Review

Diabetic Gastroparesis: Navigating Pathophysiology and

Nutritional Interventions
Alfredo Caturano 1,2, *,† , Massimiliano Cavallo 3,4,† , Davide Nilo 1 , Gaetano Vaudo 3 , Vincenzo Russo 5,6 ,
Raffaele Galiero 1 , Luca Rinaldi 7 , Raffaele Marfella 1 , Marcellino Monda 2 , Giovanni Luca 4,‡
and Ferdinando Carlo Sasso 1,‡

1 Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli,
I-80138 Naples, Italy; nilodavide@gmail.com (D.N.)
2 Department of Experimental Medicine, University of Campania Luigi Vanvitelli, I-80138 Naples, Italy
3 Internal Medicine Unit, Santa Maria Terni Hospital, I-05100 Terni, Italy; gaetano.vaudo@unipg.it (G.V.)
4 Medical Andrology and Reproductive Endocrinology Unit, Santa Maria Hospital, I-05100 Terni, Italy
5 Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and
Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
6 Division of Cardiology, Department of Medical Translational Sciences, University of Campania Luigi
Vanvitelli, I-80138 Naples, Italy
7 Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise,
I-86100 Campobasso, Italy
* Correspondence: alfredo.caturano@unicampania.it
† These authors contributed equally to this work.
‡ These authors contributed equally to this work.

Abstract: Diabetic gastroparesis (DGP) delays gastric emptying in diabetes patients, notably impact-
ing those with type 1 and long-standing type 2 diabetes. Symptoms include early satiety, fullness,
appetite loss, bloating, abdominal pain, and vomiting, arising from slow stomach-to-intestine food
movement. DGP’s unpredictable nature complicates diagnosis and blood glucose management,
leading to severe complications like dehydration, malnutrition, and bezoar formation. Understand-
Citation: Caturano, A.; Cavallo, M.; ing DGP’s mechanisms is crucial for effective management. Vagal dysfunction, disturbances in
Nilo, D.; Vaudo, G.; Russo, V.; the interstitial cells of Cajal, reduced neural nitric oxide synthase, and increased oxidative stress
Galiero, R.; Rinaldi, L.; Marfella, R.;
contribute to the complex pathophysiology. Accurate diagnosis demands a comprehensive approach,
Monda, M.; Luca, G.; et al. Diabetic
utilizing tools like gastric scintigraphy and the Gastric Emptying Breath Test. Considering the com-
Gastroparesis: Navigating
plex relationship between DGP and glycemia, managing blood glucose levels becomes paramount.
Pathophysiology and Nutritional
Nutritional interventions, tailored to each patient, address malnutrition risks, emphasizing smaller,
Interventions. Gastrointest. Disord.
2024, 6, 214–229. https://doi.org/
more frequent meals and liquid consistency. DGP’s complex nature necessitates collaborative efforts
10.3390/gidisord6010016 for enhanced diagnostic strategies, improved pathophysiological understanding, and compassionate
management approaches. This comprehensive approach offers hope for a future where individuals
Academic Editor: Richard
with DGP can experience improved well-being and quality of life.
W. McCallum

Received: 12 December 2023 Keywords: diabetic gastroparesis; nutritional intervention; pathophysiology; diabetes; diabetes complication
Revised: 26 January 2024
Accepted: 18 February 2024
Published: 22 February 2024
1. Introduction
Diabetic gastroparesis (DGP) is a debilitating gastrointestinal disorder characterized
by delayed gastric emptying in individuals with diabetes mellitus, particularly type 1 and
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
long-standing type 2 diabetes. This condition, although not widely known, significantly
This article is an open access article
impacts the quality of life of affected individuals. The symptoms of DGP, including early
distributed under the terms and satiety, excessive fullness after meals, loss of appetite, bloating, abdominal pain, and
conditions of the Creative Commons vomiting, stem from the slowed or stalled movement of food from the stomach to the small
Attribution (CC BY) license (https:// intestine [1].
creativecommons.org/licenses/by/ What makes DGP particularly challenging is its unpredictable nature. The severity
4.0/). of symptoms can vary widely among individuals, and it often occurs in the absence of

Gastrointest. Disord. 2024, 6, 214–229. https://doi.org/10.3390/gidisord6010016 https://www.mdpi.com/journal/gastrointestdisord

Gastrointest. Disord. 2024, 6 215

consistent patterns. This unpredictability not only complicates the diagnosis but also
makes managing blood glucose levels exceptionally challenging for those with diabetes,
as the absorption of ingested food becomes erratic. Furthermore, DGP can lead to serious
complications such as dehydration, malnutrition, and the formation of bezoars—solid
masses of undigested food that can obstruct the digestive tract. Consequently, individuals
with DGP often face a reduced quality of life, experiencing persistent discomfort, nutritional
deficiencies, and frequent hospitalizations due to complications [2,3].
In this context, understanding the mechanisms behind DGP, improving diagnostic
techniques, and developing effective management strategies are critical areas of research.
This exploration is not only vital for enhancing the lives of those already affected by DGP
but also holds the potential to prevent its onset or progression in individuals with diabetes,
significantly reducing the burden of this condition on both patients and the healthcare system.

