357-OR: Improved Glycemic Control in Persons with Type 2 Diabetes Improves Beta-Cell Actions of Endogenous Glucose-Dependent Insulinotropic Polypeptide

The insulinotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) is severely reduced or even absent in persons with type 2 diabetes but may be partly regained following improved glycemic control. Here, we examined the beta cell response to endogenous GIP before and after a period of plasma glucose (PG) normalization. In a randomized, double-blind design, 15 metformin-treated persons with dysregulated type 2 diabetes (HbA1c 8.3±0.3% (67±3 mmol/mol) ([mean±SEM]) were subjected to two 75 g-oral glucose tolerance tests (OGTT) with continuous infusions of GIP receptor antagonist (GIP (3-30) NH₂) and placebo (saline) , respectively, before and in the end of a 3-4 week period of PG normalization achieved using administration of empagliflozin and individually dosed insulin based on continuous glucose monitoring (CGM) (fasting PG (FPG) target: 72-1mg/mL (4.0-5.9 mmol/L) ; 2-hour postprandial PG target: <162 mg/mL (<9.0 mmol/L)) . At the end of the PG normalization period, FPG was reduced from 195±mg/mL (10.8±0.6 mmol/L) to 114±4 mg/mL (6.3±0.2 mmol/L) (P<0.001) and area under curve (AUC) for PG during OGTT diminished (3,409±95 vs. 2,428±91 mmol/L×min, P<0.001) . Before the period of PG normalization, GIP (3-30) NH2 did not affect oral glucose tolerance. PG normalization amplified GIP (3-30) NH₂-induced lowering of beta cell glucose sensitivity (∆baseline-subtracted AUC_{plasma C-peptide:PG ratio}: 1,579±380 vs. 3,296±617 pmol/mmol×min, P=0.021) and resulted in a significant effect of GIP (3-30) NH₂ on oral glucose tolerance (baseline-subtracted AUC_PG: 1,146±65 vs. 1,225±58 mmol/L×min, P=0.025) . In persons with dysregulated type 2 diabetes, a period of PG normalization increased beta cell sensitivity to GIP, translating into a detectable contribution of endogenous GIP to oral glucose tolerance.