pathogenesis of type 2 diabetes · pathogenesis of type 2 diabetes impaired insulin secretion...

PATHOGENESIS OF TYPE 2 DIABETESDIABETES

Impaired Insulin Secretion

Hyperglycemia

I d

Hyperglycemia

DecreasedDecreasedGlGlIncreased

HGPGlucoseGlucoseUptakeUptake

127401-4/04

THE DYSHARMONIOUS THE DYSHARMONIOUS QUARTETQUARTET

Decreased InsulinS ti

IncreasedSecretion Lipolysis

Inc rease dH GP

H ype rglyc em ia

E TIO LOG Y O F T 2DM

DEF N75-3/99

Dec rease d Glu coseUpt ake

Im pair ed In sulinSec retio n In crea sed Lipo lysis

HYPERGLYCEMIAHYPERGLYCEMIA

Increased


IncreasedHGP Decreased Glucose

Uptake

127401-4/04

QUINTESSENTIAL QUINTETQUINTESSENTIAL QUINTET

DecreasedIncretin Effect


IncreasedDecreased InsulinS ti

Inc rease dH GP

H ype rglyc em ia


DEF N75-3/99




IncreasedLipolysis

Secretion


IncreasedHGP

Decreased GlucoseHGP Uptake

127401-4/04

SETACEOUS SEXTETSETACEOUS SEXTETDecreased

Incretin EffectDecreased

Incretin Effect

Increased

Decreased InsulinSecretion

Inc rease dH GP

H ype rglyc em ia


DEF N75-3/99




IncreasedLipolysisIslet–cellIslet–cell


IncreasedHGP

Decreased GlucoseIncreasedIncreasedGlGl HGP UptakeGlucagonGlucagonSecretionSecretion

127401-4/04

DecreasedDecreasedSEPTICIDAL SEPTICIDAL

SEPTETSEPTET

IncreasedLipolysis




SEPTETSEPTET

Lipolysis

Islet–cellIslet–cellIncr easedH GP

Hy perg lycem ia

E TIOL OGY OF T2D M

DEF N75-3/99 De creas ed Glu coseUp take

Im paire d Ins ulinSecr etion Incre ased Lipo lysis


Islet–cellIslet–cell

IncreasedIncreased Neurotransmitter

Increased

IncreasedIncreasedGlucagonGlucagonSecretionSecretion

NeurotransmitterDysfunction

HGP Decreased GlucoseUptake

127401-4/04

PATHOGENESIS OF TYPE 2 DIABETESDIABETES

Impaired Insulin Secretion

Hyperglycemia

I d

Hyperglycemia

DecreasedDecreasedGlGlIncreased

HGPGlucoseGlucoseUptakeUptake

127401-4/04

Secretagogue-Stimulated Insulin Secretion

GlucoseGLUT 2 glucose

Insulinexocytosis

Secretion

GLUT 2 glucosetransporter

Gl ki

exocytosis

GlucokinaseMetabolism

Resting

SomatostatinCa2+

-

RestingATP/ADP

K+Diazoxidesulfonylurea

ATP/ADP

K+ CalciuminfluxSur

S+-

(Kir 6.2)(Kir 6.2)

Sur

KATP channel

•Allosteric Activators of Glucokinase: •Potential Role in Diabetes Therapy•Potential Role in Diabetes Therapy

•Joseph Grimsby,

•Science 18th July 2003:

Fig. 3. Glucose-lowering and insulin-releasing effects of RO-28-1675 in mice

Published by AAAS

J. Grimsby et al., Science 301, 370 -373 (2003)

Insulin ReceptorInsulin Receptor

Ligand simulation

Kinase activation

QUINTESSENTIAL QUINTETQUINTESSENTIAL QUINTETDecreased

Incretin EffectDecreased

Incretin Effect

IncreasedDecreased InsulinS ti

Inc rease dH GP

H ype rglyc em ia


DEF N75-3/99




IncreasedLipolysis

Secretion


IncreasedHGP

Decreased GlucoseHGP Uptake

127401-4/04

Major Pathophysiologic Defectsin Type 2 Diabetes

Glucagon(alpha cell)

