Possible Medical Interventions to Overcome Insulin Resistance

January 26, 2011 15:55-17:10Room No. 205, 2F, XICC

Xiamen International Conference & Exhibition Center, Xiamen, China

BIT’s 1st World Congress of Endocrinology and Metabolism 2011

Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University,

Kawagoe-shi, Saitama-ken, JAPAN

Matsuda, Masafumi

Session 5-1: Genetics and Pathophysiology of Diabetes

Chair: Dr. Dieter Schmoll, Professor, Sanofi-Aventis, Diabetes division, R&D, Innovation & External Networking, Industriiepark Hoechst, Germany

Insulin secretion/resistance index(disposition index)

Insulin resistance

Without intervention: Complication

Increased plasma glucose conc.

What is “Diabetes Mellitus”?

Classical Triumvirate: Muscle, Liver, and Panc. b-cellsDysharmonious Quartet: FatQuintessential Quintet: Gastrointestinal tract (incretin)Setaceous Sextet: Panc. a-cellsSepticidal Septet: KidneyOminous Octet: Brain

DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009;58:773-795.

To mange diabetic complications, management of plasma glucose is not enough.

Evaluation of Insulin Sensitivity / Resistance

Control of Plasma Glucose

Pancreas

LiverMuscle

Brain

Insulin

↑

200 g/day

120g/day

Lactic acid GlycogenGlycogenGlycogenGlycogen

(Food)(Food)

Adipocytes

Plasma Glucose

Blood Glucose

Urinary glucose

Plasma glucose conc. is strictly controlled. Even small increase is out of this control.

Insulin resistance in the liver, and reduced insulin sensitivity in the muscle are features of type 2 diabetes mellitus (T2DM).

LiverMuscle

Insulin resistance reduced insulin sensitivity

Insulin ResistanceResistance to “Insulin Treatment”

Resistance to “Insulin Action”

• Failure to lower plasma glucose conc.Himsworth HP: Diabetes mellitus: Its differentiation into insulin-sensitive and insensitive types. Lancet i:127-130, 1936.

• Insulin conc. was Higher in diabetic subjects !Yalow R, Berson S: Immunoassay of endogenous plasma insulin in man. J Clin Invest 39:1157-1175, 1960.

• More than 100 units per day• More than 1.4 units / kg body weight

Flier JS, Kahn CR, Roth J: Receptors, antireceptor antibodies and mechanisms of insulin resistance. N Engl J Med 300:413-9, 1979.

Bergman RN, Ider YZ, Bowden CR: Quantitative estimation of insulin sensitivity. Am J Physiol 236:E667-E677, 1979. 　(Glucose load: non-steady)

Turner RC, Holman RR, Matthews D, et al: Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. Metabolism 28:1086-1096, 1979. 　 (Basal ： steady)

Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mellitus. Br Med J 1:1507-13, 1962. (Insulin: non-steady)

HOMA-IR

Minimal model

DeFronzo RA, Tobin J, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-E223, 1979. 　 (insulin & glucose: steady)

［ Indirect methods ］

［ Direct methods ］

Insulin clamp

Insulin tolerence test

Assessment of Insulin Resistance/Sensitivity

Assessment of Insulin Resistance/Sensitivity

Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mellitus. Br Med J 1:1507-13, 1962. (insulin: non-steady)

Insulin Clamp

Composite Index

Insulin tolerance test

Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462-1470, 1999. 　 (Basal ： steady & Glucose load: non-steady ～ steady)

DeFronzo RA, Tobin J, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-E223, 1979. 　 (insulin & glucose: steady)

［ Indirect methods ］

［ Direct methods ］

Direct Evaluation (insulin administration) 1

Therapeutic insulin resistanceDose of insulin dose of insulin

(Himsworth HP: Lancet i:127, 1936.)Insulin tolerance testChange of PG KITT

(Lundbaek K: Brit Med J 1:1507, 1962)Insulin suppression testPG SSPG

(Shen S-W et al: J Clin Invest 49:2151, 1970)Insulin suppression test (modified by somatostatin infusion)PG SSPG

