Takuya Haraguchi

<jats:title>Abstract</jats:title> <jats:p>Glucagon plays a pivotal role in hepatic amino acid metabolism; acute high‐protein diet feeding and diabetic condition both induce enhanced glucagon secretion. However, it remains unknown whether these two conditions alter hepatic amino acid metabolism through the same or different pathways. In this study, streptozotocin‐induced diabetic (STZ‐D) and nondiabetic (ND) mice received liquid normal control (LNC) or liquid high‐protein (LHP) diet. Plasma and hepatic parameters were analyzed 2 h post‐feeding. LHP increased plasma essential amino acids in both groups. Hepatic amino acid accumulation in LHP‐fed STZ‐D mice was increased compared to that in LNC‐fed STZ‐D mice but not in ND mice. In addition, LHP reduced hepatic glycogen while the expression of amino acid metabolism and urea cycle genes remained unchanged both in ND and STZ‐D mice. Compared with ND mice, STZ‐D mice showed upregulation of genes involved in gluconeogenesis and amino acid metabolism, together with an accumulation of early glycolytic intermediates and glycogen. These findings indicate that acute high‐protein intake induces non‐transcriptional regulation of amino acid metabolism within 2 h. The altered hepatic amino acid profile in STZ‐D mice is likely to be driven by increased hepatic amino acid uptake and accelerated gluconeogenesis.</jats:p>

<jats:sec> <jats:title/> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Article Highlights</jats:title> </jats:sec>