nutrients
Review
Sarcopenia as a Little-Recognized Comorbidity of Type II
Diabetes Mellitus: A Review of the Diagnosis and Treatment
Christian Salom Vendrell 1 , Elisa García Tercero 2 , Juan Bautista Moro Hernández 3
and Bernardo Abel Cedeno-Veloz 4, *
Citation: Salom Vendrell, C.; García
Tercero, E.; Moro Hernández, J.B.;
Cedeno-Veloz, B.A. Sarcopenia as a
Little-Recognized Comorbidity of
Type II Diabetes Mellitus: A Review
of the Diagnosis and Treatment.
Nutrients 2023, 15, 4149. https://
doi.org/10.3390/nu15194149
Received: 16 August 2023
Revised: 12 September 2023
Accepted: 14 September 2023
Published: 26 September 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Nutrients 2023, 15, 4149. https://doi.org/10.3390/nu15194149
1 Hospital Universitario Doctor Peset, 46017 Valencia, Spain
2 Hospital Universitario de la Ribera, 46600 Alzira, Spain
3 Medical Science Liaison, Abbott Nutrición, 28050 Madrid, Spain; juan.moro@abbott.com
4 Hospital Universitario de Navarra, 31008 Pamplona, Spain
* Correspondence: ba.cedeno.veloz@navarra.es
Abstract: Background: Type II diabetes mellitus (T2DM) is one of the most widespread metabolic
diseases worldwide, with a significant impact on morbi-mortality. Sarcopenia has a high risk in this
population (two times more risk) and a high impact at the functional level, especially in older adults.
In addition, it poses enormous challenges in the diagnosis, prevention, and treatment of this disease
concomitantly. The objective is to review the current knowledge on the state of muscle mass and the
pathogenesis, diagnosis, and treatment of sarcopenia in people with T2DM. Methods: A bibliographic
search was conducted in the PubMed-Medline databases for articles from 2015 with previously
defined terms. Results: A loss of muscle mass in older diabetic patients who are malnourished or at
risk of malnutrition has a proven negative impact on their autonomy and is closely related to the
risk of sarcopenia as a high-impact disease, and also with frailty, as an associated multidimensional
syndrome. Notably, we found that malnutrition and protein deficiency are often underdiagnosed in
obese and overweight T2DM patients. Biochemical markers could help in the future with approaches
to managing T2DM and sarcopenia concomitantly. The four essential elements which form the
basis of care for patients with diabetes and sarcopenia are pharmacological treatment, nutrition
management, regular physical exercise, and correct daily regime. Conclusions: The increasing
prevalence of sarcopenia among older patients with T2DM has significant negative impacts on quality
of life and is a public health concern. Effective diagnosis and management require a multidisciplinary
approach involving pharmacological treatment, nutrition, exercise, and correct daily regime, with
future research needed to understand the underlying mechanisms and improve diagnostic and
treatment strategies.
Keywords: diabetes; frailty; sarcopenia; malnutrition; functional impairment; oral supplementation
-HMB and exercise
1. Introduction
Diabetes mellitus is a disorder in which an alteration in the carbohydrate metabolism
predominates, resulting from a decrease in pancreatic insulin secretion, a decreased pe-
ripheral sensitivity to insulin, or a variable combination of both. It is also characterized by
abnormalities in the lipid and protein metabolism.
Long-term persistent hyperglycemia is not just a hallmark of T2DM, but also a major
contributing factor to a wide array of organ damage. Furthermore, hyperglycemia is
intricately linked with macrovascular complications, affecting larger blood vessels and
leading to conditions such as coronary artery disease and stroke, as well as microvascular
complications that impact smaller blood vessels, resulting in issues such as retinopathy,
nephropathy, and neuropathy. The cumulative effect of these complications significantly
elevates the risk of morbidity and mortality, making the management of blood sugar levels
crucial for long-term health outcomes [1].
https://www.mdpi.com/journal/nutrients
Nutrients 2023, 15, 4149 2 of 15

T2DM represents a major health burden for older adults, affecting approximately
25% of people over the age of 65 years worldwide, with this percentage being expected to
increase further in the coming decades [1].
The VIDA study was the first to assess nutritional status in a cohort of hospitalized
older patients and found a prevalence of 21.2% malnutrition and 39.1% nutritional risk [2,3].
Malnutrition worsens with age and is more pronounced in women, and is a factor that
increases population-wide mortality rates. Later, the PREDyCES [4] and SeDREno [5]
studies showed that diabetes is significantly associated with an increased risk of developing
malnutrition.
Malnutrition may be underdiagnosed in overweight or obese patients, and dietary
restrictions may even hinder nutrient intake. These restrictions often result in a negative
energy/protein imbalance, increasing the risk of developing malnutrition, particularly
when there is a lack of protein. Several factors contribute to the degree of malnutrition in
these patients: gastroparesis due to poor intake; diabetic foot, which increases energy and
protein requirements; and diabetic renal disease because of restrictions in protein intake
in pre-dialysis patients [2,3]. However, the coexistence of obesity, T2DM, and sarcopenia
presents a challenging health scenario, often referred to as “sarcopenic obesity”, which
has severe implications for morbidity, functional decline, and quality of life [6]. The
combination of obesity and a low handgrip strength suggest an increased risk of type
2 diabetes mellitus (OR 3.57, 95% CI 2.04–6.24) [7]. Understanding this triad is essential for
developing comprehensive diagnostic and treatment strategies.
Older people with T2DM have higher rates of functional disability, concomitant
illnesses, and common geriatric conditions, irrespective of the presence of microvascular
and macrovascular complications. One of these illnesses is sarcopenia, a degenerative
condition in which there is a lack of muscle or a low muscle mass, which can be a secondary
to a disease state, medical condition, or to aging itself [5,8].
The prevalence of sarcopenia among individuals with T2DM is notably elevated,
exhibiting a considerable range of variability. According to the existing literature, these
prevalence rates fluctuate significantly, spanning from as low as 7% to as high as 29.3% [8].
Different mechanisms may explain the higher prevalence of sarcopenia in people with
T2DM. Insulin’s anabolic effect on skeletal muscle is well known; it may be gradually lost
in T2DM due to the reduced insulin sensitivity associated with this disease. In addition, the
decrease in insulin’s effect may lead to decreased protein synthesis and increased protein
degradation, resulting in reductions in muscle mass and strength (Figure 1) [9].
In both type 1 and type 2 diabetes mellitus, muscle strength and architecture are also
adversely affected, this being a pathophysiological situation that is linked to muscle mass.
For all these reasons, DM is considered to be a risk factor for developing sarcopenia [10].
Chronic hyperglycemia promotes the accumulation of advanced glycation end-products
(AGE) in the skeletal muscle, with a correlation between AGEs and a weakened grip
strength, lower leg extension ability, and slower gait speed [9,10].
Similarly, diabetes is intricately linked with a rise in inflammatory cytokines, such
as interleukin-6 and tumor necrosis factor-alpha. These elevated levels of inflammatory
markers are thought to play a pivotal role in promoting the loss of muscle mass, as well
as contributing to reduced muscle strength and function. The cascade of inflammation
can trigger catabolic pathways in the muscle tissue, leading to protein degradation and
subsequent muscle atrophy. This, in turn, can result in a diminished physical performance
and functional capacity, exacerbating the already complex health challenges faced by
individuals with T2DM [9,10].
T2DM is characterized by a metabolic imbalance in which ATP levels are adversely
affected and mitochondria play a key role. Mitochondria are the main source of reactive
oxygen species (ROS) and are essential for redox homeostasis, metabolism, and many
cellular functions, including apoptosis and maintaining Ca2+ levels [9,10].
ts 2023, 15,Nutrients
x FOR PEER 15, 4149
2023,REVIEW 3 of 15 3 of 15

