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
HYPERGLYCEMIAHYPERGLYCEMIA
IncreasedHGP Decreased Glucose
Uptake
127401-4/04
QUINTESSENTIAL QUINTETQUINTESSENTIAL QUINTET
DecreasedIncretin Effect
DecreasedIncretin Effect
IncreasedDecreased InsulinS ti
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
IncreasedLipolysis
Secretion
HYPERGLYCEMIAHYPERGLYCEMIA
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
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
IncreasedLipolysisIslet–cellIslet–cell
HYPERGLYCEMIAHYPERGLYCEMIA
IncreasedHGP
Decreased GlucoseIncreasedIncreasedGlGl HGP UptakeGlucagonGlucagonSecretionSecretion
127401-4/04
DecreasedDecreasedSEPTICIDAL SEPTICIDAL
SEPTETSEPTET
IncreasedLipolysis
DecreasedIncretin Effect
DecreasedIncretin Effect
Decreased InsulinSecretion
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
HYPERGLYCEMIAHYPERGLYCEMIA
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
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
IncreasedLipolysis
Secretion
HYPERGLYCEMIAHYPERGLYCEMIA
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
DecreasedIncretin Effect
DecreasedIncretin Effect
Decreased InsulinSecretion
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
HYPERGLYCEMIAHYPERGLYCEMIA
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
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
HYPERGLYCEMIAHYPERGLYCEMIA
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
Henry RR. Presented at ADA 2008. June 6-10, 2008; San Francisco, California. Symposia.
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)
Henry RR. Presented at ADA 2008. June 6-10, 2008; San Francisco, California. Symposia.
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.
Henry RR. Presented at ADA 2008. June 6-10, 2008; San Francisco, California. Symposia.
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