1976-P: Physiological Effects of GIP(1-30)NH2 in Healthy Subjects

Abstract

The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) circulates in at least two active forms: GIP(1-42), which besides its insulinotropic effect during hyperglycemia stimulates glucagon secretion at low plasma glucose (PG) levels and decreases bone resorption, and GIP(1-30)NH2. In vitro and rodent studies has shown similar physiological effects of GIP(1-30)NH2 and GIP(1-42), but effects in humans remain unexplored. Here, we infused GIP(1-42) and GIP(1-30)NH2 in humans to establish the physiological effects of GIP(1-30)NH2. On three separate days, 10 healthy men (mean age 23 (range 20-28) years, BMI 22.4 (20.0-25.2) kg/m2) received intravenous infusions of GIP(1-42), GIP(1-30)NH2 and saline, respectively. Both peptides were infused at 4 pmol/kg/min during 200 minutes. After 20 minutes of infusion, PG was clamped at the fasting PG level (FPG) for 60 minutes, followed by 60 minutes at FPG × 1.5, and lastly 60 minutes at FPG × 2. There were no differences in PG levels between the three interventions, but significantly more glucose was needed for the clamp with GIP(1-42) compared to saline (P = 0.022). Plasma levels of GIP(1-30)NH2 reached a mean (± SD) of 31.4 ± 29.9 pmol/l and GIP(1-42) of 97.8 ± 27.9 pmol/l. Despite this difference, both infusions resulted in robust and glucose-dependent insulin responses (as assessed by serum C-peptide) with no differences between the two peptide infusions (P = 0.187), and at FPG level only GIP(1-30)NH2 resulted in higher glucagon levels than saline (P = 0.0302). At 180 minutes, the bone resorption marker carboxy-terminal collagen I crosslinks (CTX) was suppressed to 61 ± 13% of baseline values during saline, 42 ± 16% during GIP(1-30)NH2, and 29 ± 6% during GIP(1-42) (P < 0.001). We conclude that, like GIP(1-42), GIP(1-30)NH2 is a potent insulinotropic (at high PG levels), glucagonotropic (at low PG levels) and bone resorption-inhibiting hormone in healthy subjects. Disclosure L.S.L. Krogh: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. S. Stensen: None. K. Skov-Jeppesen: None. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.