Although novel pharmacological options for the treatment of type 2 diabetes mellitus (DM2)
have been observed to modulate the functionality of several key organs in glucose homeostasis, successful
regulation of insulin resistance (IR), body weight management, and pharmacological treatment of
obesity remain notable problems in endocrinology. Leptin may be a pivotal player in this scenario, as an
adipokine which centrally regulates appetite and energy balance. In obesity, excessive caloric intake promotes
a low-grade inflammatory response, which leads to dysregulations in lipid storage and adipokine
secretion. In turn, these entail alterations in leptin sensitivity, leptin transport across the blood-brain barrier
and defects in post-receptor signaling. Furthermore, hypothalamic inflammation and endoplasmic reticulum
stress may increase the expression of molecules which may disrupt leptin signaling. Abundant
evidence has linked obesity and leptin resistance, which may precede or occur simultaneously to IR
and DM2. Thus, leptin sensitivity may be a potential early therapeutic target that demands further preclinical
and clinical research. Modulators of insulin sensitivity have been tested in animal models and
small clinical trials with promising results, especially in combination with agents such as amylin and
GLP-1 analogs, in particular, due to their central activity in the hypothalamus.
Keywords: Leptin, leptin resistance, diabetes, obesity, hyperleptinemia, insulin resistance, adipokines.
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