Fortunately, antidiabetics called glucagon-like peptide 1 (GLP-1) analogues do not have these limitations and are showing considerable potential as anti-AD drugs. To understand this, some background information is needed. GLP-1 is 1 of 2 incretin peptides, which are so named because their secretion by the intestines in response to food increases glucose-stimulated insulin release by the pancreas.52 Like insulin, GLP-1 is also produced in the brain53 and has many functions, including neuroprotection54 and potentiation of insulin sensitivity.55
Since GLP-1 is quickly metabolized, degradation-resistant analogues have been developed for use in treating T2D. Two of those approved by the FDA are exenatide (synthetic exendin-4, marketed as Byetta) and liraglutide. Both effectively reduce peripheral insulin resistance and have excellent safety profiles with a low incidence of hypoglycemia,56,57 which is expected given that GLP-1 increases glucose-stimulated, not basal, pancreatic insulin secretion. Pancreatitis has occurred in a very small number of those taking GLP-1 analogues; this may reflect the fact that the drug is prescribed for diabetes, which is a risk factor for pancreatitis.56,57 A recent meta-analysis found no evidence that GLP-1 analogues increase the risk of pancreatitis.58
Peripherally administered GLP-1 analogues, including exendin-4 and liraglutide, cross the blood-brain barrier59,60 and are thus able to bind GLP-1 receptors distributed widely in the brain, including pyramidal cells of the cerebral cortex and HF.61 The GLP-1 analogues have a remarkable number of beneficial effects on neurons, many of which may derive from their ability to block Aβ-induced neuronal insulin resistance as shown by Bomfim and colleagues13 In mouse models of AD, these drugs reduce Aβ plaque loads; block Aβ-stimulated inflammatory responses; promote neurogenesis, neuronal survival, and synaptic integrity; restore long-term potentiation; and reduce cognitive deficits.13,54,60,62 Both exendin-4 and liraglutide reduce the candidate biomarkers of brain insulin resistance (IRS-1 pS616 and IRS-1 pS636) in the APP/PS1 mouse model of AD.13,63
We have now demonstrated that liraglutide restores brain insulin sensitivity in the APP/PS1 mouse model of AD.64 Using our ex vivo stimulation method, we showed that the HF in such mice is as insulin-resistant at 7.5 months as the HF in elderly AD patients and that 2 months of daily liraglutide administration (25 nmol/kg IP) beginning at 5 months in these mice virtually restored normal HF responses to insulin in the IR→IRS-1→PI3K→Akt pathway. The same drug treatment was previously found to restore long-term potentiation and cognitive functions in this animal model of AD.62
Our most recent work suggests that liraglutide could be very potent in reducing brain insulin resistance in the HF of patients with MCI (H-Y Wang et al, unpublished data, 2013). As noted above, HF tissue from patients with MCI is insulin-resistant to a lesser degree than HF tissue from patients with AD. After exposure to 100 nM of liraglutide for an hour, the HF of patients with MCI was found to be much more responsive to 1 nM of insulin. Indeed, this treatment resulted in virtually normal insulin responsiveness in tissue from patients with non-amnestic MCI and substantially improved insulin responsiveness in tissue from patients with amnestic MCI. The same treatment also significantly improved insulin responsiveness in the HF of patients with AD, but the improvement in responsiveness remained far from normal.
GLP-1 analogues thus emerge as very promising novel treatments for AD at an early clinical stage, treatments not dependent on reducing peripheral insulin resistance to affect brain function. This puts a premium on early diagnosis of MCI due to AD, which is becoming possible with current methods to image Aβ plaque levels with positron emission tomography scans.65 The first clinical trial of liraglutide for MCI is in a subject recruitment stage at Hammersmith Hospital in London.66 The first completed clinical trial of a GLP-1 analogue (exenatide) for a neurodegenerative disorder in which dementia is associated with peripheral insulin resistance (Parkinson disease)67 raises hope, since it demonstrated the ability of such drugs to significantly improve cognition even in relatively advanced cases.68
Summary and Conclusions
AD is an age-related neurodegenerative disease leading to the most common form of dementia. Its prevalence is increasing rapidly because of the rising number of elderly persons in the population and the absence of truly effective therapies. A promising strategy is finding a treatment of brain insulin resistance, which is a common and early phenomenon in AD closely tied to cognitive decline and potentially capable of promoting the full spectrum of biological abnormalities in that disorder. This is best characterized as an insulin resistance syndrome, not T3D. Peripheral insulin resistance raises brain levels of brain Aβ and cytokines, which leads to the inhibition of IRS-1 that triggers brain insulin resistance. Exercise and a Mediterranean diet can lower peripheral (and potentially brain) insulin resistance, slow progression toward clinical stages of AD, and mitigate MCI symptom severity. Quicker and more potent effects are expected at clinical stages of AD with GLP-1 analogues, including liraglutide, which can reduce brain insulin resistance markedly in MCI but only to a much lesser degree in AD dementia. Early diagnosis of MCI due to AD is thus important in maximizing the potential of GLP-1 analogues as therapeutic agents in AD.
Dr Talbot is a Research Faculty Member in the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Dr Talbot has no disclosures to report.
Patricia L. Gerbarg, MD (peer/content reviewer), has no disclosures to report.
Helen Lavretsky, MD (peer/content reviewer), reports that she has received a research grant from Forest Research Institute and that she is a consultant for Lilly.
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