Diabetic Gastroparesis: Navigating Pathophysiology and Nutritional Interventions

“These studies revealed that mice lacking neuronal nitric oxide synthase (nNOS) exhibited a dilated stomach with hypertrophy of the circular muscle layer, indicating the importance of nNOS in maintaining normal gastric function [36].”

“Furthermore, gender differences in serotonin transporter gene polymorphisms, variations in serotonin synthesis rates, and disparities in serotonin synthesis rates have been noted [74].”

“In the evaluation of suspected gastroparesis, it is imperative to exclude mechanical obstructions through diagnostic procedures such as upper endoscopy, computed tomography, or magnetic resonance enterography [78].”

“The gastric emptying rate accounts for about 35% of the initial rise in postprandial glucose levels, contributing significantly to both early and overall postprandial glycemia [93,94].”

“Notably, in healthy male subjects, the 5-HT4 agonist tegaserod accelerated gastric emptying and small intestinal transit [48].”

“Most gastrointestinal peptide hormones typically exert an inhibitory effect on gastric emptying, suggesting that a reduction in their release cannot account for the reduced gastric emptying [8].”

“As a consequence, patients often experience distressing symptoms such as early satiety, bloating, nausea, and vomiting [20,21].”

“Studies indicate that premenopausal women tend to exhibit slower gastric emptying rates compared to their postmenopausal counterparts, suggesting a direct association between menopausal status and gastric motility [61,62].”

“Surprisingly, over 90% of the body’s serotonin is produced by enterochromaffin cells in the small intestine, impacting gut motility, secretion, and sensation [67,68].”

“Dysfunction in the nitrergic system, as evidenced by reduced nNOS expression and/or NO release, is associated with defective smooth muscle relaxation in the GI tract, leading to gastroparesis [34,35].”

“Moreover, therapeutic trials utilizing prokinetic agents for gastroparesis have revealed a lack of consistent correlation between improvements in gastric emptying and symptom relief [85].”

“…have shown greater e ffi cacy compared to conventional management, underscoring the relevance of addressing abnormal vagal signaling in managing DGP [19]. intracellular glucose metabolism of neurons occur, leading to the formation of advanced glycation end-products, osmotic and oxidative stress, as…”

“Despite its traditional role in diagnosis, delayed gastric emptying suggests a potentially stronger relevance to glycemia and, conceivably, in guiding therapeutic interventions [1,86].”

“The NO signaling involves three distinctive NOS isoform enzymes: endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) [33].”

“…in antral biopsies, blunted response of the vagus nerve in triggering pancreatic polypeptide secretion points to a malfunction in the neural signals that control gastrointestinal processes. leading to abnormal gastric slow waves, potentially causing disordered motor function and symptoms [23–26].”

“Studies in non-obese diabetic mice demonstrated that increased oxidative stress, resulting from the loss of macrophage HO-1 in the enteric nervous system, led to the loss of interstitial Cajal cells and delayed gastric emptying [43].”

“Interestingly, the induction of HO-1 reversed the delay in gastric emptying, indicating its potential as a therapeutic target [44].”

“Additionally, experiments involving animals demonstrated that reduced expression of nNOS due to disease or pharmacological interference with nitric oxide synthase could lead to impaired gastric emptying [37,38].”

“Furthermore, it has been suggested that variations in nNOS dimerization may contribute to the higher prevalence of females in this context [65].”

“According to the study results, only a very small percentage of gastroparetic patients received nutrition counseling from a qualified dietitian or followed a suggested diet to minimize gastrointestinal discomfort [99].”

“Although limited patient data on the loss of enteric neurons or nervous function exist, immunohistochemistry data from a small case series indicated a decrease in nNOS and substance-P expression in the enteric nervous system of the stomach in diabetic patients compared to controls [26].”

“Finally, it is important to note that the diagnosis of diabetes presents a complex clinical landscape marked by challenges in establishing a clear association between delayed gastric emptying and symptomatic manifestations [81].”

