Effect of insulin on alpha1-adrenergic actions in hepatocytes from euthyroid and hypothyroid rats

The effect of experimental diabetes on phenylalanine metabolism in isolated liver cells

“…Phenylalanine hydroxylation (nmol/h (results not shown). This finding is similar to that of other workers (Pushpendran et al, 1984). It appears, therefore, that a-adrenergic control of phenylalanine hydroxylase in our normal rats is exerted through a cyclic-AMP-independent mechanism.…”

Adrenergic regulation of gluconeogenesis: possible involvement of two mechanisms of signal transduction in alpha 1-adrenergic action.

“…exist, and we have proposed for the hypothesis that a,-adrenergic action involves two mechanisms-i.e., the "conventional" mechanism shared with vasopressin and angiotensin II and an "alternative" mechanism (see Fig. 1) (9)(10)(11)(12)(13)(14). Gluconeogenesis from lactate seems to be modulated by both mechanisms.…”

“…Our hypothesis is schematically represented in Fig. 1 and is based mainly on the following findings: (t) metabolic effects due to a1-adrenergic activation are clearly observed in cells incubated in the absence of extracellular calcium and even in calcium-depleted hepatocytes, whereas those of the vasopressor peptides are abolished (9,14,20); (ih) hypothyroidism markedly diminishes the metabolic effects of vasopressin and angiotensin II but not those due to a1-adrenergic activation (11, 12); (iii) insulin reduces the stimulation of glycogenolysis due to a1-adrenergic activation but not that produced by vasopressin or angiotensin II (13,16,17,20); (iv) the inhibitory action of insulin on a1-adrenergic actions is markedly magnified in calciumdepleted hepatocytes and in hepatocytes from hypothyroid rats (13,16,20); (v) in hepatocytes from adrenalectomized rats the metabolic effects due to a1-adrenergic amines became dependent on the presence of extracellular calcium (14, 23)-i.e., a1-adrenergic actions resemble those of vasopressin or angiotensin II; (vi) we have recently observed that cycloheximide, which stimulates hepatic metabolism through an a1-adrenergic mechanism (24), mimics the actions of epinephrine in an insulin-insensitive calcium-dependent fashion and that the action of cycloheximide is observed in hepatocytes from control and adrenalectomized rats but not in cells from hypothyroid animals (25). Thus, in summary, our model suggests that a1-adrenergic effects are mediated through two pathways: one of them also shared by vasopressin and angiotensin II, modulated by thyroid status, calciumdependent, insulin-insensitive, and possibly involving phosphoinositide turnover and calcium in its mechanism of transduction; and another pathway, not shared with the vasopressor peptides, modulated by glucocorticoids, calcium-independent, insulin-sensitive, and mediated through unknown second messenger(s) (see Fig.…”

“…These differences led us to propose the possible existence of two mechanisms of signal transduction for a1-adrenergic action in the liver cell (9)(10)(11)(12)(13)(14). Our hypothesis is schematically represented in Fig.…”

“…During the last 4 years we (9)(10)(11)(12)(13)(14) and others (15)(16)(17)(18)(19)(20)(21)(22) have observed differences between the action of the vasopressor peptides and those due to a1-adrenergic activation. These differences led us to propose the possible existence of two mechanisms of signal transduction for a1-adrenergic action in the liver cell (9)(10)(11)(12)(13)(14).…”