J Neurogastroenterol Motil 2024; 30(2): 143-155  https://doi.org/10.5056/jnm23100
Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis
Yu-Xin Zhang, Yan-Jiao Zhang, Min Li, Jia-Xing Tian,* and Xiao-Lin Tong*
Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
Correspondence to: *Jia-Xing Tian, MD
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, No.5 North Line Pavilion, Xicheng District, Beijing 100053, China
Tel: +86-010-88002289, E-mail: tina_yai@126.com
Xiao-Lin Tong, MD
Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, No.5 North Line Pavilion, Xicheng District, Beijing 100053, China
Tel: +86-010-88001166, E-mail: tongxiaolin@vip.163.com

Jia-Xing Tian and Xiao-Lin Tong are equally responsible for this study.
Received: July 6, 2023; Revised: October 29, 2023; Accepted: November 6, 2023; Published online: April 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP.
Keywords: Diabetes mellitus; Gastrointestinal hormones; Gastrointestinal motility; Gastroparesis; Interstitial cells of Cajal
Introduction

The International Diabetes Federation estimates that in 2021, there will be 537 million individuals with diabetes globally, including over 140 million adults in China, where the prevalence rate is 13%, the highest in the world.1 Impaired movement of the entire bowel in diabetic patients results in gastroparesis, diabetic gastroparesis (DGP) is a syndrome characterized by delayed gastric emptying and upper gastrointestinal symptoms. Its main symptoms include nausea, vomiting, early satiety, postprandial fullness, abdominal distension, upper abdominal pain, and weight loss.2 The etiology of gastroparesis is complex and can be divided into 3 categories: surgery-related gastroparesis, non-surgery-related gastroparesis, and idiopathic gastroparesis.3 Among all patients with gastroparesis, non-surgical gastroparesis accounts for 85%, and DGP is the most common type of non-surgical gastroparesis.4 Gastroparesis’ standardized incidence increased from 1.5 per 100 000 people per year in 2004 to 1.9 per 100 000 people per year in 2016, 37.5% of patients with gastroparesis have diabetes-related gastroparesis, and their mortality risk is much higher than that of individuals with idiopathic gastroparesis.5 The patient’s quality of life and productivity may be significantly affected by DGP, which can also have a significant financial and indirect social impact on society and healthcare providers.6

Diabetes causes irregular gastric emptying patterns by changing the motor activity of distinct parts of the stomach. Glucose-stimulated or glucose-inhibited neurons in the stomach inhibitory and gastric excitatory vagal circuits are impacted by abrupt changes in blood sugar levels, which results in altered gastric emptying.7 Clinical manifestations of gastroparesis and decreased gastric emptying may be brought on by physiological alterations, including motor abnormalities, dysmotility of the small intestine, diminished pyloric relaxation, antral hypomotility, and impaired accommodation of the gastric fundus/body.8,9 The inhibitory and excitatory components of the enteric nervous system (ENS), interstitial cells of Cajal (ICC), fibroblast-like cells, and gastric smooth muscle work in concert to coordinate the neuro-muscular activity necessary for normal stomach function.10,11 Neurological illnesses that impact the digestive system typically present as anomalies in motor (rather than sensory or secretory) processes, gastric motility disorders can be considered as a major source of dyspeptic and gastroparesis symptoms. Through the ENS, the motor, secretory, sensory, storage, and excretory activities of the gastrointestinal tract are intricately controlled by the external and autonomic nervous systems.12 Persistent hyperglycemia alters the molecular constituents of neurons, ICC, and smooth muscle cells (SMCs) via oxidative stress and products of polarization macrophages. These metabolites may lead to transcriptional alterations in proteins and microRNA (miRNA), altering the cellular phenotype to produce SMCs that are either hypercontractile or hypocontractile.7

To provide future research directions and identify treatment strategies for DGP, this review will summarize recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment.

Interstitial Cells of Cajal and Diabetic Gastroparesis

The destruction and loss of ICC is the most common histological aberration in people with gastroparesis, and several gastrointestinal motility issues may be related to changes in the number, shape, or density of ICC (Figure).13 Gastric emptying is carried out by antral peristalsis, whose failure is known as gastroparesis and is frequently brought on by ICC dysfunction.14 Many motor neurons (inhibitory and excitatory) form close association with ICC, indicating that ICC can mediate neurotransmission from intestinal neurons, and the number and structure of ICC are related to a variety of gastrointestinal motility disorders.15 ICC is an important part of the intestinal control system that controls how quickly the stomach empties.16 In animal models of diabetes and human gastroparesis, ICC loss is the most often and reliably observed cellular abnormality, and numerous gastrointestinal motility problems may be linked to alterations in the quantity, shape, or density of ICC. According to studies, the most prevalent histological abnormality in individuals with gastroparesis—which accounts for around 83% of cases—is destruction and loss of ICC.17 A significant reduction of ICC in the gastric sinus of diabetic rats induced with streptozotocin was observed at week 12, and a similar phenomenon was observed in non-obese diabetic mice.18,19

