Life Sciences 264 (2021) 118661

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Life Sciences
journal homepage: www.elsevier.com/locate/lifescie

Implicating the effect of ketogenic diet as a preventive measure to obesity

and diabetes mellitus
Sachin Kumar a, 1, Tapan Behl b, *, 1, Monika Sachdeva c, Aayush Sehgal b, Shilpa Kumari a,
Arun Kumar b, Gagandeep Kaur b, Harlokesh Narayan Yadav d, *, Simona Bungau e
a
Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India
b
Chitkara College of Pharmacy, Chitkara University, Punjab, India
c
Fatimah College of Health Sciences, Al Ain, United Arab Emirates
d
Department of Pharmacology, All India Institute of Medical Sciences, Delhi, India
e
Department of Pharmacy, Faculty of Pharmacy, University of Oradea, Romania

A R T I C L E I N F O A B S T R A C T

Keywords: Obesity and diabetes are the two major metabolic complications linked with bad eating habits and the sedentary
Obesity (lazy) lifestyle. In the worst-case situation, metabolic problems are a causative factor for numerous other con­
Diabetes mellitus ditions. There is also an increased demand to control the emergence of such diseases. Dietary and lifestyle im­
Ketogenic diet
provements contribute to their leadership at an elevated level. The present review, therefore, recommends the
PUFA
VLCKDs
use of the ketogenic diet (KD) in obesity and diabetes treatment. The KD involves a diet that replaces glucose
Hyperlipidemia sugar with ketone bodies and is effective in numerous diseases, such as metabolic disorders, epileptic seizures,
Metabolic disorder autosomal dominant polycystic disease of the kidney, cancers, peripheral neuropathy, and skeletal muscle at­
rophy. A lot of high profile pathways are available for KD action, including sustaining the metabolic actions on
glucose sugar, suppressing insulin-like growth factor-1 (IGF1) and phosphoinositide 3-kinase (PI3K)/protein
kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways, altering homeostasis of the systemic ketone
bodies, contributing to lowering diabetic hyperketonemia, and others. The KD regulates the level of glucose
sugar and insulin and can thus claim to be an effective diabetes approach. Thus, a stopgap between obesity and
diabetes treatment can also be evidenced by KD.

1. Introduction focus on obesity. A no. of studies suggests the correlation between

In this era of sedentary (easy) lifestyle and decreased physical ac­
tivity, the human body is vulnerable to a number (no.) of risk elements
including obesity, increased blood pressure, high blood sugars level, and
other complications. The easy lifestyle promotes the rise in body weight
which is a key initiating factor responsible for obesity and other dis­
eases. Obesity then further links diabetes or hyperglycemia and other
related metabolic complications. Obese persons are more prone to dis­
eases and other associated syndromes. In a state of overweight or
obesity, hyperglycemia that is high blood sugar and hyperlipidemia that
is high lipid content are generally present, preferring IR and metabolic
complications such as diabetes [1,2]. If we can treat obesity, we mini­
mize the risk factor for other pandemics too such as diabetes, cardio­
vascular associated risk factors, and many more. Foremost we need to
obesity and diabetes. Here in this review, we will try to focus on the
various mechanisms proposed by the low carbohydrate diet called
Ketogenic diet (KD) given reducing obesity and also decreasing the risk
of diabetes. KDs are diets that bring on a metabolic complication that is
comparable to fasting, but usually without catabolism [3]. They are
comprised of a low amount of carbohydrate but much high in fat content
and depending on the form of KD, a defined or variable content of
protein [4]. The current review is designed to provide a sketch on the
introduction of KDs in obesity & diabetes.
2. Obesity
Obesity is a hotfoot expanding worldwide [5] that has grown nearly
to twice since 1980. It is considered an individual’s health mishap in

* Corresponding authors.
E-mail addresses: tapan.behl@chitkara.edu.in (T. Behl), hnyadav@gmail.com (H.N. Yadav).
1
Authors with equal contributions.

https://doi.org/10.1016/j.lfs.2020.118661
Received 6 October 2020; Received in revised form 17 October 2020; Accepted 22 October 2020
Available online 26 October 2020
0024-3205/© 2020 Elsevier Inc. All rights reserved.
S. Kumar et al.
both the developed and developing countries [6]. A current NEJM sur­
vey has predicted that almost half of US adults will be obese by 2030,
with the epidemiology of no less than 35% in any state, [7] Overweight
and obesity the two interchangeable terms are described by unwanted
aggregation and hypertrophy of adipose tissue to a degree which affects
mental and physical health as well as the well-being of an individual [8].
It is the need of the hour to stop this pandemic if the communal risk,
mortality, morbidness, and economic expenses of the disease are taken
into consideration. In particular, the attraction of people with over­
weight to rich carbohydrates & low-fat diet is a major process, as most
foods with a rich fat content have shown their dietary preferences
[9,10]. Another concern is that obese people typically stick to highly
processed foods consisting of simple sugars or carbohydrate instead of
crude carbohydrates; thus a less-fat diet can also encourage sugar and
refined carbohydrates which may cause more sophisticated overweight
issues and also lead to dyslipidemia, mainly in people who are resistant
to insulin [11]. As a consequence of the dubious safety index of these
diets, curiosity in foods containing reduced carbohydrate content or
simply KDs has grown in recent years. The KD was first introduced in
1920 [12]. This diet accounts for a 5:1 fat store to carbohydrate content
ratio. Obesity considerably expands the probability of illness from
several chronic complications. There is a probability for obesity & type II
diabetes mellitus (T2DM) to arise simultaneously [13–15]. T2DM is
specified by diminished sensitivity towards insulin or insulin resistance
(IR) coupled with the pancreatic beta (β) cell’s inability to produce the
required quantity of insulin mainly on the demand of the organ system
for proper bodily functions. In T2DM obesity correlated with diabetes is
the major factor that initiates other metabolic defects [16]. On the other
hand, type I diabetes mellitus (T1DM) begins with the scarcity of insulin
as a result of damage to pancreatic β-cells. The rise in the level of blood
glucose catalyze conditions such as nephropathy, vasculopathy, reti­
nopathy, and cardiomyopathy [17,18]. However, adipose tissue is the
major organ involved in fat storage in obese individuals; the lipid ac­
cumulates into further non-adipose organs including β-cells, cardiac
tissue. The lipid content deposited in the liver lead to hepatic fibrosis
also called fatty liver disease. The deposition of lipid content in
pancreatic β-cells and skeletal muscle gives rise to IR, insulin secretion
dysfunction, & eventually T2DM [1,19,20]. Numerous reports suggest
that decreasing body weight in subjects with overweight having glucose
intolerance has better outcomes on hindering or managing diabetes.