Figure 1. Interaction between sarcopenia and diabetes. Adapted from Landi F. et al., 2013 [9]. First,
Figure 1. Interaction between sarcopenia and diabetes. Adapted from Landi F. et al., 2013 [9].
the insulin resistance of skeletal muscle is the most important link between sarcopenia and diabetes.
First, the
Normal b-cell response to insulin
insulin resistance ofto
resistance is skeletal
enhance muscle is the most
the secretion important
of insulin link
and the between sarcopenia and
prolonged
diabetes.
physiologic increase Normal
in the plasmabeta-cell
insulin response to insulin
concentration couldresistance is to enhance
lead to further the secretion
reduction of insulin and the
in skeletal
muscle insulin prolonged
sensitivity. physiologic
Second, increase in the plasma
hyperglycemia insulin concentration
is associated with multiplecouldmetabolic
lead to further reduction
abnormalities, potentially correlated
in skeletal muscle with
insulin muscleSecond,
sensitivity. cell damage, and muscle
hyperglycemia mitochondrial
is associated with multiple metabolic
dysfunction leads to elevated accumulation of intramyocellular lipid metabolites. Third,
abnormalities, potentially correlated with muscle cell damage, and muscle mitochondrial insulin dysfunction
deficiency leads leads
to a protein catabolic state with loss of muscle mass.
to elevated accumulation of intramyocellular lipid metabolites. Third, insulin deficiency leads
to a protein catabolic state with loss of muscle mass.
In both type 1 and type 2 diabetes mellitus, muscle strength and architecture are also
adversely affected, this
The being a pathophysiological
relationship situation metabolism,
between mitochondria, that is linkedinflammation,
to muscle mass. and the different
For all these reasons,
signalingDMpathways
is considered to beina this
involved risk complex
factor forinteraction
developingis sarcopenia
very important[10]. [9,10].
Chronic hyperglycemia
Alterationspromotes the accumulation
in the mitochondrial metabolic ofpathways
advanced(such glycation end- phosphoryla-
as oxidative
products (AGE) in the
tion andskeletal muscle, with
the tricarboxylic acidacycle)
correlation between
can induce AGEsinand
changes genea weakened
expression that can lead
to different
grip strength, lower outcomes
leg extension in immune
ability, cells.gait
and slower Forspeed
example,[9,10].M1 macrophages are adversely af-
Similarly,fected in the
diabetes tricarboxylic
is intricately cycle
linked andaenter
with rise ina inflammatory
pro-inflammatory state, while
cytokines, such M2
as macrophages
undergo β-oxidation and produce anti-inflammatory
interleukin-6 and tumor necrosis factor-alpha. These elevated levels of inflammatory responses [11].
markers are thought Mitochondria
to play a pivotalplay role
an essential role inthe
in promoting theloss
regulation
of muscle of immune responses by mod-
mass, as well
as contributingulating autophagy,
to reduced muscle endoplasmic reticulumThe
strength and function. stress, and of
cascade inflammasome
inflammationactivation
can through
various
trigger catabolic mechanisms,
pathways in the including ROS production
muscle tissue, leading toand changes
protein in mitochondrial
degradation and DNA, which
regulate
subsequent muscle and control
atrophy. This, inthe
turn,transcription
can result inof immune system
a diminished physical cells. All these features under-
performance
and functional capacity, exacerbating the already complex health challenges faced by response in
score the importance of mitochondria in the modulation of the inflammatory
individuals withT2DM [11] (Figure
Diabetes Mellitus 2).Type II [9,10].
Finally, the higher
T2DM is characterized by a metabolic prevalence of sarcopenia
imbalance in which ATP in T2DM levelsis are
alsoadversely
related to the presence
of macrovascular and microvascular complications,
affected and mitochondria play a key role. Mitochondria are the main source of reactive i.e., retinopathy, nephropathy, and
oxygen speciesneuropathy.
(ROS) and Chronic kidney
are essential disease
for redoxsecondary
homeostasis, to diabetic nephropathy
metabolism, and many may affect muscle
mass, and diabetic peripheral neuropathy
cellular functions, including apoptosis and maintaining Ca levels [9,10].may2+ lead to a reduction in physical activity and
performance due to postural instability or vision loss.
The relationship between mitochondria, metabolism, inflammation, and the different Macrovascular complications such
as peripheral vascular disease can also contribute
signaling pathways involved in this complex interaction is very important [9,10]. to induce muscle ischemia, as well as a
poorer muscle strength, mass, and physical
Alterations in the mitochondrial metabolic pathways (such as oxidativeperformance [12].
phosphorylation and the tricarboxylic acid cycle) can induce changes in gene expression
that can lead to different outcomes in immune cells. For example, M1 macrophages are
adversely affected in the tricarboxylic cycle and enter a pro-inflammatory state, while M2
macrophages undergo β-oxidation and produce anti-inflammatory responses [11].
 Mitochondria play an essential role in the regulation of immune responses by
modulating autophagy, endoplasmic reticulum stress, and inflammasome activation
through various mechanisms, including ROS production and changes in mitochondrial
DNA, which regulate and control the transcription of immune system cells. All these
Nutrients 2023, 15, 4149 features underscore the importance of mitochondria in the modulation of4 ofthe 15
inflammatory response in T2DM [11] (Figure 2).

Figure 2.
Figure 2. Biological
Biological mechanism
mechanism potentially
potentially explaining
explaining diabetes-related
diabetes-related muscle
muscle dysfunction
dysfunction [11].
[11].
Adapted from Rocha M et al., 2020 [11]. Diminished β-cell function leads to decreased
Adapted from Rocha M et al., 2020 [11]. Diminished β-cell function leads to decreased insulin insulin
secretion and increased insulin resistance, affecting multiple organs and tissues. The underlying
secretion and increased insulin resistance, affecting multiple organs and tissues. The underlying
molecular mechanisms include inflammation, lipotoxicity, mitochondrial dysfunction, and
molecular mechanisms include inflammation, lipotoxicity, mitochondrial dysfunction, and endoplas-
endoplasmic reticulum stress.
mic reticulum stress.
Finally, the higher prevalence of sarcopenia in T2DM is also related to the presence
Reduced bone mass is another significant concern commonly observed in patients who
of macrovascular and microvascular
fit the profile of having complications,
T2DM and sarcopenia. i.e., retinopathy,
This decrease nephropathy,
in bone density and
contributes
neuropathy. Chronic kidney disease secondary to diabetic nephropathy may
to an elevated risk of fragility fractures. The incidence of these fractures is particularly affect muscle
mass,among
high and diabetic
women, peripheral
who areneuropathy
already moremaysusceptible
lead to a reduction in physical
to bone-related activity
issues suchand
as
performance due to postural instability or vision loss. Macrovascular
osteoporosis. These fractures not only pose immediate health risks, but also often leadcomplications such
to
as peripheral
long-term vascular disease
complications, can also
including contribute
a reduced to induce
mobility muscleofischemia,
and quality as well as a
life [13,14].
poorerThemuscle strength,
objective mass, the
is to review andcurrent
physical performance
knowledge on the[12].
state of muscle mass and the
Reduced bone mass is another significant concern commonly
pathogenesis, diagnosis, and treatment of sarcopenia in people with T2DM. observed in patients
who fit the profile of having Diabetes Mellitus Type II and sarcopenia. This decrease in
bone
2. density contributes to an elevated risk of fragility fractures. The incidence of these
Methodology
fractures is particularly
This narrative review high among
aims women,
to provide anwho are already
in-depth analysismore susceptible
of the to bone-
existing literature
related issues such as osteoporosis. These fractures not only pose immediate
concerning the relationship between T2DM, frailty, and sarcopenia. The primary objec- health risks,
but also often lead to long-term complications, including a reduced mobility
tive is to review and synthesize the information on the pathophysiology, diagnosis, and and quality
of life [13,14].of sarcopenia as a comorbidity in T2DM patients.
management
The objective is to review the current knowledge on the state of muscle mass and the
2.1. Literature Search
pathogenesis, diagnosis, and treatment of sarcopenia in people with type II diabetes
mellitus.
A comprehensive bibliographic search was conducted using multiple databases, in-
cluding PubMed, Scopus, and Google Scholar, focusing on articles published from 2015 to
present. The search terms used were “Diabetes Mellitus Type II”, “frailty”, “sarcopenia”,
“pathophysiology”, “diagnosis”, and “treatment.”

