Update on the Pathogenesis of
Type 2 Diabetes Mellitus
Ki-Up Lee
Department of Internal Medicine
Asan Medical Center, University of Ulsan
Case Presentation
M/31 김 O 철
• C/C: weight loss, polyuria
• P/ I :
평소 건강하게 지내던 중 3개월간 약 6kg의 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
urine/serum ketone; (-)/(-)
anti-GAD Ab; (-)
HbA1c; 11.5%
C-peptide; 0.9 ng/mL
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
c-peptide; 0.3 ng/mL
started insulin therapy
HbA1c; 13.2%
urine ketone; (+) serum ketone(-)
History & Classification
of Diabetes mellitus
History of DM
Diabetes
Mellitus
“Ebers Papyrus”
Greek for
“passing water
like a siphon”
Latin for
“sweetened
with honey”
(Egyptian, 1500 B.C.)
first depiction of diabetes mellitus
- urination of excess amounts
- manipulation of diet therapy
국내 당뇨병의 역사
• 당뇨병에 관한 기술
- 향약구급방 (13세기 중엽 고려 고종) “소갈”
- 향약집성방 (조선시대 1433년 세종 15년) “소변이 달다”
- 동의보감 (조선시대 1613년 광해군 5년):
소갈증에 대한 자세한 기록
실명 등의 합병증 기록
치료, 당의 섭취제한과 안정
Discovery of Insulin
“insulin”= Latin for “island”
• 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
Frederick
Banting
Charles
Best
(1891-1941)
(1899-1978)
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
• Insulin dependency
(NDDG,1979 - WHO,1980)
(early 1970s)
juvenile onset
vs
adult onset
absolute
IDDM
insulin deficiency
vs
relative
C-peptide
NIDDM
Slowly progressive IDDM (SPIDDM)
=Latent autoimmune diabetes in adult (LADA)
Multiple hits
and/or -cell
regeneration
100
-CELL
MASS
(%)
Fulminant
Regular
NIDDM
30
20
IDDM
10
Childhood
Adolescence
Adulthood
(LADA)
(Age)
Etiologic classification of diabetes (ADA, 1997)
• 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
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
insulin Tx within 1 year
or initial DKA
30
Atypical IDDM
no insulin requirement
for more than 1 year
WJ Lee,et al., Diabetologia, 2001
IDDM in Korean subjects
Prevalence of islet auto-antibodies and mitochondrial DNA mutation
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)
WJ Lee,et al., Diabetologia, 2001
mtDNA mutation among Korean IDDM
• Maternally transmitted
OH
tRNALeu(UUR)
C3303T
A3302G
A3243G
T3250C
A3251G
A3252G
C3254T
C3256T
A3260G
T3271C
10.4 kb del
• 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)
OL
tRNALys
A8344G
“One of the possible causes of
atypical type 1 DM in Koreans”
(WJ Lee, et al., Diabetologia, 2001)
Novel subtype of IDDM in Japan
• 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
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”
more acceptable than
Etiological base
“Type 1 / Type 2 DM"
Pathogenesis of
type 2 diabetes mellitus
Pathogenesis of type 2 diabetes
Genes
Genes
Impaired Insulin
Secretion
Insulin Resistance
±Environment
±Environment
Type 2 DM
160
Meals
Glucose
140
Insulin
60
14
120
50
12
100
80
obese
Plasma Insulin
Blood Gllucose, mg/dl
Insulin resistance in obesity
10
40
8
30
6
20
4
lean
10
2
lean obese
8
12
16
20
Time
24
8
lean obese
Measurement of Insulin resistance
“Euglycemic hyperinsulinemic clamp”
Glucose
infusion
rate
30
(mg/kg/.min)
20
Control
NIDDM
25
15
10
5
Steady state
plasma glucose
level
0
0
60
120
180
300
Time (min)
Plasma
insulin
Glucose
uptake
300
Non-oxidative
Oxidative
250
(mg/m2.min)
Insulin
independent
outflow
240
200
Insulin
dependent
outflow
150
100
50
0
Control
Obesity
NIDDM
Natural history of NIDDM
(from Pima Indians)
Genetic
Susceptibility
Insulin
Resistance
IGT
Diabetes
Mellitus
Visceral fat amount & insulin resistance
Normal visceral fat
Visceral fat obesity
The glucose fatty acid cycle (Randle, 1963)
Glycogen
G6P
Glucose
HK
F-6-P
FPK
F-1,6-P2
Pyruvate
PDH
FFA overload
Acetyl-CoA
TCA cycle
Citrate
Problems of FFA theory
• 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)
*
0.5
0.4
0.3
0.2
Interstitial glycerol
(mmol/l)
Muscle TG content
(mmol/mg wet weight)
Lipolysis from skeletal muscle
in high fat-fed rats
500
LFD
400
HFD
*
300
*
200
100
0.1
0
0.0
LFD
HFD
Basal
Clamp
CH Kim, Metabolism, 2003
TG accumulation in skeletal muscle is not
the cause of insulin resistance.
