Gastric Emptying Abnormalities in Diabetes Mellitus

The new england journal of medicine

Review Article

Dan L. Longo, M.D., Editor Gastric Emptying Abnormalities in Diabetes Mellitus

Raj K. Goyal, M.D.

From the Division of Gastroenterology, iabetes mellitus is associated with a spectrum of gastric emp- Department of Medicine, Veterans Af- tying abnormalities, including transient slow gastric emptying, transient fairs Boston Healthcare System, West Roxbury, and the Division of Gastroenter- fast gastric emptying, persistent slow or delayed gastric emptying (gastro- ology, Hepatology, and Endoscopy, De- D paresis), and persistent fast gastric emptying. Transient changes in gastric empty- partment of Medicine, Beth Israel Dea- ing are counterregulatory responses and do not require treatment. Delayed gastric coness Medical Center and Harvard Medical School, Boston — both in Mas- emptying has been associated with abdominal symptoms and is considered to be sachusetts. Address reprint requests to a cause of severe illness. However, rapid gastric emptying is associated with simi- Dr. Goyal at the Division of Gastroenter- lar symptoms. Whereas delayed gastric emptying may cause difficulty in glucose ology, Department of Medicine, Veterans Affairs Boston Healthcare System, 2B101 control in patients receiving insulin therapy, rapid gastric emptying plays an im- OREA Bldg., 1400 VFW Pkwy., West Rox- portant role in the genesis and progression of type 2 diabetes mellitus. Treatment of bury, MA 02132, or at raj_goyal@ hms rapid gastric emptying is emerging as an important target for the management of .harvard.edu. postprandial hyperglycemia. N Engl J Med 2021;384:1742-51. The gastric emptying rate represents a highly regulated output of nutrients into DOI: 10.1056/NEJMra2020927 Copyright © 2021 Massachusetts Medical Society. the intestine. The stomach discharges 1 to 4 kcal of homogenized food per minute, regardless of the carbohydrate, protein, and fat composition, into the duodenum.1 This remarkable feat is achieved through integrated motor activities of different parts of the stomach, regulated by intricate neurohumoral mechanisms2 (for details, see the Supplementary Appendix, available with the full text of this article at NEJM.org). Diabetes leads to patterns of abnormal gastric emptying by altering the motor activities of various segments of the stomach. These changes are mediated by dysfunction of vagovagal neural circuits, through interstitial cells of Cajal and smooth muscle (see the Supplementary Appendix). Sudden changes in blood sugar levels affect glucose-stimulated or glucose-inhibited neurons in the gastric inhibitory and gastric excitatory vagal circuits and lead to altered gastric emptying. Persistent hyperglycemia affects the molecular elements of neurons, smooth-muscle cells, and interstitial cells of Cajal through oxidative stress and products of the polarized M1 (proinflammatory) and M2 (prohealing, or repair) macrophages. These metabo- lites may have complex effects on cellular functions. They may induce transcriptional changes in proteins and in microRNA (miRNA), with consequent alteration of the cellular phenotype to hypercontractile or hypocontractile smooth-muscle cells. Upper abdominal symptoms resembling functional dyspepsia were thought to be due to underlying delayed gastric emptying. However, similar symptoms are associated with rapid gastric emptying, suggesting that gastroparesis may not be the cause of the symptoms. The symptoms may instead be due to parallel activation of sensory receptors induced by inflammatory changes in the gastric wall. There- fore, maneuvers to accelerate gastric emptying may not provide symptomatic relief and may worsen hyperglycemia. This review summarizes the pathophysiology of gastric emptying abnormalities

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in diabetes mellitus and the rationale for their ization to the M2 or M1 type. Polarization to M2 management. The current practice of treating macrophages suppresses M1 macrophages and symptomatic gastroparesis is extensively covered their inflammatory responses and results in se- in recent reviews.3-5 vere loss of neurotransmission, loss of interstitial cells of Cajal, and conversion of smooth muscle Metabolic Changes That Affect to the hypocontractile phenotype (see the Supple- Gastric Emptying mentary Appendix).

