Lesson 3.2 :Lesson 3.2 :Relationship of Nutrition to Blood Relationship of Nutrition to Blood

Glucose ControlGlucose Control

The pancreatic secretory cellsThe pancreatic secretory cells

(-Cells)

Somatostatin

Glucagon

Insulin

Insulin peptidesInsulin peptides

Proinsulin

C peptide

Insulin

ER

Golgi

Pre/pro-hormone (11,500 kDa)

Pro-insulin (9,000 kDa)ER

Insulin (6,000kDa) + Peptide C

GolgiEnter the secretory

granulesExit by exocytosisBlood (t 1/2= 6 min)Action: via insulin

receptors

Mechanism of insulin secretionMechanism of insulin secretion

1. Glucose uptake 2. Membrane depolarization1. Glucose uptake 2. Membrane depolarization

3. Calcium uptake 4. Exocytosis3. Calcium uptake 4. Exocytosis

2Glucose

Beta cells

Glu

Ca2+Ca2+

?

Insulin3

14

-Cell

Insulin

Control of Insulin SecretionControl of Insulin Secretion

Primarily in response to elevated blood glucose Primarily in response to elevated blood glucose and other fuel molecules (AA and FA)and other fuel molecules (AA and FA)

GlucosemetabolismGlucosemetabolism

Cell

Receptor

Glucose

Insulin

Pancreas

General actions andGeneral actions and regulation of insulin regulation of insulin

Insulin Secretion

Lipoprotein lipase

activated

Cellular transportactivated

Catabolic enzymesinhibited

Anabolic enzymesactivated

Glucagon secretioninhibited

Gastrin Parasympatetic activity

Amino AcidsCCK

Glucagon Glucose

Role of insulin Role of insulin during absorptive during absorptive metabolic states metabolic states (feeding)(feeding)

Glucose Fatty acids Amino acids

Liver

Most cells AdiposeMuscle

Insulin

Intestine

Glycogen

Triglycerides

Glycogen

TriglyceridesProteins Proteins

The post-absorptive The post-absorptive metabolic states metabolic states (fasting(fasting))

Neurons

Muscle Most cells Adipose

Liver

Proteins Proteins

Glycogen

Proteins

Glycogen

Triglycerides

Triglycerides

Energy

Glucose

Ketones

Fatty Acids

Glucose-Insulin RelationshipGlucose-Insulin Relationship

IInsulin decreasensulin decreasess the concentration of glucose in the concentration of glucose in the the bloodblood, and a, and ass soon as the soon as the blood glucose blood glucose concentration fallconcentration falls the s the insulin secretion ceasesinsulin secretion ceases ( (they they regulate each otherregulate each other).).

In the absence of In the absence of insulin, most cells switch to insulin, most cells switch to alternative fuels like fatty acidsalternative fuels like fatty acids and proteins. and proteins.

• CNSCNS, however, require a constant supply , however, require a constant supply of glucose, which is provided from of glucose, which is provided from glycogenglycogen degradation degradation..

Effects of insulin on GLUT4 in the Effects of insulin on GLUT4 in the musclemuscle and fat and fat

SStimulattimulation ofion of uptake, utilization and storageuptake, utilization and storage of glucose of glucose.. TThe major transporter for uptake of glucosehe major transporter for uptake of glucose is is GLUT4GLUT4. . GLUT4 GLUT4 isis translocated totranslocated to the plasma membrane the plasma membrane through through

the action of insulin.the action of insulin. IInsulin nsulin stimulates thestimulates the fusion of fusion of GLUT4GLUT4 vesicles with the vesicles with the

plasma membraneplasma membrane.. When blood levels of insulin decrease, the When blood levels of insulin decrease, the GLUT4GLUT4

transporters are transporters are recycled backrecycled back into the cytoplasm into the cytoplasm..

Insulin receptor

Plasma membrane

GLUT4 vesicle mobilization to plasma membrane

Glucose

Insulin

Intracellular signaling cascades

Insulin Action in Muscle and Fat CellsInsulin Action in Muscle and Fat CellsMobilization of GLUT4 to the Cell SurfaceMobilization of GLUT4 to the Cell Surface

GLUT4 vesicle integration into

plasma membrane

Glucose entry into cell via GLUT4 vesicle

IntracellularGLUT4 vesicles

GLUT4=glucose transporter 4

Insulin in the liver: stimulation of glucose storage by Insulin in the liver: stimulation of glucose storage by glycogenesisglycogenesis

Insulin Insulin stimulates stimulates glucose storageglucose storage

• Glucose uptakeGlucose uptake

• Glucose phopshorylation Glucose phopshorylation (glucokinase)(glucokinase)

• Enzymes involved in glycogenesis, Enzymes involved in glycogenesis, including glycogen synthase.including glycogen synthase.

Insulin Insulin inhibits inhibits glycogen degradationglycogen degradation

• glucose-6-phosphataseglucose-6-phosphatase

Insulin and Lipids: promotion of FA synthesis and lipid storageInsulin and Lipids: promotion of FA synthesis and lipid storage

When When the liverthe liver becomebecome saturated with glycogen saturated with glycogen, , insulininsulin

promotes synthesis of fatty acidspromotes synthesis of fatty acids..