Figure 1. Mechanisms of gastrointestinal motility modulation in diabetic gastroparesis. The destruction and disappearance of interstitial cells of Cajal (ICC), abnormal levels of hormones in the gut-brain axis that affect gastric function and mitochondrial oxidative stress disorder leads to gastrointestinal dysfunction and produces gastroparesis. 5-HT, 5-hydroxytryptamine; CCK, cholecystokinin; SST, somatostatin; ROS, reactive oxygen species; SMCs, smooth muscle cells.

Structure and Function of Interstitial Cells of Cajal

As a distinct population of SMCs descended from regular mesenchymal cells, ICC may be thought of as a unique population. The membrane of the ICC, which consists of a spindle cell body with thin cytoplasm, big oval nuclei, and dendritic processes, contains numerous mitochondria, an abundance of endoplasmic reticulum, and several groups of channels.20

ICC may be divided into many sorts based on where in the body it is located anatomically and how its cells look. (1) Myenteric ICC is a multipolar cell with branching protrusions located mainly in the interstitial space between the cricoid and longitudinal muscles of the gastrointestinal tract.21 With its distinct ionic current, myenteric ICC serves as the primary pacing cell for the muscles of the stomach and small intestine. It can regulate the contraction and peristalsis of gastrointestinal smooth muscle by causing spontaneous electrical activity in gastrointestinal muscles to form electrical slow waves that propagate from the proximal stomach to the distal end at a rhythm of three cycles per minute.22 (2) Septal ICC were discovered in septal portions of the antrum that separated circular muscle bundles. The circular muscle bundles are separated by a septum, and this septum, which is home to the septal ICC, might help the myenteric ICC transfer electrical signals to other circular muscle bundles that are farther away.23 (3) In the stomach, intramuscular ICC were the first ICC reported to receive cholinergic and nitrergic neural input.24 Intestinal motor nerve primarily innervates intramuscular ICC, which also expresses receptor, transduction mechanism, and ion conduction and is closely related to the vagus afferent nerve.25 (4) The ICC of the deep muscular plexus, which can produce stimulus-dependent pacemaker activity, can be used to coordinate small bowel segmentation and cluster propulsion actions.26 (5) In the pyloric region of the colon and the stomach, respectively, the ICC of submucosa and submucosal plexus are located at the interface between the submucosal connective tissue and the innermost circular muscle layer.27 (6) The connective tissue below the mesothelium contains ICC-SS, which are stellate, multi-processed cells. These cells are organized along the axis of the longitudinal muscle fibers in the proximal colon and form an electrical network via intercellular gap junctions.28

Hyperglycemia has been shown to accelerate sluggish stomach emptying and the start of gastric dysrhythmias, as well as to cause nausea, vomiting, and pain in the abdomen. Slow waves and motility in diabetes are influenced by the level of glycemic control. Compared to the temporal dysrhythmias, the spatial dysrhythmias of stomach slow waves were demonstrated to be more common and to last longer.29 Slow wave activity is a key feature of stomach muscles that is responsible for peristaltic contractions that triturate solid foods into minute particles to promote gastric emptying and efficient digestion and absorption of nutrients in the small intestine. Myenteric ICC generates and actively propagates electrical slow waves in the stomach. Slow waves’ plateau phase is both initiated and aided by the release of Ca2+ and the activation of Ano1 channels.30 Higher slow wave velocities would result in an increase in the gastric emptying rate, according to computational simulations. A higher slow wave velocity is correlated with aging and ICC loss.31 It is well recognized that metabolic abnormalities, especially hyperglycemia, can cause arrhythmia in diabetics. Electrogastrography has shown a correlation between greater rates of dysrhythmia and ICC loss, indicating that ICC network damage predisposes to irregularities in initiation.32

