Is “Leptin Resistance” Another Key Resistance to Manage Type 2 Diabetes?

Abstract

: 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 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.

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

“…Therefore, leptin sensitivity may be a possible therapeutic target in this disease. Insulin sensitivity modulators in combination with amylin and/or GLP-1 analogues may be of interest due to their central activity in the hypothalamus [ 209 ].…”

Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links

“…This has been described among obese individuals as a component in IR and T2DM. Meanwhile, late-life weight loss has been related to low circulating levels of leptin[ 145 , 146 ]. Low brain leptin signaling has been found to worsen hippocampus functionality and decrease the neuroprotection against various central processes in the pathogenesis of AD, such as the metabolism of amyloid beta and tau[ 145 , 147 ].…”

“…Low brain leptin signaling has been found to worsen hippocampus functionality and decrease the neuroprotection against various central processes in the pathogenesis of AD, such as the metabolism of amyloid beta and tau[ 145 , 147 ]. The administration of leptin may renew insulin sensitivity by interacting with the insulin receptor and its signaling pathway[ 148 - 150 ] and by decreasing the pro-inflammatory response[ 146 ]. Likewise, in mice with AD, leptin has shown a promising therapeutic effect, improving the formation of memory, synaptic plasticity, and performance in learning activities[ 151 - 153 ].…”

TNF-α Antagonizes the Effect of Leptin on Insulin Secretion through FOXO1-Dependent Transcriptional Suppression of LepRb in INS-1 Cells

“…Leptin resistance is defined by a reduced sensitivity or a failure in response of the brain to leptin, showing a decrease in the ability of leptin to reduce appetite or enhance energy expenditure, which causes an increased food intake and finally leads to overweight, obesity, cardiovascular diseases, and other metabolic disorders. Leptin resistance is a challenge for clinical treatment or drug discovery of T2MD [ 13 ].…”