guest lecture at university of delhi - the entangled relationship between diabetes, obesity,...
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1
The entangled relationship
between Diabetes, Obesity,
Metabolic syndrome
and Aging
Dr. Vinod NikhraM.D., ICCN, PGCHM, FIMSA
Fellow Royal Society of Medicine
Hindu Rao Hospital, New Delhiwww.vinodnikhra.com
www.nikhrafoundation.org
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The Basic Facts
Obesity, diabetes and metabolic syndrome are
in essence metabolic disorders; complexly
entangled and bear a close inter-relationship.
They are life-style diseases as well, having
genesis in modifiable modern dietary habits
and technology-driven sedentary life-styles,
apart from non-modifiable genetic makeup.
They have an important impact on the morbidity
and mortality patterns directly and through
their effects on the aging process.
3
Obese-Obese World !
They are potentially diabetic, have MS, age faster
and likely to suffer from Various chronic and
dangerous diseases.
.
.
Year of Publication: 2005
Chapter 1. Obese-obese World
ISBN 8175643595
SAHNI PUBLICATIONS
3a
4
The Ingredients of Metabolic Syndrome
.
5
The Basic Facts..2
Those overweight and obese have higher
incidence of diabetes. The research has
proven that obesity leads to aging of adipose
tissue, which in turn leads to cascade of
various metabolic pathways responsible for
accelerated aging.
The diabetes, too, appears to accelerate
aging at cellular level through metabolic
alterations. The elderly people, on the other
hand, have a higher incidence of diabetes.
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The Basic Facts..3
Aging is universal,
The diabetes is common,
Obesity and Metabolic syndrome are
increasing to epidemic proportion;
and they bear a complex
Inter-relationship.
That is where, we want to Understand, Act and Prevent
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The ExerciseWe will examine along the course
of this presentation:
1. Whether the state of research indicates that
pathophysiological changes in diabetes, obesity
and metabolic syndrome are comparable to
those in a normal aging individual?
2. What is the basis of these pathophysiological
changes brought about at cellular and somatic
levels?
3. Whether these changes are modifiable?
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Evidence from Experimental Science
•The experiments in – normal mice, variously KO-
mice and Agouti mice have unfolded the under-
standing of metabolic pathways associated with
obesity, insulin resistance, development of
diabetes and aging.
•The Agouti mice - carry dominant agouti alleles
Ay or Avy – have high levels of ROS, increased
DNA damage and higher expression of
inflammatory markers*. They lack telomerase and
develop shorter telomeres during successive
generations*.
*the complex set of traits collectively referred to as the yellow mouse syndrome
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Evidence from Experimental Science ..2
• The Agouti gene expression leads to alteration
of central melanocortin pathway and induces
excess food intake, calorie excess and obesity.
• The adipose tissue from these mice shows
features of premature aging.
• Minamino et al* proposed that the link between
obesity, abnormal metabolism and Diabetes
was p53. The activation of p53 in adipose tissue
led to inflammation and insulin resistance
culminating into diabetes.
*Minamino et al, 2009, Nature Medicine 15, 2009.
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Evidence from the Experimental Science ..3
*WHO Data **US National Diabetes Statistics, 2011*Minamino et al **Rexford SA, Nature Medicine,2009
In obese states, adipose tissue is subjected to oxidative
stress, resulting DNA damage, telomere dysfunction and
aging. This activates p53, which in turn causes production
of pro-inflammatory cytokines, suppression of adiponectin,
insulin resistance and progression to diabetes.
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Evidence from Experimental Science ..4
In the allied experiments: Inhibition of p53
activity in adipose tissue ameliorated the
senescence-like changes, decreased the
expression of pro-inflammatory cytokines and
improved insulin resistance in mice with T2DM-
like disease*.
Adipose tissue from diabetics, too, show
senescence- like features. Also, there are higher
levels of p53 protein and increased expression
of inflammatory cytokines. Thus, the aging of
adipose cells is linked with diabetes.
*The Minamino Experiments
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The Role of P53
• p53, a 53-kdalton molecule, regulates the cell
cycle and functions as tumor suppressor. It has
been called ‘the guardian of the genome’.
• P53 plays an imp. role in apoptosis, genomic
stability, and inhibition of angiogenesis.
• In normal cell p53 is inactivated by its binding
with mdm2. DNA damage or other stresses
through various pathways lead to dissociation
of the p53 and mdm2 complex.
• The activated p53, then, induces cell cycle
arrest, repair or apoptosis.
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The Role of p53 ..2
p53: ‘the guardian of the genome’.
