1 / 13

Type 3 Diabetes? Use of antidiabetics in treatment of AD

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)

rafer
Download Presentation

Type 3 Diabetes? Use of antidiabetics in treatment of AD

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Type 3 Diabetes? Use of antidiabetics in treatment of AD Erin Woodard Level 2b class C Evidence

  2. 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

  3. Background • Type 2 diabetes • Inadequate insulin secretion • Peripheral insulin resistance • Increased FA • Decreased transport to muscle cells • Elevated hepatic glucose production • Increased breakdown of fat

  4. Background • Metformin • 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

  5. 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.

  6. Results – PNAS 2009 • Antagonistic effect of intracellular beta-amyloid 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.

  7. 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.

  8. Discussion – PNAS 2009 • Now add Metformin to the list - • Appear dependent on AMPK involvement • Accounting for metformins pleotropic effects • Activation coorelate with beta-amyloid up-regulation • AMPK inhibition antagonizes beta-amyloid up-regulation • 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.ama-assn.org/cgi/content/full/archneurol.2011.233

More Related