Glucose enters cells mainly through the glucose Transient Slow Gastric transporter (GLUT) and the sodium–glucose Emptying cotransporter (SGLT).6 Glucokinase converts intracellular glucose to glucose-6-phosphate, which Postprandial hyperglycemia is characteristic of undergoes glycolysis, a process that leads to the glucose intolerance in diabetes mellitus. Acute production of ATP and reactive oxygen species in hyperglycemia slows gastric emptying of digest- mitochondria.7,8 Mild oxidative stress causes tran- ible food during the digestive period and indi- scriptional up-regulation of the enzyme NADPH gestible food residues in the fasting period. oxidase 4 (NOX4), leading to moderate oxidative Deceleration of gastric emptying suppresses post- stress.9 In addition, moderate oxidative stress, prandial hyperglycemia and serves as a negative along with products of lipid oxidation, advanced feedback loop. Slowing of gastric emptying is glycation end-products, and reactive carbonyls, due to a reduction in the tone of the proximal alters the proteins of the extracellular matrix stomach and suppression of antral contractions.18 and increases macrophage adhesion and activa- Hyperglycemia also suppresses powerful con- tion. Depending on specific local signals, mac- tractions of the interdigestive migrating motor rophages10 undergo polarization to M111,12 or M2 complex,19 resulting in slow gastric emptying macrophages, producing a number of cytokines. during both digestive and interdigestive (fasting) Oxidative stress and cytokines may act through periods. transcriptional factors to modify signaling pro- As shown in Figure 1, hyperglycemia stimu- teins directly or through regulation of miRNAs.13,14 lates glucose-sensitive neurons in the vagal af- These noncoding RNAs are critical post-tran- ferents by suppressing ATP-sensitive potassium 20 scriptional regulators of gene expression. They (KATP) channels. Stimulation of the gastric in- can bind to their target messenger RNAs to sup- hibitory vagal motor circuit may affect electrical press the translation into cellular proteins and lead slow waves, as well as smooth muscle. Acute to marked changes in the cellular phenotype.9,15,16 hyperglycemia may disrupt the slow waves by Consequently, miRNAs are emerging as impor- affecting myenteric interstitial cells of Cajal, tant therapeutic targets.17 leading to isolated tachygastria (an increase in Different metabolic changes each produce the cyclic electrical activity in the stomach, with specific cellular alterations that result in distinct a frequency of >3.6 cycles per minute [cpm]),21 gastric emptying abnormalities. Immediate chang- although high glucose levels do not directly af- es in the plasma glucose level activate vagal mo- fect interstitial cells of Cajal.22 Tachygastria and tor circuits, resulting in transient gastric empty- other slow-wave abnormalities have been thought ing abnormalities. Chronic hyperglycemia in to cause reduced antral contractions; however, association with oxidative stress and macrophage slow waves do not correlate with mechanical polarization has distinctive effects on neuro- contractions.18 High glucose levels stimulate the muscular transmission, interstitial cells of Cajal, gastric inhibitory vagal motor circuit; such stim- and smooth muscle, depending on the type of ulation inhibits contractions and overcomes the macrophage polarization and the degree of oxi- hyperglycemia-mediated contraction of the iso- dative and inflammatory stress. Moderate oxida- lated smooth muscle.23 Transient slow gastric tive stress disrupts neuromuscular transmission, emptying due to acute hyperglycemia is a coun- causes a gain in the number of interstitial cells terregulatory phenomenon and does not require of Cajal, and converts smooth muscle to the treatment. The transient nature of the effects of hypercontractile phenotype. In addition, moder- hyperglycemia is attributed to the down-regula- ate oxidative stress promotes macrophage polar- tion of glucokinase.24

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Satiety

POMC PPG Dorsal motor GLP-1 Na+ G nucleus of the vagus Ci CCi G SGLT Glucose CCe Nucleus GLUT tractus solitarius GLUT

Glucose GLUT G G

Glucokinase GEVMC GIVMC Vagus nerve Glucose-6-phosphate Ach Ach Myenteric plexus Ce NANC

NG Ach ATP, NO, VIP KATP ATP + K X + K Smooth muscle ++ Depolarization Interstitial cells of Cajal Glucose-stimulated neuron Smooth-muscle contractility