Thus, effective treatment therapies for reducing obesity and alterations
to nutritious practice have favorable outcomes in obese diabetic patients
[21,22]. Recent studies [23,24] demonstrates that a diet rich in fat as
well as in polyunsaturated fatty acids (PUFA) called KD is quite useful in
minimizing the chances of overweight and other obesity associated
chronic complications. The weight of obese patients who were on a KD
of low-carbohydrate diet [25] was substantially decreased, while the
opposite happened when the diet changed to one high in carbohydrates
[26].
3. Diabetes mellitus (DM)
Diabetes mellitus (DM) is a persistent metabolic disease marked by
changes in the metabolism of proteins, carbohydrates, and fats. The
global prevalence rate of diabetes has been projected to be 9.3% (4630
lacs individuals) in the year 2019, growing to 10.2% (5780 lacs) by the
end of 2030 and 10.9% (7000 lacs) by 2045. In urban areas, which is
10.8%, the overall prevalence is higher than in rural areas, which is
7.2%, and in countries with high-income (10.4%) in comparison to
countries with low-income (4.0%) [27,28]. China (885 lacs people with
T2DM), India (659 lacs), and the United States (289 lacs) are the finest
spots of these metabolic disorders than other countries overdue to their
large population sizes [29]. The decreased or no insulin secretion or
marked inability of the β-cells of islets of Langerhans of the pancreas or
due to decreased peripheral administration of insulin leads to the pro­
gression of diabetes. DM is widely categorized into 2 different types,
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Life Sciences 264 (2021) 118661
which comprise T1DM & T2DM. Patients with T1DM are normally not
morbidly obese & are present with a risk called as diabetes ketoacidosis
[11,30]. Autoimmunity is an important factor involved in the T1DM
pathogenesis. The most prevalent form of diabetes, T2DM, or late-onset
DM is dynamically linked with obesity. T2DM has different patho­
physiology in contrast to T1DM [31]. Obesity (having body mass index
[BMI] greater than 30 kg/m2) is the critical component for T2DM
[32,33] and is linked with metabolic conditions developing insulin
resistance (IR) [33]. The precise mechanisms by which T2DM and IR are
caused by obesity remain to be explained. A misfiring of the feedback
circuits between the working of insulin and insulin discharge develops
an abnormal increase in blood glucose levels concerning the patho­
physiology of the disease [34]. Whenever there is a β-cell failure, insulin
secretion is decreased, restricting the ability of the body to regulate
physiological blood glucose levels. But at the other end, IR contributes to
greater liver glucose production and a declined glucose uptake in the
muscle, liver, and adipose tissue glucose uptake. When any of these
above processes occur early in pathogenesis, β-cell impairment is more
severe than IR, promoting the disease to progress. However, hypergly­
cemia leads to the development of T2DM as both β-cell damage and IR
occur. [35,36]. β-cell dysregulation is linked with β-cell death [37]. In-
state of obesity, the rise in blood glucose and lipids level is very com­
mon, preferring chronic inflammation & IR. Under these conditions,
β-cells, because of variation in their susceptibility towards genes, are
subjected to harmful conditions including endoplasmic reticulum, in­
flammatory, metabolic/oxidative, amyloid stress eventually brings
deprivation in islet cells cohesion [38,39]. By stimulating ER stress, it
leads to apoptotic unfolded protein response (UPR) pathways, an
abundance of free fatty acids (FFAs), and hyperglycemia contribute to
β-cell dysfunction [40]. Besides, obesity-related glucotoxicity, lip­
otoxicity, & glucolipotoxicity prompt oxidative & metabolic stress that
contributes to disruption to β-cells [41]. Stress from high concentrations
of saturated FFAs can trigger the UPR pathway through various chan­
nels, which include decreased levels of Ca2+ ATPase in Sarco/endo­
plasmic reticulum (SERCA) accountable for mobilizing endoplasmic
reticulum (ER) Ca2+; IP3 receptors activation; or specific disruption of
ER homeostasis [42]. In contrast, persistent high levels of glucose in­
crease islet amyloid polypeptides (IAAP), biosynthesis of proinsulin in
β-cells, resulting in IAAP & insulin misfolding aggregation & increased
development of reactive oxygen (ROS)-triggered oxidative protein
folding species [43]. The above mechanisms disturb physiological
endoplasmic reticulum, Ca2+ mobilization and increase pro-apoptotic
signaling, degradation of proinsulin mRNA degradation, and give rise
to the release of interleukin (IL)-1 β followed by macrophages & raise
inflammation in local islet [44]. To satisfy metabolic demand, insulin
secretion has to be controlled, as previously mentioned. For instance, to
allow β-cells to respond to metabolic requirements, appropriate islet
stability must be established. The pathogenic mechanisms described
earlier lead to disruption of the integrity/organization of the islet under
pathological conditions, hampering ideal cell to cell contact within
pancreatic islets, initiating factor to poor control of the release of
glucagon & insulin, and eventually aggravate hyperglycemia. Insulin
secretory dysfunction, the primary factor of β-cell failure, and the source
of T2DM, can be triggered by changes in the processing of any insulin
precursor or insulin alone, in addition to the detection of the secretion
process. The glucose transporters (GLUT) plays an important role in
influx, outflux, and uptake mechanisms of the glucose and lipids. In
normal physiological processes the glucose is distributed by the GLUT
transporters. In metabolic disorders there is either decreased expression
of these transporters or decreased availability or increased resistance to
these transporters. The reduced GLUT2 glucose transporter expression
will influence the downstream signaling pathway [45,46], while pro­
insulin structure folding loss is another factor generally associated with
decreased insulin production and diabetes [47].