Islet-cell dysfunctionyp

PancreasPancreas

Hepatic

Insulin resistance

Glucose uptake in

Insulin(beta cell)

glucoseoutput

Glucose uptake in muscle and fat

Hyperglycemia LiverLiver

LiverLiver Adipose Adipose tissuetissue

MuscleMuscle

Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

The Incretin Effect Is Diminished in Subjects With Type 2 Diabetesyp

Control Subjects (n=8)

Subjects With Type 2 Diabetes (n=14)

L

80

60

Normal Incretin Effect80

60

Diminished Incretin Effect

L

sulin

, mU

/ 60

40

60

40

sulin

, mU

/

IR In

s

20 20IR In

s

Time, min

0

18060 1200

0

18060 1200

Time, min

Oral glucose load Intravenous (IV) glucose infusion

Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Incretins Play an Important RoleIncretins Play an Important Role in Glucose Homeostasis

Glucose DependentGlucose DependentGlucose DependentGlucose Dependent

Food ingestionFood ingestion

Insulin from beta cells(GLP-1 and GIP)

Release of gut hormones Pancreas2,3

↑↑Glucose Glucose uptake by uptake by peripheral peripheral tissuetissue2,42,4hormones—

Incretins1,2Pancreas

ActiveGLP-1 & GIP

↓ Blood ↓ Blood glucoseglucose

GI tractGI tract

tissuetissue

Beta cellsBeta cellsAlpha cellsAlpha cells

Glucagon fromalpha cells

Glucose DependentGlucose DependentGlucose DependentGlucose Dependent

GLP 1 & GIP

DPP-4 enzyme

↓↓Glucose Glucose production production

by liverby liver

alpha cells(GLP-1)

InactiveGIP

InactiveGLP-1

1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372.3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Sitagliptin Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral

AgentAgent

Glucose dependentGlucose dependentGlucose dependentGlucose dependent

Food ingestionFood ingestion

Insulin(GLP-1 and GIP)Release of

active incretins GLP-1 and GIP

Pancreas

pppp

Glucose Glucose uptake byuptake by

peripheral tissueperipheral tissue

Blood Blood glucoseglucose

GLP-1 and GIP

DPP-4

GI tractGI tract

XBeta cellsBeta cells

Alpha cellsAlpha cells

GlucoseGlucoseXInactive

GIPInactiveGLP 1

Glucagon(GLP-1)

Glucose dependentGlucose dependentGlucose dependentGlucose dependentenzymeXJANUVIA

(DPP-4 inhibitor)

Glucose Glucose productionproduction

by liver by liver X

GIPGLP-1• Incretin hormones GLP-1 and GIP are released by the intestine throughout

the day; their levels increase in response to a meal.• JANUVIA blocks DPP-4 to enhance the level of active incretins for 24• JANUVIA blocks DPP-4 to enhance the level of active incretins for 24

hours.

DecreasedDecreasedSEPTICIDAL SEPTICIDAL

SEPTETSEPTET

IncreasedLipolysis




SEPTETSEPTET

Lipolysis

Islet–cellIslet–cellIncr easedH GP

Hy perg lycem ia

E TIOL OGY OF T2D M

DEF N75-3/99 De creas ed Glu coseUp take

Im paire d Ins ulinSecr etion Incre ased Lipo lysis


Islet–cellIslet–cell

IncreasedIncreased Neurotransmitter

Increased

IncreasedIncreasedGlucagonGlucagonSecretionSecretion

NeurotransmitterDysfunction

HGP Decreased GlucoseUptake

127401-4/04

Endocannabinoid System

The Endocannabinoid System

CB1 CB2

Brain Adipose Muscle Liver GIPredominantly in the Immune System and

Adipose TissueTissue Tract Adipose Tissue

Effects of Endocannabinoid System Overactivity

PeripheralOveractivity of EC System

Central

Adipose Liver Skeletaltissue GI tract muscle

N l bH th l

I li i

Nucleus accumbens: motivation to eat

Hypothalamus: hunger

Insulin resistance HDL-C Triglycerides Glucose uptake

Increased food intakeIncreased fat storage

Glucose uptake Adiponectin

Multisite Impact of a CB1A t i t M t b liAntagonist on Metabolism

Site of Action Mechanism(s) Clinical Implications

Hypothalamus/ Nucleus accumbens Food intake Weight loss, reduced

waist circumference

Adipose tissue Adiponectin Lipogenesis

Reduced visceral fatImproved lipidemiaInsulin sensitivityy

Muscle Glucose uptake O2 consumption

Glucose homeostasis

Liver Lipogenesis Improved lipidemia

Insulin sensitivity

GI tract Satiety Weight loss

Rimonabant the First CB Blocker:Rimonabant the First CB Blocker:

