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Revision as of 02:50, 30 May 2021

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

Synonyms and keywords:

Overview

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].

In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].

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

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

The rate of gastric emptying is mainly regulated by the neurohormonal mechanisms that regulate the motor activities of the stomach.
The stomach passes 1 to 4 kcal of homogenized food per minute, regardless of its composition whether it is protein, carbohydrate, or fat.
Diabetes affect the motor activities of the stomach by causing dysfunction of interstitial cells of Cajal and smooth muscle (vagovagal neural circuits).
Fluctuations in 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 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.^[1]
Oxidative stress and cytokines, mediated by transcriptional factors, can alter the signaling proteins directly or through regulation of microRNA (miRNA). MicroRNAs (miRNAs) are non-coding RNA that act as post-transcriptional regulators of gene expression. They bind to their target mRNAs resulting in suppression of translation and changing the cellular phenotype to hypocontractile or hypercontractile smooth muscle cells.^[2]^[3]^[4]
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 macrophages leading to polarization to M2 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.

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]).^[5]
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.^[6]
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.^[7]

Transient Rapid Gastric Emptying

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 activity).
GABAergic neurons, connected to GEVMC, are very 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.^[8]

Persistent Rapid Gastric Emptying

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 interstitial cells of Cajal.^[9]
Oxidative stress, associated with hyperglycemia, results in:^[10]^[11]^[12]
- Loss of inhibitory neuromuscular transmission
- A transcriptional increase in c-Kit
- An increased number of interstitial cells of Cajal
- Transcriptional 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 and progression of type 2 diabetes mellitus.
Metformin, short acting glucagon-like peptide 1 agonists, and amylin analogues slow gastric emptying.^[13]
Rapid gastric emptying accentuates the early postprandial hyperglycemic peak.^[14]

Persistent Delayed Gastric Emptying (Gastroparesis)

Diabetic gastroparesis is the most common gastric complication of diabetes mellitus.
In hyperglycemia, inflammatory cytokines and M1 macrophage polarization and its products tumor necrosis factor α (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 muscles. Impaired RhoA–ROCK signaling is associated with reduced sustained contraction^[15]^[16]
- Severe oxidative stress leading to loss of inhibitory neurotransmission bt the uncoupling of nNOSα and loss of nitric oxide (NO)
- Up-regulation of caspases, medited by TNF and NF-κB and leading to loss of interstitial cells of Cajal^[17]
Diabetic gastroparesis occurs with both solids and liquids; however, it starts with solid foods.^[18]
It can postpone the peak of postprandial hyperglycemia peak; however, it may result in postprandial hypoglycemia unless insulin dosage adjustment is performed.^[19]
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 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.^[20]

Causes

Disease name] may be caused by [cause1], [cause2], or [cause3].

OR

Common causes of [disease] include [cause1], [cause2], and [cause3].

OR

The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].

OR

The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here.

Differentiating ((Page name)) from other Diseases

[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].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

Epidemiology and Demographics

The prevalence of rapid gastric emptying among patients with or without upper abdominal symptoms is approximately 20% in patients with type 1 or type 2 diabetes mellitus.^[21]
The prevalence of delayed gastric emptying among patients with or without upper abdominal symptoms is approximately 40-47% in patients with type 1 diabetes and 32-47% in type 2 diabetes mellitus.^[22]

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

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].

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].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

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

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

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

↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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).
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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).
↑ 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.
↑ 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).

Template:WikiDoc Sources

[pmid25861979-1] 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.

[pmid25309675-2] 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.

[pmid25168158-3] 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.

[pmid20172487-4] 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.

[pmid19309443-5] 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.

[pmid26683376-6] 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.

[pmid26297899-7] 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.

[pmid24606905-8] 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.

[pmid7657103-9] 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.

[pmid26138467-10] 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.

[pmid28438610-11] 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.

[pmid76571032-12] 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.

[pmid25887358-13] 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.

[pmid339513632-14] 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).

[pmid27634012-15] 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.

[pmid23576331-16] 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.

[pmid27781339-17] 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.

[pmid6468877-18] 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.

[pmid28760384-19] 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.

[pmid339513633-20] 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).

[pmid18727706-21] 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.

[pmid33951363-22] 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).

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@@ Line 78: / Line 78: @@
 *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 />
-=== Persistent Delayed Gastric Emptying (Gastroparesis) ===
+===Persistent Delayed Gastric Emptying (Gastroparesis)===
-* Diabetic [[gastroparesis]] is the most common [[Stomach|gastric]] complication of [[diabetes mellitus]].
+*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>
 ==Causes==
@@ Line 107: / Line 115: @@
 *The prevalence of rapid gastric emptying among patients with or without upper abdominal 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 symptoms is approximately 40-47%.<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>
+*The prevalence of delayed gastric emptying among patients with or without upper abdominal 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>