Insulin resistance is the decreased action of insulin and metabolism
of glucose due to decreased productivity and pancreatic cell dysfunction
S. Kumar et al.
[48]. There are 3 wide types of insulin resistance or insulin-deprived
states: (1) reduced β-cell insulin discharge; (2) plasma insulin antago­
nists, either due to hormones (counter regulated) or non-hormonal
bodies impairing or signaling insulin receptors; & (3) disrupted target
tissue insulin feedback [39]. Insulin action is regulated by the interac­
tion between additional molecules in the fed state, namely IGF-1 and
growth hormone. While fasting, glucagon, glucocorticoids, and cate­
cholamines block the insulin response to avert insulin-prompted hypo­
glycemia. The insulin/glucagon ratio plays an important part in this
regulation, as it specifies the definite level of phosphorylation in the
regulatory signaling pathways of downstream enzymes. Whereas
glycogenolysis & lipolysis are promoted by muscle catabolism, cate­
cholamines, glucocorticoids, lipolysis, and gluconeogenesis. Therefore,
the induction of IR may be accountable for increased hormone secretion
[11,49]. Concerning the last group, three key insulin-sensitive extra-
pancreatic organs play a big role in the processes described above: liver,
adipose tissue, and skeletal muscle. Defective insulin action in these
tissues often boosts systemic IR production, leading to T2DM. For type 2
diabetes to develop, IR and pancreatic β-cell impairment must occur at
the same time [39,50]. There is some kind of IR in someone who is
overweight and/or obese, but diabetes only occurs in certain people who
experience a drop in insulin discharge to compare the level of IR. Insulin
may be elevated in certain individuals, but normalizing the level of
glycemia is not enough. Both obesity and T2DM have developed a sig­
nificant health issue with growing desk-bound lifestyles, increased
inactivity, & the intake of high-fat as well as foods rich in sugar. Food
and Drug Administration (FDA) has approved sodium/glucose co-
transporter 2 (SGLT2) inhibitors for the treatment of diabetes mellitus
[51]. Although, drugs under this class gives promising results in the
treatment of diabetes mellitus, but emerging data from post-marketing
studies indicated their adverse effects such as diabetic ketoacidosis,
genital and urinary tract infection, cancer, bone fracture and foot and
leg amputation [52]. Therefore, a successful strategy to avoid drug or
delay the development of T2DM in individuals at high-risk is a sound
balanced diet and physical activity to attain weight drop and decrease
obesity [38,53]. Of all the methods, the American Diabetes Association
(ADA) has recommended dietary therapy for all people with T2DM [54].
In particular, in recent clinical research, low-carbohydrate and high-fat
diets are one of the topmost common dietary remedies for patients with
obesity & diabetes [55]. Interestingly, a rise in the risk of T2DM is
associated with high consumption of a high-fat diet & increased con­
sumption of saturated fat, but this relationship is disrupted when paired
with a reduced or non-carbohydrate diet known as the KD [56]. Many
researchers have reported that KD plays a major role in glycemic regu­
lation & weight drop & can prove to be an effective intervention for
patients who are obese or diabetic [25,55–58]. Besides, relative to a
moderate glycemic index diet, a diet low in carbohydrate has greater
favorable outcomes on glycemic regulation [61].
4. Ketogenic diet (KD)
In conjunction with preparation, alteration of macronutrient intake
has become a crucial nutritional factor that appears to improve physical
characteristics, efficiency, and health effects. Ketogenic diet (KD) is a
low-carbohydrate but still high-fat diet modification that must be
planned to take into account specific successful dietary attributes (such
as macronutrient degrees) Physiological modifications (ketosis genera­
tion) among different implemented nutritional strategies [24,60]. The
composition of ketogenic diet is high fat (50–60%), protein (30–35%),
and carbohydrates (5–10%). The KD has recently committed itself to the
pledge that obesity and T2DM can be cured [63]. [64]. In the obesity-
related interventions and other associated problems, the KD has
recently emerged as a fad diet. KDs are newer than most low-
carbohydrate diets in which diet consumers are counseled to take
almost any carbohydrate, shield themselves from excess protein and eat
large quantities of fat (usually over 70% of the calorie consumption) and
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Life Sciences 264 (2021) 118661
thus produce ketones that are recognized as the diet. Awakening to­
wards diet low in carbohydrates is implicit in the failure of a low-fat diet,
to avoid an epidemic of obesity and its related rise in T2DM [65].
Various researches have shown that energy and fat loss is higher when
compared to KD with low-fat diets. A diet that causes weight loss is
accomplished by lowering the consumption of calories. The KD is not
that different when used for losing weight [64,65]. T2DM is character­
ized by intolerance to carbohydrates due to insulin resistance. Carbo­
hydrate restriction can be a major boost in glycemic regulation (like
KD), and weight loss can enhance IR through any means. However, little
evidence is found, unlike other dietary interventions that enhance gly­
caemic control, in addition to the use of balanced highly-carbohydrate
foods, including legumes, complete kidneys, and fruit even if there is
no weight loss [66,67], clearly improves carbohydrate intolerance
irrespective of obesity [68,69]. Evidence indicates that lipoprotein,
cholesterol, and apoprotein-based low-density levels of lipoprotein with
a KD, despite a drop in weight, do not improve or increase significantly
(Tables 1 and 2). While the KD has received significant interest in
treating chronic conditions, including obesity and T2DM, there is
currently little evidence of their use and the possible threats to their diet
are valid [66]. Mechanisms proposed by KD as given in Fig. 1.
5. Mechanisms linking obesity and diabetes
Obesity is a condition associated with multiple medical, social, and
psychological problems, the most harmful of which could be T2DM.
