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Update on the Pathogenesis of Type 2 Diabetes Mellitus

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Title: Update on the Pathogenesis of Type 2 Diabetes Mellitus


1
Update on the Pathogenesis of Type 2 Diabetes
Mellitus
  • Ki-Up Lee
  • Department of Internal Medicine
  • Asan Medical Center, University of Ulsan

2
Case Presentation
3
M/31 ? O ?
  • C/C weight loss, polyuria
  • P/ I ?? ???? ??? ? 3??? ? 6kg? ?? ?? ???? ??
    ???
  • ?????, ??, ?? ?? ?? ????? ?? ??
  • 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 (-)

4
M/31 ? O ?
  • 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, 3ps symptoms
  • FBS/PP2hrs 362/480 mg/dL
    HbA1c 13.2
  • c-peptide 0.3 ng/mL
    urine ketone () serum ketone(-)
  • started insulin therapy

5
History Classificationof Diabetes mellitus
6
History of DM
Mellitus Latin for sweetened with
honey
  • Diabetes
  • Greek for
  • passing water
  • like a siphon

Ebers Papyrus (Egyptian, 1500 B.C.) first
depiction of diabetes mellitus - urination of
excess amounts - manipulation of diet therapy
7
?? ???? ??
  • ???? ?? ??
  • - ????? (13?? ?? ?? ??) ??
  • - ????? (???? 1433? ?? 15?) ??? ??
  • - ???? (???? 1613? ??? 5?)
  • ???? ?? ??? ??
  • ?? ?? ??? ??
  • ??, ?? ????? ??

8
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 (1891-1941)
Charles Best (1899-1978)
9
Measurement of insulin by RIA
  • Rosalyn S. Yalow (1921- )
  • 1950s
  • first discovery of insulin antibody
  • 1960s
  • insulin immunoasay
  • 1977
  • Nobel prize for insulin RIA

10
Classification of diabetes mellitus
  • Insulin dependency
  • (NDDG,1979 - WHO,1980)
  • IDDM
  • vs C-peptide
  • NIDDM
  • Age of disease onset
  • (early 1970s)
  • juvenile onset
  • vs
  • adult onset

absolute
insulin deficiency
relative
11
  • Slowly progressive IDDM (SPIDDM)
  • Latent autoimmune diabetes in adult (LADA)

Multiple hitsand/or ?-cell regeneration
100
?-CELL MASS ()
Regular
Fulminant
NIDDM
30
20
IDDM
10
Adulthood (LADA)
Adolescence
Childhood
(Age)
12
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

13
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

14
IDDM in Korean subjects
1870
Diabetes mellitus
117
C-peptide lt 0.6 ng/mL
56
Glucagon-stimulated C-peptide lt1.0 ng/mL
26
30
Typical IDDM
Atypical IDDM
insulin Tx within 1 year or initial DKA
no insulin requirement for more than 1 year
WJ Lee,et al., Diabetologia, 2001
15
IDDM in Korean subjects
Prevalence of islet auto-antibodies and
mitochondrial DNA mutation
Typical Type 1 DM Atypical Type 1 DM Type 1 DM Typical Type 1 DM Atypical Type 1 DM Type 1 DM Typical Type 1 DM Atypical Type 1 DM Type 1 DM 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
16
mtDNA mutation among Korean IDDM
  • Maternally transmitted
  • Often associated with
  • sensorineural hearing loss
  • Usually young at onset (lt25 yr)
  • Variable clinical phenotypes
  • type 1 DM, type 2 DM
  • Tendency toward progression
  • like SPIDDM (LADA)

OH
tRNALeu(UUR)
10.4 kb del
C3303T A3302G A3243G T3250C A3251G A3252G C3254T C
3256T A3260G T3271C

OL
One of the possible causes of atypical type 1 DM
in Koreans (WJ Lee, et al., Diabetologia, 2001)
tRNALys A8344G
17
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
18
GAD antibody progression to insulin deficiency
19
Classification of diabetes mellitus in Koreans

Clinical base IDDM / NIDDM
more acceptable than
Etiological base Type 1 / Type 2 DM"
20
Pathogenesis oftype 2 diabetes mellitus
21
Pathogenesis of type 2 diabetes
Genes
Genes
Impaired Insulin
Insulin Resistance
Secretion

Environment

Environment
Type 2 DM
22
Insulin resistance in obesity
160
Meals
Glucose
Insulin
140
60
Blood Gllucose, mg/dl
14
120
50
12
100
Glucose (Mm)
10
40
80
Insulin (Pm)
8
30
obese
6
20
4
Plasma Insulin
10
lean
2
lean
lean
obese
obese
12
24
8
16
20
8
Time
23
Measurement of Insulin resistance
Euglycemic hyperinsulinemic clamp
Control
Glucose infusion rate (mg/kg/.min)
30
NIDDM
25
20
15
10
5
Steady state plasma glucose level
0
0 60 120
180 240 300

