GLP-1, the Gut-Brain, and Brain-Periphery Axes

Abstract

■ AbstractGlucagon-like peptide 1 (GLP-1) is a gut hormone which directly binds to the GLP-1 receptor located at the surface of the pancreatic β-cells to enhance glucose-induced insulin secretion. In addition to its pancreatic effects, GLP-1 can induce metabolic actions by interacting with its receptors expressed on nerve cells in the gut and the brain. GLP-1 can also be considered as a neuropeptide synthesized by neuronal cells in the brain stem that release the peptide directly into the hypothalamus. In this environment, GLP-1 is assumed to control numerous metabolic and cardiovascular functions such as insulin secretion, glucose production and utilization, and arterial blood flow. However, the exact roles of these two locations in the regulation of glucose homeostasis are not well understood. In this review, we highlight the latest experimental data supporting the role of the gutbrain and brain-periphery axes in the control of glucose homeostasis. We also focus our attention on the relevance of β-cell and brain cell targeting by gut GLP-1 for the regulation of glucose homeostasis. In addition to its action on β-cells, we find that understanding the physiological role of GLP-1 will help to develop GLP-1-based therapies to control glycemia in type 2 diabetes by triggering the gut-brain axis or the brain directly. This pleiotropic action of GLP-1 is an important concept that may help to explain the observation that, during their treatment, type 2 diabetic patients can be identified as 'responders' and 'non-responders'.

Neuroprotective properties of incretin mimetics in brain ischemia and neurodegenerative diseases

“…Такие волокна выяв-ляются также в таламусе и некоторых участках коры. В стволе ГМ они прилегают к ретикулярной фарма-ции и спинному мозгу [17].…”

“…В гипоталамусе ГПП-1Р распределены в основном в дугообразном (связан-ный с регуляцией аппетита), паравентрикулярном (выделяет окситоцин, который подавляет аппетит, поступая в вентромедиальное ядро и cоматостатин, который замедляет моторику желудка), дорсомеди-альном (регуляция АД и ЧСС) и супрахиазматиче-ском (циркадные ритмы) ядрах. Рецептор обнару-жен в дорсальном комплексе блуждающего нерва, особенно в ядре солитарного тракта и в меньшем количестве в околожелудочковых зонах: субфорни-кальном органе и area postrema (хеморецепторная зона ствола мозга, ответственная за осуществление рвотного рефлекса) [17]. В эксперименте и в клини-ке показано, что ГПП-1, ингибируя активность блуждающего нерва, снижает подвижность желудка, секрецию желудочных желез и панкреатического сока [18].…”

Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System

“…Increasing experimental and clinical evidence suggests that brain glucose metabolism is altered in patients with type 2 diabetes mellitus (T2DM) and contributes to the disturbance in whole-body glucose homeostasis (1,2). The brain receives multiple inputs including 1) hormones, such as leptin, ghrelin, peptide YY (PYY), glucagon like peptide-1 (GLP-1), and insulin, 2) nutrient-related signals that regulate fat accumulation in adipose tissue and hepatic and peripheral glucose metabolism, and 3) signals from the gastrointestinal tract through sensory nerves (1,2).…”

“…The brain receives multiple inputs including 1) hormones, such as leptin, ghrelin, peptide YY (PYY), glucagon like peptide-1 (GLP-1), and insulin, 2) nutrient-related signals that regulate fat accumulation in adipose tissue and hepatic and peripheral glucose metabolism, and 3) signals from the gastrointestinal tract through sensory nerves (1,2).…”

“…Intestinal cells secrete GLP-1 in response to glucose, and deficiency of and resistance to GLP-1 have both been described in patients with T2DM (4,5). The main actions of GLP-1 are to stimulate insulin and inhibit glucagon secretion, although other pleiotropic effects of GLP-1 have been described (2,5). Secreted GLP-1 can gain access to the central nervous system (CNS), bind to GLP1Rs, and modulate neuronal activity in different areas of human brain (3,6).…”