2. Epidemiology
DGP is a prevalent complication affecting a significant proportion of individuals with
diabetes mellitus, both type 1 and type 2. While exact prevalence rates can vary based on the
studied population and diagnostic criteria, it is widely acknowledged that DGP represents a
substantial burden within the diabetes community.
In a recent meta-analysis, it was found that approximately 9.3% of individuals with
diabetes may experience the onset of gastroparesis during the course of their illness. This
risk appears to be heightened in individuals with long-standing type 1 diabetes or type 2
diabetes lasting ten years or more [1,4]. This prevalence changes according to the geograph-
ical location, with a lower prevalence in North America (3.6%) and a higher prevalence in
Asia (12.6%), Europe (16.5%), South America (16.4%), and Australia (17.7%) [4].
In terms of regional differences, emerging studies underscore the heightened suscep-
tibility of certain populations, particularly those with elevated rates of diabetes, to the
development of DGP. This vulnerability is further accentuated by disparities in healthcare
access and awareness across regions, influencing both the diagnosis and prevalence rates
of DGP. A compelling illustration of the regional nuances in diabetes prevalence comes
from the Global Diabetes Map, which highlights China’s critical diabetes situation. China
not only ranks highest in both diagnosed and undiagnosed diabetes cases but also secures
the second position in global diabetes health expenditure. Consequently, the burden of
gastrointestinal dysfunction is pervasive among diabetic patients in the early or advanced
stages of the disease. These findings underscore the imperative of considering regional
factors in comprehending and addressing the prevalence of DGP. To address these dispari-
ties, targeted healthcare interventions and heightened awareness campaigns are crucial,
especially in regions witnessing elevated diabetes rates [2,4].
DGP affects both men and women, although some studies indicate a higher incidence
in females. In fact, in one of the most extensive population-based epidemiological studies,
which included 3604 residents from Olmsted County, Minnesota, it was observed that the
incidence of gastroparesis in women was four times greater than that in men [5]. The reasons
behind this gender difference are not entirely clear and require further investigation [2,4].
Age also plays a significant role in the epidemiology of DGP. It is often observed that
the risk of developing gastroparesis increases with age, particularly in individuals with
diabetes of long duration. 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].

3. Pathophysiology
3.1. Gastric Motility Physiology
Gastric motility, a highly complex process, is regulated by a complex interplay of
neural and hormonal signals. As ingested food fills the stomach, fundic compliance in-
creases, creating a food reservoir without a simultaneous rise in pressure. In the initial
filling phase, both pressure and peristaltic pumps remain inhibited, exhibiting no contrac-
Gastrointest. Disord. 2024, 6 216

tions. Subsequently, the filling phase transitions into a pumping phase characterized by a
gradual tonic contraction of the fundus and an escalation of peristaltic contractions in the
stomach. During this dynamic phase, a critical mechanism unfolds—the pylorus closes as
the contraction wave approaches the distal stomach, essential for the mechanical digestion
process known as trituration. This orchestrated phase promotes the thorough mixing of
ingested food with gastric acid and pepsin, facilitating its transfer to the pylorus [7].
As the food undergoes trituration, it undergoes propulsion into the pyloric grinder
through intensified contractions in the antrum. Following this, the pylorus relaxes to receive
food from the proximal antrum. Pyloric contractions play a pivotal role by generating
a robust negative pressure gradient of incompletely triturated food. Simultaneously, an
anterograde positive pressure gradient propels chyme into the duodenum [8,9]. Central
to this process is the enteric, or intrinsic, nervous system, often referred to as the “second
brain”. Comprising about a hundred million neurons, this complex network embedded
in the gastrointestinal tract wall includes the myenteric plexus, primarily responsible for
regulating gastric motility, and the submucosal plexus, which oversees gastric secretion
and absorption. Both are modulated by the extrinsic nervous system, encompassing the
parasympathetic and sympathetic components. The parasympathetic system stimulates
non-sphincteric muscles and inhibits sphincter contraction, while the sympathetic system
exerts opposing effects. Interstitial cells of Cajal, located between nerve endings and smooth
muscle cells, act as pacemaker cells for gastrointestinal muscles, generating electrical signals
that regulate smooth muscle contractions. The coordination between smooth muscle,
interstitial cells of Cajal, and the enteric and extrinsic nervous systems is essential for proper
gastric emptying [10]. 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].

