Current Tissue Microenvironment Reports

https://doi.org/10.1007/s43152-024-00056-3

REVIEW

Cellular and Molecular Mechanisms of Insulin Resistance

Preethi Chandrasekaran1 · Ralf Weiskirchen2

Accepted: 29 January 2024

© The Author(s) 2024

Abstract
Purpose of Review Although the molecular mechanism of insulin resistance involves multiple factors and several intrinsic
and extrinsic mechanisms have been identified, this comprehensive review provides key information on some of the core
mechanisms and complex interactions of the molecules involved in the signaling pathways of insulin resistance.
Recent Findings Diabetes Mellitus, the most common metabolic disorder, is one of the greatest global medical challenges
at present. There has been a significant increase in complications associated with diabetes such as heart disorders, stroke,
neuropathy, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and nephropathy. This calls for immedi-
ate strategic action to combat this complex metabolic disorder. Insulin resistance, a characteristic marker of type 2 diabetes
is a condition in which the regulation of glucose metabolism in body tissues, such as the liver, adipose tissue, and skeletal
muscle, becomes disrupted. It is generally associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and impaired
glucose homeostasis.
Summary Understanding the pathophysiological molecular mechanisms involved in insulin resistance is critical for devel-
oping new therapeutic strategies to treat this polygenic multifactorial condition. Impairment of insulin action is caused by
several factors such as lipotoxicity, increased adiposity, enhanced inflammatory signaling, endoplasmic reticulum stress,
adipokines, mitochondrial dysfunction, increased free fatty acids, and dysfunctional insulin signaling.

Keywords Adipose tissue · Free fatty acids · Adipokines · Lipotoxicity · Dyslipidemia · Obesity

Abbreviations Introduction
ER Endoplasmic reticulum
FFA(s) Free fatty acid(s) The growing burden of diabetes, amplified by unhealthy
INSR Insulin receptor eating habits, obesity, physical inactivity, and genetic muta-
IR Insulin resistance tions, poses the biggest challenge to the healthcare sector. In
IRS Insulin receptor substrate 2021, the prevalence of impaired glucose tolerance among
IRTK Insulin receptor tyrosine kinase adults aged 20–79 worldwide was around 9.1%. This figure
SOCS Suppressor of cytokine signaling is projected to increase by 10%, to around 638 million by
UPR Unfolded protein response 2045 [1••]. Due to the wide spectrum of signaling cascades,
crosstalk, and complex molecular mechanisms involved in
the progression of insulin resistance (IR), it is critical to
gain a deeper understanding of the mechanistic insights to
uncover novel, comprehensive therapeutic strategies to pre-
vent and manage this multifaceted condition. Clinically, the
* Ralf Weiskirchen term “insulin resistance” necessitates a higher concentration
[email protected] of insulin to maintain normal glucose levels. On a cellular
Preethi Chandrasekaran level, it is defined as the insufficient strength of insulin sign-
[email protected] aling from the insulin receptor (INSR) downstream to the
1
UT Southwestern Medical Center Dallas, 5323 Harry Hines
final substrates of insulin action involved in various meta-
Blvd, Dallas, TX 75390, USA bolic aspects of cellular function and crosstalk [2•].
2
Institute of Molecular Pathobiochemistry, Experimental
The regulation of glucose homeostasis is accomplished
Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH through the production of insulin by beta cells in response
University Hospital Aachen, 52074 Aachen, Germany

