Type 3 Diabetes? Use of
antidiabetics in treatment of AD
Erin Woodard
Level 2b class C Evidence
Background - Alzheimers
• B- amyloid accumulation
– Beta secretace (BACE) & gamma-secretase:
• full-length APP  amyloid peptide  plaque
– Alpha-secretase:
• APP  sAPPalpha (extracellular)
• Insulin modulates metabolism of APP
decreasing intracellular accumulation
– AD shows depletion of insulin in brain
Background
• Type 2 diabetes
– Inadequate insulin secretion
– Peripheral insulin resistance
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•
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Increased FA
Decreased transport to muscle cells
Elevated hepatic glucose production
Increased breakdown of fat
Background
• Metformin
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–
–
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Decreasing hepatic glucose production
Decreasing intestinal absorption of glucose
Increasing peripheral glucose uptake and utilization
Known action is peripheral, unknown availability in
CNS
– Utilized in DM2 as primary drug of choice
• Insulin
– Freely passes BBB into CNS
– Regulate many key processes in CNS (ie memory)
– SQ administration acts peripherally and centrally
Results- PNAS 2009
• Metformin increases beta-amyloid
generation
• Metformin effect independent of glucose
metabolism and insulin signaling
• Effect Mediated by AMPK activation
•Chen, Yaomin et al. (2009) Antidiabetic drug metformin increases biogenesis of Alzheimer’s amyloid peptides via
up-regulating BACE1 transcription. PNAS vol 106 no 10 p 3907-12.
Results – PNAS 2009
• Antagonistic effect of intracellular betaamyloid generation when metformin used
in combination with insulin
•Chen, Yaomin et al. (2009) Antidiabetic drug metformin increases biogenesis of Alzheimer’s amyloid peptides via
up-regulating BACE1 transcription. PNAS vol 106 no 10 p 3907-12.
Discussion – PNAS 2009
• BACE1 activity elevated in AD brains
• BACE1 shown to be up-regulated by
– Oxidative stress
– Chronic gliosis
– Traumatic brain injury
– Hypoxia conditions
– PPARgamma pathway
•Chen, Yaomin et al. (2009) Antidiabetic drug metformin increases biogenesis of Alzheimer’s amyloid peptides via
up-regulating BACE1 transcription. PNAS vol 106 no 10 p 3907-12.
Discussion – PNAS 2009
• Now add Metformin to the list • Appear dependent on AMPK involvement
– Accounting for metformins pleotropic effects
– Activation coorelate with beta-amyloid upregulation
– AMPK inhibition antagonizes beta-amyloid upregulation
•Chen, Yaomin et al. (2009) Antidiabetic drug metformin increases biogenesis of Alzheimer’s amyloid peptides via
up-regulating BACE1 transcription. PNAS vol 106 no 10 p 3907-12.
Potential for Concern
• Potential side effect of accelerating AD
manifestations when treating DM2 in
elderly population
• Study suggest metformin crosses BBB
• After 6 days, increases in brain AMPK
activation and BACE1 protein levels are
seen
Clinical Effect
• Data suggests these effects may be
avoided by using metformin in combination
with insulin
• Combination may even result to be
beneficial in treating DM2 and mitigating
AD progression
Summary
• AD shows insulin signaling depletion in CNS
• Insulin addition to CNS help mitigate MCI
• Metformin increases insulin sensitivity in
periphery – CNS? No. In contrast, metformin
increases BACE1 which can propigate AD
progression
• Insulin in combination with metformin overrides
this BACE and may be beneficial to comorbid
DM2 and AD suffering patients
Point to Ponder
• Insulin to CNS without affecting periphery?
• Intranasally administered insulin
– Insulin follow extracellular pathway to brain and
largely bypass periphery directly reaching CNS in 15
minutes
– Avoids hypoglycemia
• Suggested dosing in pilot study (small,
randomized)
– 20 IU in older patient
– 40 IU in younger patient
References
• Chen, Yaomin et al. (2009) Antidiabetic drug metformin
increases biogenesis of Alzheimer’s amyloid peptides via
up-regulating BACE1 transcription. PNAS vol 106 no 10
p 3907-12.
• Barclay. (2006) Antidiabetic agents show some promise
in treating alzheimer’s disease
• Gupta, A, Bisht Bharti, Dey Chinmoy. (2011) Peripheral
insulin-sensitizer drug metformin ameliorates neuronal
insulin resistance and alzheimer’s-like changes.
Neuropharmacology 60: 910-920
• Craft, S. Baker, L. Montine, T., et al (Sept 2011)
intranasal insulin therapy for alzheimer Disease and
Amnestic mild cognitive impairment. Arch Neuro.
http://archneur.amaassn.org/cgi/content/full/archneurol.2011.233