FFA
TG
Long chain fatty acyl CoA (LCAC)
insulin
signaling
CPT-1
acetyl CoA
TCA cycle
“-oxidation”
 -oxidation   LCAC  Insulin resistance
Prevention of
diabetes mellitus
by PPAR activation
OLETF (Otsuka Long-Evans
Tokushima Fatty) rats
• Obesity (esp. visceral obesity) &
maturity-onset hyperglycemia
( 30 wks)
• Hypertension & vascular dysfunction
• Dyslipidemia (hypertriglyceridemia)
No. of rats with glycosuria
Rate of diabetes development
18
78 (%)
Untreated
OLETF
16
14
12
10
8
6
4
2
0 (%)
OLETF +
Fenofibrate
0
12
14
32
34
36
38
40
Age (week)
OLETF +
Rosiglitazone
PPARs (Peroxisome proliferator activated receptors)
• 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
Body weight at 40 wks
Body weight (g)
1000
**
**
*
750
500
250
0
LETO Untreated
Rosi
OLETF
Feno
* P < 0.05, ** P < 0.001 between two groups
Visceral fat mass
LETO
*
OLETF + Rosi
*
OLETF
*
OLETF + Feno
*
Pancreas islet morphology
OLETF
LETO
18 wks
27 wks
40 wks
Untreated
Rosi
Feno
TG & FA oxidation in skeletal muscle
10000
*
*
*
Fatty acid oxidation
(dpm/g tissue)
TG content (mmol/5g protein)
7.5
5.0
2.5
0
LETO OLETF Feno
Rosi
OLETF
*
7500
5000
2500
0
LETO OLETF Feno Rosi
* P < 0.05 between two groups
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
PPAR-
Increase in fatty acid oxidation
PPAR-
Shift in lipogenic burden
Insulin action & secretion in type 2 diabetes
Type 2
Diabetes
Mellitus
“Not all obese subjects develop type 2 diabetes mellitus.”
“-cell function is also impaired in type 2 diabetes mellitus.”
Acute insulin response to IV glucose:
normal and type 2 diabetic subjects
Plasma Insulin (U/mL)
100
Glucose
100
80
80
60
60
40
40
20
20
0
Time –30
(min)
0
Normal
30
Glucose
0
Time –30
0
30
(min)
Type 2 Diabetes
Robertson & Porte. J Clin Invest. 1973
Prevalence of diabetes mellitus
1971
40
전북옥구, 김경식 등
35
전국, 김정순 등
1990
30
경기연천, 박용수 등
1993
25
경기연천, 신찬수 등
1995
15
10
전국, 보건복지부
1998
전북정읍, 박중열 등
2003
*
20
전북정읍, 김영일 등 *
1997
Prevalence (%)
BMI (kg/m2)
**
5
0
0
2
4
6
8
10
12
(%)
Caucasians Koreans Japanese Pima Indians
Americans
Insulin resistance & insulin secretary capacity
Insulin
secretion
Caucasians
Insulin
resistance
Koreans
Pathogenesis of type 2 diabetes
“Both insulin resistance and insulin deficiency
contribute to the development of type 2 diabetes.”
impaired insulin secretion
Hyperglycemia
 HGP
 Glucose
Uptake
insulin resistance
“Diminished fatty acid oxidation and increased
lipid accumulation in non-adipose tissues”
Thank you!