Update on the Pathogenesis of Type 2 Diabetes Mellitus

Ki-Up Lee

Department of Internal Medicine

Asan Medical Center, University of Ulsan

Case Presentation

• C/C: weight loss, polyuria

• P/ I : 평소 건강하게 지내던 중 3 개월간 약 6kg 의 체중 감소 발생하고 전신

쇠약감

동반되면서 , 다음 , 다뇨 증상 있어 내분비내과 외래 방문

• F/Hx: mother – current insulin treatment for DM

• P/Hx: N.C.

• ROS: weight loss (6kg/3mo) general weakness(+) polyuria(+) polydiasia(+) hearing disturbance(+)

• P/Ex: height; 172cm weight; 64kg BMI; 21.6kg/m2 WC; 84cm WHR; 0.82 slightly dehydrated tongue

• Lab : FBS; 258 mg/dL PP2hrs; 342 mg/dL HbA1c; 11.5%

urine/serum ketone; (-)/(-) C-peptide; 0.9 ng/mL

anti-GAD Ab; (-)

M/31 김 O 철

• Diagnosis: NIDDM without complications• Medication: Amaryl 1T bid

• 6 mon later: FBS/ PP2hrs; 98/179 mg/dL HbA1c; 7.1%

Amaryl 1T bid

• 1.5 year later: FBS/PP2hrs; 192/256 mg/dL HbA1c; 8.1%

C-peptide; 0.7 ng/mL

Amaryl 2T bid/ Glucophage 500mg bid

• 2 years later: weight loss, 3p’s symptoms

FBS/PP2hrs; 362/480 mg/dL HbA1c; 13.2%

c-peptide; 0.3 ng/mL urine ketone; (+) serum ketone(-)

started insulin therapy

M/31 김 O 철

History & Classification

of Diabetes mellitus

History of DM

Diabetes Greek for “passing water like a siphon”

Mellitus Latin for

“sweetened with honey”

“Ebers Papyrus” (Egyptian, 1500 B.C.)

first depiction of diabetes mellitus - urination of excess amounts - manipulation of diet therapy

국내 당뇨병의 역사

• 당뇨병에 관한 기술

- 향약구급방 (13 세기 중엽 고려 고종 ) “ 소갈”

- 향약집성방 ( 조선시대 1433 년 세종 15 년 ) “ 소변이 달다”

- 동의보감 ( 조선시대 1613 년 광해군 5 년 ):

소갈증에 대한 자세한 기록

실명 등의 합병증 기록

치료 , 당의 섭취제한과 안정

Discovery of Insulin

Frederick Banting

(1891-1941)

Charles Best

(1899-1978)

• 1889; 1st removal of pancreas from a dog to determine the effect of an absent pancreas by Oskar Minkowski

• 1921; discovery of insulin successful treatment of de-pancreatized dog with insulin

• 1922;

1st tested in a 14-year-old boy of diabetes in Toronto

• 1923; Nobel Prize in Physiology & Medicine

“insulin”= Latin for “island”

Measurement of insulin by RIA

Rosalyn S. Yalow (1921- )

• 1950s; first discovery of insulin antibody

• 1960s; insulin immunoasay

• 1977; Nobel prize for insulin RIA

Classification of diabetes mellitus

• Age of disease onset (early 1970s)

juvenile onset

vs

adult onset

• Insulin dependency (NDDG,1979 - WHO,1980)

IDDM

vs C-peptide

NIDDM

absolute

insulin deficiency

relative

Slowly progressive IDDM (SPIDDM)=Latent autoimmune diabetes in adult (LADA)

Multiple hitsand/or -cell regeneration

IDDM

Adulthood (LADA)

(Age)

AdolescenceChildhood

Regular

-CELL

MASS

(%)Fulminant

100

30

20

10

NIDDM

• Type 1 diabetes

- A: autoimmune mediated -cell destruction ICAs, islet cell autoantibodies

(Ab to insulin, GAD, ICA-512/IA-2, islet ganglioside…)

- B: idiopathic loss of -cells

no evidence of immunologic destruction of -cells

• Type 2 diabetes

• Other specific types of diabetes

• Gestational diabetes mellitus

Etiologic classification of diabetes (ADA, 1997)