Vol.:(0123456789)
 Current Tissue Microenvironment Reports

to increased blood glucose levels after food intake. The achieved by decreasing the expression of genes involved in
driving force behind this homeostasis is the insulin sensi- gluconeogenesis and lipolysis in adipose tissue [6].
tivity of various organs, including the liver, skeletal muscle, Insulin receptor tyrosine kinase (IRTK) mediates the
and adipose tissue. A tightly regulated cascade of insulin- intracellular functions of insulin. When insulin binds to the
dependent signaling controls multiple metabolic processes, extracellular domain of IRTK, it induces a conformational
such as reducing glucose production by the liver, increasing change and leads to autophosphorylation of tyrosine residues
glucose uptake by adipose tissue and skeletal muscle, and in IRTK. This activation of IRTK results in the activation
suppressing the release of free fatty acid (FFA) release from of insulin receptor substrate (IRS), growth factor receptor-
adipocytes. Insulin actions are carefully regulated to ensure bound protein (GRB) 2, GRB10, and SHC, which are phos-
proper metabolic function and maintain energy balance [3]. photyrosine binding proteins [7], which are known to play
IR, which is characterized by a dysregulation in any of these critical regulatory roles. For example, GRB10 phosphoryla-
metabolic processes and a failure of target cells to respond tion and stabilization by mTORC1, activated by insulin sign-
to normal levels of circulating insulin, is marked by both aling, provide feedback inhibition of INSR activity. Other
intrinsic and extrinsic cell signaling pathways. The intrin- substrates, such as the SH2B adapter protein 2 (SH2B2),
sic pathway controls mitochondrial function and ER stress, also known as adapter protein with a pleckstrin homology
while the extrinsic mechanisms impact adipokines, FFAs, and a Src homology 2 domain (APS), help initiate the meta-
and inflammation in the metabolic tissues [4]. The diversity bolic insulin response in certain cell types [8, 9]. The proxi-
of physiological insulin responses in the liver, white adipose mal insulin signaling pathway consists of two major arms:
tissue, and skeletal muscle is largely due to distinct distal the mitogenic arm (initiated by GRB2 and SHC) and the
effectors, while the proximal components involved in insu- metabolic arm (initiated by IRS proteins and SH2B2/APS).
lin signal transduction are similar in all insulin-responsive The characteristic positive feedback mechanism of insulin
cells. action involves the Gα-interacting vesicle-associated protein
A widely accepted notion is that obesity, which involved (GIV) potentiating of PI3K/AKT signaling and phosphatase
the accumulation of toxic metabolic by-products and inhibition by NAD(P)H oxidase 4. Negative feedback mech-
increased FFAs, directly contributes to IR. However, recent anisms involve the stabilization and recruitment of GRB10
studies revealed other mechanisms that also play a role. to INSR and the activation of S6K1 to phosphorylate and
These include the activation of inflammatory pathways and inhibit IRS proteins [10].
intracellular stress response pathways, altered metabolic To summarize, the proximal signaling events include
functions caused by lipid accumulation and lipid-derived IR activation and phosphorylation of signaling proteins,
metabolites, metabolic overload in muscle, mitochondrial particularly IRS, PI3K, and AKT isoforms. These events
stress, and dysfunction. are highly conserved in insulin target tissues and initiate
This review provides essential information and an over- the insulin response at the plasma membrane. This phos-
view of the role that these core mechanisms play in the phorylation forms the basis for substrate association with
development of IR. Additionally, it presents a unified frame- downstream signaling proteins, leading to three pathways.
work for comprehending this intricate network of signaling The PI3K-dependent pathway mediates glucose/lipid/pro-
axes. tein metabolism and insulin-stimulated glucose uptake. The
CAP/Cb1 pathway is necessary for GLUT4 translocation,
and the MAP kinase pathway controls cell proliferation
Normal Insulin Action and Signaling and differentiation. The phosphorylation of IRS, induced
by IRTK, mediates the effects of insulin action on glucose
To better understand the complex mechanisms and interac- and lipid metabolism by recruiting PI3K and catalyzing the
tions involved in IR, it is essential to shed light on normal production of PIP3 from PIP2. AKT is then activated by
insulin action and the insulin signaling mechanism. In a PKD1 and the mechanistic target of rapamycin complex 2
fasted state, the liver secretes glucose into the bloodstream (mTORC2) after being recruited to the plasma membrane by
to maintain euglycemia and provide fuel for glucose-con- PIP3. AKT activation is followed by the phosphorylation of
suming tissues. The hepatic glucose production involves various downstream substrates in skeletal muscle, adipose
glycogenolysis and the de novo synthesis of glucose, in a tissue, and the liver, enabling insulin-mediated nutrient res-
process known as gluconeogenesis [5]. After food intake, ervation in these tissues [11].
insulin secretion by the pancreatic cells suppresses catabolic In skeletal muscle, the primary substrate for INSR is
programs and stimulates skeletal muscle and adipose tissue IRS1. INSR activation in skeletal muscle has two major
to take up glucose. Insulin secretion also promotes glycogen metabolic functions: glucose uptake and glycogen storage.
and lipid synthesis in the liver, skeletal muscle, and adipose Insulin stimulates the translocation of GLUT4-containing
tissue by suppressing hepatic glucose production. This is vesicles to the plasma membrane, which is important for
Current Tissue Microenvironment Reports