Transient slow gastric emptying

Figure 1. Acute Hyperglycemia Causing Slow Gastric Emptying. Acute hyperglycemia triggers glucose-stimulated neurons of vagal afferents in the nodose ganglion (NG) and the nucleus tractus solitarius, which are part of the gastric inhibitory vagal motor circuit (GIVMC). They bear the glucose transporter (GLUT, type undefined) and sodium–glucose transporter (SGLT). Hyperglycemia results in a rapid increase in intracellular glucose levels. Glucokinase converts glucose to glucose-6-phosphate, which undergoes glycolysis to produce pyruvic acid, leading to the production of ATP in mitochondria. ATP inhibits ATP-sensitive potassium (KATP) channels, causes depolarization, and triggers afferent neurons to stimulate the GIVMC. However, the stimulatory effect of hyperglycemia is terminated because hyperglycemia also causes down-regulation of glucokinase. Activation of the GIVMC releases inhibitory transmitters (nitric oxide [NO], ATP, and vasoactive intestinal peptide [VIP]), which decrease smooth-muscle contractility and cause dysfunction of interstitial cells of Cajal, with resulting slow-wave abnormalities. Ach denotes acetylcholine, CCe catecholaminergic neuron of the excitatory pathway, CCi catecholaminergic neuron of the inhibitory pathway, Ce cholinergic neuron of the excitatory pathway, Ci cholinergic neuron of the inhibitory pathway, dorsal motor nucleus of the vagus, G γ-aminobutyric acid–producing (GABAergic) neuron, GEVMC gastric excitatory vagal motor circuit, NANC nonadrenergic noncholinergic neuron, POMC proopiomelanocortin neuron, and PPG preproglucagon neuron.

Transient Rapid Gastric tivity and thus leading to rapid gastric emptying. Emptying The GEVMC is also connected to glucagon-secret- ing alpha cells, to orexigenic (appetite-stimulating) Acute hypoglycemia causes fast gastric emptying. neurons, to the sympathoadrenal pathway, and to Iatrogenic hypoglycemia is a common and serious hypothalamic neurons involved in the counter- complication of insulin treatment. Acute hypo- regulatory responses to hypoglycemia. A blood glycemia causes activation of the gastric excit- glucose level below the normal range induces atory vagal motor circuit (GEVMC), which pro- parasympathetic activity and glucagon secretion. vides cholinergic excitatory innervation to the Further reduction of glucose levels triggers sym- gastric smooth muscle, enhancing contractile ac- pathetic activity.25

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Satiety

POMC PPG Dorsal motor GLP-1 G nucleus of the vagus Ci Glucose CCi GLUT2 Nucleus CCe tractus solitarius GIVMC GLUT Glucose G GEVMC Glucokinase GIVMC Vagus nerve Glucose-6-phosphate Ach Ach Myenteric plexus Na+/K+ ATPase Ce NANC

NG K+ leak Ach ATP, NO, VIP ATP K+ Smooth muscle ++ Cl- Interstitial cells of Cajal Glucose-inhibited Depolarization neuron Smooth-muscle contractility

Rapid gastric emptying

Figure 2. Acute Hypoglycemia Causing Rapid Gastric Emptying. GABAergic interneurons (G) in the GEVMC are very sensitive to glucose deprivation. Hypoglycemia causes loss of mitochondrial glycolysis and a decrease in ATP production. This leads to inhibition of Na+/K+ ATPase, blockade of the K+ leak channel, and, probably, opening of chloride channels, with resulting depolarization. Stimulation of GABAergic neurons leads to stimulation of the GEVMC, with release of acetylcholine at the neuromuscular junc- tion, excitation of smooth muscle, and rapid gastric emptying. A recurring episode of hypoglycemia may lead to up- regulation of glucokinase and up-regulation of alternative sources of energy, bypassing the signals of hypoglycemia.

