Lipid-induced β-cell dysfunction in vivo in models of progressive β-cell failure
Lipid-induced β-cell dysfunction in vivo in models of progressive β-cell failure
复制标题
DOI：
10.1152/ajpendo.00255.2006
复制
发表时间：
2007-02-01
影响因子：
5.1
通讯作者：
Giacca, Adria
中科院分区：
文献类型：
--
作者：
Goh, Tracy T.;Mason, Timothy M.;Giacca, Adria
进行性β细胞衰竭模型中脂质诱导的体内β细胞功能障碍。Am J Physiol Endocrinol Metab 292：E549-E560，2007.首次发表于2006年9月26日; doi：10.1152/ajpendo.00255.2006。我们在对照雌性Wistar大鼠（a组）和下列进行性β细胞功能障碍的雌性大鼠模型中测定了48小时血浆游离脂肪酸（FFA）升高对高血糖钳夹期间胰岛素分泌的影响：瘦Zucker糖尿病肥胖（ZDF）大鼠，包括野生型（B组）和瘦素受体基因中fa突变的杂合子（c组）;肥胖（fa/fa）Zucker大鼠（非糖尿病前期; d组）;肥胖糖尿病前期（fa/fa）ZDF大鼠（e组）;和肥胖（fa/fa）糖尿病ZDF大鼠（f组）。FFA在所有组中诱导胰岛素抵抗，但仅在肥胖糖尿病前期ZDF大鼠中增加C肽水平（绝对胰岛素分泌指数）。用双曲线或幂函数关系（分别为处置指数或补偿指数，这两个β细胞功能指数）校正胰岛素敏感性的胰岛素分泌被FFA降低。正常血糖杂合子瘦ZDF大鼠的下降幅度大于Wistar对照组。在伴有轻度高血糖的肥胖“糖尿病前期”ZDF大鼠中，FFA诱导的β细胞功能下降并不大于肥胖Zucker大鼠。然而，在明显患有糖尿病的肥胖ZDF大鼠中，FFA进一步损害了β细胞功能。总之，1）FFA诱导的β细胞功能损伤在单拷贝突变瘦素受体基因存在下加重，与高血糖无关。2)在轻度高血糖的糖尿病前期ZDF大鼠中，脂毒性未加重，因为β细胞对FFA诱导的胰岛素抵抗产生部分代偿反应。3)这种补偿在具有更显著的高血糖和葡萄糖感知丧失的糖尿病大鼠中丧失。
Lipid-induced beta-cell dysfunction in vivo in models of progressive beta-cell failure. Am J Physiol Endocrinol Metab 292: E549-E560, 2007. First published September 26, 2006; doi:10.1152/ajpendo.00255.2006.- We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive beta-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of beta-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in beta-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired beta-cell function. In conclusion, 1) the FFA-induced impairment in beta-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the beta-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing.