Brain Insulin Resistance in Alzheimer's Disease and its Potential Treatment with GLP-1 Analogs

Abstract

SUMMARY The prevalence of Alzheimer’s disease is increasing rapidly in the absence of truly effective therapies. A promising strategy for developing such therapies is the treatment of brain insulin resistance, a common and early feature of Alzheimer’s disease, closely tied to cognitive decline and capable of promoting many biological abnormalities in the disorder. The proximal cause of brain insulin resistance appears to be neuronal elevation in the serine phosphorylation of IRS-1, most likely due to amyloid-β-triggered microglial release of proinflammatory cytokines. Preclinically, the first line of defense is behavior-lowering peripheral insulin resistance (e.g., physical exercise and a Mediterranean diet supplemented with foods rich in flavonoids, curcumin and ω-3 fatty acids). More potent remediation is required, however, at clinical stages. Fortunately, the US FDA-approved antidiabetics exenatide (Byetta®; Amylin Pharmaceuticals, Inc., CA, USA) and liraglutide (Victoza®; Novo Nordisk A/S, Bagsvaerd, Denmark) are showing much promise in reducing Alzheimer’s disease pathology and in restoring normal brain insulin responsiveness and cognitive function.

Neuroprotective effects of glucose-dependent insulinotropic polypeptide in Alzheimer’s disease

“…Insulin signaling has been shown to be impaired in patients with AD, even in the absence of diabetes (Moloney et al, 2010;Talbot, 2014). This de-sensitization may well be one of the pathological factors that underlie cognitive impairments in the early stage of AD.…”

“…First results in clinical trials have been published: the GLP-1 receptor agonist exendin-4 improved cognitive performance in a pilot trial in patients with Parkinson's disease (Aviles-Olmos et al, 2013, 2014. In a pilot study in patients with AD, the GLP-1 analogue liraglutide protected brain activity and energy metabolism from the decline that is associated with AD disease progression (Gejl et al, 2015).…”

The diabetic brain and cognition

“…At the molecular level, BIR is characterized by a reduced response to insulin signalling generally downstream the insulin receptor (IR)-insulin receptor substrate (IRS)-phosphatidyl inositol kinase-3 (PI-3) pathway in the brain, which, particularly considering the neurotrophic, neuroprotective, and neuromodulatory roles of brain insulin, may lead to neurodegeneration and cognitive impairment as seen in AD as well as metabolic alterations in hypothalamic functions, as seen in obesity and T2DM (Kullmann et al 2016). Although some authors proposed that it might be considered as type 3 diabetes (de la Monte and Tong 2014), others strongly disagree (Talbot 2014;Talbot and Wang 2014). BIR actually represents a brain-related metabolic syndrome associated with metabolic and oxidative stresses and neuroinflammation in the brain, which may or may not be accompanied by alterations in peripheral metabolic homeostasis, since T2DM increases the risk for AD (and vice versa), but neither all T2DM patients develop AD (and vice versa) nor AD is necessarily associated with hyperglycemia (Talbot 2014;Talbot and Wang 2014;Blázquez et al 2014).…”

“…Although some authors proposed that it might be considered as type 3 diabetes (de la Monte and Tong 2014), others strongly disagree (Talbot 2014;Talbot and Wang 2014). BIR actually represents a brain-related metabolic syndrome associated with metabolic and oxidative stresses and neuroinflammation in the brain, which may or may not be accompanied by alterations in peripheral metabolic homeostasis, since T2DM increases the risk for AD (and vice versa), but neither all T2DM patients develop AD (and vice versa) nor AD is necessarily associated with hyperglycemia (Talbot 2014;Talbot and Wang 2014;Blázquez et al 2014).…”

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

“…Normal Tau polymers and amyloid oligomers are cytotoxic and may impair cognitive function. Even though premature cellular degeneration is evident in both diseases, GLP-1 has been proven to reduce Β-amyloid levels and to improve performance on cognitive tests performed on animal models [5,6].…”