Lesson 3.2 :
Relationship of Nutrition to Blood
Glucose Control
The pancreatic secretory cells
Insulin (b-Cells)
Somatostatin
Glucagon
Insulin peptides
ER
Proinsulin
Golgi
Insulin
C peptide
Pre/pro-hormone (11,500
kDa)
Pro-insulin (9,000 kDa)
ER
Insulin (6,000kDa) +
Peptide C
Golgi
Enter the secretory
granules
Exit by exocytosis
Blood (t 1/2= 6 min)
Action: via insulin
receptors
Mechanism of insulin secretion
2
1 Glucose
?
4
Glu
3 Ca2+
Beta cells
Ca2+
Insulin
Insulin
b-Cell
1. Glucose uptake 2. Membrane depolarization
3. Calcium uptake 4. Exocytosis
Control of Insulin Secretion

Primarily in response to elevated blood glucose
and other fuel molecules (AA and FA)
Glucosemetabolism
Pancreas
Cell
Insulin
Receptor
Glucose
Gastrin
Parasympatetic
activity
CCK
Amino Acids
Glucagon
Glucose
Insulin Secretion
Lipoprotein
lipase
activated
Cellular
transport
activated
Catabolic enzymes
inhibited
Anabolic
enzymes
activated
Glucagon secretion
inhibited
General actions and
regulation of insulin
Intestine
Glucose
Fatty acids
Amino acids
Glycogen
Liver
Insulin
Triglycerides
Glycogen
Triglycerides
Proteins
Proteins
Muscle
Most cells
Adipose
Role of insulin
during absorptive
metabolic states
(feeding)
Glycogen
Ketones
Neurons
Energy
Liver
Glucose
Triglycerides
Fatty Acids
Glycogen
Triglycerides
Proteins
Proteins
Proteins
Muscle
Most cells
Adipose
The post-absorptive
metabolic states
(fasting)
Glucose-Insulin Relationship
 Insulin
decreases the concentration of glucose in the
blood, and as soon as the blood glucose
concentration falls the insulin secretion ceases (they
regulate each other).
 In the absence of insulin, most cells switch to
alternative fuels like fatty acids and proteins.
• CNS, however, require a constant supply
of glucose, which is provided from
glycogen degradation.
Effects of insulin on GLUT4 in the muscle and fat
 Stimulation
of uptake, utilization and storage of glucose.
 The major transporter for uptake of glucose is GLUT4.
 GLUT4 is translocated to the plasma membrane through
the action of insulin.
 Insulin stimulates the fusion of GLUT4 vesicles with the
plasma membrane.
 When blood levels of insulin decrease, the GLUT4
transporters are recycled back into the cytoplasm.
Insulin Action in Muscle and Fat Cells
Mobilization of GLUT4 to the Cell Surface
Plasma membrane
Insulin
receptor
Intracellular
signaling
cascades
Intracellular
GLUT4 vesicles
Insulin
GLUT4 vesicle mobilization
to plasma membrane
GLUT4 vesicle
integration into
plasma membrane
GLUT4=glucose transporter 4
Glucose
Glucose entry into cell
via GLUT4 vesicle
Insulin in the liver: stimulation of glucose storage by
glycogenesis


Insulin stimulates glucose storage
• Glucose uptake
• Glucose phopshorylation
(glucokinase)
• Enzymes involved in glycogenesis,
including glycogen synthase.
Insulin inhibits glycogen degradation
• glucose-6-phosphatase
Insulin and Lipids: promotion of FA synthesis and lipid storage
When the liver become saturated with
glycogen, insulin
 promotes synthesis of fatty acids.
• lipids are
exported as
lipoproteins.
glucose

inhibits breakdown of lipids in
adipose tissues
• by inhibiting the
hormonesensitive lipase

facilitates entry of glucose to
synthesize glycerol
From the whole body perspective
Insulin has a fat-sparing effect:
 It drives most cells to preferentially oxidize
glucose instead of fatty acids for energy.
 It stimulates accumulation of lipids in adipose
tissue.
Insulin Receptor




