TY - JOUR
T1 - Chronic physiologic hyperglycemia impairs insulin-mediated suppression of plasma glucagon concentration in healthy humans
AU - Chen, Xi
AU - Merovci, Aurora
AU - DeFronzo, Ralph A.
AU - Tripathy, Devjit
N1 - Funding Information:
This work was supported by National Institutes of Health grant DK-24092-36 (to R.A.D.). D.T.'s salary is supported by the South Texas Veterans Health Care System, Audie L. Murphy VA Hospital. Part of results from this study was presented at the American Diabetes Association Annual Meetings in 2017, 2018 and 2019 and supported by Foundation for Advancing Veterans' Health Research.
Publisher Copyright:
© 2023
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
KW - Glucagon secretion
KW - Glucotoxicity
KW - Insulin resistance
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U2 - 10.1016/j.metabol.2023.155512
DO - 10.1016/j.metabol.2023.155512
M3 - Article
C2 - 36746320
AN - SCOPUS:85149721887
SN - 0026-0495
VL - 142
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
M1 - 155512
ER -