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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5330_Библиотеки_им_академика_М_И_Перельмана
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1 Background
World Health Organization has identied non- communicable
diseases [NCDs] as the leading cause of morbidity and mortality (71% of deaths yearly). Among these, cardiovascular
diseases (17.9million deaths each year), cancer (9 million
deaths each year), respiratory disease (3.9 million deaths
each year), and diabetes (1.6million deaths each year) rank
high on the charts. Furthermore, diseases such as gastrointestinal, endocrine, haematological, dermatological, neurological, hepatic, and renal conditions, trauma, disabilities such as
blindness and deafness, and mental ailments come under the
umbrella term of NCDs [1]. If not all, most of them are pretty
interlinked and share pathological deviations at molecular
levels. This set of disorders can be termed lifestyle disorders
[LsD]. Lifestyle diseases are categorized mainly as a direct
result of people’s habitual behaviour and, in particular, a
maladaptive or inappropriate relationship with their immediate environment. Unhealthy diets, nutritional irregularities,
inappropriate physical activities, and alcohol and tobacco
consumption are emphasized as signicant risk factors for
LsD [2]. It is evident that despite living in relatively improved
living conditions and consciously adopting the so-called protective lifestyles, the disease burden of [LsD], such as cancer, diabetes, cardiovascular disorders, depression, and
degenerative disorders, is huge.
LsD involves chronic pathologies of slow and steady
progress owing to the conglomeration of multiple interrelated dynamics, viz. behavioural, environmental, physiological, and genetic factors [1]. Key metabolic changes that
increase the risk of LsD while one’s lifetime consists of
hypertension, overweight, dyslipidemia, and hyperglycaemia [3]. The affordability-cost complex in screening and
treatment monitoring of LsD dramatically impacts patients’
life satisfaction and quality of life domains.
2 Insulin Resistance
Certain concomitant or interlinked deviated processes happen at subtler levels which, with their cumulative effects,
transpire into different symptoms or a disease or a syndrome.
Curiously, the fundamental errors happening subtly in seemingly different disorders may often share characteristics.
Later, due to many personalized complexities, the nal manifested disorder may invariably vary. When LsD and their
molecular level deviations are evaluated, some striking facts
relating to the shared pathogenesis of autophagy, autoimmunity, and, much more importantly, their derivate the insulin
resistance (IR). IR has been scrutinized due to its strong link
with the clinic-metabolic association in otherwise healthy
individuals [4]. IR is identied as a crucial pathological fac-
tor in the incidence and progression of various LsD, for
instance, type 2 diabetes mellitus, non-alcoholic fatty liver
disease, obesity, polycystic ovarian syndrome, dyslipidemia,
cardiovascular disease, sleep apnoea, and hormone-sensitive
cancers [5, 6]. The risk factors of LsD include raised plasma
glucose, lipid deregulation (in the form of elevated triglycerides, reduced high-density lipoproteins, and elevated lowdensity lipoproteins), hypertension, and obesity, all of which
share the common denominator of IR. This grouping is
referred to as metabolic syndrome [MS] or syndrome X, or
even IR syndrome [5].
This means that IR if screened relatively earlier is a candidate space for intervention to adopt early protective lifestyle behaviours, appropriate metabolic error-reversing
medicaments, and advocating a balanced physical activity
that would delay or halt further pathological mechanisms
that might eventually lead to life-threatening LsD and associated distress.
2.1 Shared Pathology ofAutoimmunity,
Autoinammation, Impaired
Autophagy, andGut Dysbiosis inIR
It should be understood that converse to the conventional
thinking of demarcating type 1 and type 2 diabetes, for
instance, type 1 as autoimmune and type 2 as peripheral
insulin-resistant variants, recent research studies explain the
grey area wherein autoimmunity and insulin resistance are
associated with either form though in varying grades. Most
non-communicable disease spectrum consists of intermediary phenotype expression owing to maladaptive epigenetic
mechanisms linked with inammatory processes, autoimmunity, and IR.Currently, endotypes in NCDs are viewed in an
immunological continuum triggered and shaped by specic
epigenetic deviations [7]. Heterogeneity is present even in
diabetes, cancer, NAFLD, and obesity. Analysis of autoimmunity and IR in different permutations and combinations
expressed as personalized characteristics help in the differential understanding of LsD, especially their similarities and
dissimilarities. This is important in precision medicine;
wherein protective and curative therapies are strategically
tailored to meet clinical endpoints.