Rimonabant

Rimonabant, the First CB1 Blocker:A Multi-impact Medication

Rimonabant, the First CB1 Blocker:A Multi-impact Medication

Rimonabant

Central Peripheral

Brain Adipocyte CB1CB1

Food intake Adiponectin: Insulin resistance Triglycerides G Glucose tolerance HDL cholesterolWeight loss

THE DYSHARMONIOUS THE DYSHARMONIOUS QUARTETQUARTET

Decreased InsulinS ti

IncreasedSecretion Lipolysis

Inc rease dH GP

H ype rglyc em ia


DEF N75-3/99




Increased


IncreasedHGP Decreased Glucose

Uptake

127401-4/04

Peripheral Insulin Sensitivity Decreases With Intra-abdominal FatWith Intra-abdominal Fat

Body Mass Index Intra-abdominal Fat

Insulin sensitivity index( 10–5 min– 1/pmol/L)

10 10

y

R = -0.26 R = -0.56P<0.05

10

6

8

10

6

8NS

4

2

6

4

2

6

BMI (kg/m2) Fat area (cm2)

020 22 24 26 28 30 32

2

020 22 24 26 28 30 32

2

Fujimoto W et al. Obes Res. 1994;2:364-371

BMI (kg/m ) Fat area (cm )

Skeletal Muscle Triglyceride ContentSkeletal Muscle Triglyceride Content and Insulin Sensitivity0.9

0 8r =-0.53P 0 0006

vity

ol/L

)+

17.7

)0.8

0.7

0 6

P<0.0006

ulin

Sen

sitiv

mp

log 1

0m

on•

kg F

FM + 0.6

0.5

0 4

Insu

(cla

m(m

g/m

in 0.4

0.3

0 20.2

0.11 2 3 4 5 6 7 8 9 10

Adapted from Pan DA, et al. Diabetes. 1997;46:983-988.

Skeletal muscle-associated triglyceride(mmol/g wet weight of tissue)

Sodium GlucoseSodium Glucose Cotransporter (SGLT)–Type 2 p ( ) yp

Inhibitors

Glucose TransportersGlucose Transporters

• Glucose is a polar compound that cell membranes i bl t M t li id i hare impermeable to. Movement across lipid rich

cell membranes requires membrane-associated carrier protein transportcarrier protein transport

• 2 classes of glucose transportersSodium linked active glucose transporters 6– Sodium-linked active glucose transporters–6 isoforms (SGLT1–6)(SGLT1 6)

– Facilitative passive glucose transporters–12 isoforms (GLUT1–12)

Major Renal Sodium-Glucose Cotransporters

SGLT1 SGLT2SGLT1 SGLT2Site Mostly intestine with

some in kidneyAlmost exclusively kidney

Sugar Specificity Glucose and galactose GlucoseSugar Specificity Glucose and galactose Glucose

Affinity for Glucose Highkm = 0.4 mM

Lowkm = 2 mM

Capacity for Glucose Transport

Low High

Role Dietary gut glucose/galactose absorption

Renal glucose reabsorption

Renal glucose/galactose reabsorption

Henry RR. Presented at ADA 2008. June 6-10, 2008; San Francisco, California. Symposia.