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The Role of p53 ..3
• Various stimuli (telomere dysfunction, oxidative
stress, etc.) induce irreversible cell growth
arrest - termed 'cellular senescence'. This
process is regulated by p53 and another tumor
suppressor protein, pRb.
• The research suggests a substantial
relationship between the cellular senescence
and aging of organisms.
• The p53 activation in adipose tissue appears to
be a pro-aging signal, with negative influence on
longevity*.
*A crucial role for adipose tissue p53 in the regulation of insulin resistance.
Minamino, et al. Nature Medicine 2009
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The Role of P53 ..4
The p53 regulates lipid metabolism: 1. By binding
to G6PD and inhibiting pentose phosphate
pathway; and, 2. Through aromatase pathway. In
addition, 3. p53 enhances fatty acid oxidation and
modulates lipid transport by inducing the
expression of multiple genes*.
In experiments, the hyperglycemia induced
apoptosis and p53 mobilization to mitochondria
in RINm5F cells, causing both the disruption of
mitochondrial membrane potential and an
increase in ROS.
*Goldstein and Rotter, A new role of p53 in regulating lipid metabolism J Mol Cell Biol (2013)
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Oxidative stress (OxS)
The obesity increases the formation of ROS in
adipose cells, shortens telomeres and activates
the p53. This leads to elevated level of cytokines,
insulin resistance, impaired glucose tolerance
and diabetes.
The histological and physiological changes in
aging organs are associated with oxidative
stress, genetic instability and disruption of
homeostatic pathways.
Further, aging has been linked to telomere
shortening and impaired cellular physiology*.
*J Gerontol A Biol Sci Med Sci. 2011. Mather KA, Jorm AF, Parslow RA, Christensen H
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Aging, Obesity and Diabetes Link
With the age, the prevalence of obesity, metabolic
syndrome and diabetes increases.
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Aging, Obesity and Diabetes Link ..2
Physiological and histological changes in
aging organs have been associated with
oxidative stress, disruption of homeo-
static pathways, genetic instability and
telomere shortening.
Diabetes, too, accelerates aging through
certain complex mechanisms, which
include inflammatory pathways. Adipose
tissue from diabetic shows senescence-
like changes.
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Aging, Obesity and Diabetes Link ..3
There are similarities in metabolic dys-
function and dysregulation in diabetes and
aging. Both are associated with oxidative
injury and impairment of insulin secretion
& sensitivity.
In obesity, adipose tissue shows similar
oxidative stress and pro-inflammatory
changes, telomere shortening and elevated
cytokines levels, insulin resistance, imp-
aired glucose tolerance and diabetes..
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Aging, Obesity and Diabetes Link ..4
With improved general hygiene and living
standards, there has been a fall in
infectious diseases and in general, people
are living longer.
But there has been a rise in age-related
illnesses including metabolic disorders
such as diabetes. This has off-set the 20th
and 21st C gains in human life-span.
* Obesity and Aging Link (September 26, 2009)
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Aging, Obesity and Diabetes Link ..5
The incidence of chronic diseases rises with
age. The older adults over age of 65 years :
~80% have one chronic condition, and ~50%
have at least two.
The younger ones with increased visceral fat
mass have a greater risk for DM, HTN, CHD,
neurodegenerative disease, etc. which are
otherwise associated with aging.
Degree of obesity has been correlated with
metabolic disorders, and inversely with life
expectancy.
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Aging, Obesity and Diabetes Link ..6The age-associated decline in glucose metabolism
With aging: Accumulation of adipose
tissue, Diminished lean mass, Metabolic
dysfunctions like elevated blood lipids.
Functional decline in glucose homeostasis:
Elevated fasting glucose levels, Glucose
intolerance, Insulin resistance and T2DM.
Aging affects progression of DM as well.
The clinical obesity, too, carries a similar
risk of metabolic dysfunctions.
*Oxidative stress in the etiology of age-associated decline in glucose Metabolism.
Adam B Salmon, Longevity & Healthspan 2012
Aging, Obesity and Diabetes Link ..7The age-associated decline in glucose metabolism
The adipose tissue is a dynamic endocrine organ and
changes in its function play a significant role in the
aging process as proved by mice experiments.
Aging significantly increases the production of pro-
inflammatory cytokines from macrophages and pre-
adipocytes in adipose tissue, specially WAT.
Chronic inflammation has been proposed to
significantly affect WAT to influence the progression
of several age-related diseases and pathologies,
including the decline in glucose metabolism
homeostasis.