glucose uptake and leads to increased production of intra- signaling and some of the most important effects associated
cellular glucose 6-phosphate. Additionally, the dephos- with it.
phorylation of glycogen metabolic proteins promoted by Upon insulin binding, the insulin receptor undergoes
insulin enables net glycogen synthesis. The core event autophosphorylion, which subsequently leads to the recruit-
occurring in skeletal muscle IR is the increase in glu- ment of multiple substrates. There are major branches of
cose transport, facilitated by the anchoring and fusion of insulin signaling: mitogenic (signaling, which is initiated by
the plasma membrane with GLUT4-containing vesicles. GRB2 and SHC), and metabolic (signaling, which is initi-
This process is mediated by the GTPase-activating pro- ated by IRS proteins and SH2B2/APS). Insulin signaling
tein AKT substrate. Furthermore, the promotion of the also involves feedback through Gα-interacting vesicle-asso-
GTP-bound form of RAS-related C3 botulinum toxin sub- ciated protein (GIV), which enhances phosphoinositide-3-ki-
strate 1 (RAC1) is also involved in this event. The insulin nase (PI3K)-AKT signaling, and inhibition of phosphatase
stimulation of glycogen synthesis is achieved through the by NAD(P)H oxidase 4 (NOX4)-derived H ­ 2O2. Additionally,
inhibition of glycogen kinase synthase 3 (GSK3), which there is a negative feedback through the stabilization and
subsequently activates glycogen synthase and deactivates recruitment of GRB10 to the INSR, as well as the activa-
glycogen phosphorylase [9, 12, 13]. tion of S6 kinase 1 (S6K1) to phosphorylate and inhibit IRS
The main mechanism involved in hepatic insulin signal- proteins.
ing includes AKT signaling, which activates the machin-
ery responsible for glycogen and protein synthesis. Other
transcriptionally mediated effects include upregulation of
glucokinase, reduction of gluconeogenesis, and stimula- Mechanisms of Insulin Resistance
tion of de novo lipogenesis capacity [14]. In the liver, AKT
decreases gluconeogenesis by suppressing of forkhead box Defects in Insulin Signaling and Insulin Resistance
O1 (FOXO1)-mediated expression of gluconeogenic genes.
Hepatic glycogen synthesis is increased through regulation The proximal insulin signaling abnormalities are rarely asso-
of GYS2 and glycogen phosphorylase via GSK3 and protein ciated with IR in most forms of type 2 diabetes mellitus.
phosphatase 1 [15, 16]. It has been discovered that only 2.4% of the total INSRs
The key somatic function of insulin action in white adi- are necessary for a complete biological response in insulin-
pose tissue is to inhibit lipolysis. This inhibition requires binding experiments of rat adipocytes [22]. However, defects
phosphodiesterase 3B (PDE3B), which weakens cAMP- at the receptor or post-receptor level can lead to the inactiva-
stimulated PLIN and hormone-sensitive lipase phosphoryla- tion of insulin during circulation. Over 60 mutations have
tion. Insulin stimulates the uptake of glucose through two been identified in the INSR gene, with type A INSR being
pathways: one insulin receptor, which is PI3K dependent, associated with a heterozygous mutation state that results
and a second insulin receptor, which is PI3K independent. in decreased tyrosine phosphorylation of the β subunit after
The PI3K-independent pathway uses several effectors to insulin binding [23]. Abnormal production of anti-INSR
regulate the translocation and fusion of glucose transporter antibodies can also cause this [24]. Another finding showed
storage vesicles and the plasma membrane [17]. Addition- decreased INSR activity in hyperinsulinemic ob/ob mice,
ally, insulin promotes lipogenesis in white adipose tissue by which was due to a decreased tyrosine phosphorylation state
activating SREBP1c, which stimulates the esterification of of IRS1 [25].
fatty acids and enhances the translocation of glucose or fatty Dysregulation of insulin at the post-receptor level has
acid transport proteins [18, 19]. recently gained attention. An increased TNFα level causes
Collectively, members of the IRS family play a major an increase in Ser/Thr phosphorylation of IRS1, which is
role in controlling metabolic fuel homeostasis. IRS1 serves a crucial factor in IR. Additionally, hyperinsulinemia also
as a key mediator of insulin-mediated glucose uptake and affects the concentration of IRS2, causing downstream
activation of anabolic pathways in muscle and adipose tis- changes in insulin signaling [26]. Interestingly, glycated
sue. In contrast, the liver is primarily influenced by IRS2 proteins resulting from hyperglycemia have been shown to
[20]. The insulin signaling cascade can be regulated by vari- decrease intracellular PI3K, PKB, and GSK-3 activity, thus
ous factors, including the reversal of IRS phosphorylation contributing to IR. Similarly, glucosamine, produced from
by Tyr-phosphatase 1β and the inhibition of tyrosine kinase glucose which is a major substrate for cellular glycosyla-
activity by the suppressor of cytokine signaling (SOCS)1 tion, enhances IRS1 glycosylation, reducing its activity and
and SOCS2 [20, 21•]. Understanding these core elements of insulin responsiveness [26]. Among the three isoforms of
the insulin signaling cascade, the complex network of phos- AKT, only defects in AKT2 and AKT3 are associated with
phorylation, and their modulation could lead to improved impaired insulin-stimulated glucose transport in IR, not
therapies. Figure 1 provides an overview of proximal insulin AKT1 [27, 28].
 Current Tissue Microenvironment Reports