Both T2DM & obesity have been associated with insulin resistance. KD
that connects obesity to diabetes needs to be explained through various
mechanisms, the ectopic deposition of lipids may be one of the factors of
metabolic syndrome. Most people who are overweight do not experience
hyperglycemia besides being insulin resistant. Pancreatic β-cells in the
islet of Langerhans release sufficient quantities of insulin to combat its
decrease under normal physiological situations, thus retaining normal
tolerance to glucose [76]. Normal history of T2DM indicates that
endothelial dysfunction is closely linked to obesity/IR in diabetes and
pre-diabetic complications. The development of IR and obesity, thus
triggering T2DM, cells should possess an inability to respond to impaired
insulin sensitivity. Non-esterified fatty acids (NEFAs) discharged from
Table 1
Etiology of obesity [70,71].
Factors promoting obesity
Genetic factors The several signaling molecules and receptors that are
used by regions of the hypothalamus and alimentary tract
to control food consumption can be affected by genetic
causes. Obesity rarely results from excessive number of
peptides that control intake of food (e.g. ghrelin,
neuropeptide Y, leptin) or receptor defects (for instance,
melanocortin-4 receptor).
Lifestyle choices • Unhealthy diet.
• Liquid calories.
• Inactivity.
Certain diseases and • In certain persons, obesity, as well as Prader-Willi
medications syndrome, Cushing syndrome and other disorders, can
be lead to a medical condition. Medical conditions,
including arthritis, may also result in reduced exercise
that can contribute to obesity.
• If you don’t compromise by exercise and diet, some
drugs can cause obesity. Any antidepressants, anti-
seizure drugs, diabetes medicines, antipsychotic medi­
cations, steroids, and ß - blockers are included in these
medicines.
Age At any stage, obesity can develop, even in young children.
Yet hormonal fluctuations and a less active lifestyle raise
your risk of obesity as you get older.
Other factors • Pregnancy.
• Quitting smoking.
• Lack of sleep.
• Stress.
S. Kumar et al.
Table 2
Etiology of diabetes mellitus. The origins of DM are not well known. It has now
been generally recognized that there is a multifaceted cause of DM in which both
genetic and environmental factors play a key role [72,73].
Factors T1DM
Environmental factors Chemicals, Vitamin D deficiency, Cytotoxins,
Enteroviruses etc.
Genetic factors About 18 gene loci are linked with type-1 diabetes. The
HLA (human leukocyte antigen) genes located on IDDM1
encodes for MHC proteins linked with type-1 diabetes
(Pociot, Akolkar, Concannon, et al., 2010). Whereas the
IDDM2 gene loci contains the insulin gene affecting
production of insulin (Dean, McEntyre, 2004).
Factors T2DM
Obesity/Insulin Mutations affect PPAR-γ and hyperlipidemia is associated
resistance (IR) with diabetes development.
Gestational diabetes Offspring with diabetic parent are at more risk of
developing diabetes.
Ethnicity Also varies with ethnic/race groups.
Gender and puberty There is a 30%–50% decrease in insulin sensitivity and
compensatory increase in insulin secretion. Insulin
resistance develops with the persons with family history
of diabetes. Girls are more prone and develop 1.5–3 times
more T2D as children or adolescents (270).
Family history T2DM has an increased risk with 74–100% patients
relatives.
Genetics 1. Peroxisome Proliferator-Activated Receptor-γ2 (PPAR-
γ2) Gene that regulates of lipid and glucose homeostasis.
2. Kir6.2 Gene (KCNJ11).
3. MODY genes (HNF4a and HNF1β)
4. Transcription Factor 7-like (TCF7L2) Gene: helps in the
glucose homeostasis.
5. Calpain-10 Gene: Calpains are Ca2+ dependent cystein
proteases and regulates insulin secretion and action.
Fig. 1. Different mechanisms of ketogenic diet involved in metabolic disorders.
4
Life Sciences 264 (2021) 118661
fat-storing tissue in obese individuals can contribute to the theory [38]
that IR and β-cell damage are the most important related factors.
6. Obesity and insulin resistance
During physiological functions insulin present in the body is
responsible for the metabolism of glucose. It confirms that the living cell
is equipped with necessary content obtained from fat or carbohydrate
(glucose), may deposit in the triacylglycerol form or glycogen form [77].
Decreased blood glucose levels reduce insulin levels, resulting in lower
storage and energy costs. The body is now looking for alternative fuels
[78]. Ketogenesis starts in the liver by fatty acids oxidation in the
mitochondrial matrix and releases acetyl CoA. The final by-product
(acetyl CoA) either joins the tricarboxylic acid (TCA) cycle or com­
bines to create ketone cells on account of the higher yield of acetyl CoA
in the mitochondria of the cells [79]. The primary ketone bodies, 3-
hydroxybutyrate, acetone, and acetoacetate are transferred from the
hepatic cells to the blood and then to other body tissues, which includes
the brain. Acetone is believed to be partially catabolized while acetoa­
cetate is generally chemically unsteady while 3-hydroxybutyrate with
proper levels is distributed thoroughly in the bloodstream [80]. Vari­
ability in sensitivity towards insulin arises during the normal life cycle.
For instance, IR is reported during the stages of adolescence, the
gestation period, and the older age [81]. In contrast, lifestyle changes,
such as higher intake of carbohydrates and reduced physical activity, are
correlated with an increase in insulin sensitivity [82].
Obesity is known to be the major cause of metabolic disorders. Ad­
ipose tissue influences the metabolism of lipids and sugars by hormonal
secretion, including glycerol, or others including cytokines, adiponectin,
leptin, and pro-inflammatory molecules, and by the release of NEFAs.
The release of these molecules gets increased [76] in individuals with
S. Kumar et al.
obesity. The production of elevated NEFAs causes insulin insensitivity.
Excessive production of NEFAs is seen in obesity, T2DM, and is linked
with IR in both cases [83]. Shortly after a rise in plasma NEFA con­
centrations in humans, IR begins to develop. Conversely, as the plasma,
NEFA level decreases peripheral insulin uptake and glucose control are
increased [84]. Insulin sensitivity is calculated as one of the important
elements, the distribution of body fat. IR is correlated with body mass
index (BMI) at any amount of weight gain. Insulin sensitivity varies
entirely in lean people due to variations in body fat dispersion. Subjects
with more peripheral fat dispersal have more insulin sensitivity than do
subjects with more central fat distribution (i.e., in the abdomen and
chest areas) [85].