Abnormal feeding patterns in obese people with diabetes
are associated with metabolic deregulation in the adipose tissue, which triggers low-grade chronic inammation. This is
expressed as increased amounts of inammatory markers,
for instance, free fatty acids (FFA), tumour necrosis factor
(TNFα), interleukin 6 (IL-6), macrophage chemo-attractant
protein (MCP-1) that furthermore recruits pro-inammatory
leucocytes and M1 macrophages and culminates in
IR.Sufcient evidence reinstates the role of T&B cells and
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leukocytes in IR, viz., dendritic cells, neutrophils, and NK
cells. CD 4+ and CD 8+ T cells permeate adipose tissues
after a high-fat diet, perhaps quite earlier, and a parallel proinammatory state sets in the adipose tissue (for instance,
inltration of macrophages), which reinforces the autoimmune inammatory mechanisms in IR.The fact that T cell
targeting immunotherapy improves insulin sensitivity in
peripheral tissues is thus quite obvious. Thus, proinammatory autoimmune phenotypes are candidate pathogenesis initiators in IR. Studies suggest that in diseases
associated with IR, viz. type 2 diabetes, adipose tissue, and
pancreas are plausible primary sites of auto-antigen dependent priming of T and B lymphocytes, especially under
bodily metabolic stressful states. Similarly, in IR subjects
with obesity, an enhanced major histocompatibility complex
class II expression is noted.
Furthermore, interleukin-2 and interferon-γ production,
too, sets in. Sequentially, adipocytes transform into antigenpresenting cells (APCs). Likewise, a hypothesis exists that
there is a presence of IgG antibodies formed specically for
adipocyte-derived antigens. This pathology even exists in the
pancreas, at islets. Therefore, authors believe there is an
equal chance that (i) adipose-reactive T cells generated in the
adipocyte migrate to other metabolically active tissues, such
as the liver or pancreas, where they induce IR, or (ii) isletreactive T cells generated in the pancreas, migrate to adipocyte and other metabolically active tissues where they induce
IR either by augmenting chronic tissue inammation or by
targeting protective elements for the development of IR [7].
Also, evidence states that the anti-islet antibodies’ presence
is causally linked with IR.Curiously autophagy process via
lysosomes as well as specic autophagy proteins, improve
insulin sensitivity giving leads to the fact that functional
regression in autophagy culminates in IR [8].
Gut microbiota is a candidate contributor to metabolic
errors. Those individuals with IR present with denite disproportionate bacterial phyla that hamper intestinal permeability and increase lipopolysaccharide (LPS) absorption,
which, on reaching circulation, activates inammatory pathways. Thereby impairment in insulin signalling pathways
and defective functioning of insulin receptors set in manifested as IR [9].
Thus, considering the interlinked and tangled occurrences
and complex mechanisms at gross and cellular levels that
underline the pathogenicity of IR and IR associated with other
clinical conditions, a team of inter-professionals needs to integrate for designing appropriate protective and curative guidelines entirely dependent on the prescribed endotype in
respective subjects. Also, healthcare research that goes parallel
to clinical practices should be planned so that patient- preferred
outcomes are judiciously incorporated as primary objectives in
addition to marker-assisted methods (surrogates).
3 Understanding Insulin
Insulin is a peptide hormone produced by the beta cells of
islets of Langerhans of the pancreas. Cells in the human
body need glucose (sugar) for energy, and insulin helps to
transport this glucose from the blood into the cells.
Previously, insulin was viewed as an anabolic hormone
related only to glucose metabolism, but later studies suggest
it has much broader pleiotropic effects.
The synthesis and secretion of insulin can be affected by
both nutrient and non-nutrient secretagogues. Glucose is the
primary stimulus for insulin release in the body, but other
than that, beta cells also respond to other nutrients like free
fatty acids and amino acids. The entry of glucose into beta
cells causes glucokinase to phosphorylate into glucose- 6phosphate. Glycolysis then metabolizes it to produce pyruvate, NADH, and ATP. Furthermore, the closure of
ATP-sensitive potassium channels causes membrane polarization and activation of voltage-dependent calcium channels, the consequent intracellular inux of calcium triggers
insulin secretion. Non-nutrient secretagogues include various other hormones, such as melatonin, oestrogen, leptin,
growth hormone, incretin, and glucagon-like peptide-1 also
regulate insulin secretion in the body. They stimulate insulin
secretion via neural stimuli like adrenergic and cholinergic
pathways. Approximately 0.25–1.5units per hour of insulin
are secreted by beta cells during the fasting state, which is
sufcient enough for supplying glucose to cells. This basal
insulin secretion accounts for about 50% of insulin secreted
by the body in a day. The nutrient-stimulant insulin concentration contributes to the rest of the fraction [10, 11].
