Yaney G C, Corkey B E
Boston University School of Medicine, Obesity Research Center, 650 Albany Street, Boston, MA 02118, USA.
Diabetologia. 2003 Oct;46(10):1297-312. doi: 10.1007/s00125-003-1207-4. Epub 2003 Sep 12.
Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acyl-CoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial beta-oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states.
葡萄糖或脂肪酸水平的升高通过长链酰基辅酶A生成的变化影响代谢，而长期升高的脂肪酸会增加细胞内总辅酶A水平。了解胰腺β细胞对燃料量增加的反应以及胰岛素分泌改变在肥胖和2型糖尿病的发生和维持中所起的作用至关重要。数据表明，脂肪酸的活化形式在刺激-分泌偶联中充当效应分子。葡萄糖会增加胞质长链酰基辅酶A，因为它会增加阻断线粒体β氧化的“开关”化合物丙二酰辅酶A，从而实现从脂肪酸氧化向葡萄糖氧化的转变。我们提出以下观点的论据：（i）支持正常胰岛素分泌需要外源性或内源性（由甘油三酯脂解产生）脂肪酸来源；（ii）脂肪酸的快速增加通过增加脂肪酸辅酶A或复合脂质浓度来增强葡萄糖刺激的分泌，这些物质通过调节关键酶如蛋白激酶C或胞吐机制在远端起作用；（iii）脂肪酸的长期增加通过相同机制增强基础分泌，但会促进肥胖并降低对刺激性葡萄糖的反应；（iv）升高cAMP的药物至少部分通过激活β细胞激素敏感性脂肪酶刺激脂解来充当肠促胰岛素。此外，甘油三酯储存增加可导致更高的脂解速率，从而影响基础和刺激状态下的胰岛素分泌。这些观点突出了非酯化脂肪酸、长链辅酶A及其酯化衍生物在正常和病理状态下影响胰岛素分泌中的重要作用。
