Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis

Abstract

The control of body weight and glucose homeostasis are the bedrock of type 2 diabetes medication. Therapies based on co-administration of glucagon-like peptide-1 (GLP-1) long-acting analogues and insulin are becoming popular in the treatment of T2D. Both insulin and GLP-1 receptors (InsR and GLP1-R, respectively) are expressed in brain regions critically involved in the regulation of energy homeostasis, suggesting a possible cooperative action. However, the mechanisms underlying the synergistic action of insulin and GLP-1R agonists on body weight loss and glucose homeostasis remain largely under-investigated. In this study, we provide evidence that peripheral insulin administration modulates the action of GLP-1R agonists onto fatty acids oxidation. Taking advantage of fluorescently labeled insulin and GLP-1R agonists, we found that glucoprivic condition, either achieved by insulin or by 2-deoxyglucose (2-DG), acts as a permissive signal on the blood-brain barrier (BBB) at circumventricular organs, including the median eminence (ME) and the area postrema (AP), enhancing the passage and action of GLP-1-R agonists. Mechanistically, this phenomenon relied on the release of tanycyctic vascular endothelial growth factor A (VEGF-A) and it was selectively impaired after calorie-rich diet exposure. Finally, we found that in human subjects, low blood glucose also correlates with enhanced blood-to-brain passage of insulin suggesting that changes in glycaemia also affect passage of peptide hormones into the brain in humans. In conclusion, we describe a yet unappreciated mechanism by which acute variations of glycaemia gate the entry and action of circulating energy-related signals in the brain. This phenomenon has physiological and clinical relevance implying that glycemic control is critical to harnessing the full benefit of GLP-1R agonist co-treatment in body weight loss therapy.

Pathophysiological Mechanisms That Alter the Autonomic Brain-Liver Communication in Metabolic Diseases

“…Thus, it is no surprise that physiological, counterregulatory mechanisms have evolved that are very effective in preventing or correcting hypoglycemia. Defenses against hypoglycemia include, among others, changes in pancreatic hormone secretions (reduced insulin and increased glucagon), activation of the hypothalamic-pituitary-adrenal axis (increased glucocorticoids), increased sympathoadrenal outflow (increased epinephrine), mobilization of the parasympathetic nervous system (reduced vagal outflow), activation of the sympathetic nervous system (SNS, increased norepinephrine release by the nerves) and changes in brain permeability to facilitate the entry of circulating energy-related signals ( 4 , 5 ). The net effect of the activation of these mechanisms of defense is an increase in metabolic substrates availability, such as increased hepatic glucose production and lipolysis, together with sparing of energy dissipation ( 6 ).…”