(Harano Y et al: J Clin Endocrinol Metab 45:1124, 1977)Co-administration of glucose and insulinIRI and PG during glucose and insulin infusion SSPG

(Johnston C et al: Diabetic Med 7:110, 1990)

Direct Evaluation (insulin administration) 2

Forearm perfusionPG, blood flow (PGa-PGv) x Flow

(Zierler K et al: J Clin Invest 40:2111, 1961)Euglycemic hyperinsulinemic clamp (insulin clamp)Glucose infusion GIR

(DeFronzo RA et al: Am J Physiol 237:E214, 1979)Measurement of Ra of glucose by a tracerSpecific activity of glucose, GIR Rd, EGP

(Groop LC et al: J Clin Invest 84:205, 1989)Pancreatic clampSpecific activity of glucose, GIR EGP

(Matsuda M et al: Metabolism 51:1111-1119, 2002)Analysis of insulin effectivenessInsulin and glucose infusion ISI-delta, IRI-absolute

(Matsuda M et al: Diabetologia 50:S276, 2007)

Indirect Evaluation (measurement of plasma insulin concentration) 1

Fasting insulinFasting IRI Fasting insulin

(Yalow R et al: J Clin Invest 39:1157, 1960)Fasting insulinFasting IRI (specific) Fasting insulin

(Olefsky JM et al: Diabetes 22:507, 1973)HOMA methodFasting IRI, fasting PG HOMA-IR

(Turner R et al: Diabetologia 28:1086, 1979)HOMA method updatedFasting IRI, fasting PG HOMA-%S

(Levy JC et al: Diabetes Care 21:2191, 1998)QUICKIFasting IRI, fasting PG QUICKI

(Katz A et al: J Clin Endocrinol Metab 85:2402)HOMA-AD (*)Fasting IRI, fasting PG, adiponectin HOMA-AD (Matsuhisa M et al: Diabetes Res Clin Pract, 77:151, 2007)

*: Regressed algorithm

For sensitivity; 1/FI

Indirect Evaluation (measurement of plasma insulin concentration) 2

CIGMAIRI and PG during glucose infusion CIGMA

(Hosker JP et al: Diabetologia 28:401, 1985)OGTT productIRI and PG during oral glucose load average PG x average IRI

(Levine R et al: N Engl J Med 283:237, 1970)SIIRI and PG during oral glucose load SI (Cederholm J et al: Diabetes Res Clin Pract 10:167, 1990)Composite index or Matsuda indexIRI and PG during oral glucose load ISI(Comp)

(Matsuda M et al: Diabetes Care 22:1462, 1999)Si calculated from fasting and post oral glucose loadIRI and PG during oral glucose load Sib, Si2h, SiM (Avignon A et al: Int J Obes Relat Metab Disord. 23:512, 1999)ISI (*)BMI, IRI at 120 min, PG at 90 min ISI

(Stumvoll M et al: Diabetes Care 23:295, 2000)

*: Regressed algorithm

Indirect Evaluation (measurement of plasma insulin concentration) 3

OGISIRI and PG after oral glucose load OGIS (Mari A et al: Diabetes Care 24:539, 2001)SI (oral) : minimal model indexIRI and PG during meal load SI (oral) (Caumo A et al: J Clin Endocrineol Metab 85:4396, 2000)SI (oral) : minimal model indexIRI and PG during oral glucose load SI (oral) (Brenda E et al: Diabetes 50:150, 2001)SIis OGTTIRI and PG after oral glucose load SIis (Bastard JP et al.: Diabetes Metab 33:261, 2007)Minimal model (FSIVGTT)PG and IRI after iv glucose infusion SI

(Bergman RN et al: Am J Physiol 236:E667, 1979)Minimal model (dynamic analysis)PG and IRI after iv glucose infusion SID

(Pillonetto G et al: IEEE Trans Biomed Eng 53:369, 2006)

*: Regressed algorithm

Induction of HOMA-IR (1)

(Radziuk J: J Clin Endocrinol Metab 85: 4426-4433, 2000)

iakadt

dkV

Rgk

dt

dg a

21

1

2

a

aSI

21, aa

ig,positive constant

plasma glucose, insulin conc.