a tyrosine kinase
binding of insulin causes
autophosphorylation
the activated receptor
then phosphorylates
intracellular proteins
the best known
substrate: insulin
receptor substrate 1 or
IRS-1
INSULIN signaling downstream of IRS:
Insulin receptor
Insulin
Grb
Sos
Ras
IRS
Grb
Sos
PI3 kinase
PIP3
Akt
Forkhead TF
Gene expression
PTEN
Islet cells
glucokinase
Glucokinase
?
glucose 6-phosphate/xylulose 5-phosphate
Liver
glucose/insulin
responsive
genes
GIR-glucose and insulin responsive
pIP-only insulin responsive
purely insulinresponsive
?
Organspecific
actions of
glucose and
insulin
Adipose
?
Glut4
Hexokinase
Glucose and insulin regulate insulin gene expression
a signaling metabolite
Glucose
PI3K
Insulin
Insulin receptor
SAPK
Insulin
Insulin receptor
substrates
Wortmanin
Inhibitors
b-Cell
Other Effects of Insulin
 Insulin
stimulates the uptake of amino acids
(an anabolic effect) (+)
 At low insulin (fasting state), the metabolism is
pushed toward protein degradation.
 Insulin increases the cellular uptake of K, Mg and P
• K influx is clinically important in diabetics
–Insulin activates Na/K pumps and decreases K
in plasma
Glucagon
Physiologic Effects of Glucagon
Stimulation of glucose
production in the liver.
When blood glucose levels begin to fall,
glucagon



stimulates glycogenolysis in the liver by activating
enzymes that hydrolyze glycogen and release glucose.
activates hepatic gluconeogenesis- the conversion of
amino acids to glucose.
enhances lipolysis of triglyceride in adipose tissue as an
additional way of conserving blood glucose.
Sympathetic
activity
Secretin
CCK
Parasymathetic
activity
 cells
Amino Acids
Insulin
General actions and
regulation of glucagon
Glucose
Glucagon secretion
Fatty acids
and ketones
Inhibition of
anabolism
Glycogenolysis
Gluconeogenesis
Secretion of Insulin
Abnormalities in Blood Glucose Control
Fasting hyperinsulinemia & hyperglycemia
 Fasting hyperinsulinemia
 Fasting or postprandial hypoglycemia

Dietary intakes influence blood glucose
levels by:

Contributing exogenous glucose (glycemic load)
• digestible carbohydrates

Stimulating insulin secretion
• glucose, amino acids

Facilitating insulin function
• chromium, zinc, magnesium, potassium

Affecting tissue insulin sensitivity
• simple sugars, fat, energy
• body fat distribution
Consequences of Hyperinsulinemia
and Hyperglycemia

Hyperinsulinemia
• increased SNS activity
• altered smooth muscle
cell Ca++ transport
• increased renal sodium
retention
• mitogenic effects on
smooth muscle cells
• increases plasminogen
activator inhibitor-type 1

Hyperglycemia
• responsible for cellular
injury/tissue damage
underlying complications
of poorly controlled
diabetes
Role of Diet in Control of Blood
Glucose Abnormalities
Prevention
• inhibits
• delays
Contribution
• accelerates
• exacerbates
Management
• primary treatment
• adjunct treatment
Dietary modifications to control blood
glucose are involved in management of :
•
•
•
•
•
•
•
diabetes mellitus
hypertension
hyperlipidemia
liver disease
renal disease
cancer
obesity
• trauma
• sepsis
• medication side effects
–
–
–
–
hydrochlorothiazide
prednisone
chlorpropamide
propranolol
The Postprandial Blood Glucose
Response
Blood glucose (mg/dL)
200
180
160
140
120
100
80
60
0
15
30
45
90
Minutes
120
150
180
Blood Glucose Response to Different
Sources of Carbohydrate
Blood glucose (mg/dL)
220
200
180
Typical
Simple Sugar
Soluble Fiber
Starch
160
140
120
100
80
60
0
15
30
45
90
Minutes
120
150
180
Steps in Development of Insulin
Resistance from High Glycemic Load
Rapid rise in
blood glucose
to high levels
Release of
corresponding
high amount
of insulin
Rapidly digested &
absorbed CHO with
high energy density
Step 1
Step 2
Insulin peaks at
level consistent with
blood glucose levels
Step 3
Step 4
Repeated bouts
of high
insulin levels
Downregulation of
insulin receptors
Step 5
Summary of Presentation
Introduction:
Insulin Resistance/Metabolic Dyslipidemia
Recent Observations
Animal Model of Insulin Resistance
(Fructose-Fed Syrian Golden Hamster)