Interstitial Cells of Cajal and Stem Cell Factor/c-Kit Signaling Pathway

The c-Kit is an unique marker of ICC, a receptor tyrosine kinase that affects the growth and differentiation of various progenitor cells and is involved in intracellular signaling.33 In the gastrointestinal tract, c-Kit promotes ICC formation, and this type of cells establishes gap junctions with SMCs in visceral smooth muscle and performs critical regulatory activities.34 Activation of c-Kit is dependent on the presence of its ligand stem cell factor (SCF), which has recently been shown to be critical for motor signaling in the gastrointestinal tract.35 Growth factor SCF, which is encoded at the Steel locus, can be soluble or transmembrane-bound and is crucial for a number of biological processe.36 Neuroblastoma cells and SMC express SCF in the gastrointestinal tract and may give suitable signals for ICC functional development and plasticity.37 Krüppel-like factor 11 (KLF11), a transcription factor that negatively affects KIT expression, is the target of miR-10b-5p. Through the KLF11-KIT pathway, miR-10b-5p is a crucial regulator of diabetes and gastrointestinal dysmotility. MiR-10b-5p is significantly downregulated in ICCs from diabetic mice compared to ICCs from healthy mice. Diabetes and gastroparesis are brought on by the conditional deletion of mir-10b in KIT cells or by the depletion of KIT cells in mice. Comparing the miR-10b-5p mimic to popular antidiabetic and prokinetic drugs, the miR-10b-5p mimic is more effective at enhancing glucose homoeostasis and gastrointestinal motility.38

Streptozotocin-induced DGP model rats had considerably less SCF mRNA in their gastric tissue, which also resulted in less c-Kit protein expression, the development of ICC ultrastructural lesions, and a delayed stomach emptying.39 The number and operation of ICC are regulated by exogenous SCF and c-Kit. Exogenous SCF therapy enhanced or corrected ICC-related degenerative alterations and gastrointestinal motility abnormalities in diabetes model mice, and also alleviated organ dysfunction brought on by decreased ICC number.40 According to the study, atractylenolide-1 improved ICC survival and maintained the organization of the gastric tissue network in a rat model of DGP via activating the SCF/c-Kit signaling pathway, offering new therapy options for DGP.41 Ets variation 1 (ETV1) is a survival factor expressed by ICC and is sustained by physiological levels of c-Kit, which is necessary for the upkeep of healthy ICC networks. Through the extracellular signal-regulated kinase (ERK)-ETV1-KIT pathway, hyperglycemia promotes ICC proliferation. Rapid gastric emptying is caused by hyperglycemia increasing ICC through mitogen-activated protein kinase 1 (MAPK1) and MAPK3 signaling to ETV1 and KIT.42 The voltage-dependent ion channel currents that are associated to ICC function are primarily mediated via the SCF/c-Kit signaling pathway. The study shows that SCF activates cytoplasmic mediators including PI3K/AKT, RAS/ERK, and JAK/STAT once it binds to a c-kit receptor in ICCs, which leads to downstream signaling and physiologic consequences, including those on gastrointestinal motility.43

Brain-Gut Axis and Diabetic Gastroparesis

A complex neuro-endocrine network exists between the brain and the gut, and this network links the brain to the gastrointestinal tract, hence the term brain-gut axis.44 The brain-gut axis may be stimulated by various stressors targeting the CNS, ENS and autonomic nervous system, and is a bidirectional axis of regulation of gastrointestinal tract function interacting with the nervous system.45 The gastrointestinal tract is an organ with sensory and motor functions in the body, and abnormal mental activity can lead to changes in sensory and motor functions of the gastrointestinal tract, causing gastrointestinal motility disorders.46 The regulatory function of the brain-gut axis is mainly manifested in the reception of information from the ENS and the CNS by various target cells and target organs in the gastrointestinal tract.47 In addition to neurotransmission between the brain and the gastrointestinal tract, there are also hormones in the gut-brain axis that affect gastric function regulating a variety of complex functions of the gastrointestinal tract such as motor, sensory, secretory, and absorption (Figure).48

Motilin

The frequency of the code-shifting mutation p.l u202argfster105 within the motilin receptor gene variant rs562138828 was found to be increased in patients with DGP.49 Motilin is a 22-amino acid peptide hormone that is largely generated by enteroendocrine cells in the small intestine duodenum and is expressed in the gastrointestinal tracts of humans and other species.50 Motilin’s principal organ of action is the stomach, which induces contraction of the gastric body and sinus and relaxation of the pylorus and plays an important role in encouraging gastric emptying during the interdigestive phase.51 In the fasting state, plasma motilin levels change in tandem with the migrating motor complex’s (MMC’s) phase III contractions, and causes stomach contractions via cholinergic pathways to signal famine.52 The fundic area of the stomach relaxes after a meal to handle the increase in volume without increasing pressure. By raising the proximal stomach tone, motilin administration significantly lowers the accommodation reflex in humans.53 In addition to controlling gastrointestinal motility, motilin may also play a role in the intestinal islet axis since it activates the release of insulin through neurohumoral pathways.54

