time

Time, September 4,
2000
newsweek6
Newsweek, September 4,
2000
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PRESENATATION BY
DR MISBAHUL FERDOUS
MBBS(USTC)
FMD (USTC)
PGT (CARDIOLOGY) NICVD.DHAKA
PUBLICATION- 1 (ORIGINAL ARTICLE)
METABOLIC SYNDROME AND ACUTE ST ELEVATION MI IN HOSPITAL
OUTCOME.
PUBLISHED IN B.H.J. JANUARY-2008
MD (CARDIOLOGY), COURSE
SHANDONG UNIVERSITY, CHINA.

Key words
Insulin resistance
Metabolic syndrome
Leptin
Adiponectin
resistin

Histological slide of pancreatic islets cell

5
insulin granule
Electron micrograph showing release of insulin
from . cell

C:\Documents and Settings\Ali\Desktop\adepocytokine\picture\sugar.gif

History os insulin resistance

Insulin resistance may be the underlying cause
of diabetes mellitus type 2 was first advanced
by Prof. Wilhelm Falta and published in
Vienna in 1931

THIS theory confirmed by Sir Harold Percival

Himsworth of the University College Hospital
Medical Centre in London in 1936.

Definition:
Insulin resistance is defined as a failure of
target organs to respond normally to the
action of insulin.
Insulin resistance is a condition in which cells,
particularly those of muscle, fat, and liver
tissue, display "resistance" to insulin by failing
to take up and utilize glucose for energy and
metabolism .

Factors Contributing to Insulin Resistance

Factors Contributing to Insulin Resistance

Genetics
&
Aging

Acquired

Acquired:
Central obesity
Sedentary
lifestyle
High fat diet
Medications

2006 General Mills, Inc.

DRUGS and GENETIC CAUSES OF

INSULIN RESISTANCE
Drugs :
rifampicin, isoniazid, olanzapine, risperidone,
progestogens, corticosteroids,
glucocorticoids,

Genetic causes
1.Insulin receptor mutations (Donohue Syndrome)

Insulin Resistance: Inherited and

Acquired Influences
12
Rare Mutations
Insulin receptor
Glucose transporter
Signaling proteins
Common Forms
Largely unidentified
Inactivity
Over eating
Aging
Medications
Obesity
Elevated FFAs
Acquired
Inherited

How Is Insulin Resistance

Measured?
How Is Insulin Resistance Measured?
Determination of insulin resistance is difficult
Generally measured in terms of the glucose-lowering effects
of insulin
Two common methodologies:
Hyperinsulinemic, euglycemic clamp (EHC): gold standard:
insulin and glucose infused; steady state when glucose
infusion equals rate of glucose disposal rate (GDR)
Homeostasis Model of Assessment (HOMA): fasting glucose
and insulin measured for calculation of insulin sensitivity

McClenaghan, 2005
2006 General Mills, Inc.

Preventing Type 2 Diabetes

Three Levels of Opportunity
Robust B-cells
Hyperinsulinemia
Weak B-cells
Hyperglycemia
Adipose
Tissue
Liver &
Muscle
Energy Balance
NegativeeE
Positive
Weight Loss
Fat
Accumulation
Adipokines
Fatty Acids
Insulin Resistance

Metabolic Syndrome, Insulin Resistance, and Atherosclerosis

MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.
Hyperinsulinemia/hyperproinsulinemia
Glucose
intolerance
Increased
triglycerides
Decreased
HDL cholesterol
Increased BP
Endothelial dysfunction
Small, dense
LDL
Atherosclerotic
cardiovascular
disease
Increased
PAI-1
Insulin resistance

Metabolic Syndrome
Metabolic Syndrome

Also known as:

Insulin Resistance Syndrome
Dysmetabolic Syndrome
Syndrome X
The Deadly Quartet
metabolic risk factors associated with
Type 2 diabetes (5-fold higher risk)
Cardiovascular disease (2-fold higher risk)
Underlying risk factors are abdominal obesity and
insulin resistance

