Gastroparesis in diabetes: Difference between revisions

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==Overview==
==Overview==
 
[[Diabetic gastroparesis|'''Diabetic gastroparesis''']] was first discovered by Kassander in 1958 in [[diabetic]] patients with delayed gastric emptying and gastric stasis but without mechanical obstruction, and was named '''gastroparesis diabeticorum'''. The definition has been changing by adding new symptoms such as severe [[abdominal pain]]. Based on the '''rate of [[Stomach|gastric]] [[emptying]]''', abnormalities of gastric emptying in [[Diabetes mellitus|diabetes]] may be classified as: transient slow gastric emptying, transient rapid gastric emptying, persistent slow or delayed gastric emptying ([[gastroparesis]]), and persistent rapid gastric emptying. Persistent [[hyperglycemia]] results in [[molecular]] and [[Metabolism|metabolic]] changes in [[Neuron|neurons]], [[Interstitial cell of Cajal|interstitial cells of Cajal]], and [[Smooth muscle|smooth muscle cells]]. Theses changes are caused by [[oxidative stress]] and products (cytokines) of the [[Polarization|polarized]] M1 ([[proinflammatory]]) and M2 ([[prohealing]], or repair) [[Macrophage|macrophages]]. Gastroparesis is not a separate category and is considered a part of [[functional dyspepsia]]. The most common symptoms '''"cardinal symptoms"''' of [[gastroparesis]] include early [[satiety]], [[postprandial]] [[Fullness after a meal|fullness]], [[nausea]], [[vomiting]], and [[bloating]]. '''[[Stomach|Gastric]] [[scintigraphy]]''' or '''stable-isotope 13C breath test''' can detect different gastric emptying abnormalities. The most effective [[symptomatic treatment]] of [[diabetic gastroparesis]] is the same as the treatment of [[Functional dyspepsia|'''functional dyspepsia''']].
<br />
==Historical Perspective==
==Historical Perspective==
[Disease name] was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event].


The association between [important risk factor/cause] and [disease name] was made in/during [year/event].
*[[Diabetic gastroparesis|'''Diabetic gastroparesis''']] was first discovered by Kassander in 1958 in [[diabetic]] patients with delayed gastric emptying and gastric stasis but without mechanical obstruction, and was named '''gastroparesis diabeticorum'''.<ref name="pmid30385743">{{cite journal| author=Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL | display-authors=etal| title=Gastroparesis. | journal=Nat Rev Dis Primers | year= 2018 | volume= 4 | issue= 1 | pages= 41 | pmid=30385743 | doi=10.1038/s41572-018-0038-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30385743  }}</ref>
 
*[[Gastroparesis]] was defined as “partial [[paralysis]] of the [[stomach]]” by '''Merriam-Webster’s Medical Dictionary'''.
In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].
*'''G.F. Cahill et al'''., reported that “diabetic [[gastroparesis]] is a triad of [[postprandial]] symptoms: [[nausea]], [[vomiting]], and [[abdominal distension]].”
 
*The definition has been changing by adding new symptoms such as severe [[abdominal pain]].<ref name="pmid315638772">{{cite journal| author=Grover M, Farrugia G, Stanghellini V| title=Gastroparesis: a turning point in understanding and treatment. | journal=Gut | year= 2019 | volume= 68 | issue= 12 | pages= 2238-2250 | pmid=31563877 | doi=10.1136/gutjnl-2019-318712 | pmc=6874806 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31563877  }}</ref>
In [year], [gene] mutations were first implicated in the pathogenesis of [disease name].
 
There have been several outbreaks of [disease name], including -----.
 
In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name].


==Classification==
==Classification==
Based on the rate of [[Stomach|gastric]] [[emptying]], abnormalities of gastric emptying in [[Diabetes mellitus|diabetes]] may be classified as:  
Based on the '''rate of [[Stomach|gastric]] [[emptying]]''', abnormalities of gastric emptying in [[Diabetes mellitus|diabetes]] may be classified as:  


* Transient slow gastric emptying
*Transient slow gastric emptying
* Transient rapid gastric emptying  
*Transient rapid gastric emptying
* Persistent slow or delayed gastric emptying ([[gastroparesis]])  
*Persistent slow or delayed gastric emptying ([[gastroparesis]])
* Persistent rapid gastric emptying
*Persistent rapid gastric emptying