Fig. 1  The insulin signaling cascade. When insulin binds to its The levels of ceramides increase due to mitochondrial dysfunction,
receptor, it leads to autophosphorylation and recruitment of insulin decreased lipid oxidation, and accumulation. These factors also cause
receptor substrates (IRS) that become phosphorylated. This, in turn, oxidative stress and the production of reactive oxygen species (ROS).
enhances the phosphoinositide-3-kinase (PI3K)-AKT signaling cas- This further impacts the insulin cascade, leading to mitophagy and
cade, which is crucial for glucose metabolism. It promotes glycoly- apoptosis. Additionally, elevated lipids result in higher levels of dia-
sis and prevents gluconeogenesis. AKT activity is further regulated cylglycerols (DAG), which excessively activate protein kinase C
by protein phosphatase 2A (PP2A), which is activated by ceramides. (PKC) and inhibit insulin signaling, causing induce insulin resistance

Insulin Resistance in Skeletal Muscle For example, one study showed that the glucose-fatty acid
cycle is inoperative in pyruvate dehydrogenase kinase 2/4
The skeletal muscle plays an important role in insulin-stim- (Pdk2/4)-double knockout mice, as these mice preferentially
ulated glucose consumption, which means that muscular IR oxidize glucose in an inflexible manner [34]. However, Ran-
can have various effects in overall body metabolism [29]. dle’s proposal is still physiologically relevant for the control
Early studies on the skeletal muscle of obese and diabetic of oxidative substrate selection and can be seen as a cell-
individuals showed a decrease in surface INSR content and autonomous response to the overall regulation of substrate
a decrease in the activity of purified receptors [30••]. availability, promoting efficient glucose oxidation in the fed
Multiple studies have found that impaired translocation of state and fatty acid oxidation in the fasted state [35]. For
GLUT4 protein is responsible for IR in skeletal muscle [31]. instance, in lipid infusion models, there is an increase in
Additionally, defects in proximal insulin signaling, specifi- intramyocellular G6P concentration and a decrease in gly-
cally in the activities of IRTK, IRS1, PI3K, and AKT, could colytic flux, followed by the development of significant IR
also contribute to IR in skeletal muscle. This is supported by after 3 h of acute lipid infusion. This aligns with Randle’s
the reduced activity in the skeletal muscle of obese/diabetic glucose-fatty acid hypothesis [36].
mice [32]. In 1963, Randle et al. proposed that lipid-induced
IR in skeletal muscle is caused by a decrease in glucose Insulin Resistance in Liver and Adipose Tissue
utilization due to an increase in fatty acid oxidation. This
increase in fatty acid oxidation leads to an accumulation The liver controls the post-prandial glucose level by sup-
of G6P and intramyocellular glucose, as well as a decrease pressing hepatic glucose production and promoting the stor-
in glucose uptake [33]. Some models have challenged the age of glucose as glycogen [37•]. In individuals with type 2
relevance of the glucose-fatty acid cycle in lipid-induced IR. diabetes mellitus, the main cause of fasting hyperglycemia
Current Tissue Microenvironment Reports

