Abstract
Our previous studies showed that physiologic concentrations of insulin suppress the expression of the EGFr-like tyrosine kinase receptor, ErbB3, in cultured rat hepatocytes. The ligands for this receptor are known to have proliferative and differentating effects in other tissues. To test the hypothesis that insulin is a physiologic regulator of ErbB3 in vivo, we studied the hepatic expression of ErbB3 in two models of insulin deficiency: streptozotocin (STZ) induced diabetes and fasting. Data are expressed as mean ± SD, and analyzed by paired t-test: * P<.05 vs age matched controls; ** P <.05 vs diabetics. Male S-D rats(100-150gm) were treated with a single ip injection of STZ, 65 mg/kg, and fed a normal diet ad libitum. Blood glucose was monitored daily(86± 9.6 vs 369± 13 mg/dl*, control vs diabetics, d 8). 3 diabetic animals received 3-15 units of human Ultralente insulin sc daily until the glucose was £ 200 mg/dl (90±88 mg/dl**). In a second study, 8 rats were fasted for 48 hr; 4 of the animals were refed for 48 hr (weights: 197 ± 12 vs 145 ±7*vs 181 ± 8 gm; control vs fasted vs refed). Livers were harvested and ErbB3 was immunoprecipitated from liver lysates, resolved on 6% polyacrylamide gels, transfered to nitrocellulose membranes, and detected using HRP-coupled anti-ErbB3 antibodies. Densitometric analysis (arbitrary units) of the 185 kDa ErbB3 band was carried out in a digital scanner. Results: Control (n=4) 2826 ± 691; Untreated Diabetics(n=2) 4895 ± 890*; Treated Diabetics (n=3) 1362 ± 1155**; Fasted(n=4) 4157 ± 836*; Fasted/Refed (n=4) 3908 ± 557. These data demonstrate that insulin deficiency induced by fasting or STZ diabetes upregulates the expression of the hepatic growth factor receptor ErbB3in vivo, and that insulin replacement represses this expression in diabetic rats. 48hr of refeeding is insufficient to reverse the effects of fasting. We speculate that the expression, and thus the signalling, of ErbB3 can be regulated by changes in hepatic insulin levels, and, indirectly, by metabolic status. Further studies may elucidate the interactions between insulin action, nutritional status and proliferative or differentiating signals in liver. They may have particular relevance to the diabetic state. Support: DK44557 (WER)
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