The activation of GEVMC is due to stimula- Persistent Rapid Gastric tion of GLUT2-expressing, γ-aminobutyric acid– Emptying producing (GABAergic) neurons in the nucleus tractus solitarius. Hypoglycemia leads to a de- Formerly, persistent rapid gastric emptying was crease in intracellular glucose and lowers intra- not seriously considered as a complication of cellular ATP levels, causing reduced Na+/K+ diabetes mellitus. Almost 20% of patients with ATPase activity and membrane depolarization26 poorly controlled, long-standing, type 1 or type (Fig. 2). Responses to acute hypoglycemia are 2 diabetes mellitus, regardless of the presence or transient because of the rapid up-regulation of absence of upper abdominal symptoms, have glucokinase and the use of energy sources other rapid gastric emptying even in late stages of the than glucose. Transient rapid gastric emptying is disease.28-30 Dumping syndrome, with symptoms part of the counterregulatory response and should of postprandial nausea, bloating, light-headedness, not be treated. In recurrent hypoglycemia, these flushing, palpitation, abdominal pain, cramps, changes may serve as protective mechanisms borborygmi, and diarrhea, occurs after gastric- against hypoglycemia-associated autonomic failure bypass surgery.31 However, such symptoms do not and impaired awareness of hypoglycemia, which occur in patients with an intact stomach. Upper are potentially life-threatening conditions.26,27 abdominal symptoms are indistinguishable from

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Table 1. Prevalence of Normal, Rapid, and Delayed Gastric Emptying among Patients with Diabetes.*

Prevalence among Patients with or with- Prevalence among out Upper Abdominal Patients with Upper Effect on Postprandial Gastric Emptying Symptoms Abdominal Symptoms Hyperglycemia

percent Normal 33–46 43–52 No effect Rapid 20–22 20–37 Accentuates early postprandial hyperglycemic peak Delayed (diabetic gastro- 40–47 19–28 Delays early postprandial hyper- paresis) glycemic peak

* Patients with diabetes and upper abdominal symptoms have normal, rapid, or delayed gastric emptying; there is no specific relationship between the presence of symptoms and delayed gastric emptying. Patients who have diabetes with or without upper abdominal symptoms have similar distributions of gastric emptying abnormalities. Rapid gastric emptying may worsen postprandial hyperglycemia, whereas delayed gastric emptying postpones the hyperglycemic peak. Data for patients with or without upper abdominal symptoms are from Bharucha et al.28,29 Data for patients with upper abdominal symptoms are from Park et al.32 and Chedid et al.33

those of functional dyspepsia or gastroparesis. stress leads to loss of inhibitory neuromuscular Approximately 20 to 37% of patients with diabe- transmission, a transcriptional increase in c-Kit, tes and upper abdominal symptoms have rapid and an increased number of interstitial cells of gastric emptying.32,33 This rate is similar to that Cajal.39 Oxidative stress also causes transcrip- among patients with long-standing diabetes, tional down-regulation of miRNA-133a, leading whether or not they have upper abdominal symp- to up-regulation of the small guanosine triphos- toms28-30 (Table 1), which suggests that upper phatase protein RhoA and Rho-associated pro- abdominal symptoms are not specifically related tein kinase (RhoA–ROCK) signaling.44,45 These to rapid gastric emptying. The disorder may re- changes result in impaired gastric accommoda- spond to intensive insulin therapy in patients tion and increased contractility, promoting rapid with type 1 diabetes.29,34 gastric emptying.46 Products of M2 macrophages Rapid gastric emptying has a profound effect such as interleukin-10 and the enzyme heme on glucose intolerance,35 and it has been impli- oxygenase suppress M1 macrophages and prevent cated in the genesis and propagation of type 2 gastroparesis. Increased smooth-muscle contrac- diabetes mellitus.36 Correction of rapid gastric tility in other parts of the gut may involve other emptying by means of dietary manipulations and signaling pathways47 (see the Supplementary Ap- pharmacologic therapy is central to the manage- pendix for details). ment of postprandial hyperglycemia.37 Amylin or leptin deficiency is associated with chronic hyper- Gastroparesis glycemia and rapid gastric emptying.38,39 Agents such as metformin, amylin analogues, and short- Diabetic gastroparesis is the most talked-about acting glucagon-like peptide 1 agonists deceler- gastric complication of diabetes mellitus. Simply ate gastric emptying.34,40-42 stated, diabetic gastroparesis is a gastric motility Rapid gastric emptying is associated with complication of diabetes characterized by persis- reduced relaxation and increased contractility of tent delayed gastric emptying. Mechanical outlet the fundus as a result of impaired inhibitory obstruction and other coexisting conditions that transmission and enhanced smooth-muscle con- affect gastric emptying must be ruled out to es- tractility. Antral peristaltic contractions are aug- tablish the diagnosis. mented because of increased smooth-muscle contractility and possibly because of an increase Motor Abnormality in the number of myenteric interstitial cells of The prevalence of delayed gastric emptying in Cajal.43 untreated cases is 40 to 47% among patients with As shown in Figure 3, moderate oxidative type 1 diabetes mellitus and 32 to 47% among