==Pathophysiology==
==Pathophysiology==


* The rate of gastric emptying is mainly regulated by the [[neurohormonal]] mechanisms that regulate the [[Motor coordination|motor]] activities of the [[stomach]].
===Metabolic Changes That Affect Gastric Emptying in Diabetes===
* The stomach passes 1 to 4 kcal of homogenized food per minute, regardless of its composition whether it is [[protein]], [[carbohydrate]], or [[fat]].
* [[Diabetes mellitus|Diabetes]] affect the [[Motor coordination|motor]] activities of the [[stomach]] by causing dysfunction of [[interstitial cells of Cajal]] and [[smooth muscle]] ([[Vagovagal reflex|vagovagal]] neural circuits).
* Fluctuations in [[Blood sugar|blood glucose]] levels affect glucose-stimulated or glucose-inhibited neurons in the gastric inhibitory and gastric excitatory vagal circuits; therefore, changes the rate of gastric emptying.
* Persistent [[hyperglycemia]] results in [[molecular]] and [[Metabolism|metabolic]] changes in [[Neuron|neurons]], [[Interstitial cell of Cajal|interstitial cells of Cajal]], and [[Smooth muscle|smooth muscle cells]]. Theses changes are caused by [[oxidative stress]] and products of the [[Polarization|polarized]] M1 ([[proinflammatory]]) and M2 ([[prohealing]], or repair) [[Macrophage|macrophages]] followed by [[Transcriptional regulation|transcriptional]] changes in [[Protein|proteins]] and [[microRNA]] ([[MiRNA|miRN]]), changing the [[cellular]] [[phenotype]] to [[Hypocontractile left ventricle|hypocontractile]] or [[hypercontractile]] [[smooth muscle cells]].


==Causes==
*The rate of gastric emptying is mainly regulated by the [[neurohormonal]] mechanisms that regulate the [[Motor coordination|motor]] activities of the [[stomach]].
Disease name] may be caused by [cause1], [cause2], or [cause3].
*The stomach passes 1 to 4 kcal of homogenized food per minute, regardless of its composition whether it is [[protein]], [[carbohydrate]], or [[fat]].
*[[Diabetes mellitus|Diabetes]] affect the [[Motor coordination|motor]] activities of the [[stomach]] by causing dysfunction of [[interstitial cells of Cajal]] and [[smooth muscle]] ([[Vagovagal reflex|vagovagal]] neural circuits).
*Fluctuations in [[Blood sugar|blood glucose]] levels affect glucose-stimulated or glucose-inhibited neurons in the gastric inhibitory and gastric excitatory vagal circuits; therefore, changes the rate of gastric emptying.
*Persistent [[hyperglycemia]] results in [[molecular]] and [[Metabolism|metabolic]] changes in [[Neuron|neurons]], [[Interstitial cell of Cajal|interstitial cells of Cajal]], and [[Smooth muscle|smooth muscle cells]].
*Theses changes are caused by [[oxidative stress]] and products (cytokines) of the [[Polarization|polarized]] M1 ([[proinflammatory]]) and M2 ([[prohealing]], or repair) [[Macrophage|macrophages]].<ref name="pmid25861979">{{cite journal| author=Varol C, Mildner A, Jung S| title=Macrophages: development and tissue specialization. | journal=Annu Rev Immunol | year= 2015 | volume= 33 | issue=  | pages= 643-75 | pmid=25861979 | doi=10.1146/annurev-immunol-032414-112220 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25861979  }}</ref>
*[[Oxidative stress]] and [[cytokines]], mediated by [[transcriptional factors]], can alter the signaling proteins directly or through regulation of  [[microRNA]] ([[MiRNA|miRNA]]). [[MicroRNA|MicroRNAs]] ([[miRNA]]<nowiki/>s) are [[Non-coding RNA|non-coding]] [[RNA]] that act as post-transcriptional regulators of [[gene expression]]. They bind to their target [[Messenger RNA|mRNA]]<nowiki/>s resulting in suppression of [[translation]] and changing the [[cellular]] [[phenotype]] to [[Hypocontractile left ventricle|hypocontractile]] or [[hypercontractile]] [[smooth muscle cells]].<ref name="pmid25309675">{{cite journal| author=Joshi SR, Comer BS, McLendon JM, Gerthoffer WT| title=MicroRNA Regulation of Smooth Muscle Phenotype. | journal=Mol Cell Pharmacol | year= 2012 | volume= 4 | issue= 1 | pages= 1-16 | pmid=25309675 | doi= | pmc=4190587 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25309675  }}</ref><ref name="pmid25168158">{{cite journal| author=Neshatian L, Gibbons SJ, Farrugia G| title=Macrophages in diabetic gastroparesis--the missing link? | journal=Neurogastroenterol Motil | year= 2015 | volume= 27 | issue= 1 | pages= 7-18 | pmid=25168158 | doi=10.1111/nmo.12418 | pmc=4409126 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25168158  }}</ref><ref name="pmid20172487">{{cite journal| author=Cai Y, Yu X, Hu S, Yu J| title=A brief review on the mechanisms of miRNA regulation. | journal=Genomics Proteomics Bioinformatics | year= 2009 | volume= 7 | issue= 4 | pages= 147-54 | pmid=20172487 | doi=10.1016/S1672-0229(08)60044-3 | pmc=5054406 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20172487  }}</ref>
*Moderate [[oxidative stress]] affects the [[neuromuscular]] transmission, resulting in an increase in in the number of [[interstitial cells of Cajal]], and converting [[smooth muscle]] to the hypercontractile phenotype.
*Moderate [[oxidative stress]] affects [[polarization]] of [[Macrophage|macrophages]] leading to polarization to M2 [[Macrophage|macrophages]] that inhibit M1 macrophages and their inflammatory responses and leads to significant loss of [[neurotransmission]], loss of interstitial cells of Cajal, and conversion of [[smooth muscle]] to the hypocontractile [[phenotype]].


