Glucagon Stimulation Test and Insulin Secretory Capacity in the Clinical Assessment of Incretin-Based Therapy for Diabetes

Evaluation of insulin secretory capacity is essential to understand the pathophysiologic condition of individuals with diabetes and assess the efficacy of drugs used in the treatment of this disease. The 1-mg i.v. glucagon stimulation test (GST) is widely used to evaluate residual β-cell function; we previously reported that GST assessment of insulin secretory capacity is useful in assessing the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs). However, recent reports have indicated that pharmacologic concentrations of glucagon stimulate insulin secretion through GLP-1 receptors, confounding the issue. The current studies were undertaken to reassess the reliability of the GST for evaluation of insulin secretory capacity under GLP-1RAs and dipeptidyl peptidase 4 inhibitors (DPP-4is). Our first study included individuals receiving GLP-1RA treatment, evaluated by the GST before and after treatment. Although the fasting C-peptide response (CPR) levels were elevated after treatment, the induction of insulin secretion by glucagon was significantly reduced. Our second study compared glucagon-induced insulin secretion between DPP-4i users and nonusers, assessed by the GST after propensity score matching. Although the fasting CPR levels were similar in the two investigations, glucagon-induced insulin secretion was significantly lower with DPP-4i use. These results suggest that the GST might underestimate insulin secretory capacity under incretin-based therapy.

• The current studies were undertaken to reassess the reliability of the 1-mg i.v. glucagon stimulation test (GST) for evaluation of insulin secretory capacity under glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4is).

• We aimed to determine whether the amount of insulin secretion induced by pharmacologic glucagon stimulation is reduced under these incretin-based therapies, because they both act through GLP-1 receptors.

• We found that GLP-1RA and DPP-4i treatments significantly reduced insulin secretion on the GST.

• The GST underestimates insulin secretory capacity under incretin-based therapy by a novel regulatory system of glucagon and GLP-1 signaling in β-cells.