Insulin mediates energy availability to the body in both
fasting and fed states. It works synchronized to facilitate
energy storage during fasting and ensure energy expenditure
and uptake during the fed state. In healthy individuals, the
amount of insulin secreted is proportionate to the body’s
metabolic demand. During fasting, there will be low insulin
concentration in the portal circulation. To maintain the optimum concentration, the insulin clearance rate of the liver
also becomes considerably high during fasting. The glucose
production in such conditions will be modulated to meet the
requirement of essential glucose-dependent tissues like neurons and red blood cells. In response to the fall of insulin in
the blood, another hormone, glucagon, gets activated, which
facilitates glycogenolysis and gluconeogenesis. In the
absence of insulin, cells become deprived of taking up glucose and searching for alternate fuels resulting in lipolysis
with the release of non-esteried fatty acids. In the fed state,
there will be an increased concentration of insulin and glucose in the circulation. This inhibits glycogenolysis and gluconeogenesis but promotes energy accumulation through
glycogenesis and lipogenesis [12, 13].
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Insulin reaches multiple organ tissues like the liver, muscles, and adipose tissues through the extracellular insulin
receptor on their plasma membrane. The endocrine effect of
insulin on these organs depends on the interstitial insulin concentration, which is further inuenced by the exogenous insulin secretion and clearance from circulation. Insulin has a
profound effect on carbohydrate and lipid metabolism and
protein and mineral metabolism. It also stimulates the liver to
store a signicant fraction of glucose absorbed from the small
intestines as glycogen Insulin, through its receptors, inuences multiple physiological processes in the body, including
reproduction, mitogenesis, cognition, and lifespan. It is a
tyrosine kinase receptor with 2 alpha and 2 beta glycoprotein
subunits bound together with a disulde bond. Following
insulin binding to the extracellular domain, the receptor activates a complex intracellular signalling network through
insulin-responsive substrate (IRS) proteins. IRS binds to
other signalling molecules, mediating various cellular functions through different pathways. Derangements in insulin
signalling in the liver and beta cells are recently being highlighted as a “new biology of diabetes,“ causing insulin resistance and glucose intolerance [5]. Figure1 corresponds to the
functional range of insulin—the anabolic hormone [14].
3.1 Dening Insulin Resistance (IR)
Insulin has intricate effects on cell growth and differentiation,
and metabolism. IR is recognized as a compromised biological response to insulin stimulation of target tissues, principally the liver, muscle, and adipose tissue. IR impairs glucose
disposal, resulting in a compensatory rise in beta cell insulin
production and hyperinsulinemia. The metabolic magnitudes
of IR, as cited above, relate to the occurrence of but are not
limited to, hypertension, hyperglycaemia visceral adiposity,
dyslipidaemia, hyperuricemia, raised inammatory indicators, endothelial dysfunction, and a prothrombic state, the
preponderate consequence of IR being type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD) [15].
IR syndrome is the term used to collectively describe
abnormalities that may occur in insulin-resistant individuals.
This includes glucose intolerance, dyslipidaemia, endothelial
dysfunction, elevated procoagulant factors, hemodynamic
changes, elevated inammatory markers, abnormal uric acid
metabolism, increased ovarian testosterone secretion, and
sleep disorder. The clinical conditions individuals with insulin
resistance are at high risk of developing include type 2 diabetes mellitus, obesity, metabolic syndrome, lipodystrophies,
Fig. 1 Multiaxial functional
dimension of insulin
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polycystic ovary syndrome, certain types of cancers, and
chronic infections. Acanthosis nigricans, visceral obesity,
acne, hirsutism, and hepatic steatosis are the major clinical
markers of IR.Figure2 details the pathogenic magnitude of IR
that inuences the occurrences of various pathological
conditions.
3.2 IR Causative Factors
The aetiology of IR includes both genetic and environmental
factors. A gene proling study reports the association of
more than 180 genes with insulin sensitivity in skeletal muscle cells [16]. Environmental factors include increased calorie intake, reduced physical activity, smoking, and regular
intake of some drugs. Mostly combined genetic and environmental factors contribute to the development of IR.Hormonal
disorders like Cushing’s syndrome, acromegaly, and hypothyroidism can also cause IR.IR can be developed temporarily, i.e., gestational diabetes developed due to certain
hormones secreted by the placenta. The condition is reversible, but the off springs of these women are at high risk of
developing adolescent obesity and type 2 DM in the future.
Studies also suggest that unrecognized glucose intolerance
and insulin resistance begin in these women before conception, especially in those who are obese before conception.
Lifestyle measures, including diet and physical activity,
avoid obesity in women before conception and can signicantly prevent gestational diabetes and related complications. Increased supplementation of micronutrients like zinc,
magnesium, etc., to women in the reproductive age group is
also highlighted to play a positive role [17, 18]. Table1 com-
prehends the plausible risk and causative factors of IR.
3.3 Gross Pathological Process inIR
The primary sites affected by insulin resistance include muscle, adipose tissues, and hepatic tissues. Maximum glucose
uptake happens in muscles with every calorie intake and its
conversion to glucose. However, with an excessive calorie
load, the muscles cannot up take all the glucose produced.
