Insulin exerts metabolic and growth-promoting effects by a direct action on the liver in vivo: clarification of the functional significance of the portal vascular link between the beta cells of the pancreatic islets and the liver.

Abstract

The functional significance of the portal vascular link between the beta cells of the pancreatic islets and the liver has not been established. Previous studies indicated that insulin does not acutely regulate glucose metabolism by a direct hepatic effect. More recent observations suggest that the role of insulin in regulating body growth may be mediated, at least in part, by the liver. Our experiments were designed to test whether insulin can promote body growth and regulate glucose metabolism by a direct hepatic action in vivo. Rats were made diabetic by injections of streptozotocin, and insulin or solvent was infused into the jugular vein (JV) or the hepatic portal vein (HPV) for 14 days using catheters that were attached to osmotic minipumps. Infusion of a low dose of insulin (2 units per kg per day) into the JV had no effects on the hyperglycemia, body weight gain, tail growth, tibial epiphysial cartilage plate thickness, or serum levels of somatomedin C in the diabetic rats. However, the same dose given into the HPV caused a 30% reduction of blood glucose and stimulated a significant degree of growth, as determined by all indices. Infusion of a higher dose of insulin (5 units per kg per day) into either vein caused full restoration of body weight gain and tail growth and it restored the glycemic status almost to normal. However, it did not increase the tibial epiphysial plate width or serum somatomedin C levels above those of the rats given the low dose of the hormone into the HPV. These results indicate that insulin can act directly on the liver to promote body growth and to regulate glucose metabolism. The significance of direct delivery of insulin from the pancreatic beta cells to the liver may be as much for growth control as for glucose homeostasis.

Metabolic hormones modulate the effect of growth hormone (GH) on insulin-like growth factor-I (IGF-I) mRNA level in primary culture of salmon hepatocytes

“…Insulin, thyroid hormones and low concentrations of glucocorticoids potentiate GH-stimulated IGF-I mRNA expression, whereas glucagon and high concentrations of glucocorticoids inhibit basal or GH-stimulated IGF-I expression (Tollet et al 1990, Boni-Schnetzler et al 1991, Houston & O'Neill 1991, Denver & Nicoll 1994, Brameld et al 1995, Beauloye et al 1999. In vivo data support a physiologically significant positive role for insulin in the regulation of GH sensitivity (Griffen et al 1987). Within the hepatocyte, changes in GH sensitivity occur at both the receptor and post-receptor level (Thissen et al 1994.…”

“…Insulin potentiated the GH response at the level of IGF-I protein secretion into medium in chicken and rat hepatocytes (Houston & O'Neill 1991, Villafuerte et al 1992. Studies in diabetic mammals support a requirement for normal portal insulin levels to maintain liver IGF-I production, plasma IGF-I levels and growth (Griffen et al 1987). As far as we are aware, no study in any tetrapod species has shown inhibition by insulin of basal or GH-dependent hepatocyte IGF-I mRNA expression or protein secretion.…”

Differential regulation of Igf1 and Igf2 mRNA levels in tilapia hepatocytes: effects of insulin and cortisol on GH sensitivity

“…Insulin secretion into the hepatic portal vessels results in exposure of the liver to high concentrations of insulin. Maintenance of insulin levels is necessary to maintain liver GH sensitivity, liver igf1 gene expression, blood Igf1 levels, and growth (Griffen et al 1987, Rodgers et al 1994, Thissen et al 1994, Phillips et al 1998, Butler et al 2003. Insulin levels in the portal vessels are also elevated in fish (Plisetskaya & Sullivan 1989).…”

“…Metabolically responsive hormones link the anabolic/ catabolic state of the animal to liver GH sensitivity. Insulin directly increases hepatocyte Igf1 production, and strongly increases hepatocyte responsiveness to GH in vivo (Griffen et al 1987, Butler et al 2003, and in mammalian and avian primary hepatocyte culture (Tollet et al 1990, Boni-Schnetzler et al 1991, Houston & O'Neill 1991, Phillips et al 1998. Glucocorticoids induce liver GH resistance (Rodgers et al 1994, Brameld et al 1995, Beauloye et al 1999.…”

Enhanced proteolytic activity directed against the N-terminal of IGF-I in diabetic rats

“…A role for insulin in the growth hormone signal transduction mechanism has been proposed by a number of investigators (Daughaday et al 1976, Scott & Baxter 1986, Griffen et al 1987, Salamon et al 1989) and the lack of response to growth hormone by diabetic animals may be an indirect consequence of insulin deficiency.…”