Effects Of Hyperglucagonemia Research Articles

Effect of hyperglucagonemia on hepatic glycogenolysis and gluconeogenesis after a prolonged fast

The aim of this study was to determine if glucagon can stimulate hepatic glucose production in prolonged fasted (7 days) animals. Two protocols were used; in one ("hormone replacement"; n = 4), intraportal basal replacement amounts of insulin and glucagon were given during a somatostatin infusion, whereas, in the other ("glucagon excess"; n = 5) basal insulin was given along with somatostatin and excess glucagon. Plasma insulin levels were similar and constant throughout both protocols (6 +/- 1 microU/ml). The plasma glucagon was basal in the hormone-replacement protocol (49 +/- 9 pg/ml) but rose from 46 +/- 7 to 448 +/- 35 pg/ml (P less than 0.05) in the other protocol. Plasma glucose levels and the rates of glucose production were unchanged during hormone replacement but rose from 100 +/- 5 to 199 +/- 28 mg/dl and from 1.5 +/- 0.1 to a peak of 5.6 +/- 0.2 mg.kg-1.min-1 at 15 min (P less than 0.05) and an eventual plateau of 2.7 +/- 0.2 mg.kg-1.min-1 (P less than 0.05) in response to glucagon excess. Because of the sluggish increase in gluconeogenic parameters, the early marked rise in glucose production was attributable to increased glycogenolysis. Eventually, however, the gluconeogenic rate rose, with net hepatic uptake of alanine increasing 50% and fractional alanine extraction doubling. Gluconeogenic efficiency and conversion increased in response to glucagon excess by 0.30 +/- 0.05 and 159 +/- 48%, respectively, although it should be noted that these parameters rose 0.15 +/- 0.06 and 150 +/- 49% in the hormone-replacement protocol. In conclusion, even after a prolonged fast physiological glucagon can cause hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hyperglucagonemia on whole-body leucine metabolism in immature pigs before and during a meal.

Leucine metabolism was measured isotopically in 12 immature female pigs to assess the effect of acute hyperglucagonemia on leucine kinetics in both the fed and fasting states. After an overnight fast, immature pigs were infused with alpha-[3H]ketoisocaproate and [14C]leucine. After a 2-h equilibration period, an infusion of either saline or 7 pg.kg-1.min-1 of glucagon was begun, which increased plasma glucagon from approximately 140 to approximately 640 pg/ml and doubled the insulin concentrations. Two hours later, pigs were fed small meals to which [5,5,5-2H3]leucine was added to trace absorption. By subtracting absorption from total leucine flux, an estimate of endogenous proteolysis during the meal was made. In the fasting state, glucagon increased proteolysis, relative to controls, by approximately 20% (P less than 0.05) and increased oxidation by approximately 50% (P less than 0.05). No significant glucagon-related changes in any other flux parameters occurred in the fasting state. Ingestion of the meals caused oxidation to increase 41% in control animals, whereas in glucagon-infused animals, oxidation increased 84% (P less than 0.05 control vs. glucagon response to meal). Additionally, animals infused with glucagon suppressed endogenous proteolysis 43% after the meal compared with a 55% decrease in control animals (P less than 0.05 basal period vs. fed period). These data indicate that glucagon stimulates whole-body proteolysis in both the fasting and fed states.

Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency.

The physiological significance of the hyperglucagonemia that occurs in patients with many catabolic conditions is unclear. The effect of hyperglucagonemia on resting metabolic rate (RMR) was studied in six normal subjects. Infusion of somatostatin (SRIH; 500 micrograms/h for 210 min) resulted in a 5-fold decrease in plasma C-peptide and a 2-fold decrease in plasma insulin and glucagon concentrations, but did not change RMR significantly. When glucagon (0.2 micrograms/kg X h), was infused with SRIH (500 micrograms/h for 210 min), the decreases in plasma C-peptide and insulin were similar to that during the infusion of SRIH alone, but plasma glucagon increased from 160 +/- 24 (+/- SEM) to 560 +/- 80 pg/mL (P less than 0.001). There was a significant increase in RMR during the entire period (210 min) of glucagon infusion (P less than 0.01). During the last hour of the glucagon plus SRIH infusion, the RMR was 1.38 +/- 0.10 Cal/min, which was 15% higher than the preinfusion RMR (1.19 +/- 0.10 Cal/min; P less than 0.01) and 14% higher than the RMR during the same period when SRIH alone was infused (1.21 +/- 0.11 Cal/min; P less than 0.01). When SRIH and glucagon were infused, protein oxidation (calculated from urinary nitrogen loss) was 52 +/- 5 mg/min, 29% higher than when SRIH alone was infused (40 +/- 5 mg/min; P less than 0.05). These results indicate that hyperglucagonemia during insulin deficiency results in an increase in energy expenditure, which may contribute to the catabolic state in many conditions.

