RESUMO
GLP-1 was described as an incretin over 30 years ago. GLP-1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP-1 activates GLP-1 receptors (GLP-1r) on the ß-cell to induce insulin secretion in a glucose-dependent manner. GLP-1 also inhibits α-cell secretion of glucagon. As few, if any, GLP-1r are expressed on α-cells, indirect regulation, via ß- or δ-cell products has been thought to be the primary mechanism by which GLP-1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP-1r on α-cells for direct regulation as well. Although the predominant source of circulating GLP-1 is the intestine, the α-cell becomes a source of GLP-1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP-1 is also be important in regulating nutrient-induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg-derived protein produced by the α-cell, in stimulating insulin secretion by acting on GLP-1r. Altogether, these data clearly demonstrate the important role of Gcg-derived peptides in regulating insulin secretion. Because of GLP-1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus. © 2020 American Physiological Society. Compr Physiol 10:577-595, 2020.
Assuntos
Diabetes Mellitus/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células Secretoras de Glucagon/metabolismo , Hormônios Pancreáticos/metabolismo , Animais , Homeostase/fisiologia , HumanosRESUMO
Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 1 (P-Rex1) is a Rho guanine nucleotide exchange factor synergistically activated by PIP3 and Gßγ that plays an important role in the metastasis of breast, prostate, and skin cancer, making it an attractive therapeutic target. However, the molecular mechanisms behind P-Rex1 regulation are poorly understood. We determined structures of the P-Rex1 pleckstrin homology (PH) domain bound to the headgroup of PIP3 and resolved that PIP3 binding to the PH domain is required for P-Rex1 activity in cells but not for membrane localization, which points to an allosteric activation mechanism by PIP3. We also determined structures of the P-Rex1 tandem Dbl homology/PH domains in complexes with two of its substrate GTPases, Rac1 and Cdc42. Collectively, this study provides important molecular insights into P-Rex1 regulation and tools for targeting the PIP3-binding pocket of P-Rex1 with a new generation of cancer chemotherapeutic agents.