• lipids are lipids are exported as exported as lipoproteinslipoproteins..

inhibits breakdown of inhibits breakdown of lipidslipids in in adipose tissueadipose tissuess

• by by inhibiting the inhibiting the hormone-sensitive hormone-sensitive lipaselipase

facilitates entry of glucose facilitates entry of glucose to to synthesize synthesize glycerolglycerol

• glycerol and fatty acid glycerol and fatty acid formform triglyceridetriglyceride stores stores in fat cellsin fat cells..

glucose

From From the the whole body perspectivewhole body perspective

IInsulin has a fat-sparing effectnsulin has a fat-sparing effect:: ItIt drive drivess most cells to preferentially oxidize most cells to preferentially oxidize

glucoseglucose instead of fatty acids for energy instead of fatty acids for energy.. It It stimulates accumulation of stimulates accumulation of lipids lipids i inn adipose adipose

tissue.tissue.

Insulin ReceptorInsulin Receptor

a tyrosine kinasea tyrosine kinase bbinding of insulin causesinding of insulin causes

autophosphorylatautophosphorylation ion tthe activated receptorhe activated receptor

then then phosphorylates phosphorylates intracellular proteinsintracellular proteins

the best known the best known substrate: substrate: insulin insulin receptor substratereceptor substrate 1 or 1 or IRS-1IRS-1

INSULIN signaling downstream of IRS:INSULIN signaling downstream of IRS:

SosGrb

Ras

Grb

Insulin receptorIRS

Sos

Gene expression

PTENPI3 kinase

Akt

Insulin

PIP3

Forkhead TF

glucokinaseglucose/insulin responsive genes

glucose 6-phosphate/xylulose 5-phosphate

purely insulin-responsive

Liver

Adipose

Islet cells

Organ-Organ-specific specific actions of actions of glucose and glucose and insulininsulin

Glucokinase

HexokinaseGlut4

?

?

?

GIR-glucose and insulin responsivepIP-only insulin responsive

Glucose and insulin regulate insulin gene expressionGlucose and insulin regulate insulin gene expression

a signaling metabolite

PI3K SAPK

Insulin receptor substrates

InhibitorsInsulin receptor

Glucose

Wortmanin

InsulinInsulin

Cell

Other Effects of InsulinOther Effects of Insulin

Insulin stimulates theInsulin stimulates the uptake of amino acids uptake of amino acids

(an anabolic effect) (+)(an anabolic effect) (+) At low At low insulininsulin ( (fasting statefasting state), ), the the metabolismmetabolism is is

pushed toward protein degradation.pushed toward protein degradation. IInnsulin insulin increasecreases s thethe cellular uptake of K, Mg and P cellular uptake of K, Mg and P

• K influxK influx is is clinically clinically important important in diabetics in diabetics–Insulin activates Na/K pumps and decreases K Insulin activates Na/K pumps and decreases K

in plasmain plasma

GlucagonGlucagon

Physiologic Effects of GlucagonPhysiologic Effects of Glucagon

SSttimulatimulation ofion of glucose glucose production in the liver. production in the liver.

WWhen blood glucose levels begin to fallhen blood glucose levels begin to fall, , glucagonglucagon

stimulatstimulates es glycogenolysisglycogenolysis in the in the liver liver by by activatactivatinging enzymes that enzymes that hydrolyzehydrolyze glycogen and release glucose. glycogen and release glucose.

activates hepatic activates hepatic gluconeogenesisgluconeogenesis- the conversion of - the conversion of amino acids to glucoseamino acids to glucose..

enhancenhanceses lipolysislipolysis of triglyceride in adipose tissue of triglyceride in adipose tissue as an as an additionadditionalal way way of conserving blood glucoseof conserving blood glucose..

General actions and General actions and regulation of glucagonregulation of glucagon

cells

Glucagon secretion

Sympatheticactivity

Fatty acids and ketones

Gluconeogenesis

Glycogenolysis

Inhibition of anabolism

Secretion of Insulin

SecretinCCK

Parasymatheticactivity

Insulin

Amino Acids

Glucose

Abnormalities in Blood Glucose ControlAbnormalities in Blood Glucose Control

Fasting hyperinsulinemia & hyperglycemiaFasting hyperinsulinemia & hyperglycemia Fasting hyperinsulinemiaFasting hyperinsulinemia Fasting or postprandial hypoglycemiaFasting or postprandial hypoglycemia

Dietary intakes influence blood glucose Dietary intakes influence blood glucose levels by: levels by:

Contributing exogenous glucose (glycemic load)Contributing exogenous glucose (glycemic load)• digestible carbohydratesdigestible carbohydrates

Stimulating insulin secretionStimulating insulin secretion• glucose, amino acidsglucose, amino acids

Facilitating insulin functionFacilitating insulin function• chromium, zinc, magnesium, potassiumchromium, zinc, magnesium, potassium

Affecting tissue insulin sensitivityAffecting tissue insulin sensitivity• simple sugars, fat, energysimple sugars, fat, energy

• body fat distributionbody fat distribution

Consequences of Hyperinsulinemia Consequences of Hyperinsulinemia and Hyperglycemiaand Hyperglycemia

HyperinsulinemiaHyperinsulinemia• increased SNS activityincreased SNS activity

• altered smooth muscle altered smooth muscle cell Cacell Ca++++ transport transport

• increased renal sodium increased renal sodium retentionretention

• mitogenic effects on mitogenic effects on smooth muscle cellssmooth muscle cells

• increases plasminogen increases plasminogen activator inhibitor-type 1activator inhibitor-type 1

HyperglycemiaHyperglycemia• responsible for cellular responsible for cellular

injury/tissue damage injury/tissue damage underlying complications underlying complications of poorly controlled of poorly controlled diabetesdiabetes

Role of Diet in Control of Blood Role of Diet in Control of Blood Glucose AbnormalitiesGlucose Abnormalities

PreventionPrevention• inhibitsinhibits

• delaysdelays

ContributionContribution• acceleratesaccelerates

• exacerbatesexacerbates

ManagementManagement• primary treatmentprimary treatment

• adjunct treatmentadjunct treatment

Dietary modifications to control blood Dietary modifications to control blood glucose are involved in management of :glucose are involved in management of :

