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Lesson 3.2 : Relationship of Nutrition to Blood Glucose Control

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Title: Lesson 3.2 : Relationship of Nutrition to Blood Glucose Control


1
Lesson 3.2 Relationship of Nutrition to Blood
Glucose Control
2
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3
The pancreatic secretory cells
4
Insulin peptides
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
ER
Golgi
Insulin
C peptide
5
Mechanism of insulin secretion
2
  • 1. Glucose uptake 2. Membrane depolarization
  • 3. Calcium uptake 4. Exocytosis

6
Control of Insulin Secretion
  • Primarily in response to elevated blood glucose
    and other fuel molecules (AA and FA)

7
Glucosemetabolism
8
General actions and regulation of insulin
9
Role of insulin during absorptive metabolic
states (feeding)
10
The post-absorptive metabolic states (fasting)
11
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.

12
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.

13
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14
Insulin Action in Muscle and Fat
CellsMobilization 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
Glucose entry into cell via GLUT4 vesicle
Glucose
GLUT4glucose transporter 4
15
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

16
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.
  • inhibits breakdown of lipids in adipose tissues
  • by inhibiting the hormone-sensitive lipase
  • facilitates entry of glucose to synthesize
    glycerol
  • glycerol and fatty acid form triglyceride stores
    in fat cells.

glucose
17
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.

18
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

19
INSULIN signaling downstream of IRS
Insulin receptor
Insulin
IRS
Grb
Grb
Sos
Sos
Ras
PI3 kinase
PTEN
PIP3
Akt
Forkhead TF
Gene expression
20
Organ-specific actions of glucose and insulin
glucokinase
Glucokinase
?
GIR-glucose and insulin responsive pIP-only
insulin responsive
?
?
Glut4
Hexokinase
21
Glucose and insulin regulate insulin gene
expression
b-Cell
22
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

23
Glucagon
24
Physiologic Effects of Glucagon
  • Stimulation of glucose production in the liver.

25
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.

26
General actions and regulation of glucagon
27
Abnormalities in Blood Glucose Control
  • Fasting hyperinsulinemia hyperglycemia
  • Fasting hyperinsulinemia
  • Fasting or postprandial hypoglycemia

28
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

29
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

30
Role of Diet in Control of Blood Glucose
Abnormalities
  • Prevention
  • inhibits
  • delays
  • Contribution
  • accelerates
  • exacerbates
  • Management
  • primary treatment
  • adjunct treatment

31
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

32
The Postprandial Blood Glucose Response
33
Blood Glucose Response to Different Sources of
Carbohydrate
34
Steps in Development of Insulin Resistance from
High Glycemic Load
Rapid rise in blood glucose to high levels
Insulin peaks at level consistent with blood
glucose levels
Repeated bouts of high insulin levels
Release of corresponding high amount of insulin
Rapidly digested absorbed CHO with high energy
density
Downregulation of insulin receptors
35
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36
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

37
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
Insulin resistant peripheral tissues
Increased insulin action in more sensitive
tissues or biochemical pathways
Pancreas
38
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

39
Putative Candidate Gene Mutations in
Putative Candidate Gene Mutations in
Insulin Resistance
Insulin Resistance
Glucose Metabolism
Insulin Sensitization/
Glucose Metabolism
Insulin Sensitization/
desensitization
desensitization


Glut 1
Glut 1
Lipid Metabolism
Lipid Metabolism


Glut 4
Glut 4


Hormone Sensitive Lipase
Hormone Sensitive Lipase

PPAR
g
g

PPAR


Hexokinase
Hexokinase
II
II


ISPK-1
ISPK-1
Insulin Action
Obesity
Insulin Action
Obesity

GSK-3(
a
a
,
b
b
)

GSK-3(
,
)


Insulin Receptor
Insulin Receptor


Leptin
Leptin

PPIC (
a
a
,
b
b
,
g
g
)

PPIC (
,
,
)


IRS-1/2
IRS-1/2


Leptin
Leptin
Receptor
Receptor


PPIG
PPIG


Shc
Shc


b2-
b2-
adrenergic
adrenergic
receptor
receptor


Glycogen
Glycogen
Synthase
Synthase


PI3-
PI3-
kinase
kinase


UCP-1
UCP-1

GS-inhibitor-2

GS-inhibitor-2
a
b

UCP-2

Protein
Kinase
B (
a
,
b
)

UCP-2

Protein
Kinase
B (
,
)