Type 1 diabetes in different ethnic groups

• Caucasians

- mostly, about 90-95%:

auto-antibodies to islet cells

• Koreans

- about half:

auto-antibodies to islet cells

- significant remainder without autoimmune evidence:

other possible causes

IDDM in Korean subjects

1870

Diabetes mellitus

117

C-peptide < 0.6 ng/mL

56

Glucagon-stimulated C-peptide <1.0 ng/mL

26

Typical IDDM

30

Atypical IDDM

insulin Tx within 1 yearor initial DKA

no insulin requirement for more than 1 year

WJ Lee,et al., Diabetologia, 2001

Typical Type 1 DM Atypical Type 1 DM Type 1 DM

ICA 50%(13/26) 23%(7/30) 36%(20/56)

Anti-GAD antibody 35%(9/26) 23%(7/30) 29%(16/56)

Anti-ICA512 antibody 50%(13/26) 23%(7/30) 36%(20/56)

One or more of the above 77%(20/26) 57%(17/30) 66%(37/56)

mtDNA mutation 0%(0/26) 10%(3/30) 5%(3/56)

Prevalence of islet auto-antibodies and mitochondrial DNA mutation

IDDM in Korean subjects

WJ Lee,et al., Diabetologia, 2001

tRNALeu(UUR)

C3303TA3302GA3243GT3250CA3251GA3252GC3254TC3256TA3260GT3271C

OH

OL tRNALys

A8344G

10.4 kb del

mtDNA mutation among Korean IDDM

• Maternally transmitted

• Often associated with sensorineural hearing loss

• Usually young at onset (<25 yr)

• Variable clinical phenotypes: type 1 DM, type 2 DM

• Tendency toward progression: like SPIDDM (LADA)

“One of the possible causes of atypical type 1 DM in Koreans” (WJ Lee, et al., Diabetologia, 2001)

• Some (11/20) patients with

idiopathic type 1 DM

- non-autoimmune cause: absence of insulitis and autoantibodies

- abrupt onset, fulminant course: prone to diabetic ketoacidosis

- pancreatic exocrine dysfunction: high level of pancreatic enzyme

Novel subtype of IDDM in Japan

Imagawa A, et al., N Engl J Med, 2000

GAD antibody & progression to insulin deficiency

Classification of diabetes mellitus in Koreans

Clinical base

“IDDM / NIDDM”

Etiological base

“Type 1 / Type 2 DM"

more acceptable than

Pathogenesis of

type 2 diabetes mellitus

Genes Genes

Type 2 DM

Insulin ResistanceImpaired InsulinSecretion

± Environment ± Environment

Pathogenesis of type 2 diabetes

Insulin resistance in obesity

obese

Blo

od G

llu

cose

, mg/

dl

lean

Meals

Time

Pla

sma

Insu

lin

80

100

120

140

160

8 12 16 20 24 8

Glucose Insulin

Glu

cose

(M

m)

Insu

lin (

Pm

)

14

12

8

4

6

10

2

60

50

40

30

20

10

lean leanobese obese

Measurement of Insulin resistance

Steady stateplasma glucoselevel

Plasma insulin

Insulindependent outflow

Insulin independent outflow

“Euglycemic hyperinsulinemic clamp”

0

50

100

150

200

250

300

Control Obesity NIDDM

Non-oxidativeOxidative

0

5

10

15

20

25

30 ControlNIDDM

Glucose uptake (mg/m2.min)

0 60 120 180 240 300

Time (min)

Glucose infusion rate (mg/kg/.min)

Natural history of NIDDM (from Pima Indians)

Genetic Susceptibility

Insulin Resistance IGT

DiabetesMellitus

Visceral fat amount & insulin resistance

Normal visceral fat Visceral fat obesity

The glucose fatty acid cycle (Randle, 1963)

FFA overload

Glucose G6P

Pyruvate

Glycogen

TCA cycle

PDH

F-6-P

F-1,6-P2

FPK

HK

Acetyl-CoACitrate

• Weak correlation between insulin sensitivity and

plasma FFA concentration

- correlation coefficient: less than 0.6

• The rate of FA oxidation in skeletal muscle

- determined not only by plasma FFA concentration

released from adipose tissue, but also by FA supplied

by local lipolysis of TG stored in skeletal muscle

( high TG content in skeletal muscle in insulin resistance)

Problems of FFA theory

Lipolysis from skeletal musclein high fat-fed rats

CH Kim, Metabolism, 2003

Mu

scle

TG

con

ten

t

LFD HFD0.0

0.1

0.2

0.3

0.4

0.5 *

(mm

ol/m

g w

et w

eigh

t)

Basal Clamp0

100

200

300

400

500

*

*

LFD

HFD

Inte

rsti

tial

gly

cero

l(m

mol

/l)

TG accumulation in skeletal muscle is not the cause of insulin resistance.

