RT Journal Article
SR Electronic
T1 Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 3610
OP 3620
DO 10.2337/db16-0668
VO 65
IS 12
A1 Cochran, Blake J.
A1 Hou, Liming
A1 Manavalan, Anil Paul Chirackal
A1 Moore, Benjamin M.
A1 Tabet, Fatiha
A1 Sultana, Afroza
A1 Cuesta Torres, Luisa
A1 Tang, Shudi
A1 Shrestha, Sudichhya
A1 Senanayake, Praween
A1 Patel, Mili
A1 Ryder, William J.
A1 Bongers, Andre
A1 Maraninchi, Marie
A1 Wasinger, Valerie C.
A1 Westerterp, Marit
A1 Tall, Alan R.
A1 Barter, Philip J.
A1 Rye, Kerry-Anne
YR 2016
UL http://diabetes.diabetesjournals.org/content/65/12/3610.abstract
AB Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.