Insulin sensitivity

k the fractional disappearance rate of glucose(insulin action)

V the volume of distribution of glucose

aR the glucose input rate

iakadt

dkV

Rgk

dt

dg a

21

Insulin sensitivity 　（ steady state ）

Steady state:

0

0

dt

dkdt

dg

ig

VR

igV

R

a

a

i

kS aaI

1

2

const

ig

S I

1IRHOMA

(Radziuk J: J Clin Endocrinol Metab 85: 4426-4433, 2000)

Induction of HOMA-IR (2)

ISI=𝑆 𝐼=𝑐𝑜𝑛𝑠𝑡𝑔・𝑖

MCR (metabolic clearance rate)Dose of glucoseAUC of PG conc.(non- steady state)

=

Glucose Dose PG

0 ~180min

mean

MCR

After glucose administration

Insulin Sensitivity during OGTT

MCR of glucoseAverage Insulin conc.

Dose of glucose

　 PG × 　 Insulin=

can be estimated by

After glucose administration

Insulin sensitivity indices obtained from oral glucose

tolerance testing

(FPG X FPI)X(G X I)

10,000ISI(comp)=

120

G= ∫ g(t) dt0120

1

I= ∫ i(t) dt0120

1 120

0 120

mean

Matsuda M, DeFronzo RA.: Diabetes Care 22(9):1462-70, 1999.

World Diabetes DayPicture by Kawagoe

City Public Relations Office

November 14, 2009

Intervention

to Overcome Insulin Resistance

DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009;58:773-795.

● Life style modification・ Malmö feasibility study (Eriksson, 1991)・ Malmö Prfevention Trial (Eriksson, 1998)・ DaQing IGT and Diabetes Study (Pan, 1997)・ Finnish Diabetes Prevnetion Study (Tuomilehto, 2001)・ Japan Diabetes Prevention Study (Kuzuya)・ Stockholm Diabetes Prevention Program (Bjärås)

● Drug intervention・ Diabetes Prevention Program (DPP Research Group, 2002)・ STOP-NIDDM (Chiasson, 2002)・ TRIPOD (Buchanan, 2001)・ EDIT (Holman, 2003)・ NAVIGATOR (Rury R. Holman, 2010) negative・ DREAM (Boche, 2006)・ ACT NOW (DeFronzo ， 2008)・ ONTARGET (ONTARGET group, 2008)

STOP-NIDDM ： Study To Prevent NDDM, TRIPOD ： Troglitazone In Prevention of Diabetes EDIT ： Early Diabetes Intervention Trial, NAVIGATOR ： Natglinide and Valsartan in Impaired Glucose Tolerance Outcome ReaserachDREAM ： Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications

Primary Prevention of Type 2 Diabetes Mellitus

Intervention

Lifestyle modification itself is a procedure to cancel insulin resistance. Anti-obesity medications should have favorable effects.

58%less

31%less

~1,000 per group

Cumulative Incidence of Diabetes According to Study GroupsIn the Diabetes Prevention Program

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group.: N Engl J Med. 2002 Feb 7;346(6):393-403.

Hazard rates for diabetes by metabolic variables at baseline and mean changes from baseline

Dia

bet

es H

azar

d r

ates

(p

er 1

000)

Change from base line

Standardized baseline value

The Diabetes Prevention Program Research Group: Role of Insulin Secretion and Sensitivity in the Evolution of Type 2 Diabetes in the Diabetes Prevention Program Effects of Lifestyle Intervention and Metformin Diabetes 54:2404–2414, 2005

Metformin

Metformin overcomes insulin resistance through activation of AMPK.

Rory Curtis, Bard J.Geesaman & Peter S.DiStefano: Nature Reviews Drug Discovery 4, 569-580, 2005.

Hyperglycemia

TREATMENT OF TYPE 2 DIABETES: A SOUND APPROACH BASED UPON ITS

PATHOPHYSIOLOGY

Impaired Insulin Secretion

Hyperglycemia

Decreased GlucoseUptake

Increased Lipolysis

DPP-IV InhibitorsSU/glinides

MetforminTZDs

TZDs

TZDsGLP-1 analogues

IncreasedHGP

TZDsMetformin

Pioglitazone

Pioglitazone, PPARgamma against, is able to ameliorate the defective problems in the liver and the muscle, thus preserves pancreatic beta cells, resulting prolonged good plasma glucose control.