Grundy et al., 2005; Kahn et al., 2005

2006 General Mills, Inc.

The

Metabolic Syndrome

Also known as:

Syndrome X
Insulin Resistance
Syndrome
The Deadly Quartet
The Dysmetabolic
Syndrome

789
Glucose
Intolerance,
Diabetes
Visceral
Obesity
Hypertension
Dyslipidemia

Prevalence of Metabolic Syndrome

Prevalence of Metabolic Syndrome
24%- 50%
50% with
85% with
87% with

with coronary heart disease

hypertension
low HDL and high TG
type 2 diabetes

Affects nearly of adults

Ford et al. 2002; Alexander et al., 2003; Duncan et al., 2004
2006 General Mills, Inc.

Metabolic
Syndrome
Dyslipidemia
Hypertension
Glucose
Intolerance
Grundy et al., 2005; Kahn et al., 2005
Metabolic Syndrome
Metabolic Syndrome
Insulin Resistance Abdominal Obesity
Genetic
Lifestyle
2006 General Mills, Inc.

Diagnosing Metabolic Syndrome

Waist Circumference
oGreater than 35 inches in women and 40 inches in men (abdominal obesity)
Triglyceride
oLevels of 150 milligrams per deciliter (mg/dl) or higher
Blood Pressure
o130/85 millimeters of mercury or higher
Fasting blood glucose
oLevel of 110 mg/dl or higher
High-density lipoprotein cholesterol (HDL)
oLower than 50 mg/dl in women and 40 mg/dl for men

PBRC 2009
According to the National Cholesterol Education Program (NCEP), the presence of
three or more of the following traits indicates metabolic syndrome:
heartmetabolism_9476

Diagnosis of metabolic syndrome

The American Association of Clinical Endocrinologists (AACE)

clinical criteria for diagnosis of insulin resistance syndrome include
the following:
BMI of 25 kg/m2 or higher
Triglyceride level of 150 mg/dL or higher
HDL-C level of less than 40 mg/dL in men or less than 50 mg/dL in
women
Blood pressure of 130/85 mm Hg or higher
Glucose level of more than 140 mg/dL 2 hours after administration of
75 g of glucose
Fasting glucose level of 110-126 mg/dL

Treatment of metabolic syndrome

Lose weight
oLosing as little as 5 to 10% of your body weight can reduce insulin levels and
high
blood pressure, thus reducing your risk of diabetes.
Exercise
oWalking just 30 minutes a day or engaging in other aerobic activities can help
prevent the serious diseases associated with MS.
Stop smoking
oSmoking cigarettes increases insulin resistance and worsens health
consequences associated with MS.
Eat fiber-rich foods
oWhole grains, beans, fruits and vegetables are high in dietary fiber.
These are important foods to eat since dietary fiber is known to
lower insulin levels.

PBRC 2009
Although metabolic syndrome creates a real risk for developing diabetes, stroke
or heart disease,
these conditions can be prevented. Metabolic syndrome can be controlled by the f
ollowing: no_smoking
High_Fiber_Diet
scales

Adipose tissue act as an endocrine organ

(1) Adipose tissue is secrete free fatty acids
(FFA) ,which have well described physiological
and pathophysiological effects on glucose
homeostasis

(2) secrets proteins, termed adipocytokines,

that act in an autocrine, paracrine, or endocrine
fashion to control various metabolic functions

-Adipose tissue is an anatomical term for loose connective tissue composed

of adipocytes (or fat cells).
Adipose tissue adipose tissue copie.jpg
-Its main role is to store fatty
acids in the form of
triglycerides, thus providing
the organism with effective
fuel storage
-besides that it cushions and
thermally insulates the body.
Adipose tissue Adipocyte + capillary

adipose tissue
-adipose tissue has an important endocrine function as it produces
adipokines and inflammatory mediators, amongst others, leptin,
adiponectin, resistin , adipsin, TNFa, IL-6 and PAI-1
Because of the production
of inflammatory
mediators, an excess of
adipose tissue leads to a
chronic mild
inflammatory-state that
may play a role in late
onset diabetes (insulin
resistance). adipocytes umich-edu.jpg
adipose subcutaneous copie.gif
subcutaneous
adipose tissue
mouse adipocytes