*WHO Data **US National Diabetes Statistics, 2011 23
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Aging, Obesity and Diabetes Link ..8The age-associated decline in glucose metabolism
OxS promotes cellular senescence in adipocytes;
which then secrete pro-inflammatory cytokines.
The pro-inflammatory cytokines including TNFα
and IL-6, inhibit insulin signaling.
OxS disrupts insulin signaling, impairs IR-insulin
binding and reduces its internalization, inhibits
insulin receptor auto-phosphorylation, GLUT4
translocation and glucose uptake.
The age-associated insulin resistance is also due
to diminished function of insulin signaling
proteins.
*Al-Aubaidy H, Jelinek H: Oxidative DNA damage and obesity in T2DM. Eur J Endocrinol 2011
Tale of Obesity & Loss of Physical Fitness
But, u may not act. Fail to consult a fitness expert. Don’t go to this person, called Doctor.
You have piled so many hopes to Realize your Potential, come Obesity, Loss of fitness, and a Chronic Disease; u struggle and adjust urself to an Average Life.
25
We r perpetually afraid of discovering Chronic
disease and Infirmity that come with unhealthy
lifestyle. In the course we deny ourselves Health.
26
Endocrinology of Obesity, Diabetes
and Aging
Adipose tissue is the only endocrine tissue that
does not undergo age-related involution but
rather increases with age. Fat mass, BMI and
percentage of body fat are known to increase
from age 20 years and level off at ~80 years.
WAT produces inflammatory mediators, some of
which then induce adipo-genesis leading to
adipocyte hypertrophy and hyperplasia. Further,
aggravating the WAT-generated inflammation.
* Nature Reviews Endocrinology, April 2013. Oxidative stress & ageing endocrine system
27
Endocrinology of Obesity, Diabetes
and Aging ..2
With aging, there is a progressive decline in
cellular function and physical fitness, and
increased risk of age-related diseases and death.
The endocrine system is involved in modulation
of OxS through several hormones. Conversely,
OxS has a role in the aging of endocrine glands
and pathogenesis of several endocrine diseases*.
The pancreatic endocrine function, too,
deteriorates with age and there is a deficit in beta-
cell mass.
* Nature Reviews Endocrinology, April 2013. Oxidative stress & ageing endocrine system
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Endocrinology of Obesity, Diabetes
and Aging ..3
The β-cells are highly sensitive to OxS because of
their low antioxidant defence. OxS activates
UCPs, resulting in protons leak from
mitochondria. It reduces ATP synthesis and
availability in β-cells, impairing insulin secretion.
The mitochondrial dysfunction is a central
contributor to the failure of β-cell function*.
Simultaneously, there are changes in metabolic
processes, disruption of insulin signaling,
insulin-insulin receptor binding and the glucose
uptake.*β-Cell Mass and Turnover in Humans: Effects of obesity and aging
Yoshifumi Saisho et al Diabetes Care, Jan 2013.
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Endocrinology of Obesity, Diabetes
and Aging ..4
There occurs increased insulin resistance and
decreased β-cell function. Ultimately, leading to
pathophysiological manifestations that cause type
2 diabetes.
There are specific functional changes in
adipocytes, muscle cells, β cells and the liver.
contributing to impaired glucose homeostasis.
OxS-Endocrine interaction is, thus, involved in
development of obesity and metabolic syndrome,
and the ageing phenotype through cellular
senescence*.
* Nature Reviews Endocrinology, April 2013. Oxidative stress & ageing endocrine system
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Whether obesity-mediated aging is
modifiable/reversible?
CRAN has been shown to reduce aging and improve
glucose homeostasis. In response to CR, sirtuins are up-
regulated.
The actions of SIRT1 and AMPK exhibit substantial
overlap. Both are activated in response to exercise,
fasting, and CR. Their activities are diminished by high-fat
diet, with obesity and insulin resistance.
Like the effects of AMPK activation, SIRT1 activity lowers
blood glucose, improves insulin sensitivity, decreases
hepatic triglycerides, and increases fatty acid oxidation.
*WHO Data **US National Diabetes Statistics, 2011
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Whether obesity-mediated aging is
modifiable/reversible? ..2
SIRT1 is sensitive to changes in intracellular redox state.
AMPK is a master regulator of cellular energy homeostasis
and is activated in response to stresses that deplete cellular
ATP.
CR has been the most successful means so far to extend
lifespan of many species in experiments. It prevents
Obesity, insulin resistance and elevated
insulin levels, and diabetes.
CRAN postpones many signs of aging
and protects against many
age-related diseases.
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