OR
===Transient Slow Gastric Emptying===


Common causes of [disease] include [cause1], [cause2], and [cause3].
*It occurs as a result of  a reduction in the proximal [[stomach]] [[muscle tone]], inhibition of [[antral]] contractions, and inhibition of the powerful contractions of the interdigestive [[migrating motor complex]].
*Acute hyperglycemia causes a delay in gastric emptying of digestible food in the digestive period and indigestible food during the fasting period.
*Delayed gastric emptying decreases [[postprandial]] [[hyperglycemia]] and acts as a [[negative feedback]] loop.
*[[Hyperglycemia]] inhibits [[ATP-sensitive potassium channel|ATP-sensitive potassium]] ([[KATP]]) channels  leading to activation of glucose-sensitive [[Neuron|neurons]] in the vagal afferents.  Activation of the gastric inhibitory  vagal motor circuit can influence electrical slow waves and smooth muscle.
*Acute hyperglycemia can cause dysfunction of [[Myenteric plexus|myenteric]] interstitial cells of Cajal, resulting in isolated [[tachygastria]] (an increase in the cyclic electrical activity in the stomach, with a frequency of >3.6 cycles per minute [cpm]).<ref name="pmid19309443">{{cite journal| author=Coleski R, Hasler WL| title=Coupling and propagation of normal and dysrhythmic gastric slow waves during acute hyperglycaemia in healthy humans. | journal=Neurogastroenterol Motil | year= 2009 | volume= 21 | issue= 5 | pages= 492-9, e1-2 | pmid=19309443 | doi=10.1111/j.1365-2982.2008.01235.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19309443  }}</ref>
*Elevated blood glucose levels activates the gastric inhibitory vagal motor circuit, suppressing the stomach contractions and can overcome the hyperglycemia-mediated contraction of the smooth muscle.<ref name="pmid26683376">{{cite journal| author=Hien TT, Turczyńska KM, Dahan D, Ekman M, Grossi M, Sjögren J | display-authors=etal| title=Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization. | journal=J Biol Chem | year= 2016 | volume= 291 | issue= 7 | pages= 3552-68 | pmid=26683376 | doi=10.1074/jbc.M115.654384 | pmc=4751395 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26683376  }}</ref>
*Transient slow gastric emptying as a result of acute hyperglycemia is considered a counter-regulatory phenomenon and does not need any treatment.
*The transient effect is due to [[Downregulation|down-regulation]] of [[glucokinase]].<ref name="pmid26297899">{{cite journal| author=Halmos KC, Gyarmati P, Xu H, Maimaiti S, Jancsó G, Benedek G | display-authors=etal| title=Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes. | journal=Neuroscience | year= 2015 | volume= 306 | issue=  | pages= 115-22 | pmid=26297899 | doi=10.1016/j.neuroscience.2015.08.023 | pmc=4575893 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26297899  }}</ref>


OR
===Transient Rapid Gastric Emptying===


The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].
*It is mainly caused by acute [[hypoglycemia]].
*Acute hypoglycemia is associated with [[stimulation]] of the gastric excitatory vagal motor circuit (GEVMC), that is a source of [[cholinergic]] nerve supply to the gastric smooth muscle (increases the [[Parasympathetic nervous system|parasympathetic]] activity).
*[[GABAergic]] [[Neuron|neurons]], connected to GEVMC, are very [[Sensitive Skin|sensitive]] to [[hypoglycemia]]. Hypoglycemia leads to failure of mitochondrial [[glycolysis]] and reduction in [[ATP]] production. This inhibits [[Na+/K+ ATPase]], blocks the K+ channel, and open the chloride channels, leading to [[depolarization]]. Activation of [[GABAergic]] neurons results in activation of the GEVMC, leading to release of [[acetylcholine]] at the [[neuromuscular junction]], increasing the [[contractility]] of [[gastric]] [[smooth muscle]], and rapid gastric emptying.
*Also, the GEVMC is also linked to [[glucagon]]-secreting cells, to [[orexigenic]] (appetite-stimulating) neurons, to the sympathoadrenal pathway, and to [[hypothalamic]] [[neurons]] involved in the counter-regulatory responses to hypoglycemia.
*The transient nature is due to rapid up-regulation of [[glucokinase]] and using alternative energy sources.
*It does not require treatment.
*In case of recurrent [[hypoglycemia]], such changes may play a protective role against hypoglycemia-associated [[autonomic]] failure and impaired awareness of hypoglycemia, which can be fatal.<ref name="pmid24606905">{{cite journal| author=Lamy CM, Sanno H, Labouèbe G, Picard A, Magnan C, Chatton JY | display-authors=etal| title=Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. | journal=Cell Metab | year= 2014 | volume= 19 | issue= 3 | pages= 527-38 | pmid=24606905 | doi=10.1016/j.cmet.2014.02.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24606905  }}</ref>


OR
<br />


The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click [[Pericarditis causes#Overview|here]].
===Persistent Rapid Gastric Emptying===


