Effects of Pharmacological GIP Infusion on Insulin, Glucagon, and Cardiovascular Responses During Hyperglycemia in Type 2 Diabetes

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. Article Highlights 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.