Physiology_Levy

Physiology_Levy. Insulin has a short half-life of about 5 minutes and is cleared rapidly from the circulation. It is degraded by insulin-degrading enzyme (IDE; also called insulinase) in the liver, kidney, and other tissues. Because insulin is secreted into the hepatic portal vein, it is exposed to liver IDE before it enters the peripheral circulation. About half the insulin is degraded before leaving the liver. Thus peripheral tissues are exposed to significantly less serum insulin concentrations than the liver. Recombinant human insulin and insulin analogues with different characteristics of speed of onset and duration of action and peak activity are now available. Serum insulin levels normally begin to rise within 10 minutes after ingestion of food and reach a peak in 30 to 45 minutes. The higher serum insulin level rapidly lowers blood glucose to baseline values.


Physiology_Levy

Physiology_Levy. Glucose is the primary stimulus of insulin secretion (“steps” in glucose-stimulated insulin secretion described in the discussion that follows refer to


Physiology_Levy

Physiology_Levy. Fig. 39.8 ). Entry of glucose into beta cells is facilitated by the GLUT2 transporter (step 1). Once glucose enters the beta cell, it is phosphorylated to G6P by the low-affinity hexokinase glucokinase (step 2). Glucokinase is referred to as the “glucose sensor” of the beta cell because the rate of glucose entry is correlated to the rate of glucose phosphorylation, which in turn is directly related to insulin secretion. Metabolism of G6P through glycolysis, the TCA cycle, and oxidative phosphorylation by beta cells increases the intracellular ATP : ADP ratio (step 3) and closes an ATP-sensitive K+ channel (step 4). This results in depolarization of the beta cell membrane (step 5), which opens voltage-gated Ca++ channels (step 6). Increased intracellular [Ca++] activates microtubule-mediated exocytosis of insulin/proinsulincontaining secretory granules (step 7).


Physiology_Levy

Physiology_Levy. Ingested glucose has a greater effect on insulin secretion than injected glucose. This phenomenon, called the incretin effect, is due to stimulation by glucose of incretin hormones from the gastrointestinal tract. One clinically relevant incretin hormone is glucagon-like peptide 1 (GLP-1), which is released by L cells of the ileum in response to glucose in the ileal lumen ( Fig. 39.9 ). As a hormone, GLP-1 enters the circulation and ultimately binds to the Gs-coupled GLP1 receptor (GLP1R) on beta cells. This GLP1R/Gs/adenylyl cyclase/protein kinase A (PKA) signaling pathway amplifies the intracellular effects of Ca++ on insulin secretion. GLP-1 is rapidly degraded in the circulation by dipeptidyl peptidase 4 (DPP-4).


Physiology_Levy

Physiology_Levy. 706 SECTION8Berne & Levy Physiology •Fig. 39.8 Secondaryregulatorsofinsulinsecretion.Seetextforexplanationofabbreviations.Specific amino acids (Eating a meal) AA transporter ATP ˜CA2+ °cAMP ˛ CELL ˜cAMP M3R (Gq)ACh Parasympathetic innervation (Anticipating & ingesting a meal) Norepinephrine, epinephrine Sympathetic innervation adrenal medulla (Exercise, Hypoglycemia) ? ˛2AR (Gs) ˛2AR Agonists ˙2AR (Gi) ˙2AR Agonists Insulin Fig. 39.10 ). Insulin secretion is primarily dampened by sympathetic autonomic regulation through α2-adrenergic receptors. Binding of norepinephrine or epinephrine to α2-adrenergic receptors decreases cyclic adenosine mono-phosphate (cAMP), possibly by closing Ca++ channels (see


Physiology_Levy

Physiology_Levy. Fig. 39.6 ). Adrenergic inhibition of insulin serves to protect against hypoglycemia, especially during exercise. Beta cells also express Gs-coupled β2-adrenergic receptors that normally play a minor role in promoting insulin secretion. Note, however, that β-adrenergic receptor agonists oppose the actions of insulin on overall metabolism and may antagonize the actions of administered insulin in diabetics. Conversely, β-blockers (i.e., β-adrenergic receptor antagonists) may increase the severity of hypoglycemic episodes in patients receiving exogenous insulin.


Physiology_Levy

Physiology_Levy. TheATP-sensitiveK+ channelisanoctamericproteincomplexthatcontainsfourATP-bindingsubunitscalledSUR subunits. Thesesubunitsareboundbysulfonylurea drugs, whichalsoclosetheK+ channelandarewidelyusedasoralhypoglycemicstotreathyperglycemiainpatientswithpartiallyimpairedbetacellfunction.Hypoglycemiaisasignificantsideeffectofsulfonylureadrugsifusedinexcessorincorrectlyincombinationwithotherdrugs,owingtoinappropriatelyhighreleaseofinsulin. BothDPP-4–resistant analogues of GLP-1 andinhibitors of DPP-4 arecurrentlyapprovedfortreatmentofpatientswithtype2DMwithsomebetacellfunction.Importantlythesedrugsarepermissive totheactionsofglucoseonthebetacellandthusonlyweaklyincreaseinsulinsecretionintheabsenceofglucose.ThusGLP-1analoguesinducehypoglycemiamuchlessfrequentlythansulfonylureadrugs.


Physiology_Levy

Physiology_Levy. The insulin receptor (InsR) is a member of the receptor tyrosine kinase (RTK) gene family (see ). Most of the actions of insulin on metabolism involve activation of the protein kinase Akt, which in turn has pleiotropic actions on cell metabolism. The InsR is expressed on the cell membrane as a homodimer, with each monomer containing a tyrosine kinase B InsRec IRS protein Metabolic actions Anabolic actions of insulin • Utilization of glucose for ATP & anabolic pathways • Storage of FFAs as TG • Protein synthesis from AAs • Macromolecular synthesis (e.g., RNA, DNA, lipids) • Organelle formation • Cell proliferation/renewal Mitogenic actions Merabolic actions PIP2PIP3 RAS/ RAF MAPK/ ERK PI3K Akt


Physiology_Levy

Physiology_Levy. GLUT 4 Translocation Glucose import Glycolysis, Glycogenesis, PDH, DNL Glucogenolysis Gluconeogensis FFA ˜ oxidation Ketogenesis Lipolysis Proteolysis autophagy Protein synthesis Gycolysis, PPP, DNL Gluconeo-genesis, VLDL export Protein phoshatases mTORC1 SREBP-1C FOX01 Akt •Fig. 39.9 A,Structureofdimerizedinsulinreceptorincellmembrane.B,SimplifieddiagramoftheAktkinaseandMAPKpathwaysdownstreamoftheInsR.C,Summarizedactionsofinsulin/InsR-activatedAktkinase.


Physiology_Levy

Physiology_Levy. Insulingeneexpressionandisletcellbiogenesisaredependentonseveraltranscriptionfactorsspecifictothepancreas,liver,andkidney.Thesetranscriptionfactorsincludehepatocyte nuclear factor 4α (HNF-4α), HNF-1α, insulin promoter factor 1 (IPF-1), HNF-1β, and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/β2). Aheterozygousnullmutationofoneofthesefactorsresultsinprogressivelyinadequateproductionofinsulinandmaturity-onset diabetes of the young (MODY) beforetheageof 25.MODYischaracterizedbynonketotichyperglycemia,oftenasymptomatic,thatbeginsinchildhoodoradolescence.Inadditiontothefivetranscriptionfactors,mutationsinglucokinase alsogiverisetoMODY. •Fig. 39.10 Divergentproteolyticcleavagepatternsoftheproglucagonmolecule.GLUC,glucagon;GLP,glucagon-likepeptide;GRPP,glucagon-relatedpolypeptide. domain on the cytosolic side (see


Physiology_Levy

Physiology_Levy. •Fig. 39.10 Divergentproteolyticcleavagepatternsoftheproglucagonmolecule.GLUC,glucagon;GLP,glucagon-likepeptide;GRPP,glucagon-relatedpolypeptide. domain on the cytosolic side (see Fig. 39.10A ). Binding of insulin to the receptor induces cross-phosphorylation of the subunits. These phosphotyrosine residues are then bound by the insulin receptor substrate (IRS) proteins (i.e., IRS proteins are “recruited” to the InsR). The IRS proteins themselves are phosphorylated by the InsR on specific tyrosines, which then recruits phosphoinositide-3-kinase (PI3K) to the IRS protein bound to the InsR (see


Physiology_Levy

Physiology_Levy. Fig. 39.10B ). PI3K converts phosphoinositol-4,5-bisphosphate (PIP2) to phosphoinositol-3,4,5-trisphosphate (PIP3). PIP3 is an informational lipid that recruits proteins to the membrane. In this pathway, PIP3 recruits Akt protein kinase to the cell membrane where it becomes activated. This pleiotropic Akt protein kinase signaling pathway orchestrates the numerous metabolic actions of insulin in hepatocytes, skeletal muscle, and adipocytes, including (see Fig. 39.10C 1. translocation of the GLUT4 glucose transporter to the cell membrane, thereby allowing import of glucose into skeletal myocytes and adipocytes; 2. activation of protein phosphatases, which in turn regulate the activity of multiple metabolic enzymes in all insulin target cells; 3. activation of the protein complex mechanistic target of rapamycin complex 1 (mTORC1), which promotes protein synthesis and may inhibit proteosomal-mediated protein degradation in insulin target cells; 4.


Physiology_Levy

Physiology_Levy. activation of the transcription factor sterol response element binding protein 1 (SREBP1). SREBP1 is especially important for insulin effects on the liver, where it orchestrates glycolysis and de novo lipogenesis (DNL) for production of phospholipids, FAs, and TGs from excessive ingested glucose and fructose. InsR/Akt signaling stimulates SREBP1 directly as well as indirectly through activation of mTORC1, which also activates SREBP1. SREBP1 also induces the enzyme that catalyzes the first reaction in the oxidative arm of the pentose phosphate pathway (PPP). This reaction generates the coenzyme NADPH, which is required for DNL. 5. inactivation of the transcription factor FOXO1. Aktmediated phosphorylation of FOXO1 promotes nuclear exclusion of FOXO1. In the absence of insulin/Akt signaling, FOXO1 induces expression of genes encoding


Physiology_Levy

Physiology_Levy. VLDL assembly and export. All these actions of Akt will be discussed in more detail later. The InsR also promotes proliferation/renewal of some target cells through the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway (see Fig. 39.10B ). The MAPK pathway also participates in some metabolic regulation. Glucagon is the primary counterregulatory hormone that increases blood glucose levels, primarily through its effects on liver glucose output. Glucagon also enhances intramitochondrial fatty acid oxidation and ketogenesis in hepatocytes. Glucagon is a member of the secretin gene family. The precursor preproglucagon harbors the AA sequences for glucagon, GLP-1, and GLP-2 (


Physiology_Levy

Physiology_Levy. Glucagon is a member of the secretin gene family. The precursor preproglucagon harbors the AA sequences for glucagon, GLP-1, and GLP-2 ( Fig. 39.11 ). Preproglucagon is proteolytically cleaved in the alpha cell in a cell-specific manner to produce the peptide glucagon. Glucagon circulates in an unbound form and has a short half-life of about 6 minutes. The predominant site of glucagon degradation is the liver, which degrades as much as 80% of circulating glucagon in one pass. Because glucagon enters the hepatic portal vein and is carried to the liver before reaching the systemic circulation, a large portion of the hormone never reaches the systemic circulation. The liver is the primary target organ of glucagon, with lesser effects on adipocytes. Skeletal muscle does not express the glucagon receptor.


Physiology_Levy

Physiology_Levy. The glucagon receptor is is a Gs-linked G protein– coupled receptor that increases adenylyl cyclase activity and thus cAMP levels. Glucagon exerts many rapid actions through PKA signaling. Glucagon also exerts some transcription effects through phosphorylation and activation of transcription factors such as CREB (cAMP response element binding) protein. The insulin-glucagon ratio determines the net effect of metabolic pathways on blood glucose. A major stimulus for secretion of glucagon is a decline in blood glucose. Insulin inhibits glucagon secretion, so low blood glucose has an CHAPTER 39 Hormonal Regulation of Energy Metabolism 709 indirect effect on glucagon secretion through removal of ˜ Cell Insulin inhibition by insulin ( Fig. 39.12 ). Some recent evidence also indicates that low glucose has a direct effect on alpha (+) cells to increase glucagon secretion.


