The pharmacological actions of glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D) remain incompletely defined. We evaluated the acute effects of intravenous GIP infusion at a pharmacological dose on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D. Ten participants, whose T2D was managed by diet and/or metformin monotherapy (n = 4 men and 6 women; mean ± SEM age 68.2 ± 3.4 years, BMI 31.7 ± 1.2 kg/m2, HbA1c 6.9% ± 0.6%), were studied on two occasions in a double-blind, randomized, crossover design. During each study visit, hyperglycemia (∼15 mmol/L) was maintained for 210 min by variable intravenous (IV) glucose infusion, and GIP(1–42) (4 pmol/kg/min) or 0.9% saline was infused IV. Plasma insulin, C-peptide, glucagon, glucose infusion requirements, mean glucose/insulin ratio (M/I ratio; a surrogate for insulin sensitivity), heart rate, and blood pressure were assessed. GIP increased baseline-subtracted insulin and C-peptide responses between 0 and 210 min (mean ± SEM 8,717 ± 1,827 vs. 3,074 ± 698 mU/L*min, P = 0.003; and 383.1 ± 58.9 vs. 185.0 ± 35.0 nmol/L*min, P = 0.0005, respectively) and increased glucose infusion requirements to maintain hyperglycemia (mean ± SEM 6.1 ± 0.6 vs. 4.9 ± 0.4 mg/kg/min; P = 0.02), but attenuated glucagon suppression (P = 0.03) and reduced the M/I ratio (P < 0.0001). GIP also increased heart rate and reduced systolic and diastolic blood pressures (P < 0.01 each). These findings demonstrate that pharmacological GIP retains substantial biological activity in relatively well-controlled T2D, influencing both glucose metabolism and cardiovascular regulation.
- The clinical success of dual glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has renewed interest in the pharmacological actions of GIP in type 2 diabetes (T2D), although its metabolic and cardiovascular effects remain incompletely understood.
- The study evaluated the effects of a pharmacological GIP infusion on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D.
- GIP stimulated insulin secretion and increased whole-body glucose disposal during hyperglycemia while modestly attenuating glucagon suppression and impairing insulin sensitivity. GIP also augmented heart rate and reduced blood pressure.
- Our findings demonstrate that GIP remains biologically active in T2D and pharmacological doses modulate glucose metabolism and cardiovascular function.
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