Normal
Tabetes
Courtesy of Wilfred Y. Fujimoto, MD.
Visceral Fat Distribution:
Normal vs Type 2 Diabetes

LEPTIN
Four-helix bundle
Size 2,0x2,5x4,5 nm
Cys-96 <-> cys-146
Product of the obese gene (ob) , conserved
residues in purple colour (receptor binding
sites not yet determined)
PDB : 1ax8 conserved residues leptin + domain architecture.jpg

LEPTIN
Greek word leptos meaning thin .
First discover in 1994 .
Leptin is a 167-amino acid protein
secreted by adipocytes in proportion to adipocyte
tissue mass .

The Ob(Lep) gene [Ob for obese, Lep for leptin] is

located on chromosome 7 in humans.

Synthesis of Leptin
1. White adipose tissue :major source of leptin
1. brown adipose tissue,
2. placenta (syncytiotrophoblasts)
3. ovaries,
4.skeletal muscle
5. stomach (lower part of fundic glands)
6.mammary epithelial cells,
7.bone marrow
8. liver.

Leptin structure
.146 a.a residue non glycosylated polypeptide
.Member of helical cytokine family

PRIMSTRUC
PRIMSTRUC2
PRIMSTRUC3
Primary structure of leptin

FUNCTION OF LEPTIN
key role in regulating energy intake and
energy expenditure, including appetite and
metabolism.
Leptin circulates at levels proportional to body
fat.
It controls food intake and energy expenditure
by acting on receptors in the mediobasal
hypothalamus
There are five Ob-R isoforms; the best
characterized one is Ob-Rb, which activates
the Jak-Stat signal transduction pathway

Leptin receptor(s)
Synonym: receptor for obesity facto, Ob-R leptin receptors model.jpg

focus on leptin signalling

Leptin receptor dimerization.jpg

focus on leptin signalling

Leptin receptor dimerization.jpg

Hypothalamus
arcuate nucleus
Leptin
receptor
JAK-STAT
Appetite is
suppressed
CNS
Adipose
Adipose stores are HIGH
Leptin
Periphery
+
Metabolic activity
increases to burn fat
Figure 2. The leptin signaling system and its effects when adipose stores are "h
igh"
.MSH
POMC:
pro-opiomelanocortin
(from peptide-amine hormone
biosynthesis lecture)
Wide upward diagonal
Large checker board
.MSH
.

Appetite is
enhanced
CNS
Adipose
Adipose stores are low
Leptin
receptor
JAK-STAT
. Leptin
Figure 2. The leptin signaling system and its effects when adipose stores are
"
. Metabolic activity decreases
limiting fat burning
+
Periphery
Hypothalamus
. .MSH
. AGRP from hunger neurons
Block .MSH binding

low

congenital leptin deficiency human)

- voracious appetite

- morbid obesity

- immunosuppression

- hypothalamic hypogonadism

LEPTIN AND INSULIN RESISTANCE

Mice that are deficient in leptin (ob/ob) exhibit
hyperphagia, obesity,hypercortisolemia,infertility,and
diabetes.
Exogenous leptin administration reverses these
abnormalities
Leptin may also improve insulin sensitivity by directly
acting on peripheral tissues such as skeletal muscle
and liver

ADIPONECTIN
Adiponectin is a 247-amino acid
It has multiple name, like-AcrP30,AdipoQ, apM1,
and gelatin binding protein.
In human cross-sectional studies, plasma adiponectin
levels are negatively correlated with obesity
,adiposity, and waist to hip ratio, diabetic
dyslipidemia,CVD, and insulin resistance .
Adiponectin knockout mice showed high levels of
TNF-a and increased insulin resistance.