IntramuscularFat

IntrahepaticFat

IntraabdominalFat

SubcutaneousFat

Effect of Thiazolidinediones on Fat Topography

High FFA FFA

TZD

Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 2004;89:463-78..

Intra-arterialFat Artery

Mechanisms of pioglitazone to preserve beta-cells

AdipocytesMuscle

Pioglitazone

Beta-cell preservationImprovement of beta-

cell function

pancreas

Reduced TNF-a

Reduced oxidative

stress

GlucotoxicityLipotoxicity Improvement

Liver

bABCA1 (ATP-binding cassette transporter )PPARg

P<0.0001

mean

-0.3

MET（ n=588 ）

-1

-2

0

1

3

2

-3

-4

（ μU/mL ）

-2.4-2.8

+2.1

P<0.001

PIO（ n=588 ）

PIO（ n=616 ）

GLIC（ n=616 ）

Campbell I.W.:Int.J.Clin.Pract.,58 （ 2 ） ,192,2004

-1.41 -1.43

-0.5

-1.0

0

-1.5

MET（ n=588 ）

PIO（ n=588 ）

PIO（ n=616 ）

GLIC（ n=616 ）

-1.50-1.35

（ % ）

NS NS

HbA1C F-IRI

-2.0

chan

ge

fro

m b

asel

ine

chan

ge

fro

m b

asel

ine

Pioglitazone Reduces Serum Insulin Level

Randomized into PIO 15~45mg/day or MET 850~2,550mg/day or GLIC 80~320mg/day and followed 52 weeks.

Kawasaki F, Matsuda, M et al: Am. J. Physiol Endocrinol Metab 288:E510-E518, 2005

b-cell protective effect of pioglitazone (db/db) mice ）

No treatment Pioglitazone

Pioglitazone

12week

18week

TIME TO OCCURRENCE OF DIABETES (KAPLAN MEIER)

0.30

0.25

0.20

0.15

0.10

0.05

0

100 20 30 40 50

HR = 0.19(95%, CI)= 0.09,0.39

p<0.00001

6.8%per year

1.5%per year

Pioglitazone

Placebo

# at risk PLAC 299 PIO 303

215220

Cu

mu

lati

ve H

azar

d

Months

EFFECT OF PIOGLITAZONE AND PLACEBO ON MATSUDA INDEX OF INSULIN SENSITIVITY

4

6

8

10

2

0

Placebo Pioglitazone

Pre Post Pre Post

Ma

tsu

da

Ind

ex

P<0.001

EFFECT OF PIOGLITAZONE AND PLACEBO ON INSULIN SECRETION / INSULIN RESISTANCE INDEX

3

4

5

6

2

1

0Pre Post Pre Post

I/

G x

Ma

tsu

da

(0-

120

)

Placebo Pioglitazone

P<0.005

Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,2010 2:16-22, 2010. 　

Prevention of Diabetes MellitusTrial

publication

follow-up, year

drugNo. of new

on-set of DMNo.(total)

eventper 1000

person-yearscontrol

No. of newon-set of DM

No.(total)event

per 1000 person-years

Thiazolidine

*DPP 2005 0.9 Troglitazone 10 387 28.7Placebo

MetforminILS

372116

391397393

105.158.845.2

TRIPOD 2002 2.5 Troglitazone 17 114 59.6 Placebo 37 122 121.3

PIPOD 2006 3.0 Pioglitazone 11 86 42.6 -

*DREAM 2006 3.0 Rosiglitazone 306 2365 43.1 Placebo 686 2634 86.8

*ACTNOW 2008 4.0 Pioglitazone 10 303 8.3 Placebo 45 299 37.6

*CANOE 2010 3.9 Met+Rosi 14 103 34.9 Placebo 41 104 101.1

Other (α-GI, statin, fibrate, glinide)

