Stimulation Of Hepatic Glucose Production Research Articles

Importance of raised growth hormone levels in mediating the metabolic derangements of diabetes.

To evaluate the importance of the raised levels of growth hormone that characterize poor diabetic control, we gave growth hormone for 21 to 45 hours in the form of hourly 100-micrograms pulses to 14 diabetics being treated by insulin pump. Insulin-pump settings and meals were kept constant. Mean 24-hour levels of growth hormone (+/- S.E.M.) rose from 8 +/- 1 to 16 +/- 2 ng per milliliter--values identical to those observed in 12 other patients with poorly controlled diabetes (17 +/- 3 ng per milliliter). Plasma glucose concentrations doubled within 8 to 10 hours and remained elevated until growth hormone was discontinued (fasting glucose level rose from 86 +/- 11 to 204 +/- 17 mg per deciliter at 18 hours and to 240 +/- 20 mg per deciliter at 42 hours). The hyperglycemia was due mainly to a marked stimulation of hepatic glucose production that occurred without changes in levels of free insulin or glucagon. Levels of circulating free fatty acids, ketones, and branched-chain amino acids were also increased. The moderate elevations in growth hormone levels that occur in poorly controlled diabetes can themselves reproduce the whole spectrum of abnormal metabolic fuel concentrations that are associated with poor diabetic control, despite optimized insulin treatment. Thus, hypersecretion of growth hormone may be the cause as much as the consequence of poor diabetic control.

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

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.

Sham feeding-induced cephalic phase insulin release in the rat.

The effect of the cephalic phase of food ingestion on plasma insulin and glucagon concentration was assessed in the sham-feeding rat, bearing chronically implanted gastric drainage fistulas. It was found that continuous sham feeding produced a significant and phasic peripheral insulin response in the absence of any significant changes of glycemia. The response was almost completely blocked by prior intravenous administration of 2 mg/kg of atropine methyl nitrate and potentiated by prior intravenous administration of 1.0 or 2.5 mg/kg of phentolamine. In spite of the larger insulin response after phentolamine, there was no hypoglycemia detected. Furthermore, continuous sham feeding did not produce a significant glucagon response, whereas real feeling did. The results demonstrate that cholinergic insulin release is triggered phasically by continuous ingestion of familiar food and that this insulin response is inhibited by an alpha-adrenergic sympathetic tone. It is further concluded that the increased glucose disposal produced by the neurally released insulin is not counteracted by a concomitant glucagon response or by direct adrenergic stimulation of hepatic glucose production.

Theophylline potentiates glucagon-induced hepatic glucose production in man but does not prevent hepatic downregulation to glucagon

Prolonged hyperglucagonemia causes only a transient increase in hepatic glucose production. To determine whether activation of hepatic phosphodiesterase by glucagon is responsible for the transient nature of this response, the effect of infusion of the phosphodiestrase inhibitor theophylline alone, glucagon alone, and glucagon plus theophylline on isotopically determined glucose production was examined in normal human subjects. Infusion of theophylline alone did not alter rates of glucose production or utilization. Infusion of glucagon alone increased glucose production transiently from a basal rate of 1.9 ± 0.1 mg/kg/min to a maximum at min 30 of 2.8 ± 0.3 mg/kg/min followed by a return to rates no different from basal by min 60; plasma glucose increased from 89 ± 3 mg/dl to a maximum of 114 ± 5 mg/dl. Infusion of glucagon in the presence of theophylline resulted in greater increases in both plasma glucose (maximum at min 60 of 134 ± 9 mg/dl) and glucose production (maximum at min 30 of 3.5 ± 0.3 mg/kg/min) than had occurred during infusion of glucagon alone; the increase in glucose production, however, was not sustained. Thus theophylline potentiated glucagon-induced stimulation of hepatic glucose production, but it did not prevent the evanescent hepatic response to sustained hyperglucagonemia. Therefore, the present studies indicate that glucagon activation of hepatic phosphodiesterase does not appear to be responsible for the transient nature of the increase in hepatic glucose production observed during prolonged hyperglucagonemia.