Motilin accelerates gastric emptying in DGP, and motilin receptors such as erythromycin derivatives may be effective in the treatment of disrupted gastric emptying in diabetic individuals.55 Motilin accelerates gastric emptying in DGP, and motilin receptors such as erythromycin derivatives may be effective in the treatment of disrupted gastric emptying in diabetic individuals. Motilin receptors are expressed in the muscles and myenteric plexus of the human colon and are important therapeutic targets for the treatment of gastrointestinal motility disorders.49 Motilin receptor agonists promote enteric cholinergic activity in a short- or long-lasting way, which promotes stomach emptying. Low doses of a motilin receptor agonist that specifically activates nerve receptors in the stomach rather than smooth muscle receptors to stimulate gastric emptying and the vagus nerve to increase appetite and lessen nauseous symptoms are available.56

Ghrelin

Ghrelin, an acylated peptide mostly generated by the stomach, was shown to be a natural ligand of the growth hormone secretagogue receptor 1a (GHS-R1a) in 1999, and Ghrelin was initially detected in the stomach of rats. Ghrelin is mostly produced by endocrine cells in the fundus and corpus of the stomach in humans, with smaller amounts also being produced by the antrum, duodenum, jejunum, ileum, and colon.57 Ghrelin and motilin hormones and receptors are members of the same sub-family of G-protein coupled receptors. Similar functions in the stomach are performed by the peptides ghrelin and motilin, which both promote gastric motility and acid output.58 The release of many peptide hormones, including motilin and ghrelin, contributes to gut-brain signaling with implications for hunger and satiety management.59 Therefore, ghrelin and its receptor may affect ICCs in the mouse small intestine to modify gastrointestinal motility.60 Ghrelin acts centrally and peripherally through binding to the GHS-R1a receptor. Ghrelin maintains energy balance, promotes food intake, and induces the release of growth hormone centrally. Ghrelin’s peripheral actions include regulating gastrointestinal contractility and gastric emptying.61 In healthy human volunteers, ghrelin has been demonstrated to enhance stomach motility and quicken gastric emptying. During this early interdigestive MMC, the stomach tone increased gradually.62

In the early stages of diabetes mellitus, the stomach secretes much more ghrelin into the plasma, and higher plasma ghrelin levels are associated with faster gastrointestinal motility and hyperphagic food in diabetics. Late diabetes may cause a drop in plasma ghrelin levels, which may be caused by a delayed gastrointestinal transit.63 Due to its ability to improve stomach emptying in patients with DGP, ghrelin has been suggested as a target for the therapy of gastrointestinal motility issues like this condition.64

5-Hydroxytryptamine

DGP is more closely related to 5-hydroxytryptamine (5-HT) receptors. Gastrointestinal 5-HT regulates gastrointestinal function through 5-HT receptors distributed throughout the gastrointestinal tract.65 About 95% of 5-HT in the body is synthesized by gastrointestinal enterochromaffin (EC) cells, human EC cells can function as glucose sensors during meal digestion and respond by secreting 5-HT.66 5-HT is released in response to a variety of mechanical forces, which in turn trigger or support gut neural reflexes that control motility and secretion, peristaltic waves, mixing movements (in the fed state), the MMC (in the fasted state), and mass movement during the defecation reflex.67

Functional gastrointestinal diseases can be effectively treated by targeting 5-HT signaling molecules. Through activation of a wide family of 5-HT receptors on intrinsic and extrinsic afferent nerve fibers that are situated in the lamina propria, 5-HT produced from EC cells regulates various gastrointestinal activities, including peristalsis, secretion, vasodilation, and experience of pain or nausea.68 5-HT4 agonists were found to be successful therapies for a variety of functional gastrointestinal motility problems like constipation, constipation-predominant irritable bowel syndrome, functional dyspepsia, and DGP.69

Gastrin and Somatostatin

The levels of gastrin and somatostatin (SST) can be used as a reference index for the clinical diagnosis of DGP. Patients with DGP have markedly high gastrin and low SST. The main reason for this pathology may be the inhibition of vagal activity by high blood glucose, which leads to a decrease in the level of SST, which further diminishes the inhibitory effect on gastrin and leads to a further increase in gastrin levels. In addition, the occurrence of gastroparesis in diabetic patients will reduce the secretion of gastric acid, gastrin will be compensated for the increase in gastrin, reducing the secretion of SST.70