“…of the patient’s medical history, focusing on symptoms such as early satiety, postprandial fullness, nausea, vomiting, and erratic blood glucose control, especially in individuals with a long-standing history of diabetes, particularly those with type 1 or longstanding type 2 diabetes [7,76,77].”

“These hormonal fluctuations during pregnancy contribute to disturbances in gastrointestinal motility, potentially explaining common symptoms such as nausea, vomiting, and delayed gastric emptying [55–60].”

“Moreover, various hormones, such as gastrin, cholecystokinin (CCK), secretin, gastric inhibitory polypeptide (GIP), glucagon, vasoactive intestinal peptide (VIP), glucagon-like peptide-1 (GLP-1), motilin, and ghrelin, play pivotal roles in influencing gastrointestinal motility [11,12].”

“Moreover, metoclopramide, functioning as both a 5-HT4 agonist and a dopamine D2 antagonist, enhances contractions in the esophagus, antrum, and small bowel, leading to an acceleration of gastric emptying [73].”

“This diagnostic uncertainty is further compounded by the observation that a significant number of patients with delayed gastric emptying are asymptomatic, and that symptom profiles in diabetes mellitus patients with normal or delayed gastric emptying often exhibit striking similarities [83,84].”

“These factors include glucose absorption, disposal, endogenous glucose production, meal composition, gastric emptying rate, small intestine processes (such as glucose absorption and incretin release), insulin secretion, and hepatic and peripheral glucose disposal [90–92].”

“Other animal experiments have indicated that impaired gastric emptying results from decreased expression or inhibition of neural nitric oxide synthase [29].”

“Studies have reported that during the luteal phase, characterized by elevated levels of these hormones, gastric emptying rates tend to be slower [50,51].”

“In intervention studies with Type 2 diabetes patients, inhibiting gastric emptying with opiates markedly decreased glycemic excursions, while prokinetic erythromycin administration had opposite effects [96].”

“The enteric nervous system’s development and maintenance are also influenced by serotonin, with serotonergic neurons proving essential for mediating gastrointestinal propagating contractile complexes [69,70].”

“Research indicates that gender differences in serotonergic signaling regulate gastric emptying, and studies involving 5-HT receptor agonists/antagonists have shown promise in improving gut motility [71,72].”

“Human studies have also demonstrated the depletion of gastric interstitial cells of Cajal in up to 50% of patients with gastroparesis [28].”

“Histological examinations have identified alterations in both myelinated and unmyelinated vagal nerve fibers among DGP patients [16].”

“In diabetic autonomic neuropathy, there’s a correlation with antral hypomotility [11], diminished fasting proximal gastric tone, and decreased postprandial accommodation of the gastric fundus [13].”

“Moreover, the impaired neuromuscular function in the antrum of streptozocin-induced diabetic rats was attributed to the loss of dimerization of the active nNOS enzyme, further highlighting the complex mechanisms underlying gastric dysfunction in diabetes [31].”

“Notably, patients with gastroparesis in Type 1 diabetes require reduced early postprandial insulin compared to those with a normal gastric emptying rate [95].”

“DGP often coexists with complications such as retinopathy, neuropathy, nephropathy, and poor glycemic control [76,87,88].”

“Early studies in DGP revealed impaired pancreatic polypeptide response and reduced gastric secretion during sham feeding, indicating vagal dysfunction [14,15].”

“Studies have reported that during the luteal phase, characterized by elevated levels of these hormones, gastric emptying rates tend to be slower [50,51].”

“Research indicates that gender differences in serotonergic signaling regulate gastric emptying, and studies involving 5-HT receptor agonists/antagonists have shown promise in improving gut motility [71,72].”

“…these mechanisms are primarily described in the peripheral nervous system, it is essential to note that similar processes are As a consequence, patients often experience distressing symptoms such as early satiety, bloating, nausea, and vomiting [20,21]. present in the enteric nervous system [30].”

“The presence of estrogen receptors along the brain–gut axis introduces a complex interplay between central and peripheral hormonal mechanisms that collectively shape gut function [49].”

“Additionally, experiments involving animals demonstrated that reduced expression of nNOS due to disease or pharmacological interference with nitric oxide synthase could lead to impaired gastric emptying [37,38].”