Physiology_Levy

Physiology_Levy. Fig. 39.12 ). Some recent evidence also indicates that low glucose has a direct effect on alpha (+) cells to increase glucagon secretion. Circulating catecholamines, which inhibit secretion of glucose insulin via α2-adrenergic receptors, stimulate secretion of glucagon via β2-adrenergic receptors (see Fig. 39.12 (If low) Serum AAs promote secretion of glucagon. This means a glucose protein meal will increase postprandial levels of both insulin and glucagon (which protects against hypoglycemia), whereas a carbohydrate meal stimulates only insulin. Catecholamines: Epinephrine (–) and Norepinephrine


Physiology_Levy

Physiology_Levy. Catecholamines: Epinephrine (–) and Norepinephrine The other major counterregulatory factors are the catechol- amines epinephrine and norepinephrine. Epinephrine is the primary product of the adrenal medulla (see ), whereas norepinephrine is released from postganglionic sympathetic nerve endings (see ). Catecholamines are released in response to decreased glucose concentrations, various forms of stress, and exercise. Decreased glucose levels (i.e., hypoglycemia) are primarily • Fig. 39.11 Integrated regulation of blood glucose by insulin and sensed by neurons in the CNS, which initiate an integrated the counterregulatory factors glucagon and catecholamines (norepinephrine, epinephrine).


Physiology_Levy

Physiology_Levy. Fructose-1,6-bisP OA Acetyl CoA • Fig. 39.12 Metabolic pathways in hepatocytes during digestive (“D” numbers) and fasting (“F” numbers) phases. Reactions/pathways: 1D, glucokinase; 1F; G6Pase; 2D, glycogen synthesis; 2F, glycogenolysis; 3D, phosphofructokinase 1; 3F, fructose-1,6-bisphosphatase; 4D, glucose-6-phosphate dehydrogenase; 5D, pyruvate kinase; 6D, pyruvate dehydrogenase; 6F, pyruvate carboxylase; 7F, phosphoenolpyruvate carboxykinase; 8D, ATP-citrate lyase; 9D, acetyl CoA carboxylase; 9F, malonyl CoA decarboxylase; 10D fatty acid synthase; 11D, glycerol phosphate/fatty acyl CoA transferase and other enzymes involved in esterification and formation of TG; 12D, inhibition by malonyl CoA (Mal CoA) of fatty acyl CoA transporter, carnitine/palmitoyl transporter 1 (CPT1) on outer mitochondrial membrane; 13F, movement of fatty acyl CoA into mitochondrion through CPT1 and beta-oxidation to acetyl CoA.


Physiology_Levy

Physiology_Levy. sympathetic response through the hypothalamus. The direct metabolic actions of catecholamines are mediated primarily by α1-, β2-, and β3-adrenergic receptors located on muscle, adipose, and liver tissue (see later). Like the glucagon receptor, β-adrenergic receptors (β2 and β3) increase intracellular cAMP. The α1-adrenergic receptor is also expressed by some organs, especially the liver. Hormonal Regulation of Specific Metabolic Reactions and Pathways This section discusses the main pathways in hepatocytes, skeletal myocytes, and adipocytes that contribute to integrated metabolism. For even more detailed description, the student is referred to biochemistry textbooks. Hepatocyte Metabolism: Digestive vs. Fasting Phases Some of the key metabolic steps regulated by insulin and glucagon (and catecholamines) in the liver are as follows (refer to


Physiology_Levy

Physiology_Levy. Fig. 39.13 for numbered reactions; D denotes digestive phase, F denotes fasting phase): 1. Trapping vs. releasing intracellular glucose. Although glucose enters hepatocytes through insulin-independent GLUT2 transporters, insulin increases hepatic retention and utilization of glucose by increasing expression of glucokinase (reaction 1D). Insulin increases glucokinase gene expression through increased expression and activation of the transcription factor sterol regulatory element–binding protein 1C (SREBP1C), which acts as a “master switch” in the fed state to coordinately increase levels of several enzymes involved in glucose utilization and TG synthesis. Hepatocytes also express the enzyme G6Pase (reaction 1F), which converts G6P back to glucose, which can then exit the hepatocyte via the GLUT2 transporter. Insulin prevents the futile cycle of glucose phosphorylation-dephosphorylation by repressing gene expression of the enzyme G6Pase. The transcription factor FOXO1 stimulates gene


Physiology_Levy

Physiology_Levy. GLUT2 transporter. Insulin prevents the futile cycle of glucose phosphorylation-dephosphorylation by repressing gene expression of the enzyme G6Pase. The transcription factor FOXO1 stimulates gene expression of G6Pase. Insulin-activated Akt kinase phosphorylates and inactivates FOXO1. During the fasting phase, FOXO1 is active and promotes G6Pase expression, whereas SREBP1C is inactive and does not stimulate glucokinase expression. The reciprocal regulation of SREBP1C and FOXO1 are thus regulated primarily by the presence or absence of insulin.


Physiology_Levy

Physiology_Levy. 2. Glycogen synthesis vs. breakdown. Insulin indirectly increases glycogen synthesis through increased expression of glucokinase because high levels of G6P allosterically increase glycogen synthase activity. Through stimulation of specific protein phosphatases, insulin promotes dephosphorylation and thereby activation of glycogen synthase (reaction 2D). Insulin also prevents the futile cycle of glycogen synthesis to glycogenolysis through inhibition of glycogen phosphorylase (reaction 2F). Glucagon-activated PKA phosphorylates phosphorylase kinase, which in turn phosphorylates and activates glycogen phosphorylase. 3. Increasing glycolysis. A. Activating phosphofructokinase 1 (PFK1) and inhibiting fructose-2,6-bisphosphatase. Insulin increases the activity of PFK1, which phosphorylates •Fig. 39.13 Insulinandcounterregulatoryhormoneregulationofphosphofructokinase1(PFK1;reaction3Din Fig.39.12) andfructose-1,6-bisphosphatase(F1,6BPase;reaction3Fin


Physiology_Levy

Physiology_Levy. Fig.39.12) throughchangingtheactivityofthebifunctionalenzymephosphofructokinase2/fructose-2,6-bisphosphatase(PKFBP)andthusthelevelsoftheallostericregulatorymetabolitefructose-2,6-bisphosphate(F-2,6-bisP).Insulin/Akt-activated protein phosphatase F-2,6BPase F-1,6BPase F-1,6-bisPATP, citrate AMP PKFBP-P PFK1 (–) (–) (+) Glucagon & NE/E-activated protein kinase A (PKA) HepatocytecytoplasmPKFBP PFK2 F-2,6-bisP F6P •Fig. 39.14 Metabolisminskeletalmuscleduringdigestive(“D”reactions)vs.fasting(“F”reactions)phases.Reactions/pathways:1D,translocationofGLUT4transportertocellmembrane;1F,lossoftranslocationofGLUT4transportertocellmembrane;2D,glycogensynthesis;2F,glycogenolysis;3D,glycolysisandlactatedehydrogenase,orpyruvatedehydrogenase/TCAcycle/oxidativephosphorylation(OxPhos),dependingonmusclefibertype;3F,β-oxidationofFFAsorketolysisfollowedbytheTCAcycleandOxPhos.GLUT4 GLUT4 Transporters FFAs, KBsAcetyl CoAATP GLUT4 storage vesicle Cell membrane GlucoseGlucoseGlycogen 1D 1F 2F 2D 3D 3F GLUT4


Physiology_Levy

Physiology_Levy. GLUT4 Transporters FFAs, KBsAcetyl CoAATP GLUT4 storage vesicle Cell membrane GlucoseGlucoseGlycogen 1D 1F 2F 2D 3D 3F GLUT4 Skeletal myocyte fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (reaction 3D). This reaction is referred to as the “commitment” reaction for glycolysis. Insulin also inhibits the reverse reaction, as catalyzed by the gluconeogenic enzyme fructose-1,6-bisphosphatase. Insulin regulates these two enzymes through an indirect two-step mechanism that is diagramed in


Physiology_Levy

Physiology_Levy. Fig. 39.14 . This mechanism involves the bifunctional enzyme phosphofructokinase-2/ fructose bisphosphatase (PKFBP; see Fig. 39.14 ). Insulin/Akt-activated protein phosphatases promote dephosphorylation of PKFBP, thereby activating the kinase function and lessening the phosphatase function. This phosphorylates F6P to fructose-2,6bisphosphate (F-2,6-bisP). F-2,6-bisP in turn allosterically activates PFK1, thereby driving glycolysis. F-2,6-bisP also competitively inhibits fructose-1,6bisphosphatase, thereby blocking the futile cycle of F6P to fructose-1,6-bisphosphate to F6P. B. Activatingpyruvatekinase(PK).PKcatalyzestheirreversibleconversionofphosphoenolpyruvate(PEP)topyruvate(seereaction5Din Fig. 39.12 ).Again,insulin/AktkinaseactivationofaproteinphosphatasedephosphorylatesPK,whichactivatestheenzyme.InsulinalsoincreasesPK geneexpressionthroughSREBP1C.Finally,fructose-1,6-bisphosphate(productofreaction3D)allostericallyactivatesPK. 4.


Physiology_Levy

Physiology_Levy. 4. Activating pyruvate dehydrogenase (PDH) complex. PDH converts pyruvate to acetyl CoA, which can then enter the TCA cycle upon condensation with oxaloacetate (OA) to form citrate. Insulin increases PDH activity through Akt kinase activation of PDH phosphatase, which in turn dephosphorylates and activates PDH (reaction 6D). 5.


Physiology_Levy

Physiology_Levy. Increasing synthesis of intrahepatic TG. During the digestive phase, some acetyl CoA is transferred from the mitochondria to the cytosol in the form of citrate, which is then converted back to acetyl CoA and oxaloacetate by the cytosolic enzyme ATP-citrate lyase (reaction 8D). Insulin increases ATP-citrate lyase gene expression through transcription factor SREBP1C. Once in the cytoplasm, acetyl CoA can enter fatty acid synthesis. The first step involves conversion of acetyl CoA to malonyl CoA by the enzyme acetyl-CoA carboxylase (reaction 9D). Insulin stimulates acetyl-CoA carboxylase gene expression through the transcription factor SREBP1C. Insulin also promotes dephosphorylation of acetyl-CoA carboxylase, which activates the enzyme. Malonyl CoA is converted to the 16-carbon fatty acid palmitoyl CoA by repetitive additions of acetyl groups (contributed by malonyl CoA) by the fatty acid synthase (FASN) complex (reaction 10D). FASN gene expression is enhanced by insulin through the


Physiology_Levy

Physiology_Levy. palmitoyl CoA by repetitive additions of acetyl groups (contributed by malonyl CoA) by the fatty acid synthase (FASN) complex (reaction 10D). FASN gene expression is enhanced by insulin through the transcription factor SREBP1C. Insulin also stimulates palmitoyl-CoA desaturase, which produces unsaturated fatty acids, and glycerol phosphate–fatty acyl transferases that esterify FFAs to G3P to form intrahepatic TG.


Physiology_Levy

Physiology_Levy. Palmitate synthesis requires the coenzyme NADPH. A major source of NADPH is the pentose phosphate pathway (PPP; see Fig. 39.12 ). The first reaction converts G6P to 6-phosphogluconolactone by the enzyme glucose-6-phosphate dehydrogenase (G6PD; reaction 4D). Insulin increases G6PD gene expression through the transcription factor SREBP1C. By activating steps that lead to generation of malonyl CoA, insulin indirectly inhibits oxidation of FFAs. Malonyl CoA inhibits the activity of CPT-I, which transports FFAs from the cytosol into the mitochondria (reaction 12D). As a result, FFAs that are synthesized by DNL cannot be transported into mitochondria, where they undergo β-oxidation (reaction 13F). Thus increased malonyl CoA prevents the futile cycle of FFA synthesis to FFA oxidation.


Physiology_Levy

Physiology_Levy. FFAs are converted to TGs by the liver (reaction 11D) and are either stored in the liver or transported to adipose tissue and muscle in the form of VLDL (see later). Insulin acutely promotes degradation of the VLDL apoprotein apoB-100. This keeps the liver from secreting VLDL during a meal when the blood is rich with chylomicrons. Thus the lipid made in response to insulin during a meal is released as VLDL during the interdigestive and fasting phases and provides an important source of energy to skeletal and cardiac muscle.