This excess glucose returns to the liver triggering de novo
lipogenesis (DNL). DNL increases the concentration of triglycerides and free fatty acids, causing ectopic fat deposition
in the liver, muscle, and adipose tissue [19]. The glucolipotoxicity induces metabolic stress in the beta cells of the pancreas and other insulin-sensitive tissues. This metabolic
stress causes the tissues to produce and release proinammatory mediators like cytokines and chemokines.
These abnormal pro-inammatory mediators cause apoptosis, amyloidosis, and brosis in beta cells of the pancreas,
impairing insulin resistance. In the peripheral insulin-
sensitive tissues of the body, activation of various other
inammatory happens, impairs the phosphorylation of insulin signalling pathways resulting in systemic insulin
resistance. The oxidative stress induced due to glucolipotoxicity is the primary culprit which impairs glucose secretion
and induces insulin resistance in peripheral tissues [20, 21].
Once IR sets in, endogenous insulin production has a
compensatory rise. Insulin, an anabolic hormone, gradually
gains weight and further intensies IR.As the condition progresses, a functional decline in pancreatic beta cell activity is
noted against the increase of insulin put forth by an established IR.This is manifested as hyperglycaemia. If the situation consistently persists, the patient is diagnosed with type
2 diabetes mellitus [15]. If not found to respond to antiglycaemic agents, the patient is put on exogenous insulin.
Physicians believe patients requiring more than 1unit/kg/
day of exogenous insulin to maintain glycaemic control are
to be recognized as IR.Patients requiring more than 200units
of exogenous insulin daily are considered severely IR.
As mentioned earlier, signicant sites of primary IR
expression include muscular tissues, liver, and adipose tissues. Muscle accounts for a major share of glucose clearance. Thus, of all sites, muscles correspond to the rst and
foremost site of IR activity via the immune-mediated inammatory pathways and release of excess free fatty acids, which
eventually transpires into ectopic lipid deposition [22]. If not
properly disposed of due to impaired muscular glucose
uptake, the excess glucose returns to the liver, raising lipogenesis and subsequent increase of circulating free fatty
acids that further contribute to the pathogenicity of
IR.Likewise, visceral adipose tissue suffers the brunt due to
the functional decline of insulin, which subsequently results
in reduced lipolysis. These increases circulating free fatty
acids (FFA). Higher levels of circulating FFAs, in turn, affect
both hepatic and muscle metabolism, further aggravating
insulin resistance.
Strikingly IR and reduced uptake of insulin by muscle
end up in accelerated glucose delivery to the liver, which in
turn triggers lipogenesis and ectopic lipid deposition. This
whole phenomenon is linked to the inammatory mechanism. A parallel rise in glucose production in the liver and a
postprandial glucose rise. These mechanisms when crosses
the threshold at cellular levels, and toxicity sets in that further hastens IR [15].
3.4 Indicators ofIR
Although not clinically relevant, the marker for investigating
IR is identied as the hyperinsulinemic-euglycemic glucose
clamp technique. Clinically useful surrogates include
HOMA-IR, HOMA2, QUICKI, serum triglyceride, and triglyceride/HDL ratio. Furthermore, IR is also quantied with
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Fig. 2 The pathogenic magnitude of IR at varied biological systems and their derivate disorders
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Table 1 The plausible risk-causative factors and common presentation
of IR
Specic physiologic
abnormalities which
increase the risk of
insulin resistance
syndrome Other factors Common presentations
Impaired glucose
tolerance or impaired
fasting glucose
Abnormaluric acid
metabolism
Dyslipidemia
(increased
triglycerides,
decreased HDL-C, or
small, dense LDL)
Hemodynamic
changes such as
elevated blood
pressure
Prothrombic factors
(PAI-1, brinogen)
Markers of
inammation (CRP,
WBC, etc.)
Endothelial
dysfunction
Body mass index
(BMI) greater
than or equal to
2
25kg/m
Diagnosis of
CVD, PCOS,
NAFLD, or
Acanthosis
nigricans
A family history
of T2DM,
hypertension, or
CVD
Sedentary
lifestyle
Age greater than
40years
The asymptomatic
patients with obesity,
hypertension, or
hyperlipidemia
Metabolic syndrome
prediabetes or type 2
diabetes mellitus
Type A or type B
insulin resistance
PCOS (menstrual
irregularities,
hirsutism, acne, and
alopecia)
Xanthelasma or
xanthomas
Acanthosis nigricans
Symptomatic
microvascular disease
(retinopathy,
neuropathy,
ornephropathy)
Macrovascular
disease
(Stroke, PAD, and
CAD)
serum glucose and insulin response to a glucose challenge
[15]. It is a fact that, more often than not, physicians resort to
clinical endpoints such as ‘how the patient feels, functions,
or survives (without unusual/ distressing events)’, rather than
trying to understand the pathological process reversal that
eventually results in clinical endpoints.
signalling pathways integrate and inuence each other. So
specic pathognomy deviations may be shared in different
functional systems. This is precisely the case with
IR. Impairment of the signalling pathway, insulin receptor
defects, and defective insulin secretion can all contribute to
insulin resistance.