==Differentiating ((Page name)) from other Diseases==
*It occurs due to enhanced [[contractility]] of the [[fundus]] and [[antrum]] as a result of loss of [[inhibitory]] signals, increased [[smooth muscle]] contractility, and possibly an increase in the number of [[Myenteric plexus|myenteric]] [[Interstitial cell of Cajal|interstitial cells of Cajal]].<ref name="pmid7657103">{{cite journal| author=Frank JW, Saslow SB, Camilleri M, Thomforde GM, Dinneen S, Rizza RA| title=Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus. | journal=Gastroenterology | year= 1995 | volume= 109 | issue= 3 | pages= 755-65 | pmid=7657103 | doi=10.1016/0016-5085(95)90382-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7657103  }}</ref>
[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].
*[[Oxidative stress]], associated with [[hyperglycemia]], results in:<ref name="pmid26138467">{{cite journal| author=Singh J, Kumar S, Rattan S| title=Bimodal effect of oxidative stress in internal anal sphincter smooth muscle. | journal=Am J Physiol Gastrointest Liver Physiol | year= 2015 | volume= 309 | issue= 5 | pages= G292-300 | pmid=26138467 | doi=10.1152/ajpgi.00125.2015 | pmc=4556951 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26138467  }}</ref><ref name="pmid28438610">{{cite journal| author=Hayashi Y, Toyomasu Y, Saravanaperumal SA, Bardsley MR, Smestad JA, Lorincz A | display-authors=etal| title=Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying. | journal=Gastroenterology | year= 2017 | volume= 153 | issue= 2 | pages= 521-535.e20 | pmid=28438610 | doi=10.1053/j.gastro.2017.04.020 | pmc=5526732 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28438610  }}</ref><ref name="pmid76571032">{{cite journal| author=Frank JW, Saslow SB, Camilleri M, Thomforde GM, Dinneen S, Rizza RA| title=Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus. | journal=Gastroenterology | year= 1995 | volume= 109 | issue= 3 | pages= 755-65 | pmid=7657103 | doi=10.1016/0016-5085(95)90382-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7657103  }}</ref>
**Loss of inhibitory [[neuromuscular transmission]]
**A [[Transcriptional regulation|transcriptional]] increase in [[c-Kit]]
**An increased number of [[Interstitial cell of Cajal|interstitial cells of Cajal]]
**[[Transcriptional regulation|Transcriptional]] [[Downregulation|down-regulation]] of [[miRNA]]-133a, resulting in up-regulation of the small guanosine triphosphatase protein [[RhoA]] and Rho-associated protein  kinase ([[RhoA–ROCK]]) signaling
*Rapid gastric emptying significantly affects [[glucose intolerance]] and it plays a major role in the [[Genesis Health System|genesis]] and progression of [[Diabetes mellitus type 2|type 2 diabetes mellitus]].
*[[Metformin]], short acting [[Glucagon-like peptide 1 receptor|glucagon-like peptide 1]] agonists, and [[amylin]] analogues slow [[gastric emptying]].<ref name="pmid25887358">{{cite journal| author=Meier JJ, Rosenstock J, Hincelin-Méry A, Roy-Duval C, Delfolie A, Coester HV | display-authors=etal| title=Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial. | journal=Diabetes Care | year= 2015 | volume= 38 | issue= 7 | pages= 1263-73 | pmid=25887358 | doi=10.2337/dc14-1984 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25887358  }}</ref>
*Rapid gastric emptying accentuates the early [[postprandial]] [[Hyperglycemia|hyperglycemic]] [[Peak flow|peak]].<ref name="pmid339513632">{{cite journal| author=Goyal RK| title=Gastric Emptying Abnormalities in Diabetes Mellitus. | journal=N Engl J Med | year= 2021 | volume= 384 | issue= 18 | pages= 1742-1751 | pmid=33951363 | doi=10.1056/NEJMra2020927 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33951363  }}</ref><br />