“Intriguingly, these symptoms overlap with those of functional dyspepsia or indigestion, adding complexity to the diagnostic procedure [89].”

“This diagnostic uncertainty is further compounded by the observation that a significant number of patients with delayed gastric emptying are asymptomatic, and that symptom profiles in diabetes mellitus patients with normal or delayed gastric emptying often exhibit striking similarities [83,84].”

“These factors include glucose absorption, disposal, endogenous glucose production, meal composition, gastric emptying rate, small intestine processes (such as glucose absorption and incretin release), insulin secretion, and hepatic and peripheral glucose disposal [90–92].”

“DGP often coexists with complications such as retinopathy, neuropathy, nephropathy, and poor glycemic control [76,87,88].”

“These findings demonstrate a biphasic loss of the nitrergic component, possibly induced by the accumulation of toxic substances or increased oxidative stress observed in both animal models and diabetic patients [40].”

“Adjustments in insulin regimens or therapies to enhance gastric emptying predictability, typically by accelerating it, should be considered based on these measurements [97,98].”

“The patient ingests the WMC after a standardized nutrient meal, and normal emptying should occur within 5 h. WMC pressure measurements can distinguish between patients with DGP and healthy individuals, demonstrating fewer contractions and motility indices in the former [80].”

“Intriguingly, BH4 supplementation in diabetic female rats has shown promise in restoring the impaired nitrergic system and accelerating gastric emptying, suggesting a potential therapeutic avenue for diabetes-induced gastroparesis [31,32,64].”

“Delayed gastric emptying is diagnosed if there is greater than 60% retention at 2 h or 10% retention at 4 h. Mild, moderate, and severe classifications are made based on 10–15%, 16–35%, and >35% gastric retention after 4 h, respectively [79].”

“Early studies in DGP revealed impaired pancreatic polypeptide response and reduced gastric secretion during sham feeding, indicating vagal dysfunction [14,15].”

“Additionally, the sympathetic component of the autonomic nervous system in DGP has shown histological changes in axon-dendritic structures and alterations in gene expression within prevertebral ganglia [17,18].”

“This gender-specific modification contributes to a significant impairment of nitrergic relaxation, ultimately resulting in delayed gastric emptying [66].”

“Adjustments in insulin regimens or therapies to enhance gastric emptying predictability, typically by accelerating it, should be considered based on these measurements [97,98].”

“In a recent investigative study, the comparison of ICC in the antrum and pylorus smooth muscle was conducted among 38 individuals with severe refractory gastroparesis, encompassing both diabetic males and females [75].”

“Notably, other potential causes of unexplained vomiting encompass cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome, further underscoring the need for a meticulous and comprehensive diagnostic approach to differentiate these conditions accurately [7].”

“Sex hormones, particularly estrogen and progesterone, transcend their well-established roles in reproductive health to exert a profound influence on the intricate functioning of the gastrointestinal system [46–48].”

“In-depth investigations, both in vitro and in vivo, further illuminate the inhibitory effects exerted by progesterone, either in isolation or in conjunction with estrogen, on gastrointestinal smooth muscle [52–54].”

“These hormonal fluctuations during pregnancy contribute to disturbances in gastrointestinal motility, potentially explaining common symptoms such as nausea, vomiting, and delayed gastric emptying [55–60].”

“The coordination between smooth muscle, interstitial cells of Cajal, and the enteric and extrinsic nervous systems is essential for proper gastric emptying [10].”

“While delayed gastric emptying is often considered a hallmark of gastroparesis, the strength of its correlation with the daily symptoms experienced by individuals with diabetes mellitus remains elusive [82].”

“Additionally, the sympathetic component of the autonomic nervous system in DGP has shown histological changes in axon-dendritic structures and alterations in gene expression within prevertebral ganglia [17,18].”

“As the global population continues to age and the incidence of diabetes rises, the prevalence of DGP is expected to increase, posing a growing challenge for healthcare systems worldwide [4,6].”

“Despite its traditional role in diagnosis, delayed gastric emptying suggests a potentially stronger relevance to glycemia and, conceivably, in guiding therapeutic interventions [1,86].”