• diabetes mellitusdiabetes mellitus

• hypertensionhypertension

• hyperlipidemiahyperlipidemia

• liver diseaseliver disease

• renal diseaserenal disease

• cancercancer

• obesityobesity

• traumatrauma

• sepsissepsis

• medication side effectsmedication side effects– hydrochlorothiazidehydrochlorothiazide

– prednisoneprednisone

– chlorpropamidechlorpropamide

– propranololpropranolol

The Postprandial Blood Glucose The Postprandial Blood Glucose ResponseResponse

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Blood Glucose Response to Different Blood Glucose Response to Different Sources of CarbohydrateSources of Carbohydrate

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Simple Sugar

Soluble Fiber

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Steps in Development of Insulin Steps in Development of Insulin Resistance from High Glycemic Load Resistance from High Glycemic Load

Step 1 Step 2 Step 3 Step 4 Step 5

Rapidly digested & absorbed CHO with high energy density

Rapid rise in blood glucose to high levels

Release of corresponding high amount of insulin

Insulin peaks at level consistent with blood glucose levels

Downregulation of insulin receptors

Repeated bouts of high insulin levels

Summary of PresentationSummary of Presentation

Introduction:Introduction:

Insulin Resistance/Metabolic DyslipidemiaInsulin Resistance/Metabolic Dyslipidemia

Recent ObservationsRecent Observations

Animal Model of Insulin ResistanceAnimal Model of Insulin Resistance(Fructose-Fed Syrian Golden Hamster)(Fructose-Fed Syrian Golden Hamster)

Evidence for Evidence for HepaticHepatic VLDL OverproductionVLDL Overproduction

Evidence for Evidence for Hepatic Insulin ResistanceHepatic Insulin Resistance

Evidence for Evidence for Intestinal Lipoprotein OverproductionIntestinal Lipoprotein Overproduction

The diverse biological manifestations of the insulinresistant state arise as a consequence of botha blunted insulin action as well as the compensatoryhyperinsulinemia per se.

Insulin ResistanceInsulin Resistance

Insulin resistantperipheral tissues

Insulin

Increased insulin action in more sensitive tissues or biochemical pathwaysPancreas

Clinical spectrum of Clinical spectrum of insulin resistant statesinsulin resistant states

Rare (genetic) forms of insulin resistanceRare (genetic) forms of insulin resistance

Obesity (central, abdominal, visceral, android)Obesity (central, abdominal, visceral, android)

Fasting hyperglycemia/Impaired glucose Fasting hyperglycemia/Impaired glucose tolerancetolerance

Type 2 diabetes mellitusType 2 diabetes mellitus

Putative Candidate Gene Mutations inPutative Candidate Gene Mutations in Insulin Resistance Insulin Resistance

•• Glut 1Glut 1•• Glut 4Glut 4•• HexokinaseHexokinase II II•• ISPK-1ISPK-1•• GSK-3(GSK-3(,,))•• PPIC (PPIC (,,,,))•• PPIGPPIG•• GlycogenGlycogen Synthase Synthase•• GS-inhibitor-2GS-inhibitor-2•• GlycogeninGlycogenin•• PhosphofructokinasePhosphofructokinase

•• Hormone Sensitive LipaseHormone Sensitive Lipase

•• Insulin ReceptorInsulin Receptor•• IRS-1/2IRS-1/2•• ShcShc•• PI3-PI3-kinasekinase•• ProteinProtein Kinase Kinase B ( B (,,))

•• PPARPPAR

•• LeptinLeptin•• LeptinLeptin Receptor Receptor•• b2-b2-adrenergicadrenergic receptor receptor•• UCP-1UCP-1•• UCP-2UCP-2•• NPYNPY•• NPY receptorNPY receptor isoforms isoforms

Glucose MetabolismGlucose Metabolism

Lipid MetabolismLipid Metabolism

Insulin Sensitization/Insulin Sensitization/desensitizationdesensitization

Insulin ActionInsulin Action ObesityObesity

Disorders associated with insulin resistanceDisorders associated with insulin resistance

DyslipidemiaDyslipidemia HypertensionHypertension Polycystic ovarian diseasePolycystic ovarian disease HyperuricemiaHyperuricemia Thrombogenic/fibrinolytic abnormalitiesThrombogenic/fibrinolytic abnormalities AtherosclerosisAtherosclerosis

Features of Metabolic Dyslipidemia

•• HypertriglyceridemiaHypertriglyceridemiaTG,TG, ApoB ApoBVLDL-TG and VLDL-apoB secretionVLDL-TG and VLDL-apoB secretionSmall Dense LDLSmall Dense LDL( LDL particle density)( LDL particle density)

• • Reduced HDL-CReduced HDL-C

• • Increase FFAIncrease FFA

FFA

FA

VLDL

DNL

Adipose tissue

Muscle

Liver

Intestine

TG mobilizationby tissue lipases

TG, CE

ApoB

Cytosolic TGstores

Oxidation

Lipases

LPL

Mechanisms of VLDL overproduction Mechanisms of VLDL overproduction in Insulin Resistancein Insulin Resistance

Hepatic Insulin Resistance

Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425.Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.

