Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease.
BACKGROUND
Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid beta-peptide (Abeta) in vitro in neuronal cultures and in vivo in the CSF of normal older adults.


OBJECTIVE
To determine whether insulin affected plasma Abeta levels and whether such effects differed for patients with AD compared with normal older adults.


METHODS
Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU.kg(-1).min(-1)) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU.kg(-1).min(-1)) and higher (1.67 mU.kg(-1).min(-1)) rate. Plasma insulin and Abeta were measured after 120 minutes of infusion.


RESULTS
Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Abeta levels at the middle (1.0 mU.kg(-1).min(-1)) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Abeta levels at the two higher doses (1.0 and 1.67 mU.kg(-1).min(-1)).


CONCLUSIONS
These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid beta-peptide (Abeta) elevation. Abnormal regulation of peripheral Abeta by insulin may contribute to AD risk.
Kulstad
J J
JJ
Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
Green
P S
PS
Cook
D G
DG
Watson
G S
GS
Reger
M A
MA
Baker
L D
LD
Plymate
S R
SR
Asthana
S
S
Rhoads
K
K
Mehta
P D
PD
Craft
S
S
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood*; D016229:Amyloid beta-Peptides / Q000097:blood*; D001057:Apolipoproteins E / Q000235:genetics; D015992:Body Mass Index; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D007328:Insulin; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)