2.2. Inclusion and Exclusion Criteria

The inclusion criteria were articles that provided insights into the relationship between
T2DM and sarcopenia, its prevalence in diabetic patients, its underlying pathophysiology,
and its inflammatory component. Studies that offered management recommendations or
Nutrients 2023, 15, 4149 5 of 15

discussed the history of diabetes and diabetic control were also included. The exclusion
criteria were articles that did not focus on T2DM or sarcopenia, were not peer-reviewed, or
were published before 2015.

2.3. Review Process

After the initial search, a pool of authors reviewed the articles to assess their relevance
and quality. A total of 2506 articles met the defined search criteria, and 56 were selected for
the narrative review based on the selection criteria. These articles were then thoroughly
reviewed to extract their key findings, which were categorized into various sub-topics such
as diagnostic methods, treatment options, and future directions.

2.4. Data Synthesis

The data extracted from the selected articles were synthesized to provide a cohesive
understanding of the relationship between T2DM, frailty, and sarcopenia. This included
aspects such as the relationship between diabetes and sarcopenia, its prevalence in diabetic
patients, and its pathophysiology and inflammatory components, as well as management
recommendations and the history of diabetes and diabetic control.

3. Results
In our comprehensive literature search, we identified a total of 2506 articles that met
the defined search criteria. After a rigorous review process conducted by the pool of
authors, 56 articles were selected for inclusion in this narrative review. These articles were
chosen based on their relevance to the key questions that we aimed to answer:
(A) What is the pathophysiology and prevalence of a loss of muscle mass and function
associated with T2DM?
(B) What is the best treatment for a loss of muscle mass and function in T2DM patients?
(C) How feasible is the measurement of muscle mass and function in T2DM?
The main results are presented below:

3.1. Diagnostic Methods

As we have mentioned, diabetic patients are at a higher risk for sarcopenia and
malnutrition. The prevalence of sarcopenia in these patients varies due to the lack of
unified diagnostic criteria across the different series that have been reported (muscle
strength, muscle quantity/quality, and physical performance), as well as techniques for
quantitative assessments of muscle mass (dual-energy X-ray absorptiometry or bioelectrical
impedance analyses) [8]; so, until a common assessment method is developed and unified,
it is advisable for diagnoses to be made based on the existing available methods in each unit.
With respect to malnutrition in diabetic patients, an early nutritional assessment
using any validated screening tool is essential. There are no specific tools for diabetics,
although they do exist for the different settings in which they may be performed (inpatient,
outpatient, or older patient), which can be seen in Table 1 [15].
The Geriatric Nutritional Risk Index (GNRI) is an indicator of nutritional status. It is a
simple and accurate screening tool that includes objective factors, such as weight, height,
and serum albumin. The GNRI is associated with the presence of sarcopenia in people with
T2DM [16].
This index is calculated using the formula: (1.489 × albumin, g/L) + (41.7 × current
weight/ideal weight).
Patients are graded as serious risk (GNRI < 82), moderate risk (GNRI 82 to <92), mild
risk (GNRI 92 to 98), or no risk (GNRI > 98) [16].
It should be noted that, although many patients with T2DM are obese based on their
BMI, they may also have sarcopenia, so it is important to consider more specific measures
of body composition other than weight in these patients [8].
Nutrients 2023, 15, 4149 6 of 15

Table 1. Parameters required for the diagnosis of undernutrition/malnutrition.

Diagnostic Method Objective

Assess history for malabsorption: previous GI procedures, taste disorders, anorexia, nausea,
vomiting, gastrointestinal motility disorders, dysphagia, oral health issues, history of pulmonary
Medical history
aspiration, diabetic gastroparesis, allergies, drug use,
nutritional supplements, and medications, etc.
Assess loss of fat and muscle in specific body regions: orbital, temporal, and intercostal spaces, etc
Physical
Muehrcke’s lines in the fingernails suggest hypoalbuminemia, alopecia is associated with protein
examination
deficiency, and scaling of the scalp results from essential fatty acid deficiency.
Anthropometric data Calculate body mass index (BMI) and percentage of unintentional weight loss.
Use questionnaires to assess nutritional risk: Nutritional Risk Screening 2002 (NRS 2002), Subjective
Nutrition
Global Assessment (SGA), Mini Nutritional Assessment (MNA), Malnutrition Universal Screening
assessment
Tool (MUST), and Short Nutritional Assessment Questionnaire (SNAQ).
Bioelectrical Bioelectrical impedance analysis (BIA) provides a detailed description of body composition (fat mass,
methods fat-free mass, body water, lean body mass, and vector analysis).
The use of muscle ultrasonography to assess the quadriceps provides a simple, quick, and
Imaging tests cost-effective way of estimating total body muscle quantity and quality, but the cut-off points for this
tool have not yet been validated in the population.
Changes in biochemical parameters such as ghrelin, leptin, adiponectin, myostatin, cancer-associated
Biochemical
fibroblast (CAF), tumor necrosis factor-alpha (TNF-a), Interleukin-1 (IL-1), Interleukin-6 (IL-6),
laboratory markers
growth hormone (GH)/Insulin-like growth factor I (IGF-1), and testosterone.

Assessments of patients’ overall functional capacity can be performed with the Senior
Fitness Test battery of tests or the Short Physical Performance Battery (SPPB), which have
the advantage of not requiring sophisticated equipment, being easy to use, comparison
values in terms of sex and age being available and, moreover, can be applied in both the
hospital and extra-hospital settings [17].
These tests provide us with a general idea of physical fitness and some of its compo-
nents, but they are not very helpful for prescribing exercise loads according to results.
On the other hand, there are more reproducible and specific techniques for assessing
functional performance or the physical quality that we want to work on, and these can serve
as a reference for planning the workload. Among these are, for example, an estimation
or measurement of the maximal oxygen uptake (peak oxygen consumption), ventilatory
thresholds, actual maximum heart rate, or maximal force (one-repetition maximum, 1RM)
of the muscle groups that we want to train. These techniques require more sophisticated,
expensive equipment and require more physical space as well as a greater degree of
specialization by the professionals who perform the assessments [17].
Key biochemical markers such as myostatin, Irisin, Brain-Derived Neurotrophic Fac-
tor (BDNF), pro-inflammatory cytokines, Growth Hormone/Insulin-like Growth Factor
1 (GH/IGF1), and testosterone play significant roles in the pathogeneses of these inter-
connected conditions and their pathways could, in the future, help with diagnoses [18].
For instance, Myostatin and Irisin are directly involved in muscle metabolism and can be
indicative of muscle atrophy, while BDNF and pro-inflammatory cytokines are linked to
inflammation, a common underlying factor in both T2DM and sarcopenia. GH/IGF1 and
testosterone levels can also provide insights into the metabolic and hormonal imbalances
that exacerbate these conditions. Accurate diagnoses and effective treatment strategies
must, therefore, consider these biochemical markers to provide a comprehensive approach
to managing T2DM and sarcopenia concomitantly.

3.2. Treatment
3.2.1. Choosing a Glucose-Lowering Drug
Glucose-lowering medications appear to have a significant role in the development or
mitigation of sarcopenia among patients with diabetes. These drugs vary in their impacts
 treatment strategies must, therefore, consider these biochemical markers to provide a
comprehensive approach to managing T2DM and sarcopenia concomitantly.