3.2. Diabetic Gastroparesis

The pathophysiology of DGP is complex and multifaceted, with various hypotheses
pointing to potential factors like elevated blood glucose levels, vagal dysfunction, distur-
bances in the interstitial cells of the Cajal network, diminished expression of neural nitric
oxide synthase in the myenteric plexus and increased oxidative stress (Figure 1). Studies
in both animal models and humans have illuminated some underlying processes, but
significant gaps in our understanding still exist. This complexity underscores the need for
further research to unravel the complex mechanisms behind gastric motility dysfunction in
diabetes [7].
Vagal innervation plays a pivotal role in modulating antral contractions, responsible
for breaking down solid food into smaller particles and facilitating its passage through the
pylorus. Under normal circumstances, the vagus nerve also stimulates pancreatic polypep-
tide secretion following a meal, ensuring the coordinated movement of food through
the digestive tract. However, in individuals with DGP, this essential function is signifi-
cantly compromised. 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]. The blunted response of the vagus nerve in
triggering pancreatic polypeptide secretion points to a malfunction in the neural signals
that control gastrointestinal processes. Early studies in DGP revealed impaired pancreatic
polypeptide response and reduced gastric secretion during sham feeding, indicating vagal
dysfunction [14,15]. Histological examinations have identified alterations in both myeli-
nated and unmyelinated vagal nerve fibers among DGP patients [16]. 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]. 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]. Instead, the impact of aberrant vagal signaling on gastric
Gastrointest. Disord. 2024, 6 217

function, particularly pyloric function, appears to be more pertinent. Pylorospasm, a conse-

quence of vagal neuropathy described in DGP, is notable. Treatments specifically targeting
the pylorus, such as G-POEM, have shown greater efficacy compared to conventional man-
Gastrointest. Disord. 2024, 6, FOR PEER REVIEW 4
agement, underscoring the relevance of addressing abnormal vagal signaling in managing
DGP [19].

Figure 1.1.Main pathophysiological

Main mechanisms
pathophysiological associated
mechanisms with diabetic
associated withgastroparesis
diabetic development.
gastroparesis
development. AGE—advanced glycation end-product.
AGE—advanced glycation end-product.

Hyperglycemia
Vagal innervation exacerbates abnormally
plays a pivotal increased pyloric
role in modulating contractility,responsible
antral contractions, leading to
reduced antral pressure waves, diminished antral motor activity, and
for breaking down solid food into smaller particles and facilitating its passage throughincreased pyloric
pressure waves. As a consequence, patients often experience distressing
the pylorus. Under normal circumstances, the vagus nerve also stimulates pancreatic symptoms such as
early satiety, bloating, nausea, and vomiting [20,21].
polypeptide secretion following a meal, ensuring the coordinated movement of food
Interstitial
through Cajal cell
the digestive dysfunction
tract. However,serves as the “pacemaker”
in individuals with DGP,ofthistheessential
stomach by generat-
function is
ing action potentials. Impaired insulin and IGF-1 signaling have been linked
significantly compromised. In diabetic autonomic neuropathy, there’s a correlation with to damaged
myenteric
antral cholinergic neurons
hypomotility and ICCs in
[11], diminished animalproximal
fasting studies [22]. Additionally,
gastric tone, and DGP patients
decreased
often exhibit reduced ICC numbers in antral biopsies, leading to abnormal
postprandial accommodation of the gastric fundus [13]. The blunted response of the vagus gastric slow
waves, potentially causing disordered motor function and symptoms [23–26]. Concurrently,
nerve in triggering pancreatic polypeptide secretion points to a malfunction in the neural
a decrease in or loss of nNOS has been observed, contributing to the disrupted coordination
signals that control gastrointestinal processes. Early studies in DGP revealed impaired
of gastric motility [26,27].
pancreatic polypeptide response and reduced gastric secretion during sham feeding,
In murine models of DGP, myopathy and depletion of interstitial cells of Cajal have
indicating vagal dysfunction [14,15]. Histological examinations have identified alterations
been reported, preceding neuropathy. Human studies have also demonstrated the depletion
in both myelinated and unmyelinated vagal nerve fibers among DGP patients [16].
of gastric interstitial cells of Cajal in up to 50% of patients with gastroparesis [28]. Other
Additionally, the sympathetic component of the autonomic nervous system in DGP has
animal experiments have indicated that impaired gastric emptying results from decreased
shown histological changes in axon-dendritic structures and alterations in gene
expression or inhibition of neural nitric oxide synthase [29]. These findings emphasize the
expression within prevertebral ganglia [17,18]. Most gastrointestinal peptide hormones
multifaceted nature of DGP, involving complex interactions between interstitial cells of
typically exert an inhibitory effect on gastric emptying, suggesting that a reduction in their
Cajal dysfunction, impaired signaling pathways, and disrupted neuronal coordination in
release cannot account for the reduced gastric emptying [8]. Instead, the impact of
the stomach’s motility processes.
aberrant vagal
Enteric signaling
neurons andon gastric function,
interstitial cells of particularly pyloric function,
Cajal are particularly appears
vulnerable to be
to hyper-
more pertinent.
glycemia. Pylorospasm, aepisodes
When hyperglycemic consequence of vagal
are frequent, orneuropathy describedisin
when hyperglycemia DGP, is
persistent,
notable. Treatments specifically targeting the pylorus, such as G-POEM,
shifts in the intracellular glucose metabolism of neurons occur, leading to the formation have shown
greater efficacy compared to conventional management, underscoring
of advanced glycation end-products, osmotic and oxidative stress, as well as inflamma- the relevance of
addressing abnormal vagal signaling in managing DGP [19].
tion. Collectively, these processes result in cellular damage and, ultimately, cell death, a
Hyperglycemia
phenomenon commonly exacerbates
referred to abnormally
as glucose increased pyloric
neurotoxicity. Whilecontractility, leadingare
these mechanisms to
reduced antral
primarily pressure
described in thewaves, diminished
peripheral nervous antral motor
system, activity,
it is essentialand
to increased
note that pyloric
similar
pressure waves. As a consequence, patients often experience distressing
processes are present in the enteric nervous system [30]. This heightened vulnerability symptoms such
to
as early satiety, bloating, nausea, and vomiting [20,21].
hyperglycemia further underscores the complex nature of DGP, where disruptions in multi-
Interstitial Cajal cell dysfunction serves as the “pacemaker” of the stomach by
generating action potentials. Impaired insulin and IGF-1 signaling have been linked to
damaged myenteric cholinergic neurons and ICCs in animal studies [22]. Additionally,
DGP patients often exhibit reduced ICC numbers in antral biopsies, leading to abnormal
gastric slow waves, potentially causing disordered motor function and symptoms [23–26].
Gastrointest. Disord. 2024, 6 218

