The kinetics of glucagon action on the liver during insulin-induced hypoglycemia

Abstract

Glucagon’s effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg−1·min−1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg−1·min−1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg−1·min−1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg−1·min−1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease

“…Glucagon upregulates glutaminase, the enzyme that deaminates glutamine into glutamate and ammonium ( 41 ), supporting our findings of a negative association between glucagon and glutamine. Further, glucagon increases glutamine uptake in the liver ( 42 , 43 ). Finally, the observed negative association between glucagon and glycine has previously been explained by glucagon-induced upregulation of the glycine cleavage system ( 44 , 45 , 46 ).…”

Carbohydrate-Restricted Exercise With Protein Increases Self-Selected Training Intensity in Female Cyclists but Not Male Runners and Cyclists

“…Furthermore, following a minimally invasive protocol, we did not quantify circulating glucoregulatory hormones. However, it is known that ingesting protein or amino acids increases plasma glucagon concentration (13) and such increases in glucagon will be associated with a counter reduced catecholamine response (11) even during hypoglycemia (33). Therefore, the metabolic outcome of ingesting the protein supplement in the current study is likely owing to both an increase in plasma glucagon and decrease in catecholamine concentrations.…”