The effect of hyperglucagonaemia on blood glucose concentrations and on insulin requirements during fasting in insulin dependent diabetes mellitus.

The effect of sustained hyperglucagonaemia on blood glucose concentrations and on insulin requirements was evaluated in 6 fasting insulin dependent diabetic subjects whose blood glucose concentrations were being controlled with a closed loop insulin infusion system. Subjects were iv infused initially with either saline or glucagon and subsequently with the other infusate. All determinations were performed following the period during which transient increases in glucagon stimulated glucose production have been reported to occur. Plasma glucagon concentrations were significantly higher during the glucagon study period (491 +/- 65 vs 70 +/- 13 pg/ml +/- SD, P less than 0.001) as were blood glucose concentrations (104 +/- 2 vs 84 +/- 7 mg/ml +/- SD, P less than 0.001) and insulin requirements (3.5 to 36.5 vs 0 to 2.3 mU/kg/h, P less than 0.05). Sustained hyperglucagonaemia continues to have an effect on glucose homeostasis for at least 2 h following the initiation of a continuous infusion.

Evidence for an intrahepatic contribution to the waning effect of glucagon on glucose production in the conscious dog.

We previously showed that infusion of glucagon at four times the basal rate into conscious dogs given somatostatin and basal replacement amounts of insulin caused hyperglycemia (217 15 mg/dl) for at least 3 h and an initial increment in hepatic glucose production of 5.5 0.8 mg/kg . min. After 3 h, however, the effect of hyperglucagonemia on glucose production had declined by 85%. The aim of the present study was to determine the importance of hyperglycemia in the "downregulation" of the action of glucagon. Six overnight-fasted conscious dogs were given somatostatin (0.8 microgram/kg . min) plus basal intraportal replacement amounts of insulin (263 microunits/kg . min) and glucagon (0.65 ng/kg . min). Hyperglycemia (276 12 md/dl) was established after 2 h by the infusion of exogenous glucose. The glucagon infusion rate was then increased fourfold 1 h later, so that the plasma glucagon level rose from 95 16 to 227 35 pg/ml. The glucose concentration was maintained at a fixed value despite the increase in glucagon by decreasing the glucose infusion rate by an amount equal to the increase in endogenous glucose production induced by the hormone. Glucose production was measured using a primed infusion of 3H-glucose. With the insulin (11 2 microunits/ml) and glucose levels fixed, the elevation in glucagon caused an initial increment of 5.1 0.7 mg/kg . min in glucose production which was followed by a fall of only 2.5 0.4 mg/kg . min (50%) over the next 3 hr. Thus, when the plasma glucagon level is raised fourfold under conditions in which insulin mobilization cannot occur, the effect of hyperglucagonemia on glucose production will be partially offset by the resulting hyperglycemia and partly inhibited by an hepatic factor(s).

PERSISTENT EFFECT OF SUSTAINED HYPERGLUCAGONEMIA ON GLUCOSE PRODUCTION IN MAN

In man prolonged infusions of glucagon cause a transient increase in glucose production. To determine whether this represents complete loss of effect of hyperglucagonemia on the liver or merely decreased hepatic responsiveness, glucagon (3 ng/kg/min) was infused in six normal subjects to produce sustained hyperglucagonemia for 180 min; at this time glucagon infusions were stopped for 60 min, then restarted at the same rate for 60 min and finally increased to 7.5 ng/kg/min for 30 min. Glucose production (Ra) and utilization (Rd) were measured isotopically. Initially glucagon infusion increased Ra transiently from 1.8 +/- 0.1 mg/kg/min to a maximum at 15 min of 2.5 +/- 0.2 mg/kg/min (p less than .01); Ra returned to basal values by 60 min and remained there until the glucagon infusion was stopped, whereupon it abruptly declined to a nadir of 1.4 +/- 0.1 mg/kg/min, a value significantly below baseline levels, p less than .005. Upon restarting the glucagon infusion, Ra increased to a similar extent as observed with the initial infusion and then returned to basal levels; when the glucagon infusion rate was increased to 7.5 ng/kg/min, Ra again increased. These results indicate that sustained hyperglucagonemia, despite apparent waning of its effect, continues to modulate hepatic glucose production.

The effect of hyperglucagonemia on blood glucose concentrations and on insulin requirements in insulin-requiring diabetes mellitus

The effect of hyperglucagonemia on blood glucose concentrations and on insulin requirements in insulin-requiring diabetes mellitus