ple pathways, including ICC dysfunction and neural damage, contribute to the complexity
of the condition [30].
The nitrergic system, composed of inhibitory enteric neurons embedded in the gut wall
musculature, assumes a pivotal role in the regulation of gastric motility [31]. These neurons
express neuronal nitric oxide synthase (nNOS), an enzyme responsible for synthesizing
and secreting nitric oxide (NO), a primary inhibitory neurotransmitter in the GI tract
that induces relaxation of the stomach’s smooth muscle [32]. The NO signaling involves
three distinctive NOS isoform enzymes: endothelial NOS (eNOS), inducible NOS (iNOS),
and neuronal NOS (nNOS) [33]. The term “nitrergic signaling” encompasses the release
of NO from these enteric neurons, which collectively governs muscle tone in various GI
structures, including the lower esophagus, antrum, pylorus, sphincter of Oddi, and anus.
NO also plays a crucial role in regulating gastric accommodation and intestinal peristalsis.
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]. Early studies provided evidence for the involvement of nitrergic
nerves in gastric motility. 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].
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]. 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].
Several proposed mechanisms explain the decreased nNOS expression. Studies on
non-obese diabetic (NOD) mice suggested a reversible loss of gastric nNOS expression,
indicating down-regulation of nNOS without the loss of nitrergic neurons in the diabetic
state [39]. Another study in streptozocin-induced diabetic rats found a reversible loss
of nNOS after 4–8 weeks, which progressed to irreversible loss after 12 weeks, due to
apoptosis. 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]. 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].
Oxidative stress is a significant factor contributing to the loss of nitrergic function.
In diabetes, persistent high blood glucose levels and mitochondrial dysfunction en-
hance the production of reactive oxygen species, intensifying oxidative stress [41,42]. Heme-
oxygenase-1 (HO-1), up-regulated during oxidative stress, is an enzyme that catalyzes
heme degradation into products such as carbon monoxide and biliverdin. These products
are known for their antioxidative effects, offering protection against free radicals in the
enteric nervous system. 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]. Another study
in mice linked the development of diabetes with an increased number of macrophages
and the up-regulation of HO-1 in the enteric nervous system. The progression of dia-
betes was marked by delayed gastric emptying, correlating with the loss of a subset of
HO-1-positive macrophages. Interestingly, the induction of HO-1 reversed the delay in
gastric emptying, indicating its potential as a therapeutic target [44]. Furthermore, in
both mouse models and diabetic patients with gastroparesis, the depletion of HO-1 ex-
pressed by CD206+ M2 macrophages was observed, while the number of HO-1-negative
M1 macrophages increased. HO-1 expression, up-regulated in response to oxidative stress
in diabetic mice, appears to have a protective role against the development of gastroparesis.
Consequently, the up-regulation of HO-1 expression has been suggested as a potential
Gastrointest. Disord. 2024, 6 219

strategy for managing gastroparesis, with research supporting this approach, showing a
positive relationship between CD206+ cell expression and the number of interstitial Cajal
cells in diabetic patients with gastroparesis [38].

3.3. Gender Difference

The gender difference in the occurrence of DGP has been linked to factors such as a
naturally slower stomach in females, elevated levels of sex steroid hormones, diminished
expression of neuronal nitric oxide, and potential alterations in serotonergic signaling.
Additionally, there seems to be no correlation with the quantity of interstitial cells of Cajal
in the antral and pyloric smooth muscle [45].