4.2 IR andMetabolic Syndrome
Metabolic syndrome (MetS) refers to a conglomeration of
several clinical signs, viz. increased waist circumference,
elevated triglycerides, reduced high-density lipoprotein
(HDL), elevated fasting glucose levels, and elevated blood
pressure. Mets have profound health implications as they
predispose individuals to cardiovascular and cerebrovascular
disorders and associated morbidity and mortality. The fundamental pathogenic process in MetS is adipose tissue dysfunction and resultant IR. As cited earlier, inammatory
materials released from an impaired adipocyte adversely
alter peripheral insulin sensitivity. Sequentially the vicious
cycle of impaired insulin signalling mechanisms, receptors
decits, and altered insulin secretion reinforces IR.Earlier
signs of MetS and associated errors manifest as autonomic
and vascular changes. Visceral adipocytes react critically
when compared to subcutaneous fat cells, though both are
involved in MetS and IR.
MetS unfavourably impacts several body tissues. IR in
MetS causes microvascular insult, which inclines a patient
towards endothelial irregularities, hypertension, and vessel
wall inammation, ending in vascular resistance. Endothelial
damage can impact the body’s homeostasis causing atherosclerotic disease, fatty liver, and hypertension. Additionally,
hypertension undesirably affects bodily physiology and
results in peripheral vascular disease, cardiomyopathies, and
renal functional impairment [23].
4.3 IR andEndocrine Errors andPoly Cystic
Ovarian Syndrome
4 Shared Mechanism ofInsulin
Resistance inDiverse Clinical
Syndromes
4.1 IR Targeted Basic Metabolic Errors,
Shared Molecular andHistological
Mechanisms
When it comes to human pathogenic mechanisms, mathematical predictive models of individual histocompatibility
are more often than not absurd. Molecular mechanisms and
Hormones maintain an antagonistic effect on insulin secretion and signalling pathways. As a result of these aggressive
reactions, there is a remarkably decreased glucose utilization
at the periphery compared to its synthesis in the liver. A
cumulative effect of this progression hampers insulin secretion and establishes insulin resistance. Therefore, in endocrine disorders, such as growth hormone deciencies,
acromegaly, Cushing’s syndrome, thyroid-parathyroid dysfunctions, adrenal disorders, hypogonadism, or neuroendocrine, tumours impair glucose metabolism and utilization
due to progressive IR.Most importantly, polycystic ovarian
syndrome (PCOS), a distressing condition causally
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associated with infertility, is quite a concern these days.
PCOS- related IR is an essential cause of non- insulindependent diabetes mellitus in women. Excess serine phosphorylation of the insulin receptors is a candidate cause of IR
in PCOS.Serine or threonine kinase, an extrinsic factor controlling insulin receptor signalling, plausibly causes this
pathogenic process of excess phosphorylation. Through its
receptors, insulin enhances ovarian and adrenal steroidogenesis and pituitary LH discharge. The fact that PCOS has a
menarche age of onset, the ontogeny of insulin signalling
pathways, and other metabolic faults are to be screened for
genetic errors. PCOS women are predisposed to cardiovascular disease owing to lipid abnormalities, dysbrinolysis,
and IR [15]. PCOS is currently managed with metformin,
incretins, and glitazones. Integrated practices are genuinely
needed in these conditions that appropriately manage insulin
sensitivity and glucose metabolism [24].
4.4 IR, Neuro-Inammation,
andNeurodegenerative Disorders
In addition to regulating glucose metabolism and energy utilization at the periphery, insulin can cross the blood–brain
barrier and inuence neuronal survival and growth, dopaminergic transmission, and maintenance of synapses and pathways involved in cognition. Brain insulin resistance and
insufciency, along with neuro-inammation, results in denite degenerative pathologies in atrophied cortices, nuclei,
and white matter and hastened astrocytosis, gliosis, and
microvascular pathologies. Markers such as hyperphosphorylated tau (pTau)-containing cytoskeletal lesions,
increased amyloid-beta (Aβ42) deposits in plaques, vessels,
and neurons, and increased ubiquitin immune-reactivity in
degenerating neurons are candidate signatures of neurodegeneration, for instance, the Alzheimer’s disease. It is a concern that brain glucose and oxygen metabolism issues are not
incorporated into the cluster of neurodegenerative indicators.
This results in a limited understanding of interconnected
pathogenic mechanisms in degenerative conditions. Thus, it
limits the opportunity to fully understand the disease’s natural course and plan holistic therapeutic strategies efcacious
in decelerating the progression. Increased expression of
inammatory markers near degenerative plaques or proteins
indicates inammation hastens degeneration. Chronic
inammation exacerbates IR in Alzheimer’s (AD) and
Parkinson’s’ disease (PD) [25]. Also, there is sufcient evidence that IR and degenerative disorders such as PD share
similar dysregulated pathways. There is evidence that even
without type 2 diabetes manifestation, peripheral IR is found
in PD.All this information suggests that the insulin signalling pathway may be a candidate target for disease modication concerning neurodegenerative conditions [26].
