The Glucagonotropic Effect of GIP Is Negated During Insulin-Induced Hypoglycemia in Type 1 Diabetes: A Randomized, Placebo-Controlled, Crossover Study

Glucose-dependent insulinotropic polypeptide (GIP1–42) increases glucagon levels in the presence of normal-to-low plasma glucose concentrations in individuals with type 1 diabetes (T1D), suggesting its potential use as a safeguard against hypoglycemia. We investigated the dose-dependent effects of exogenous full-length GIP1–42 and its truncated variant GIP1–30NH2 on glucagon concentrations during insulin-induced hypoglycemia in individuals with T1D. In a randomized, double-blind, placebo-controlled, crossover study, 10 men with C-peptide–negative T1D participated in five experimental visits. On each visit, participants received a 135-min intravenous infusion of GIP1–42 or GIP1–30NH2 (both at 4 or 8 pmol/kg/min), or placebo. The infusion period included a 30-min euglycemic period, a 60-min insulin-induced hypoglycemic clamp (target glucose 2.5 mmol/L), and a 45-min recovery phase. During the euglycemic period, glucagon concentrations were higher with all GIP infusions compared with placebo, reaching statistical significance only for GIP1–30NH2 (P 0.05 for both high-dose 8 pmol/kg/min and low-dose 4 pmol/kg/min). However, the insulin infusion suppressed glucagon to similarly low levels for all interventions. Both GIP variants increased norepinephrine levels, and high-dose GIP1–42 slightly reduced the amount of glucose required to recover from hypoglycemia. These findings demonstrate that although GIP acutely increases glucagon concentrations during euglycemia in T1D, insulin infusion overrides this effect, indicating that elevated GIP levels alone cannot effectively restore the glucagon response to insulin-induced hypoglycemia in T1D. Article Highlights The glucose-dependent glucagonotropic effects of glucose-dependent insulinotropic polypeptide (GIP) variants in type 1 diabetes (T1D) are incompletely understood. We investigated whether native full-length GIP1–42 and its truncated variant GIP1–30NH2 increase glucagon concentrations during insulin-induced hypoglycemia in individuals with T1D. During euglycemia, both GIP variants increased glucagon statistically significantly for GIP(1–30)NH2 only and norepinephrine, but insulin suppressed glucagon levels similarly across interventions. High-dose GIP1–42 was associated with slightly reduced glucose requirements during recovery from hypoglycemia, suggestive of increased hepatic glucose production through either glucagon or norepinephrine action.