OR
===Persistent Delayed Gastric Emptying (Gastroparesis)===


[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].
*Diabetic [[gastroparesis]] is the most common [[Stomach|gastric]] complication of [[diabetes mellitus]].
*In [[hyperglycemia]], inflammatory [[Cytokine|cytokines]] and [[M1 protein|M1]] [[macrophage]] [[polarization]] and its products '''tumor necrosis factor α''' ([[Tumor necrosis factor-alpha|'''TNF-α''']]) which  leads to:
**Up-regulation of '''miRNA-133a''' through the transcription factor '''nuclear factor κB (NF-κB)''', and in turn, this results in an a decrease in '''RhoA–ROCK''' signaling in the [[Smooth muscle|smooth muscles]]. Impaired RhoA–ROCK signaling is associated with reduced sustained [[contraction]]<ref name="pmid27634012">{{cite journal| author=Singh J, Boopathi E, Addya S, Phillips B, Rigoutsos I, Penn RB | display-authors=etal| title=Aging-associated changes in microRNA expression profile of internal anal sphincter smooth muscle: Role of microRNA-133a. | journal=Am J Physiol Gastrointest Liver Physiol | year= 2016 | volume= 311 | issue= 5 | pages= G964-G973 | pmid=27634012 | doi=10.1152/ajpgi.00290.2016 | pmc=5130548 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27634012  }}</ref><ref name="pmid23576331">{{cite journal| author=Bhetwal BP, An C, Baker SA, Lyon KL, Perrino BA| title=Impaired contractile responses and altered expression and phosphorylation of Ca(2+) sensitization proteins in gastric antrum smooth muscles from ob/ob mice. | journal=J Muscle Res Cell Motil | year= 2013 | volume= 34 | issue= 2 | pages= 137-49 | pmid=23576331 | doi=10.1007/s10974-013-9341-1 | pmc=3651903 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23576331  }}</ref>
**Severe [[oxidative stress]] leading to loss of [[Inhibitory synapses|inhibitory]] [[neurotransmission]] bt the uncoupling of nNOSα and loss of [[nitric oxide]] ([[Nitric oxide|NO]])
**Up-regulation of caspases, medited by [[TNF-alpha|TNF]] and [[NF-κB]] and leading to loss of [[Interstitial cell of Cajal|interstitial cells of Cajal]]<ref name="pmid27781339">{{cite journal| author=Eisenman ST, Gibbons SJ, Verhulst PJ, Cipriani G, Saur D, Farrugia G| title=Tumor necrosis factor alpha derived from classically activated "M1" macrophages reduces interstitial cell of Cajal numbers. | journal=Neurogastroenterol Motil | year= 2017 | volume= 29 | issue= 4 | pages=  | pmid=27781339 | doi=10.1111/nmo.12984 | pmc=5367986 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27781339  }}</ref>
*[[Diabetic gastroparesis]] occurs with both [[Solid|solids]] and [[Liquid|liquids]]; however, it starts with [[solid]] foods.<ref name="pmid6468877">{{cite journal| author=Feldman M, Smith HJ, Simon TR| title=Gastric emptying of solid radiopaque markers: studies in healthy subjects and diabetic patients. | journal=Gastroenterology | year= 1984 | volume= 87 | issue= 4 | pages= 895-902 | pmid=6468877 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6468877  }}</ref>
*It can postpone the peak of [[postprandial]] [[hyperglycemia]] peak; however, it may result in [[postprandial]] [[hypoglycemia]] unless [[insulin]] [[dosage]] adjustment is performed.<ref name="pmid28760384">{{cite journal| author=Camilleri M, McCallum RW, Tack J, Spence SC, Gottesdiener K, Fiedorek FT| title=Efficacy and Safety of Relamorelin in Diabetics With Symptoms of Gastroparesis: A Randomized, Placebo-Controlled Study. | journal=Gastroenterology | year= 2017 | volume= 153 | issue= 5 | pages= 1240-1250.e2 | pmid=28760384 | doi=10.1053/j.gastro.2017.07.035 | pmc=5670003 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28760384  }}</ref>
*Lack of [[inhibitory]] [[neurotransmission]], with subsequent impaired relaxation (loss of [[accommodation]]) and decreased [[tonic contractions]] (delayed gastric emptying) are observed in the gastric [[fundus]].
*Lack of [[cholinergic]] [[Excitatory neurotransmitter|excitatory]] [[Neuromuscular transmission|neurotransmission]], [[slow waves]] abnormalities, and [[smooth muscle]] weakness result in impaired propulsive contraction of the [[antrum]] with subsequent impairment of food [[grinding]] and [[gastric emptying]].<ref name="pmid339513633">{{cite journal| author=Goyal RK| title=Gastric Emptying Abnormalities in Diabetes Mellitus. | journal=N Engl J Med | year= 2021 | volume= 384 | issue= 18 | pages= 1742-1751 | pmid=33951363 | doi=10.1056/NEJMra2020927 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33951363  }}</ref>


==Epidemiology and Demographics==
==Differentiating Diabetic Gastroparesis from other Diseases==
The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.


OR
*[[Diabetic gastroparesis]] must be differentiated from [[Dyspepsia|'''functional dyspepsia''']] which is common, occurring approximately 10% of the general population.
*Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) and gastroparesis Cardinal Symptom Index (GCSI)  were designed for that purpose; however, it could not distinguish between [[functional dyspepsia]] and [[diabetic gastroparesis]].
*Consequently, gastroparesis is not a separate category and is considered a part of [[functional dyspepsia]].


In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
==Epidemiology and Demographics==


OR
*The [[prevalence]] of rapid gastric emptying among patients with or without upper [[abdominal]] [[Symptom|symptoms]] is approximately 20% in patients with type 1 or type 2 [[diabetes mellitus]].<ref name="pmid18727706">{{cite journal| author=Bharucha AE, Camilleri M, Forstrom LA, Zinsmeister AR| title=Relationship between clinical features and gastric emptying disturbances in diabetes mellitus. | journal=Clin Endocrinol (Oxf) | year= 2009 | volume= 70 | issue= 3 | pages= 415-20 | pmid=18727706 | doi=10.1111/j.1365-2265.2008.03351.x | pmc=3899345 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18727706  }}</ref>
*The prevalence of delayed gastric emptying among patients with or without upper [[abdominal]] [[Symptom|symptoms]] is approximately 40-47% in patients with type 1 diabetes and 32-47% in type 2 [[diabetes mellitus]].<ref name="pmid33951363">{{cite journal| author=Goyal RK| title=Gastric Emptying Abnormalities in Diabetes Mellitus. | journal=N Engl J Med | year= 2021 | volume= 384 | issue= 18 | pages= 1742-1751 | pmid=33951363 | doi=10.1056/NEJMra2020927 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33951363  }}</ref>


In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.
==Diagnosis==
 
 
 
Patients of all age groups may develop [disease name].
 