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GEVMC GIVMC Vagus nerve

Ach Ach

Chronic Myenteric plexus hyperglycemia Ce NANC ATP, NO Inhibitory Relaxation NMT Ach ATP, NO, VIP X Smooth muscle Oxidative stress miR133a RhoA–ROCK Muscle contractility + Interstitial cells of Cajal + Transcriptional c-Kit ICC changes (ETV1) Impaired relaxation Increased smooth-muscle contractility M2 > M1 Interleukin-10 M1 Prevents gastroparesis Impaired accommodation More M2 than M1 Rapid gastric emptying macrophages

Figure 3. Pathogenesis of Rapid Gastric Emptying in Diabetes Mellitus. Chronic hyperglycemia may be complicated by moderate oxidative stress and the production of cytokines (e.g., interleukin-10) by M2 macrophages. Oxidative stress causes loss of purinergic and nitrergic neuromuscular transmitters (NMT), leading to loss of inhibitory neurotransmission. In addition, oxidative stress can down-regulate microRNA- 133a (miR133a), which leads to reciprocal up-regulation of RhoA and Rho-associated protein kinase (RhoA–ROCK) signaling and sustained smooth-muscle contractility. Oxidative stress also causes a gain of interstitial cells of Cajal (ICC) as a result of up-regulation of c-Kit.

those with type 2 diabetes.28-30 Diabetic gastro- duced accommodation, and poor tonic contrac- paresis does not change over time,29,48 and it tion impairs gastric emptying. occurs with both liquids and digestible solids, as A decrease in the propulsive contractions in well as with indigestible food residues. However, the gastric antrum leads to poor grinding and impaired gastric emptying of indigestible solids mixing of food and ejection into the duodenum. may be an earlier abnormality.49 These changes involve loss of cholinergic excit- Delayed gastric emptying may have a benefi- atory neuromuscular transmission and weakness cial effect in type 2 diabetes, since it postpones of the smooth muscle. In addition, abnormali- the postprandial hyperglycemic peak. In patients ties of slow waves may contribute to contractile receiving insulin therapy for diabetes, however, weakness. The gastric antrum may have periods such a delay may result in episodes of early post- of rapid slow-wave activity. Normally, the rate of prandial hypoglycemia unless careful adjustments slow-wave activity varies between 2.4 cpm and are made in the dose of insulin and the timing 3.6 cpm. Tachygastria indicates a slow-wave rate of administration. Treatment to hasten gastric greater than 3.6 cpm, and bradygastria indicates emptying may even worsen glycemic control.50 a rate less than 2.4 cpm. Abnormalities in the Diabetic gastroparesis is associated with mo- rate of slow waves may contribute to contractile tor abnormalities in various components of the weakness. However, the slow-wave abnormali- stomach, including defects in smooth muscles, ties correlate with symptoms of nausea rather interstitial cells of Cajal, and neurotransmission. than weakness of the contraction and may serve The gastric fundus is characterized by loss of re- as the electrical marker of nausea.51 Diabetic laxation due to suppression of inhibitory neuro- gastroparesis is characterized by abnormal ini- transmission, as well as reduced tonic contrac- tiation and conduction of slow waves on high- tion because of impaired muscle contractility. resolution electrical mapping. These abnormali- There are no phasic contractions or slow waves ties may contribute to disordered propagation of in the fundus. Reduced relaxation results in re- contractions and slow gastric emptying.52