“Simultaneously, an anterograde positive pressure gradient propels chyme into the duodenum [8,9].”

“A BMI 20 kg/m 2 or unintentional weight loss of 5–10% of body weight within the last 3–6 months are considered severe clinical markers of malnutrition [100,101].”

“…nitrergic dysfunction and inflammation in normoglycemic diabetes-prone rats emphasize the role of aminoguanidine, a selective inhibitor of the iNOS enzyme, in counteracting inflammation-induced nitrergic dysfunction and preventing intestinal dysmotility, independent of hyperglycemia [45].”

“Elevated levels of estradiol-17b (E2) in females correlate with increased NO levels, resulting in a more pronounced relaxation of gastric smooth muscle cells compared to males [63].”

“To address these disparities, targeted healthcare interventions and heightened awareness campaigns are crucial, especially in regions witnessing elevated diabetes rates [2,4].”

“In summary, the main nutritional suggestions for diabetic individuals experiencing gastroparesis are as follows (Figure 2) [102]:”

“Intriguingly, BH4 supplementation in diabetic female rats has shown promise in restoring the impaired nitrergic system and accelerating gastric emptying, suggesting a potential therapeutic avenue for diabetes-induced gastroparesis [31,32,64].”

“The insulin and IGF-1 signaling have been linked to damaged myenteric cholinergic neurons and ICCs in animal studies [22].”

“Some researchers are exploring technological solutions to improve gastric tolerance to fibers in gastroparetic individuals [103].”

“To address these disparities, targeted healthcare interventions and heightened awareness campaigns are crucial, especially in regions witnessing elevated diabetes rates [2,4].”

“Surprisingly, over 90% of the body’s serotonin is produced by enterochromaffin cells in the small intestine, impacting gut motility, secretion, and sensation [67,68].”

“The enteric nervous system’s development and maintenance are also influenced by serotonin, with serotonergic neurons proving essential for mediating gastrointestinal propagating contractile complexes [69,70].”

“DGP often coexists with complications such as retinopathy, neuropathy, nephropathy, and poor glycemic control [76,87,88].”

“Dysfunction in the nitrergic system, as evidenced by reduced nNOS expression and/or NO release, is associated with defective smooth muscle relaxation in the GI tract, leading to gastroparesis [34,35].”

“As a consequence, patients often experience distressing symptoms such as early satiety, bloating, nausea, and vomiting [20,21].”

“In-depth investigations, both in vitro and in vivo, further illuminate the inhibitory effects exerted by progesterone, either in isolation or in conjunction with estrogen, on gastrointestinal smooth muscle [52–54].”

“Consequently, individuals with DGP often face a reduced quality of life, experiencing persistent discomfort, nutritional deficiencies, and frequent hospitalizations due to complications [2,3].”

“Additionally, exploring lesser-known myokines, hepatokines, miRNA, and adipocytokines as potential therapeutic targets may offer novel strategies for managing insulin resistance [207–210].”

“Moreover, diabetic gastroparesis generated by diabetic neuropathy may seriously impair gastric emptying in patients with diabetes [6,7].”

“The postulated mechanism causing gastroparesis involves injury to the vagus nerve with ensuing poor autonomic control of the stomachs’ motility, albeit underlying diabetes control is also a contributing factor [3,4].”

“…hyperglycemia inhibit gastric motility by reducing vagal cholinergic activity, impairing fundic relaxation, slowing antral peristalsis, and diminishing pyloric compliance, creating a self-perpetuating cycle between worsening metabolic control and gastro-intestinal symptoms [6, 23, 92, 103, 104].”

“28 P-gp serves as an exclusion barrier for several xenobiotics and drugs, hence, its expression and activity regulate the quantities of drugs entering the circulation.”

“…mellitus (DM) due to abnormal gastric emptying (1), it typically manifests as nausea, postprandial fullness, vomiting, early satiety, and bloating (2), DGP affects patients with long-standing diabetes mellitus (DM), with a prevalence between 5 and 15% (1, 3), although it is more commonly…”