Diet and Insulin Resistance Diet and Insulin Resistance

Diet -induced/responsiveDiet -induced/responsive adaptive response to repeated adaptive response to repeated

exposure to postprandial exposure to postprandial hyperinsulinemiahyperinsulinemia• downregulation of insulin downregulation of insulin

receptorsreceptors decreased hepatic insulin decreased hepatic insulin

clearanceclearance

Diet-responsiveDiet-responsive post-receptor defect in signal post-receptor defect in signal

transductiontransduction• glucose transporter glucose transporter

synthesis/activitysynthesis/activity

• changes in membrane changes in membrane fluidity and integrityfluidity and integrity

increase in stress hormonesincrease in stress hormones• injuryinjury

• sepsissepsis

Characteristics of Insulin Resistance Characteristics of Insulin Resistance Obesity vs DM2Obesity vs DM2

ObesityObesity• peripheral effectsperipheral effects

• hepatic glucose output hepatic glucose output unaffectedunaffected

• nonoxidative glucose nonoxidative glucose disposal decreaseddisposal decreased

DM2DM2• peripheral effectsperipheral effects

• hepatic glucose output hepatic glucose output not suppressednot suppressed

• adipocyte lipogenesis adipocyte lipogenesis and oxidative glucose and oxidative glucose metabolism affectedmetabolism affected

Glycemic LoadGlycemic Load

Described by the area under the curve (AUC) of Described by the area under the curve (AUC) of blood glucose vs time after ingestion blood glucose vs time after ingestion

Characteristic of type of carbohydrateCharacteristic of type of carbohydrate A function of energy intakeA function of energy intake Influenced by rate of gastric emptyingInfluenced by rate of gastric emptying Reflects efficiency of digestionReflects efficiency of digestion Reflects rate of absorptionReflects rate of absorption

The Glycemic IndexThe Glycemic Index

Physiological measure of effects of foods on Physiological measure of effects of foods on blood glucoseblood glucose

Calculated as the AUC of a test food Calculated as the AUC of a test food expressed as a percentage of the AUC of a expressed as a percentage of the AUC of a glucose standard glucose standard

Compares foods based on equivalent amounts Compares foods based on equivalent amounts of available CHOof available CHO

Characteristic of foods, not individualsCharacteristic of foods, not individuals

Glycemic Index of Mixed MealsGlycemic Index of Mixed Meals

Glycemic indexes calculated for individual Glycemic indexes calculated for individual foodsfoods

Individual foods weighed by a factor based on Individual foods weighed by a factor based on percentage of carbohydrate contributed by the percentage of carbohydrate contributed by the food to the total carbohydrate content of the food to the total carbohydrate content of the mealmeal

Accurately predicts differences in blood Accurately predicts differences in blood glucose responses to different mealsglucose responses to different meals

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

Food AUC mg/L at3 hours

Standardx 100

White bread 866 100Whole wheat bread 811 94Rice 652 75Cornflakes 954 110Oatmeal (coarse) 424 49Spaghetti 583 67Potatoes (boiled) 638 74Lentils 263 30Chickpeas 263 30Kidney beans 258 30

Clinical Significance of Glycemic Index Clinical Significance of Glycemic Index

Low Gl FoodsLow Gl Foods• decrease insulin secretiondecrease insulin secretion

• improve blood glucose improve blood glucose control in DM2/DM1control in DM2/DM1

• normalize blood glucose, normalize blood glucose, insulin & amino acid insulin & amino acid levels in cirrhosislevels in cirrhosis

Low GI Foods/MealsLow GI Foods/Meals• increase satietyincrease satiety

• enhance performanceenhance performance

Glycemic Effect Depends on Nutrient Glycemic Effect Depends on Nutrient CompositionComposition

Simple sugarsSimple sugars

• solubilitysolubility StarchesStarches

• digestibilitydigestibility FiberFiber

• viscosityviscosity

FatFat• fatty acid fatty acid

compositioncomposition ProteinProtein

• amino acid amino acid compositioncomposition

Carbohydrate and Blood Glucose Carbohydrate and Blood Glucose ControlControl

Simple SugarsSimple Sugars high solubility = high load high solubility = high load liquids > solidsliquids > solids diminished by fiberdiminished by fiber enhanced by high energy enhanced by high energy

intakeintake enhanced by Naenhanced by Na++

StarchesStarches high digestibility = high high digestibility = high

loadload amylopectin > amyloseamylopectin > amylose amylose > resistant starch amylose > resistant starch refined starch > simple refined starch > simple

sugars + fibersugars + fiber

Simple Sugar (SS]Simple Sugar (SS]+ or - Soluble Dietary Fiber (SDF+ or - Soluble Dietary Fiber (SDF) )

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SS & SDF

Blood Glucose Response: Blood Glucose Response: Starch+ or - Soluble Dietary Fiber Starch+ or - Soluble Dietary Fiber (SDF(SDF))

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Viscous (Soluble) Dietary Fiber and Viscous (Soluble) Dietary Fiber and Blood Glucose ControlBlood Glucose Control

Decreases rate of digestionDecreases rate of digestion• slows access of digestive enzymes slows access of digestive enzymes

Decreases rate of absorptionDecreases rate of absorption• slows rate of diffusion across unstirred layerslows rate of diffusion across unstirred layer

Found in small amounts in all plant foods Found in small amounts in all plant foods Richest source are oats, barley, citrus fruit, Richest source are oats, barley, citrus fruit,

legumes, psylliumlegumes, psyllium

Energy Intake and Blood Glucose Energy Intake and Blood Glucose ControlControl

Contributes to weight gain/lossContributes to weight gain/loss Contributes nutrients that affect insulin Contributes nutrients that affect insulin Contributes to abdominal fat depositionContributes to abdominal fat deposition

• high portal concentration of free fatty acids high portal concentration of free fatty acids inhibits hepatic insulin clearanceinhibits hepatic insulin clearance

• higher insulin requirement for glucose uptakehigher insulin requirement for glucose uptake

