Gastroparesis in diabetes
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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
- 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.[1]
- Gastroparesis was defined as “partial paralysis of the stomach” by Merriam-Webster’s Medical Dictionary.
- 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.[2]
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.[3]
- 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.[4][5][6]
- 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]).[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
- 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.[10]
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.[11]
- Oxidative stress, associated with hyperglycemia, results in:[12][13][14]
- 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.[15]
- Rapid gastric emptying accentuates the early postprandial hyperglycemic peak.[16]
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[17][18]
- 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[19]
- Diabetic gastroparesis occurs with both solids and liquids; however, it starts with solid foods.[20]
- It can postpone the peak of postprandial hyperglycemia peak; however, it may result in postprandial hypoglycemia unless insulin dosage adjustment is performed.[21]
- 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.[22]
Differentiating Diabetic Gastroparesis from other Diseases
- Diabetic gastroparesis must be differentiated from 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.
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.[23]
- 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.[24]
Diagnosis
Diagnostic Study of Choice
Gastric scintigraphy or stable-isotope 13C breath test can detect different gastric emptying abnormalities.
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
- ↑ 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.
- ↑ 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. - ↑ 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).