diabetes in older adults - american geriatrics society · remaining questions about dm in older...
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Diabetes in Older Adults
NICOLAS MUSI, MD
Barshop Institute for Longevity and Aging Studies San Antonio GRECC
University of Texas Health Science Center San Antonio, TX
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Metabolic Alterations in Aging
Sarcopenia
Muscle Mass
Strength
Quality
Type 2 DM
Obesity
Low Bone
Mineralization
Altered Brain
Metabolism (AD)
Dyslipidemia
CV Disease
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Incidence (per 1,000) of major diabetes complications among adults with diabetes, by age, 2009.
Jeffrey B. Halter et al. Diabetes 2014;63:2578-2589
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Impaired Glucose Tolerance
(Prediabetes)
Undiagnosed
Type 2 Diabetes
Diagnosed
Type 2 Diabetes
50
45
40
35
30
25
20
15
10
5
0
Perc
en
t of
Pop
ula
tion
20–44 45–54 55–64 65
Age (years)
Adapted from Harris MI. Consultant 1997;37(Suppl):S9.
Prevalence of Type 2 Diabetes,
Undiagnosed Diabetes, and IGT
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One in every two people age 65 and older
have diabetes or pre-diabetes
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Why Diabetes Risk Increases With Age?
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Insulin Resistance
Low Physical Act. Sarcopenia
Visceral
Adiposity Decreased
Insulin Action
b Cell Failure
Type 2 Diabetes in Aging
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Young
Older Normal Glucose Tolerant
Old Impaired Glucose Tolerant
Effect of Age on Insulin Secretion
0
50
100
150
200
250
0 15 30 45 60 75 90 105 120
Time (min)
0
50
100
150
200
250
0 15 30 45 60 75 90 105
Blood Glucose (mg/dl)
0
10
20
30
40
50
60
70
80
90
- 15 - 10 0 15 30 45 60 75 9 0 105 120
Time (min)
- -
Pancreas
Insulin (mU/ml)
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Metabolic Signaling Pathways in Aging
Insulin
P P
P
Akt
IRS
P P
IKK-NFkB
Mitochondrial Dysfunction
ROS
Lipids
Fatty Acids
mTOR Ribosome
(Synthesis)
P
Glucose
Proteasome (Breakdown)
MuRF1
Atrogin
Ub
Ub
TLR4
TNF-R
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Effect of Age on Insulin Sensitivity
0
1
2
3
4
5
6
7
8
Young
BMI=23.8
Older
BMI=25.1
Petersen, Science, 2003
(27 years)
(70 years)
Insulin Sensitivity (M) m
g/k
g-F
FM
.mim
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0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Young Older
Perc
en
t (27 years)
(70 years)
Intramyocellular Lipid Content
Effect of Age on Lipid Content
EMCL-CH2
IMCL-CH2
EMCL-CH3
IMCL-CH3
PPM
EMCL-CH2
IMCL-CH2
EMCL-CH3
IMCL-CH3
PPM
Magnetic Resonance Spectroscopy
Petersen, Science, 2003
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Effect of age on Mitochondrial ATP Production
Luciferase assay
(ATP synthesis rate)
* *
*P<0.05 vs. older group.
0
20
40
60
80
Younger
Older
AT
P s
ynth
esis
rate
(nm
ol/m
g p
rote
in/m
in)
Mitochondria
Alone
Glutamate +
Malate
Pyruvate +
Malate
Succ +
Rotenone
*
* *
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Effect of aerobic exercise on Mitochondrial
ATP production in older subjects
Mito
alo
ne
S + R
G +
MP+ M
0
20
40
60
80
Before exercise
After exercise
ATP
synth
esi
s ra
te
(nm
ol/m
g p
rote
in/m
in) * *
*
*, P<0.05 vs. older group before exercise.
S+R: Succinate + Rotenone; G+M: Glutamate + Malate; P+M: Pyruvate + Malate
Level in
Young
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Factors involved in mitochondrial biogenesis
MITOCHONDRIA
NUCLEUS
PGC-1
NRF1
TFAM TFAM
mtDNA
mRNA
Mitochondrial biogenesis
Modified from Vina et al Adv Drug Del Rev. 2009
a b g
AMPK
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LPS Concentration in Aging
0.0
0.1
0.2
0.3
0.4
*Younger
Older
Pla
sm
a e
nd
oto
xin
(E
U/m
l)
Ghosh et al, J Geron (2014)
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Rera, PNAS (2012)
Intestinal Barrier Dysfunction and Aging
Intestinal Barrier
Dysfunction
Predicts Death
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How should older adults be treated for diabetes?
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Recommendations (ADA, AGS)
Goals of Treatment (Tight Control?)
Consider: 1) Functional Status 2) Life expectancy 3) Cognitive Function 4) Clinical Heterogeneity (prone to complications?)
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Does every diabetic person develops (mv) complications?
No – approximately 20-40%
How long does it take to develop (mv) diabetic complications?
15 years, on average
How much does the A1c level matter?
It matters – a lot
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How long does it take to develop diabetic complications?
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How much does the A1c level matter?
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0.0
00
.25
0.5
00
.75
1.0
0
0 1000 2000 3000 4000 5000Time, Days
Not Frail Pre-Frail
Frail
Kaplan-Meier Survival Curves by Frailty Status
Frail
Not Frail
Espinoza, Hazuda (SALSA)
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Goals of Treatment (Tight Control?)
Functional, Cognitively Intact, Significant Life Expectancy:
- Similar Goals as Younger Person - A1c ~ 7%
Recommendations (ADA, AGS)
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Goals of Treatment (Tight Control?)
Decreased Function/Cognition, Short Life Expectancy:
- Glycemic Control can be Relaxed - Avoid Hyperglycemic Complications!
Recommendations (ADA, AGS)
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Antihyperglycemic therapy T2DM (ADA Standards, 2016)
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Remaining Questions About DM in Older Adults
- Epidemiology of diabetes and complications
- Etiology
- Screening and diagnosis
- Preventative strategies (lifestyle and pharmacological)
- Treatment – goals, target, and interventions
- Clinical trials for prevention and treatment
- DM complications
Halter et al, Diabetes. 2014 Aug;63(8):2578-89.