Abstract
Aims: One of the hallmarks of diabetes is dysregulated glucagon secretion from pancreatic alpha cells. Glucagon-Like Peptide 1 (GLP1) is secreted from gut enteroendocrine L cells, potentiating insulin secretion, and GLP-1 levels are reduced in Type 2 diabetes. Despite the important role of these cell types in glycaemic control, the mechanisms regulating their secretory function are not well defined.
We have previously identified that ACC1, the rate-limiting enzyme of de novo lipogenesis, plays a critical role in the growth and function of beta cells. The aim of the current project was to explore the role of ACC1 in pancreatic alpha and gut L-cell function.
Methods: ACC1 was ablated in alpha and L cells in vivo using a glucagon-driven Cre–Lox strategy, and in vitro using pharmacological inhibitors.
Results: Pharmacological inhibition of ACC impaired glucagon secretion from transformed alpha cells, primary mouse and human islets, as well as impairing GLP-1 secretion from transformed enteroendocrine cells and primary gut crypts. To investigate these mechanisms in vivo, we generated mice with ACC1 ablated in alpha and L cells (Glu-ACC1KO). Glu-ACC1KO mice were glucose intolerant, relative to littermate control mice, with lower fasting glucagon levels that were unresponsive to glucose administration. Correspondingly, the secretion of glucagon and GLP-1 from islets and gut crypts isolated from Glu-ACC1KO mice was severely impaired, relative to controls, and consistent with our in vitro ACC inhibitor data.
Summary: Our data reveals a critical role for ACC1 in controlling alpha and L-cell function and whole-body glucose homeostasis.
We have previously identified that ACC1, the rate-limiting enzyme of de novo lipogenesis, plays a critical role in the growth and function of beta cells. The aim of the current project was to explore the role of ACC1 in pancreatic alpha and gut L-cell function.
Methods: ACC1 was ablated in alpha and L cells in vivo using a glucagon-driven Cre–Lox strategy, and in vitro using pharmacological inhibitors.
Results: Pharmacological inhibition of ACC impaired glucagon secretion from transformed alpha cells, primary mouse and human islets, as well as impairing GLP-1 secretion from transformed enteroendocrine cells and primary gut crypts. To investigate these mechanisms in vivo, we generated mice with ACC1 ablated in alpha and L cells (Glu-ACC1KO). Glu-ACC1KO mice were glucose intolerant, relative to littermate control mice, with lower fasting glucagon levels that were unresponsive to glucose administration. Correspondingly, the secretion of glucagon and GLP-1 from islets and gut crypts isolated from Glu-ACC1KO mice was severely impaired, relative to controls, and consistent with our in vitro ACC inhibitor data.
Summary: Our data reveals a critical role for ACC1 in controlling alpha and L-cell function and whole-body glucose homeostasis.
| Original language | English |
|---|---|
| Article number | A33 |
| Pages (from-to) | 16-17 |
| Number of pages | 2 |
| Journal | Diabetic Medicine |
| Volume | 36 |
| Issue number | S1 |
| Early online date | 5 Mar 2019 |
| DOIs | |
| Publication status | Published - Mar 2019 |
| Event | Diabetes UK Professional Conference 2019 - ACC Liverpool, Liverpool, United Kingdom Duration: 6 Mar 2019 → 8 Mar 2019 |