4.5 IR andCancer
IR and the subsequently enhanced bioavailability of insulinlike growth factor (IGF-I) are antagonists to the hepatic synthesis of sex hormone-binding globulin. At the same time,
these hormones stimulate the ovarian synthesis of sex steroids. Sex steroids affect breast epithelium and endometrium.
It can promote cell proliferation and inhibit apoptosis. Thus
hormone-mediated tumour initiation and progression are
causally associated with IR.Moreover, IR in adipocytes stimulates systemic inammation, overproduction of inammatory cytokines and other markers, and reactive oxygen species
(ROS) that hastens mutagenesis and carcinogenesis [27].
4.6 Psycho-Neuro-Immuno-Endocrinal
Axis, Stress, andIR
As science advances, newer interactive mechanisms and
interconnected pathways come into light that has clinical signicance. Psycho-neuro-immuno-endocrinal axis thus
describes the inuence of neural, psychological (stressrelated), and endocrine mechanisms on immune responses
and immune responses triggering neural, psychological, and
endocrine conditions. The role of stress-related conditions in
the manifestation of IR, metabolic syndrome, cardiovascular
diseases, and psychiatric diseases is depicted in Fig.3.
4.7 Prognosis andComplications
Associated withIR
The prognosis of IR categorically depends on the particular
variant of the disease (endotype), the severity of IR, histocompatibility of metabolic tissues, genes, the onset of complications, and personalized characteristic responses to
therapeutic measures. The stages may vary from mild IR in
asymptomatic individuals to subjects with denite cardiovascular or cerebrovascular decits or degeneration and
accompanying morbidity and mortality or with loss of reproductive capability associated with PCOS.
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Fig. 3 The complex
multi-axial interaction in
psycho-neuro-endocrineimmune pathways
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5 Current Treatment Strategies
forInsulin Resistance andScope
forIntegrative Medicine
Accommodating Herbal Drugs
5.1 Current Management Strategies
Adopted inIR-Associated Clinical
Conditions
It is a matter of disquiet that there are no predened clinical
practice guidelines or consensus in treating patients with
IR. Insulin therapy has been the rst line of management.
However, there is sufcient evidence that despite higher insulin doses, glycaemic targets are not achieved in patients with
severe IR [28]. Moreover, they suffer brunt in the form of
weight gain or sudden episodes of hypoglycaemia. Metformin
extended release is now recommended, which is also advocated in IR and IR-linked disorders [29]. Glucagon- like peptide one inhibitor (GLP-1) receptor agonists and metformin
have joined the race lately for better glycaemic control, especially in obese patients. The same is true with Sodium-glucose
co-transporter two (SGLT2) inhibitors and pramlintide.
Dipeptidyl peptidase-4 inhibitors (DPP-4) extend the activity
of endogenous GLP-1 and gastric inhibitory polypeptide
(GIP) by preventing their breakdown. Thiazolidinediones
(TZDs) increase insulin sensitivity by enhancing insulindependent glucose disposal in muscle and adipose tissue and
decelerating hepatic glucose yield. It is of prime importance
that, more often than not patient specic characters dictate the
drug of choice or elective procedures. For instance, gastric
sleeve, banding, and bypass surgery are indicated in IR individuals with obesity. The excess fat loss associated with bariatric surgery decreases insulin resistance [28].
Management strategies adopted in pre-diabetic and diabetic states that mark IR generally intend to instil a balanced
lifestyle through monitored physical activity and calorie
restriction—reduced high glycaemic index dietary articles.
Recent research advances give evidence in the form of proof
of principle for methods, viz. enhancing phosphorylation and
perpetuating the crucial kinases activity of the insulin receptor and its protein substrates following insulin stimulation.
Also, enhancing the action of phosphatidylinositol 3-kinase
and other essential providers of insulin signalling and metabolic pathways are being tested. The causal role of proinammatory cytokines, adipocyte hormones, fatty acids, the
vicious cycle of glucotoxicity, and the protective mechanisms
offered by certain metabolic enzymes, vitamins- minerals,
and co-factors in IR-associated states are under scrutiny for
identifying feasible therapeutic targets [30]. IR seems inadequate despite these advances, as is evident from the rise of
NCDs and other global IR-associated conditions. The aforecited interlinked phenomena of autoimmunity, autophagy,
auto-inammation, and gut dysbiosis signicantly add to the
challenges in targeting IR in IR-associated syndromes.
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5.2 Adverse Eects ofCommonly
Prescribed Medicaments
Metformin, the most commonly prescribed medicine to manage IR, is also reported to cause gastrointestinal side effects.
