Enhanced secretion of glucagon-like peptide-1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

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Chemokine ligands and receptors regulate the directional migration of leukocytes. Post-translational modifications of chemokine receptors including O-glycosylation and tyrosine sulfation have been reported to regulate ligand binding and resulting signaling. Through in silico analyses, we determined potential conserved O-glycosylation and sulfation sites on human and murine CC chemokine receptors. Glyco-engineered CHO cell lines were used to measure the impact of O-glycosylation on CC chemokine receptor CCR5, while mutation of tyrosine residues and treatment with sodium chlorate were performed to determine the effect of tyrosine sulfation. Changing the glycosylation or tyrosine sulfation on CCR5 reduced the receptor signaling by the more positively charged CCL5 and CCL8 more profoundly compared to the less charged CCL3. The loss of negatively charged sialic acids resulted only in a minor effect on CCL3-induced signal transduction. The enzymes GalNAc-T1 and GalNAc-T11 were shown to be involved in the process of chemokine receptor O-glycosylation. These results indicate that O-glycosylation and tyrosine sulfation are involved in the fine-tuning and recognition of chemokine interactions with CCR5 and the resulting signaling.

Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of protecting GIP from degradation for their clinical effects is unknown. We included 12 patients with type 2 diabetes (mean±SD; BMI 27±2.6 kg/m2, HbA1c 7.1±1.4% (54±15 mmol/mol) in this double-blind, placebo-controlled, crossover study to investigate the contribution of endogenous GIP to the effects of the DPP-4 inhibitor sitagliptin. Participants underwent two randomized 13-day treatment courses of sitagliptin (100 mg/day) and placebo, respectively. At the end of each treatment period, we performed two mixed meal tests with infusion of the GIP receptor antagonist GIP(3-30)NH2(1,200 pmol/kg/min) or saline placebo. Sitagliptin lowered mean fasting plasma glucose by 1.1 mmol/L compared to placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared to saline (ΔAUC%±SEM; +7.3±2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved beta cell function by 37±12% during DPP-4 inhibition by sitagliptin. This was determined by the insulin secretion rate / plasma glucose ratio. We calculated an estimate of the ‘absolute sitagliptin-mediated impact of GIP on beta cell function’ as the insulinogenic index during sitagliptin treatment plus saline infusion minus the insulinogenic index during sitagliptin plus GIP(3-30)NH2. This estimate was expressed relative to the maximal potential contribution of GIP to the effect of sitagliptin (= 100%), defined as the difference between the full sitagliptin treatment effect, including actions mediated by GIP (sitagliptin plus saline) and the physiological response minus any contribution by GIP (placebo treatment plus GIP(3-30)NH2). We demonstrate insulinotropic and glucose-lowering effects of endogenous GIP in patients with type 2 diabetes, and that endogenous GIP contributes to the improved beta cell function observed during DPP-4 inhibition.

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