3.2. Treatment
Nutrients 2023, 15, 4149 3.2.1. Choosing a Glucose-Lowering Drug 7 of 15
Glucose-lowering medications appear to have a significant role in the development
or mitigation of sarcopenia among patients with diabetes. These drugs vary in their
impacts
on muscleonmass
muscle
andmass and function,
function, largely
largely due due to differences
to differences in their mechanisms
in their mechanisms of
of action [19]
action [19]
(Figure 3): (Figure 3):

Figure
Figure 3. Plausible
Plausible mechanisms
mechanisms by by which
which glucose-lowering
glucose-lowering drugs
drugs might
might impact
impact on
on sarcopenia
sarcopenia
acting
acting on sarcopenia. DPP-4i, dipeptidyl peptidase-4
peptidase-4 inhibitors;
inhibitors; GLP-1
GLP-1 Ras,
Ras,glucagon-like
glucagon-likepeptide-1
peptide-
1receptor
receptoragonists;
agonists;GLUT4,
GLUT4,glucose
glucosetransporter
transporter type
type 4;
4; SGLT2i,
SGLT2i, sodium-glucose
sodium-glucose transport
transport protein
protein
22 inhibitors; ↑, increase; ↓,
inhibitors; and TZDs, thiazolidinediones. ↑, increase; ↓, decrease. Blue color and continue lines
and TZDs, thiazolidinediones. decrease. Blue color and continue lines
indicate a beneficial effect on sarcopenia; yellow color and dotted lines indicate a detrimental effect
indicate a beneficial effect on sarcopenia; yellow color and dotted lines indicate a detrimental effect
on sarcopenia [19]. Adapted from Massimino E et al., 2021 [19].
on sarcopenia [19]. Adapted from Massimino E et al., 2021 [19].

While
While numerous
numerous studies
studies have
have attempted
attempted to to evaluate
evaluate the
the effects
effects of
of glucose-lowering
glucose-lowering
medications on sarcopenia [20–41], these investigations are
medications on sarcopenia [20–41], these investigations are often marredoften marred by several
by several limita-
limitations. These include small sample sizes, inconsistent or varying techniques
tions. These include small sample sizes, inconsistent or varying techniques for assessing for
assessing sarcopenia, and a focus on sarcopenia as a secondary objective rather
sarcopenia, and a focus on sarcopenia as a secondary objective rather than as the primary than as
the primary focus of the study. Additionally, these studies often involve populations
focus of the study. Additionally, these studies often involve populations of varying age of
varying
ranges andagelack
ranges and lack comprehensive
comprehensive data onorcomorbidities
data on comorbidities usual physicaloractivity
usual levels.
physical
activity levels. findings have suggested that insulin does not appear to have a significant
Preliminary
effect on the development or progression of sarcopenia. Dipeptidyl peptidase-4 (DPP-4)
inhibitors, on the other hand, seem to have neutral effects on muscle mass and function.
Interestingly, the use of Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors has been
associated with an increased likelihood of developing sarcopenia, particularly in patients
already at risk [19].
Identifying patients at a higher risk for sarcopenia and choosing the most appropriate
glucose-lowering drug may help reduce the risk of it developing.

3.2.2. Nutritional Intervention

A mainstay of the treatment for these patients is medical nutrition therapy, both for
adequate control of their diabetes and to prevent disease-related malnutrition [42].
Malnutrition is present in more than 20% of hospitalized older diabetic patients.
Malnutrition in patients with diabetes worsens if not corrected and leads to a poorer
prognosis and longer hospitalizations [3].
Nutrients should preferably be provided orally and, where this is not possible, via the
enteral route; parenteral feeding should be reserved for those cases when the digestive route
is contraindicated. As a more specialized route, post-pyloric feeding may be considered in
cases where there is severe gastroparesis [43,44].
Whenever patients require artificial feeding, the enteral route, if not contraindicated,
should be used, since parenteral nutrition is associated with a higher frequency of hyper-
glycemia and greater insulin requirements. For example, enteral nutrition should be started
early for critical care patients, preferably within the first 24 h of admission, after they have
achieved hemodynamic stability [43,44].
Nutrients 2023, 15, 4149 8 of 15

Diets specifically designed to manage hyperglycemia, which incorporate carbohy-

drates with a low glycemic index, high fiber content, and enrichment with monounsaturated
fatty acids, have been shown to be effective in achieving optimal glycemic control. Notably,
these specialized diets also have the added benefit of reducing the need for insulin, thereby
offering a more holistic approach to diabetes management [45].
For patients who are grappling with both malnutrition and diabetes, it is strongly
advised that their protein energy requirements be carefully calculated. This calculation
should take into account various factors such as the level of physical activity engaged in by
the patient and any additional disease conditions or stress factors they may be experiencing,
among others. Furthermore, in scenarios where the patient is also dealing with obesity,
these protein energy requirements should be adjusted to align with the patient’s weight to
ensure the optimal nutritional balance and disease management [45].
With respect to the formulas used in enteral and oral nutrition, diabetes-specific
formulas must have the following characteristics [46,47]: a low carbohydrate content, low
glycemic index, moderate to high monounsaturated fat content in relation to the total
caloric value, and high fiber content, although the effects of the latter on postprandial
glycemic control do not appear to be very significant.
It should be remembered that, while there are no specific recommendations on mi-
cronutrients for patients with diabetes, supplementation with β-hydroxy-β-methylbutyrate
(HMB), a metabolite of leucine catabolism, seems to be helpful in preventing muscle atrophy
in diabetic patients [48].
Research has demonstrated that the implementation of outpatient nutrition counseling
programs, specifically designed to prevent sarcopenia in patients with T2DM who are at a
high risk, can be highly effective. These programs are not only associated with a marked
decrease in the incidence of sarcopenia, but also offer a proactive approach to managing
this common comorbidity in diabetic patients [46,47].

3.2.3. Physical Activity

Muscle strength and architecture are affected in diabetic patients who are also at a high
risk for developing myopathy. It is therefore important and necessary to begin an exercise
training program based on therapeutic exercises from the earliest stages of their diabetes in
order to achieve better glycemic control, prevent the progression of other complications,
and increase the active life expectancy of these patients [49].
The American Diabetes Association guidelines [50] recommend physical exercise as
part of diabetes treatment, as it helps to improve glycemic control, as well as improve the
control of cardiovascular risk factors, weight, and a better quality of life.
Traditionally, different types of exercise are classified in binary terms as endurance or
strength exercises. However, this classification is oversimplified. Further classifications of
exercise are metabolically related (aerobic vs. anaerobic) or related to the type of muscle
contraction: isotonic, when the contraction against a force causes the length of the muscle
to shorten (concentric) or lengthen (eccentric), and isometric (static or without change in
muscle length).
Aerobic exercise is a form of physical activity that involves sustained and repetitive
movements engaging the large muscle groups, primarily aimed at improving cardiovascu-
lar and respiratory function. This category includes a variety of activities, such as walking,
cycling, jogging, and swimming, each offering different levels of intensity and specific
health benefits. Resistance or strength training, on the other hand, focuses on building
muscle mass and enhancing muscle strength. This type of training incorporates a range of
exercises that utilize free weights, weight machines, body weight, or resistance bands to
target specific muscle groups. Flexibility exercises are designed to improve the range of
motion in the joints, thereby enhancing overall mobility. These exercises are particularly
beneficial for maintaining joint health and preventing stiffness. Balance exercises aim to
improve stability and coordination, which are crucial for gait and fall prevention. These
exercises are especially important for older adults or individuals with conditions that affect
Nutrients 2023, 15, 4149 9 of 15

balance. Activities such as tai chi and yoga offer a holistic approach by combining elements
of flexibility, balance, and resistance training. These activities not only improve physical
health, but also have the added benefit of enhancing mental well-being [50] (Table 2).

Table 2. Quality classification of physical activities.

