Hypothyroidism and Diabetes-Related Dementia: Focused on Neuronal Dysfunction, Insulin Resistance, and Dyslipidemia

Abstract

The incidence of dementia is steadily increasing worldwide. The risk factors for dementia are diverse, and include genetic background, environmental factors, sex differences, and vascular abnormalities. Among the subtypes of dementia, diabetes-related dementia is emerging as a complex type of dementia related to metabolic imbalance, due to the increase in the number of patients with metabolic syndrome and dementia worldwide. Thyroid hormones are considered metabolic regulatory hormones and affect various diseases, such as liver failure, obesity, and dementia. Thyroid dysregulation affects various cellular mechanisms and is linked to multiple disease pathologies. In particular, hypothyroidism is considered a critical cause for various neurological problems-such as metabolic disease, depressive symptoms, and dementia-in the central nervous system. Recent studies have demonstrated the relationship between hypothyroidism and brain insulin resistance and dyslipidemia, leading to diabetes-related dementia. Therefore, we reviewed the relationship between hypothyroidism and diabetes-related dementia, with a focus on major features of diabetes-related dementia such as insulin resistance, neuronal dysfunction, and dyslipidemia.

Keywords: diabetes-related dementia; dyslipidemia; hypothyroidism; insulin resistance; thyroid hormone.

Figure 1

TH crosses blood brain barrier into the brain. T3 and T4, secreted from thyroid gland, cross the blood–brain barrier (BBB) into the brain through MCT8 and OATP1C1 TH transporters in neuron and OATP1C1 TH transporters in astrocytes. T4 is converted to T3 by type II 5′-deiodinase enzyme (DIO2) in astrocyte.

Figure 2

TH regulates glucose metabolism and the secretion of neurotransmitters in hypothyroidism. TH controls glucose uptake and insulin sensitivity by maintaining the expression of glucose transporters such as glucose transporter (GLUT) in CNS cells. TH prevents the cell death process and promotes neurite outgrowth and synaptic plasticity through several genes, such as the Nrgn, Reln and Srg1 genes, and through the CaMK/4/CREB signaling in neuron. TH modulates the expression of neurotransmitters, including dopamine, glutamate, GABA, and BDNF, through several kinds of signaling, and can ultimately control brain functions. Additionally, TH increases the activation of PI3K/Akt signaling, and GSK3β signaling is related to the enhancement of insulin sensitivity. TH boosts the expression of BDNF, leading to the activation of PI3K/Akt signaling, which is involved in cognitive function. Finally, the improvement of insulin sensitivity leads to the enhancement of cognitive function. In hypothyroidism, reduced levels of TH lead to impaired synaptic plasticity, cognitive deficit, abnormal neurotransmitter release, impaired neurite outgrowth, and insulin resistance.

Figure 3

TH regulates dyslipidemia in hypothyroidism. TH modulates the secretion of cholesterol, the expression of HMG-CoA reductase, and the synthesis of LCL-cholesterol and HDL-cholesterol. Additionally, TH controls the expression of the acetyl-CoA carboxylase and fatty acid synthase (ACC/FAS) ACC/FAS gene involved in lipid metabolism. TH promotes the expression of the FGF21 gene and activates proliferator-activated receptor α (PPARα) signaling, which is related to triglycerides. In hypothyroidism, reduced levels of TH lead to impaired synaptic plasticity, cognitive deficit, abnormal neurotransmitter release, impaired neurite outgrowth, and dyslipidemia.