Novel agonist and antagonist radioligands for the GLP-2 receptor. Useful tools for studies of basic GLP-2 receptor pharmacology.

BACKGROUND: Glucagon-like peptide-2 (GLP-2) is a pro-glucagon-derived hormone secreted from intestinal enteroendocrine L cells with actions on gut and bones. GLP-2(1-33) is cleaved by DPP-4, forming GLP-2(3-33), having low intrinsic activity and competitive antagonism properties at GLP-2 receptors. We created radioligands based on these two molecules. EXPERIMENTAL APPROACH: The methionine in position 10 of GLP-2(1-33) and GLP-2(3-33) was substituted with tyrosine (M10Y) enabling oxidative iodination, creating [125 I]-hGLP-2(1-33,M10Y) and [125 I]-hGLP-2(3-33,M10Y). Both were characterized by competition binding, on-and-off-rate determination and receptor activation. Receptor expression was determined by target-tissue autoradiography and immunohistochemistry. KEY RESULTS: Both M10Y-substituted peptides induced cAMP production via the GLP-2 receptor comparable to the wildtype peptides. GLP-2(3-33,M10Y) maintained the antagonistic properties of GLP-2(3-33). However, hGLP-2(1-33,M10Y) had lower arrestin recruitment than hGLP-2(1-33). High affinities for the hGLP-2 receptor were observed using [125 I]-hGLP-2(1-33,M10Y) and [125 I]-hGLP-2(3-33,M10Y) with KD values of 59.3 and 40.6 nM. The latter (with antagonistic properties) had higher Bmax and faster on and off rates compared to the former (full agonist). Both bound the hGLP-1 receptor with low affinity (Ki of 130 and 330 nM, respectively). Autoradiography in wildtype mice revealed strong labelling of subepithelial myofibroblasts, confirmed by immunohistochemistry using a GLP-2 receptor specific antibody that in turn was confirmed in GLP-2 receptor knock-out mice. CONCLUSION AND IMPLICATIONS: Two new radioligands with different binding kinetics, one a full agonist and the other a weak partial agonist with antagonistic properties were developed and subepithelial myofibroblasts identified as a major site for GLP-2 receptor expression.

Comparison of non-insulin antidiabetic agents as an add-on drug to insulin therapy in type 2 diabetes: a network meta-analysis.

We aimed to evaluate the comparative efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), or thiazolidinedione (TZD) as an adjunctive treatment in patients with poorly controlled type 2 diabetes mellitus (T2DM) on insulin therapy. We searched Medline, Embase, the Cochrane Library, and ClinicalTrials.gov through April 2016. Bayesian network meta-analyses were performed with covariate adjustment. The primary outcome was the change in glycated hemoglobin A1c (HbA1c) from baseline. Fifty randomized controlled trials covering 15,494 patients were included. GLP-1RA showed the greatest HbA1c-lowering effect compared to the control (-0.84%; 95% credible interval, -1.00% to -0.69%), followed by TZD (-0.73%; -0.93 to -0.52%), SGLT2i (-0.66%; -0.84% to -0.48%), and DPP4i (-0.54%; -0.68% to -0.39%). SGLT2i showed the greatest fasting plasma glucose reduction. GLP-1RA and SGLT2i showed greater body weight reduction, whereas TZD increased body weight. TZD was ranked the highest in terms of insulin dose reduction. The risk of hypoglycemia was increased with TZD or GLP-1RA. The study provides the best available evidence on the comparative efficacy and safety of non-insulin anti-diabetic agents on top of pre-existing insulin therapy for inadequately controlled T2DM patients.