Physiology_Levy

Physiology_Levy. 6. Activation vs. inhibition of the gluconeogenic enzymes pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK). Pyruvate can also be converted to OA by PC (reaction 6F). However, this reaction is indirectly inhibited by insulin in several ways. First, insulin activates PDH as just discussed, thereby diverting pyruvate away from the PC reaction. Additionally, PC is allosterically activated by high levels of intramitochondrial acetyl CoA. Insulin keeps intramitochondrial levels of acetyl CoA low by activation of cytosolic DNL, which promotes removal of acetyl CoA via citrate from the mitochondria. Another key mechanism is to prevent β-oxidation of FFAs within the mitochondria, which generates high levels of acetyl CoA. By stimulating DNL, insulin also increases levels of cytosolic malonyl CoA, which inhibits transport of FFAs into the mitochondria (reaction 12D). Also, inhibitory actions of insulin on glucagon secretion and on lipolysis of TG within adipocytes


Physiology_Levy

Physiology_Levy. of cytosolic malonyl CoA, which inhibits transport of FFAs into the mitochondria (reaction 12D). Also, inhibitory actions of insulin on glucagon secretion and on lipolysis of TG within adipocytes prevents release of FFAs by adipose tissue and their import into hepatocytes.


Physiology_Levy

Physiology_Levy. In contrast, during the fasting phase, low insulin coupled with high glucagon and/or catecholamines stimulate release of FFAs from adipocytes (see later), which increases the flow of FFAs into hepatocytes. Glucagon also phosphorylates and activates the enzyme malonyl decarboxylase, which converts malonyl CoA back to acetyl CoA (reaction 9F). Enhanced malonyl CoA decarboxylase, along with generally low DNL due to low insulin, reduces malonyl CoA levels and thus removes the inhibition on the CPT1 transporter. This allows FFAs to enter the mitochondria and undergo β-oxidation (reaction 13F), generating high levels of intramitochondrial acetyl CoA, activating PC (reaction 6F) and also allosterically inhibiting PDH (reaction 6D).). The enzymes involved in β-oxidation are activated by PKA signaling. Glucagon also activates the transcription factor PPARα, which further induces expression of enzymes involved in β-oxidation. Fibrate drugs activate PPARα, promoting oxidation of intrahepatic TG


Physiology_Levy

Physiology_Levy. Glucagon also activates the transcription factor PPARα, which further induces expression of enzymes involved in β-oxidation. Fibrate drugs activate PPARα, promoting oxidation of intrahepatic TG and ameliorating insulin resistance.


Physiology_Levy

Physiology_Levy. Insulin also represses gene expression of the gluconeogenic enzyme PEPCK (reaction 7F), which converts pyruvate (by way of malate transferase out of the mitochondria) to phosphoenolpyruvate. PEPCK is primarily regulated at the level of transcription. Similar to its actions on G6Pase, FOXO1 stimulates transcription of PEPCK during the fasting phase, and insulin/Akt kinase signaling inactivates FOXO1 during the digestive phase. Glucagon and catecholamines also increase PEPCK gene expression through PKA-CREB signaling during the fasting phase. Skeletal Muscle and Adipose Tissue Metabolism: Digestive vs. Fasting Phases 1.


Physiology_Levy

Physiology_Levy. Fig. 39.15 ). Glucose tolerance refers to the ability of an individual to minimize the increase in blood glucose concentration after a meal. A primary way by which insulin promotes glucose tolerance is activation of glucose transporters in skeletal muscle. Insulin stimulates translocation of preexisting GLUT4 transporters to the cell membrane (reaction 1D). Insulin also promotes storage of glucose in muscle as glycogen (reaction 2D) and promotes oxidation of glucose through glycolysis (reaction 3D). During the fasting phase, low insulin results in a low number of GLUT4 transporters at the membrane (reaction 1F), so these cells consume less glucose (glucose sparing). Skeletal muscle fibers with mitochondria switch to the use of FFAs from adipocytes and KBs from hepatocytes (reaction 3F). Skeletal myocytes do not express glucagon receptors. Uptake of FFAs and KBs and their oxidation for ATP is largely upregulated by intracellular Ca++ levels and a high AMP:ATP ratio. Exercise also


Physiology_Levy

Physiology_Levy. Skeletal myocytes do not express glucagon receptors. Uptake of FFAs and KBs and their oxidation for ATP is largely upregulated by intracellular Ca++ levels and a high AMP:ATP ratio. Exercise also activates these pathways, as does glycogenolysis (reaction 2F), through adrenergic receptor stimulation.


Physiology_Levy

Physiology_Levy. 2. (Fig. 39.16A ). Insulin also stimulates GLUT4-dependent uptake of glucose and subsequent glycolysis in adipose tissue (reactions 1D and 2D). Adipose tissue uses glycolysis for energy needs but also for generating G3P (reaction 3D), which is required for esterification of FFAs into TGs (reaction 4D). During the fasting phase, insulin is low, so GLUT4 movement to the cell membrane is blocked (reaction 1F). 2. Adipocytes → FFAs and TG (see Fig. 39.16B ). Insulin stimulates expression of lipoprotein lipase (LPL) •Fig. 39.15 A, Glucose metabolism in an adipocyte during digestive (“D” reactions) and fasting (“F” reactions) phases. Reactions/pathways:1Dand1F(alsosee


Physiology_Levy

Physiology_Levy. Fig.39.14 legend);2D,glycolysis,pyruvatedehydrogenase/TCAcycle/OxPhos;3D,glycerol-3-phosphatedehydrogenase;4D,esterificationofFFAstoG3Ptoformtriglyceride.B, Lipid metabolism in adipocyte during digestive (“D” reactions) and fasting (“F” reactions) phases. Reactions/pathways:1D,synthesisoflipoproteinlipase(LPL)andLPLsecretionintosubcapillaryspace,bindingtoGPI-anchoredprotein(red box),


Physiology_Levy


Physiology_Levy

Physiology_Levy. 714 SECTION8Berne & Levy Physiology •Fig. 39.16 Roleoflipoproteinsinenergymetabolism.A,Digestivephase.B,Fastingphase.Dietary fats Adipose capillaries Dietary sugar & carbs Glucose fructose CM Adipose capillaries LPL CR Cardiac muscle capillaries LPL FFAs FFAs A B FFAs FFAs Cardiac & skel muscle capillaries LPL Cardiac & skeletal muscle Steroidogenic cells Growing cells FFAs TG TG Adipocyte Adipocyte TG Liver VLDL Glucose fructose Cardiac muscle ATP Skeletal muscle ATP KBs TG Liver ATP CHOL ATP IDL LDL IDL within adipocytes and its migration to the apical side of endothelia in adipose capillaries (reaction 1D). This action of insulin allows LPL to extract FFAs from chylomicrons within adipose tissue capillary beds (reaction 2D). The chylomicron remnants (discussed later) are removed by the liver. Insulin also stimulates activation of imported FFAs by their conversion to fatty acyl CoAs (reaction 3D). Insulin stimulates glycolysis in adipocytes, which generates the G3P required for


Physiology_Levy

Physiology_Levy. the liver. Insulin also stimulates activation of imported FFAs by their conversion to fatty acyl CoAs (reaction 3D). Insulin stimulates glycolysis in adipocytes, which generates the G3P required for reesterification of FFAs into TGs (reaction 4D). Insulin directly inhibits hormone-sensitive lipase (HSL; reaction 5D), thereby promoting storage of FFAs as opposed to their release. During the fasting phase, glucagon and catecholamines phosphorylate and activate HSL (reaction 1F), thereby promoting release of FFAs and glycerol from stored TG (reaction 2F). In the absence of insulin these two products of lipolysis are exported into the blood.


Physiology_Levy

Physiology_Levy. Protein Metabolism in All Hormone Target Cells: Digestive vs. Fasting Phases Insulin promotes protein synthesis in muscle and adipose tissue by stimulating AA uptake and mRNA translation. Insulin also inhibits proteolysis. Although the liver uses AAs for ATP synthesis, insulin also promotes synthesis of proteins during the digestive phase and attenuates the activity of urea cycle enzymes in the liver. Glucagon and catecholamines activate proteosomal degradation of proteins and release of AAs during the fasting phase. Metabolic Roles of Lipoproteins: Digestive vs. Fasting Phases This section deals with lipoproteins in some detail. For more details, consult a biochemistry textbook.


Physiology_Levy

Physiology_Levy. FFAs circulate in the blood primarily bound to albumin. However, TG, free cholesterol, cholesterol esters, phospholipids and some lipid-soluble vitamins, all of which are hydrophobic and would partition into the membranes of endothelial cells instead of circulating, are transported through blood within lipid aggregations (i.e., a mix of the above) bound by specific apoproteins. These lipid-protein complexes are referred to as lipoproteins. The TG-rich lipoproteins are chylomicrons and VLDL and primarily function to deliver FFAs (as TG) to skeletal and cardiac muscle for energy and to adipocytes for storage. The cholesterol-rich lipoproteins include low-density lipoprotein (LDL) and high-density lipoprotein (HDL), which deliver cholesterol to proliferating cells, steroidogenic cells, and bile-producing hepatocytes. HDL also removes excess cholesterol (i.e., from macrophage-engulfed dead cells) from the periphery. There are also “remnants” of lipoproteins that have their lipid cargo


Physiology_Levy

Physiology_Levy. bile-producing hepatocytes. HDL also removes excess cholesterol (i.e., from macrophage-engulfed dead cells) from the periphery. There are also “remnants” of lipoproteins that have their lipid cargo partially digested and then cleared from the circulation by the liver.


Physiology_Levy

Physiology_Levy. Digestive Phase: Chylomicrons and Chylomicron Remnants TGs in a meal are enzymatically digested to FFAs and 2-monoglycerides within the lumen of the intestine. •Fig. 39.17 Leptinandhypothalamiccentersinvolvedinregulationofappetite.Seetextforexplanationsofabbreviations. Intestinal enterocytes import both of these lipids and reesterify them to form TGs. TGs, along with fat-soluble vitamins, cholesterol, cholesterol esters, and phospholipids, are complexed with the protein ApoB48 to form chylomicrons. Chylomicrons are secreted, move into lymphatics, and then ultimately enter the circulation. While in the blood, other apoproteins such as ApoE and ApoC2 are transferred to the chylomicrons from HDL particles (one function of HDL is to provide a circulating reservoir of various apoproteins). This converts nascent chylomicrons into mature chylomicrons.


Physiology_Levy

Physiology_Levy. When chylomicrons enter the capillaries of adipose tissue during the digestive phase, they are partially digested by lipoprotein lipase (LPL). LPL is synthesized by adipocytes and secreted into the subendothelial space. LPL then binds to the endothelial membrane GPI-anchored protein GPIHBP1, which transports LPL to the luminal (apical) surface of the capillary endothelial cell. Once in this position, LPL molecules come into contact with chylomicrons. ApoC2 within chylomicrons is an activator of LPL dimerization and activity. FFAs are released from chylomicrons by LPL-mediated lipolysis of TG. (See earlier discussion and Fig. 39.16B for an explanation of the processing of FFAs to stored TG within adipocytes. LPL is also expressed in cardiac and skeletal muscle. Cardiac muscle preferentially uses FFA for energy and obtains most FFAs from lipoprotein particles (


Physiology_Levy

Physiology_Levy. LPL is also expressed in cardiac and skeletal muscle. Cardiac muscle preferentially uses FFA for energy and obtains most FFAs from lipoprotein particles ( Fig. 39.17 ). Thus cardiac muscle also extracts FFA from chylomicrons during the digestive phase. The activity of LPL in cardiomyocytes is highly regulated by local factors such as the local concentration of FFAs within the coronary capillary beds. LPL activity in skeletal muscle is relatively low during the digestive phase.


