Abstract 64: Pancreatic ß-Cell--Specific Deletion of ABCA1 and ABCG1 Perturbs Glucose Metabolism and Increases Adiposity in Mice
Background: Evidence suggests that pancreatic lipid accumulation causes β-cell dysfunction. Mice with β-cell specific ABCA1 deletion and global knockout of ABCG1 have increased β-cell sterol levels, impaired glucose tolerance, raised fasting plasma glucose levels and impaired glucose-stimulated insulin secretion. However, as mice with global deletion of ABCG1 also have low adipose tissue mass and do not become glucose intolerant or insulin resistant when challenged with a high fat diet, that study did not provide an insight into the specific impact of β-cell dysfunction on glucose metabolism.
Aim: Investigate the effects of isolated β-cell-specific deletion of ABCA1 and ABCG1 on glucose metabolism in mice.
Methods: β-cell specific knockout mice were generated by crossing Ins2-cre and Abca1fl/flAbcg1fl/fl mice. Animals were maintained on a chow diet from the time of weaning until 16 weeks of age. Body weight and food intake were monitored weekly. At 16 weeks of age, mice were subjected to glucose (2 g/kg) and insulin (1 U/kg) tolerance tests. Blood glucose and insulin levels were measured with a glucometer and by RIA, respectively. Plasma MCP-1 and IL-6 levels were measured by ELISA. Fat and muscle mass were assessed by MRI.
Results: Islet ABCA1 and ABCG1 expression was reduced by 76% and 70%, respectively, in knockout mice compared to control. ABCA1 and ABCG1 expression was comparable in all other tissues. Control and knockout animals had comparable islet mass and insulin content, but the knockout mice were markedly glucose intolerant (AUC 2649±230 vs 1539±189) and had reduced fasting insulin levels (0.67±0.18 vs 1.11±0.17 ng/mL). Insulin levels increased 1.5 fold in response to a glucose challenge in control animals, while no increase was observed in knockout animals. Both knockout and control animals were insulin sensitive. Despite similar weight and food intake, the knockout mice had a 28% increase in adiposity and a 10% reduction in muscle mass and plasma IL-6 and MCP-1 levels were increased 3.5- and 5-fold, respectively, relative to the control animals.
Conclusion: β-cell specific deletion of ABCA1 and ABCG1 in mice reduces both acute and chronic insulin secretion, impairs glucose metabolism, alters body composition and increases systemic inflammation.
Author Disclosures: B.J. Cochran: None. L. Hou: None. B.M. Moore: None. A. Sultana: None. A.R. Tall: None. P.J. Barter: None. K. Rye: None.
- © 2014 by American Heart Association, Inc.