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Although smooth muscle appears morpho- In some cases, clinically significant pyloric ob- logically normal in most cases of diabetic gastro- struction may be documented with the use of paresis, in very advanced cases, smooth-muscle techniques such as Endoflip impedance planim- degeneration, fibrosis, collagen deposits, and etry. Sham-controlled trials are needed to estab- eosinophilic inclusion bodies are observed.53 lish the usefulness of pyloric interventions to However, functional studies show that the con- promote gastric emptying in specifically defined tractility of smooth muscle is impaired in dia- cases of gastroparesis.3 It is known that place- betic gastroparesis. Augmentation of antral con- ment of a wide cannula in the pylorus does not tractions is one of the main mechanisms of accelerate gastric emptying in the absence of action of the gastric prokinetic agents used to efficient antral contractions. enhance gastric emptying.3,4,54 As shown in Figure 4, diabetic gastroparesis In diabetic gastroparesis, pyloric and duode- is associated with M1 macrophage polarization nal relaxation may be impaired, resulting in and release of inflammatory products. These outflow obstruction. Loss of pyloric relaxation products cause severe oxidative stress, leading to and antroduodenal coordination is caused by the loss of inhibitory neurotransmission through loss of inhibitory neuromuscular transmission.55,56 the uncoupling of nNOSα and scavenging of the In mice that lack neuronal nitric oxide synthase released neurotransmitter, nitric oxide. Severe isoform α (nNOSα −/−), the failure of inhibitory oxidative stress also causes loss of purinergic in- neuromuscular transmission has been associated hibitory transmission.46 with functional outlet obstruction. However, in The loss of interstitial cells of Cajal is due to diabetic gastroparesis, impaired smooth-muscle tumor necrosis factor (TNF) or TNF-α and tran- contractility may weaken the outlet obstruction. scriptional up-regulation of caspase.57 Interstitial

Chronic hyperglycemia

Oxidative stress

M1 > M2 More M1 than M2 GEVMC GIVMC macrophages Vagus nerve

Ach Ach Inflammatory mediators Myenteric plexus Ce NANC Oxidative stress ATP, NO Inhibitory Smooth-muscle NMT relaxation Ach ATP, NO, VIP X Smooth muscle TNF-α miR133a RhoA–ROCK Smooth-muscle contraction X Interstitial cells of Cajal X TNF-α NF-κB Caspase ICC Loss of relaxation Loss of smooth-muscle contractility

Loss of accommodation Delayed gastric emptying

Figure 4. Pathophysiological Features of Gastroparesis. Inflammatory stress and products of M1 macrophages such as tumor necrosis factor α (TNF-α) may cause a transcriptional increase of miR133a and reciprocal suppression of RhoA–ROCK signaling. Impaired RhoA–ROCK signaling leads to impaired sustained contraction. Defective smooth-muscle contractility due to impaired RhoA–ROCK signaling has been reported in ob/ob mice. NF-κB denotes nuclear factor κB.

