Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans

Abstract

Objective: To evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m(2), and HbA(1c) 5.5 ± 0.1%).

Research design and methods: Saline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia.

Results: During hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P < 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. -11 ± 8 pmol/L per 90 min, P < 0.005). During hyperglycemia, comparable suppression of plasma glucagon (-461 ± 81 vs. -371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P < 0.0001).

Conclusions: In healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.

FIG. 1.

Glucose and GIP plasma concentrations of glucose (upper panel) and GIP (lower panel) during euglycemia (dark blue curves, circles), hypoglycemia (blue curves, diamonds), and hyperglycemia (turquoise curves, squares) on days with GIP infusions (filled symbols) and days with saline infusion (open symbols). Concomitant glucose infusions (grams per body weight per 15-min time intervals) are depicted as bar graphs in the upper panel. Data are means ± SEM.

FIG. 2.

Insulin, C-peptide, and ISR plasma concentrations of insulin (upper panel), C-peptide (middle panel), and ISR derived by deconvolution analysis (lower panel) over 90 min of GIP infusions (filled symbols) and saline infusions (open symbols) during euglycemia (dark blue curves, circles), insulin-induced hypoglycemia (blue curves, diamonds), and hyperglycemia (turquoise curves, squares). Data are means ± SEM. Statistical analysis was done by repeated-measures ANOVA. *Significant differences (P < 0.05).

FIG. 3.

Glucagon plasma concentrations of glucagon during 90 min (upper panel) or the initial 30 min (lower panel) of GIP infusions (filled symbols) or saline infusions (open symbols) during euglycemia (dark blue curves, circles), insulin-induced hypoglycemia (blue curves, diamonds), and hyperglycemia (turquoise curves, squares). Insets in lower panel are the iAUCs of glucagon concentrations during the initial 30 min. Data are means ± SEM. Statistical analysis was done by repeated-measures ANOVA followed by Bonferroni posttests or by paired t tests. *Significant differences (P < 0.05).

FIG. 4.

Glucagon and C-peptide. The in vivo relation of plasma glucagon (dark blue curves, squares) and serum C-peptide (light blue curves, circles) to selected PG values between 3 and 12 mmol/L in the presence of stimulated GIP concentrations (broken lines, filled symbols) or basal levels (full lines, open symbols). Data are means ± SEM. *Significant differences (P < 0.05) according to paired t tests.