These variations in the distribution of adipose tissues illustrate the
mechanism of the metabolic behavior of fats varies according to
different body parts. Intra-abdominal fat possesses a close association
with the genes secreting the proteins accountable for energy production.
Adiponectin releases by adipocytes are more than that provided by
subcutaneously-extracted adipocytes. Besides, the quantity produced
from these cells or adipocytes is oppositely associated with a rise in body
weight [86]. The production of NEFAs to various tissues may be varied
by their origin. Also, fat of the abdomen is found to be more lipid-
producing than subcutaneous fat & therefore does not react simply to
the lipogenic mechanism of insulin that induces IR to intra-abdominal
fat and therefore diabetes [85,86]. Marcial et al. [89] also help
explain the various molecular mechanisms of IR, inflammation, and the
progression of diabetes. Insulin is an anabolic hormone responsible for
the synthesis of glycogen in the muscles and liver. This, in turn, initiates
protein synthesis that inhibits the proteolysis activity. Fat/lipid accu­
mulation & metabolization are other essential elements contributing to
IR. Obesity & β-cell dysregulation, despite their fragility, exhibits a
crucial action in the regulation of insulin release. The amount of insulin
secreted by β-cells varies and refined depending on the amount, exis­
tence, & induction of the stimulus. Pancreatic cells exhibit a vital
function in indicating that blood glucose concentration in healthy or fit
individuals with normal physiological and health conditions [90].
Obesity reduces the sensitivity of insulin & the regulation of
pancreatic cell function [91]. Insulin-resistant people, whether obese or
non-obese, have more insulin signals & reduced liver insulin clearance
as compared to individuals which are insulin-sensitive. The constant
feedback correlation between pancreatic β-cells and insulin-sensitive
tissues in a normal healthy person [92]. If the demand for glucose
rises in the fat tissue, liver, and muscles, this would result in an increase
in the supply of insulin to pancreatic β-cells. If glucose amount needs
stabilization, alterations in insulin action and sensitivity must be
balanced by a moderately opposite change in circulating insulin con­
centration. The inability to do so contributes to the imbalance of glucose
levels & the production of DM. In normal healthy people, there is
adaptive feedback to IR, which contributes to the preservation of normal
glucose concentrations. However, when pancreatic cells are compro­
mised, irregular glucose tolerances may occur, which may even be
accompanied by the development of T2DM [93].
A persistent decrease in pancreatic β-cell action is a major pathway
that pancreatic β-cell dysregulation triggers insufficient insulin
discharge, the fasting of blood sugar or glucose, and an after food intake
elevation in blood glucose. Similarly, there will be a decline in the ef­
ficacy of muscle & hepatic uptake of glucose due to a lack of inhibition of
the production of liver glucose. Additionally, a rise in blood glucose
amount, cause disease severity through a range of glucotoxicity out­
comes on pancreatic β-cells & opposite outcomes on insulin absorption
& peripheral tissue sensitivity [94]. The healthy subjects when tends to
increase their sugar level for more than 20 h this causes an increased
insulin uptake and has the opposite effect [76]. These steps demonstrate
that the genetic factor at risk is also accountable for the development of
cell function disability. Genetic background and earlier family records of
diabetes strongly raise the likelihood of IR and overall pancreatic β-cell
dysfunction [38]. Another variable that triggers cell function loss is the
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Life Sciences 264 (2021) 118661
rise in plasma NEFA levels. NEFAs share a major contribution in the
normal physiological functioning of insulin release, whereas on
continued exposure to NEFAs they create changes in glucose triggered
insulin secretion pathways & also alter the biosynthesis of insulin.
Growing NEFA concentrations due to increased lipids and impairment of
regulatory pathways simultaneously raise diabetes and obesity risk [95].
Increased lipid concentrations related to increased NEFA levels in obese
people increase the harmful effects of glucose and lipids described as
glucolipotoxicity, another significant mechanism linking the risk of
developing metabolic disorders such as diabetes in obese individuals
[96].
7. Pathogenesis underlie both obesity and diabetes mellitus
While two distinct lesions – obesity-induced IR and β cell failure —
are commonly associated with obesity and T2DM, both conditions may
contribute to an underlying condition. This “unified field hypothesis”
poses concerns about whether excess weight and metabolization faults
also lead to β-cell decompensation [97]. Sustained exposure to nutrient
concentrations exceeding energy requirements may be a possible cor­
relation. Detrimental effects of nutrient overload over pancreatic cells
can involve inflammatory signal impairment, endoplasmic reticulum
stress, and excessive production of ROS, mitochondrial dysregulation,
accumulated intermediate serine-threonine kinases, and triglycerides
and/or fatty acyl. Such reactions are not mutually absolute & one can
cause another, which contributes to a cascade of damages [20]. A
cellular injury linked to obesity can in turn enlist and stimulate mac­
rophages & other immune cells that worsen the tissue inflammation
[98]. Together, these reactions lead to the pathogenesis of IR in the liver,
skeletal muscles, and tissue adipose, with some (for example, acquired
mitochondrial dysfunction and inflammation) occurring even in β cells,
through the above-mentioned mechanisms [99]. Therefore, obesity-
induced metabolic disability in susceptible individuals will promote IR
on the one side and progressive β-cell dysfunction on the other. The
nutrient excess problem can also be aggravated by increasing circulating
glucose sugar, FFAs, & other nutritious components. Thus, a vicious
cycle occurs, in which obesity-induced nutrient overload, activates re­
sponses towards inflammation which give rise to resistance to insulin,
places increased demand on β-cells and decreases in cellular tension in
nutrient excesses.