Physiology_Levy

Physiology_Levy. After lipolytic digestion within adipose tissue capillary beds, chylomicrons are converted to smaller, denser chylomicron remnants (CR) that now have reduced TG content. CR particles are able to penetrate the tunica intima of blood vessels at sites with endothelial dysfunction and thus are atherogenic. Because they still have ApoE protein associated with them, they can bind to one of several membrane receptors that recognize ApoE. CRs can also bind to specific glycolipids. Bound CRs are then endocytosed by hepatocytes (see Fig. 39.17 ). Remaining FFAs that are released after endocytosis of CRs are reesterified into intrahepatic TG. Fasting Phase: VLDL, IDL, and LDL The source of circulating TG during the fasting phase is primarily the liver (see


Physiology_Levy

Physiology_Levy. Fasting Phase: VLDL, IDL, and LDL The source of circulating TG during the fasting phase is primarily the liver (see Fig. 39.17 ). During the digestive phase, intrahepatic TGs accumulate from de novo lipogenesis using the carbons in cytosolic citrate and from endocytosed CRs. Intrahepatic TG, along with other lipids including cholesterol and cholesterol esters, is exported by hepatocytes as VLDL. VLDL particles are assembled as lipids complexed to the ApoB100 protein. Expression of ApoB100, along with other components involved in VLDL assembly, is stimulated by transcription factor FOXO1. FOXO1 in turn is inhibited by the insulin signaling pathway. This means that hepatic VLDL production is minimal during the time when blood is rich in chylomicrons. During the fasting phase, insulin levels are low, so FOXO1 activity is high, and VLDL assembly and secretion resumes. Once VLDL particles enter the circulation, they accept other apoproteins (e.g., ApoE, ApoC2) and become mature VLDL.


Physiology_Levy

Physiology_Levy. Adipocytes display low LPL activity during the fasting phase, in part owing to low insulin levels. However, cardiomyocytes and skeletal myocytes express LPL, which digests VLDL and provides FFA to these muscle cell types during the fasting phase. Lipolytic extraction of some FFAs from VLDL generates a remnant particle called intermediate-density lipoprotein (IDL). IDL circulates to the liver, where it s processed in one of two ways (see


Physiology_Levy

Physiology_Levy. Fig. 39.17 ). About half of the IDL binds to one of several ApoErecognizing receptors, undergoes receptor-mediated endocytosis, and is digested in endolysosomes. Released lipids can be reassembled into VLDL particles and returned to the circulation to provide fuel for cardiac and skeletal muscle as the fasting phase progresses. The other half of the IDL undergoes further digestion from the hepatocyte-specific LPL-related enzyme hepatic lipase. Hepatic lipase extracts most of the remaining TG in the IDL, forming the final remnant of VLDL, LDL. LDL is TG poor but cholesterol rich. It should be noted that both mature chylomicrons and VLDL can receive additional cholesterol from HDL while in the circulation through the action of cholesterol ester transport protein (CETP), so cholesterol content of the remnant particles (ChyR, IDL, and LDL) can vary. In any case the LDL particle is a small, dense, cholesterol-rich particle that is potentially very atherogenic in the face of endothelial


Physiology_Levy

Physiology_Levy. of the remnant particles (ChyR, IDL, and LDL) can vary. In any case the LDL particle is a small, dense, cholesterol-rich particle that is potentially very atherogenic in the face of endothelial damage. LDL particles are safely imported into cells through the LDL receptor. It should be noted that in the conversion of IDL to LDL, the ApoE protein disassociates from the particle. This means that only receptors for which ApoB100 is a ligand can remove LDL from the blood. In contrast to the multiple ApoE receptors, only one receptor, the LDL receptor, can recognize and bind ApoB100. Thus loss or decrease of a functional LDL receptor has significant clinical consequences (see


Physiology_Levy

Physiology_Levy. At the Cellular box). LDL receptor is expressed on proliferating cells, including some cancer cells, which need to synthesize new cell membranes. LDL receptor is also expressed on steroidogenic cells, which use cholesterol to make steroid hormones. The major site of LDL uptake is the liver, which secretes cholesterol as well as cholesterol-based bile acids, as bile into the biliary tree. Some cholesterol is excreted by the intestines. Other cholesterol byproducts (e.g., steroid hormones) are excreted primarily at the kidney.


Physiology_Levy

Physiology_Levy. White adipose tissue (WAT) is composed of several cell types. The TG-storing cell is called the adipocyte. These cells develop from preadipocytes during gestation in humans. This process of adipocyte differentiation, which may continue throughout life, is promoted by several transcription factors. One of these factors is SREBP1C, which is activated by lipids as well as insulin and several growth factors and cytokines. Another important transcription factor in WAT is PPARγ. Activated PPARγ promotes expression of genes involved in TG storage. Thus an increase in food consumption leads to activation of SREBP1C and PPARγ, which increase the differentiation of preadipocytes into small adipocytes and upregulation of enzymes within these cells to allow storage of excess fat. Adipose tissue produces paracrine and endocrine factors, including adiponectin, TNF-α, resistin, interleukin-6, angiotensinogen, and acylation-stimulating protein.


Physiology_Levy

Physiology_Levy. Adipose tissue produces paracrine and endocrine factors, including adiponectin, TNF-α, resistin, interleukin-6, angiotensinogen, and acylation-stimulating protein. Leptin is an adipocyte-derived protein that signals information to the hypothalamus about the degree of adiposity and nutrition, which in turn controls eating behavior and energy expenditure. Leptin-deficient mice and humans become morbidly obese. These findings originally raised hope that leptin therapy could be used to combat morbid obesity. However, administration of leptin to individuals who suffer from diet-induced obesity does not have a significant anorectic or energy-consuming effect. In fact, obese individuals already have elevated endogenous circulating levels of leptin and appear to have developed leptin resistance.


Physiology_Levy

Physiology_Levy. Leptin has an important role in liporegulation in peripheral tissues. Leptin protects peripheral tissues (e.g., liver, skeletal muscle, cardiac muscle, beta cells) from accumulation of too much lipid by directing storage of excess caloric intake into adipose tissue. This action of leptin, though opposing the lipogenic actions of insulin, contributes significantly to maintenance of insulin sensitivity (as defined by insulin-dependent glucose uptake) in peripheral tissues. Leptin also acts as a signal that the body has sufficient energy stores to allow reproduction and to enhance erythropoiesis, lymphopoiesis, and myelopoiesis. For example, in women suffering from anorexia nervosa, leptin levels are extremely low and result in low ovarian steroids, amenorrhea (lack of menstrual bleeding), anemia from low red blood cell production, and immune dysfunction. Structure, Synthesis, and Secretion


Physiology_Levy

Physiology_Levy. Structure, Synthesis, and Secretion Leptin, a 16-kDa protein secreted by mature adipocytes, is structurally related to cytokines. Thus it is sometimes SREBP2 wasdiscoveredasatranscriptionfactorthatresidesinthemembraneoftheendoplasmicreticulum(ER).Inthepresenceofhighintracellularcholesterol,SREBP2isheldintheERbyalipid-sensingproteincalledSCAP (SREBPcleavage–activatingprotein).Inresponsetodepletedsterols,SCAPescortsSREBP2totheGolgi,whereSREBPiscleavedsequentiallybyproteasesandreleasedintothecytoplasm.SREBP2thentranslocatestothenucleusandincreasesthetranscriptionofgenesinvolvedinsynthesisanduptakeofcholesterol.AmorerecentlydiscoveredmemberofthistranscriptionfactorfamilyisSREBP1C, whichishighlyexpressedinadiposeandliver.IncontrasttoSREBP2,SREBP1CstimulatesgenesinvolvedinsynthesisofFAandTG.RegulationofSREBP1CoccursatthetranscriptionalleveloftheSREBP1C gene,withcleavageinducedbypolyunsaturatedfattyacidsandactivationbytheMAPKpathway.


Physiology_Levy


Physiology_Levy

Physiology_Levy. referred to as an adipocytokine. Circulating levels of leptin have a direct relationship with adiposity and nutritional status. Leptin output is increased by insulin, which prepares the body for correct partitioning of incoming nutrients. Leptin is inhibited by fasting and weight loss and by lipolytic signals (e.g., increased cAMP and β3-agonists). Diet-induced obesity, advanced age, and T2DM are associated with leptin resistance. Thus mechanisms that turn off leptin signaling are potential therapeutic targets. The amount of energy stored by an individual is determined by caloric intake and calories expended as energy per day. In many individuals, input and output are in balance, so weight remains relatively constant. However, the abundance of inexpensive high-fat, high-carbohydrate food, along with more sedentary lifestyles, is currently contributing to a pandemic of obesity and the pathological sequelae of obesity, including T2DM and cardiovascular disease.


Physiology_Levy

Physiology_Levy. The preponderance of stored energy consists of fat, and individuals vary greatly in the amount and percentage Thethiazolidinediones areexogenousligandsforPPARγ.Althoughtheypromoteweightgain,moderatelevelsofthiazolidinedionessignificantlyimproveinsulinsensitivity.PPARγ alsostimulatessecretionofadiponectin, whichpromotesoxidationoflipidsinmuscleandfatandtherebyimprovesinsulinsensitivity.PPARα isabundantlyexpressedinliverandtoalesserextentinskeletalandcardiacmuscleandkidney.PPARα promotesuptakeandoxidationofFFAs.ThusPPARα isanantisteatoticmolecule.Thefibrates areexogenousligandsofPPARα andareusedtoreduceTGdepositsinmuscleandliver,therebyimprovinginsulinsensitivity.Athirdmember,PPARδ, similarlypromotesfattyacidoxidationinadiposeandmuscletissue.PPARδ promotesdevelopmentofslow-twitchoxidativemusclefibersandincreasesmusclestamina.PPARδ hasapositiveeffectonlipoproteinmetabolismbyincreasingproductionofApoAapoproteinsandthenumberofHDLparticles.


Physiology_Levy

Physiology_Levy. of body weight that is accounted for by adipose tissue. About 25% of the variance in total body fat appears to be due to genetic factors. A genetic influence on fat mass is supported by (1) the tendency for the body mass of adopted children to correlate better with that of their biological parents than with that of their adoptive parents; (2) the greater similarity of adipose stores in identical (monozygotic) twins, whether reared together or apart, than in fraternal (dizygotic) twins; (3) the greater correlation between gains in body weight and abdominal fat in identical twins than in fraternal twins when they are fed a caloric excess; and (4) the discovery of several genes that cause obesity.


Physiology_Levy

Physiology_Levy. In addition, the gestational environment has a profound effect on body mass of the adult. The effect of maternal diet on the weight and body composition of offspring is called fetal programming. Low birth weights correlate with increased risk for obesity, cardiovascular disease, and diabetes. These findings suggest that the efficiency of fetal metabolism has plasticity and can be altered by the in utero environment. The development of a “thrifty” metabolism would be advantageous to an individual born to a mother


Physiology_Levy

Diabetes mellitus

Physiology_Levy. Diabetes mellitus


Physiology_Levy

Physiology_Levy. Diabetesmellitusiscurrentlyclassifiedastype 1 (T1DM) ortype 2 (T2DM). T2DMisbyfarthemorecommonformandaccountsfor90%ofdiagnosedcases.However,T2DMisusuallyaprogressivediseasethatremainsundiagnosedinasignificantpercentageofpatientsforseveralyears.T2DMisoftenassociatedwithvisceralobesityandlackofexercise—indeed,obesity-relatedT2DMisreachingepidemicproportionsworldwide.UsuallytherearemultiplecausesforthedevelopmentofT2DMinagivenindividualthatareassociatedwithdefectsintheabilityoftargetorganstorespondtoinsulin(i.e.,insulin resistance),alongwithsomedegreeofbeta cell deficiency. InsulinsensitivitycanbecompromisedattheleveloftheInsRoratthelevelofpostreceptorsignaling.T2DMappearstobetheconsequenceofinsulinresistance,followedbyreactivehyperinsulinemia,butultimatelybyrelative hypoinsulinemia (i.e.,inadequatereleaseofinsulintocompensatefortheend-organresistance)andbeta cell failure.


Physiology_Levy

Physiology_Levy. Theunderlyingcausesofinsulinresistancedifferamongpatients.Threemajorunderlyingcausesofobesity-inducedinsulinresistanceare: 1.Decreased ability of insulin to increase GLUT4-mediated uptake of glucose, especially by skeletal muscle. Thisfunction,whichisspecificallyapartofglucometabolic regulation by insulin, maybeduetoexcessiveaccumulationofTGinmuscleinobeseindividuals.Excessivecaloricintakeinduceshyperinsulinemia.Initiallythisleadstoexcessiveglucoseuptakeintoskeletalmuscle.Justasintheliver,excessivecaloriesintheformofglucosepromotelipogenesisand,throughgenerationofmalonylCoA,repressionoffattyacylCoAoxidation.ByproductsoffattyacidandTGsynthesis(e.g.,diacylglycerol,ceramide)mayaccumulateandstimulatesignalingpathways(e.g.,proteinkinaseC–dependentpathways)thatantagonizesignalingfromtheInsRorIRSproteins,orboth.Thusinsulinresistanceintheskeletalmuscleofobeseindividualsmaybeduetolipotoxicity. 2.