3.3.1. Sex Hormones

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]. The pervasive distribution of estrogen and progesterone re-
ceptors throughout the gastrointestinal tract, encompassing smooth muscle, mucosal layers,
and endothelial tissues, underscores the systemic impact of these hormones. 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].
The menstrual cycle introduces a temporal dimension to these hormonal dynamics,
with fluctuations in estrogen and progesterone levels. 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-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].
Pregnancy introduces its own set of complexities, with conflicting reports regarding its
impact on gastric emptying. However, a consistent theme emerges in the form of changes
in sex steroid hormones, particularly elevated levels of estradiol and progesterone, noted
as gestational age advances. 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 transition to menopause, characterized by a significant decline in estrogen and
progesterone levels, marks another pivotal phase in the interplay between sex hormones
and gastrointestinal function. 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].

3.3.2. Nitric Oxide Signaling

The impact of gender on gastroparesis becomes apparent as estrogen, a key female sex
hormone, is revealed to modulate the regulation of nNOS. Elevated levels of estradiol-17b
(E2) in females correlate with increased NO levels, resulting in a more pronounced relax-
ation of gastric smooth muscle cells compared to males [63]. Studies involving diabetic rats
and mice, particularly females, further underscore the vulnerability of the nitrergic system
in the context of gastroparesis. Reduced levels of tetrahydrobiopterin (BH4), an essential
cofactor for NO synthesis, are implicated in impaired NO generation and subsequent gas-
tric motility issues. Intriguingly, BH4 supplementation in diabetic female rats has shown
promise in restoring the impaired nitrergic system and accelerating gastric emptying, sug-
gesting a potential therapeutic avenue for diabetes-induced gastroparesis [31,32,64]. In
addition, studies evaluating 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 prevent-
ing intestinal dysmotility, independent of hyperglycemia [45]. Furthermore, it has been
suggested that variations in nNOS dimerization may contribute to the higher prevalence
of females in this context [65]. This hypothesis derives from an examination of nitrergic
Gastrointest. Disord. 2024, 6 220

relaxation in healthy females that revealed intriguing nuances, with a more pronounced
relaxation potentially attributed to the increased expression of the active dimeric form of
nNOS alpha and heightened gastric BH4 content [66]. In the same investigation, it was
reported that chronic hyperglycemia leads to a more pronounced reduction in both gastric
pyloric BH4 content and active forms of nNOS specifically in females. This gender-specific
modification contributes to a significant impairment of nitrergic relaxation, ultimately
resulting in delayed gastric emptying [66].

3.3.3. Serotoninergic Signaling

The role of serotonin (5-HT) extends beyond its well-established function as a neuro-
transmitter in the brain, encompassing significant involvement in various gut functions.
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 contrac-
tile 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]. Notably, in healthy male subjects, the
5-HT4 agonist tegaserod accelerated gastric emptying and small intestinal transit [48].
Moreover, metoclopramide, functioning as both a 5-HT4 agonist and a dopamine D2 an-
tagonist, enhances contractions in the esophagus, antrum, and small bowel, leading to
an acceleration of gastric emptying [73]. Furthermore, gender differences in serotonin
transporter gene polymorphisms, variations in serotonin synthesis rates, and disparities in
serotonin synthesis rates have been noted [74]. Despite these valuable insights, the precise
extent to which gender-related treatment responses to serotonin agents are tied to differ-
ences in serotonin synthesis or signaling in individuals with gastroparesis remains unclear.
This underscores the need for further well-designed studies to unravel the complexities
of this intriguing interplay and achieve a comprehensive understanding of the role of
serotonin in gastrointestinal function and its implications for conditions like gastroparesis.

3.3.4. Interstitial Cells of Cajal

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, the study, predominantly
composed of females (66%, n = 25), revealed no statistically significant difference in the
number of ICC between the two genders. However, distinct patterns emerged when
examining ICC depletion in specific regions. In the antrum, 40% of females exhibited ICC
depletion, mirroring the percentage observed in males (38%). Conversely, in the pylorus,
68% of females demonstrated ICC depletion, in contrast to 80% of males. These findings
shed light on potential gender-related variations in the distribution of ICC in the context of
severe refractory gastroparesis. In addition, the study prompts a crucial inquiry into the
role of ICC as a potential marker for chronic injury leading to gastroparesis and underscores
the need for larger-scale studies to validate and expand upon these initial observations.

