Glucagon's actions are modified by the combination of epinephrine and gluconeogenic precursor infusion

It was previously shown that glucagon and epinephrine have additive effects on both gluconeogenic and glycogenolytic flux. However, the changes in gluconeogenic substrates may have been limiting and thus may have prevented a synergistic effect on gluconeogenesis and a reciprocal inhibitory effect on glycogenolysis. Thus the aim of the present study was to determine if glucagon has a greater gluconeogenic and a smaller glycogenolytic effect in the presence of both epinephrine and clamped gluconeogenic precursors. Two groups (Epi and G + Epi + P) of 18-h-fasted conscious dogs were studied. In Epi, epinephrine was increased, and in G + Epi + P, glucagon and epinephrine were increased. Gluconeogenic precursors (lactate and alanine) were infused in G + Epi + P to match the rise that occurred in Epi. Insulin and glucose levels were also controlled and were similar in the two groups. Epinephrine and precursor administration increased glucagon's effect on gluconeogenesis (4.5-fold; P < 0.05) and decreased glucagon's effect on glycogenolysis (85%; P = 0.08). Thus, in the presence of both hormones, and when the gluconeogenic precursor supply is maintained, gluconeogenic flux is potentiated and glycogenolytic flux is inhibited.

Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog

Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was to determine how the two hormones interact in controlling glucose production. In 18-h-fasted conscious dogs, a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which one of four protocols was instituted. In G + E, glucagon (1.5 ng · kg−1 · min−1; portally) and epinephrine (50 ng · kg−1 · min−1; peripherally) were increased; in G, glucagon was increased alone; in E, epinephrine was increased alone; and in C, neither was increased. In G, E, and C, glucose was infused to match the hyperglycemia seen in G + E (∼250 mg/dl). The areas under the curve for the increase in NHGO, after the change in C was subtracted, were as follows: G = 661 ± 185, E = 424 ± 158, G + E = 1,178 ± 57 mg/kg. Therefore, the overall effects of the two hormones on NHGO were additive. Additionally, glucagon exerted its full glycogenolytic effect, whereas epinephrine exerted its full gluconeogenic effect, such that both processes increased significantly during concurrent hormone administration.

Interaction of free fatty acids and epinephrine in regulating hepatic glucose production in conscious dogs

To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Δ568 ± 77 and Δ527 ± 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 ± 73 to 1,633 ± 101 and 746 ± 112 to 1,898 ± 237 μmol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 ± 0.3 to 3.1 ± 0.4 mg · kg−1 · min−1( P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 ± 0.2 to 2.1 ± 0.3 mg · kg−1 · min−1) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 ± 0.2 to 0.9 ± 0.2 and 1.6 ± 0.2 to 0.7 ± 0.2 mg · kg−1 · min−1by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 ± 0.1 to 1.2 ± 0.1 mg · kg−1 · min−1( P < 0.05; by 3 h) and 0.7 ± 0.1 to 1.6 ± 0.1 mg · kg−1 · min−1( P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic glucose production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver.

Normal pancreastatin-like and increased post-glucose insulin levels in young offspring of insulin-resistant non-obese essential hypertensive patients

Pancreastatin is a regulatory peptide known to inhibit insulin secretion and insulin action with a glycogenolytic effect in the liver. This peptide is present in and secreted by many endocrine and chromaffin cells. Abnormalities of glucose, insulin and lipoprotein metabolism are common in patients with hypertension, as well as their first-degree relatives. We have recently studied a group of non-obese hypertensive subjects in which pancreastatin-like levels were increased compared with controls, and correlated with norepinephrine levels. We hypothesized that pancreastatin alongside the sympathoadrenal system might have a part in the insulin resistance of these patients, and this metabolic syndrome could play a role in the pathogenesis and complications of hypertension. In this article, we studied the normotensive offspring of these non-obese hypertensive patients and looked for metabolic abnormalities as well as plasma pancreastatin, glucagon and catecholamine levels. The subjects were separated into two groups: (1) offspring from non-insulin-resistant patients and (2) offspring from insulin-resistant patients. We found that after an intravenous glucose load, offspring from insulin-resistant patients were already hyperinsulinemic, although glucose clearance was normal, suggesting an early alteration in insulin sensitivity, whereas pancreastatin and catecholamine levels were normal compared with matched controls. However, offspring from non-insulin-resistant patients had no differences with controls. These results suggest that pancreastatin and catecholamines may not play an important role in triggering insulin resistance, although they may be important once the syndrome is established. Journal of Endocrinology (1997) 153, 313–318