Lack of effect of parathyroid hormone on hepatic glucose metabolism in the dog

It has been suggested that raised levels of parathyroid hormone (PTH) may induce glucose intolerance and impair insulin action in primary as well as secondary hyperparathyroidism. Furthermore, PTH is known to stimulate glycogenolysis in isolated hepatocytes and renal cortical cells. We administered a bolus of bovine 1:84 PTH to 8 awake dogs, and measured hepatic glucose production by the primed-constant 3H-3-Glucose infusion technique for 2 hr. PTH injection had no effect on fasting plasma glucose concentration or hepatic glucose production. Plasma insulin and glucagon, serum ionized and total calcium, and serum phosphate did not show any significant change following PTH administration. Synthetic bovine 1:34 PTH, administered to another 3 dogs using the same experimental protocol, also failed to affect any of the measured parameters. To investigate the possible synergism between PTH and other glycoactive hormones, we infused glucagon (3 ng/min · kg, 5 dogs) or epinephrine (0.1 ng/min · kg, 6 dogs) with or without 1:84 PTH in matched experiments. Glucagon alone caused a 22% rise (p < 0.01) in plasma glucose concentration and a 27% rise (p < 0.05) in hepatic glucose production; epinephrine alone induced a 54% rise (p < 0.01) in plasma glucose and a 39% increase (p < 0.01) in glucose production. When PTH injection was combined with glucagon or epinephrine infusion, no further stimulation of hepatic glucose production was observed. In another 6 awake dogs with portal and hepatic venous and arterial catheters, the hepatic response to PTH was determined both by measuring net hepatic glucose balance (hepatic plasma flow times transhepatic glucose concentration difference) and by tracer methodology. While the two techniques showed excellent agreement, both failed to show any effect of PTH. Four dogs in this group received 1:84 PTH obtained from commercial source. In all the other studies here reported, 1:84 PTH prepared in our laboratory was used. Both preparations caused a marked rise in phosphate excretion in dogs, and had the same potency as standard synthetic bovine 1:34 PTH in stimulating c-AMP generation by isolated renal tubular membranes. We conclude that the acute administration of PTH does not stimulate hepatic glucose production in the dog.

Role of cyclic AMP in glucagon-induced stimulation of hepatic glucose output in man

The interrelationship between glucagon action on splanchnic glucose output and cyclic AMP production was studied in healthy volunteers after hepatic venous catheterization. Glucagon was infused according to four different protocols to achieve arterial levels ranging from 300 to 9000 ng/l. Infusion of glucagon which resulted in arterial levels of the hormone of 4000-9000 ng/l was associated with a marked increase in net splanchnic cyclic AMP production and in the arterial levels of the cyclic nucleotide. The rise in cyclic AMP efflux from the splanchnic area was transient but an augmented splanchnic production was still evident after 30 min of glucagon infusion. Splanchnic glucose output rose 3-5 fold. Infusion of glucagon at lower rates, resulting in arterial levels of 300-900 ng/l, did not measureably stimulate the efflux of cyclic AMP from the splanchnic area. In spite of this, splanchnic glucose output rose 2-3 fold and the blood glucose level increased 20-50% during glucagon infusion at these lower rates. It is concluded that (1) factors other than cyclic AMP are rate limiting in the stimulation of hepatic glucose production, and (2) although cyclic AMP is an established 'second messenger' of glucagon action, other factors may also be of importance in mediating the physiological response of this hormone.

Evanescent effects of hypo- and hyperglucagonemia on blood glucose homeostasis

Hypoglucagonemia (induced by somatostatin) and hyperglucagonemia (induced by infusion of physiologic amounts of glucagon) have only evanescent effects on blood glucose regulation. Despite on-going glucagon suppression by somatostatin, fasting hyperglycemia develops within 4-6 hr of insulin suppression, indicating that (1) basal glucagon secretion is not essential for the development of the diabetic state; and (2) insulin-deficiency (rather than altered glucagon secretion) is the dominant long-term factor determining glucose homeostasis in the diabetic. With respect to hyperglucagonemia, only a transient increase in splanchnic glucose output is observed in normal and diabetic subjects in response to physiologic increments in this hormone. The exaggerated hyperglycemic effect of glucagon observed in diabetics1 is thus a consequence of the failure to metabolize the glucose traniently released into the systemic circulation in response to the glucagon rather than a result of persistent stimulation of hepatic glucose production. These observations thus further underscore the essentiality of insulin deficiency in the diabetogenic action of glucagon.