Gastrin is a gastroduodenal hormone that promotes gastric fundic mucosa development and acid secretion.71 The most effective stomach secretagogue currently understood is gastrin, which can be elevated through mechanical or chemical stimulation. G cells in the antral and duodenal mucosa are the primary source of gastrin production and subsequent release to blood in healthy adult people.71 Gastrin’s biological targets in the stomach are the histamine-producing enterochromaffin-like (ECL) cell and the parietal cell, which secretes acid. Gastrin is a trophic hormone that promotes parietal and ECL cell proliferation as well as maintaining the health of the gastric mucosa.72 Gastrin has complex effects on gastric motility, slowing down gastric emptying, causing the gastric antrum to contract, and improving the stomach’s ability to crush food.73 Augmented gastrin responses in diabetic patients with autonomic neuropathy may be the early manifestation of DGP. There is a significant reduction of gastric emptying rate and elevated gastrin concentrations in diabetic patients with autonomic neuropathy.74

SST is an important gastrointestinal hormone with a wide range of inhibitory effects, and can inhibit the secretion of various gastrointestinal hormones, such as motilin, gastrin, and cholecystokinin (CCK).75 It also has a great effect on gastrointestinal motility. SST, a substance found in the D cells of the gastric pyloric and oxyntic mucosa, is the primary inhibitor of acid production, especially during the interdigestive phase. Somatostatin inhibits the release of gastrin from G cells, histamine from ECL cells, and acid from parietal cells in a tonic paracrine manner. This restriction is removed by priming and maximizing acid secretion during feeding by activating cholinergic neurons.72 The brain and gastrointestinal system both benefit from the action of SST and somatostatin receptors (SSTRs). The physiological processes of digestion and absorption in the gastrointestinal system are inhibited by SST-SSTRs. gastrointestinal function may be modulated by SST via its receptors, which are released by the pituitary and found in circulating blood.76

Cholecystokinin

Gastrin and CCK are members of the same family of gastrointestinal peptides that control a range of digestive and nervous system processes.77 CCK is a hormone generated by I cells in the small intestine that regulates postprandial gallbladder contraction and bile evacuation, gallbladder emptying, pancreatic secretion, delayed gastric emptying, and food intake inhibition.73 In patients with type 2 diabetes mellitus with gastroparesis, serum CCK levels decreased, and CCK levels decreased as the disease worsened, and there was a negative correlation between gastric half-emptying and CCK levels.78 CCK is a prototype of gastric braking hormones and it is released by neuroendocrine cells in the duodenum by stimuli such as hydrochloric acid, amino acids, and fatty acids.79 CCK acts to stimulate the stomach inhibitory vagal circuit at numerous levels. CCK activates vagal afferent ends of the vagal inhibitory circuit in a paracrine fashion, may operate on nodose ganglion, and may boost synaptic neurotransmission at the vagal afferent second-order neurons by enhancing release of glutamate in the nucleus tractus solitarius.80 CCK also exerts its stomach inhibitory effect by stimulating the myenteric non-adrenergic non-cholinergic inhibitory neurons.81 The use of CCK1 antagonists as prokinetics for the treatment of gastric reflux disease, bowel disorders, and gastroparesis may also have therapeutic potential for the treatment of pancreatic disorders.82 Research indicates that CCK1 antagonists may be useful in treating gastroparesis, and that CCK2 antagonists may also affect the secretion of stomach acid.82

Oxidative Stress and Diabetic Gastroparesis

Oxidative stress is responsible for various diabetic complications leading to gastric mucosal damage and gastric motility disorders, such as DGP. Vitamin C attenuated oxidative stress, maintained gastric fundic and pyloric cholinergic contractile responses, and showed significant improvement in impaired gastric emptying in diabetic rats.83 Macrophages play a crucial role in maintaining homeostasis and protecting the body from different pathogens. Muscularis propria macrophages are found near cells that regulate gastrointestinal motor activity, such as ICC and myenteric neurons. Decreased networks of ICC and loss of macrophages that produce cytoprotective markers have been linked to the development of delayed stomach emptying in animal models of DGP.84 Studies on diabetic colony-stimulating factor 1 gene (Csf1op/op) and wild-type mice indicated that delayed stomach emptying was linked to increased production of inflammatory factors and decreased production of anti-inflammatory factors by macrophages, which resulted in loss of ICC.85 Heme oxygenase (HO) shields tissues from oxidative stress not only directly but also by polarizing and activating macrophages. In diabetic animal models, activation of macrophages with high levels of HO1 expression protects against the development of delayed gastric emptying, HO1 and macrophage targeting may therefore be therapeutic options for DGP.86 Rats with diabetes-related gastroparesis showed excessive reactive oxygen species production, lost MAPK phosphatase-1, a MAPK pathway negative regulator, and consequent activation of the c-Jun N-terminal kinase 2 and p38MAPK pathways. No discernible pathway activation was seen in diabetic rats without gastroparesis.87

