The incretin hormone glucagon-like peptide 1 (GLP-1) is well known for exerting a wide range of p... more The incretin hormone glucagon-like peptide 1 (GLP-1) is well known for exerting a wide range of physiological actions that contribute to the maintenance of normal glucose tolerance. GLP-1 agonists have recently been approved for clinical use in the treatment of type 2 diabetes, with evidence suggesting that the central GLP-1 system may act directly on specific peripheral tissues involved in the regulation of glucose metabolism. However, whether pancreatic β-cells are directly regulated by neuronal GLP-1 receptors (GLP-1R) is currently unknown. In order to unravel the role of brain GLP-1R on β-cell function, we administered intracerebroventricular (ICV) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), both in an acute and a chronic setting. We observed that acute ICV GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired the glucose excursion after a glucose load. However, sustained activation of CNS GLP-1R did not produce any effect, neither on GSIS nor on glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with ICV GLP-1 displayed no differences as compared to controls. Additionally, in mice fed a high-fat diet (HFD) we observed that acute ICV GLP-1 infusion improves glucose tolerance without changes in GSIS, while chronic GLP-1R activation has no effect on glucose homeostasis. Our results indicate that, under non clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents.
Current therapies for the treatment of type 1 diabetes include daily administration of exogenous ... more Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.
The incretin hormone glucagon-like peptide 1 (GLP-1) is well known for exerting a wide range of p... more The incretin hormone glucagon-like peptide 1 (GLP-1) is well known for exerting a wide range of physiological actions that contribute to the maintenance of normal glucose tolerance. GLP-1 agonists have recently been approved for clinical use in the treatment of type 2 diabetes, with evidence suggesting that the central GLP-1 system may act directly on specific peripheral tissues involved in the regulation of glucose metabolism. However, whether pancreatic β-cells are directly regulated by neuronal GLP-1 receptors (GLP-1R) is currently unknown. In order to unravel the role of brain GLP-1R on β-cell function, we administered intracerebroventricular (ICV) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), both in an acute and a chronic setting. We observed that acute ICV GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired the glucose excursion after a glucose load. However, sustained activation of CNS GLP-1R did not produce any effect, neither on GSIS nor on glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with ICV GLP-1 displayed no differences as compared to controls. Additionally, in mice fed a high-fat diet (HFD) we observed that acute ICV GLP-1 infusion improves glucose tolerance without changes in GSIS, while chronic GLP-1R activation has no effect on glucose homeostasis. Our results indicate that, under non clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents.
Current therapies for the treatment of type 1 diabetes include daily administration of exogenous ... more Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.
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Papers by Eva Tudurí