OR
 
The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
 
OR
 
[Disease name] commonly affects individuals younger than/older than [number of years] years of age.
 
OR
 
[Chronic disease name] is usually first diagnosed among [age group].
 
OR
 
[Acute disease name] commonly affects [age group].
 
 
 
There is no racial predilection to [disease name].
 
OR
 
[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
 
 
 
[Disease name] affects men and women equally.
 
OR
 
[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.
 
 
 
The majority of [disease name] cases are reported in [geographical region].
 
OR
 
[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].
 
==Risk Factors==
There are no established risk factors for [disease name].
 
OR
 
The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
 
OR
 
Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
 
OR
 
Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.
 
==Screening==
There is insufficient evidence to recommend routine screening for [disease/malignancy].
 
OR
 
According to the [guideline name], screening for [disease name] is not recommended.
 
OR
 
According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].


==Natural History, Complications, and Prognosis==
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
OR
Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
OR
Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
==Diagnosis==
===Diagnostic Study of Choice===
===Diagnostic Study of Choice===
The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].
'''[[Stomach|Gastric]] [[scintigraphy]]''' or '''stable-isotope 13C breath test''' can detect different gastric emptying abnormalities.
 
OR
 
The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].
 
OR


The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].
[[File:GastricEmptying.jpg|thumb|A gastric emptying scan (scintigraphy) that is used as an assessment tool to show the ability of stomach to empty its contents]]
 
OR
 
There are no established criteria for the diagnosis of [disease name].


===History and Symptoms===
===History and Symptoms===
The majority of patients with [disease name] are asymptomatic.
The most common symptoms '''"cardinal symptoms"''' of [[gastroparesis]] include early [[satiety]], [[postprandial]] [[Fullness after a meal|fullness]], [[nausea]], [[vomiting]], and [[bloating]].
 
OR
 
The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
 
===Physical Examination===
Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
 
OR
 
Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
The presence of [finding(s)] on physical examination is diagnostic of [disease name].
 
OR
 
The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
 
===Laboratory Findings===
An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
 
OR
 
Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
 
OR
 
[Test] is usually normal among patients with [disease name].
 
OR
 
Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
 
OR
 
There are no diagnostic laboratory findings associated with [disease name].
 
===Electrocardiogram===
There are no ECG findings associated with [disease name].
 
OR
 
An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
===X-ray===
There are no x-ray findings associated with [disease name].
 
OR
 
An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===Echocardiography or Ultrasound===
There are no echocardiography/ultrasound  findings associated with [disease name].
 
OR
 
Echocardiography/ultrasound  may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no echocardiography/ultrasound  findings associated with [disease name]. However, an echocardiography/ultrasound  may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===CT scan===
There are no CT scan findings associated with [disease name].
 
OR
 
[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===MRI===
There are no MRI findings associated with [disease name].
 
OR
 
[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
 
===Other Imaging Findings===
There are no other imaging findings associated with [disease name].
 
OR
 
[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
===Other Diagnostic Studies===
There are no other diagnostic studies associated with [disease name].
 
OR
 
[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
 
OR
 
Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
There is no treatment for [disease name]; the mainstay of therapy is supportive care.
The most effective [[symptomatic treatment]] of [[diabetic gastroparesis]] is the same as the treatment of [[Functional dyspepsia|'''functional dyspepsia''']].
 
OR
 
Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].
 
OR
 
The majority of cases of [disease name] are self-limited and require only supportive care.
 
OR
 
[Disease name] is a medical emergency and requires prompt treatment.
 
OR
 
The mainstay of treatment for [disease name] is [therapy].
 
OR
 
The optimal therapy for [malignancy name] depends on the stage at diagnosis.
 
OR
 
[Therapy] is recommended among all patients who develop [disease name].
 
OR
 
Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
 
OR
 
Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
 
OR
 
Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
 
OR
 
Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
 
===Surgery===
Surgical intervention is not recommended for the management of [disease name].
 
OR
 
Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]
 
OR
 
The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].
 
OR
 
The feasibility of surgery depends on the stage of [malignancy] at diagnosis.
 
OR
 
Surgery is the mainstay of treatment for [disease or malignancy].
 
===Primary Prevention===
There are no established measures for the primary prevention of [disease name].
 
OR
 
There are no available vaccines against [disease name].
 
OR
 
Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
 
OR
 
[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].
 
===Secondary Prevention===
There are no established measures for the secondary prevention of [disease name].
 
OR
 
Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].


