[excerpt starts]

There are many substances that can regulate GI function both as paracrine and endocrine regulators. One example is cholecystokinin, which is released from the duodenum in response to dietary protein and lipid. It acts as a paracrine regulator on nerve terminals and also affects the pancreas. The role of neural regulation in GI function will be discussed further in the section on Neural Regulation of Gastrointestinal Function.

Nerves and neurotransmitters play a crucial role in regulating the GI tract. Neural regulation occurs when a neurotransmitter is released from a nerve terminal in the GI tract and affects the innervated cell. However, in some cases, there are no synapses between motor nerves and effector cells in the GI tract. Neural regulation is important within an organ and between different parts of the GI tract.

The gut contains multiple receptor subtypes for the peptide hormones released by endocrine cells in its wall. The selectivity of receptors to peptide hormones is determined by post-translational modifications, which confer receptor selectivity. An example of this is peptide YY (PYY). PYY is released from endocrine cells in the gut wall, primarily in response to fatty acids. It binds to Y1, Y2, and Y5 receptors. However, it can also be cleaved to PYY3-36 by the enzyme dipeptidyl peptidase IV, which makes it more selective for the Y2 receptor. Thus, the presence of the enzyme that cleaves the peptide can alter the biological response to PYY secretion.

Glucagon-like peptide 1 (GLP-1) is a regulatory peptide released from EEC cells in the gut wall in response to luminal carbohydrate and lipids. GLP-1 is derived from the glucagon gene, which is also expressed in the pancreas and gives rise to glucagon. GLP-1 is involved in regulating blood glucose levels through stimulation of insulin secretion and insulin biosynthesis. Agonists of the GLP-1 receptor have been shown to improve insulin sensitivity in diabetic animal models and human subjects. Administration of GLP-1 also reduces appetite and food intake and delays gastric emptying, which may contribute to improving glucose tolerance. Long-acting agonists for the GLP-1 receptor, such as exenatide, have been approved for the treatment of type 2 diabetes.

The neural regulation of the GI tract is surprisingly complex. It is innervated by two sets of nerves: the extrinsic and intrinsic nervous systems. Extrinsic nerves, part of the autonomic nervous system, innervate the gut with cell bodies located outside the gut wall. The intrinsic nervous system, also known as the enteric nervous system, has cell bodies contained within the gut wall. Some GI functions depend heavily on the extrinsic nervous system, while others can occur independently of it and are mediated entirely by the enteric nervous system. However, extrinsic nerves can often modulate the function of the intrinsic nervous system.

[excerpt ends]
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.