is increased hepatic gluconeogenesis. This is primarily hepatic IR in patient with type 2 diabetes mellitus and non-
linked to impaired lipolysis in adipose tissue and the fail- alcoholic fatty liver disease [41]. Furthermore, additional
ure to suppress the FOXO1 transcription factor in the liver evidence suggests that the knockout of fat transport proteins,
[37•]. Additionally, IR is associated with defects in the abil- such as CD36, increases insulin-mediated glucose uptake in
ity of insulin to stimulate glycogen synthesis. It is important skeletal muscle, while liver-specific knockdown of FATP2
to note that hepatic IR reduced the extent of hepatic glyco- reduces hepatic lipid accumulation and improves glucose
gen metabolism during fasting and feeding [38]. Similarly, tolerance [42, 43].
to the liver and muscle, individuals with type 2 diabetes Several lipid metabolites such as diacylglycerol,
mellitus experience diminished tyrosine kinase activity. lysophosphatidic acid, ceramides, and acylcarnitine are
This, along with a decrease in plasma membrane INSR involved in the ectopic lipid accumulation-induced IR in the
content, leads to IR in the adipose tissue [39]. Figure 2 liver and skeletal muscle [44]. This popular theory suggests
illustrates the inter-organ communication between muscle, that lipid-induced hepatic IR occurs due to the accumula-
liver, adipose tissue, pancreas, gut, and adipose tissue in tion of lipids caused by impaired fatty acid oxidation. This
obesity-induced IR that leads to ectopic lipid storage in dif- impairment leads to the redirection of long-chain acyl CoA
ferent organs [40]. molecules into endoplasmic reticulum (ER)-localized and
cytosolic lipid species, such as diacylglycerols, ceramides,
and triglycerides. In the liver and skeletal muscle, elevated
Ectopic Lipid Accumulation levels of diacylglycerol trigger the movement of nuclear
protein kinase C (PKC) to the plasma membrane. This, in
As suggested by numerous studies, ectopic fat accumulation turn, hinders IRTK activity by phosphorylating Thr1160,
in peripheral tissues such as the liver and skeletal muscle ultimately leading to the deactivation of IRS2, PI3K, and
can lead to severe IR. It has been demonstrated that leptin AKT2 [45]. Numerous studies provide evidence supporting
treatment or moderate weight loss can dramatically reverse the diacylglycerol hypothesis of IR. For instance, an early

Fig. 2  Inter-organ communication in obesity-induced insulin resist- very low-density lipoprotein-TAG and the lipoprotein lipase (LPL).
ance. Lipid overload and overnutrition provoke an increased uptake Additionally, this leads to higher concentrations of circulating non-
of triacylglycerol (TAG) through chylomicron triacylglycerol parti- esterified fatty acids (NEFA) and triacylglycerol. In the long term,
cles (CM-TAG) from the gut. If the adipose tissue’s absorption and impaired lipid oxidation leads to fat accumulation in different organs,
storage capacity is overwhelmed, elevated TAG is then transferred the development of insulin resistance, and significantly higher levels
into different organs, such as the liver, muscles, and pancreas, via of circulating glucose
 Current Tissue Microenvironment Reports

study revealed increased PKC levels in the soleus muscles the muscle, heart, and liver, and elevated secretion of insulin
of diabetic rats and livers of obese rats [46]. and β-cell apoptosis.
Ceramides have been shown to mediate lipid-induced IR,
but the exact mechanism has not yet been demonstrated.
Ceramide is a crucial bioactive sphingolipid that is produced Role of Inflammation in Insulin Resistance
from an intracellular fatty acid and sphingosine [47]. In one
study, it was found that liver-specific knockout of Cers6 led The most important contributor to obesity-induced IR is the
to a decrease in hepatic ceramide levels, which protected systemic chronic inflammatory response caused by altered
against high-fat diet-induced obesity and improved glucose cytokine production and activation of inflammatory sign-
tolerance [48]. Although the precise molecular mechanisms aling pathways [51]. In obesity, there is an increase in fat
of ceramide-induced IR are still unclear, a few theories have accumulation in the adipose tissue, leading to larger adi-
been proposed. One theory suggests that ceramide negatively pocyte sizes, expansion of adipose tissue, and changes in
regulates insulin action by inhibiting AKT/PKB, a serine/ pro-inflammatory cytokines. Additionally, obesity leads to
threonine kinase that plays a central role in glucose uptake an increase in the infiltration of macrophages, which contrib-
and metabolism [49]. Ectopic fat accumulation in obesity is utes to cytokine production [51]. The inflammatory response
primarily caused by the action of inflammatory chemokines is connected to IR in two ways. Firstly, the stimulation of
and adipocytokines from macrophages and other cells that inflammatory signaling intermediates directly leads to ser-
infiltrate the adipose tissue [50•]. Figure 3provides a brief ine phosphorylation of IRS1 in hepatocytes and myocytes,
illustration of the pathophysiology behind ectopic fat accu- inducing IR. Secondly, within the adipose tissue, inflamma-
mulation that is promoted by adipocyte dysfunction, IR in tory cell infiltration may alter adipocyte lipid metabolism,

