Melin B, Caron M, Cherqui G, Blivet M J, Bailbe D, Picard J, Capeau J, Portha B
Laboratoire de Biologie Cellulaire, INSERM U. 181, Faculté de Médecine Saint-Antoine, Paris, France.
Endocrinology. 1991 Apr;128(4):1693-701. doi: 10.1210/endo-128-4-1693.
Previous studies have shown that Wistar rats injected at birth (n0) with STZ (n0-STZ) develop as adults a noninsulin-dependent diabetic state characterized by a lack of insulin response to glucose in vivo, a mild basal hyperglycemia, and an impaired glucose tolerance. Our former in vivo studies using the insulin-glucose clamp technique revealed an increased insulin action upon hepatic glucose production in these animals. We have now cultured hepatocytes from these mildly diabetic rats in parallel with hepatocytes from control rats, to examine more closely basal and insulin-regulated glucose production and glucose incorporation into glycogen. In addition, we extended our investigation to other hepatic functions such as lipid synthesis and amino acid transport, which could not be studied in vivo. Although glucose production from glycogenolysis or gluconeogenesis in absence or presence of glucagon was identical in the two cell populations, glucagon-stimulated glycogenolysis was more sensitive to insulin action in diabetic hepatocytes. Similarly, insulin action on glucose incorporation into glycogen, lipogenesis, and amino acid transport were enhanced in diabetic hepatocytes. The hormone effect was manifested by an increase in the sensitivity and/or in the responsiveness, reflecting the multiplicity of the pathways whereby the insulin signal is transduced through the insulin receptor to multiple postreceptor sites. To gain insight into the possible mechanism of these disturbances, we evaluated the initial insulin receptor interaction and the kinase activity of the receptor beta-subunit. In accordance with our previous study on intact livers, we found no alteration in either of these parameters in n0-STZ rat hepatocytes. Thus, the present study clearly demonstrates that these diabetic rats exhibit a postreceptor hyperresponsiveness to insulin at the cellular level. It strengthens the notion that a beta-cell deficiency with glucose intolerance does not necessarily lead to a hepatic insulin resistance.
先前的研究表明，出生时注射链脲佐菌素（STZ）的Wistar大鼠（n0-STZ）成年后会发展为非胰岛素依赖型糖尿病状态，其特征为体内对葡萄糖缺乏胰岛素反应、轻度基础高血糖以及糖耐量受损。我们之前使用胰岛素-葡萄糖钳夹技术进行的体内研究显示，这些动物肝脏葡萄糖生成的胰岛素作用增强。我们现在将这些轻度糖尿病大鼠的肝细胞与对照大鼠的肝细胞并行培养，以更仔细地研究基础和胰岛素调节的葡萄糖生成以及葡萄糖合成糖原的情况。此外，我们将研究扩展到其他肝脏功能，如脂质合成和氨基酸转运，这些功能在体内无法进行研究。尽管在有无胰高血糖素的情况下，两个细胞群体中糖原分解或糖异生产生的葡萄糖相同，但胰高血糖素刺激的糖原分解在糖尿病肝细胞中对胰岛素作用更敏感。同样，胰岛素对糖尿病肝细胞中葡萄糖合成糖原、脂肪生成和氨基酸转运的作用增强。激素效应表现为敏感性和/或反应性增加，反映了胰岛素信号通过胰岛素受体转导至多个受体后位点的途径的多样性。为了深入了解这些紊乱的可能机制，我们评估了初始胰岛素受体相互作用和受体β亚基的激酶活性。与我们之前对完整肝脏的研究一致，我们发现n0-STZ大鼠肝细胞的这些参数均无改变。因此，本研究清楚地表明，这些糖尿病大鼠在细胞水平上对胰岛素表现出受体后高反应性。这强化了β细胞缺陷伴葡萄糖不耐受不一定导致肝脏胰岛素抵抗的观点。
