Roles of AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1) in controlling pancreatic islet hormone secretion
Author(s)
Sun, Gao
Type
Thesis
Abstract
Pancreatic islets of Langerhans play an essential role in controlling whole body glucose metabolism by releasing key regulating hormones, such as insulin and glucagon. Defective insulin or glucagon secretion has been implicated in several metabolic diseases, such as obesity and diabetes. Therefore, intrinsically well-regulated insulin and glucagon release from the islets is key to maintaining glucose homeostasis.
AMP-activated protein kinase (AMPK), an ancient energy (AMP/ATP) sensor and its principal upstream kinase, STK11 (liver kinase B1, LKB1), a tumour suppressor, have been found to regulate glucose metabolism in several peripheral tissues such as the liver, muscle, hypothalamus, and adipose tissue, and are found to be expressed in both pancreatic β and α cells. However, the role of AMPK and LKB1 in pancreatic islets in controlling hormone secretion and thus the whole body glucose metabolism has never been investigated in vivo.
In this study, I sought to understand how AMPK and LKB1 modulate insulin and glucagon secretion from pancreatic β and α cells respectively, by deleting AMPK or LKB1 in β cells or α cells in the mouse using the LoxP/Cre system.
Deletion of both AMPK α1 and α2 catalytic subunits in islet β cells and certain populations of neuronal cells in the hypothalamus achieved by crossing AMPK α1 whole body knockout and α2 flox'd mice with rat Ins2 promoter (RIP2)-Cre deleter mice, led to severely elevated circulating glucose and diminished insulin secretion in vivo. By contrast, deletion of LKB1, made possible by crossing LKB1 flox'd mice with the same deleter mice, led to an opposite metabolic phenotype. Hind-limb paralysis was also observed, due possibly to an effect on neuronal cell differentiation in the sensory part of the brain. The findings argue against a simple and linear LKB1-AMPK signalling pathway in pancreatic islet β cells.
On the other hand, mice lacking LKB1 or AMPK in pancreatic α cells, generated using a preproglucagon promoter (PPG)-Cre deleter strain, showed reduced glucagon secretion both in vivo and in vitro.
Therefore, LKB1 and AMPK represent two distinct regulators in controlling insulin and glucagon secretion, thus the whole body glucose metabolism. Drugs targeting LKB1 or AMPK, or their respective downstream targets might serve as a promising approach for the treatment of diabetes.
AMP-activated protein kinase (AMPK), an ancient energy (AMP/ATP) sensor and its principal upstream kinase, STK11 (liver kinase B1, LKB1), a tumour suppressor, have been found to regulate glucose metabolism in several peripheral tissues such as the liver, muscle, hypothalamus, and adipose tissue, and are found to be expressed in both pancreatic β and α cells. However, the role of AMPK and LKB1 in pancreatic islets in controlling hormone secretion and thus the whole body glucose metabolism has never been investigated in vivo.
In this study, I sought to understand how AMPK and LKB1 modulate insulin and glucagon secretion from pancreatic β and α cells respectively, by deleting AMPK or LKB1 in β cells or α cells in the mouse using the LoxP/Cre system.
Deletion of both AMPK α1 and α2 catalytic subunits in islet β cells and certain populations of neuronal cells in the hypothalamus achieved by crossing AMPK α1 whole body knockout and α2 flox'd mice with rat Ins2 promoter (RIP2)-Cre deleter mice, led to severely elevated circulating glucose and diminished insulin secretion in vivo. By contrast, deletion of LKB1, made possible by crossing LKB1 flox'd mice with the same deleter mice, led to an opposite metabolic phenotype. Hind-limb paralysis was also observed, due possibly to an effect on neuronal cell differentiation in the sensory part of the brain. The findings argue against a simple and linear LKB1-AMPK signalling pathway in pancreatic islet β cells.
On the other hand, mice lacking LKB1 or AMPK in pancreatic α cells, generated using a preproglucagon promoter (PPG)-Cre deleter strain, showed reduced glucagon secretion both in vivo and in vitro.
Therefore, LKB1 and AMPK represent two distinct regulators in controlling insulin and glucagon secretion, thus the whole body glucose metabolism. Drugs targeting LKB1 or AMPK, or their respective downstream targets might serve as a promising approach for the treatment of diabetes.
Date Issued
2011
Date Awarded
2011-12
Advisor
Leclerc, Isabelle
Rutter, Guy
Creator
Sun, Gao
Publisher Department
Medicine: Diabetes, Endocrinology and Metabolism
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)