Exercise and and Blood Glucose ControlExercise and and Blood Glucose Control

• inhibits weight gaininhibits weight gain

• increases muscle mass/fat mass ratioincreases muscle mass/fat mass ratio

• mobilizes free fatty acids from adipocytes mobilizes free fatty acids from adipocytes

• increases skeletal muscle uptake of FFAincreases skeletal muscle uptake of FFA– enhances glycogenesis for 24-48 hoursenhances glycogenesis for 24-48 hours

Fat and Blood Glucose ControlFat and Blood Glucose Control

Total FatTotal Fat slows gastric slows gastric

motility/emptyingmotility/emptying predisposes to weight predisposes to weight

gaingain effects exaggerated if effects exaggerated if

abdominal obesity abdominal obesity presentpresent

Type of FatType of Fat saturated fatsaturated fat

membrane fluiditymembrane fluidity number of glucose number of glucose

transporterstransporters polyunsaturated fatpolyunsaturated fat

-3 -3 insulin sensitivity insulin sensitivity monounsaturated fatmonounsaturated fat

• stimulates insulin releasestimulates insulin release

Protein and Blood Glucose ControlProtein and Blood Glucose Control

Influences insulin/glucagon ratioInfluences insulin/glucagon ratio• blood glucoseblood glucose

• tissue protein accretiontissue protein accretion • cholesterol synthesischolesterol synthesis

– HMG-CoA reductaseHMG-CoA reductase

High arginine/lysine ratio stimulates insulinHigh arginine/lysine ratio stimulates insulin

Micronutrients and Blood Glucose Micronutrients and Blood Glucose ControlControl

C o fac to rs fo ro x id a tive & no no x id a tive

g lu co se m e ta b o lism

P o ta ssiumM ag ne sium

Im prov es bo thh ypog lycem ia &

h ype rg lyce m ia a fte r 2 m oso f su pp lem en ta tion

Im prov e s insu lin re sp on sein m a ln ou rished ch i ld ren ,m idd lea g ed ad u lts , ID D M ,

& he a lth y a du lts

C h ro m ium

9 0 0 IU /d inc re asesfa stin g & 2 h r in su lin

& stim u la te s n on o xid a tiveg lu co se m e ta b o lism

P ro te cts ce ll m e m b ra nefrom lip id p erox ida tion

V itam in E

G luco se T o le ran ce

Meal Patterns and Blood Glucose Meal Patterns and Blood Glucose ControlControl

Favorable EffectsFavorable Effects• frequent small meals frequent small meals

• low-moderate glycemic low-moderate glycemic loadsloads

• low energy densitylow energy density

• consumed prior to or consumed prior to or following periods of following periods of activityactivity

Unfavorable EffectsUnfavorable Effects• few large mealsfew large meals

• frequent meals frequent meals contributing high contributing high glycemic loadsglycemic loads

• consumed prior to period consumed prior to period of inactivityof inactivity

SummarySummary

Diet can affect short-term insulin responseDiet can affect short-term insulin response Diet can affect long-term insulin responseDiet can affect long-term insulin response Glycemic response is not a simple function of Glycemic response is not a simple function of

amount and type of carbohydrateamount and type of carbohydrate Glycemic response can be affected by nutrients Glycemic response can be affected by nutrients

other than carbohydrateother than carbohydrate

Comparison of Insulin Responses with Comparison of Insulin Responses with Different Patterns of Blood GlucoseDifferent Patterns of Blood Glucose

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Insulin A

Insulin B

Insulin C

Diabetes and ObesityDiabetes and Obesity

- Type 2 diabetes (90% of diabetes cases) is - Type 2 diabetes (90% of diabetes cases) is strongly linked to obesitystrongly linked to obesity

- >80% of sufferers are obese- >80% of sufferers are obese

- Insulin is less able to promote the uptake of - Insulin is less able to promote the uptake of glucose into muscles and fat, and to inhibit the glucose into muscles and fat, and to inhibit the production of glucose by the liverproduction of glucose by the liver

- How increased energy storage in adipocytes - How increased energy storage in adipocytes promotes insulin resistance in other organs is promotes insulin resistance in other organs is not knownnot known

LipotoxicityLipotoxicity

Lipolysis

FFA Mobilization

Insulin Secretion

Hyperglycemia

FFA Oxidation

Glucose Utilization

FFA Oxidation

Gluconeogenesis

Muscle LiverPancreas

What is Leptin?What is Leptin?

A peptide hormone which is coded for by the obese gene (ob)A peptide hormone which is coded for by the obese gene (ob) Influences the quantity of food consumed relative to the amount of energy Influences the quantity of food consumed relative to the amount of energy

expendedexpended• When leptin levels are high, appetite is reduced and energy expenditure is When leptin levels are high, appetite is reduced and energy expenditure is

increasedincreased Leptin has been found in gastric epithelium, placenta and adipose tissueLeptin has been found in gastric epithelium, placenta and adipose tissue

• Most abundant in white adipose tissueMost abundant in white adipose tissue

White Adipose Tissue (WAT)White Adipose Tissue (WAT)

Composed mainly of adipocytes (fat cells)Composed mainly of adipocytes (fat cells)

• Store energy in the form of triglycerides in times of nutritional affluenceStore energy in the form of triglycerides in times of nutritional affluence

• Release free fatty acids during nutritional deprivationRelease free fatty acids during nutritional deprivation WAT mass is determined by the balance between energy intake and WAT mass is determined by the balance between energy intake and

expenditureexpenditure

• This is influenced by genetic, neuroendocrine, and environmental factorsThis is influenced by genetic, neuroendocrine, and environmental factors Under normal conditions this system is carefully regulated so that WAT mass Under normal conditions this system is carefully regulated so that WAT mass

remains constant and close to well defined ‘set point’remains constant and close to well defined ‘set point’ Disruption of the steady state can lead to chronic decreases or increases in the Disruption of the steady state can lead to chronic decreases or increases in the

quantity of WATquantity of WAT

• Decreaased amounts are associated with weight alterations during peroids Decreaased amounts are associated with weight alterations during peroids of diet, malnutrition, eating disorders, etcof diet, malnutrition, eating disorders, etc

• Increased amounts indicate obesityIncreased amounts indicate obesity

How Does Leptin Interact?How Does Leptin Interact?