Many studies link it to cause mild to moderate renal failure,
and it is contraindicated in those individuals with elevated
serum urea, creatinine, and high glomerular ltration rate.
Other categories of drugs, like glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter 2 inhibitors,
also have serious side effects in long-term usage, including
changes in renal function and an increased chance of genital
infections, especially in women with a history of mycotic
infections. Drugs like thiazolidinediones improve insulin
sensitivity in type 2 DM and PCOS cases but have been
linked with severe side effects, including heart failure and
fractures. The long-term outcomes of many of these drugs,
including metformin in pregnancy, are not studied well yet
[28]. Another major challenge is that the responsiveness of
various ethnic populations to many of these medicines varies
considerably. Ethnic differences considerably affect insulin
sensitivity as well as treatment/dosage choices. Research
suggests that a precision medicine approach is required to
get optimum results in managing IR [31, 32]. Episodic hypoglycaemia is another issue concerning oral antidiabetics and
insulin usage. The risk is more with the usage of sulphonylurea usage and comparatively less for metformin. However,
metformin, in some instances, has been associated with
inducing lactic acidosis signicantly when the clinical conditions worsen [33].
5.3 Scope ofTraditional Systems
ofMedicines (TMs) asanArm
ofIntegrative Medicine inIR-Associated
States
Tackling such non-linear and complex functional deviations
in IR, in this era of rapidly emerging diseases and healthcare
challenges, awareness and interest in traditional medicines
(TMs) and their role and relevance worldwide are entirely
renewed. Universal health coverage is achieved only by an
inclusive attitude of incorporating all available healthcare
practices in the mainstream. In addition, with more people
from developing countries opting for traditional healthcare
systems to treat common and sporadic diseases and prevent
lifestyle disorders, there is a clear trend in health seeker
behaviour.
The pattern and predictors of traditional, complementary,
and alternative medicine use in non-communicable and
chronic ailments are associated with various disease-specic
demographic factors and endotypes [34]. The integrative
approaches accommodating TMs and standard care proto-
cols should explore lifestyle manipulations, and administration of immune-modulating anti-inammatory, and
adaptogenic drugs in distinct IR endotypes. Integrative
approaches and herbs should effectively target gut microbiota revitalization, develop operative management strategies
for a functionally regressed autophagy phase, counter autoinammation, and bring in immune modulation to enhance
tissue compatibility and insulin sensitivity in tissues. Most
importantly, precision medicine in the form of personalized
therapeutic approaches in varied endotype-driven presentations of IR especially targeting the clinical reversal of symptoms in conditions such as DM, NAFLD, PCOS, obesity,
etc., seems to be the most novel and robust method.
Patient community turnover to TMs for managing LsD
and related functional deviations wherein the quality of life,
recovery and rehabilitation, correction of metabolic errors,
and management of complications such as neuropathies,
depression, infertility, etc., are the categorically expected
outcomes. As the current approaches in IR that focus on therapies that address gene mutation, polymorphism, and individualistic markers seem indeterminate in many aspects,
traditional medicine like Ayurvedic Sciences, which are
advocated and categorically accepted by masses in LsD and
related inammatory, autoimmune, and degenerative pathologies should come up with an integrative research mind-set.
Such holistic systems of medicine addressing patient distress
should also rigorously validate the proof of mechanisms by
accommodating surrogate markers to clinical endpoints such
as gene signatures, metabolome, genotype-phenotype interactions, and epigenetics when it comes to conditions involving IR. Thus, targeted multifaceted precision-based
personalized medicine in an integrative mode seems the correct solution.
6 Herbal Medicine fortheManagement
ofIR andOther Associated States
ofLsD
TMs suggest various herbs and polyherbal preparations for
managing metabolic syndrome, obesity, neoplastic presentations, neurodegenerative disorders, and endocrine pathologies like PCOS associated with IR. In Ayurvedic herbal
medicine, the drugs are used as a whole, where therapeutic
efcacy is expected to come from the combined activity of
various phytochemicals. Despite promising clinical efcacy,
the complexity of formulations and the inability to explain
the mode of action have been the primary reasons limiting
the R&D of these traditional medicine practices. Much
research has focused on developing new drugs from traditional herbal medicine practices by isolating various active
ingredients. The discovery of guggulsterone from
Commiphora mukul, boswellic acid from Boswellia serrata,
The Importance and Scope of Medicinal Plants Suggested in Traditional Medicine in the Holistic Care of Occupational Lifestyle…
https://t.me/medicina_free
23
and reserpine from Raufolwia serpentina show how herbal
medicine-based empirical practices have guided innovative
drug discovery [35]. The current book chapter here after
focus on a few medicinal plants extensively used in traditional medicine practices to treat occupational lifestyle diseases and the associated IR.An attempt has been made to
review the mode of action of a few medicinal plants and their
monomers in improving IR and associated occupational lifestyle disorders in various experimental models and clinical
trials.
