Type-2 Diabetes, Pancreatic Amylin, and Neuronal Metabolic Remodeling in Alzheimer's Disease

Abstract

Type-2 diabetes raises the risk for Alzheimer's disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic β-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid β (Aβ) pathology, in both sporadic and familial Alzheimer's disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. This review summarizes recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggests nutritional and medical effects of food constituents that might prevent and/or ameliorate amylin-mediated neuronal metabolic remodeling.

Keywords: Alzheimer's disease; amylin; diabetes; metabolism; vascular cognitive impairment and dementia (VCID).

Figure 1.. Proposed role of pancreatic amyloid-forming amylin in neuronal metabolic remodeling and Alzheimer’s dementia.

The pancreatic hormone amylin is co-released with insulin and participates in glucose homeostasis (left pathway). Prediabetic hypersecretion of amylin and amyloidogenicity of human amylin contribute to pancreatic amyloid formation, and also promote amylin accumulation in the brain leading to amylin-Aβ plaque formation (upper-right). Amylin dysregulation is associated with altered synthesis of amino acids such as phenylalanine (a catecholamine precursor) in various tissues, including the brain, which suggests a potential effect of amylin dysregulation in inducing neuronal metabolic reprogramming (lower-center). Nutritional interventions might ameliorate amylin-mediated dysregulation of amino acid synthesis (bottom arrow).