                                                                            Leptin System:Leptin System:

Regulating Food Intake and Regulating Food Intake and Energy ExpenditureEnergy Expenditure

Leptin binds to its receptor which is expressed primarily in the Leptin binds to its receptor which is expressed primarily in the brains hypothalamus regionbrains hypothalamus region

In turn the hypothalamus modulates food intake and energy In turn the hypothalamus modulates food intake and energy expenditure expenditure

When low leptin levels are detected, the body is warned of limited When low leptin levels are detected, the body is warned of limited energy suppliesenergy supplies

If high leptin levels are detected, the hypothalamus senses the body If high leptin levels are detected, the hypothalamus senses the body as being overweightas being overweight

• This then trigger the body to eat less and expend more energyThis then trigger the body to eat less and expend more energy When energy intake and output are equal, leptin reflects the amount When energy intake and output are equal, leptin reflects the amount

of triglyceride stored in the bodies adipose tissueof triglyceride stored in the bodies adipose tissue

Metabolic Affects of LeptinMetabolic Affects of Leptin Decreases intracellular lipid concentration through reduction of fatty acid Decreases intracellular lipid concentration through reduction of fatty acid

and triglyceride synthesis and a concomitant increase in lipid oxidationand triglyceride synthesis and a concomitant increase in lipid oxidation

It has been postulated that leptin inhibits acetyl-CoA carboxylaseIt has been postulated that leptin inhibits acetyl-CoA carboxylase

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

• Together the inhibition of acetyl-CoA to malonyl-CoA encourages the mobilization Together the inhibition of acetyl-CoA to malonyl-CoA encourages the mobilization of fatty acids from storage sites and simultaneously discourages synthesisof fatty acids from storage sites and simultaneously discourages synthesis

Carnitine acyl transferase I, which is normally inhibited by malonyl-CoA, Carnitine acyl transferase I, which is normally inhibited by malonyl-CoA, is then available to aid in lipid oxidationis then available to aid in lipid oxidation

• This enzyme is required for the transport of Acyl CoA molecules across the inner This enzyme is required for the transport of Acyl CoA molecules across the inner mitochondrial membranemitochondrial membrane

• Without this step, fatty acid breakdown is inhibitedWithout 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 MiceExperimentation on Mice

Mice leptin has an 84% resemblance to human analogMice leptin has an 84% resemblance to human analog Some obese mice have been found to have mutation in ob gene caused by Some obese mice have been found to have mutation in ob gene caused by

premature stop codonpremature stop codon

• Results in absolute lack of leptin which leads to severe obesityResults in absolute lack of leptin which leads to severe obesity Experimentation done on both obese and normal miceExperimentation done on both obese and normal mice Intravenous, intraperitoneal, an intracerebroventricular injections were givenIntravenous, intraperitoneal, an intracerebroventricular injections were given Results most significant for intracerebroventricular injectionsResults most significant for intracerebroventricular injections

• All mice showed affectedAll mice showed affected

• Lower dosages requiredLower dosages required Varying degrees of body weight loss related to dosage and timeVarying degrees of body weight loss related to dosage and time Decreased food intake and metabolic rate increasedDecreased food intake and metabolic rate increased Significant amounts of WAT mass lostSignificant amounts of WAT mass lost

Experimentation on HumansExperimentation on Humans

Few experiments done at this pointFew experiments done at this point Leptin is said to circulate freely or attached to a binding proteinLeptin is said to circulate freely or attached to a binding protein

• It has been found that obese individuals have more circulating It has been found that obese individuals have more circulating bound leptin than lean individualsbound leptin than lean individuals

The greater the initial level, the more it declines with dietingThe greater the initial level, the more it declines with dieting Levels tend to vary greatly from person to personLevels tend to vary greatly from person to person Typically females have more leptin than malesTypically females have more leptin than males

• Adipose tissue accounts for 20-25% of weight in females and Adipose tissue accounts for 20-25% of weight in females and only 15-20% in malesonly 15-20% in males

In general the greater the body mass and percent body fat, the higher In general the greater the body mass and percent body fat, the higher the levels the levels • People suffering from obesity have extremely high levelsPeople suffering from obesity have extremely high levels

How does Leptin work in ObesityHow does Leptin work in Obesity

Appears that leptin is primarily a signal that is Appears that leptin is primarily a signal that is active in response to insufficient energy active in response to insufficient energy supply rather than one that is activated to supply rather than one that is activated to prevent an oversupply of energyprevent an oversupply of energy

Apparent ineffectiveness of leptin in obese Apparent ineffectiveness of leptin in obese persons despite high circulating levels raises persons despite high circulating levels raises questions of whether "leptin resistance" is questions of whether "leptin resistance" is operating in these individuals & whether it operating in these individuals & whether it can be overcome to benefit overweight can be overcome to benefit overweight patientspatients

Possible Reasons For Increased Possible Reasons For Increased Leptin In Obese Individuals Leptin In Obese Individuals