Physiology_Levy

Physiology_Levy. 2. Decreased ability of insulin to repress hepatic glucose production. Thelivermakesglucosebyglycogenolysisintheshorttermandbygluconeogenesisinthelongterm.Theabilityofinsulintorepresskeyhepaticenzymesinboththesepathwaysisattenuatedininsulin-resistantindividuals.Insulinresistanceinthelivermayalsobeduetolipotoxicityinobeseindividuals(e.g.,fatty liver orhepatic steatosis).Visceraladiposetissueislikelytoaffectinsulinsignalingattheliverinseveralways,inadditiontotheeffectsoflipotoxicity.Forexample,visceraladiposetissuereleasesthecytokinetumor necrosis factor (TNF)-α, whichhasbeenshowntoantagonizeinsulinsignalingpathways.Also,TGinvisceraladiposetissuehasahighrateofturnover(possiblybecauseofrichsympatheticinnervation),sotheliverisexposedtohighlevelsofFFAs,whichfurtherexacerbateshepaticlipotoxicity. 3.


Physiology_Levy

Physiology_Levy. 3. Inability of insulin to repress hormone-sensitive lipase or increase LPL in adipose tissue (or both). HighHSLandlowLPLaremajorfactorsinthedyslipidemiaassociatedwithinsulinresistanceanddiabetes.AlthoughthefactorsthatresisttheactionsofinsulinonHSLandLPLarenotcompletelyunderstood,thereisevidenceforincreasedproductionofparacrinediabetogenicfactorsinadiposetissue,suchasTNF-α.ThedyslipidemiaischaracterizedashypertriglyceridemiawithlargeTG-richVLDLparticlesproducedbytheliver.BecauseoftheirhighTGcontent,largeVLDLsandIDLsaredigestedveryefficiently,therebygivingrisetosmall,denseLDLparticlesthatareveryatherogenic.Inaddition,HDLtakesonexcessTGinexchangeforcholesterolesters,whichappearstoshortenthecirculatinghalf-lifeofHDLandApoAproteins.ThustherearelowerlevelsofHDLparticles,whichnormallyplayaprotectiveroleagainstvasculardisease.T1DM ischaracterizedbydestructionofbetacells,almost alwaysbyanautoimmunemechanism.T1DMisalsotermedinsulin-dependent diabetes mellitus. CharacteristicsofT1DMare: 1.


Physiology_Levy

Physiology_Levy. 5. Isletcellautoantibodiesarefrequentlypresentaroundthetimeofonset.IfT1DMisinducedbyavirus,theautoantibodiesaretransient.Occasionallyantibodieswillpersistlongterm,particularlyiftheyareassociatedwithotherautoimmunedisorders.About50%ofT1DMisrelatedtoproblemswiththemajorhistocompatibilitycomplexonchromosome6.Itiscorrelatedwithanincreasedfrequencyofcertainhumanleukocyteantigen(HLA)alleles.TheHLAtypesDR3andDR4aremostcommonlyassociatedwithdiabetes. who received poor nutrition and into a life that meant chronic undernourishment. A measure of adiposity is the body mass index (BMI). The BMI of an individual is calculated as: Equation 38.1 The BMI of healthy lean individuals ranges from 20 to 25. A BMI greater than 25 indicates that the individual is overweight, whereas a BMI higher than 30 indicates obesity. The condition of being overweight or obese is a risk factor for multiple pathologies, including insulin resistance, dyslipidemia, diabetes, cardiovascular disease, and hypertension.


Physiology_Levy

Physiology_Levy. WAT tissue is divided into subcutaneous and intraabdominal (visceral) depots. Intraabdominal WAT refers primarily to omental and mesenteric fat and is the smaller of the two depots. These depots receive different blood supplies that are drained in a fundamentally different way in that venous return from intraabdominal fat leads into the hepatic portal system. Thus intraabdominally derived FFAs are mostly cleared by the liver, whereas subcutaneous fat is the primary site for providing FFAs to muscle during exercise or fasting. Regulation of intraabdominal and subcutaneous adipose tissue also differs. Abdominal fat is highly innervated by autonomic neurons and has a greater turnover rate. Furthermore, these two depots display differences in hormone production and enzyme activity.


Physiology_Levy

Physiology_Levy. Men tend to gain fat in the intraabdominal depot (android [apple-shaped] adiposity), whereas women tend to gain fat in the subcutaneous depot, particularly in the thighs and buttocks (gynecoid [pear-shaped] adiposity). Clearly an excess of abdominal fat poses a greater risk factor for the pathologies mentioned earlier. Thus another indicator of body composition is circumference of the waist (measured in inches around the narrowest point between the ribs and hips when viewed from the front after exhaling) divided by the circumference of the hips (measured at the point where the buttocks are largest when viewed from the side). This waist-hip ratio may be a better indicator of body fat than BMI, especially as it relates to risk for development of diseases. A waist-hip ratio of greater than 0.95 in men or 0.85 in women is linked to a significantly higher risk for development of diabetes and cardiovascular disease.


Physiology_Levy

Physiology_Levy. In recent years, numerous hormones and neuropeptides have been implicated in both chronic and acute regulation of appetite, satiety, and energy expenditure in humans. One CHAPTER 39 Hormonal Regulation of Energy Metabolism simplified model involves two peptide hormones, leptin Fig. 39.17 ), already discussed. Leptin acts on at least two neuron types in the arcuate nucleus of the hypothalamus. In the first, leptin represses production of neuropeptide Y (NPY), a very potent stimulator of food- seeking behavior (energy intake) and an inhibitor of energy expenditure. Norepinephrine, another appetite stimulator, co-localizes with NPY in some of these neurons. At the same time, leptin represses production of agouti-related peptide (AGRP), an endogenous antagonist that acts on


Physiology_Levy

Physiology_Levy. MC4R, a hypothalamic receptor for the anorexigenic peptide α-melanocyte–stimulating hormone (α-MSH), which inhibits food intake. In another type of arcuate neuron, leptin stimulates production of proopiomelano cortin (POMC) products, one of which is α-MSH, and production of cocaine-amphetamine–regulated transcript (CART), both of which inhibit food intake. Thus leptin diture by simultaneously inhibiting NPY and the α-MSH Fig. 39.17 ). These second-order neuropeptides are transmitted to and interact with receptors in neurons of the and lateral hypothalamic nucleus (“hunger” neurons). In activity (especially sympathetic outflow) with diverse endo crine actions on thyroid gland function, reproduction, and growth.


Physiology_Levy

Physiology_Levy. Another regulator of food intake and body energy stores is melanin-concentrating hormone (MCH). This antagonizing the satiety effect of α-MSH downstream from the interaction of α-MSH with its MC4R receptor. The probable importance of this molecule is demonstrated by the fact that it is the only regulator whose ablation by gene knockout actually results in leanness. To maintain overall energy homeostasis, the system must example, carbohydrate intake with carbohydrate oxidation.


Physiology_Levy

Physiology_Levy. To maintain overall energy homeostasis, the system must example, carbohydrate intake with carbohydrate oxidation. neurotransmitter responses to meals. Serotonin produces satiety after ingestion of glucose. Gastrointestinal hormones such as cholecystokinin and GLP-1 produce satiety by humoral effects, but their local production in the brain may participate in nutrient and caloric regulation. The recently discovered hormone ghrelin is an acylated peptide with potent orexigenic activity that arises in cells of the oxyntic glands in the stomach. Plasma levels of ghrelin rise in humans in the 1 to 2 hours that precede their normal meals. Plasma levels of ghrelin fall drastically to minimum values about 1 hour after eating. Ghrelin appears to stimulate food intake by reacting with its receptor in hypothalamic neurons that express NPY. 1. Cells make ATP to meet their energy needs. ATP is made by glycolysis and by the TCA cycle coupled to oxidative phosphorylation. 2.


Physiology_Levy

Physiology_Levy. 1. Cells make ATP to meet their energy needs. ATP is made by glycolysis and by the TCA cycle coupled to oxidative phosphorylation. 2. Cells can oxidize carbohydrate (primarily in the form of glucose), AAs, and FFAs to make ATP. Additionally the liver makes KBs for other tissues to oxidize for energy in times of fasting. 3. Some cell types are limited in the energy substrates they can oxidize for energy. The brain is normally exclusively dependent on glucose for energy. Thus blood glucose must be maintained above 60 mg/ dL for normal autonomic and CNS function. Conversely, inappropriately high levels of glucose (i.e., fasting glucose > 100 mg/dL) promote glucotoxicity and thereby lead to the long-term complications of diabetes. 4. The endocrine pancreas produces the hormones insulin, glucagon, somatostatin, gastrin, and pancreatic polypeptide. 5.


Physiology_Levy

Physiology_Levy. 4. The endocrine pancreas produces the hormones insulin, glucagon, somatostatin, gastrin, and pancreatic polypeptide. 5. Insulin is an anabolic hormone that is secreted in times of excess nutrient availability. It allows the body to use carbohydrates as energy sources and store nutrients. 6. Major stimuli for insulin secretion include increased serum glucose and some AAs. Activation of cholinergic (muscarinic) receptors also increases insulin secretion, whereas activation of α2-adrenergic receptors inhibits insulin secretion. The gastrointestinal tract releases incretin hormones that stimulate pancreatic insulin secretion. GLP-1 is particularly potent in augmenting glucose-dependent stimulation of insulin secretion (GSIS). GLP-1 is degraded by dipeptidyl peptidase (DPP)-4. DPP-4– resistant GLP-1 analogues and inhibitors of DPP-4 are currently used to increase GSIS in patients with type 2 diabetes. 7.


Physiology_Levy

Physiology_Levy. 7. Insulin binds to the insulin receptor (InsR), which is linked to multiple pathways that mediate the metabolic (Akt kinase) and growth effects (MAPK) of insulin. 8. During the digestive phase, insulin acts on the liver to promote trapping of glucose as G6P. Insulin also increases glycogenesis, glycolysis, and de novo lipogenesis (DNL) in the liver. Insulin inhibits gluconeogenesis, glycogenolysis, and assembly of lipids into VLDL. 9. Insulin increases GLUT4-mediated glucose uptake in muscle and adipose tissue. 10. Insulin increases glycogenesis, glycolysis, and in the presence of caloric excess, lipogenesis in muscle. 11. Insulin increases glycolysis and generation of G3P in adipocytes. Insulin induces expression of LPL and its transport to the luminal side of capillary endothelial cells. Insulin promotes uptake and activation of FFAs and esterification of fatty acyl CoAs to G3P to form TG, and it decreases hormone-sensitive lipase activity in adipocytes. 12.


Physiology_Levy

Physiology_Levy. TG, and it decreases hormone-sensitive lipase activity in adipocytes. 12. Insulin increases AA uptake and protein synthesis in skeletal muscle but also essentially all insulin target cells. Insulin/Akt kinase signaling activates mTORC1 and S6K to promote synthesis of ribosomal proteins and proteins involved in mRNA translation, as well as other types of proteins. Insulin inhibits proteosomal degradation of protein. 13. Glucagon is a catabolic counterregulatory hormone. Its secretion increases during periods of food deprivation, and it acts to mobilize nutrient reserves. It also mobilizes glycogen, fat, and even protein. 14. Glucagon is released in response to decreased serum glucose (and therefore decreased insulin) and increased serum AA levels and β-adrenergic signaling. 15.


Physiology_Levy

Physiology_Levy. 14. Glucagon is released in response to decreased serum glucose (and therefore decreased insulin) and increased serum AA levels and β-adrenergic signaling. 15. Glucagon binds to the glucagon receptor, which is linked to PKA-dependent pathways. The primary target organ for glucagon is the liver. Glucagon increases liver glucose output by increasing glycogenolysis and gluconeogenesis. It increases β-oxidation of fatty acids and ketogenesis. 16. Glucagon regulates hepatic metabolism both by regulation of gene expression and through posttranslational PKA-dependent pathways. 17. The major counterregulatory factors in muscle and adipose tissue are the adrenal hormone epinephrine and the sympathetic neurotransmitter norepinephrine. These two factors act through β2-and β3-adrenergic receptors to increase cAMP levels. Epinephrine and norepinephrine enhance glycogenolysis and fatty acyl oxidation in muscle and increase hormone-sensitive lipase in adipose tissue. 18.