Pancreastatin: further evidence for its consideration as a regulatory peptide

ABSTRACT Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from the porcine pancreas, and whose biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A (CGA), which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. Both intracellular and extracellular processing of CGA can yield pancreastatin. This processing is tissue-specific, with the pancreatic islet and antral gastric endocrine cells being the major source of fully processed pancreastatin. Most of the circulating CGA is secreted by chromaffin tissue. Therefore, peripheral processing of CGA is probably the major indirect source of pancreastatin. Pancreastatin seems to have a general modulatory control on endocrine (insulin, glucagon, parathormone) and exocrine (pancreatic, gastric) secretion from tissues close to the source of production. This has led to the assumption that pancreastatin may be a peptide with an autocrine and paracrine function. It has recently been revealed to be a peptide with a metabolic function counter-regulatory to insulin action. This effect, in conjunction with the inhibitory effect on insulin and pancreatic exocrine secretion, points to a role in the physiology of stress. The molecular mechanism of the glycogenolytic effect of pancreastatin is better known, although further work is still needed. In general, more studies should be carried out at the molecular level to investigate the mechanism of action of pancreastatin and thus to clarify its physiological role in the neuroendocrine system.

The early stimulation of glycolysis by epidermal growth factor in isolated rat hepatocytes is secondary to the glycogenolytic effect

We have studied the relationship between the effect of epidermal growth factor (EGF) on glycogen metabolism and its effect on glycolysis, in rat hepatocyte suspensions. Although 10 nM glucagon or 10 microM adrenaline increased glycogen degradation by more than 120%, 10 nM EGF increased glycogenolysis by less than 20% in hepatocytes incubated in glucose-free medium. Both glucagon and adrenaline increased phosphorylase a activity by more than 130%; EGF increased this activity by about 30%. Under basal conditions, 65% of the glucosyl residues were released as free glucose and about 30% ended up as C3 molecules (lactate and pyruvate). Both glucagon and adrenaline decreased the proportion of glucosyl units that rendered glycolysis end-products (to 2% for glucagon and 6% for adrenaline) and increased the proportion that ended up as free glucose (to 94% and 88% of the glucosyl residues for glucagon and adrenaline respectively). EGF increased the production of both free glucose and lactate+pyruvate, but the proportion of glucosyl residues that ended up as free glucose or glycolysis end-products was unchanged. In glycogen-depleted hepatocytes incubated in the presence of 25 mM glucose, EGF affected neither glycogen deposition nor glycolysis. EGF increased cytosolic free Ca2+, and neomycin decreased both the Ca2+ signal and the glycogenolytic effect. In conclusion, our results indicate that the effect of EGF on glycolysis is secondary to the Ca(2+)-mediated stimulation of glycogenolysis in rat hepatocyte suspensions.

Glycogenolytic effect of adenosine involves ATP from hepatocytes and eicosanoids from Kupffer cells

In the perfused liver, infusion of adenosine (50 microM) caused an increase in portal pressure and glucose output as well as a brief increase in oxygen uptake followed by a transient decrease within 1 min. Half-maximal glycogenolytic effect was observed with approximately 20 microM adenosine, and the stimulation was maximal at concentrations > 50 microM. The effect of adenosine was blocked when Kupffer cells were destroyed with gadolinium chloride treatment (10 mg/kg iv), supporting the hypothesis that eicosanoid release from Kupffer cells participates in the effect of adenosine in the liver. Although adenosine has been reported to increase eicosanoid release from perfused liver (S. vom Dahl, M. Wettstein, W. Gerok, and D. Hussinger, Biochem. J. 270: 39-44, 1990), in this study adenosine failed to stimulate prostaglandin release from cultured Kupffer cells at concentrations ranging from 1 microM to 1 mM, casting doubt on the hypothesis that Kupffer cells are totally responsible for the effect of adenosine. In contrast, adenosine increased ATP transiently from 4 to 15 nM in effluent from perfused livers concomitant with a transient increase in carbohydrate output and portal pressure. To assess which type of hepatic cells released ATP after addition of adenosine, parenchymal, Kupffer, and endothelial cells were isolated and incubated with adenosine. Adenosine increased ATP concentrations in culture media of parenchymal cells but not from Kupffer or endothelial cells. Furthermore, ATP stimulated prostaglandin release from cultured Kupffer cells, whereas ATP (10 microM) infusion caused glucose release with kinetics similar to adenosine in perfused livers, an effect that was blocked by destroying Kupffer cells.(ABSTRACT TRUNCATED AT 250 WORDS)