• Walking
• Swimming
• Dancing

Aerobic activities • Cycling

• Ellipticals
• Low-impact aerobics
• Water aerobics
• Resistance band exercises
• Self-loading or with a load
• Climbing stairs
Strength exercises • Sit-to-stand
• Carrying things
• Some tai chi exercises
• Yoga
• Balance

To improve • Agility
balance or • Coordination
neuromotor
• Gait
fitness
• Proprioceptive training
• Multifaceted activities: tai chi and yoga

Flexibility • Take joints through a set of range of motion exercises at the start of each session and perform
different sets of stretches at various times throughout the session

In hospitalized older adults with DM, multicomponent exercise interventions, together

with the Vivifrail exercise program [50], have been found to be effective in improving
performance status, as measured with the SPPB, in addition to improving handgrip strength
and functionality.
Regular cardiorespiratory exercise increases insulin sensitivity, reduces time of hyper-
glycemia, and results in a reduction in glycosylated hemoglobin (HbA1c) by between 0.3%
and 0.6% [51]. Performed at a high intensity, these cardiorespiratory exercises have greater
benefits for glycemic control than if they are performed at a low intensity [52].
On the other hand, resistance training increases lean muscle mass, which, in turn,
is known to be related to insulin sensitivity. Hence, this form of exercise is of greater
importance to diabetic patients with pre-sarcopenia [53].
For individuals with T2DM to lose visceral fat, a moderately high volume of exercise
(approximately 500 kcals) performed 4–5 times per week is necessary [54].

3.2.4. Correct Daily Regime

The endogenous circadian system modulates the timing of behavioral rhythms and
physiological processes. There are interindividual differences in the timing of circadian
rhythms defined as chronotypes and these are related to health and behavioral problems,
especially when evening types are compared to morning types [55] Evening types, when
compared to morning types, are significantly associated with diabetes (OR 1.73; 95% CI,
Nutrients 2023, 15, 4149 10 of 15

1.01–2.95), metabolic syndrome (OR 1.74; 95% CI, 1.05–2.87), and sarcopenia (OR 3.16; 95%
CI, 1.36–7.33), especially in men.
Among the interventions for correcting daily regime, nutrition, physical activity, and
behavioral therapy stand out as the key components of lifestyle interventions for resetting
chronotypes [56], improving glycemic control, and preventing or treating T2DM and
sarcopenia.
Within the dietary recommendations, which are known as chrononutrition, are a
Mediterranean-style dietary pattern, macronutrient composition with a low glycemic index
and load carbohydrates, high in fiber and protein and accompanied by fat and/or protein
to reduce glucose and insulin spikes, and a food sequence of first consuming low-energy
dense foods that contain water, such as soups, vegetables, or fruits, followed by protein-rich
foods and then starch-rich foods to improve glycemic and insulin responses [56].
In relation to exercise, because the time of day when exercise is performed can influ-
ence its effect on circadian rhythm, mitochondrial function, and muscle performance, a
personalized exercise prescription is recommended according to the chronotype of each
individual [57].
Behavioral therapy uses cognitive and behavioral techniques to help people change
their eating habits, physical activity, and stress management. It provides regular feedback
and support from a trained professional, either in person or through technology, to improve
the adherence to and maintenance of a healthy life plan. Improving the adherence to
interventions for diabetes and sarcopenia is key to their effectiveness [56].

4. Discussion
Diabetes is a major health issue due to its high incidence and prevalence, as well as
the impact of increased morbidity and mortality on patients afflicted with it.
A loss of muscle mass in older diabetic patients who are malnourished or at risk for
malnutrition has a demonstrably negative impact on their autonomy. It is closely related
to the risk of sarcopenia, a high-impact disease, and also to frailty, a multidimensional
syndrome associated with adverse health events and, ultimately, disability [58,59].
The prevalence of malnutrition is high in both institutionalized and hospitalized older
adults. However, preventive measures can be instituted when older patients live in their
own homes, so it is worth choosing tools that allow for assessments to be made of the risk
for malnutrition presented by each patient. This should be conducted not only at the time
of screening, but also on a continuous basis once the nutrition intervention begins. The first
difficulty that arises is the validation of the questionnaire, considering the heterogeneity of
the population and the lack of a single model or standard test [58,59].
From a clinical point of view, it is extremely important to implement improvements
in the methods used to identify sarcopenia and its associated risk factors in patients with
T2DM, and hence to institute therapeutic strategies focused on adequate intake and regular
physical activity and correct daily regimes in a timely manner [60].
In light of the current review, it is crucial to adopt a multidimensional approach to
the screening, prevention, and management of T2DM and sarcopenia. Screening methods
should ideally involve medical history, physical exams, and nutritional assessments. The
Short Physical Performance Battery (SPPB) stands out as a practical approach to sarcopenia
for assessing functional capacity due to its simplicity and easy reproducibility. Regarding
pharmacological interventions, the potential modification of hypoglycemic drugs should
be evaluated on a case-by-case basis, with SGLT2 inhibitors being the only ones directly
related to sarcopenia. Dietary interventions can play a significant role, with high-protein
diets and HMB showing promise in improving muscle mass. Exercise regimens should
be tailored to individuals, focusing on multicomponent exercise interventions. Vivifrail
offers an exercise program based on SPPB that improves the functional capacity in this
population. Special attention should be given to the timing of insulin administration to
avoid hypoglycemia during physical activity. Behavioral therapy employs cognitive and
behavioral techniques to help people to change their eating habits, physical activity levels,
Nutrients 2023, 15, 4149 11 of 15

and stress management strategies. These considerations form the basis of a comprehensive
approach to managing these complex conditions.
Due to the scant evidence available, trials aimed at developing specific physical
activity programs and interventions using supplementation for patients with this profile
are needed.

5. Future Directions
The current review sheds light on the under-recognized issue of sarcopenia as a
comorbidity in patients with T2DM. While we explored the existing literature to understand
the pathophysiology, prevalence, diagnostic methods, and treatment options, there are
several avenues for future research that could provide more comprehensive insights into
this complex relationship.

5.1. Pathophysiology
Understanding the molecular mechanisms that link T2DM and sarcopenia could be a
fertile ground for future research. Identifying specific biomarkers and pathways could lead
to targeted therapies that can mitigate the effects of sarcopenia in T2DM patients.

5.2. Diagnostic Methods

The review highlighted various diagnostic methods such as dual-energy X-ray ab-
sorptiometry and bioelectrical impedance analyses. However, there is a need for more
cost-effective and accessible diagnostic tools that can be used in primary care settings.

5.3. Treatment Options

While we discussed the roles of glucose-lowering medications and nutritional inter-
ventions, future studies should focus on the efficacy of combining these treatments with
physical exercise and other lifestyle modifications such as correct daily regimes. Clinical
trials comparing different treatment modalities could provide valuable data.

5.4. Prevalence
The wide range of prevalence rates (7% to 29.3%) indicates a need for large-scale
epidemiological studies to obtain a more accurate picture. Understanding the factors
contributing to this variability can help with targeted interventions.

5.5. Technology Integration

The use of wearable technology for the continuous monitoring of muscle mass and
function could offer real-time data, aiding in early diagnoses and treatment adjustments.

5.6. Patient-Centered Approaches

Future research should also focus on the quality of life and functional outcomes
from the patient’s perspective. This could involve developing patient-reported outcome
measures specific to T2DM and sarcopenia.
By addressing these areas, we can hope to build a more comprehensive understanding
of sarcopenia in the context of T2DM, ultimately leading to better diagnostic and treatment
strategies that can improve patient outcomes.