4. Diagnosis
DGP presents a diagnostic challenge, demanding a comprehensive approach for ac-
curate identification and management. The clinical diagnosis begins with a meticulous
evaluation 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]. A thorough physical examination is crucial, encom-
passing abdominal assessments to detect signs like distension or tenderness, alongside an
evaluation of nutritional status. Exclusion of other conditions that mimic DGP symptoms,
such as peptic ulcer disease or intestinal obstruction, involves tests like upper endoscopy,
Gastrointest. Disord. 2024, 6 221

imaging studies, and medication reviews to rule out potential causes. In the evaluation of
suspected gastroparesis, it is imperative to exclude mechanical obstructions through diag-
nostic procedures such as upper endoscopy, computed tomography, or magnetic resonance
enterography [78]. In cases where no obstructions are detected, specialized gastrointestinal
function tests become instrumental in diagnosing disturbances associated with diabetic
gastroenteropathy.
Specialized diagnostic tests play a pivotal role in confirming delayed gastric emp-
tying and differentiating DGP from other motility disorders. Gastric scintigraphy (GES),
considered the gold standard, evaluates gastric emptying non-invasively by employing a
standard low-fat meal, tracking both solid and liquid phases. 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]. Notably, sex differences impact solid gastric emptying
rates, with females being approximately 15% slower than males. GES limitations include
variations in protocols across institutions, limited access to gamma-camera facilities, and
radiation exposure concerns, restricting its use in specific populations, such as pregnant
women or children.
The Gastric Emptying Breath Test (GEBT) offers a noninvasive approach to assess
gastric emptying rates. Utilizing a 13 C-labeled substrate in a standardized meal, GEBT
measures exhaled 13 CO2 at intervals (45, 90, 120, 150, 180, and 240 min) [6]. The 13 C
substrate is absorbed in the duodenum, releasing 13 CO2 in breath samples. While GEBT is
radiation-free, cost-effective, and suitable for certain populations, it remains an indirect
measure of gastric emptying, with individual metabolism variations not fully understood.
The Wireless Motility Capsule (WMC) has served as a safe alternative to GES. This
small wireless transmitting capsule records and transmits pH, pressure, and temperature
data as it travels through the gastrointestinal tract. Gastric emptying time is determined by
a pH shift as the capsule moves from the acidic stomach to the alkaline duodenum. 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]. However, despite its historical significance, the WMC is no longer available.
Additionally, the Ambulatory Motilis 3D-Transit System, although holding promise
for advancing our understanding of gastrointestinal motility, is currently not available
in clinical practice. This innovative system monitors electromagnetic capsules as they
traverse the gastrointestinal tract, furnishing detailed insights into gut contractile activity,
movement velocity, orientation, and regional transit times. The system’s capability to
provide valuable anatomical information enables a comprehensive analysis of colonic
motility, encompassing motor patterns and dynamics [80].
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]. 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].
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]. Moreover, therapeutic trials utilizing prokinetic agents for
gastroparesis have revealed a lack of consistent correlation between improvements in
gastric emptying and symptom relief [85]. In this context, exploring the intricacies of
the diagnostic process becomes imperative, shedding light on the limitations of existing
techniques and emphasizing the importance of considering subjective symptoms alongside
objective measures during gastric emptying studies for a more nuanced and accurate
diagnosis. Despite its traditional role in diagnosis, delayed gastric emptying suggests
a potentially stronger relevance to glycemia and, conceivably, in guiding therapeutic
Gastrointest. Disord. 2024, 6 222

interventions [1,86]. Our evolving understanding prompts a nuanced perspective that goes
beyond the conventional view of delayed gastric emptying as the hallmark feature.

5. Differential Diagnosis
DGP often coexists with complications such as retinopathy, neuropathy, nephropathy,
and poor glycemic control [76,87,88]. In the realm of type 2 diabetes, individuals face
an elevated risk of various organic gastrointestinal (GI) disorders, encompassing reflux
esophagitis, gallstones, and GI malignancies. Consequently, the diagnostic process necessi-
tates careful consideration of differential diagnoses, including gastric outlet obstruction,
rumination syndrome, functional dyspepsia, chronic pancreatitis, and biliary colic.
The symptoms exhibited in DGP closely mirror those of gastric outlet obstruction,
comprising nausea, vomiting, weight loss, abdominal bloating, early satiety, and abdominal
discomfort. Intriguingly, these symptoms overlap with those of functional dyspepsia or
indigestion, adding complexity to the diagnostic procedure [89]. While gastroesophageal
reflux disease can sometimes be mistaken for gastroparesis, reflux typically manifests as a
less prominent symptom in gastroparesis, where sensations of bloating and fullness take
precedence. Patients with reflux primarily experience regurgitation immediately after food
intake, distinguishing it from vomiting, which occurs hours after ingestion. Additionally,
rumination syndrome should be contemplated in the list of differentials. 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].