Evidence for Hepatic VLDL Overproduction

Evidence for Hepatic Insulin Resistance

Evidence for Intestinal Lipoprotein Overproduction
Insulin Resistance
The diverse biological manifestations of the insulin
resistant state arise as a consequence of both
a blunted insulin action as well as the compensatory
hyperinsulinemia per se.
Insulin
Pancreas
Increased insulin action
in more sensitive tissues
or biochemical pathways
Insulin resistant
peripheral tissues
Clinical spectrum of
insulin resistant states

Rare (genetic) forms of insulin resistance

Obesity (central, abdominal, visceral, android)

Fasting hyperglycemia/Impaired glucose
tolerance

Type 2 diabetes mellitus
Putative Candidate Gene Mutations in
Insulin Resistance
Glucose Metabolism
Insulin Sensitization/
desensitization
• Glut 1
Lipid Metabolism
• Glut 4
• Hormone Sensitive Lipase
• PPAR g
• Hexokinase II
• ISPK-1
Insulin Action
Obesity
• GSK-3(
GSK-3(,b)
• Insulin Receptor
• Leptin
• PPIC (
(,b,g)
• IRS-1/2
• Leptin Receptor
• PPIG
• Shc
• b2-adrenergic receptor
• Glycogen Synthase
• PI3-kinase
• UCP-1
• GS-inhibitor-2
• UCP-2
• Protein Kinase B (
(,b)
• Glycogenin
• NPY
• Phosphofructokinase
• NPY receptor isoforms
Disorders associated with insulin resistance






Dyslipidemia
Hypertension
Polycystic ovarian disease
Hyperuricemia
Thrombogenic/fibrinolytic abnormalities
Atherosclerosis
Features of Metabolic Dyslipidemia
• Hypertriglyceridemia
TG, ApoB
VLDL-TG and VLDL-apoB secretion
Small Dense LDL
( LDL particle density)
• Reduced HDL-C
• Increase FFA
Mechanisms of VLDL overproduction
in Insulin Resistance
Adipose tissue
Intestine
LPL
TG mobilization
by tissue lipases
Hepatic
Insulin Resistance
FFA
Liver
DNL
FA
Muscle
Lipases
Oxidation
ApoB
TG, CE
Cytosolic TG
stores
Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425.
Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.
VLDL
Diet and Insulin Resistance
Diet -induced/responsive
 adaptive response to repeated
exposure to postprandial
hyperinsulinemia
Diet-responsive
 post-receptor defect in signal
transduction
• glucose transporter
synthesis/activity
• changes in membrane
fluidity and integrity
• downregulation of insulin
receptors

decreased hepatic insulin
clearance

increase in stress hormones
• injury
• sepsis
Characteristics of Insulin Resistance
Obesity vs DM2

Obesity
• peripheral effects
• hepatic glucose output
unaffected
• nonoxidative glucose
disposal decreased

DM2
• peripheral effects
• hepatic glucose output
not suppressed
• adipocyte lipogenesis
and oxidative glucose
metabolism affected
Glycemic Load
Described by the area under the curve (AUC) of
blood glucose vs time after ingestion
 Characteristic of type of carbohydrate
 A function of energy intake
 Influenced by rate of gastric emptying
 Reflects efficiency of digestion
 Reflects rate of absorption