Time (min)
Plasma insulin
Glucose uptake (mg/m2.min)
300
Non-oxidative
Oxidative
250
200
Insulin independent outflow
Insulin dependent outflow
150
100
50
0
Control
Obesity
NIDDM
24
Natural history of NIDDM (from Pima
Indians)
Genetic Susceptibility
Insulin Resistance
IGT
Diabetes Mellitus
25
(No Transcript)
26
Visceral fat amount insulin resistance
27
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
Citrate
TCA cycle
28
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)

29
Lipolysis from skeletal musclein high fat-fed
rats
CH Kim, Metabolism, 2003
30
TG accumulation in skeletal muscle is not the
cause of insulin resistance.
TG
FFA
insulin signaling
Long chain fatty acyl CoA (LCAC)
CPT-1
acetyl CoA
TCA cycle
?-oxidation
? ?-oxidation ? ? LCAC ? Insulin resistance
31
Prevention ofdiabetes mellitusby PPAR activation
32
OLETF (Otsuka Long-Evans Tokushima Fatty) rats
  • Obesity (esp. visceral obesity)
  • maturity-onset hyperglycemia
  • (? 30 wks)
  • Hypertension vascular dysfunction
  • Dyslipidemia (hypertriglyceridemia)

33
Rate of diabetes development
Untreated OLETF
18
78 ()
16
14
12
10
No. of rats with glycosuria
8
6
OLETF Fenofibrate
4
2
0 ()
0
OLETF Rosiglitazone
12
14
32
34
36
38
40
Age (week)
34
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 gtgt muscle,
    islet
  • PPAR-?
  • - lowers plasma triglyceride levels
  • - up-regulates fat oxidation enzymes
    expression
  • - abundant in non-adipose tissue esp. in
    liver

35
Body weight at 40 wks



1000
750
Body weight (g)
500
250
0
Feno
Rosi
Untreated
LETO
OLETF
P lt 0.05, P lt 0.001 between two groups
36
Visceral fat mass
LETO
OLETF


OLETF Rosi
OLETF Feno


37
Pancreas islet morphology
OLETF
Feno
LETO
Untreated
Rosi
18 wks
27 wks
40 wks
38
TG FA oxidation in skeletal muscle
7.5
10000




7500
5.0
Fatty acid oxidation (dpm/g tissue)
5000
TG content (mmol/5?g protein)
2.5
2500
0
0
Feno
Rosi
LETO
OLETF
Feno
Rosi
LETO
OLETF
OLETF
OLETF
P lt 0.05 between two groups
39
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
40
Prevention of fat overload in non-adipose
tissues PPAR-? vs.
PPAR-? activation
PPAR-?
Increase in fatty acid oxidation
PPAR-?
Shift in lipogenic burden
41
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.
42
Acute insulin response to IV glucosenormal and
type 2 diabetic subjects
G
l
u
c
o
s
e
1
0
0
G
l
u
c
o
s
e
1
0
0
8
0
8
0
6
0
6
0
Plasma Insulin (?U/mL)
4
0
4
0
2
0
2
0
0
0
T
i
m
e
T
i
m
e
3
0
0

3
0
3
0
0

3
0
(
m
i
n
)
(
m
i
n
)
T
y
p
e

2

D
i
a
b
e
t
e
s
N
o
r
m
a
l
Robertson Porte. J Clin Invest. 1973
43
Abnormal glucose and insulin profilesin type 2
diabetes
Insulin (?U/mL)
Glucose (mg/dL)
Normal
120
400
100
300
80
60
200
40
100
20
0600
1000
1800
1400
0200
2200
0600
0600
1000
1800
1400
0200
2200
0600
B
L
D
B
L
D
Bbreakfast Llunch Ddinner
Time of day
Polonsky KS et al. N Engl J Med. 1988
44
Prevalence of diabetes mellitus
1971
????, ??? ?
??, ??? ?
1990
1993
????, ??? ?
1995
????, ??? ?
????, ??? ?
1997
??, ?????
1998
????, ??? ?
2003
()
0
2
4
6
8
10
12
45
Insulin resistance insulin secretary capacity
Insulin secretion
Insulin resistance
Caucasians
Koreans
46
Pathogenesis of type 2 diabetes
Both insulin resistance and insulin deficiency
contribute to the development of type 2
diabetes.
Diminished fatty acid oxidation and increased
lipid accumulation in non-adipose tissues
47
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