6.1 Curcuma longa L.
C. longa, commonly known as turmeric, is an herb used in
traditional Indian medicine for its broad therapeutic activity.
Apart from medicinal uses, it is also used in households as a
spice and food preservative. Matured rhizomes of C. longa
contain a yellow-coloured substance, a combined form of
resin and oil called curcumin. Curcumin is the principal bioactive constituent responsible for its pharmacological activity [36]. In the chronic high-fat diet-fed (HFD) mouse model,
long-term dietary curcumin administration prevented weight
gain and obesity. It also improved glucose disposal by stimulating insulin sensitivity. Curcumin supplementation could
also prevent HFD-impaired insulin-stimulated protein kinase
B (PKB) phosphorylation in adipocyte tissues and the liver.
It was concluded that the antioxidant and anti-inammatory
activity of curcumin on adipocytes were the underlying
mechanism that reduced IR, obesity, and prevented diabetes
in the animal models [37]. Adiponectin, an adipocyte-derived
hormone, has been reported to reduce IR by reducing triglyceride levels in the muscle and liver of obese animal models
[38]. Studies have shown that in skeletal muscle cells,
adiponectin- induced autophagy could alleviate IR and metabolic dysfunction [39]. Oral administration of curcumin has
been reported to increase the expression of adipocytes and
thereby improve insulin sensitivity in animal models [40].
Insulin receptors and insulin-linked glucose transporters in
the brain are responsible for various cognitive functions,
including learning and memory. Experiments have shown
that oral administration of curcumin could improve glucose
homeostasis and could increase the gene expression of cholinergic, Glut 3, and insulin receptors in the cerebellum of
streptozotocin (STZ) induced diabetes mellitus (DM) rats
[41]. Bio-enhanced turmeric extract supplementation has
also been reported to decrease IR and increase beta cell function in experimental models.
Decreasing IR increased glucose uptake and fatty acid
oxidation in the skeletal muscles of treated animals, causing
weight loss. Compared to the regular extract, the bioenhanced extracts treated group showed an increased concentration of curcumin and its derivatives in the pancreas
[42]. In a randomized, double-blind, placebo-controlled
clinical trial of 100 individuals with type 2 DM curcuminoids (500mg/day) daily dose along with piperine (5 mg/
day), the administration showed a benecial effect on the
glycaemic and hepatic parameters. The serum concentration
of insulin, HbA1c, and homeostasis model assessment estimated insulin resistance (HOMA-IR) signicantly reduced
in both the study groups. Weight and BMI reduction was signicant in the curcuminoids-treated group [43]. Systematic
reviews and meta-analysis studies of RCTs recommend that
curcumin be administered as an adjunct to patients with type
2 DM to improve insulin resistance and control glycaemic
control. The study results were more signicant to individuals habituated in Asian and Middle Eastern countries [44].
6.2 Emblica ocinalis Gatertn
E. ofcinalis, also known as the Indian gooseberry or amla,
is a drug extensively used in indigenous traditional practices like Ayurveda for its medicinal properties and nutritional values. Medicinal properties are attributed to different
parts of E. ofcinalis, but fruits are the most preferred
choice for therapeutic purposes. Fruits are rich in phytoconstituents such as polyphenols, tannins, avonoids, and
vitamins responsible for diverse pharmacological activity
[45]. Hyperinsulinemia accompanied by IR leads to
derangement of the lipid metabolism in the body. It leads to
the overproduction of very low-density lipoprotein (VLDL),
low- density lipoprotein (LDL), and triglycerides, and a
decrease in high- density lipoproteins [46]. In the postmenopausal animal model with atherogenic dyslipidaemia,
amla extract supplementation prevented IR, decreased
LDL, and increased HDL levels. The study suggested that
amla can be protective in preventing coronary heart disease
in vulnerable post- menopausal groups by increasing insulin sensitivity [47]. Combinations of turmeric and amla are
used in traditional medicine to manage DM.Standardized
extract of both drugs containing curcuminoids (23.89%),
gallic acid (5.27%), and tannins (25.44%) administered in
high-fat diet and STZ- induced type 2 DM rat models signicantly ameliorated the IR. The result was consistent
with all three models of IR assessment, i.e., in HOMA-IR,
quantitative insulin sensitivity check index (QICKI), and
Matsuda index [48]. Research ndings support that reactive
oxygen species (ROS) play a crucial role in the pathogenesis of IR and other related chronic diseases [49]. Amla
extracts have exhibited good antioxidant activity in DPPH
radical scavenging and ROS inhibition assay suggesting its
protective role against IR [50]. Many studies are reported
on the crucial role amla fruit constituents like gallic acid
and ellagic acid play in activating the insulin signalling
pathways, reducing IR, and improving signal transduction
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