6. Conclusions
The prevalence of sarcopenia is increasing among older patients with T2DM. Differ-
ent mechanisms may explain the association between the two, such as impaired insulin
sensitivity, chronic hyperglycemia, the accumulation of advanced glycation end-products
(AGEs), subclinical inflammation, and microvascular and macrovascular complications.
The high negative impact of this situation on quality of life, affecting physical and
psychosocial health, makes it a public health concern.
Nutrients 2023, 15, 4149 12 of 15

The four essential elements that form the basis of care for patients with diabetes are
pharmacological treatment, nutrition management, regular physical exercise, and correct
daily regime.
Health professionals should be vigilant about sarcopenia, paying special attention to
older and/or diabetic patients, in order to implement the appropriate nutritional, phar-
macological, and physical activity measures. With this, we will be able to reduce the
prevalence, severity, and disability of this geriatric syndrome in the older population. Fu-
ture research should focus on elucidating the molecular mechanisms linking T2DM and
sarcopenia, developing cost-effective diagnostic tools, and evaluating the efficacy of com-
bined treatment modalities. These efforts aim to provide a comprehensive understanding
that can improve diagnostic accuracy and patient outcomes.

Author Contributions: C.S.V.: conceptualization, writing original draft, reviewing and editing.
E.G.T.: conceptualization, writing original draft, reviewing and editing. J.B.M.H.: conceptualization,
reviewing and editing. B.A.C.-V.: conceptualization, writing original draft, reviewing and editing,
supervision. All authors have read and agreed to the published version of the manuscript.
Funding: This research was sponsored by Abbott Nutrition. The sponsor had no role in the design,
execution, interpretation, or writing of the study.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: C.S.V.: reports receiving speaker honorarium from Abbott Laboratories,
Fresenius-Kabi, Vegenat, Persan, Nestlé, Nutricia and Ordesa. E.G.T.: receiving consulting fees
from Abbott Laboratories, Persan and Nestlé Health Science and financial support for attending
symposia from Fresenius Kabi. J.B.M.H.: Medical Department employee at Abbott Laboratories.
B.A.C.-V.: reports receiving speaker honorarium from Nutricia, and Abbott Laboratories, and grant
support from Abbott. The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest. C.S.V.,
E.G.T. and B.A.C.-V. did not receive funding from Abbott Nutrition for this work.

References
1. Glovaci, D.; Fan, W.; Wong, N.D. Epidemiology of Diabetes Mellitus and Cardiovascular Disease. Curr. Cardiol. Rep. 2019, 21, 21.
[CrossRef] [PubMed]
2. Sanz Paris, A.; García, J.M.; Gómez-Candela, C.; Burgos, R.; Martín, A.; Matía, P.; Martín Palmero, Á. Malnutrition prevalence in
hospitalized elderly patients. Nutr. Hosp. 2013, 28, 592–599. [PubMed]
3. Gómez-Candela, C.; Pérez, L.; Sanz París, A.; Burgos, R.; Matía, P.; García, J.M.; Martín Palmero, Á. Análisis del perfil de los
pacientes ancianos diabéticos hospitalizados que participaron en el estudio VIDA. Nutr. Hosp. 2016, 33, 31–36. [CrossRef]
4. Álvarez Hernández, J.; León Sanz, M.; Planas Vilá, M.; Araujo, K.; García de Lorenzo, A.; Celaya Pérez, S. Prevalence and costs of
malnutrition in hospitalized dysphagic patients: A subanalysis of the predyces study. Nutr. Hosp. 2015, 32, 1830–1836. [CrossRef]
[PubMed]
5. Murillo, A.Z.; Petrina-Jáuregui, M.E.; Ripa-Ciáurriz, C.; Sánchez, R.S.; Villazón-González, F.; Faes, G.-D.; Fernández-López,
C.; Calles-Romero, L.; Martín-Palmero, Á.; Riestra-Fernández, M.; et al. SeDREno study-prevalence of hospital malnutrition
according to GLIM criteria, ten years after the PREDyCES study. Nutr. Hosp. 2021, 38, 1016–1025. [CrossRef]
6. Donini, L.M.; Busetto, L.; Bischoff, S.C.; Cederholm, T.; Ballesteros-Pomar, M.D.; Batsis, J.A.; Bauer, J.M.; Boirie, Y.; Cruz-Jentoft,
A.J.; Dicker, D.; et al. Definition and Diagnostic Criteria for Sarcopenic Obesity: ESPEN and EASO Consensus Statement. Obes.
Facts 2022, 15, 321–335. [CrossRef] [PubMed]
7. Cuthbertson, D.J.; Bell, J.A.; Ng, S.Y.; Kemp, G.J.; Kivimaki, M.; Hamer, M. Dynapenic obesity and the risk of incident Type 2
diabetes: The English Longitudinal Study of Ageing. Diabet. Med. 2016, 33, 1052–1059. [CrossRef] [PubMed]
8. Izzo, A.; Massimino, E.; Riccardi, G.; Della Pepa, G. A Narrative Review on Sarcopenia in Type 2 Diabetes Mellitus: Prevalence
and Associated Factors. Nutrients 2021, 13, 183. [CrossRef]
9. Landi, F.; Onder, G.; Bernabei, R. Sarcopenia and diabetes: Two sides of the same coin. J. Am. Med. Dir. Assoc. 2013, 14, 540–541.
[CrossRef] [PubMed]
10. Tan, S.; Gunendi, Z.; Meray, J.; Yetkin, İ. The evaluation of muscle strength and architecture in type 1 diabetes mellitus: A
cross-sectional study. BMC Endocr. Disord. 2022, 22, 153. [CrossRef]
Nutrients 2023, 15, 4149 13 of 15