6. Effects of Diabetic Gastroparesis on Glycemia

The gastrointestinal tract plays a crucial role in glucose homeostasis, with gastric
emptying rates influencing blood glucose concentrations. While fasting blood glucose levels
are regulated by insulin and glucagon secretion, hepatic and peripheral glucose uptake,
and postprandial glucose levels are influenced by various factors. 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]. 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, patients with
gastroparesis in Type 1 diabetes require reduced early postprandial insulin compared to
those with a normal gastric emptying rate [95]. 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]. Understanding
the relationship between slowing gastric emptying and reductions in glycemia is crucial.
Precise evaluation using intraduodenal glucose infusions spanning physiological rates
demonstrated a nonlinear glycemic response, emphasizing the significance of even modest
changes in intestinal glucose flux. Moreover, studies indicate that accelerated gastric
emptying leads to postprandial hyperglycemia, while abnormally delayed emptying might
predispose individuals to hypoglycemia. Therefore, measuring gastric emptying in insulin-
treated diabetes patients with unexplained hypoglycemic episodes, particularly in the early
postprandial period, is vital. Adjustments in insulin regimens or therapies to enhance
gastric emptying predictability, typically by accelerating it, should be considered based on
these measurements [97,98].

7. Nutritional Management of Diabetic Gastroparesis

DGP is a clinical condition characterized by an increased risk of malnutrition, both in
quantitative and qualitative terms. Data from The NIDDK Gastroparesis Clinical Research
Consortium (GpCRC) in 2011 revealed that more than 60% of the 305 patients enrolled in
the study experienced malnutrition, failing to meet the minimum required levels of calories,
and many of them presented severe vitamin deficiencies. This registry encompasses
Gastrointest. Disord. 2024, 6 223

all patients with gastroparesis, regardless of the presence of type 1 or type 2 diabetes.
Particularly in type 2 diabetic individuals, the data showed a significant number of patients
who were overweight, contrary to the common idea that identifies underweight as the sole
hallmark of malnutrition. 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]. All these data underscore the
crucial importance of nutritional assessment in all individuals affected by gastroparesis,
with special attention to diabetic individuals due to implications for glucose management.
In the absence of evidence-based guidelines, nutritional management of DGP relies on
expert recommendations, observational studies, and clinical consensus. Initially, all patients
diagnosed with DGP should undergo an assessment for malnutrition. A BMI < 20 kg/m2
or unintentional weight loss of 5–10% of body weight within the last 3–6 months are con-
sidered severe clinical markers of malnutrition [100,101]. Being overweight, as discussed
below, does not exclude the presence of a risk or actual malnutrition. In diabetic individuals,
the presence of early morning satiety could be an indirect sign of gastroparesis. To avoid
excluding overweight individuals from nutritional surveillance, a weight goal, above which
clinical intervention must be performed, should be identified for all individuals affected by
DGP, leading to a specific nutritional plan tailored to each patient. One of the general rec-
ommendations is to avoid large meals. For individuals with DGP, six or eight meals during
the day are suggested. Large meals, indeed, both slow gastric emptying and reduce lower
esophageal sphincter pressure. Food consistency is crucial. Unlike solids, liquid meals do
not require antral contraction to pass through the stomach, emptying simply by gravity.
Moreover, well-prepared liquid meals can be highly caloric. If feasible, transitioning from
solid to liquid meals could be suggested for all gastroparetic patients. Consuming liquid
meals in the later part of the day could alleviate gastroparetic symptoms. Parrish et al.
suggest in their work a specific semi-liquid meal pattern combining liquid foods and liquid
supplements. Moreover, they suggest enhancing the protein and caloric load, flavor, and
palatability of liquid foods [102]. Experts also recommend avoiding a supine position
in the first hours after a meal, as antigravity effects and duodenal compression by the
spine could immediately worsen gastroparetic symptoms. For the same reason, elevating
the head by 6–8 cm during sleep is suggested to minimize reflux. Patients with DGP are
prone to the formation of bezoars due to their incapability to properly eliminate fibers.
Generally, fibers are contraindicated in patients with DGP, although their possible effect
in minimizing the glycemic index of foods is recognized. Some researchers are exploring
technological solutions to improve gastric tolerance to fibers in gastroparetic individu-
als [103]. Suresh et al. have recently demonstrated that some fibers characterized by low
viscosity (PHGG—partially hydrolyzed guar gum or Arabic gum) are better tolerated in
terms of gastrointestinal symptoms than high viscosity ones (psyllium husk) in people
affected by DGP presenting the same effects in mitigating glycemic index. These results
seem encouraging in a new definition of the role of fibers in DGP [103]. Fats, in general,
reduce gastric emptying, although they may be better tolerated in liquid form. Limiting
their consumption to general dietary recommendations in people with diabetes, based
on the patients’ gastric tolerance, could be encouraged. Another aspect to consider is
that hyperglycemia (glycemia > 200 mg/dL) itself inhibits gastric emptying. Trying to
avoid glycemic variability and adapting insulin administration following a basal-bolus
regimen to the nutritional habits of the patient affected by DGP is a fundamental goal for
diabetologists, also aiming to improve the quality of life and reduce gastric symptoms in
patients. To date, there are no recommendations for choosing specific insulin analogs over
others. In summary, the main nutritional suggestions for diabetic individuals experiencing
gastroparesis are as follows (Figure 2) [102]:
• Eating smaller and more frequent meals;
• Eating slowly (30 min meals);
• Avoiding the supine position for at least the first hour after a meal;
• Sleeping with the head elevated 6–8 inches from the bed to minimize reflux;
Gastrointest. Disord. 2024, 6 224
Gastrointest. Disord. 2024, 6, FOR PEER REVIEW 13

