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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
Metabolic Alterations in Aging
Sarcopenia
Muscle Mass
Strength
Quality
Type 2 DM
Obesity
Low Bone
Mineralization
Altered Brain
Metabolism (AD)
Dyslipidemia
CV Disease
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
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
One in every two people age 65 and older
have diabetes or pre-diabetes
Why Diabetes Risk Increases With Age?
Insulin Resistance
Low Physical Act. Sarcopenia
Visceral
Adiposity Decreased
Insulin Action
b Cell Failure
Type 2 Diabetes in Aging
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)
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
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
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
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
*
* *
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
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
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)
Rera, PNAS (2012)
Intestinal Barrier Dysfunction and Aging
Intestinal Barrier
Dysfunction
Predicts Death
How should older adults be treated for diabetes?
Recommendations (ADA, AGS)
Goals of Treatment (Tight Control?)
Consider: 1) Functional Status 2) Life expectancy 3) Cognitive Function 4) Clinical Heterogeneity (prone to complications?)
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
How long does it take to develop diabetic complications?
How much does the A1c level matter?
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)
Goals of Treatment (Tight Control?)
Functional, Cognitively Intact, Significant Life Expectancy:
- Similar Goals as Younger Person - A1c ~ 7%
Recommendations (ADA, AGS)
Goals of Treatment (Tight Control?)
Decreased Function/Cognition, Short Life Expectancy:
- Glycemic Control can be Relaxed - Avoid Hyperglycemic Complications!
Recommendations (ADA, AGS)
Antihyperglycemic therapy T2DM (ADA Standards, 2016)
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.