Nikoulina S E, Ciaraldi T P, Abrams-Carter L, Mudaliar S, Park K S, Henry R R
Department of Medicine, University of California, San Diego, and the Veterans Affairs Medical Center 92161, USA.
Diabetes. 1997 Jun;46(6):1017-24. doi: 10.2337/diab.46.6.1017.
Human skeletal muscle cultures (HSMCs) from type II diabetic subjects were used to determine whether metabolic abnormalities such as hyperglycemia or hyperinsulinemia contribute to the defective muscle glycogen synthase (GS) activity present in this disorder. Following approximately 6 weeks of growth, diabetic cultures were fused for 4 days in normal, hyperglycemia, or hyperinsulinemia medium. Fusion of diabetic HSMCs in hyperglycemia medium (20 mmol/l vs. 5.5 mmol/l) had no effect on GS fractional velocity (FV) or mRNA levels, but impaired acute insulin-stimulation of glycogen synthesis and GS activity at 0.1 mmol/l glucose-6-phosphate, and reduced GS protein content by approximately 15% (P < 0.05). Fusion of diabetic muscle cultures in hyperinsulinemia medium (30 micromol/l vs. 22 pmol/l) improved basal GS activity, increasing the reduced GS FV by approximately 50% (P < 0.05), and decreasing the elevated Km(0.1) (half-maximal substrate concentration) by approximately 47% (P < 0.05). Hyperinsulinemia also significantly increased (P < 0.05) the reduced GS mRNA and protein levels of diabetic muscle to levels similar to that in nondiabetic subjects. In contrast to the improvements in the basal state, hyperinsulinemia completely abolished acute insulin responsiveness of GS activity and glycogen synthesis in muscle of type II diabetic subjects. The combination of hyperinsulinemia and hyperglycemia produced effects on both basal and insulin-responsive GS FV and mRNA similar to hyperinsulinemia alone, but hyperinsulinemia prevented hyperglycemia's effect of lowering GS protein and glycogen synthesis. We concluded that, in diabetic muscle, hyperinsulinemia may serve to partially compensate for the impaired basal GS activity and for the adverse effects of hyperglycemia on GS protein content, activity, and glycogen formation by both pre- and posttranslational mechanisms. Despite these beneficial effects, hyperinsulinemia also induces severe impairment of insulin-stimulated GS activity and glycogen formation, which may contribute to acquired muscle insulin resistance of type II diabetes.
来自II型糖尿病患者的人骨骼肌培养物（HSMCs）被用于确定诸如高血糖或高胰岛素血症等代谢异常是否导致该疾病中存在的肌肉糖原合酶（GS）活性缺陷。在生长约6周后，将糖尿病培养物在正常、高血糖或高胰岛素血症培养基中融合4天。在高血糖培养基（20 mmol/l对比5.5 mmol/l）中融合糖尿病HSMCs对GS分数速度（FV）或mRNA水平没有影响，但在0.1 mmol/l葡萄糖-6-磷酸时损害了糖原合成和GS活性的急性胰岛素刺激，并使GS蛋白含量降低约15%（P < 0.05）。在高胰岛素血症培养基（30 μmol/l对比22 pmol/l）中融合糖尿病肌肉培养物改善了基础GS活性，使降低的GS FV增加约50%（P < 0.05），并使升高的Km(0.1)（半最大底物浓度）降低约47%（P < 0.05）。高胰岛素血症还显著增加（P < 0.05）了糖尿病肌肉中降低的GS mRNA和蛋白水平，使其达到与非糖尿病受试者相似的水平。与基础状态的改善相反，高胰岛素血症完全消除了II型糖尿病患者肌肉中GS活性和糖原合成的急性胰岛素反应性。高胰岛素血症和高血糖的组合对基础和胰岛素反应性GS FV以及mRNA产生的影响与单独高胰岛素血症相似，但高胰岛素血症阻止了高血糖降低GS蛋白和糖原合成的作用。我们得出结论，在糖尿病肌肉中，高胰岛素血症可能通过翻译前和翻译后机制部分补偿基础GS活性受损以及高血糖对GS蛋白含量、活性和糖原形成的不利影响。尽管有这些有益作用，高胰岛素血症也会导致胰岛素刺激的GS活性和糖原形成严重受损，这可能导致II型糖尿病获得性肌肉胰岛素抵抗。
