Impaired Insulin Action Is Associated With Increased Glucagon Concentrations in Nondiabetic Humans

J Clin Endocrinol Metab. 2018 Jan 1;103(1):314-319. doi: 10.1210/jc.2017-01197.


Context: Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear.

Objective: We sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance.

Design: This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance.

Setting: An inpatient clinical research unit at an academic medical center.

Participants: A total of 310 nondiabetic persons participated in this study.

Interventions: Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control.

Main outcome measure(s): We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants.

Results: Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of β-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations.

Conclusions: In nondiabetic participants, glucagon secretion was altered by changes in insulin action.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / blood
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Cross-Sectional Studies
  • Female
  • Follow-Up Studies
  • Glucagon / blood*
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / pathology*
  • Glucose Tolerance Test
  • Humans
  • Hyperglycemia / physiopathology*
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology*
  • Insulin Resistance*
  • Male
  • Middle Aged
  • Prediabetic State / physiopathology*
  • Prognosis


  • Biomarkers
  • Blood Glucose
  • C-Peptide
  • Hypoglycemic Agents
  • Insulin
  • Glucagon