The Glycemic Index
 Physiological
measure of effects of foods on
blood glucose
 Calculated as the AUC of a test food
expressed as a percentage of the AUC of a
glucose standard
 Compares foods based on equivalent amounts
of available CHO
 Characteristic of foods, not individuals
Glycemic Index of Mixed Meals
 Glycemic
indexes calculated for individual
foods
 Individual foods weighed by a factor based on
percentage of carbohydrate contributed by the
food to the total carbohydrate content of the
meal
 Accurately predicts differences in blood
glucose responses to different meals
Glycemic Indexes of Various Foods
(Equivalent Amounts of Available
CHO)
Food
White bread
Whole wheat bread
Rice
Cornflakes
Oatmeal (coarse)
Spaghetti
Potatoes (boiled)
Lentils
Chickpeas
Kidney beans
AUC mg/L at
3 hours
866
811
652
954
424
583
638
263
263
258
Standard
x 100
100
94
75
110
49
67
74
30
30
30
Clinical Significance of Glycemic Index
Low Gl Foods
• decrease insulin secretion
• improve blood glucose
control in DM2/DM1
• normalize blood glucose,
insulin & amino acid
levels in cirrhosis
Low GI Foods/Meals
• increase satiety
• enhance performance
Glycemic Effect Depends on Nutrient
Composition

Simple sugars

• solubility


• fatty acid
composition
Starches
• digestibility
Fiber
• viscosity
Fat

Protein
• amino acid
composition
Carbohydrate and Blood Glucose
Control
Simple Sugars
 high solubility = high load
 liquids > solids
 diminished by fiber
 enhanced by high energy
intake
 enhanced by Na+
Starches
 high digestibility = high
load
 amylopectin > amylose
 amylose > resistant starch
 refined starch > simple
sugars + fiber
Simple Sugar (SS]
+ or - Soluble Dietary Fiber (SDF)
Blood glucose (mg/dL)
220
200
180
160
Standard
SS
SS & SDF
140
120
100
80
60
0
15
30
45
90
120 150 180
Minutes
Blood Glucose Response:
Starch+ or - Soluble Dietary Fiber
(SDF)
Blood glucose (mg/dL)
200
180
160
Standard
Starch
Starch & SDF
140
120
100
80
60
0
15
30
45
90 120 150 180
Minutes
Viscous (Soluble) Dietary Fiber and
Blood Glucose Control

Decreases rate of digestion
• slows access of digestive enzymes

Decreases rate of absorption
• slows rate of diffusion across unstirred layer
Found in small amounts in all plant foods
 Richest source are oats, barley, citrus fruit,
legumes, psyllium

Energy Intake and Blood Glucose
Control
Contributes to weight gain/loss
 Contributes nutrients that affect insulin
 Contributes to abdominal fat deposition

• high portal concentration of free fatty acids
inhibits hepatic insulin clearance
• higher insulin requirement for glucose uptake
Exercise and and Blood Glucose Control
•
•
•
•
inhibits weight gain
increases muscle mass/fat mass ratio
mobilizes free fatty acids from adipocytes
increases skeletal muscle uptake of FFA
– enhances glycogenesis for 24-48 hours
Fat and Blood Glucose Control
Total Fat
 slows gastric
motility/emptying
 predisposes to weight
gain
 effects exaggerated if
abdominal obesity
present
Type of Fat
 saturated fat
•  membrane fluidity
•  number of glucose
transporters

polyunsaturated fat
• -3  insulin sensitivity

monounsaturated fat
• stimulates insulin release
Protein and Blood Glucose Control

Influences insulin/glucagon ratio
• blood glucose
• tissue protein accretion
• cholesterol synthesis
– HMG-CoA reductase

