Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in nondiabetic subjects

Am J Physiol Endocrinol Metab. 2021 Nov 1;321(5):E728-E736. doi: 10.1152/ajpendo.00284.2021. Epub 2021 Oct 18.


Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and endogenous glucose production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (nonsuppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50-g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose, and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to nonsuppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight, and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.NEW & NOTEWORTHY In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

Keywords: endogenous glucose production; glucagon; hepatic insulin action; insulin action; minimal model.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Female
  • Glucagon / antagonists & inhibitors
  • Glucagon / metabolism*
  • Glucagon / pharmacology
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Healthy Volunteers
  • Humans
  • Insulin / pharmacology
  • Insulin Secretion / drug effects*
  • Insulin Secretion / physiology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Male
  • Middle Aged
  • Postprandial Period / drug effects
  • Postprandial Period / physiology
  • Somatostatin / pharmacology*


  • Blood Glucose
  • Insulin
  • Somatostatin
  • Glucagon
  • Glucose