Differences in the fat production rate of leptinDifferences in the fat production rate of leptin• Some obese people may make leptin at greater rate to compensate Some obese people may make leptin at greater rate to compensate

for faulty signaling process or actionfor faulty signaling process or action Resistance to leptin at its site of actionResistance to leptin at its site of action

• If resistance is partial, not complete, more leptin may be required If resistance is partial, not complete, more leptin may be required for action for action

A combination of both could influence eating behaviors and A combination of both could influence eating behaviors and energy use to cause obesityenergy use to cause obesity

All these possibilities indicate that obese individuals are in a state All these possibilities indicate that obese individuals are in a state of percieved starvationof percieved starvation

Leptin responsible for adaptation to low energy intake rather than Leptin responsible for adaptation to low energy intake rather than a brake on over-consumption and obesitya brake on over-consumption and obesity• Regulated by insulin induced changes of adipocyte metabolismRegulated by insulin induced changes of adipocyte metabolism• Fat & fructose intake do not initiate insulin secretion – reduce Fat & fructose intake do not initiate insulin secretion – reduce

leptin levels leading to overeating and weight gain in population leptin levels leading to overeating and weight gain in population with high intake of these macronutrientswith high intake of these macronutrients

What research has told us about LeptinWhat research has told us about Leptin It was quickly apparent that leptin is generally ineffective It was quickly apparent that leptin is generally ineffective

as signal for excessive body fat, since obese people as signal for excessive body fat, since obese people generally have higher, not lower, levels of leptin, but yet generally have higher, not lower, levels of leptin, but yet remain obeseremain obese

Probably more important role of leptin is to signal to body Probably more important role of leptin is to signal to body that body fat has fallen to dangerously low levels (for that body fat has fallen to dangerously low levels (for example during starvation) & thus signal that appropriate example during starvation) & thus signal that appropriate metabolic changes should occur to preserve metabolic metabolic changes should occur to preserve metabolic resources. This current view of leptin was supported by the resources. This current view of leptin was supported by the results of clinical trials of leptin on overweight individuals. results of clinical trials of leptin on overweight individuals.

What research has told us about LeptinWhat research has told us about Leptin

Over 200 candidate genes for obesity-most Over 200 candidate genes for obesity-most remain unidentified in humansremain unidentified in humans

Considerable amount of research has focused on Considerable amount of research has focused on hypothetical link between obesity & type 2 hypothetical link between obesity & type 2 diabetes in region of leptin receptor gene diabetes in region of leptin receptor gene

But sequence variations that have been detected But sequence variations that have been detected have not yet been linked to body fat masshave not yet been linked to body fat mass

What we know about LeptinWhat we know about Leptin

Women have higher leptin levels than men, even Women have higher leptin levels than men, even after accounting for estrogen status (e.g., there after accounting for estrogen status (e.g., there are no consistent differences among are no consistent differences among premenopausal women, postmenopausal women, premenopausal women, postmenopausal women, and postmenopausal women on estrogen and postmenopausal women on estrogen replacement)replacement)

There is a possibility that testosterone in men There is a possibility that testosterone in men might have a suppressive effect on production of might have a suppressive effect on production of leptin by the adipocyteleptin by the adipocyte

What we know about Leptin- A key What we know about Leptin- A key factor is body energy statusfactor is body energy status

Short-term energy restriction leads to a marked fall Short-term energy restriction leads to a marked fall in circulating leptin levels, even after adjusting for in circulating leptin levels, even after adjusting for changes in adipose masschanges in adipose mass

Fall is associated with increased hunger, which may Fall is associated with increased hunger, which may be an early impediment to compliance with a low-be an early impediment to compliance with a low-energy diet to achieve weight lossenergy diet to achieve weight loss

While a number of potential signals could mediate While a number of potential signals could mediate the acute fall in leptin with energy restrictionthe acute fall in leptin with energy restriction

Plasma insulin concentrations decline in parallel Plasma insulin concentrations decline in parallel with leptin levels in this conditionwith leptin levels in this condition

What we know about Leptin-Dietary What we know about Leptin-Dietary CompositionComposition

Dietary composition can affect leptin Dietary composition can affect leptin production by the adipocyteproduction by the adipocyte

High-fat diet reduces leptin levels more High-fat diet reduces leptin levels more than a high-carbohydrate diet doesthan a high-carbohydrate diet does

Fructose reduces leptin levels more than Fructose reduces leptin levels more than glucose doesglucose does

These findings have obvious implications These findings have obvious implications for the relation of dietary composition-for the relation of dietary composition-specifically high-fat diets-to weight gain specifically high-fat diets-to weight gain

Latest Research Finding about LeptinLatest Research Finding about Leptin

Researchers have successfully used Researchers have successfully used hormone leptin to treat patients suffering hormone leptin to treat patients suffering from lipodystrophy-rare & difficult-to-treat from lipodystrophy-rare & difficult-to-treat disorder that shares some characteristics of disorder that shares some characteristics of typical type 2 diabetestypical type 2 diabetes

People with lipodystrophy have few or no People with lipodystrophy have few or no fat cells & thus lack leptin, a hormone fat cells & thus lack leptin, a hormone produced by & stored in fat cellsproduced by & stored in fat cells

Latest Research Finding about Leptin – Latest Research Finding about Leptin – What is What is lipodystrophy?lipodystrophy?

Because they have no fat cells, people with Because they have no fat cells, people with condition usually store huge amounts of lipids condition usually store huge amounts of lipids (fat) in inappropriate places like muscle or liver & (fat) in inappropriate places like muscle or liver & have extremely high levels of lipids in their bloodhave extremely high levels of lipids in their blood

They are likely to be insulin resistant-meaning They are likely to be insulin resistant-meaning their bodies don't readily respond to insulin-their bodies don't readily respond to insulin-hormone that allows muscle & fat cells to properly hormone that allows muscle & fat cells to properly use glucose. use glucose.