Physiology_Levy

Physiology_Levy. 18. Diabetes mellitus is classified as type 1 (T1DM) and type 2 (T2DM). T1DM is characterized by destruction of pancreatic beta cells, and exogenous insulin is required for treatment. T2DM can be due to numerous factors but is usually characterized as insulin resistance coupled to some degree of beta cell deficiency. Patients with T2DM may require exogenous insulin at some point to maintain blood glucose levels. 19. Obesity-associated T2DM is currently at epidemic proportions worldwide and is characterized by insulin resistance due to lipotoxicity, hyperinsulinemia, and inflammatory cytokines produced by adipose tissue. T2DM is often associated with obesity, insulin resistance, hypertension, and coronary artery disease. This constellation of risk factors is referred to as the metabolic syndrome. 20. Major symptoms of diabetes mellitus include hyperglycemia, polyuria, polydipsia, polyphagia, muscle wasting, electrolyte depletion, and ketoacidosis (in T1DM).


Physiology_Levy

Physiology_Levy. 20. Major symptoms of diabetes mellitus include hyperglycemia, polyuria, polydipsia, polyphagia, muscle wasting, electrolyte depletion, and ketoacidosis (in T1DM). 21. The long-term complications of poorly controlled diabetes are due to excess intracellular glucose (glucotoxicity), especially in the retina, kidney, and peripheral nerves. This leads to retinopathy, nephropathy, and neuropathy. Bailey CJ, et al. Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol. 2016;4:350-359. Davidson JA, et al. Glucagon therapeutics: dawn of a new era for diabetes care. Diabetes Metab Res Rev. 2016;doi:10.1002/dmrr.2773; [Epub ahead of print]. Font-Burgada J, et al. Obesity and cancer: the oil that feeds the flame. Cell Metab. 2016;23:48-62. 22. Adipose tissue has an endocrine function, especially in terms of energy homeostasis. Hormones produced by adipose tissue include leptin and adiponectin. Leptin acts on the hypothalamus to promote satiety.


Physiology_Levy

Physiology_Levy. Klein MS, Shearer J. Metabolomics and type 2 diabetes: translating basic research into clinical application. J Diabetes Res. 2016;2016:3898502. doi:10.1155/2016/3898502; [Epub 2015 Nov 9]. Marion-Letellier R, et al. Fatty acids, eicosanoids and PPAR gamma. Eur J Pharmacol. 2016;785:44-49. Pawlak M, et al. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in nonalcoholic fatty liver disease. J Hepatol. 2015;62:720-733. Upon completion of this chapter the student should be able to answer the following questions: 1. Describe the pool of serum calcium and phosphate, including ionized, complexed, and protein bound. Describe the normal concentration ranges of these ions and the major routes of influx and efflux. 2. Discuss the role of the parathyroid gland in the regulation of serum calcium and explain the role of the calcium-sensing receptor in the regulation of parathyroid hormone (PTH) secretion. 3.


Physiology_Levy

Physiology_Levy. 2. Discuss the role of the parathyroid gland in the regulation of serum calcium and explain the role of the calcium-sensing receptor in the regulation of parathyroid hormone (PTH) secretion. 3. Describe the production of 1,25-dihydroxyvitamin D, including sources of vitamin D precursor, sites and key regulators of vitamin D hydroxylation, and transport of vitamin D metabolites in the blood. 4. List the target organs of PTH and describe its effects on calcium and phosphate mobilization or handling at each of these sites. 5. List the target organs and key actions of 1,25-dihydroxyvitamin D. 6. Discuss the regulation of phosphate metabolism by FGF23. 7. Predict the hormone responses that would be triggered by perturbations of serum calcium and phosphate or by vitamin D deficiency, and discuss the consequences of these compensatory hormone actions.


Physiology_Levy

Physiology_Levy. Predict the hormone responses that would be triggered by perturbations of serum calcium and phosphate or by vitamin D deficiency, and discuss the consequences of these compensatory hormone actions. alcium (Ca) and phosphate are essential to human life because they play important structural roles in hard tissues (i.e., bones and teeth) and important regulatory roles in metabolic and signaling pathways. In biological systems, inorganic phosphate (Pi) consists of a mixture of dihydrogen phosphate (H2PO4 −) and hydrogen phosphate (HPO4 −). The two primary sources of circulating Ca and Pi are the diet and the skeleton ( Fig. 40.1 ). Two hormones, 1,25-dihydroxyvitamin D (also called calcitriol) and parathyroid hormone (PTH), regulate intestinal absorption of Ca and Pi and release of Ca and Pi into the circulation after bone resorption. The primary processes for removal of Ca and Pi from blood are renal excretion and bone mineralization (see


Physiology_Levy

Physiology_Levy. Fig. 40.1 ). 1,25-Dihydroxyvitamin D and PTH regulate both processes. Other hormones and paracrine growth factors also regulate Ca and Pi homeostasis. Crucial Roles of Calcium and Phosphate in Cellular Physiology Ca is an essential dietary element. In addition to obtaining Ca from the diet, humans contain a vast store (i.e., >1 kg) of Ca in bone mineral, which can be called upon to maintain normal circulating levels of Ca in times of dietary restriction and during the increased demands of pregnancy and nursing. Circulating Ca exists in three forms (


Physiology_Levy

Physiology_Levy. Table 40.1): free ionized Ca++ , protein-bound Ca, and Ca complexed with anions (e.g., phosphates, HCO3 − , citrate). The ionized form represents about 50% of circulating Ca. Since it is critical to so many cellular functions, [Ca++] in both the extracellular and intracellular compartments is tightly controlled. Circulating Ca++ is under direct hormonal control and normally maintained within a relatively narrow range. Either too little calcium (hypocalcemia; total serum calcium < 8.7 mg/dL [2.2 mM]) or too much Ca (hypercalcemia; total serum Ca > 10.4 mg/dL [2.6 mM]) in blood can lead to a broad range of pathophysiological changes, including neuromuscular dysfunction, central nervous system dysfunction, renal insufficiency, calcification of soft tissue, and skeletal pathology.


Physiology_Levy

Physiology_Levy. Pi is also an essential dietary element, and it is stored in large quantities in mineral. Most circulating Pi is in the free ionized form, but some Pi (<20%) circulates as a protein-bound form or complexed with cations (see Table 40.1 ). Because soft tissues contain 10-fold more Pi than Ca, tissue damage (e.g., crush injury with massive muscle cell death) can result in hyperphosphatemia, whereupon the increased Pi complexes with Ca++ to cause acute hypocalcemia. Pi is a key intracellular component. Indeed, it forms the high-energy phosphate bonds of adenosine triphosphate (ATP) that maintain life. Phosphorylation and dephosphorylation of proteins, lipids, second messengers, and cofactors represent key regulatory steps in numerous metabolic and signaling pathways, and phosphate also serves as the backbone for nucleic acids. •Fig. 40.1 DailyCa++ andPiflux. Ca8.5–10.250%45%5%Pi3–4.584%10%6%


Physiology_Levy

Physiology_Levy. •Fig. 40.1 DailyCa++ andPiflux. Ca8.5–10.250%45%5%Pi3–4.584%10%6% Ca++ isbound(i.e.,complexed)tovariousanionsinplasma,includingHCO3− ,citrate,andSO42− .Piiscomplexedtovariouscations,includingNa+ andK+ .FromKoeppenBM,StantonBA.Renal Physiology. 4thed.Philadelphia:Mosby;2007. Physiological Regulation of Calcium and Phosphate: Parathyroid Hormone and 1,25-Dihydroxyvitamin D C PTH and 1,25-dihydroxyvitamin D are the two physiologically most important hormones dedicated to mainte- nance of normal blood Ca and Pi in humans. As such they are referred to as calciotropic hormones. The structure, synthesis, and secretion of these two hormones and their receptors will be discussed first. In the following section, the detailed actions of PTH and 1,25-dihydroxyvitamin D on the three key sites of Ca/Pi homeostasis (i.e., gut, bone, and kidney) are discussed. The predominant parenchymal cell type in the parathyroid B gland is the principal (also called chief) cell ( Fig. 40.2


Physiology_Levy

Physiology_Levy. The predominant parenchymal cell type in the parathyroid B gland is the principal (also called chief) cell ( Fig. 40.2 PTH is the primary hormone that protects against hypocalcemia. The primary targets of PTH are bone and the kidneys. PTH also functions in a positive feed-forward loop by stimulating production of 1,25-dihydroxyvitamin D. •Fig. 40.2 AandB,Histologyofparathyroidglands.A,adiposetissuewithinparathyroidglands;C,capillaries;O,oxyphilcells;P,principalorchiefcells.(FromYoungBetal.Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.) Structure, Synthesis, and Secretion PTH is secreted as an 84–amino acid polypeptide and is synthesized as a prepro-PTH, which is proteolytically processed to pro-PTH in the endoplasmic reticulum and then to PTH in the Golgi and secretory vesicles. PTH has a short half-life in the circulation (2 minutes), consistent with its role in minute-to-minute regulation of plasma calcium.


Physiology_Levy

Physiology_Levy. Because the PTH receptor also binds PTH-related peptide (PTHrP), it is usually referred to as the PTH/PTHrP receptor. The PTH/PTHrP receptor is expressed on osteoblasts in bone and in the proximal and distal tubules of the kidney, and it is the receptor that mediates the systemic actions of PTH. However, the PTH/PTHrP receptor is also expressed in many developing organs in which PTHrP has important paracrine functions. One such example is regulation of chondrocyte proliferation in the growth plate during endochondral bone growth. Vitamin D is a prohormone that must undergo two successive hydroxylation reactions to become the active form known as 1,25-dihydroxyvitamin D or calcitriol ( Fig. 40.5 ). This hormone plays a critical role in Ca absorption Extracellular[Ca++]issensedbytheparathyroidchiefcellthroughaplasmamembranecalcium-sensing receptor (CaSR). TheprimarysignalthatstimulatesPTHsecretionisadecreaseincirculating[Ca++](


Physiology_Levy


Physiology_Levy

Physiology_Levy. Fig.40.3 ).Itshouldbenoted,however,thatduringahypocalcemicchallenge,thedecreasein[Ca++]overridestheinhibitoryeffectof1,25-dihydroxyvitaminDonPTHtranscription,allowingbothofthesehormonestobeelevatedsimultaneously. •Fig. 40.3 RegulationofPTH geneexpressionandsecretion.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)Gq + Gi PTH PTH CaSR Downstream signaling pathway 1,25 Vitamin D CaSR Ca++ proPTH preproPTH preCaSR CaSR mRNA (+) (–) (–) (–) PTH mRNA Parathyroid cell membrane Nucleus CaSR gene PTH gene •Fig. 40.4 Sigmoidalrelationshipbetweenserum[Ca++]andserumPTH,whichreflectstherateofPTHsecretion.(ModifiedfromPor-terfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)100 50 5 1.00 1.301.201.10 1.40 Serum PTH (% of maximum) Free Ca++ in blood (mM)


Physiology_Levy

Physiology_Levy. Hormonal Regulation of Calcium and Phosphate Metabolism 1,25-(OH)2D3 24,25-(OH)2D3 •Fig. 40.5 Biosynthesisof1,25-dihydroxyvitaminD.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) and to a lesser extent Pi absorption by the small intestine. It also regulates bone remodeling and renal reabsorption of Ca and Pi. Structure, Synthesis, and Transport of Active Vitamin D Metabolites


Physiology_Levy

Physiology_Levy. Structure, Synthesis, and Transport of Active Vitamin D Metabolites Vitamin D3 (also called cholecalciferol) is synthesized via conversion of 7-dehydrocholesterol by ultraviolet B •Fig. 40.6 VitaminDmetabolism.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)7-Dehydrocholesterol Vit D-DBP and Vit D-chylomicron 25(OH) Vit D-DBP Vit D-chylomicron Lymphatic Vit D-DBP 1,25-Dihydroxyvitamin D Portal blood Caval blood Peripheral blood Vitamin D3 Enterocyte Dietary vitamin D3 and vitamin D2 Vit D UV-B Hepatocyte Vit D 25-Hydroxyvitamin D 25-Hydroxylase 24-Hydroxylase 24-Hydroxylase25-Hydroxyvitamin D 24,25-Dihydroxyvitamin D 1, 25-Dihydroxyvitamin D 1,24,25-Trihydroxyvitamin D Biological effects at gut, bone, kidney, etc. 1˜-Hydroxylase (UVB) light in the more basal layers of the skin (Fig. 40.6 ). Chemically, vitamin D3 is a secosteroid in which one of the cholesterol rings is opened (see


