Dysmetabolism and Neurodegeneration: Trick or Treat?

Abstract

Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.

Type 2 diabetes mellitus-associated cognitive impairment and management

“…[24] Once thought to be an insulin-insensitive organ, the brain is now recognized as a target for insulin action, with IR density particularly high in areas of the CNS such as the hippocampus, which is involved in memory, the hypothalamus, which is important for metabolic control, and other areas such as the olfactory bulb, cerebellum, amygdala, and cerebral cortex [Figure 1]. [25] GSK-3β and tau phosphorylation GSK-3's function was initially assumed to be the phosphorylation of just GS, which inactivated GS. The main factor causing insulin resistance in the brains of people with Alzheimer and disease is elevated levels of oxidative stress.…”

Impact of Sugars on Hypothalamic Satiety Pathways and Its Contribution to Dysmetabolic States

“…Glucose is the primary energy source used by humans; it is crucial in maintaining the body's functions. The major hallmark of T2D is hyperglycaemia, which results from defects in insulin production and secretion [4,30]. This state is caused by a wavering of the regulatory circuits that maintain glucose levels within the normal range.…”

“…Apart from impacting hypothalamic satiety pathways, sugar also impacts reward systems due to its additive, palatable, and rewarding characteristics, which may lead to compulsive eating [30,61]. As described in Section 2, hypothalamic neurocircuits project to the mesolimbic pathway, which is composed of the VTA and the NAc, called the reward system, and is important in the control of hedonic hunger [7,16].…”

Sleep disorders contribute to the development of dementia and Alzheimer’s disease

“…The hypothalamus is the major regulator that is responsible for controlling the body's internal balance. Hypothalamic control is based on the coordination of major bodily functions such as the heart rate and blood pressure, body temperature, fluid and electrolyte balance, appetite, body weight, fatigue, sleep cycle, and function of the gastrointestinal tract [13].…”