11. Rocha, M.; Apostolova, N.; Diaz-Rua, R.; Muntane, J.; Victor, V.M. Mitochondria and T2D: Role of Autophagy, ER Stress, and
Inflammasome. Trends Endocrinol. Metab. 2020, 31, 725–741. [PubMed]
12. Çakmak, G.; Ganidağlı, S.; Efendioğlu, E.M.; Öztürk, E.; Öztürk, Z.A. Do Long-Term Complications of Type 2 Diabetes Increase
Susceptibility to Geriatric Syndromes in Older Adults? Medicina 2021, 57, 968. [CrossRef] [PubMed]
13. Ni, Y.; Fan, D. Diabetes mellitus is a risk factor for low bone mass-related fractures: A meta-analysis of cohort studies. Medicine
2017, 96, e8811. [CrossRef] [PubMed]
14. Pechmann, L.M.; Petterle, R.R.; Moreira, C.A.; Borba, V.Z.C. Osteosarcopenia and trabecular bone score in patients with type 2
diabetes mellitus. Arch. Endocrinol. Metab. 2021, 65, 801–810. [CrossRef] [PubMed]
15. Fernández-Pombo, A.; Rodríguez-Carnero, G.; Castro, A.I.; Cantón-Blanco, A.; Seoane, L.M.; Casanueva, F.F.; Crujeiras, A.B.;
Martínez-Olmos, M.A. Relevance of nutritional assessment and treatment to counteract cardiac cachexia and sarcopenia in
chronic heart failure. Clin. Nutr. 2021, 40, 5141–5155. [CrossRef]
16. Takahashi, F.; Hashimoto, Y.; Kaji, A.; Sakai, R.; Kawate, Y.; Okamura, T.; Kitagawa, N.; Okada, H.; Nakanishi, N.; Majima, S.; et al.
Association between Geriatric Nutrition Risk Index and The Presence of Sarcopenia in People with Type 2 Diabetes Mellitus: A
Cross-Sectional Study. Nutrients 2021, 13, 3729. [CrossRef]
17. Rikli, R.E.; Jones, C.J. Development and validation of criterion-referenced clinically relevant fitness standards for maintaining
physical independence in later years. Gerontologist 2013, 53, 255–267. [CrossRef] [PubMed]
18. Ladang, A.; Beaudart, C.; Reginster, J.Y.; Al-Daghri, N.; Bruyère, O.; Burlet, N.; Cesari, M.; Cherubini, A.; da Silva, M.C.; Cooper,
C.; et al. Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the
Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical
and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de
Recherche et d’Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating
Center for the Epidemiology of Musculoskeletal Conditions and Aging. Calcif. Tissue Int. 2023, 112, 197–217.
19. Massimino, E.; Izzo, A.; Riccardi, G.; Della Pepa, G. The Impact of Glucose-Lowering Drugs on Sarcopenia in Type 2 Diabetes:
Current Evidence and Underlying Mechanisms. Cells 2021, 10, 1958. [CrossRef] [PubMed]
20. Koshizaka, M.; Ishikawa, K.; Ishibashi, R.; Takahashi, S.; Sakamoto, K.; Yokoh, H.; Baba, Y.; Ide, S.; Ide, K.; Ishi kawa, T.; et al.
Comparison of Visceral Fat Reduction by Ipragliflozin and Metforminin Elderly Type 2 Diabetes Patients: Sub-Analysisofa
Randomized-Controlled Study. Diabetes Ther. 2021, 12, 183–196. [CrossRef] [PubMed]
21. Ishii, S.; Nagai, Y.; Kato, H.; Fukuda, H.; Tanaka, Y. Effect of the Dipeptidyl Peptidase- 4 Inhibitor Sitagliptin on Muscle Mass and
the Muscle/Fat Ratio in Patients with Type 2 Diabetes. J. Clin. Med. Res. 2020, 12, 122–126. [CrossRef] [PubMed]
22. Yajima, T.; Yajima, K.; Takahashi, H.; Yasuda, K. The effect of dulaglutide on body composition in type 2 diabetes mellitus patients
on hemodialysis. J. Diabetes Complicat. 2018, 32, 759–763. [CrossRef] [PubMed]
23. Perna, S.; Guido, D.; Bologna, C.; Solerte, S.B.; Guerriero, F.; Isu, A.; Rondanelli, M. Liraglutide and obesity in elderly: Efficacy
in fat loss and safety in order to prevent sarcopenia. A perspective case series study. Aging Clin. Exp. Res. 2016, 28, 1251–1257.
[CrossRef] [PubMed]
24. Rondanelli, M.; Perna, S.; Astrone, P.; Grugnetti, A.; Solerte, S.B.; Guido, D. Twenty-four-Week effects of liraglutide on body
composition, adherence to appetite, and lipid profile in overweight and obese patients with type 2 diabetes mellitus. Patient
Prefer. Adherence 2016, 10, 407–413. [PubMed]
25. Hong, J.Y.; Park, K.Y.; Kim, B.J.; Hwang, W.M.; Kim, D.H.; Lim, D.M. Effects of Short Term Exenatide Treatment on Regional Fat
Distribution, Glycated Hemoglobin Levels, and Aortic Pulse Wave Velocity of Obese Type 2 Diabetes Mellitus Patients. Endocrinol.
Metab. 2016, 31, 80–85. [CrossRef] [PubMed]
26. Tsurutani, Y.; Nakai, K.; Inoue, K.; Azuma, K.; Mukai, S.; Maruyama, S.; Lizuka, T.; Matsuzawa, Y.; Saito, J.; Omura, M.; et al.
Comparative study of the effects of ipragliflozin and sitagliptin on multiple metabolic variables in Japanese patients with type 2
diabetes: A multicentre, randomized, prospective, open-label, active-controlled study. Diabetes Obes. Metab. 2018, 20, 2675–2679.
[CrossRef] [PubMed]
27. Sano, M.; Meguro, S.; Kawai, T.; Suzuki, Y. Increased grip strength with sodium-glucose cotransporter 2. J. Diabetes 2016, 8,
736–737. [CrossRef] [PubMed]
28. Shimizu, M.; Suzuki, K.; Kato, K.; Jojima, T.; Iijima, T.; Murohisa, T.; Iijima, M.; Takekawa, H.; Usui, I.; Hiraishi, H.; et al.
Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, on hepatic steatosis and fibrosis using
transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes. Metab. 2019, 21,
285–292. [CrossRef]
29. Sugiyama, S.; Jinnouchi, H.; Kurinami, N.; Hieshima, K.; Yoshida, A.; Jinnouchi, K.; Nishimura, H.; Suzuki, T.; Miyamoto, F.;
Kajiwara, K.; et al. Dapagliflozin Reduces Fat Mass without Affecting Muscle Mass in Type 2 Diabetes. J. Atheroscler. Thromb.
2018, 25, 467–476. [CrossRef]
30. Yamakage, H.; Tanaka, M.; Inoue, T.; Odori, S.; Kusakabe, T.; Satoh Asahara, N. Effects of dapagliflozin on the serum levels of
fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled
trial. J. Diabetes Investig. 2020, 11, 653–661. [CrossRef] [PubMed]
31. Tobita, H.; Sato, S.; Miyake, T.; Ishihara, S.; Kinoshita, Y. Effects of Dapagliflozin on Body Composition and Liver Tests in Patients
with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study.
Curr. Ther. Res. Clin. Exp. 2017, 87, 13–19. [CrossRef]
Nutrients 2023, 15, 4149 14 of 15

