Guest Lecture at University of Delhi - The Entangled Relationship between Diabetes, Obesity, Metabolic syndrome and Aging

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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.

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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

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The Ingredients of Metabolic Syndrome

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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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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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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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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


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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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.

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We r perpetually afraid of discovering Chronic

disease and Infirmity that come with unhealthy

lifestyle. In the course we deny ourselves Health.

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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

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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.


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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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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*.


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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.

Health & Medicine

Guest Lecture at University of Delhi - The Entangled Relationship between Diabetes, Obesity, Metabolic syndrome and Aging