However, as not all overweight or obese people experience hyper­
glycemia, an underlying pancreatic b-cell deformity must coexist with
nutrient overload to sustain type 2 diabetes [45,98]. If obesity is linked
with impaired energy balance and insulin action controlling neuro­
circuits, IR caused by obesity can occur, not only as of the direct effect of
excessive adipose mass but also by neuronal pathways. The available
literature reports also suggests that disrupted neurocircuits may also
deteriorate pancreatic β-cell dysfunction that links obesity and its
complications progress [99,100]. The link between two is shown in
Fig. 2.
8. Epidemiological proof of a causal association between obesity
and type 2 diabetes mellitus
A report indicated that preventing the whole population to weigh
just one BMI unit would result in a 12.4–13% decrease in the incidence
of T2DM [103]. Diabetes risks increase dose-dependently with BMI
growth [104], and weight gain during adult life is linked to a greater risk
of diabetes development [14]. The program on diabetes prevention
clearly shows that weight loss and rising physical activity can slow
diabetes growth. Lifestyle improvements have been successful more
than metformin therapy [105], and diabetes worsens with increasing
BMI [106]. Additional evidence for lifestyle change effectiveness in the
prevention of progression from impaired glucose diabetes tolerance has
been provided by studies such as the Finish Diabetes Prevention Study
[107], the Indian Diabetes Prevention Report [108] and the Chinese Da
S. Kumar et al.
Fig. 2. Obesity in relation to diabetes mellitus.
Qing Impaired Glucose tolerance study and diabetes Study [109]. The
XENDOS (XENical in Obese Subjects Diabetes Prevention) report
showed that the addition of Orlistat to lifestyle changes has lowered
possibilities of frank diabetes production in persons with disrupted
glucose tolerance [110].
9. Ketogenic diet as a preventing factor to obesity and diabetes
mellitus
Obesity is a serious chronic disease related to various chronic dis­
eases. It is also a significant factor at risk for T2DM & IR [111]. Ectopic
aggregation of lipid content, especially in the region of skeletal muscles
& liver, is frequently linked to this state of IR. One of the foundations of
recovery, such as physical exercise, is weight loss. In the literature,
metabolic syndrome is associated with diets high in carbohydrates, and
especially low in fructose & refined sugars [112]. Therefore, various
diets have been recommended to lose weight. In particular, restrictions
on carbohydrates have been suggested as the single most successful
technique to minimize all the characteristics of the syndrome related to
metabolism [111,112]. Low-carbohydrate diets, especially KDs, have
become more prominent. These diets are popular for their carbohy­
drates, but are typically rich in protein and/or fat content. Generally,
6
Life Sciences 264 (2021) 118661
KDs are characterized by a decrease in carbohydrate content (typically
lower than 50 g/day) & a comparative rise in amounts of fat & protein
proportions [115]. Recent studies in different laboratories have shown
that a diet rich in a polyunsaturated (ketogenic) fatty acid is very
beneficial for limiting bodyweight & risk attributes for different chronic
conditions. A report showed that the weight of obese patients who were
on a KD was substantially decreased [25]. Ketosis is caused by the body’s
fuel conversion from carbohydrate to fat. Unfinished oxidation of the
liver fatty acids allows the body to accumulate ketone bodies. A rise in
acetoacetate & D-β-hydroxybutyrate characterizes the body by a KD
[116].
Diets highly rich in fat are commonly thought to give rise to obesity
and a variety of other disorders, including coronary artery disease,
diabetes, and cancer. In this regard, the key question is whether a high
proportion of fat in diet encourages overweight over a reduced intake of
fat. As fat contains calorific density higher than in carbohydrates, a diet
high in fat is expected to be followed by higher consumption of energy
[117]. Recent research from the Dashti et al. laboratory [23] and
numerous other laboratories have, however, reported that KDs can be
used as a treatment for weight drop in patients suffering from a condi­
tion called obesity [116,117]. However, this view is based on research in
rodents with polyunsaturated fatty acids rich high-fat diet. Both of the
S. Kumar et al.
recent studies are corresponding to the current study in this respect.
Brehm and coworkers [120] found that obese women lost 8.5 kg over six
months in the low-carbon KD, as against 4.2 kg in the low-fat diet (P <
0.001) group. The study was carried out in 20 subjects fed with low-
carbon KD and 20 fed with a low-fat diet. Both groups reduced their
energy consumption by around 450 kcal from the baseline stage. In
another research [121], the less carbohydrate KD indicated a greater
loss of weight. A KD is thus clinical and experimental in anti-obesity
treatments; however, its molecular mechanisms are yet to be
explained. KD and mouse obesity (obese or not obese) studies have
shown that KD is involved in weight loss [61,120]. The mice fed with KD
also increased energy expenses and lost the respiratory exchange ratio
pattern diurnal, which suggested that fatty acids were continuously used
as an energy substrate [123]. Another research examined this growth in
energy expenditure, which showed KD encourages weight loss (20% of
the total body weight) by increasing energy intake. Rats fed with KD had
Fig. 3. Ketogenic diet targeting pathological mechanisms linking obesity and diabetes mellitus.
7
Life Sciences 264 (2021) 118661
a decreased excretion of urinary nitrogen due to the lower intake of
protein and energy-to‑nitrogen urine rate almost twice that of the other
diets. Increased gene expression in the oxidation of fatty acids and
decreased expression of lipid synthesis genes [124]. Ketosis mediated
appetite reduces another theory of KD-induced weight loss [25]. Ketosis
mediated therapy means involvement of ketogenic diet, high fat, low
carbohydrate diet, with adequate amount of proteins that helps in
reducing the risk of obesity and other related metabolic disorders. Some
reports also propose digestive metabolic modifications: when patients
had a ketogenic low-energy diet, levels of ghrelin were decreased as well
as subjective appetite (usually increased with a hypocaloric diet) [125].
Interestingly, under ketosis, leptin concentrations were lower [70].
Thus (listed by order of evidence available) we can outline the
theoretical mechanisms of KD’s weight drop outcomes:
(1) Appetite falls due to excessive protein satiety outcomes [126],
effects on appetite regulation hormone [125], and potential ketone body
S. Kumar et al.
direct appetite suppressant action [127];
(2) Lipogenesis reduction and lipolysis increase [128];
(3) Greater metabolic efficiency in the intake of fats signified by
reduced resting respiratory quotient [116,127];
(4) Increased gluconeogenesis metabolic costs and protein thermal
effects [124,128].
