Brain insulin resistance: role in neurodegenerative disease and potential for targeting

Introduction: This review evaluates the novel strategy of treating Alzheimer’s and Parkinson’s disease (AD and PD) withdrugs that initially have been developed to treat type 2 diabetes. As insulin signalling has been found to be de-sensitized in the brains of patients, drugs that can re-sensitize insulin signalling have been tested to evaluate if this strategy can alter disease progression.Areas covered: The review will give an overview of preclinical and clinical tests in AD and PD of drugs activating insulin receptors, glucagon-like peptide -1 (GLP-1) receptors, and glucose-dependent insulinotropic polypeptide (GIP) receptors.Expert opinion: Insulin, GLP-1 and GIP receptor agonists have shown good effects in preclinical studies. First clinical trials in MCI/AD patients have shown that insulin can improve on key pathological symptoms of AD such as memory impairment, brain activity, neuronal energy utilization, and inflammation markers. A GLP-1 receptor agonist has shown disease-modifying effects in PD patients, and first pilot studies have shown encouraging effects of a GLP-1 receptor agonist in AD patients. Novel dual GLP-1/GIP receptor agonists that cross the blood brain barrier show superior neuroprotective effects compared to single GLP-1 or GIP receptor agonists, and show great promise as novel treatments of AD and PD.