High arginine/lysine ratio stimulates insulin
Micronutrients and Blood Glucose
Control
Glucose Tolerance
Potassium
Magnesium
Chromium
Vitamin E
Cofactors for
oxidative & nonoxidative
glucose metabolism
Improves insulin response
in malnourished children,
middleaged adults, IDDM,
& healthy adults
Protects cell membrane
from lipid peroxidation
Improves both
hypoglycemia &
hyperglycemia after 2 mos
of supplementation
900 IU/d increases
fasting & 2 hr insulin
& stimulates nonoxidative
glucose metabolism
Meal Patterns and Blood Glucose
Control

Favorable Effects
• frequent small meals
• low-moderate glycemic
loads
• low energy density
• consumed prior to or
following periods of
activity

Unfavorable Effects
• few large meals
• frequent meals
contributing high
glycemic loads
• consumed prior to period
of inactivity
Summary
Diet can affect short-term insulin response
 Diet can affect long-term insulin response
 Glycemic response is not a simple function of
amount and type of carbohydrate
 Glycemic response can be affected by nutrients
other than carbohydrate

Blood glucose (mg/dL)
Comparison of Insulin Responses with
Different Patterns of Blood Glucose
240
220
200
180
160
140
120
100
80
60
Glucose
Insulin A
Insulin B
Insulin C
0
15
30
45
90
Minutes
120
150
180
Diabetes and Obesity
- Type 2 diabetes (90% of diabetes cases) is
strongly linked to obesity
- >80% of sufferers are obese
- Insulin is less able to promote the uptake of
glucose into muscles and fat, and to inhibit the
production of glucose by the liver
- How increased energy storage in adipocytes
promotes insulin resistance in other organs is
not known
Lipotoxicity
 Lipolysis
 FFA Mobilization
Muscle
 FFA Oxidation
Pancreas
Liver
 FFA Oxidation
 Insulin Secretion
 Gluconeogenesis
 Glucose Utilization
Hyperglycemia
What is Leptin?


A peptide hormone which is coded for by the obese gene (ob)
Influences the quantity of food consumed relative to the amount of energy
expended
• When leptin levels are high, appetite is reduced and energy expenditure is
increased

Leptin has been found in gastric epithelium, placenta and adipose tissue
• Most abundant in white adipose tissue
White Adipose Tissue (WAT)




Composed mainly of adipocytes (fat cells)
• Store energy in the form of triglycerides in times of nutritional affluence
• Release free fatty acids during nutritional deprivation
WAT mass is determined by the balance between energy intake and
expenditure
• This is influenced by genetic, neuroendocrine, and environmental factors
Under normal conditions this system is carefully regulated so that WAT mass
remains constant and close to well defined ‘set point’
Disruption of the steady state can lead to chronic decreases or increases in the
quantity of WAT
• Decreaased amounts are associated with weight alterations during peroids
of diet, malnutrition, eating disorders, etc
• Increased amounts indicate obesity
How Does Leptin Interact?
Leptin System:
Regulating Food Intake and
Energy Expenditure





Leptin binds to its receptor which is expressed primarily in the
brains hypothalamus region
In turn the hypothalamus modulates food intake and energy
expenditure
When low leptin levels are detected, the body is warned of limited
energy supplies
If high leptin levels are detected, the hypothalamus senses the body
as being overweight
• This then trigger the body to eat less and expend more energy
When energy intake and output are equal, leptin reflects the amount
of triglyceride stored in the bodies adipose tissue
Metabolic Affects of Leptin

Decreases intracellular lipid concentration through reduction of fatty acid
and triglyceride synthesis and a concomitant increase in lipid oxidation