Fig. 3  Adipocyte dysfunction in ectopic fat accumulation and associ- FFA. Ectopic fat induced in these organs is associated with insu-
ated consequences. Elevated fat uptake leads to adipocyte hypertro- lin resistance, mitochondrial dysfunction, and key features typical
phy, which in turn increases the number of infiltrating macrophages of type 2 diabetes. Examples include increased secretion of VLDL,
that release inflammatory adipokines. Over time, this dysfunction in hepatic steatosis, and the development of non-alcoholic fatty liver dis-
adipose tissue impairs the uptake of free fatty acid (FFA). The liver, ease (NAFLD)
muscles, heart, and pancreas then take up higher concentrations of
Current Tissue Microenvironment Reports

with TNF-α promoting lipolysis and changes in cytokine to other organs and tissues [63]. Pro-inflammatory factors
production, such as IL-6 [52]. This is supported by studies such as IL-6, TNF-α, ROS, and hypoxia reduce plasma
showing reduced IR in rodents and humans when TNF-α is adiponectin levels in obese and diabetic animal models
knocked out [53]. The role of TNF-α in IR is mediated by [64]. Adiponectin activates AMPK and PPAR-α signal-
JNK1 which phosphorylates serine 307 of IRS1 [54]. ing through Adiponectin receptors 1 and 2, respectively.
Strikingly, it has been reported that the heterogeneous This promotes enhanced fatty acid oxidation and glucose
deletion of another inflammatory signaling intermediate uptake in muscle, while suppressing gluconeogenesis in
IKK-β alleviates IR in obese rodents on a high-fat diet liver tissues. Therefore, the deletion of adipoR1 induces
[55]. The trademark identification of the inflammatory IR by increasing endogenous glucose production, and the
serine kinase involved in IR is Jun kinase 1. Improved deletion of Adiponectin receptor 2 induces IR by decreas-
insulin sensitivity has been demonstrated in JNK1 knock- ing PPAR-α signaling pathway activity [65••].
out mice and increased JNK activity has been reported in A milestone discovery was made regarding the
obese rodents and humans [56]. mutated gene “leptin” found in ob/ob mice, which
A fascinating study suggests that SOCS3, which par- exhibit hyperlipidemia and IR. Another discovery was
ticipates in negative feedback loops in cytokine signal- made regarding adiponectin, which modulates glucose
ing, is reported to be increased in obese rodents [57]. In homeostasis and cell insulin sensitivity. Both leptin and
the same context, in vitro studies suggest that SOCS3 adiponectin are categorized as “anti-diabetogenic” due
directly interacts with the INSR, inhibiting IRS1 tyros- to their capability to decrease triglyceride synthesis and
ine phosphorylation and decreasing insulin-stimulated activate beta-oxidation. This leads to enhanced insu-
glycogen synthesis in cultured myotubes [58]. In rodents lin action in the liver and skeletal muscle by activating
on a high-fat diet, it has been observed that there is an 5′-AMP-activated protein kinase [66].
increase in macrophage infiltration of adipose tissue and It is worth noting that adiponectin levels are decreased,
expression of MCP-1, which recruits monocytes to sites and leptin levels are increased in obese animals and
of injury. This supports the fact that IR is due to infiltrat- humans with IR. This suggests that obesity leads to defi-
ing immune cells and changes in cytokine production by ciency in adiponectin deficient and resistance to leptin
the liver in response to chronic lipid exposure [59, 60]. [67]. Additionally, leptin has been found to play a crucial
It is worth noting that the pathophysiological adipose role in rescuing insulin action in lipodystrophic mouse
tissue microenvironment induces a significantly increased models, improving IR in these mice [68]. Leptin binds to
expression of miR-210-3p. This miRNA promotes NF-κB the leptin receptor (LepRb) and activates the JAK/STAT3
activation-dependent proinflammatory cytokine expression pathway, directly affecting insulin action [69]. Leptin and
and down-regulates anti-inflammatory cytokines [61••]. insulin both play important roles in regulating glucose
In the respective study, the authors demonstrated that miR- homeostasis. Leptin limits insulin secretion and increases
210-3p binds to the 3′-UTR of SOCS1 mRNA, leading to the insulin sensitivity, while also decreasing hepatic glucose
silencing its expression. As a result, the proteosomal deg- production. In turn, insulin stimulates the production of
radation of NF-κB is prevented, supporting the notion that leptin in adipose tissue [70]. Interestingly, high levels
specific miRNAs could be targeted to interfere with obesity- of leptin associated with IR promote the release of pro-
induced type 2 diabetes [61••]. Interestingly, several other inflammatory components such as IL-6, TNF-α, and IL-12
miRNAs, including miR-126, miR-222-3p, miR-182, let- by monocytes and macrophages [71].
7b-5p, and miR-1-3p, showed reduced expression in samples Interestingly, recent data emphasizes the role of dys-
taken from patients with type 2 diabetes. On the other hand, functional circulating mediators such as resistin in the
miRNAs such as miR-21, miR-30d, miR-148a-3p, miR-146b, onset of obesity, IR, and cardiovascular diseases [72]. The
and miR-486 showed increased expression [62•]. These genes responsible for regulating lipid and glucose home-
findings suggest that several miRNAs have the potential to ostasis are controlled by chemerin, a highly expressed
impact the pathogenesis of type 2 diabetes. chemokine in the liver and white adipose tissue. The regu-
latory functions of this chemokine include IRS1 tyrosine
phosphorylation, enhancing GLUT4 expression, fatty acid
Adipokines and Insulin Resistance synthase, and adiponectin, ultimately leading to insulin
sensitivity in adipose tissue [73]. In summary, adipose tis-
Adipocytes play a major role in the development of IR due sue acts as a central hub for various adipokines and bioac-
to their capacity to store excess lipids in obese individuals. tive lipid mediators in the molecular mechanisms involved
This storage leads to an abnormal redistribution of lipids in the pathophysiology of IR.
 Current Tissue Microenvironment Reports