Comparatively to the control group, DGP rats showed a decrease in the number of gastric ICCs, an alteration in the ultrastructure of the stomach, and a decrease in the quantity of cell organelles, particularly mitochondria.88 In gastric SMCs, apoptosis and abnormalities in energy metabolism were found during the onset of DGP. AMPK was activated in response to high glucose levels, and this protein can encourage glycolysis, inhibit mitochondrial energy metabolism, and affect the method by which cells metabolize energy.89 A basic leucine zipper transcriptional factor called nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in the induction of antioxidant enzymes.90 Nrf2 is tightly linked to immune modulation and oxidative stress, by restoring normal inflammation and oxidative stress brought on by obesity-induced chronic diabetes, Nrf2 activation restores nitrergic-mediated stomach motility and gastric emptying.91 Nrf2 activation restored neuronal nitric oxide synthase (nNOS) in primary enteric neural crest cells (pENCs) cells by reducing inflammatory markers. A negative feedback mechanism for the activation of glycogen synthase kinase 3 is shown by Nrf2 inhibition. Nrf2 reduces hyperglycemia-induced nNOS impairment in adult mouse pENCs and restores stomach function.92

Multi-omics Research and Diabetic Gastroparesis

Human gastroparesis has been linked to immunological dysregulation based on macrophages, as determined by more thorough molecular characterization employing transcriptomics and proteomics.93 Full-thickness gastric body biopsies were performed on DGP, diabetic non-gastroparetic controls and 111 genes showed altered expression in DGP. Genes related to macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis, the osteoarthritis pathway, and differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F were among the top canonical pathways in DGP. Validation studies were chosen for 5 highly differentially expressed genes in DGP. According to the results of the RNA sequencing research, 4 of these (APOLD1, CXCR4, CXCL2, and FOS) were considerably downregulated in DGP.94 Full-thickness gastric antrum biopsies were taken from 9 DGP patients and 5 nondiabetic controls in order to identify the wider protein expression (proteomics) and protein-based signaling pathways in patients with the condition. Comparing DGP to controls, 73 proteins were altered. Changes in protein expression point to complement activation in DGP as the primary cause of the immunological dysregulation caused by macrophages in gastroparesis. Symptoms and a delay in stomach emptying in DGP were linked to proteins in the prostaglandin production and complement pathways.95

A study compared the expression of mRNAs and miRNA between patients with diabetic gastroenteropathy (DGE) and healthy controls, and investigated the association between the transcriptome and clinical characteristics in DGE using duodenal mucosal biopsies as a substitute for gastric neuromuscular tissue. Between DGE and healthy controls, there were 3175 duodenal mucosal genes that were differently expressed. Oxidative phosphorylation and mitochondrial dysfunction were the pathways that were most substantially enriched with the differentially expressed genes. A neuropathy and delayed gastric emptying in DGE were linked to a principal component, which was identified by reduced expression of 10 of 12 mitochondrial DNA and increased expression of all 58 nuclear DNA oxidative phosphorylation genes. In comparison to controls, DGE patients had considerably lower levels of mitochondria, and these variations in mitochondrial genes represented by mitochondrial DNA and nuclear DNA were inversely linked with a number of differentially expressed miRNAs.96

To sequence the promoter region of the genomic DNA in the blood of people with diabetes and no symptoms of gastroparesis, diabetes and symptoms of gastroparesis, and people who have gastroparesis. Research tested for relationships with gastroparesis using statistical analyses of short (< 29), medium and long (> 32) repeat alleles as well as changes in allele length. As compared to non-diabetic controls, type 2 diabetics with gastroparesis had allele lengths that were the longest. Among the HO1 gene, longer poly-GT repeats are more prevalent in African Americans with gastroparesis. In subjects with longer alleles, the symptoms of nausea are worse.97

Treatment of Diabetic Gastroparesis

Prokinetic Medicines for Diabetic Gastroparesis Therapy

Prokinetic therapy should be taken into consideration as a way to improve gastric emptying and gastroparesis symptoms because prokinetics improve the coordination among the gut’s segments, which is required for the propulsion of bowel luminal contents.98 Prokinetic medicines are drugs that improve the coordinate movement of food through the gastrointestinal tract, primarily by amplifying and coordinating the muscle contractions of the gastrointestinal tract.99

Dopamine receptor antagonist (metoclopramide and domperidone)

