Chronic physiologic hyperglycemia impairs insulin-mediated suppression of plasma glucagon concentration in healthy humans

Xi Chen, Aurora Merovci, Ralph A. DeFronzo, Devjit Tripathy

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background and aims: Hyperglucagonemia is a characteristic feature of type 2 diabetes mellitus (T2DM). We examined the effect of chronic (48–72 h) physiologic increase (+50 mg/dl) in plasma glucose concentration on suppression of plasma glucagon concentration by insulin and by hyperglycemia in normal glucose tolerance (NGT) individuals. Materials and methods: Study One: 16 NGT subjects received OGTT and 3-step hyperinsulinemic (10, 20, 40 mU/m2·min) euglycemic clamp before and after 48 hour glucose infusion to increase plasma glucose by ~50 mg/dl. Study Two: 20 NGT subjects received OGTT and 2-step hyperglycemic (+125 and + 300 mg/dl) clamp before and after 72 hour glucose infusion. Plasma insulin, C-peptide and glucagon concentrations were measured during OGTT, euglycemic hyperinsulinemic and hyperglycemic clamps. Ratio of plasma glucagon/insulin was used as an index of insulin-mediated suppression of glucagon secretion. Results: During all 3 insulin clamp steps (Study 1), plasma glucagon concentration was increased compared to baseline study, and plasma glucagon/insulin ratio was significantly reduced by 24 % (p < 0.05). The rate of insulin-stimulated glucose disposal was inversely correlated with plasma glucagon/insulin ratio (r = −0.44, p < 0.05) and with glucagon AUC (r = −0.48, p < 0.05). During the 2-step hyperglycemic clamp (Study 2) plasma glucagon was similar before and after 72 h of glucose infusion; however, glucagon/insulin ratio was significantly reduced (p < 0.05). Incremental area under plasma insulin curve during the first (r = −0.74, p < 0.001) and second (r = −0.85, p < 0.001) hyperglycemic clamp steps was strongly and inversely correlated with plasma glucagon/insulin ratio. Conclusion: Sustained (48–72 h) physiologic hyperglycemia (+50 mg/dl) caused whole body insulin resistance and impaired insulin-mediated suppression of glucagon secretion, suggesting a role for glucotoxicity in development of hyperglucagonemia in T2DM.

Original languageEnglish (US)
Article number155512
JournalMetabolism: Clinical and Experimental
Volume142
DOIs
StatePublished - May 2023

Keywords

  • Glucagon secretion
  • Glucotoxicity
  • Insulin resistance

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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