Renal Handling of Glucose, Non-Diabetic Individual

GlucoseVirtually all the glucose

SGLT2

filtered is reabsorbed and glucose does not

appear in the urine

S1 segment of proximal tubule

~ 90%

SGL

Reabsorption

~ 90%

~ 10%

T 1

Collecting duct

Distal S2/S3 segment of proximal tubule

No Gl

proximal tubule


Renal Glucose ReabsorptionRenal Glucose Reabsorption• Filtered glucose is reabsorbed across

the apical (luminal) membrane bythe apical (luminal) membrane by several types of transporters arranged in seriesin series– Active transport of glucose (~ 90% via

SGLT2 and 10% via SGLT1) against itsSGLT2 and ~ 10% via SGLT1) against its concentration gradient, coupled to Na+ ion transporttransport

– Facilitative passive diffusion across the basolateral membrane via GLUT2 (and (GLUT1)


SGLT2 Mediates Glucose Reabsorption in theSGLT2 Mediates Glucose Reabsorption in the Kidney

Lumen Blood

GlucoseGlucoseNa+

Glucose

S1 Proximal Tubule

SGLT2

GLUT2

Na+ and Glucose at1:1 stoichiometry

K+Na+Glucose Na+

ATPase

SGLT2 catalyzes the active transport of glucose uphill across the apical (luminal) membrane against a concentration gradient by coupling it with the downhill transport of Na+ The inward Na+ gradient across the luminal epithelium is maintained by ATP drivenNa+. The inward Na+ gradient across the luminal epithelium is maintained by ATP-driven active extrusion of Na+ across the anti-luminal surface into blood. Glucose diffuses passively out of the cell down a concentration gradient via basolateral GLUT2 (and GLUT1) facilitative transporters.


Sodium Glucose Co transporter 2 Inhibitor for Type 2

Kidney/Glomeru

Sodium Glucose Co-transporter 2 Inhibitor for Type 2 Diabetes (SGLT2)

Glucose

Bl dSGLT1

SGLT2

Blood

Small Intestine Proximal tubuleSGLT2

SGLT1

SGLT2 i hibitSGLT2 inhibitorRenal tissue contributes substantially to glucose homeostasis by reabsorbing

Uriney g

180 g of glucose per dayKey role for SGLT2

Rationale for SGLT2 Inhibitor Therapy

• Normalizing blood glucose levels in diabetic patients is a major t t t ltreatment goal

• Hyperglycemia per se leads to– Microvascular complications– Impaired function in major target tissues of diabetes (called

“glucotoxicity”) – muscle, liver, pancreas• Reduction of SGLT2 function results in partial inhibition of p

glucose reabsorption in the renal proximal tubule (reduces Tmaxfor glucose) and leads to increased glucosuria

• Increased glucosuria results in reduced blood glucose levels g gwith less glucotoxicity and complications

Lipotoxicityp y Lipolysis

FFA Mobilization

M l LiMuscle LiverPancreas

FFA Oxidation FFA Oxidation Insulin Secretion

FFA Oxidation

Glucose Utilization

Hyperglycemia

Gluconeogenesis

GlucotoxicityyLiver

Muscle

InsulinPancreas

Hyperglycemia

InsulinAction

yp g y

Intestine

Insulin Secretion

Postprandial Postprandial

PharmacoGenomicsPharmacoGenetics

Personalized Medicine

Genetic Factors for warfarin Dose PredictionClin Chem 53, 2007

Giuseppe LippiGiuseppe LippiEnzymes CYP2C9 VKORC1

Gene polymorphisms determineGene polymorphisms determine dose requirements

Lesser response to i t i tiangiotensin-converting-

enzyme inhibitor therapy inenzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction N Engl J Meddysfunction.N Engl J Med.

2001 May 3;344(18):1351-7.Exner DV, Dries DL,

Using angiotensin converting Us g a g o e s co e genzyme inhibitors in African-

American hypertensives: a new ypapproach to treating hypertension

and preventing target-organ p g g gdamage.Flack JM, Mensah GA,

Ferrario CM.

Curr Med Res OpinCurr Med Res Opin.2000;16(2):66-79.; ( )

Prisant LM, Mensah GA Related Articles LinksUseGA.Related Articles, LinksUse

of beta-adrenergic receptor blockers in blacks.J Clin

Pharmacol 1996Pharmacol. 1996 Oct;36(10):867-73. Review.

Statin MyopathyStatin Myopathy

pathogenesis of type 2 diabetes · pathogenesis of type 2 diabetes impaired insulin secretion...

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