IN-VIVO GLUCOSAMINE INFUSION INDUCES INSULIN-RESISTANCE IN NORMOGLYCEMIC BUT NOT IN HYPERGLYCEMIC CONSCIOUS RATS
IN-VIVO GLUCOSAMINE INFUSION INDUCES INSULIN-RESISTANCE IN NORMOGLYCEMIC BUT NOT IN HYPERGLYCEMIC CONSCIOUS RATS
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DOI：
10.1172/jci118013
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
BARZILAI, N
中科院分区：
文献类型：
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作者：
ROSSETTI, L;HAWKINS, M;BARZILAI, N
为了验证这一假设，即增加通过氨基己糖生物合成途径的流量可以诱导体内骨骼肌胰岛素抵抗，我们监测葡萄糖摄取，糖酵解，和糖原合成在胰岛素钳夹研究在6小时禁食清醒大鼠的存在下，持续（7小时）增加葡萄糖胺（GlcN）的可用性。在对照组（CON;血浆葡萄糖[PG] = 7.4+/-0.2 mM）、糖尿病组（D; PG = 19.7+/-1.1）和根皮苷治疗（3周）的糖尿病大鼠（D + PHL; PG = 7.6+/-0.9）中，用盐水或GlcN输注进行正常血糖（类似于7 mM）胰岛素（类似于2，500 pM）钳夹。生理盐水7小时血糖正常的高胰岛素血症没有显著降低R（d）（360-420分钟= 39.2+/-3.6 vs. 60-120分钟= 42.2+/-3.7 mg/kg）。min; P = NS）。在所有组中，GlcN输注将血浆GlcN浓度升高至类似于1.2 mM，并将肌肉和肝脏UDP-GlcNAc水平增加4-5倍。GlcN显著降低CON的R（d）（360-420 min = 30.4+/-1.3 vs. 60-120 min = 44.1+/-3.5 mg/ kg）。min; P < 0.01）和D + PHL（360-420 min = 29.4+/-2.5 vs. 60-120 min = 43.8+/-2.9 mg/kg . min; P < 0.01），但在D中没有（5-7 h = 21.5+/-0.8 vs. 0-2 h = 24.3+/-1.1 mg/kg . min; P = NS）。因此，增加GlcN的可用性诱导严重的骨骼肌胰岛素抵抗血糖正常，但在慢性高血糖大鼠。缺乏GlcN和慢性高血糖症（实验性糖尿病）的累加效应为以下假设提供了支持：骨骼肌中通过GlcN途径的通量增加可能在体内葡萄糖诱导的胰岛素抵抗中起重要作用。
To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (similar to 7 mM) insulin (similar to 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4+/-0.2 mM), diabetic (D; PG = 19.7+/-1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6+/-0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease R(d) (360-420 min = 39.2+/-3.6 vs. 60-120 min = 42.2+/-3.7 mg/kg . min; P = NS). GlcN infusion raised plasma GlcN concentrations to similar to 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased R(d) in CON (360-420 min = 30.4+/-1.3 vs. 60-120 min = 44.1+/-3.5 mg/ kg . min; P < 0.01) and D + PHL (360-420 min = 29.4+/-2.5 vs. 60-120 min = 43.8+/-2.9 mg/kg . min; P < 0.01), but not in D (5-7 h = 21.5+/-0.8 vs. 0-2 h = 24.3+/-1.1 mg/kg . min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.