLUT4 transporters in membranes, allowingefficient glucose entry into cells.Increasing glycogen production from excess glucose, tofacilitate storage.Inhibiting glycogenolysis, to maintain the glycogenstorage.■Inhibiting gluconeogenesis, to prevent production andrelease of glucose back into the blood.All of these factors rapidly reduce the blood glucose concentration when insulin is present. Furthermore, insulin also haseffects on lipid metabolism by:■■Inhibiting hormone-sensitive lipase in adipose tissue,which decreases lipolysis and reduces the amount ofcirculating free fatty acids.Inhibiting oxidation of fatty acids (especially in theliver), which decreases keto acid formation.344Endocrine PhysiologyOnce the receptor phosphorylation occurs, the entire receptorcomplex is internalized and then is degraded, stored, or reinserted in the membrane.
Insulin also has the ability to downregulate its receptors through increased degradation anddecreased synthesis.Insulin is a critical metabolic hormone; without it mostcells cannot take up glucose. The exception is in brain,liver, and exercising muscle, which have adequate normalglucose uptake due to the presence of GLUT2 transporters (andup-regulation of GLUT4 in exercising muscle). Until the discovery of insulin, type 1 diabetes was a fatal disease.GlucagonWhen blood glucose levels fall during periods of fasting, glucagon is released. In opposition to insulin, glucagon promotesthe use of the cellular energy stores, releasing glucose into theblood (Fig. 29.5). The glucagon receptor is a G protein–coupled receptor and is a member of the secretin-glucagonfamily of receptors, sharing homology with secretin and GIPreceptors.
Unlike insulin receptors, glucagon receptors aremainly on the cell membranes in the liver and kidney. Theliver has stores of glycogen as well as the ability to oxidize fattyacids at a high rate, and glucagon stimulates gluconeogenesisin both organs.GlucagonMuscleGlycogenGlucoseGlucose-PAminoacidsPyruvateCO2LiverGlucoseFree fatty acidsKeto acidsAdiposetissueFigure 29.5 Actions of Glucagon Glucagon is considered the “fuel mobilization” hormone, because itbreaks down glycogen, protein, and lipids, releasing glucose, amino acids, fatty acids, and keto acids into theblood to serve metabolic demand. Glucagon is stimulated by low blood glucose and promotes glycogenolysisand gluconeogenesis in the liver, increasing blood glucose. Glucagon also stimulates lipolysis and release offatty acids from adipose tissue, which are oxidized to keto acids in the liver. Lastly, in muscle, glucagon inhibitsprotein synthesis providing amino acids for conversion to glucose via gluconeogenesis in the liver.The Endocrine PancreasBinding of glucagon with its receptor stimulates cAMP, whichthen activates kinases that phosphorylate various enzymes.These enzymes contribute to the hyperglycemic effect of glucagon by:■■■Both insulin and glucagon are stimulated by certainamino acids.
Although this may seem counterintuitive, ifa meal is high in protein, but low in carbohydrates, insulin willbe increased, stimulating both amino acid and glucose uptakeinto cells—this lowers the plasma glucose concentrations andwould produce hypoglycemia, if not for the increase in glucagon.Thus, glucagon is modulating the insulin response.inhibiting glycolysisincreasing gluconeogenesisincreasing glycogenolysis, breaking down glycogenstores, and releasing the glucose into the bloodIn addition, although both insulin and glucagon reduce plasmaamino acid concentrations by increasing uptake into the hepatocytes, their objectives are different.
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