Fex M, Nitert M Dekker, Wierup N, Sundler F, Ling C, Mulder H
Department of Experimental Medical Science, Division of Diabetes, Metabolism, and Endocrinology, Lund University, Lund, Sweden.
Diabetologia. 2007 Jan;50(1):74-83. doi: 10.1007/s00125-006-0464-4. Epub 2006 Nov 9.
AIM/HYPOTHESIS: Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance.
C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology.
HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area.
CONCLUSIONS/INTERPRETATION: We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation.
目的/假设：高胰岛素血症在胰岛素抵抗状态下维持血糖正常。β细胞适应的精确细胞机制仍未明确。一种外周来源的信号，如循环脂肪酸增加，可能会指示β细胞启动适应性程序以维持葡萄糖稳态。当这一过程失败时，就会发生2型糖尿病。由于线粒体在β细胞病理生理学中起关键作用，我们检验了线粒体代谢对β细胞适应胰岛素抵抗至关重要这一假设。
给C57BL/6J小鼠喂食高脂（HF）饮食12周。然后我们分析了胰岛激素分泌以及体内和体外的代谢情况，还有β细胞形态。
HF饮食导致胰岛素抵抗和葡萄糖不耐受，但未发展为明显的糖尿病。HF小鼠分离的胰岛基础胰岛素分泌升高，高糖几乎不会引发额外反应。相比之下，当用需要线粒体代谢的燃料（如谷氨酸、谷氨酰胺、α-酮异己酸和琥珀酸）刺激HF小鼠的胰岛时，会出现强烈的分泌反应。此外，虽然HF小鼠胰岛的葡萄糖氧化受损，但谷氨酰胺和棕榈酸的氧化增强。对HF小鼠胰岛的超微结构分析显示，β细胞中脂滴积累，线粒体面积增加两倍。
结论/解读：我们提出，在胰岛素抵抗状态下，暴露于脂质通量增加环境中的β细胞会通过增加线粒体体积做出反应。这种扩张与线粒体代谢增强相关，是β细胞的一种代偿方式。
