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.