Insulin Resistance in Brain and Possible Therapeutic Approaches
Sevki Cetinkalp, Ilgin Y. Simsir and Sibel Ertek
Affiliation: Department of Endocrinology and Metabolic Diseases, Ege University Medical School, 35100 Bornova- IZMIR- TURKEY.
Keywords: Brain, hypothalamus, insulin resistance, leptin.
Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin
has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral
insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin
sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin
has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory.
Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may
damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus,
where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy
metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial
dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus
(DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously
practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin
sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.
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