The Indispensable Role of Mitochondrial diacylglycerols, ceramide, and reactive oxygen species
Dysfunction in Insulin Resistance (ROS), and mitochondrial damage, ultimately inhibiting
insulin signaling and inducing the development of IR [81].
Multiple studies have shown that IR can stem from mito-
chondrial dysfunction. One study suggests that the loss of
mitochondrial function due to aging causes the accumula- Endoplasmic Reticulum Stress and Insulin
tion of intramyocellular lipids, resulting in IR in elderly Resistance
subjects [74]. In the same context, young individuals who
are offspring of parents with type 2 diabetes were found Several interesting mechanisms explain the development of
to have a 60% increase in intramyocellular content, a 38% IR in obese or dyslipidemic individuals. One such mecha-
reduction in mitochondrial density, and a 50% increase nism is ER stress, which is enhanced in obesity and causing
in serine phosphorylation of IRS1 [75]. These pieces of IR in the liver and pancreatic β-cells [80]. In the scenario
evidence collectively suggest that severe mitochondrial of metabolic overload or overnutrition, the liver produces
dysfunction is linked to IR and diabetes. an excess of enzymes to process these, which stimulates the
Recently, it has been suggested that chronic exposure of unfolded protein response (UPR) by accumulating unfolded
skeletal muscle to lipids increases the expression of genes proteins in the ER [82••]. This is supported by a finding
involved in the fatty acid β-oxidation pathway. Interest- that showed oral administration of chemical chaperones like
ingly, there is a lack of coordination between the upregula- 4-phenyl butyric acid alleviates ER stress and increases insu-
tion of β-oxidation enzymatic machinery and downstream lin signaling and sensitivity in ob/ob mice [83].
metabolic pathways such as the tricarboxylic acid cycle Similarly, pancreatic β-cells develop ER stress in chronic
and the electron transport chain. This lack of coordina- hyperglycemic states [84]. In diet-induced obesity models,
tion leads to the incomplete metabolism of fatty acids in elevated ER stress markers in the liver and adipose tissue
β-oxidation pathways and the accumulation of lipid metab- are linked to activation of c-Jun-N terminal kinase (JNKs),
olites in mitochondria [76]. which phosphorylates IRS1 and interferes with insulin
This is evidenced by increased rates of incomplete fatty action. Overexpression of XBP1, a downstream transcrip-
acid oxidation in isolated mitochondria of insulin-resistant tion factor modulating the URP, prevents JNK activation in
rat skeletal muscle and accumulation of several long- and liver cells treated with agents that cause ER stress. Addition-
medium-chain acylcarnitine in the muscle of obese rats ally, XBP1 deletion increased susceptibility of mice to diet-
compared to lean rats [77]. Furthermore, insulin sensitiv- induced IR. This IR is partly controlled by induction of the
ity and glucose tolerance were restored in association with ER stress response, which connects to core insulin signaling
increased tricarboxylic acid cycle activity in these animals pathways [80]. In conjunction, ER stress has emerged as a
on a high-fat diet through exercise intervention [77]. key player in IR and could be a potential therapeutic target
Another phenomenon known as “metabolic inflex- for diabetes.
ibility” in isolated and whole-body muscle mitochondria
demonstrates that obesity causes impaired switching from
fatty acid to carbohydrate substrates during the fasting- Increased Concentration of Free Fatty Acids
fed transition and a decrease in several tricarboxylic acid
cycle intermediates [78]. In the case of muscle-specific Several studies have established associations between IR and
IR, mitochondrial dysfunction is characterized by meta- the increased availability of FFAs resulting from obesity. In
bolic abnormalities and diminished oxidative phospho- obese individuals, adipose tissue releases higher levels of
rylation, decreased electron transport chain activity, and TNF-α, which triggers the secretion of FFA’s into circula-
low expression levels of PGC1α, a master transcriptional tion [85]. TNFα mediates the repression of multiple genes
regulator of mitochondrial biogenesis [79]. involved in glucose and FFA uptake and storage. For exam-
Another interesting finding is the relevance of reduced ple, in 3T3-L1 adipocytes, it has been shown that TNF-α
coenzyme Q associated with IR in humans. Coenzyme enhances lipolysis, leading to increased release of FFAs and
Q is a crucial component of the electron transport chain, cytokines. Additionally, TNF-α-dependent gene upregula-
responsible for transferring electrons from complex 1 or tion or downregulation occurs through obligatory activation
2 to complex 3. Reduced coenzyme Q leads to reductive of NF-κB [86]. In muscle tissue, TNF-α and FFAs impair
stress in complexes 1 and 2, resulting in increased pro- insulin signaling by promoting increased NADH/NAD+
duction of reactive oxygen species and exacerbating IR and acetyl-CoA/CoA ratios. Furthermore, β-oxidation is
[80]. In summary, mitochondrial dysfunction leads to the insufficient to effectively remove these elevated fatty acids
accumulation of FFAs and lipids, promotion formation of from circulation, resulting in the storage of excess FFAs
Current Tissue Microenvironment Reports