WOSCOP 2001 5 Pravastation 57 2999 3.8 Placebo 82 3975 5.5

*STOP- NIDDM 2002 3.3 Acarbose 221 682 98.2 Placebo 285 686 125.9

BIP 2004 6.2 Bezafibrate 66 156 68.2 Placebo 80 147 87.8

*VICTORY 2009 4 Voglibose 50 897 13.9 Placebo 106 881 30.0

*NAVIGATOR 2010 6.5 Nateglinide 1674 3726 69.1 Placebo 1580 3747 64.9

GLP-1 agonists/DPP4-inhibitors

GLP-1 agonists and DPP4-inhibitors can suppress increased glucagon secretion in T2DM patients, resulting apparent reduction of insulin resistance.

Postprandial glucagon and glucose levels in subjects with NGT, patients with T2DM, and patients with T1DM during infusions of saline or GLP-1. Incremental AUC from -30 to 180 min for glucagon (A) and glucose (B) during a standardized meal consumed during infusion of saline (open bars) or GLP-1 (0.75 pmol/kg_min; filled bars) in subjects with NGT, T2DM, or T1DM. Mean ± SEM, n = 8–9 subjects per group.

Gutniak M, Ørskov C, Holst JJ, Ahre´n B, Efendic S: Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316–1322, 1992.

Effect of GLP-1 to type 1 and type 2 diabetic patients

Ralph A. DeFronzo, Ted Okerson, Prabhakar Viswanathan, Xuesong Guan, John H. Holcombe and Leigh MacConell: CURRENT MEDICAL RESEARCH AND OPINION 24, 2943–2952, 2008.

100mg10mg

Postprandial glucagon concentration during meal ingestion at baseline and after treatment with exenatide or sitagliptin

?

Suppression of RAS

Suppression of renin-angiotensin system is alternative way to improve insulin sensitivity, and ARB or ACEI is a choice of medication in T2DM patients with hypertension.

P110

PI 3-kinase

P-Ser-

-Tyr-

P

-Tyr-

P

P-Ser-

AⅡ

AT-R

P-S

er-

-Tyr-P

-Tyr-P

-Tyr-P

αβ

InsulinReceptor

IRS-1

P85

Diagram of AⅡ signaling interactions with the insulin receptor, IRS-1, and PI 3 kinase in RASMC

Folli et al: J. Clin. Invest. 100:2158–2169, 1997

Trial publicationfollow-

up, yeardrug

No. of newon-set of DM

No.(total)event

per 1000 person-years

controlNo. of new

on-set of DMNo.(total)