==References==
==References==

Latest revision as of 21:13, 31 May 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Riad, M.D.[2]

Synonyms and keywords:

Overview

Diabetic gastroparesis was first discovered by Kassander in 1958 in diabetic patients with delayed gastric emptying and gastric stasis but without mechanical obstruction, and was named gastroparesis diabeticorum. The definition has been changing by adding new symptoms such as severe abdominal pain. Based on the rate of gastric emptying, abnormalities of gastric emptying in diabetes may be classified as: transient slow gastric emptying, transient rapid gastric emptying, persistent slow or delayed gastric emptying (gastroparesis), and persistent rapid gastric emptying. Persistent hyperglycemia results in molecular and metabolic changes in neurons, interstitial cells of Cajal, and smooth muscle cells. Theses changes are caused by oxidative stress and products (cytokines) of the polarized M1 (proinflammatory) and M2 (prohealing, or repair) macrophages. Gastroparesis is not a separate category and is considered a part of functional dyspepsia. The most common symptoms "cardinal symptoms" of gastroparesis include early satiety, postprandial fullness, nausea, vomiting, and bloating. Gastric scintigraphy or stable-isotope 13C breath test can detect different gastric emptying abnormalities. The most effective symptomatic treatment of diabetic gastroparesis is the same as the treatment of functional dyspepsia.

Historical Perspective

Classification

Based on the rate of gastric emptying, abnormalities of gastric emptying in diabetes may be classified as:

  • Transient slow gastric emptying
  • Transient rapid gastric emptying
  • Persistent slow or delayed gastric emptying (gastroparesis)
  • Persistent rapid gastric emptying

Pathophysiology

Metabolic Changes That Affect Gastric Emptying in Diabetes

Transient Slow Gastric Emptying

  • It occurs as a result of a reduction in the proximal stomach muscle tone, inhibition of antral contractions, and inhibition of the powerful contractions of the interdigestive migrating motor complex.
  • Acute hyperglycemia causes a delay in gastric emptying of digestible food in the digestive period and indigestible food during the fasting period.
  • Delayed gastric emptying decreases postprandial hyperglycemia and acts as a negative feedback loop.
  • Hyperglycemia inhibits ATP-sensitive potassium (KATP) channels leading to activation of glucose-sensitive neurons in the vagal afferents. Activation of the gastric inhibitory vagal motor circuit can influence electrical slow waves and smooth muscle.
  • Acute hyperglycemia can cause dysfunction of myenteric interstitial cells of Cajal, resulting in isolated tachygastria (an increase in the cyclic electrical activity in the stomach, with a frequency of >3.6 cycles per minute [cpm]).[7]
  • Elevated blood glucose levels activates the gastric inhibitory vagal motor circuit, suppressing the stomach contractions and can overcome the hyperglycemia-mediated contraction of the smooth muscle.[8]
  • Transient slow gastric emptying as a result of acute hyperglycemia is considered a counter-regulatory phenomenon and does not need any treatment.
  • The transient effect is due to down-regulation of glucokinase.[9]

Transient Rapid Gastric Emptying


Persistent Rapid Gastric Emptying

Persistent Delayed Gastric Emptying (Gastroparesis)

Differentiating Diabetic Gastroparesis from other Diseases

Epidemiology and Demographics

Diagnosis

Diagnostic Study of Choice

Gastric scintigraphy or stable-isotope 13C breath test can detect different gastric emptying abnormalities.

A gastric emptying scan (scintigraphy) that is used as an assessment tool to show the ability of stomach to empty its contents

History and Symptoms

The most common symptoms "cardinal symptoms" of gastroparesis include early satiety, postprandial fullness, nausea, vomiting, and bloating.

Treatment

Medical Therapy

The most effective symptomatic treatment of diabetic gastroparesis is the same as the treatment of functional dyspepsia.