as triglyceride droplets in the muscle [87]. In adipose tis- In muscle tissue, excess lipids accumulate due to incom-
sue, FFAs inhibit the lipoprotein lipase, leading to impaired plete metabolism in the mitochondria, resulting in impaired
clearance of FFAs from circulation. The excess FFAs are insulin signaling.
then transported as triglycerides by VLDL to non-adipose Given the diversity of molecular mechanisms involved in
tissues [88]. the development of IR, a holistic approach is necessary. This
A significant relationship exists between glucocorticoids approach should consider several factors such as overnutri-
and FFAs. Glucocorticoids impair peripheral glucose uptake tion, the inflammatory response, and energy imbalance, to
and increase the availability of FFAs. This, in turn, reduces effectively combat this complex condition.
glucose oxidation and uptake by peripheral tissues. Gluco-
Funding Open Access funding enabled and organized by Projekt
corticoids directly enhance hormone-sensitive lipase, inhibit DEAL. RW is supported by the German Research Foundation (grants
lipoprotein lipase, and increase the conversion of noradrena- WE2554/13–1, WE2554/15–1, and WE 2554/17–1), the Deutsche
line. These actions promote lipolysis in adipose tissue [89]. Krebshilfe (grant 70115581), and the Interdisciplinary Centre for
In summary, it is widely accepted that the increase in FFAs Clinical Research within the Faculty of Medicine at the RWTH Aachen
University (grant PTD 1–5). The funders had no role in the design of
caused by obesity leads to IR and hyperglycemia. this article or in the decision to publish it.
In summary, diabetes mellitus is a chronic disorder that
affects over 170 million people worldwide. It is projected to Declarations
affect over 365 million people by 2030 [90]. Additionally,
the global prevalence of diabetes is expected to increase to Competing interests The authors declare no competing interests.
700 million by 2045, making it a global health emergency
[91•]. There is growing evidence suggesting that several Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
mechanisms, such as ectopic lipid accumulation in periph- tion, distribution and reproduction in any medium or format, as long
eral tissues, are strongly associated with IR. Other factors as you give appropriate credit to the original author(s) and the source,
include ER stress, dysregulation of adipokine, and inflam- provide a link to the Creative Commons licence, and indicate if changes
mation. These mechanistic pathways involved in IR often were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
run parallel to each other, meaning that the involvement of otherwise in a credit line to the material. If material is not included in
one mediator does not exclude the involvement of another. the article's Creative Commons licence and your intended use is not
Therefore, a multidisciplinary strategy should be developed permitted by statutory regulation or exceeds the permitted use, you will
to treat this complex condition, targeting both physiological need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
and metabolic impairments.

Conclusions References

The major target tissues of insulin are skeletal muscle, the

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