Many substances can be both paracrine and endocrine regulators of GI function. For example, cholecystokinin, which is released from the duodenum in response to dietary protein and lipid, acts locally on nerve terminals in a paracrine fashion and also affects the pancreas. This will be discussed in more detail in
Neural Regulation of Gastrointestinal Function
Nerves and neurotransmitters play an important role in regulating the function of the GI tract. In its simplest form, neural regulation occurs when a neurotransmitter is released from a nerve terminal located in the GI tract and the neurotransmitter has an effect on the cell that is innervated. However, in some cases there are no synapses between motor nerves and effector cells in the GI tract. Neural regulation of GI function is very important within an organ, as well as between distant parts of the GI tract.
Therearemultiplereceptorsubtypesfortheregulatorypeptidehormonesreleasedfromendocrinecellsinthewallofthegut.Theselectivityofreceptorstopeptidehormonesisdeterminedbyposttranslationalmodifications,whichthenconfersreceptorselectivity.AnexampleofthisispeptideYY(PYY).TherearemultiplereceptorsubtypesforPYY,classifiedasY1toY7.PYYisreleasedfromendocrinecellsinthewallofthegut,mainlyinresponsetofattyacids.Itisreleasedasa36–aminoacidpeptideandbindstotheY1,Y2,andY5receptors;however,itcanbecleavedtoPYY3-36bytheenzymedipeptidylpeptidaseIV,amembranepeptidase.ThisformofthepeptideismoreselectivefortheY2receptor.ThusthepresenceoftheenzymethatcleavesthepeptidecanalterthebiologicalresponsetoPYYsecretion.
Glucagon-likepeptide1(GLP-1)isaregulatorypeptidereleasedfromEECscellsinthegutwallinresponsetothepresenceofluminalcarbohydrateandlipids.GLP-1arisesfromdifferentialprocessingoftheglucagongene,thesamegenethatisexpressedinthepancreasandthatgivesrisetoglucagon.GLP-1isinvolvedinregulationofthebloodglucoselevelviastimulationofinsulinsecretionandalsoinsulinbiosynthesis.AgonistsoftheGLP-1receptorimproveinsulinsensitivityindiabeticanimalmodelsandhumansubjects.AdministrationofGLP-1alsoreducesappetiteandfoodintakeanddelaysgastricemptying,responsesthatmaycontributetoimprovingglucosetolerance.Long-actingagonistsfortheGLP-1receptor(e.g.,exenatide)havebeenapprovedforthetreatmentoftype2diabetes.
Neural regulation of the GI tract is surprisingly complex. The gut is innervated by two sets of nerves, the extrinsic and intrinsic nervous systems. The extrinsic nervous system is defined as nerves that innervate the gut, with cell bodies located outside the gut wall; these extrinsic nerves are part of the autonomic nervous system (ANS). The intrinsic nervous system, also referred to as the enteric nervous system, has cell bodies that are contained within the wall of the gut (submucosal and myenteric plexuses). Some GI functions are highly dependent on the extrinsic nervous system, yet others can take place independently of the extrinsic nervous system and are mediated entirely by the ENS. However, extrinsic nerves can often modulate intrinsic nervous system function (
Fig. 27.6 •Fig. 27.6 HierarchicalneuralcontrolofGIfunction.StimulitotheGItractfromameal(e.g.,chemical,mechanical,osmotic)willactivateboththeintrinsicandextrinsicsensory(afferent)pathways,whichinturnwillactivatetheextrinsicandintrinsicneuralreflexpathways.