References

  1. ↑ Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL; et al. (2018). "Gastroparesis". Nat Rev Dis Primers. 4 (1): 41. doi:10.1038/s41572-018-0038-z. PMID 30385743.
  2. ↑ Grover M, Farrugia G, Stanghellini V (2019). "Gastroparesis: a turning point in understanding and treatment". Gut. 68 (12): 2238–2250. doi:10.1136/gutjnl-2019-318712. PMC 6874806 Check |pmc= value (help). PMID 31563877.
  3. ↑ Varol C, Mildner A, Jung S (2015). "Macrophages: development and tissue specialization". Annu Rev Immunol. 33: 643–75. doi:10.1146/annurev-immunol-032414-112220. PMID 25861979.
  4. ↑ Joshi SR, Comer BS, McLendon JM, Gerthoffer WT (2012). "MicroRNA Regulation of Smooth Muscle Phenotype". Mol Cell Pharmacol. 4 (1): 1–16. PMC 4190587. PMID 25309675.
  5. ↑ Neshatian L, Gibbons SJ, Farrugia G (2015). "Macrophages in diabetic gastroparesis--the missing link?". Neurogastroenterol Motil. 27 (1): 7–18. doi:10.1111/nmo.12418. PMC 4409126. PMID 25168158.
  6. ↑ Cai Y, Yu X, Hu S, Yu J (2009). "A brief review on the mechanisms of miRNA regulation". Genomics Proteomics Bioinformatics. 7 (4): 147–54. doi:10.1016/S1672-0229(08)60044-3. PMC 5054406. PMID 20172487.
  7. ↑ Coleski R, Hasler WL (2009). "Coupling and propagation of normal and dysrhythmic gastric slow waves during acute hyperglycaemia in healthy humans". Neurogastroenterol Motil. 21 (5): 492–9, e1–2. doi:10.1111/j.1365-2982.2008.01235.x. PMID 19309443.
  8. ↑ Hien TT, Turczyńska KM, Dahan D, Ekman M, Grossi M, Sjögren J; et al. (2016). "Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization". J Biol Chem. 291 (7): 3552–68. doi:10.1074/jbc.M115.654384. PMC 4751395. PMID 26683376.
  9. ↑ Halmos KC, Gyarmati P, Xu H, Maimaiti S, Jancsó G, Benedek G; et al. (2015). "Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes". Neuroscience. 306: 115–22. doi:10.1016/j.neuroscience.2015.08.023. PMC 4575893. PMID 26297899.
  10. ↑ Lamy CM, Sanno H, Labouèbe G, Picard A, Magnan C, Chatton JY; et al. (2014). "Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion". Cell Metab. 19 (3): 527–38. doi:10.1016/j.cmet.2014.02.003. PMID 24606905.
  11. ↑ Frank JW, Saslow SB, Camilleri M, Thomforde GM, Dinneen S, Rizza RA (1995). "Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus". Gastroenterology. 109 (3): 755–65. doi:10.1016/0016-5085(95)90382-8. PMID 7657103.
  12. ↑ Singh J, Kumar S, Rattan S (2015). "Bimodal effect of oxidative stress in internal anal sphincter smooth muscle". Am J Physiol Gastrointest Liver Physiol. 309 (5): G292–300. doi:10.1152/ajpgi.00125.2015. PMC 4556951. PMID 26138467.
  13. ↑ Hayashi Y, Toyomasu Y, Saravanaperumal SA, Bardsley MR, Smestad JA, Lorincz A; et al. (2017). "Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying". Gastroenterology. 153 (2): 521–535.e20. doi:10.1053/j.gastro.2017.04.020. PMC 5526732. PMID 28438610.
  14. ↑ Frank JW, Saslow SB, Camilleri M, Thomforde GM, Dinneen S, Rizza RA (1995). "Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus". Gastroenterology. 109 (3): 755–65. doi:10.1016/0016-5085(95)90382-8. PMID 7657103.
  15. ↑ Meier JJ, Rosenstock J, Hincelin-Méry A, Roy-Duval C, Delfolie A, Coester HV; et al. (2015). "Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial". Diabetes Care. 38 (7): 1263–73. doi:10.2337/dc14-1984. PMID 25887358.
  16. ↑ Goyal RK (2021). "Gastric Emptying Abnormalities in Diabetes Mellitus". N Engl J Med. 384 (18): 1742–1751. doi:10.1056/NEJMra2020927. PMID 33951363 Check |pmid= value (help).
  17. ↑ Singh J, Boopathi E, Addya S, Phillips B, Rigoutsos I, Penn RB; et al. (2016). "Aging-associated changes in microRNA expression profile of internal anal sphincter smooth muscle: Role of microRNA-133a". Am J Physiol Gastrointest Liver Physiol. 311 (5): G964–G973. doi:10.1152/ajpgi.00290.2016. PMC 5130548. PMID 27634012.
  18. ↑ Bhetwal BP, An C, Baker SA, Lyon KL, Perrino BA (2013). "Impaired contractile responses and altered expression and phosphorylation of Ca(2+) sensitization proteins in gastric antrum smooth muscles from ob/ob mice". J Muscle Res Cell Motil. 34 (2): 137–49. doi:10.1007/s10974-013-9341-1. PMC 3651903. PMID 23576331.
  19. ↑ Eisenman ST, Gibbons SJ, Verhulst PJ, Cipriani G, Saur D, Farrugia G (2017). "Tumor necrosis factor alpha derived from classically activated "M1" macrophages reduces interstitial cell of Cajal numbers". Neurogastroenterol Motil. 29 (4). doi:10.1111/nmo.12984. PMC 5367986. PMID 27781339.
  20. ↑ Feldman M, Smith HJ, Simon TR (1984). "Gastric emptying of solid radiopaque markers: studies in healthy subjects and diabetic patients". Gastroenterology. 87 (4): 895–902. PMID 6468877.
  21. ↑ Camilleri M, McCallum RW, Tack J, Spence SC, Gottesdiener K, Fiedorek FT (2017). "Efficacy and Safety of Relamorelin in Diabetics With Symptoms of Gastroparesis: A Randomized, Placebo-Controlled Study". Gastroenterology. 153 (5): 1240–1250.e2. doi:10.1053/j.gastro.2017.07.035. PMC 5670003. PMID 28760384.
  22. ↑ Goyal RK (2021). "Gastric Emptying Abnormalities in Diabetes Mellitus". N Engl J Med. 384 (18): 1742–1751. doi:10.1056/NEJMra2020927. PMID 33951363 Check |pmid= value (help).
  23. ↑ Bharucha AE, Camilleri M, Forstrom LA, Zinsmeister AR (2009). "Relationship between clinical features and gastric emptying disturbances in diabetes mellitus". Clin Endocrinol (Oxf). 70 (3): 415–20. doi:10.1111/j.1365-2265.2008.03351.x. PMC 3899345. PMID 18727706.
  24. ↑ Goyal RK (2021). "Gastric Emptying Abnormalities in Diabetes Mellitus". N Engl J Med. 384 (18): 1742–1751. doi:10.1056/NEJMra2020927. PMID 33951363 Check |pmid= value (help).


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