Oral dopamine antagonists were found to be more effective for gastroparesis in a network meta-analysis than a placebo.100 Metoclopramide, a dopamine and 5-HT receptor antagonist.101 Metoclopramide’s efficacy in treating DGP can be attributed to 2 mechanisms-a peripheral influence on accelerating stomach emptying and a central effect on lowering nausea and vomiting.102 Metoclopramide enhances the tone of the lower esophageal sphincter and the peristalsis of the duodenum and jejunum, which results in a more normal pace of gastric emptying. It also stimulates the upper gastrointestinal tract and increases the amplitude of gastric contractions.103 The chemoreceptor trigger zone, which receives information from the gastrointestinal tract, vestibular system, and higher centers in the brain and thalamus, is situated in the dorsal surface of the medulla oblongata, on the floor of the fourth ventricle.104 Metoclopramide reduces nausea and vomiting by blocking dopamine D2 and 5-HT3 receptors at the chemoreceptor trigger zone.105 Metoclopramide is presently the only medicine authorized by the United States Food and Drug Administration (FDA) for the treatment of gastroparesis.106 Several dosage forms of metoclopramide are offered, including parenteral, liquid, nasal spray and oral dissolving tablets as well as oral tablets. In diabetic individuals with gastroparesis symptoms, metoclopramide nasal spray provides better symptom management than metoclopramide oral tablets.107,108 Metoclopramide can pass the blood-brain barrier, which allows it to have more severe extrapyramidal adverse effects include tremors, sadness, anxiety, and, in rare instances, tardive dyskinesia.109,110 Metoclopramide was given a black box warning by the FDA because of these risks in 2009.111 Since the safety and effectiveness of metoclopramide in pediatric patients have not been demonstrated, it is only advised for use in adults, and it should not be administered for more than 12 weeks at a time.102 Through the immunomodulatory actions of metoclopramide, bovine serum albumin/metoclopramide nanoparticles could be regarded a new modality for the treatment of gastroparesis, which can treat diabetes and avoid its consequences.112

Domperidone functions similarly to metoclopramide on dopamine D2 receptors, but since it does not cross the blood-brain barrier, it has fewer negative effects on the central nervous system.113 Domperidone’s gastrokinetic effects can be partially explained by its interference with secretin and dopamine receptors in the stomach since dopamine regulates gastric motility, and domperidone has a strong affinity for gastrointestinal tissue.114 For individuals with gastroparesis who have not reacted to other prokinetics or have had limited exposure to them due to their negative effects, domperidone should be taken into consideration.115 The gastroparesis cardinal symptom index-daily diary (GCSI-DD) was used to assess the effectiveness of domperidone for gastroparesis symptoms. It was discovered that domperidone lessens early satiety, postprandial fullness, and nausea related to the condition as well as the overall severity of gastroparesis symptoms.116 The treatment with domperidone greatly reduced the symptoms of gastroparesis, according to the extensive Gastroparesis Clinical Research Consortium database.117

Motilin agonists (erythromycin and azithromycin)

The most prevalent motilin receptor agonists are macrolides, a class of antibiotics that activates the gastrointestinal tract’s motilin receptors. The macrolide that is most frequently examined is erythromycin.98 Erythromycin affects gastrointestinal motility in a manner similar to that of the gastrointestinal polypeptide motilin, most likely as a result of its ability to bind to the receptors for motilin and act as an agonist.118 By acting on the inhibitory nerves of the antrum’s pylorus, erythromycin causes phasic contractions in the antrum and stimulates pyloric relaxation.119 It has been demonstrated that erythromycin stimulates motilin receptors to cause premature phase III activity.120 Erythromycin may be a helpful prokinetic drug, according to early trials in mice with experimental gastroparesiss.121 Clinical studies suggest that erythromycin is both effective and well tolerated.122 Gastric retention was minimized and symptomatic relief was attained in human studies of both chronic oral erythromycin and intravenous erythromycin in individuals with DGP refractory to other prokinetic medications. Both erythromycin and metoclopramide agents improve tolerance to intragastric enteral feeding, however erythromycin may be more effective than metoclopramide in improving gastric motility.123

However, erythromycin has some adverse effects. Azithromycin is among the macrolides that are currently offered in the United States in addition to erythromycin.124 Azithromycin has less gastrointestinal side effects, a longer half-life, fewer medication interactions, and a lower frequency of QTc interval prolongation. Azithromycin use may be advantageous for patients with small bowel and stomach dysmotility.125 In patients with gastrointestinal dysmotility, azithromycin causes activity fronts in the antrum followed by duodenal contractions more frequently than erythromycin does, moreover azithromycin has a longer duration of effect.126 The prokinetic properties of azithromycin may make it useful in the treatment of small bowel dysmotility and gastroparesis.125

