Upload
mariah-reed
View
216
Download
2
Embed Size (px)
Citation preview
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!