Physiology_Levy

Physiology_Levy. Fig. 40.5 ). Vitamin D2 (ergocalciferol) is produced in plants. Vitamin D3 and to a lesser extent vitamin D2 are absorbed from the diet and are equally effective after conversion to active hydroxylated forms. The balance between UVB-dependent endogenously synthesized vitamin D3 and absorption of the dietary forms of vitamin D becomes important in certain situations. Individuals with higher melanin content in skin who live at higher latitudes convert less 7-dehydrocholesterol to vitamin D3 and thus are more dependent on vitamin supplements or dietary sources of vitamin D (natural or fortified, e.g., milk). Institutionalized elderly patients who stay indoors and avoid dairy products are particularly at risk for development of vitamin D deficiency. Vitamin D is transported in blood from the skin to the liver. Dietary vitamin D reaches the liver directly via transport in the portal circulation and indirectly via chylomicrons (see


Physiology_Levy

Physiology_Levy. Vitamin D is transported in blood from the skin to the liver. Dietary vitamin D reaches the liver directly via transport in the portal circulation and indirectly via chylomicrons (see Fig. 40.6 ). In the liver, vitamin D is hydroxylated at the 25-carbon position to yield 25-hydroxyvitamin D. The hepatic 25-hydroxylase is constitutively expressed and unregulated, so circulating levels of 25-hydroxyvitamin D reflect the amount of precursor available for 25-hydroxylation. For this reason, and because of its relatively long half-life in the circulation (2–3 weeks), measurement of 25-hydroxyvitamin D levels is used to assess vitamin D status. 25-Hydroxyvitamin D undergoes further hydroxylation in the proximal tubule of the kidney (see Figs. 40.5 40.6).


Physiology_Levy

Physiology_Levy. 25-Hydroxyvitamin D undergoes further hydroxylation in the proximal tubule of the kidney (see Figs. 40.5 40.6). Hydroxylation at the 1α position generates 1,25-dihydroxyvitamin D, the most active form of vitamin D. Hydroxylation at the 24 position generates 24,25-dihydroxyvitamin D, which does not play a major biological role and serves as an inactivation pathway. Renal 1α-hydroxylase is tightly regulated by a number of factors ( Fig. 40.7). PTH and hypophosphatemia are the primary inducers of 1α-hydroxylase activity, resulting in 25(OH)D3 1˜-hydroxylase 1,25(OH)2D3 25(OH)D3 CYP27B1 FGFRKIotho •Fig. 40.7 Regulationof1α-hydroxylasegene(CYP27B1) expressionintheproximaltubule,showingstimulationbyPTHandinhibitionbyFGF23and1,25-dihydroxyvitaminD.Hypophosphatemiaprobablystimulates1α-hydroxylasebyreducingFGF23levelsatleastinpart.


Physiology_Levy

Physiology_Levy. increased levels of 1,25-dihydroxyvitamin D. Conversely, [Ca++] and 1,25-dihydroxyvitamin D, the enzyme product, inhibit it. Fibroblast growth factor (FGF)23, a major regulator of Pi metabolism (see later), also represses 1α-hydroxylase activity; a reduction of FGF23 levels likely mediates the effect of hypophosphatemia on 1,25-dihydroxyvitamin D production at least in part. Vitamin D and its metabolites circulate in blood primarily bound to vitamin D–binding protein (DBP). DBP is a serum glycoprotein that is synthesized by the liver. DBP binds more than 85% of 1,25-hydroxyvitamin D and 24,25-dihydroxyvitamin D. Because of binding to other proteins, only 0.4% of 1,25-dihydroxyvitamin D circulates as free hormone. DBP transports the highly lipophilic vitamin D in blood and provides a reservoir of vitamin D that protects against vitamin D deficiency.


Physiology_Levy

Physiology_Levy. 1,25-Dihydroxyvitamin D Receptor 1,25-Dihydroxyvitamin D exerts its actions primarily through binding to the nuclear vitamin D receptor (VDR), which is a member of the nuclear hormone receptor family. The VDR is a ligand-dependent transcription factor that binds to cognate DNA sequences (vitamin D response elements) as a heterodimer with the retinoid X receptor (RXR). Thus the primary action of 1,25-dihydroxyvitamin D is to regulate gene expression in its target tissues, including the small intestine, bone, kidneys, and parathyroid gland.


Physiology_Levy

Physiology_Levy. The genomic actions of 1,25-dihydroxyvitamin D mediated by the VDR occur over a period of hours to days. 1,25-Dihydroxyvitamin D also has rapid effects (seconds to minutes). For example, 1,25-dihydroxyvitamin D rapidly induces absorption of Ca++ by the duodenum. The VDR is also expressed in the plasma membrane of cells and is linked to rapid signaling pathways (e.g., G proteins, phosphatidylinositol-3′-kinase). Current molecular modeling has led to development of ligands that specifically bind Hormonal Regulation of Calcium and Phosphate Metabolism to the nuclearversus the membrane-localized VDR, paving the way for selective treatment of disorders related to the rapid versus slow actions of 1,25-dihydroxyvitamin D with synthetic vitamin D analogues. Regulation of [Ca++] and [Pi] by Small Intestine and Bone An overview of the regulation of [Ca++] and Pi] by the action of PTH and 1,25-dihydroxyvitamin D on the small intestine, bone, and parathyroid glands is summarized in


Physiology_Levy

Physiology_Levy. An overview of the regulation of [Ca++] and Pi] by the action of PTH and 1,25-dihydroxyvitamin D on the small intestine, bone, and parathyroid glands is summarized in Table 40.2 and in the following paragraphs. For details on renal handling of Ca++ , consult Chapter 36.


Physiology_Levy

Physiology_Levy. Table 40.2 and in the following paragraphs. For details on renal handling of Ca++ , consult Chapter 36. Calcitonin isapeptidehormoneproducedbythemedullarycells,orC-cells,ofthethyroidgland.Calcitoninsecretionispositivelyregulatedbyserum[Ca++]viatheCaSR.Thecalcitoninreceptorisexpressedinosteoclasts,wherecalcitoninactsrapidlyanddirectlytoinhibitboneresorption.However,inhumans,calcitonindoesnotappeartoplayamajorroleinregulatingserumCa.Insupportofthisview,productionofexcesscalcitoninorcompleteabsenceofcalcitonin(e.g.,followingthyroidectomy)doesnotperturbserumCalevels.Morepotentformsofthehormone(e.g.,salmoncalcitonin)havebeenusedtherapeuticallyasanantiresorptiveinthetreatmentofPaget’s disease (characterizedbyexcessiveosteoclasticboneresorption)andinosteoporosis.Calcitoninisalsoausefulhistochemicalmarkerofmedullarythyroidcancer.


Physiology_Levy

Physiology_Levy. Dietary intake of Ca can vary widely among individuals and from day to day. Assuming an intake of 1000 mg (the RDA for ages 19–50), 350 mg would typically be absorbed, counterbalanced by 150 mg secreted by the intestine, for a net intake of 200 mg. Most Ca++ absorption takes place in the proximal small intestine. Importantly, absorption of Ca++ is stimulated by 1,25-dihydroxyvitamin D, so absorption is more efficient in the face of declining dietary Ca++ . Ca++ is absorbed from the duodenum and jejunum by both a Ca++-regulated and a hormonally regulated transcellular route and by a passive paracellular route. The transcellular route of Ca++ absorption is summarized in Fig.


Physiology_Levy

Physiology_Levy. Fig. 40.8 . Movement of Ca++ from the gastrointestinal lumen into the enterocyte, which is driven by both chemical and electrical gradients, occurs via apical calcium channels called TRPV5 and TRPV6. Once inside the cell, Ca++ ions bind to calbindin-D9K, which maintains a low cytoplasmic [Ca++], preserving the favorable transluminal membrane Ca++ gradient. Calbindin-D9K also plays a role in apical-to-basolateral shuttling of Ca++, which is transported across the basolateral membrane against an electrochemical gradient by plasma membrane calcium ATPase (PMCA). The Na+/Ca++ exchanger (NCX) also contributes to the CASR,calcium-sensingreceptor;M-CSF,monocytecolony-stimulatingfactor;NPT2,Na+/Picotransporter;OPG,osteoprotegerin;PTH,parathyroidhormone; RANKL,receptoractivatorofnuclearfactorκ-B.


Physiology_Levy

Physiology_Levy. CASR,calcium-sensingreceptor;M-CSF,monocytecolony-stimulatingfactor;NPT2,Na+/Picotransporter;OPG,osteoprotegerin;PTH,parathyroidhormone; RANKL,receptoractivatorofnuclearfactorκ-B. •Fig. 40.8 IntestinalabsorptionofCa++viathetranscellularroute.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)LuminalsideTRPV5/6SerosalsideCa++Ca++Ca++Ca++-cal indin9KCal indin9KPMCA transport of Ca++ out of enterocyte. 1,25-Dihydroxyvitamin D stimulates expression of all the components involved in absorption of Ca++ by the small intestine. The fraction of dietary Pi absorbed by the jejunum remains relatively constant at about 70% and is under minor hormonal control by 1,25-dihydroxyvitamin D. The limiting process in transcellular Pi absorption is transport across the apical brush border, which is mediated by the Na+/Pi cotransporter (NPT2).


Physiology_Levy

Physiology_Levy. Bone stores vast amounts of Ca and Pi. Once peak bone mass has been achieved in an adult, the skeleton is constantly remodeled through the concerted activities of bone cells. The processes of bone formation and bone resorption are in balance in a healthy, physically active, and well-nourished individual. Of the 1 kg of Ca immobilized in bone, about 500 mg (i.e., 0.5%) is mobilized from and deposited into bone each day. However, the process of bone remodeling can be modulated to provide a net gain or loss of Ca++ and Pi into blood and is responsive to physical activity (loading), diet, age, and hormonal regulation. Because the integrity of bone is absolutely dependent on Ca and Pi, chronic dysregulation of these ions or the hormones that regulate them lead to pathological changes in bone. Physiology of Bone


Physiology_Levy

Physiology_Levy. Physiology of Bone The processes of pattern formation, growth, and remodeling of the skeleton is complex and beyond the scope of this chapter. The key elements required for understanding the role of adult bone in the hormonal regulation of Ca and Pi metabolism are discussed. In adults, bone remodeling involves (1) destruction of fatigued or microdamaged bone with the release of Ca++, Pi, and hydrolyzed fragments of bone matrix into blood and (2) synthesis of osteoid (yet to be mineralized bone matrix) at the site of resorption, followed by controlled mineralization of the osteoid by Ca++ and Pi to form new bone. Bone remodeling occurs continually at about 2 million discrete sites throughout the skeleton by packets of bone cells referred to as the basic multicellular units (BMU).


Physiology_Levy

Physiology_Levy. The cells involved in bone remodeling fall into two major classes: cells that form bone (osteoblasts) and cells that destroy or resorb bone (osteoclasts). The process of bone remodeling is a highly integrated process (


Physiology_Levy

Physiology_Levy. Fig. 40.9 ). Osteoblast-lineage cells express factors that induce differentiation of osteoclasts from progenitors of the monocyte/ macrophage lineage and also promote mature osteoclast function. Osteoblasts release monocyte colony-stimulating factor (M-CSF), which expands and differentiates early hematopoietic progenitors (CFU-GM) into preosteoclasts that express a cell surface receptor called RANK (receptor •Fig. 40.9 Osteoblastregulationofosteoclastdifferentiationandfunction.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) activator of nuclear factor [NF]-κB). Osteoblast-lineage cells display RANK ligand (RANKL) on their cell surface. RANKL then binds to RANK on preosteoclasts and induces osteoclastogenesis. This process involves fusion of several osteoclast precursors, giving rise to a large multinucleated osteoclast. The perimeter of the osteoclast membrane facing mineralized bone adheres tightly to the bone and seals off the area of


Physiology_Levy

Physiology_Levy. several osteoclast precursors, giving rise to a large multinucleated osteoclast. The perimeter of the osteoclast membrane facing mineralized bone adheres tightly to the bone and seals off the area of osteoclast-bone contact (see


Physiology_Levy

Physiology_Levy. Fig. 40.9 ). The region within the sealed zone forms a highly invaginated membrane called the ruffled border, from which HCl and hydrolytic lysosomal enzymes are secreted. The acidic enzyme-rich microenvironment beneath the osteoclast dissolves the bone mineral, thereby releasing Ca++ and Pi into blood, and also degrades the bone matrix. There is an additional inhibitory component of the RANK/RANKL system. Osteoblast-lineage cells can also produce a soluble factor called osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and inhibits osteoclast differentiation and function (see Fig. 40.9 ). Therefore the balance between RANKL and OPG expression by osteoblasts determines how much osteoclast differentiation and bone resorption will occur.