Glycogenin

Glycogenin

NPY

NPY

Phosphofructokinase

Phosphofructokinase

NPY receptor
isoforms

NPY receptor
isoforms
40
Disorders associated with insulin resistance
  • Dyslipidemia
  • Hypertension
  • Polycystic ovarian disease
  • Hyperuricemia
  • Thrombogenic/fibrinolytic abnormalities
  • Atherosclerosis

41
Features of Metabolic Dyslipidemia




Hypertriglyceridemia
Hypertriglyceridemia
TG,
TG,
ApoB
ApoB
VLDL-TG and VLDL-apoB secretion
VLDL-TG and VLDL-apoB secretion
Small Dense LDL
Small Dense LDL
( LDL particle density)
( LDL particle density)

Reduced HDL-C

Reduced HDL-C


Increase FFA
Increase FFA
42
Mechanisms of VLDL overproduction in Insulin
Resistance
Intestine
Adipose tissue
Hepatic Insulin Resistance
LPL
FFA
TG mobilization by tissue lipases
Liver
DNL
FA
Oxidation
Muscle
ApoB
TG, CE
Lipases
Cytosolic TG stores
Adeli K. et al. (2000) J. Biol. Chem. 275
8416-8425. Adeli K. et al. (2002) J. Biol. Chem.
277793-803.
VLDL
43
Diet and Insulin Resistance
  • Diet-responsive
  • post-receptor defect in signal transduction
  • glucose transporter synthesis/activity
  • changes in membrane fluidity and integrity
  • increase in stress hormones
  • injury
  • sepsis
  • Diet -induced/responsive
  • adaptive response to repeated exposure to
    postprandial hyperinsulinemia
  • downregulation of insulin receptors
  • decreased hepatic insulin clearance

44
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45
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46
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

47
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

48
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

49
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

50
Glycemic Indexes of Various Foods (Equivalent
Amounts of Available CHO)
51
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

52
Glycemic Effect Depends on Nutrient Composition
  • Simple sugars
  • solubility
  • Starches
  • digestibility
  • Fiber
  • viscosity
  • Fat
  • fatty acid composition
  • Protein
  • amino acid composition

53
Carbohydrate and Blood Glucose Control
  • Simple Sugars
  • high solubility high load
  • liquids gt solids
  • diminished by fiber
  • enhanced by high energy intake
  • enhanced by Na
  • Starches
  • high digestibility high load
  • amylopectin gt amylose
  • amylose gt resistant starch
  • refined starch gt simple sugars fiber

54
Simple Sugar (SS or - Soluble Dietary
Fiber (SDF)
55
Blood Glucose Response Starch or - Soluble
Dietary Fiber (SDF)
56
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

57
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

58
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

59
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

60
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

61
Micronutrients and Blood Glucose Control
62
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

63
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

64
Comparison of Insulin Responses with Different
Patterns of Blood Glucose
65
Diabetes and Obesity
  • - Type 2 diabetes (90 of diabetes cases) is
    strongly linked to obesity
  • - gt80 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

66
Adipose Tissue An Endocrine OrganRole in
Insulin resistance, Obesity Diabetes
Adiponectin
Leptin
TNF-?
Angiotensinogen
IL-6
etc
Resistin
67
Lipotoxicity
? Lipolysis
? FFA Mobilization
Liver
Pancreas
Muscle
? FFA Oxidation
? FFA Oxidation
? Insulin Secretion
? Gluconeogenesis
? Glucose Utilization
Hyperglycemia
68
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

69
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

70
How Does Leptin Interact?
71
Leptin System
72
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

73
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
  • Enzyme involved in the committed step of fatty
    acid synthesis
  • This inhibition leads to decrease in malonyl-CoA
    levels
  • 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

74
Leptin deficiency and receptor defects in rodents
cause marked obesity as well as hyperglycemia and
hyperinsulinemia
75
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 intracerebroventricul
    ar 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

76
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

77
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

78
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

79
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.

80
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

81
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

82
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
    low-energy 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

83
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 composition-specifically
    high-fat diets-to weight gain

84
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

85
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
    insulin-hormone that allows muscle fat cells to
    properly use glucose.

86
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.

87
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

88
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

89
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 a (TNFa) and leptin TNFa 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
90
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 insulins ability
to stimulate glucose uptake
91
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-?- new oral anti diabetic therapy)
    increase levels of adiponectin exert insulin
    sensitizing effect via this mechanism ?

92
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
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