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cells of Cajal are very fragile and can be reduced dyspepsia. Upper abdominal symptoms suggestive through other pathways, including reduced insu- of functional dyspepsia occur in up to 10% of lin and insulin-like growth factor signaling,22 the general population.66 Delayed gastric empty- myopathy of smooth muscle and subsequent loss ing is reported in 19 to 28% of patients with dia- of the stem-cell factor,58 and loss of nitric oxide.59 betes who have upper abdominal symptoms32,33 Reduced muscle contractility may be due to (Table 1). Cherian et al., in their study of symp- M1 macrophage polarization, with release of toms of diabetic gastroparesis, included patients TNF, interleukin-6, and other inflammatory cyto- with coexisting medical conditions who were kines.60 TNF is known to cause up-regulation of receiving treatment with opiates or psychothera- miRNA-133a through the transcription factor peutic agents that may produce symptoms unre- nuclear factor κB, with an associated decrease in lated to diabetic gastroparesis.67 A revised GCSI RhoA–ROCK signaling in gastrointestinal smooth with a daily diary score for symptoms was devel- muscles.44 Severe oxidative stress may lead to oped to quantitate the severity of the symptoms. reduced muscle contractility.45 Reduced RhoA– No significant correlation was found between ROCK signaling associated with hypocontractile the symptom score and gastric emptying.67 smooth muscle has been reported in diabetic The available studies do not support a causal gastroparesis.61 These observations from studies relationship between motor abnormalities and carried out in experimental models resemble symptoms in diabetic gastroparesis. The most transcriptomic signatures of immune dysregula- telling argument against gastric motor abnor- tion in human gastroparesis.54,62 malities in diabetic gastroparesis is the fact that patients with diabetes and upper abdominal Upper Abdominal Symptoms symptoms have normal, delayed, or rapid gastric Diabetic gastroparesis was originally described emptying32,33 (Table 1). The frequency of reduced in 1958 by Kassander63 in a group of patients with gastric accommodation is not higher among pa- diabetes who had irreversible delayed gastric emp- tients with gastroparesis than among those with tying and gastric stasis without mechanical ob- normal or accelerated gastric emptying.33 More- struction (gastroparesis diabeticorum), which was over, the normalization of gastric emptying does thought to be due to an abnormality of gastric not ameliorate symptoms with any consisten- motility. Later, patients with diabetic gastropa- cy,68-71 nor does the amelioration of symptoms resis were found to have upper gastrointestinal result in improved gastric emptying.72 symptoms. Merriam-Webster’s Medical Dictionary de- In recognizing that there is no causal relation- fines gastroparesis as “partial paralysis of the ship between motor abnormalities and symp- stomach” and, citing G.F. Cahill et al., notes that toms, some clinicians wondered whether gastro- “diabetic gastroparesis is characterized by a triad paresis is a separate entity or simply part of of postprandial symptoms: nausea, vomiting, and dyspepsia.73 Moreover, the use of invasive ma- abdominal distension.” Diabetic gastroparesis with neuvers to target gastric emptying for the relief upper abdominal symptoms has been called “clin- of symptoms has been discouraged.74 The obser- ical or symptomatic gastroparesis.” Other symp- vation that acceleration of gastric emptying may toms, including severe upper abdominal pain, worsen hyperglycemia50 further arouses concern have been added to the definition of gastropare- about the indiscriminate use of such interven- sis, resulting in ever-changing definitions.3-5,64 tions. It appears that functional dyspepsia–like To identify symptoms of diabetic gastropare- symptoms in gastroparesis may arise not through sis that are distinct from those of functional motility changes but rather through the parallel dyspepsia, the Gastroparesis Cardinal Symptom effects of oxidative stress and inflammation on Index (GCSI) and the Patient Assessment of Gas- nociceptors and on other afferents that produce trointestinal Disorders Symptom Severity Index the symptoms.75 Recent concepts of the mecha- (PAGI-SYM) were developed. Cardinal symptoms nism of functional dyspepsia suggest the involve- of gastroparesis included postprandial fullness, ment of low-grade inflammation and noxious early satiety, nausea, vomiting, and bloating, which mediators in symptoms related to functional did not distinguish between functional dyspep- dyspepsia.76 The effective treatment of symptoms sia and clinical gastroparesis.65 Therefore, clinical in diabetic gastroparesis may be similar to the gastroparesis is considered to be part of functional treatment of functional dyspepsia.

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Conclusions ing as an important mechanism in postprandial hyperglycemia. Studies in animals have shown that The recent development of easy-to-use, reproduc- vagus nerves may control gastric emptying through ible tests (gastric scintigraphy or a stable-isotope vagovagal circuits and that metabolic products as- 13C breath test) has helped to identify different sociated with hyperglycemia may have distinct ef- gastric emptying abnormalities, particularly rapid fects on gastric motility. An understanding of the gastric emptying. Recent studies have shown that mechanisms of these complications may help to symptoms attributed to gastroparesis are not spe- identify new targets for rational treatment. cific but can also be seen in rapid or normal gastric Disclosure forms provided by the author are available with the emptying. Rapid gastric emptying is now emerg- full text of this article at NEJM.org.

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