Direct alpha-adrenergic stimulation of hepatic glucose production in human subjects

Abstract

Six normal humans each underwent infusions of 1) saline; 2) propranolol; 3) somatostatin; 4) somatostatin with propranolol; and 5) somatostatin with propranolol plus phentolamine on separate occasions. Propranolol alone had no effect on glucose production or plasma glucose. Somatostatin alone produced the expected initial decrease followed by an increase in both hepatic glucose production and plasma glucose. beta-Adrenergic blockade with propranolol displaced the glucose production (MANOVA, P = 0.0220) and plasma glucose (MANOVA, P = 0.0057) somatostatin response curves to higher levels, whereas alpha-adrenergic blockade with phentolamine combined with beta-adrenergic blockade displaced the glucose production (MANOVA, P = 0.0281) and plasma glucose (MANOVA, P = 0.0134) somatostatin response curves to lower levels. Because plasma insulin, C-peptide, and glucagon were suppressed comparably under all three conditions and plasma glucose concentrations were comparable initially, this represents direct alpha-adrenergic stimulation of hepatic glucose production in postabsorptive humans demonstrable when the primary glucoregulatory hormones are withdrawn and beta-adrenergic mechanisms are blocked. It is best attributed to sympathetic neural norepinephrine release.

Epinephrine supports the postabsorptive plasma glucose concentration and prevents hypoglycemia when glucagon secretion is deficient in man.

“…There is considerable evidence that glucagon normally supports postabsorptive glucose production and functions in concert with insulin to maintain the postabsorptive plasma glucose concentration (10,11,13). The present studies were not designed to reassess this concept, but the findings are consistent with it.…”

“…Therefore, we hypothesized that adrenergic mechanisms support the postabsorptive plasma glucose concentration and prevent hypoglycemia when glucagon secretion is deficient. In an initial study (13) we found that combined a-and f3-adrenergic blockade blunts the late increase in glucose production and plasma glucose that follows their initial decrease during combined insulin and glucagon deficiency produced by infusion of somatostatin. Adrenergic blockade did not, however, result in a progressive decline in plasma glucose.…”

“…Further, the small decrement in plasma glucose that follows induction of glycosuria in dogs is converted to a substantial decrement when glucagon secretion is suppressed by somatostatin (12). Despite decrements in plasma glucose, however, glucagon deficiency per se does not produce absolute hypoglycemia (10)(11)(12)(13). On the other hand, adrenergic mechanisms do not support postabsorptive glucose production (2) in normal humans, and postabsorptive plasma glucose concentrations are not discernibly reduced in epinephrine-deficient (adrenalectomized) persons (3,9).…”

Beta‐adrenergic blockade restores glucose's antiketogenic activity after exercise in carbohydrate‐depleted athletes.

“…Although infusions of adrenaline, noradrenaline and salbutamol in normal and insulin-dependent diabetic humans, have, in some studies (Schade & Eaton, 1977Silverberg, Shah, Haymond & Cryer, 1978;Giindogdu, Brown, Juul, Sachs & Sonksen, 1979;Clutter, Bier, Shah & Cryer, 1980;Pernet, Walker & Gill, 1983;Keller, Gerber & Stauffacher, 1984;Bahnsen, Burrin, Johnston, Pernet, Walker & Alberti, 1984;Berk, Clutter, Skor, Shah, Gingerich, Parvin & Cryer, 1985), been shown to cause moderate increases in the blood ketone body concentration, fl-adrenergic blockade has, to our knowledge, not previously been shown to have any antiketogenic effect (Rosen, Clutter, Shah, Miller, Bier & Cryer, 1983;Kosugi, Harano, Nakano, Suzuki, Kashiwagi & Shigeta, 1983;Beylot, Sautot, Dechaud, Cohen, Riou, Serusclat & Mornex, 1985;Oberhaensli, Schwendimann & Keller, 1985), except partially in somatostatin-induced hyperketonaemia (Beaufrere, Beylot, Riou, Serusclat, Cohen, Souquet & Mornex, 1983;Rosen et al 1983). This would indicate that f-adrenergic blockade will normally lower the blood ketone body concentration only in the absence of both insulin and glucagon.…”

Glucagon, in Concert With Insulin, Supports the Postabsorptive Plasma Glucose Concentration in Humans

“…First, the glycemic response to suppression of both endogenous insulin and glucagon (among other effects) with somatostatin is biphasic, with an initial transient decrease in glucose production (3)(4)(5) and the plasma glucose concentration (4 -6), followed by an increase in glucose production (3)(4)(5) and the plasma glucose concentration (4 -6) in healthy humans. While these findings suggest an initial tonic effect of basal glucagon secretion to support the postabsorptive plasma glucose concentration, they suggest that suppression of insulin secretion is the dominant glycemic effect of somatostatin and, therefore, that insulin is the primary determinant of the postabsorptive plasma glucose concentration.…”