TG

Long chain fatty acyl CoA (LCAC)

CPT-1

“-oxidation”TCA cycle

FFA

-oxidation LCAC Insulin resistance

acetyl CoA

insulin signaling

Prevention ofdiabetes mellitus

by PPAR activation

• Obesity (esp. visceral obesity) &

maturity-onset hyperglycemia

( 30 wks)

• Hypertension & vascular dysfunction

• Dyslipidemia (hypertriglyceridemia)

OLETF (Otsuka Long-Evans

Tokushima Fatty) rats

Rate of diabetes development

Age (week)

12 14 32 34 36 38 40

0

2

4

6

8

10

12

14

16

18

No.

of

rats

wit

h gl

ycos

uria

Untreated OLETF78 (%)

OLETF +Fenofibrate0 (%)

OLETF +Rosiglitazone

• PPAR-

- insulin sensitizing effect

- essential factor for fat cell differentiation

- reduce fat accumulation in non-adipose tissue

- distribution: adipose tissue >> muscle, islet

• PPAR- - lowers plasma triglyceride levels

- up-regulates fat oxidation enzymes expression

- abundant in non-adipose tissue esp. in liver

PPARs (Peroxisome proliferator activated receptors)

Body weight at 40 wks

* P < 0.05, ** P < 0.001 between two groups

LETO Feno Rosi0

250

500

750

1000 ** * **B

ody

wei

ght (

g)

OLETF

Untreated

Visceral fat mass

LETO OLETF

* *

* *

OLETF + Rosi OLETF + Feno

Pancreas islet morphology

18 wks

27 wks

40 wks

LETO

OLETF

FenoRosiUntreated

LETO OLETF Feno Rosi 0

2.5

5.0

7.5

* *

TG

con

ten

t (m

mol

/5g

pro

tein

)

LETO OLETF Feno Rosi0

2500

5000

7500

10000

* P < 0.05 between two groups

Fat

ty a

cid

oxi

dat

ion

(d

pm

/g t

issu

e)

* *

TG & FA oxidation in skeletal muscle

OLETF OLETF

Summary

Fenofibrate Rosiglitazone

DM prevention yes yes

Body weight decrease increase

Visceral fat mass decrease no change

Islet hypertrophy prevent not prevent

Islet destruction prevent prevent

FA oxidation increase increase

TG in muscle decrease decrease

Prevention of fat overload in non-adipose tissues: PPAR- vs. PPAR- activation

Shift in lipogenic burdenPPAR-

PPAR- Increase in fatty acid oxidation

Type 2DiabetesMellitus

“Not all obese subjects develop type 2 diabetes mellitus.”

Insulin action & secretion in type 2 diabetes

“-cell function is also impaired in type 2 diabetes mellitus.”

Acute insulin response to IV glucose:normal and type 2 diabetic subjects

Robertson & Porte. J Clin Invest. 1973

Pla

sma

Insu

lin (U

/mL

)

Time(min)

Normal

Glucose

300–300

40

20

60

80

100

Time(min)

Type 2 Diabetes

300–300

40

20

60

80

100 Glucose

Prevalence of diabetes mellitus

*25

0

5

10

15

20

JapaneseAmericans

Pima IndiansCaucasians Koreans

30

35

40

Prevalence (%)BMI (kg/m2)

0 2 4 6 8 10 12

2003

1998

1997

1995

1993

1990

(%)

1971 전북옥구 , 김경식 등

전국 , 김정순 등

경기연천 , 박용수 등

경기연천 , 신찬수 등

전북정읍 , 김영일 등 *

전국 , 보건복지부

전북정읍 , 박중열 등 **

Insulin resistance & insulin secretary capacity

Caucasians Koreans

Insulin secretion

Insulin resistance

“Both insulin resistance and insulin deficiency contribute to the development of type 2 diabetes.”

Pathogenesis of type 2 diabetes

Hyperglycemia

HGP

impaired insulin secretion

insulin resistance

GlucoseUptake

“Diminished fatty acid oxidation and increased lipid accumulation in non-adipose tissues”

Thank you!