The Ketogenic diet thus suggests various mechanistic approaches
that targets obesity and Diabetes as depicted in Fig. 3.
Therefore, these pathways suggest the better function of KD in
weight loss and obesity reduction and other associated risks such as
metabolic syndromes. The lactate shuttle between astrocytes and neu­
rons is an essential component of a metabolic pathway providing the
neuron with alternative energy sources. Lactate dehydrogenase (LDH), a
key metabolic enzyme regulates this lactate shuttle and is necessary to
provide glucose-deprived (via lactate) neurons with energy. The shuttle
helps in the restoration of the energy deprived neurons and helps in the
recovery of this metabolic pathway. Tsuyoshi Inoue’s group showed in
seminal landmark research that inhibition of LDH hyperpolarize neu­
rons and prevent seizures [129,130]. Remarkably, stiripentol, an anti­
epileptic drug that has been clinically used for the syndrome of Dravet,
has also been found to be a molecular target [133]. These results were
astonishing & indicate that the inhibition of this metabolic pathway will
mimic the effects of KD therapy, contributing to the progression of KD,
as the main factors are investigating mechanisms for KD induced weight
loss.
Increased gluconeogenesis due to carbohydrate constraints, ketosis-
caused appetite suppression, and improvements to levels of leptin, adi­
ponectin, lipoproteins, lipogenesis, & insulin was also found in the KD-
intake and calorie restrictions to be an important basis for weight drop &
metabolic syndrome [68,132,133]. The KD-dependent aspect of the
fatty acid oxidative gene & impaired gene expression affecting lipid
biosynthesis contributed to lower abdominal circumference & decreased
obesity like condition [122]. KDs have been shown to minimize lipid
serum levels and increase lipid profiles, reduce body fat, and reduce
overall body weight in animals and humans, and increase human energy
intake [136]. MCTs have also been shown to minimize insulin resistance
and to increase tolerance to glucose in both animal models [137] and
type 2 patients [138]. While it remains unclear about the mechanistic
explanation of these results, these findings indicate that MCTs have a
beneficial function in treating T2DM & its related glucose-responsive
metabolic conditions. KDs are more limited in the advantage of type 1
patients than in T2DM patients, including scientific records of patients
with T1DM and loosely managed epilepsy and/or anecdotal evidence
[139].
The possible life-alarming complication of diabetic ketoacidosis is a
major concern regarding the adoption of a KD in patients with diabetes,
in particular T1DM, since low insulin facilitates ketosis & fatty acid
oxidation. Impairment in mitochondrial function has also been known to
play a key role in IR and subsequently in diabetes pathology. In addition
to the elevated levels of reactive oxygen species [140], attributed to
insulin resistance, patients with type 2 diabetes [141] were also found to
have functional impairments with mitochondrial dysfunction [142].
Genetic changes and modifications in the gene expression of the mito­
chondrial biogenesis coactivator-1 have also been suggested that it play
a role in the pathogenesis of diabetes. Given these results, a therapeutic
effect on diabetes treatment may be a function of decanoic acid as a
Peroxisome proliferator-activated receptor (PPAR-α) agonist. Increasing
mitochondrial biogenesis, combined with an improved function of
mitochondria & an increase in antioxidant capacity, may thus form
active protection against the detrimental outcomes of mitochondrial
dysfunction in diabetic conditions [143]. KD often causes insulin and
glucose resistance, while KD possesses a better regulation of glucose
homeostasis and a decrease in antidiabetic drugs in type 2 diabetic
humans. However, these changes tend to be limited in time [141].
Previous research has shown that a very limited amount of
carbohydrates/high-level fat carbohydrates (CDs) lead to a weight
8
Life Sciences 264 (2021) 118661
reduction in diabetic obesity, glycemic regulation, and metabolic pa­
rameters in T2DM [56]. For example, KD low in carbohydrate not only
decreased blood glucose near normal but stabilized the size of islets and
the β-cell number in rats with diabetes. Limited carbohydrate may easily
be hypothesized as less glycogen storage contributes to lower blood
glucose levels. in this study, glycemic control of KD was also excellent in
comparison with earlier studies in rodents [139,142]. An overall in­
crease in the energy reserve and energy charge of the brain was recorded
by a study. KDs can prevent diabetic complications, naturally the blood
ketones, and also lowering blood glucose levels [145]. A special problem
with diabetic complications is also to survive reversal, amid the
normalization of the blood glucose [146], a metabolic memory phe­
nomenon [147]. A similar case with the estradiol hormone has been
previously noted. This gives rise to progression in neuroendocrine out­
comes which occurs moreover when estradiol is removed and that
glucose hypothesized will cause similar permanent molecular effects
which would be irreversible through the normalization of glucose [148].
This was recorded next year [149]. Fascinating documents subsequently
show similar hysteretic behavior in the lac operon [150]. These in­
vestigators showed that lac operon was persistently induced to help
induction at the extent of the earlier inducer, which was unable to
induce operon i.e. pre-induction now appears to increase inducer’s
susceptibility. This is similar to genes that are mediated by elevated
glucose, including fibronectin 36 or p39,65, that maintain induction
following returning to it. Fatty acids that are blood-free are usually only
increased during fasting, to provide a source of alternate glucose for ATP
production in peripheral cells, which can be easily demonstrated in
sleep, including humans, with indirect calorimetry. Thus, the fact that
lipid metabolites are a sign of nutrient deficiency, the hypothalamus, in
particular, promotes overweight in the presence of ad libitum, is highly
compatible with physiology and that, if anything, blood glucose is an
indicator for adequate or even satiety nutrients consistent with several
studies [149,150]. In the meantime, we have demonstrated in recent
studies on hypothalamic neurons in glucose sensing shows that ketone 3-
hydroxybutyric acid (3-OHB) effectively choked the glucose-sensing
effects, especially on the orexigenic neuropeptide control of Agouti-
related protein (AgRP). KD, therefore, helps to minimize increased
body weight and risk of diabetes through different mechanisms
mentioned above [153]. KD lowers glucose metabolism, lowering blood
sugar levels to below normal. KDs also raise ketone blood levels and
decrease blood glucose to avoid diabetic complications [130]. Inade­
quate carbohydrate content in KD induces hunger and induces lipids &
fat to break down into ketones in your body. This produces a condition
of ketosis, that provide fuel depending on ketones derived from fatty
acids released into hepatitis, specifically during the dysfunction of he­
patic glycogen and blood glucose [153].