Low plasma adiponectin was an independent risk

factor for future development of type 2 diabetes .
Adiponectin may play a causative role in the
development of insulin resistance and the metabolic
syndrome.
The mechanisms by which adiponectin may
ameliorate insulin resistance have not been fully
elucidated.
One proposed mechanism is that adiponectin
decreases circulating FFA by increasing fatty acid
oxidation in skeletal muscle This results in
decreased triglyceride content in muscle that has
been associated with improved insulin sensitivity

KEY MESSAGE ABOUT ADIPONECTIN

Adiponectin is an adipocyte-derived plasma
protein with insulin sensitizing,
antiinflammatory, and antiatherogenic
properties.
Although its physiological and
pathophysiological role has not been fully
elucidated.
its low levels in insulin resistance states
suggest that therapeutic modulation of
adiponectin may provide a novel treatment
modality for insulin resistance.

RESISTIN
Grrr.png
Crystallographic structure of a hexamer of mouse resistin
(rainbow colored, N-terminus = blue, C-terminus = red).

RESISTIN
Resistin is a adipocyte-secreted polypeptide.
first described in 2001 by the group of Dr Mitchell
A. Lazar from the University of Pennsylvania
School of Medicine
Resistin is a member of a family of tissue-specific
signaling molecules,called resistin-like molecules .
The resistin mRNA encodes a 114-amino acid
polypeptide with a 20-amino acid signal
sequence.
Resistin is secreted as a disulfide-linked dimmer.

Resistin, a novel 12.5 kDa cysteine-rich protein, is

secreted by adipocytes.

Serum resistin levels are significantly increased in

insulin-resistant mice and genetic or diet-induced
obese mice

In addition, neutralization of endogenous resistin

with antibodies significantly suppresses
hyperglycaemia in diet-induced obese mice by
improving insulin sensitivity.

TNF-a
TNF-a is a proinflammatory cytokine that has
been implicated in the pathogenesis of insulin
resistance.
Increased TNF- a production has been
observed in adipose tissue derived from
animal models of obesity and insulin
resistance as well as human subjects

probable mechanisms by which adipose

tissue TNF- a increases insulin resistance is1. increased release of FFA by adipocytes
2. reduction in adiponectin synthesis
3. impairment of insulin signaling
Additional human studies are needed to
understand its role in the pathogenesis of
insulin resistance in humans.

LIPODYSTROPHY AND INSULIN RESISTANCE

in the absence of adipose tissue,excess
calories cannot be diverted to normal storage
depots(adipocytes)
Than they accumulate, instead as triglyceride
stores in liver, skeletal muscle, cardiac muscle,
and pancreatic islet cells.
Abnormal intracellular TG accumulation leads
to impaired insulin secretion and action,
leading to diabetes

leptin levels are very low in generalized

lipodystrophy.
low leptin levels correlate significantly with
markers of insulin resistance.
In lipodystrophic patients, leptin replacement
therapy improved glycemic control and
decreased TG levels .
Leptin treatment improved insulin-stimulated
hepatic and peripheral glucose metabolism and
was associated with a reduction in hepatic and
muscle TG content.

SUMMURY
The mechanisms by which adipocytokines
promote insulin resistance are still complex,
and our understanding incomplete.
the presence of adipose tissue is vital in the
prevention of insulin resistance, at least in
part, via secretion of the following cytokines:
leptin and adiponectin.

Finally, determining the relative contribution

of adipocytokines to glucose homeostasis and
insulin resistance and elucidating the dynamic
interactions between adipocytokines should
be a focus of our research in the future.

The END!
Thank You!
Oh, sorry, not the END, just the beginning!
53
Email: misbahul_ferdous@yahoo.com
house no: 26. house name:TAKHDIR.
SUGANDHA. R/A ,CHITTAGONG
BANGLADESH