Understanding the Role of Insulin in Alzheimer’s Disease and Neurodegeneration

Considerable overlap has been identified between the risk factors, comorbidities, and pathophysiological mechanisms associated with both Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) (1). Understanding insulin pathways and insulin resistance in both of these morbidities is essential to understanding this fascinating crossover (1). Emerging data suggests that insulin not only plays a role in brain glucose metabolism, but also is crucial in cerebral functions such as memory and cognition. These findings ultimately shed light on how insulin resistance is implicated in neurodegenerative diseases, such as Alzhemier’s disease (2). 

Insulin, a large hormone produced by the pancreas, regulates blood glucose levels and is often discussed in the context of biological metabolism (2). Glucose is the primary fuel for the brain, so deficits will result in starvation, oxidative stress, impairments in homeostasis, and increased cell death (3). Likewise, inulin and insulin-like growth factor (IGF) pathways support neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, cytoskeletal assembly, synapse formation, neurotransmitter function and plasticity (3). As a result, impaired insulin/IGF signaling has adverse effects on the central nervous system’s structural and functional integrity (3). Insulin has also been found to act in selective regions of the human brain to increase glucose and metabolism to support learning and memory, regulate neurotransmitters associated with cognition, and contribute to the formation of synapses between neurons (3,4). This data supports the idea that insulin may play an important role in regulating normal cognitive function (4). In fact, in instances of neurotrauma and neurodegenerative diseases, studies have found reduced sensitivity or resistance to insulin (2).  

More recently, AD has been associated with decreased brain capacity to efficiently utilize glucose and respond to insulin (1). Deficits in cerebral glucose utilization due to insulin resistance are found to be present early in the course of the disease and continue to worsen with progression of the disease. Consequently, recent studies have suggested a third type of diabetes, type 3 diabetes (T3DM), where insulin resistance specifically manifests in the brain and results in neurodegeneration (1,5).

Impairment of brain glucose metabolism due to insulin resistance also disrupts brain energy balance, increases oxidative stress, increases reactive oxygen species production, increases DNA damage, and increases mitochondrial dysfunction. All of these then drive pro-apoptosis and pro-inflammatory cascades seen in AD (1). In both human and animal model studies, it has been shown that insulin reduces phosphorylation of amyloid precursor protein and inhibits  phosphorylation of tau protein (4). Since beta-amyloid plaques and phosphorylated tau are conventional biomarkers for AD, these findings further support the notion that insulin may act as a protective factor against AD (4,6).

While AD continues to be a multifactorial disease that impacts millions of lives, this insight into how insulin resistance plays a role in AD pathology will influence the pharmacological and therapeutic strategies used to address AD. Intranasal administration of insulin and insulin-sensitizing agents are at the current forefront of clinical trials (4). Additionally, early and effective therapies that target insulin resistance at its early stages will hopefully be able to prevent great loss in cognition (4). 

Sources: 

1. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168-181. doi:10.1038/nrneurol.2017.185
2. Shaughness M, Acs D, Brabazon F, Hockenbury N, Byrnes KR. Role of Insulin in Neurotrauma and Neurodegeneration: A Review. Front Neurosci. 2020;14. doi:10.3389/fnins.2020.547175
3. de la Monte SM. Type 3 Diabetes is Sporadic Alzheimer’s disease: Mini-Review. Eur Neuropsychopharmacol. 2014;24(12):1954-1960. doi:10.1016/j.euroneuro.2014.06.008
4. Berlanga-Acosta J, Guillén-Nieto G, Rodríguez-Rodríguez N, et al. Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review. Front Endocrinol (Lausanne). 2020;11. doi:10.3389/fendo.2020.560375
5. Nguyen TT, Ta QTH, Nguyen TKO, Nguyen TTD, Van Giau V. Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int J Mol Sci. 2020;21(9). doi:10.3390/ijms21093165 
6. Lloret A, Esteve D, Lloret M-A, et al. When Does Alzheimer′s Disease Really Start? The Role of Biomarkers. Int J Mol Sci. 2019;20(22). doi:10.3390/ijms20225536