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Increased Insulin Action in Cultured Hepatocytes from Rats with Diabetes Induced by Neonatal Streptozotocin^*

Laboratoire de Biologie Cellulaire (B.M., M.C., G.C., M.-J.B., J.P., J.C.), INSERM U. 181, Faculte de Medecine Saint-Antoine 75571 Paris Cedex 12, France
Laboratoire de Physiologie du Deueloppement (D.B., B.P.), CNRS URA 307, Universite Paris 7 Tour 33, 75251 Paris Cedex 05, France

Address all correspondence and requests for reprints to: Dr. Jacqueline Capeau, Laboratoire de Biologie Cellulaire, INSERM U. 181, Faculté de Médecine Saint-Antoine, 27, rue Chaligny, 75571 Paris Cédex 12, France.

Abstract

Previous studies have shown that Wistar rats injected at birth (nO) with STZ (nO-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 β-subunit. In accordance with our previous study on intact livers, we found no alteration in either of these parameters in nO-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 β-cell deficiency with glucose intolerance does not necessarily lead to a hepatic insulin resistance. (Endocrinology 128: 1693–1701,1991)

Footnotes

^* This work was supported by grants from INSERM (CRE no. 874013) and from the Universite Pierre et Marie Curie (Paris, France).

Received August 16, 1990.