Ling Charlotte, Poulsen Pernille, Carlsson Emma, Ridderstråle Martin, Almgren Peter, Wojtaszewski Jørgen, Beck-Nielsen Henning, Groop Leif, Vaag Allan
Department of Endocrinology, Lund University, Wallenberg Laboratory, Malmö University Hospital, Malmö, Sweden.
J Clin Invest. 2004 Nov;114(10):1518-26. doi: 10.1172/JCI21889.
Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPARgamma coactivator 1alpha (PGC-1alpha) and PGC-1beta genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1alpha gene. Insulin increased and aging reduced skeletal muscle PGC-1alpha and PGC-1beta mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1alpha Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1alpha in a complex fashion. Whereas expression of PGC-1alpha in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1beta expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1alpha and PGC-1beta expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1alpha and PGC-1beta on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
遗传和环境因素导致了2型糖尿病的年龄依赖性易感性。最近的研究报道，2型糖尿病患者骨骼肌中PPARγ共激活因子1α（PGC-1α）和PGC-1β基因的表达降低，但尚不清楚这是遗传性缺陷还是后天获得性缺陷。为了解决这个问题，我们研究了从胰岛素刺激前后的年轻和老年同卵及异卵双胞胎（无已知糖尿病）获取的肌肉活检样本中这些基因的表达，并将其表达与PGC-1α基因中的Gly482Ser变异相关联。胰岛素增加而衰老降低了骨骼肌中PGC-1α和PGC-1β的mRNA水平。这种肌肉基因表达的年龄依赖性降低部分是可遗传的，并受PGC-1α Gly482Ser多态性的影响。此外，性别、出生体重和有氧运动能力以复杂的方式影响PGC-1α的表达。虽然肌肉中PGC-1α的表达与胰岛素刺激的葡萄糖摄取和氧化呈正相关，但PGC-1β的表达与脂肪氧化和非氧化葡萄糖代谢呈正相关。我们得出结论，骨骼肌中PGC-1α和PGC-1β的表达受胰岛素刺激而受衰老抑制。数据还表明PGC-1α和PGC-1β在肌肉细胞的葡萄糖和脂肪氧化上具有不同的调节功能。这些调节氧化磷酸化的关键基因的表达随年龄下降受遗传控制这一发现，可能为环境触发因素（年龄）如何改变2型糖尿病的遗传易感性提供一种解释。