• Avoiding tight clothes that could compress the abdomen;

• Avoiding meals in the later part of the day;
•Parenteral nutrition could be reserved only in selected cases, considering the high rate of
Avoiding fats and fibers;
complications associated
• Avoiding chewing withthat
gums its use in diabetic
increase individuals. Nutritional management of
air swallowing;
patients affected by DGP continues to pose a difficult
• Avoiding CATS: caffeine, alcohol, tobacco, and stress; clinical challenge for diabetologists
and nutritionists who must balance a proper diet
• Avoiding all foods that can reduce lower esophageal in both qualitative
sphincter and peppermint,
pressure: quantitative
terms, glycemicfat,
chocolate, control, and gastric symptoms to enhance the quality of life [99].
and caffeine.

Figure 2.
Figure 2. Main
Main nutritional
nutritional interventions
interventions in
in patients
patients with
with diabetic
diabetic gastroparesis.
gastroparesis.

8. Conclusions
Some experts have suggested a specific semi-liquid dietary plan divided into six meals,
also indicating
In summary, carbohydrate counts to ahelp
DGP presents patients choose
multifaceted the correct
challenge, rapid insulincomplex
intertwining analog
dose, minimizing glycemic variability [102]. Finally, it is possible to
pathophysiology, diverse symptoms, diagnostic intricacies, and the imperative need for consider enteral
nutrition
tailored if patients with
nutritional DGP fail to maintain
interventions. the weight goal,
The understanding continuegastric
of delayed to lose weight,
emptying,or
experience multiple hospitalizations for refractory gastric symptoms,
coupled with the spectrum of symptoms, underscores the necessity for nuanced which could lead to
dehydration and starvation. As is well known, enteral nutrition represents
diagnostic approaches. Nutritional intervention emerges as a crucial component in the best option
in terms of symptoms
managing artificial nutrition, ensuring
and enhancing thepatients’
quality ofboth
lifebalanced nutrition
for affected and hydration
individuals, together
and
with the need for personalized approaches guided by expert recommendations. As the
a reliable means of drug delivery (e.g., antiemetic or prokinetic), preserving we
functionality
navigate the of the gastrointestinal
complexities tube and helping
of this condition, diabetologists
collaboration betweenand patients themselves
researchers, clinicians,
better control glycemic
and patients variability due
remains paramount, to a direct
offering hopecorrelation
for a future between
with nutrients,
more effectiveglycemic
and
variation, and administered insulin doses. Parenteral nutrition could be reserved only in
compassionate management of DGP.
selected cases, considering the high rate of complications associated with its use in diabetic
individuals. Nutritional
Author Contributions: managementA.C.
Conceptualization, of patients
and M.C.;affected by DGP draft
writing—original continues to pose
preparation, a
A.C.,
difficult clinical challenge for diabetologists and nutritionists who must balance a
M.C. and D.N.; writing—review and editing, A.C., M.C., V.R., G.V., R.G., L.R. and D.N.; supervision proper
diet
G.L.,inR.M.,
bothM.M.
qualitative and All
and F.C.S. quantitative terms,
authors have readglycemic
and agreedcontrol, and
to the gastric symptoms
published to
version of the
enhance
manuscript.the quality of life [99].
Funding:
8. This research received no external funding.
Conclusions
Institutional Review
In summary, Board
DGP Statement:
presents The authors
a multifaceted have reviewed
challenge, literature
intertwining data and
complex have
patho-
reported results coming from studies approved by the local ethics committee.
physiology, diverse symptoms, diagnostic intricacies, and the imperative need for tailored
nutritional interventions.
Informed Consent The
Statement: understanding
Not applicable. of delayed gastric emptying, coupled with
Data Availability Statement: No dataset was generated for the publication of this article.
Gastrointest. Disord. 2024, 6 225

the spectrum of symptoms, underscores the necessity for nuanced diagnostic approaches.
Nutritional intervention emerges as a crucial component in managing symptoms and en-
hancing the quality of life for affected individuals, together with the need for personalized
approaches guided by expert recommendations. As we navigate the complexities of this
condition, collaboration between researchers, clinicians, and patients remains paramount,
offering hope for a future with more effective and compassionate management of DGP.

Author Contributions: Conceptualization, A.C. and M.C.; writing—original draft preparation,

A.C., M.C. and D.N.; writing—review and editing, A.C., M.C., V.R., G.V., R.G., L.R. and D.N.;
supervision G.L., R.M., M.M. and F.C.S. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The authors have reviewed literature data and have reported
results coming from studies approved by the local ethics committee.
Informed Consent Statement: Not applicable.
Data Availability Statement: No dataset was generated for the publication of this article.
Conflicts of Interest: The authors declare no conflicts of interest.

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