The conventional definition of long-chain triglycerides based on fatty
acid (LCTs) has been promoted as constituents of KDs, and in recent
years the better option was ketogenic mid-chain triglycerides (MCTs) of
about 40% decanoic acid & 60% octanoic because of their rapid meta­
bolism and effective ketone levels [152,153]. Then lipase enzymes
catalyze the breakdown of water in MCTs to medium-chain FAs, which
are consumed by the liver mitochondria and rapidly β-oxidated to
discharge ketone bodies into systemic circulation in association with the
non-metabolized fats [156]. This leads to a predominant source of fuel &
adenosine triphosphate (ATP) through a rise in enzyme-associated
acetyl-CoA, adenine dinucleotide nicotinamide (NAD+), and citric
acid cycle intakes [157]. Acetyl CoA is primarily converted into acetone
with acetoacetate and β-hydroxybutyrate through the intervention of
hydroxymethyl glutaryl lyases and hydroxybutyrates via the Kreb cycle,
which then passes through the blood-brain barrier into the extrahepatic
tissues through monocarboxylic transporters or into the brain. The pri­
mordial circulating ketone body is, however, β-hydroxybutyrate,
whereas acetone & acetoacetate have less stability & insufficiently
metabolized [154,156]. KD typically raises blood ketone levels between
0.2 and 5 mM. Compared to glucose, ketone cells reduce NAD+ to NADH
S. Kumar et al.
for energy production, allowing increased free NAD+ molecules for
various operations, together with metabolic therapy & cell health.
Increased NAD+/NADH mitigates metabolic disruption, especially
concerning mitochondrial activity, cellular respiration, chromosomes,
ADP-ribosylation, and posttranslational deacetylation [157,158]. Be­
sides, the extended consumption of KD contributes to the total physio­
logical depletion of glucose and the excess of fatty acids, with the main
mode for energy production being fatty acid oxidation [118]. The main
mechanism of KD involves increased mitochondrial biogenesis, citrate
synthase, and catalase activities, decreased ROS, and late-onset mito­
chondrial myopathy, and regulated Cytochrome C oxidase functions. KD
also raises the amount of mitochondrial GSH & antioxidant lipoic acid,
guarding in case of inappropriate methylation of DNA and consequent
DNA damage [159,160]. KDs are typically enriched in polyunsaturated
fatty acids (PUFAs), which activates mitochondrial cysteine ligase (GCL)
& GCL heterodimers, give rise to elevated GSH levels & lower oxidative
stress levels by upregulating the nuclear receptor-proliferator-activated
receptors-α or μ & the nuclear factor-derived erythroid- 2-associated
elements [161,162]. On the other hand, a rise in oxidation of unsatu­
rated FAs discharges oxidized species in response to mitochondrial
antioxidant levels, which increase and attenuate destruction to ge­
nomes. Disruption in discharge of mitochondrial energy & encepha­
lopathy induces many metabolic effects, for instance, with stroke-like
symptoms, lactic acidosis, dystonia, spasticity, ataxia, and PUFA
enriched KDs boost respiratory chain acivities & minimize the risk of
heteroclassic disorder [159,163]. Overall, KD covers the number of
mechanisms, particularly for mitochondrial functions and its biogenesis,
which together reduce obesity and diabetes [77]. KDs have also shown
to be a protective factor for obesity, diabetes and other associated
medical disturbances.
10. Other preventive measures to minimize obesity and
diabetes-related complications
• Lifestyle improvements, for instance, increasing physical activity and
dietary changes, are likely to remain central to the management of
obesity.
• Cut sugar and refined carbs out of your diet
• Follow a sensible diet; maintain a balanced lifestyle with regularly
scheduled meals.
• Don’t skip your meals.
• Exercise daily
• Keep yourself well hydrated (get plenty of fluids).
• Drink water as your main beverage.
• Stop sedentary activity
• Maximize the vitamin D amount
• Eat a high-fiber diet
• Consider taking these natural herbs: berberine, curcumin, etc.
• Quitting cigarettes and alcohol consumption
• Lifestyle in walking societies & facilities like parks and other nearby
recreation facilities has generally been connected with the best levels
of mental as well as physical activities in children, teenagers, &
adults.
• A well-furnished design of colleges & schools, for instance, large
playgrounds, basketball hoops, and better design of buildings like
signage encouraging the use of stairs and faster approach to stairs
comparison to elevators, have been correlated with a good level of
physical activity in young people and adults [102,164–166].
The above mentioned preventive measures must be taken to prevent
the risk of weight gain and developing obesity and other associated risk
factors.
11. Conclusion
Diet is the key factor responsible for triggering some kind of health
9
Life Sciences 264 (2021) 118661
problems that accompany the lifestyle. Obesity is the biggest component
of the unhealthy diet that encourages a novelty in health problems.
Obesity is associated with multiple metabolic problems, which are
alarming in diabetes. There is also a clear need to resolve these com­
plications. Many medications have their side effects in individuals with
such complications to effectively minimize the incidence and burden of
such diseases by adopting a KD with no alteration in their lifestyle. KDs
are the best way to manage the associated health risks.
Funding source
None.
CRediT authorship contribution statement
Sachin Kumar Wrote the article
Tapan Behl Conceived the idea and improved the article
Monika Sachdeva Data survey
Aayush Sehgal Literature Review
Shilpa Kumari Data Curation
Arun Kumar Figure Work
Gagandeep Kaur Data compilation
Harlokesh Narayan Yadav Proof Read
Simona Bungau Proof Read
Declaration of competing interest
None.
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