Cognitive disorder and dementia in type 2 diabetes mellitus

Abstract

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer's disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

Keywords: Alzheimer´s disease; Cognitive decline; Diabetes mellitus; Insulin; Vascular dementia.

Figure 1

Diabetes Mellitus and its association with Dementia. The alteration in the peripheric and central glucose levels increases the risk of cerebrovascular accidents due to different causes associated with vascular or mixed dementia. The figure has been designed using some resources from Falticon.com.

Figure 2

Insulin and insulin-like growth factor 1 production. Both can be produced at the periphery and transported to the brain through the blood-brain barrier, but pyramidal neurons can also produce them. The figure has been designed using some resources from Freepik.com and Flaticon.com. IGF-1: Insulin-like growth factor 1.

Figure 3

Tau protein regulation. A: Insulin and Tau protein with no insulin increase hyperphosphorylate of Tau folding the protein; B: O-GlcNAcylation and Tau protein can regulate glucose amination to serine and threonine decrease the formation of Tau folding. Some pictures were taken from Qiagen Pathways. GSK3: Glycogen synthase kinase-3; IGF-1: Insulin-like growth factor 1; Pi3K: Phosphoinositide-3 kinase; Akt: Serine/threonine specific protein kinase; GlcNAc: O-GlcNAcylation.

Figure 4

Neuroinflammation in patients with Alzheimer’s disease. Inflammation leads to the production of inflammation cytokines in central nervous system, activating x that impacts the transcription of pro-inflammatory genes. Some pictures were taken from Qiagen Pathways. TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin 6; NF-κB: Nuclear factor kappa beta; CNS: Central nervous system.

Figure 5

Synaptic transmission and memory. Insulin increases the density of insulin receptors, its activity, the activation of routes such as phosphoinositide-3 kinase, mitogen-activated protein kinase, and extracellular signal-regulated kinase and regulates the binding of acetylcholine with its receptors, modulating cognition, memory, neurotransmission, and neurogenesis. Some pictures were taken from Qiagen Pathways. AChE: Acetylcholine; Pi3K: Phosphoinositide-3 kinase; MAPK: Mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinase.

Figure 6

Insulin resistance and Alzheimer’s disease. A: Amyloid beta (Aβ) relationship with insulin, the effect of Aβ plaques on insulin signaling, Aβ increases insulin resistance; B: Neuroinflammation and insulin inflammation disrupts insulin signaling pathways by impacting metabolic transducers. Some pictures were taken from Qiagen Pathways. Aβ: Amyloid beta; Pi3K: Phosphoinositide-3 kinase; Akt: Serine/threonine specific protein kinase; TNF-α: Tumor necrosis factor alpha.

Figure 7

Relation type 2 diabetes mellitus and Alzheimer’s disease. The interconnection between β-amyloid protein, Tau protein and amylin increases the accumulation of amyloid deposit, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance and cell death; factors that explain the evolution to type 2 diabetes mellitus and Alzheimer’s disease. Some pictures were taken from Qiagen Pathways.