Effect of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats
Effect of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats
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DOI：
10.2337/diabetes.50.5.1076
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发表时间：
2001-05-01
期刊：
影响因子：
7.7
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Bergeron, R;Previs, SF;Shulman, GI
用5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）活化AMP-活化蛋白激酶（AMPK）通过胰岛素非依赖性途径增加骨骼肌中的葡萄糖转运。为了检查AMPK激活对胰岛素抵抗大鼠模型中骨骼肌葡萄糖转运活性和全身碳水化合物和脂质代谢的影响，清醒的肥胖Zucker fa/fa大鼠（n = 26）和它们的瘦（rt = 23）同窝出生的大鼠仅用AICAR、胰岛素或盐水输注90分钟。选择胰岛素输注速率（4 mU kg-1 min-1），以匹配瘦大鼠AICAR（推注，100 mg/kg;恒定，10 mg kg-1 min-1）等糖钳夹期间的葡萄糖需求。这些相同的AICAR和胰岛素输注速率的作用随后在肥胖的Zucker大鼠中进行检查。AICAR输注使瘦大鼠和肥胖大鼠的肌肉AMPK活性增加了五倍以上（与对照组和胰岛素相比P < 0.01）。通过[2-C-13]甘油评估的血浆甘油三酯、脂肪酸浓度和甘油周转率在输注AICAR的瘦大鼠和肥胖大鼠中均降低（P < 0.05 vs.基础），而胰岛素对肥胖大鼠中的这些参数没有影响。通过[U-C-13]葡萄糖测量的内源性葡萄糖产生速率在AICAR和胰岛素输注期间在瘦大鼠和肥胖大鼠中仅被抑制> 50%（与基础相比P < 0.05）。在瘦大鼠中，在AICAR和胰岛素输注期间，全身葡萄糖处置率增加了2倍以上（与基础相比P < 0.05）;在输注AICAR或胰岛素的瘦大鼠的比目鱼肌和红腓肠肌中，[H-3]2-脱氧-D-葡萄糖转运活性增加了相似的程度，>2.2倍（与对照相比P <0.05）。在肥胖的Zucker大鼠中，AICAR和胰岛素都没有刺激全身葡萄糖处置或比目鱼肌葡萄糖转运活性。然而，AICAR使肥胖大鼠红色腓肠肌的葡萄糖转运活性增加了2.4倍（与对照组相比P < 0.05），而胰岛素没有影响。总之，在胰岛素抵抗大鼠模型中急性输注AICAR激活骨骼肌AMPK并增加红腓肠肌中的葡萄糖转运活性，同时抑制内源性葡萄糖产生和脂解。由于2型糖尿病的特征是胰岛素刺激的葡萄糖摄取率降低以及内源性葡萄糖产生和脂解的基础率增加，这些结果表明AICAR相关化合物可能代表一类新的抗糖尿病药物。
Activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-beta -D-ribofurano- side (AICAR) increases glucose transport in skeletal muscle via an insulin-independent pathway. To examine the effects of AMPK activation on skeletal muscle glucose transport activity and whole-body carbohydrate and lipid metabolism in an insulin-resistant rat model, awake obese Zucker fa/fa rats (n = 26) and their lean (rt = 23) Littermates mere infused for 90 min with AICAR, insulin, or saline. The insulin infusion rate (4 mU kg-l min-l) was selected to match the glucose requirements during AICAR (bolus, 100 mg/kg; constant, 10 mg kg-l min-l) isoglycemic clamps in the lean rats. The effects of these identical AICAR and insulin infusion rates mere then examined in the obese Zucker rats. AICAR infusion increased muscle AMPK activity more than fivefold (P < 0.01 vs. control and insulin) in both lean and obese rats. Plasma triglycerides, fatty acid concentrations, and glycerol turnover, as assessed by [2-C-13]glycerol, mere all decreased in both lean and obese rats infused with AICAR (P < 0.05 vs. basal), whereas insulin had no effect on these parameters in the obese rats. Endogenous glucose production rates, measured by [U-C-13]glucose, mere suppressed by > 50% during AICAR and insulin infusions in both lean and obese rats (P < 0.05 vs. basal). In lean rats, rates of whole-body glucose disposal increased by more than two-fold (P < 0.05 vs. basal) during both AICAR and insulin infusion; [H-3]2-deoxy-D-glucose transport activity increased to a similar extent, by >2.2-fold (both P < 0.05 vs, control), in both soleus and red gastrocnemius muscles of lean rats infused with either AICAR or insulin. In the obese Zucker rats, neither AICAR nor insulin stimulated whole-body glucose disposal or soleus muscle glucose transport activity. However, AICAR increased glucose transport activity by similar to2.4-fold (P < 0.05 vs. control) in the red gastrocnemius from obese rats, whereas insulin had no effect. In summary, acute infusion of AICAR in an insulin-resistant rat model activates skeletal muscle AMPK and increases glucose transport activity in red bastrocnemius muscle while suppressing endogenous glucose production and lipolysis. Because type 2 diabetes is characterized by diminished rates of insulin-stimulated glucose uptake as well as increased basal rates of endogenous glucose production and lipolysis, these results suggest that AICAR-related compounds may represent a new class of antidiabetic agents.