CONTEXT: Patients with type 2 diabetes mellitus (T2DM) have clinically relevant disturbances in the effects of the hormone glucose-dependent insulinotropic polypeptide (GIP).

OBJECTIVE: We aimed to evaluate the importance of the prevailing plasma glucose levels for the effect of GIP on responses of glucagon and insulin and glucose disposal in patients with T2DM.

DESIGN AND SETTING: We performed a single center, placebo-controlled, cross-over, experimental study.

PATIENTS: We studied twelve patients with T2DM (age: 62 ± 1 years [mean ± SEM], body mass index: 29 ± 1 kg/m(2); glycosylated hemoglobin A1c: 6.5 ± 0.1% [48 ± 2 mmol/mol]).

INTERVENTION: We infused physiological amounts of GIP (2 pmol × kg(-1) × min(-1)) or saline.

MAIN OUTCOME MEASURES: We measured plasma concentrations of glucagon, glucose, insulin, C-peptide, intact GIP, and amounts of glucose needed to maintain glucose clamps.

RESULTS: During fasting glycemia (plasma glucose ∼8 mmol/L), GIP elicited significant increments in both insulin and glucagon levels, resulting in neutral effects on plasma glucose. During insulin-induced hypoglycemia (plasma glucose ∼3 mmol/L), GIP elicited a minor early-phase insulin response and increased glucagon levels during the initial 30 minutes, resulting in less glucose needed to be infused to maintain the clamp (29 ± 8 vs 49 ± 12 mg × kg(-1), P < .03). During hyperglycemia (1.5 × fasting plasma glucose ∼12 mmol/L), GIP augmented insulin secretion throughout the clamp, with slightly less glucagon suppression compared with saline, resulting in more glucose needed to maintain the clamp during GIP infusions (265 ± 21 vs 213 ± 13 mg × kg(-1), P < .001).

CONCLUSIONS: In patients with T2DM, GIP counteracts insulin-induced hypoglycemia, most likely through a predominant glucagonotropic effect. In contrast, during hyperglycemia, GIP increases glucose disposal through a predominant effect on insulin release.