32. Sasaki, T.; Sugawara, M.; Fukuda, M. Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and
simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: The Components of Weight Loss in
Japanese Patients with Type 2 Diabetes Mellitus) Study. J. Diabetes Investig. 2019, 10, 108–117. [CrossRef]
33. Bouchi, R.; Terashima, M.; Sasahara, Y.; Asakawa, M.; Fukuda, T.; Takeuchi, T.; Nakano, Y.; Murakami, M.; Minami, I.; Izumiyama,
H.; et al. Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: A pilot study. Cardiovasc. Diabetol.
2017, 16, 32. [CrossRef]
34. Inoue, M.; Hayashi, A.; Taguchi, T.; Arai, R.; Sasaki, S.; Takano, K.; Inoue, Y.; Shichiri, M. Effects of canagliflozin on body
composition and hepatic fat content in type 2 diabetes patients with non- alcoholic fatty liver disease. J. Diabetes Investig. 2019, 10,
1004–1011. [CrossRef] [PubMed]
35. Inoue, H.; Morino, K.; Ugi, S.; Tanaka Mizuno, S.; Fuse, K.; Miyazawa, I.; Kondo, K.; Sato, D.; Ohashi, N.; Ida, S.; et al. SUMS-
ADDIT-1 Research group. Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces body weight and fat mass, but not
muscle mass, in Japanese type 2 diabetes patients treated with insulin: A randomized clinical trial. J. Diabetes Investig. 2019, 10,
1012–1021. [CrossRef] [PubMed]
36. Yamamoto, C.; Miyoshi, H.; Ono, K.; Sugawara, H.; Kameda, R.; Ichiyama, M.; Yamamoto, K.; Nomoto, H.; Nakamura, A.;
Atsumi, T. Ipragliflozin effectively reduced visceral fat in Japanese patients with type 2 diabetes under adequate diet therapy.
Endocr. J. 2016, 63, 589–596. [CrossRef]
37. Iemitsu, K.; Kawata, T.; Iizuka, T.; Takihata, M.; Takai, M.; Nakajima, S.; Minami, N.; Umezawa, S.; Kanamori, A.; Takeda, H.;
et al. Efficacy and Safety of Ipragliflozin in Patients with Type 2 Diabetes ASSIGN-K Study. J. Endocrinol. Metab. 2019, 9, 51–62.
[CrossRef]
38. Kato, M.; Sakai, K.; Saito, K.; Tsutsui, K.; Yamashita, S.; Kato, N. Efficacy and safety of ipragliflozin in Japanese patients with
type 2 diabetes receiving conventional therapy: Clinical implication of the importance of exercise habits during treatment with
ipragliflozin. Diabetol. Int. 2017, 8, 275–285. [CrossRef]
39. Miyake, T.; Yoshida, S.; Furukawa, S.; Sakai, T.; Tada, F.; Senba, H.; Yamamoto, S.; Koizumi, Y.; Yoshida, O.; H irooka, M.; et al.
Ipragliflozin Ameliorates Liver Damage in Non-alcoholic Fatty Liver Disease. Open Med. 2018, 13, 402–409. [CrossRef] [PubMed]
40. Matsuba, R.; Matsuba, I.; Shimokawa, M.; Nagai, Y.; Tanaka, Y. Tofogliflozin decreases body fat mass and improves peripheral
insulin resistance. Diabetes Obes. Metab. 2018, 20, 1311–1315. [CrossRef] [PubMed]
41. Ferrari, U.; Then, C.; Rottenkolber, M.; Selte, C.; Seissler, J.; Conzade, R.; Linkohr, B.; Peters, A.; Drey, M.; Thorand, B. Longitudinal
association of type 2 diabetes and insulin therapy with muscle parameters in the KORA-Age study. Acta Diabetol. 2020, 57,
1057–1063. [CrossRef]
42. Burgos Peláez, R.; García Almeida, J.M.; Matía Martín, P.; Palma Milla, S.; Sanz Paris, A.; Zugasti Murillo, A.; Alfaro Martínez, J.J.;
Artero-Fullana, A.; Calañas Continente, A.; Chinchetru, M.J.; et al. Abordaje de la desnutrición en pacientes hospitalizados con
diabetes/hiperglucemia y otras patologías [Malnutrition management of hospitalized patients with diabetes/hyperglycemia and
concurrent pathologies]. Nutr. Hosp. 2022, 39, 1–8. (In Spanish) [CrossRef] [PubMed]
43. Sanz Paris, A.; Álvarez Hernandez, J.; Ballesteros-Pomar, M.A.; Botella-Romero, F.; León-Sanz, M.; Martín-Palmero, A.; Olmos,
M.M.; Olveira, G. Evidence-based recommendations and expert consensus on enteral nutrition in the adult patient with diabetes
mellitus or hyperglycemia. Nutrition 2017, 41, 58–67. [CrossRef] [PubMed]
44. Barazzoni, R.; Deutz, N.E.P.; Biolo, G.; Bischoff, S.; Boirie, Y.; Cederholm, T.; Cuerda, C.; Delzenne, N.; Leon Sanz, M.; Ljungqvist,
O.; et al. Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group. Clin. Nutr.
2017, 36, 355–363. [CrossRef] [PubMed]
45. Vaquerizo Alonso, C.; Grau Carmona, T.; Juan Díaz, M.; Spanish Society of Intensive Care Medicine and Coronary Units-Spanish
Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE). Recomendaciones para el soporte nutricional y metabólico
especializado del paciente crítico. Actualización. Consenso SEMICYUC-SENPE: Hiperglucemia y diabetes mellitus [Guidelines
for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive
Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): Hyperglycemia
and diabetes mellitus]. Med. Intensiva 2011, 35 (Suppl. S1), 48–52. (In Spanish) [CrossRef]
46. Chan, L.C.; Yang, Y.C.; Lin, H.C.; Wahlqvist, M.L.; Hung, Y.J.; Lee, M.S. Nutrition counseling is associated with less sarcopenia in
diabetes: A cross-sectional and retrospective cohort study. Nutrition 2021, 91–92, 111269. [CrossRef]
47. Velázquez-Alva, M.C.; Irigoyen-Camacho, M.E.; Zepeda-Zepeda, M.A.; Lazarevich, I.; Arrieta-Cruz, I.; D’Hyver, C. Sarcopenia,
nutritional status and type 2 diabetes mellitus: A cross-sectional study in a group of Mexican women residing in a nursing home.
Nutr. Diet. 2020, 77, 515–522. [CrossRef]
48. Holeček, M.; Vodeničarovová, M.; Fingrová, R. Dual Effects of Beta-Hydroxy-Beta-Methylbutyrate (HMB) on Amino Acid, Energy,
and Protein Metabolism in the Liver and Muscles of Rats with Streptozotocin-Induced Type 1 Diabetes. Biomolecules 2020, 10,
1475. [CrossRef]
49. de Luis Román, D.; Garrachón Vallo, F.; Carretero Gómez, J.; López Gómez, J.J.; Tarazona Santabalbina, F.J.; Guzmán Rolo, G.;
García Almeida, J.M.; Sanz Paris, A. La masa muscular disminuida en la diabetes de tipo 2. Una comorbididad oculta que
debemos tener en cuenta [Decreased muscle mass in type-2 diabetes. A hidden comorbidity to consider]. Nutr. Hosp. 2023, 11,
59–66. (In Spanish) [CrossRef]
Nutrients 2023, 15, 4149 15 of 15

50. Colberg, S.R.; Sigal, R.J.; Yardley, J.E.; Riddell, M.C.; Dunstan, D.W.; Dempsey, P.C.; Horton, E.S.; Castorino, K.; Tate, D.F. Physical
Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016, 39, 2065–2079.
[CrossRef]
51. Umpierre, D.; Ribeiro, P.A.B.; Kramer, C.K.; Leitão, C.B.; Zucatti, A.T.N.; Azevedo, M.J.; Gross, J.L.; Ribeiro, J.P.; Schaan, B.D.
Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: A systematic
review and meta-analysis. JAMA 2011, 305, 1790–1799. [CrossRef] [PubMed]
52. Grace, A.; Chan, E.; Giallauria, F.; Graham, P.L.; Smart, N.A. Clinical outcomes and glycaemic responses to different aerobic
exercise training intensities in type II diabetes: A systematic review and meta- analysis. Cardiovasc. Diabetol. 2017, 16, 37.
[CrossRef] [PubMed]
53. Viecelli, C.; Aguayo, D. May the Force and Mass Be with You-Evidence-Based Contribution of MechanoBiological Descriptors of
Resistance Exercise. Front. Physiol. 2022, 12, 686119. [CrossRef]
54. Ida, S.; Kaneko, R.; Imataka, K.; Murata, K. Relationship between frailty and mortality, hospitalization, and cardiovascular
diseases in diabetes: A systematic review and meta-analysis. Cardiovasc. Diabetol. 2018, 18, 81. [CrossRef]
55. Yu, J.H.; Yun, C.H.; Ahn, J.H.; Suh, S.; Cho, H.J.; Lee, S.K.; Yoo, H.J.; Seo, J.A.; Kim, S.G.; Choi, K.M.; et al. Evening chronotype is
associated with metabolic disorders and body composition in middle-aged adults. J. Clin. Endocrinol. Metab. 2015, 100, 1494–1502.
[CrossRef]
56. Papakonstantinou, E.; Oikonomou, C.; Nychas, G.; Dimitriadis, G.D. Effects of Diet, Lifestyle, Chrononutrition and Alternative
Dietary Interventions on Postprandial Glycemia and Insulin Resistance. Nutrients 2022, 14, 823. [CrossRef]
57. Choi, Y.; Cho, J.; No, M.H.; Heo, J.W.; Cho, E.J.; Chang, E.; Park, D.H.; Kang, J.H.; Kwak, H.B. Re-Setting the Circadian Clock
Using Exercise against Sarcopenia. Int. J. Mol. Sci. 2020, 21, 3106. [CrossRef] [PubMed]
58. Sanz, A. Special Issue Diabetes and Muscle: From the Assessment to Treatment. Nutrients. Available online: https://www.mdpi.
com/journal/nutrients/special_issues/3A1M1755Y5 (accessed on 13 September 2023).
59. Gamgaram, V.K.D.; Olivares, M.G.; Fuster, G.O. Olveira Fuster, Diabetes y sarcopenia. Nutr. Clin. Med. 2023, XVII, 75–88.
60. Hashimoto, Y.; Takahashi, F.; Okamura, T.; Hamaguchi, M.; Fukui, M. Diet, exercise, and pharmacotherapy for sarcopenia in
people with diabetes. Metabolism 2023, 144, 155585. [CrossRef]

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