Ghrelin agonists

Ghrelin agonists are new prokinetic medicines for the treatment of gastroparesis, and when compared to placebo, ghrelin agonists are efficacious and well-tolerated for the treatment of DGP.127 Gastric motility has been studied using ghrelin receptor agonists such as TZP101 (IV Ulimorelin), TZP102 (PO Ulimorelin), and RM131 (Relamorelin).128 Ulimorelin, a potent prokinetic and small molecule ghrelin agonist, was effective in animal models of gastroparesis and delayed transit.129 The usage of TZP-101 and TZP-102 considerably decreased the frequency and intensity of nausea and vomiting as well as the overall severity of gastroparesis symptoms.130,131 In patients with type 1 diabetes and documented delayed gastric emptying, RM-131 significantly speeds up gastric emptying of solids, decreases upper gastrointestinal symptoms, and lowers total GCSI-DD and composite scores.132

Gastric Electrical Stimulation for Diabetic Gastroparesis Therapy

Gastric electrical stimulation (GES) is a treatment for intractable DGP that involves providing an electric current to the gastric smooth muscle via electrodes.133 Long-pulse GES may enhance stomach emptying by encouraging ICC regeneration and restoring the injury of SMCs through the insulin-like growth factor 1 signaling pathway.134,135 GES increases ICC proliferation, which may be associated to the 5-HT/5-HT2B signal pathway, and affects the enteric nervous system, in part through glial cell line-derived neurotrophic factor expression.136 Furthermore, studies have shown that long-pulse GES can reshape gastric motility by inducing synaptic vesicle regeneration in the intermuscular plexus.137

Other Treatments for Diabetic Gastroparesis

The shock wave is a longitudinal sound wave that travels through human tissue at the speed of ultrasound in water, and low-energy extracorporeal shockwave therapy (LESW) is recognized as a therapeutic tool in various medical fields.138 In streptozotocin-induced diabetes mellitus rats, LESW therapy retained pancreatic islet function and increased the number of beta cells. This was most likely due to the fact that LESW therapy increased angiogenesis, cell proliferation, and tissue healing potency while decreasing pancreatic tissue inflammation, apoptosis, and oxidative stress.139 According to studies, 6 weeks of LESW can enhance myenteric plexus and axonal regeneration, which in turn can boost gastric contraction and emptying.140

Gastric peroral endoscopic myotomy (G-POEM) is considered a safe and promising technique for the management of refractory DGP.141 Several meta-analyses have shown that G-POEM treatment is effective in improving the clinical symptoms of patients with gastroparesis, and that GCSI scores and gastric emptying scintigraphy are significantly improved.142,143 An evaluation of the long-term outcome of patients with refractory gastroparesis treated with GPOEM reveals a clinical success of 86.5% for DGP at 4 years of follow-up, with a significant improvement in patients’ quality of life.144

Conclusions

DGP is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of ICC cells, abnormalities in the neuro-endocrine system and hormone levels. Prokinetic therapy can be used as a method to improve gastric emptying and gastrointestinal motility, and prokinetic drugs are valuable tools in the treatment strategy of DGP.

A greater knowledge of DGPs has resulted from advancements made in recent decades. However, challenges remain in expanding the understanding of the etiology of DGP and establishing targeted treatment options. Further research on DGP from the perspective of gastrointestinal dynamics is needed, as well as basic and clinical studies to comprehensively assess the efficacy and mechanisms of prokinetic drugs to improve diabetes-induced gastrointestinal dysfunction. Future initiatives will presumably build on this improvement, allowing DGP to be prevented, assessed, and treated with more precision and success.

Financial support:

This study was supported by Clinical Research Center Construction Project of Guang’anmen Hospital, China Academy of Chinese Medical Sciences (CACMS) (Grant No. 2022LYJSZX12), CACMS Outstanding Young Scientific and Technological Talents Program (ZZ13-YQ-026), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202001), and Open Project of National Facility for Translational Medicine (TMSK-2021-407).

Conflicts of interest

None.

Author contributions

Conceptualization, Jia-Xing Tian; writing, review, and editing, Yu-Xin Zhang, Yan-Jiao Zhang, Min Li, and Xiao-Lin Tong; supervision, Jia-Xing Tian and Xiao-Lin Tong; and funding acquisition, Jia-Xing Tian and Xiao-Lin Tong. All authors have read and agreed to the published version of the manuscript.

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