eventper 1000

person-years

antihypertensive drug

CAPPP 1999 6.1 ACEI 337 5183 10.7 β blocker 380 5230 11.9

STOP-2 1999 4.0 ACEI 93 1970 11.8β blockerDiuretic

CCB

97

95

1960

1935

12.4

12.1

HOPE 2001 4.5 ACEI 102 2837 8.0 Placebo 155 2883 11.9

ALLHAT 2002 4.0 ACE 119 4096 7.3 CCBDiuretic

154302

39546766

9.711.2

PEACE 2004 4.8 ACEI 335 3432 20.3 Placebo 399 3472 23.9

ANBP-2 2005 4.1 ACEI 138 2800 12.0 Diuretic 200 2826 17.3

AASK 2006 3.8 ACEI 45 410 28.9 β blockerCCB

7032

405202

45.541.7

*DREAM 2006 3.0 ACEI 449 2623 57.1 Placebo 489 2646 61.6

LIFE 2002 4.8 ARB 242 4020 12.5 β blocker 320 3979 16.8

*ALPINE 2003 1.0 ARB 1 196 5.1 Diuretic 8 196 40.8

CHARM 2003 3.1 ARB 163 2715 19.4 Placebo 202 2721 23.9

SCOPE 2003 3.7 ARB 93 2167 11.6 Placebo 115 2175 14.3

VALUE 2004 4.2 ARB 690 5087 32.3 CCB 845 5074 39.7

CASE-J 2007 3.2 ARB 38 1343 8.8 CCB 59 1342 13.7

*ProFESS 2008 2.5 ARB 125 7306 6.8 Placebo 151 7283 8.3

*ONTARGET 2008 4.7 ARB 399 8542 10.0 ACEI 366 8576 9.2

*ONTARGET 2008 4.7 ARB+ACEI 323 8502 8.1 ACEI 366 8576 9.2

*TRANSCEND 2008 4.7 ARB 319 2954 26.4 Placebo 395 2972 28.8

*HIJ-CREATE 2009 4.2 ARB 7 645 2.6 Placebo 18 624 6.9

*Kyoto Heart 2009 3.27 ARB+X 58 1116 51.6 X 86 998 76.7

*NAVIGATOR 2010 6.5 ARB 1532 3748 62.9 Placebo 1722 3725 71.1

Matsuda M.; Endocrinology ＆ Diabetology;26,1,35-41,2008.

Prevention of Diabetes Mellitus

Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA.: Effects of angiotensin-converting enzyme inhibitors, Ca2+ channel antagonists, and alpha-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension. Diabetes. 1995 Jun;44(6):665-71.

Insulin sensitivity after administration of ACE-I, CaCB, and alpha AB

Insulin-medicated glucose uptake, glucose oxidation, and non-oxidative glucose disposal during the euglycemic clamp before (open bars) and after (solid bars) 3 months of treatment with doxazossin.

Improvement of Insulin Resistance

LenderAm.J.Hypertens.,1999LenderAm.J.Hypertens.,1999

CCBAmlodipine

CCBAmlodipine

normal glucose Hypertension

normal glucose Hypertension

FalknerAm.J.Hypertens.,1997FalknerAm.J.Hypertens.,1997

ACE-ILisinoprilACE-I

Lisinopril

normal glucose Black

Hypertension

normal glucose Black

Hypertension

YamasakiJ.Hum.Hypertens,1999YamasakiJ.Hum.Hypertens,1999

α1-BPrazosinα1-B

Prazosinnormal glucoseHypertension

normal glucoseHypertension

FuruhashiHypertension,2003FuruhashiHypertension,2003

ARBCandesartan

ARBCandesartan

normal glucoseHypertension

normal glucoseHypertension

16w clamp9% increase16w clamp

9% increase

12w clamp16% increase12w clamp

16% increase

4w clamp17% increase

4w clamp17% increase

2w clamp45% increase

2w clamp45% increase

ARB protects β-cell function（ after 14 weeks ： db/db mice ）

Shao J., Watada H. et al.:Biochem. Biophys. Res. Commun.,2006;344:1224. .

Shao J., Watada H. et al.:Biochem. Biophys. Res. Commun.,2006;344:1224. .

0

406080

120140160

20

100

0

5

10

15

20

25

30

Normal(db/m)

Control(db/db)

Candesartan(db/db)

（ mg ） （ % ）

Candesartan (db/db)Control (db/db)Normal(db/m)

Insu

lin

β-c

ell

mas

s

Sta

inin

g d

ensi

ty o

f In

sulin

（%

o

f N

orm

al ）

Normal(db/m)

Control(db/db)

Candesartan(db/db)

p<0.05 p<0.05 p<0.05 p<0.05

（ n=11 each ）

High Quality Of Life same as healthy individuals,And the same duration of life as healthy individuals

Prevention of Microvascular complications, and Macrovascular complications

Good control of Blood glucose, Weight control,

Blood pressure, Lipid

Treatment Goal of Diabetic Patients～ Japan Diabetes Society ： Treatment of Diabetes Guideline 2010 ～

Maintain the same QOL as healthy people,secure the same duration of life as healthy people

Preventing onset and progression of diabetic microvascular disease （ retinopathy, nephropathy, neuropathy ） and macrovascular disease

（ ischemic heart disease, cerebrovascular disease, arteriosclerosis obliterans ）

Long-term persistence of tight blood glucose control and fundamental

treatment of underlying pathophysiological condition

Medical Interventions to Overcome Insulin Resistance Can Achieve the Goal of Diabetic Treatment

Stain

Suppression of RAS

Not SU [Pio, Met, DPP4I]

Slowing of Disease Progression through: Preservation of b-Cell Function and Lowering

Blood Pressure

(Never use glibenclamide)