It has been postulated that leptin inhibits acetyl-CoA carboxylase
•

This inhibition leads to decrease in malonyl-CoA levels
•

Enzyme involved in the committed step of fatty acid synthesis
Together the inhibition of acetyl-CoA to malonyl-CoA encourages the mobilization
of fatty acids from storage sites and simultaneously discourages synthesis
Carnitine acyl transferase I, which is normally inhibited by malonyl-CoA,
is then available to aid in lipid oxidation
•
•
This enzyme is required for the transport of Acyl CoA molecules across the inner
mitochondrial membrane
Without this step, fatty acid breakdown is inhibited
Leptin deficiency and receptor defects in rodents cause
marked obesity as well as hyperglycemia and
hyperinsulinemia
Experimentation on Mice








Mice leptin has an 84% resemblance to human analog
Some obese mice have been found to have mutation in ob gene caused by
premature stop codon
• Results in absolute lack of leptin which leads to severe obesity
Experimentation done on both obese and normal mice
Intravenous, intraperitoneal, an intracerebroventricular injections were given
Results most significant for intracerebroventricular injections
• All mice showed affected
• Lower dosages required
Varying degrees of body weight loss related to dosage and time
Decreased food intake and metabolic rate increased
Significant amounts of WAT mass lost
Experimentation on Humans






Few experiments done at this point
Leptin is said to circulate freely or attached to a binding protein
• It has been found that obese individuals have more circulating
bound leptin than lean individuals
The greater the initial level, the more it declines with dieting
Levels tend to vary greatly from person to person
Typically females have more leptin than males
• Adipose tissue accounts for 20-25% of weight in females and only
15-20% in males
In general the greater the body mass and percent body fat, the higher
the levels
• People suffering from obesity have extremely high levels
How does Leptin work in Obesity
Appears that leptin is primarily a signal that is
active in response to insufficient energy
supply rather than one that is activated to
prevent an oversupply of energy
 Apparent ineffectiveness of leptin in obese
persons despite high circulating levels raises
questions of whether "leptin resistance" is
operating in these individuals & whether it
can be overcome to benefit overweight
patients

Possible Reasons For Increased
Leptin In Obese Individuals

Differences in the fat production rate of leptin
• Some obese people may make leptin at greater rate to compensate
for faulty signaling process or action

Resistance to leptin at its site of action
• If resistance is partial, not complete, more leptin may be required
for action



A combination of both could influence eating behaviors and
energy use to cause obesity
All these possibilities indicate that obese individuals are in a state
of percieved starvation
Leptin responsible for adaptation to low energy intake rather than
a brake on over-consumption and obesity
• Regulated by insulin induced changes of adipocyte metabolism
• Fat & fructose intake do not initiate insulin secretion – reduce
leptin levels leading to overeating and weight gain in population
with high intake of these macronutrients
What research has told us about Leptin


It was quickly apparent that leptin is generally ineffective
as signal for excessive body fat, since obese people
generally have higher, not lower, levels of leptin, but yet
remain obese
Probably more important role of leptin is to signal to body
that body fat has fallen to dangerously low levels (for
example during starvation) & thus signal that appropriate
metabolic changes should occur to preserve metabolic
resources. This current view of leptin was supported by the
results of clinical trials of leptin on overweight individuals.
What research has told us about Leptin
Over 200 candidate genes for obesity-most
remain unidentified in humans
 Considerable amount of research has focused on
hypothetical link between obesity & type 2
diabetes in region of leptin receptor gene
 But sequence variations that have been detected
have not yet been linked to body fat mass

What we know about Leptin
Women have higher leptin levels than men, even
after accounting for estrogen status (e.g., there
are no consistent differences among
premenopausal women, postmenopausal women,
and postmenopausal women on estrogen
replacement)
 There is a possibility that testosterone in men
might have a suppressive effect on production of
leptin by the adipocyte