                                                                            

Another Latest Research FindingAnother Latest Research Finding

Establishes a new connection in metabolic Establishes a new connection in metabolic machinery, tying leptin to crucial pathway in machinery, tying leptin to crucial pathway in fat metabolism in musclefat metabolism in muscle

Pathway suggests a role for leptin in clearing Pathway suggests a role for leptin in clearing fat out of cells and sheds light on connection fat out of cells and sheds light on connection between diabetes & obesity.between diabetes & obesity.

                                                                            

Another Latest Research FindingAnother Latest Research Finding

In light of new knowledge about leptin's role In light of new knowledge about leptin's role in fuel metabolism, it makes sense to revisit in fuel metabolism, it makes sense to revisit idea of targeting leptin's actions to treat idea of targeting leptin's actions to treat obesityobesity

Obese people develop resistance to leptin, so Obese people develop resistance to leptin, so ability to target downstream pathway & ability to target downstream pathway & bypass leptin resistance may be more bypass leptin resistance may be more beneficial than treating with leptin itselfbeneficial than treating with leptin itself

Future Treatment in Weight Future Treatment in Weight RegulationRegulation

Leptins dual action of reducing appetite while increasing energy Leptins dual action of reducing appetite while increasing energy expenditure makes it a good candidate for weight regulationexpenditure makes it a good candidate for weight regulation

Has applications for both dieters and obese individualsHas applications for both dieters and obese individuals Dieters:Dieters:

• Prevent reduced energy expenditure normally associated with Prevent reduced energy expenditure normally associated with decreased food intakedecreased food intake

• Prevent the regaining of weightPrevent the regaining of weight– The lower leptin levels associated with dieting are said to make the body The lower leptin levels associated with dieting are said to make the body

respond as if in period of starvationrespond as if in period of starvation– Administering leptin will decrease cravings and speed up metabolism to Administering leptin will decrease cravings and speed up metabolism to

prevent weight from returning to set pointprevent weight from returning to set point Obese Individuals:Obese Individuals:

• Prevent health problems associated with obesityPrevent health problems associated with obesity– high blood pressure, heart attack, arthritis, stroke, etchigh blood pressure, heart attack, arthritis, stroke, etc

Reduce WAT mass for both groupsReduce WAT mass for both groups

Diabetes and ObesityDiabetes and Obesity

Levels of fatty acids are higher in obese peopleLevels of fatty acids are higher in obese people

Fatty acids can induce insulin resistance by unknown Fatty acids can induce insulin resistance by unknown mechanismmechanism

Adipocytes secrete tumor-necrosis factor Adipocytes secrete tumor-necrosis factor (TNF (TNF) and ) and leptinleptin

TNFTNF is involved in insulin resistance but does not account is involved in insulin resistance but does not account for full insulin resistancefor full insulin resistance

LeptinLeptin? Its absence causes obesity in rodents and returning ? Its absence causes obesity in rodents and returning reverses resistance. However, leptin levels are high in reverses resistance. However, leptin levels are high in obese peopleobese people

Other factorsOther factors must be involved must be involved

Diabetes and ObesityDiabetes and Obesity

The missing link with obesity?The missing link with obesity?

Steppan et al. Hormone resistin links obesity to diabetes. Steppan et al. Hormone resistin links obesity to diabetes. (2001) Nature, 409, 307-312 (2001) Nature, 409, 307-312

ResistinResistin - for resistance to insulin (anti-insulin) - for resistance to insulin (anti-insulin)

Expressed in adipocytes, overexpressed in obese animalsExpressed in adipocytes, overexpressed in obese animals

Secreted into bloodstreamSecreted into bloodstream

Anti-diabetic drugs (thiazoladinediones) reduce its Anti-diabetic drugs (thiazoladinediones) reduce its expressionexpression

Administration of the protein reduces obesity, antibodies Administration of the protein reduces obesity, antibodies against the protein decrease the effectagainst the protein decrease the effect

Resistin suppresses insulin’s ability to stimulate glucose Resistin suppresses insulin’s ability to stimulate glucose uptakeuptake

Diabetes and ObesityDiabetes and Obesity

Adiponectin Adiponectin • Adipocyte derived peptideAdipocyte derived peptide

• Anti-inflammatory and insulin sensitizing effectAnti-inflammatory and insulin sensitizing effect– Increases tissue fatty acid oxidation therefore reducing FFA Increases tissue fatty acid oxidation therefore reducing FFA

and triglyceridesand triglycerides

• High concentrations associated with reduction of risk for High concentrations associated with reduction of risk for developing DM2developing DM2

• PPAR (peroxisome proliferating activator receptor-PPAR (peroxisome proliferating activator receptor-- new - new oral anti diabetic therapy) increase levels of adiponectin – oral anti diabetic therapy) increase levels of adiponectin – exert insulin sensitizing effect via this mechanism ?exert insulin sensitizing effect via this mechanism ?

ReferencesReferences

Journal of Endocrinological Investigation : 25(10); Journal of Endocrinological Investigation : 25(10); 855-861 Nov 2002855-861 Nov 2002

Diabetes Metabolism Research and Reviews : Diabetes Metabolism Research and Reviews : 18(5); 345-356 Sep-Oct 200218(5); 345-356 Sep-Oct 2002

Current Opinion in Lipidology : 13(1); 51-59 Feb Current Opinion in Lipidology : 13(1); 51-59 Feb 20022002

: 13(3); 201-256 : 13(3); 201-256 June June

20022002