Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism.
Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism.
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作者：
Cochran BJ;Hou L;Manavalan AP;Moore BM;Tabet F;Sultana A;Cuesta Torres L;Tang S;Shrestha S;Senanayake P;Patel M;Ryder WJ;Bongers A;Maraninchi M;Wasinger VC;Westerterp M;Tall AR;Barter PJ;Rye KA
胰腺β细胞胆固醇水平升高损害胰岛素分泌并降低血浆胰岛素水平。本研究证实低血浆胰岛素水平对两个主要胰岛素靶组织：脂肪组织和骨骼肌有不利影响。通过条件删除β-细胞中atp结合盒转运体ABCA1和ABCG1，产生β-细胞胆固醇水平升高的小鼠（β-DKO小鼠）。在基础和高糖条件下，这些小鼠的胰岛素分泌受损，葡萄糖的处理从骨骼肌转移到脂肪组织。β-DKO小鼠体内脂肪和脂肪组织巨噬细胞含量增加，血浆白细胞介素-6和MCP-1水平升高，骨骼肌质量下降。然而，他们没有胰岛素抵抗。当血浆胰岛素水平通过补充胰岛素恢复正常时，脂肪组织扩张和骨骼肌质量减少，但没有全身性炎症或脂肪组织巨噬细胞含量增加被逆转。这些研究确定了β细胞胆固醇稳态的扰动和胰岛素分泌受损增加肥胖、减少骨骼肌质量和引起全身炎症的机制。他们进一步确定β细胞功能障碍是患2型糖尿病风险增加人群的潜在治疗靶点。
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.
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影响因子：
7.7
作者：
Kruit JK;Wijesekara N;Westwell-Roper C;Vanmierlo T;de Haan W;Bhattacharjee A;Tang R;Wellington CL;LütJohann D;Johnson JD;Brunham LR;Verchere CB;Hayden MR
通讯作者：
Hayden MR
影响因子：
16.8
作者：
Asturias, FJ;Chadick, JZ;Smith, S
通讯作者：
Smith, S
影响因子：
7
作者：
Karp, Natasha A.;McCormick, Paul S.;Lilley, Kathryn S.
通讯作者：
Lilley, Kathryn S.
影响因子：
8.2
作者：
Montgomery, M. K.;Hallahan, N. L.;Turner, N.
通讯作者：
Turner, N.
影响因子：
16.2
作者：
Cali AM;Man CD;Cobelli C;Dziura J;Seyal A;Shaw M;Allen K;Chen S;Caprio S
通讯作者：
Caprio S