Physiology_Levy

Physiology_Levy. Following bone resorption in the BMU, there is a brief reversal phase, then adjacent osteoblasts migrate into the resorbed area and begin to lay down osteoid. Several components within osteoid (pyrophosphate, alkaline phosphatase, specific glycoproteins) promote slow, controlled mineralization, a process that removes Ca++ and Pi from blood. As the osteoblasts become surrounded by and entrapped within bone, they become osteocytes that sit within small spaces called lacunae. Osteocytes remain interconnected through cell processes that run within canaliculi and form communicating junctions with adjacent cell processes. The new concentric layers of bone, along with the interconnected osteocytes and the central canal, are referred to collectively as a Haversian system or osteon. Emerging evidence indicates that osteocytes are able to sense mechanical stress in bone and signal that additional local bone formation is needed. They can also detect microdamage in bone that serves to initiate


Physiology_Levy

Physiology_Levy. indicates that osteocytes are able to sense mechanical stress in bone and signal that additional local bone formation is needed. They can also detect microdamage in bone that serves to initiate remodeling at that location.


Physiology_Levy


Physiology_Levy

Physiology_Levy. °PTH °1,25(OH)2D3 ˜1,25(OH)2D3 Regulation of Serum Phosphate by FGF23


Physiology_Levy

Physiology_Levy. Study of hypophosphatemic disorders has led to the discovery that FGF23, a peptide hormone produced by osteocytes, is a regulator of Pi metabolism. FGF23 binds to a receptor complex in proximal tubule cells and, like PTH, inhibits NPT2 to promote Pi excretion. Several diseases are associated with excess production of FGF23, including rickets in children and osteomalacia secondary to hypophosphatemia in adults. In autosomal dominant hypophosphatemic rickets (ADHR), a mutation in FGF23 prevents its cleavage and inactivation. X-linked hypophosphatemic rickets (XLHR) is caused by a mutation of the PHEX gene (protein with homology to endopeptidases on the X chromosome), which also causes overproduction of FGF23. Finally, FGF23 is sometimes ectopically produced by slow-growing occult mesenchymal tumors, causing a hypophosphatemic paraneoplastic syndrome. In addition to inhibition of Pi reabsorption, FGF23 also inhibits expression of 1α-hydroxylase in the proximal tubule, thereby inhibiting


Physiology_Levy

Physiology_Levy. tumors, causing a hypophosphatemic paraneoplastic syndrome. In addition to inhibition of Pi reabsorption, FGF23 also inhibits expression of 1α-hydroxylase in the proximal tubule, thereby inhibiting production of 1,25-dihydroxyvitamin D and exacerbating hypophosphatemia. The physiological role of this pathway is not completely understood, and many questions remain, °GI °1,25(OH)2D3 absorption •Fig. 40.10 IntegratedhormoneresponsestoperturbationsofCa++ (A),Pi(B),andvitaminD(C).


Physiology_Levy

Physiology_Levy. including how and where Pi levels are sensed. Pi is not as tightly regulated as calcium, either temporally or with respect to concentration range, but recent evidence suggest that long-term elevation of Pi is associated with increased production of FGF23. In what appears to be an emerging negative feedback loop, 1,25-dihydroxyvitamin D decreases production of FGF23 by osteocytes.


Physiology_Levy

Physiology_Levy. Gonadal and adrenal steroid hormones have profound effects on bone. 17β-Estradiol (E2; see has important anabolic effects on bone and is a potent regulator of osteoblast and osteoclast function. Estrogen promotes survival of osteoblasts and apoptosis of osteoclasts, thereby favoring bone formation over resorption. Androgens also have bone anabolic effects, although some of these effects are due to local conversion of testosterone to E2 in men (see ). The combined effects of testosterone and E2 account for the higher peak bone mass observed in men. In postmenopausal women, estrogen deficiency results in an initial phase of rapid bone loss that lasts about 5 years, followed by a second phase of slower age-related bone loss that is similar in both sexes. For this reason, women are susceptible to postmenopausal osteoporosis.


Physiology_Levy

Physiology_Levy. Glucocorticoids at high therapeutic doses promote bone resorption and inhibit intestinal Ca absorption. However, the most critical adverse effect is inhibition of osteoblast differentiation, which impairs bone formation. Therefore patients treated with high levels of a glucocorticoid as an antiinflammatory or immunosuppressive drug are at risk for glucocorticoid-induced osteoporosis and should be monitored carefully. Integrated Physiological Regulation of Ca++/Pi Metabolism The integrated response of PTH and 1,25-dihydroxyvitamin D to a hypocalcemic challenge is shown in


Physiology_Levy

Physiology_Levy. Fig. 40.10A . A decrease in serum [Ca++] detected by the CaSR on parathyroid chief cells stimulates secretion of PTH. In the kidney, PTH increases Ca++ reabsorption in the distal tubule and to a lesser extent in the distal thick ascending limb of the loop of Henle. In bone, elevated PTH stimulates osteoblast lineage cells to express RANKL, which increases osteoclast activity and leads to increased bone resorption and release of Ca++ and Pi into blood. PTH stimulates 1α-hydroxylase expression in the proximal renal tubule, thereby increasing 1,25-dihydroxyvitamin D levels. 1,25-Dihydroxyvitamin D stimulates absorption of Ca and Pi in the small intestine and upregulates osteoblast expression of RANKL, thereby amplifying the effect of PTH on bone resorption. In the kidney, PTH inhibits NPT2 in the proximal tubule to lower Pi reabsorption and increase Pi clearance, thereby counterbalancing Pi mobilized from the bone and gut.


Physiology_Levy

Physiology_Levy. Although not as tightly regulated as Ca++ , perturbations in serum Pi will also elicit hormonal responses (see Fig. 40.10B ). Low serum Pi stimulates production of 1,25-dihydroxyvitamin D in the kidney, which in turn will mobilize Ca and Pi from the intestine. The rise in Ca++ will suppress PTH secretion to prevent hypercalcemia. This drop in PTH will enhance Pi reabsorption in the proximal tubule to help restore serum Pi. Over a longer time course, a decrease in serum Pi will inhibit FGF23 production, which will favor Pi reabsorption in the proximal tubule. These integrated responses will allow correction of hypophosphatemia while maintaining normocalcemia. For hormonal responses to vitamin D deficiency, see the In the Clinic box and Fig. 40.10C


Physiology_Levy

Physiology_Levy. 1. Serum [Ca++] is determined by the rate of Ca 2. Serum [Pi] is determined by the rate of Pi absorption absorption by the gastrointestinal tract, bone by the gastrointestinal tract, soft tissue influx and formation and resorption, and renal excretion. Serum efflux, bone formation and resorption, and renal [Ca++] is normally maintained within a very narrow excretion. Serum [Pi] normally fluctuates over a range. relatively wider range. 3. The major physiological hormones regulating serum [Ca++] and [Pi] are PTH, 1,25-dihydroxyvitamin D (calcitriol), and FGF23. 4. Vitamin D is synthesized from 7-dehydrocholesterol in skin in the presence of UVB light or acquired in the diet. It is hydroxylated to 25-hydroxycholecalciferol in the liver and activated by renal 1α-hydroxylase to 1,25-dihydroxyvitamin D. 5. 1,25-Dihydroxyvitamin D promotes intestinal Ca++ absorption and modestly increases Pi absorption. 6.


Physiology_Levy

Physiology_Levy. 5. 1,25-Dihydroxyvitamin D promotes intestinal Ca++ absorption and modestly increases Pi absorption. 6. The flux of Ca++ and Pi into and out of bone is determined by the relative rates of osteoblastic Bhattacharyya N, et al. Fibroblast growth factor 23: state of the field and future directions. Trends Endocrinol Metab. 2012;23:610-618. Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res. 2013;92:860-867. Christakos S, et al. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96:365-408. bone formation and osteoclastic bone resorption. 7. The PTH/PTHrP receptor is expressed on osteoblasts, not on osteoclasts. PTH has both anabolic and catabolic actions in bone depending on the dose and timing of administration. PTH promotes bone resorption by upregulation of M-CSF and RANKL in osteoblasts. 8.


Physiology_Levy

Physiology_Levy. 8. 1,25-Dihydroxyvitamin D binds to the VDR in osteoblasts to support osteoclast differentiation via RANKL and promotes bone mineralization by maintaining appropriate serum [Ca++] and [Pi]. Upon completion of this chapter the student should be able to answer the following questions: 1. Describe the structure and composition of the pituitary gland and its structural and functional relationship to magnocellular and parvicellular hypothalamic neurons. 2. Discuss the mechanisms by which the neurohormones antidiuretic hormone (ADH) and oxytocin are synthesized, transported, and released by magnocellular neurons. 3. Diagram a basic scheme illustrating the components and feedback loops of a typical endocrine axis, including central input, hypothalamic releasing factors, pituitary hormones, and a peripheral endocrine gland. Explain the concept of a set point. 4.


Physiology_Levy

Physiology_Levy. 4. List the endocrine cell types of the adenohypophysis and the tropic hormones they produce, noting hormones that share a common subunit. 5. Contrast the axes of somatotropes and lactotropes with the classic endocrine axes and explain how they differ. 6. Discuss the actions of growth hormone (GH) and insulinlike growth factor I (IGF-I) inthe regulation of growth, and the role of growth hormone in the fasted state. 7. Describe the role of prolactin in the initiation and maintenance of lactation. he pituitary gland (also called the hypophysis) is a small (≈0.5 g in weight) yet complex endocrine structure at the base of the forebrain (


Physiology_Levy

Physiology_Levy. he pituitary gland (also called the hypophysis) is a small (≈0.5 g in weight) yet complex endocrine structure at the base of the forebrain ( Fig. 41.1 ). It is composed of an epithelial component called the adenohypophysis and a neural structure called the neurohypophysis. The adenohypophysis is composed of five cell types that secrete six hormones. The neurohypophysis releases several neurohormones. All endocrine functions of the pituitary gland are regulated by the hypothalamus and by negativeand positive-feedback loops. Microscopic examination of the pituitary reveals two distinct types of tissue: epithelial and neural (


Physiology_Levy

Physiology_Levy. Microscopic examination of the pituitary reveals two distinct types of tissue: epithelial and neural ( Fig. 41.2 ). The epithelial portion of the human pituitary gland is called the adenohypophysis. The adenohypophysis makes up the anterior portion of the pituitary and is often referred to as the anterior lobe of the pituitary, and its hormones are referred to as anterior pituitary hormones. The adenohypophysis is composed of three parts: (1) the pars distalis, which makes up about 90% of the adenohypophysis, (2) the pars tuberalis, which wraps around the stalk, and (3) the pars intermedia, which regresses and is absent in adult humans.


Physiology_Levy

Physiology_Levy. The neural portion of the pituitary is called the neurohypophysis and represents a downgrowth of the hypothalamus. The most inferior portion of the neurohypophysis is called the pars nervosa, also called the posterior lobe of the pituitary (or simply posterior pituitary). At the superior end of the neurohypophysis, a funnel-shaped swelling called the median eminence develops. The portion of the neurohypophysis that extends from the median eminence down to the pars nervosa is called the infundibulum. The infundibulum and the pars tuberalis make up the pituitary stalk—a physical connection between the hypothalamus and pituitary gland (see Fig. 41.2).


Physiology_Levy

Physiology_Levy. Fig. 41.2). The pituitary gland (anterior and posterior lobes) is situated within a depression of the sphenoid bone called the sella turcica. Generally, cancers of the pituitary have only one way to expand, which is up into the brain and against the optic chiasma. Thus any increase in size of the pituitary is commonly associated with visual field or visual acuity abnormalities and headaches. The sella turcica is sealed off from the brain by a membrane called the diaphragma sellae. The Neurohypophysis