• Mikkel B Christensen, Salvatore Calanna, Jens J Holst, Tina Vilsbøll, and Filip K Knop.
• Diabetes Research Division (M.B.C., S.C., T.V., F.K.K.), Department of Medicine, Copenhagen University Hospital Gentofte, Hellerup DK-2900, Denmark; Department of Biomedical Sciences (J.J.H., M.B.C., F.K.K.), the Panum Institute; University of Copenhagen, DK-2100 Copenhagen, Denmark; and Department of Clinical and Molecular Biomedicine (S.C.), University of Catania, 95124 Catania, Italy.
• J. Clin. Endocrinol. Metab. 2014 Mar 1; 99 (3): E418-26.

ContextPatients with type 2 diabetes mellitus (T2DM) have clinically relevant disturbances in the effects of the hormone glucose-dependent insulinotropic polypeptide (GIP).ObjectiveWe 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 SettingWe performed a single center, placebo-controlled, cross-over, experimental study.PatientsWe 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]).InterventionWe infused physiological amounts of GIP (2 pmol × kg(-1) × min(-1)) or saline.Main Outcome MeasuresWe measured plasma concentrations of glucagon, glucose, insulin, C-peptide, intact GIP, and amounts of glucose needed to maintain glucose clamps.ResultsDuring 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).ConclusionsIn 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.

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