What we know about Leptin- A key
factor is body energy status




Short-term energy restriction leads to a marked fall
in circulating leptin levels, even after adjusting for
changes in adipose mass
Fall is associated with increased hunger, which may
be an early impediment to compliance with a lowenergy diet to achieve weight loss
While a number of potential signals could mediate
the acute fall in leptin with energy restriction
Plasma insulin concentrations decline in parallel
with leptin levels in this condition
What we know about Leptin-Dietary
Composition
 Dietary
composition can affect leptin
production by the adipocyte
 High-fat diet reduces leptin levels more
than a high-carbohydrate diet does
 Fructose reduces leptin levels more than
glucose does
 These findings have obvious implications
for the relation of dietary compositionspecifically high-fat diets-to weight gain
Latest Research Finding about Leptin
 Researchers
have successfully used
hormone leptin to treat patients suffering
from lipodystrophy-rare & difficult-to-treat
disorder that shares some characteristics of
typical type 2 diabetes
 People with lipodystrophy have few or no
fat cells & thus lack leptin, a hormone
produced by & stored in fat cells
Latest Research Finding about Leptin –
What is lipodystrophy?
Because they have no fat cells, people with
condition usually store huge amounts of lipids
(fat) in inappropriate places like muscle or liver &
have extremely high levels of lipids in their blood
 They are likely to be insulin resistant-meaning
their bodies don't readily respond to insulinhormone that allows muscle & fat cells to properly
use glucose.

Another Latest Research Finding
 Establishes
a new connection in metabolic
machinery, tying leptin to crucial pathway in
fat metabolism in muscle
 Pathway suggests a role for leptin in clearing
fat out of cells and sheds light on connection
between diabetes & obesity.
Another Latest Research Finding
 In
light of new knowledge about leptin's role
in fuel metabolism, it makes sense to revisit
idea of targeting leptin's actions to treat
obesity
 Obese people develop resistance to leptin, so
ability to target downstream pathway &
bypass leptin resistance may be more
beneficial than treating with leptin itself
Future Treatment in Weight
Regulation



Leptins dual action of reducing appetite while increasing energy
expenditure makes it a good candidate for weight regulation
Has applications for both dieters and obese individuals
Dieters:
• Prevent reduced energy expenditure normally associated with
decreased food intake
• Prevent the regaining of weight
– The lower leptin levels associated with dieting are said to make the body
respond as if in period of starvation
– Administering leptin will decrease cravings and speed up metabolism to
prevent weight from returning to set point

Obese Individuals:
• Prevent health problems associated with obesity
– high blood pressure, heart attack, arthritis, stroke, etc

Reduce WAT mass for both groups
Diabetes and Obesity
Levels of fatty acids are higher in obese people
Fatty acids can induce insulin resistance by unknown
mechanism
Adipocytes secrete tumor-necrosis factor  (TNF) and
leptin
TNF is involved in insulin resistance but does not
account for full insulin resistance
Leptin? Its absence causes obesity in rodents and returning
reverses resistance. However, leptin levels are high in
obese people
Other factors must be involved
Diabetes and Obesity
The missing link with obesity?
Steppan et al. Hormone resistin links obesity to diabetes.
(2001) Nature, 409, 307-312
Resistin - for resistance to insulin (anti-insulin)
Expressed in adipocytes, overexpressed in obese animals
Secreted into bloodstream
Anti-diabetic drugs (thiazoladinediones) reduce its
expression
Administration of the protein reduces obesity, antibodies
against the protein decrease the effect
Resistin suppresses insulin’s ability to stimulate glucose
uptake
Diabetes and Obesity

Adiponectin
• Adipocyte derived peptide
• Anti-inflammatory and insulin sensitizing effect
– Increases tissue fatty acid oxidation therefore reducing FFA
and triglycerides
• High concentrations associated with reduction of risk for
developing DM2
• PPAR (peroxisome proliferating activator receptor-g- new
oral anti diabetic therapy) increase levels of adiponectin –
exert insulin sensitizing effect via this mechanism ?
References
Journal of Endocrinological Investigation : 25(10);
855-861 Nov 2002
 Diabetes Metabolism Research and Reviews :
18(5); 345-356 Sep-Oct 2002
 Current Opinion in Lipidology : 13(1); 51-59 Feb
2002
: 13(3); 201-256
June 2002
