Dan Kawamori

Aims/Introduction: Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti‐diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)‐derived pancreatic islet‐like spheroid (SC‐islet) models.Materials and Methods: Human iPSCs are differentiated into SC‐islets by three‐dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC‐islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC‐islets. SC‐islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP.Results: Metformin perturbed SC‐islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF‐β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin.Conclusions: Imeglimin does not perturb differentiation of SC‐islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.

Glucagon has been defined as an ‘insulin counteracting hormone’, which raises blood glucose levels. Recent progress in basic research has shown that glucagon is closely involved in glucose and amino acid metabolism. Additionally, its secretion is intricately, but precisely, regulated by various mechanisms involving molecules in addition to glucose, thus showing its critical role in systemic nutrient metabolism. An innovative dual‐antibody‐linked immunosorbent assay for glucagon that improves measurement accuracy has been developed, and substantial clinical findings have been obtained using this new system. This discovery expanded the pathophysiological significance of glucagon and accelerated the development of its clinical applications in diabetes.

Residual pancreatic endocrine function is important for maintaining metabolic status after pancreatectomy and is closely related to patient nutritional status and prognosis. In contrast to insulin secretion, the significance of glucagon secretion following pancreatectomy remains unclear. In this study, we assessed the changes in pancreatic glucagon secretion during pancreatectomy to determine their pathophysiological significance. We evaluated glucagon and insulin secretion using a liquid meal tolerance test before and after pancreatectomy in patients scheduled to undergo pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). After pancreatectomy, fasting plasma glucagon levels were significantly decreased in both the PD (n = 10) and DP (n = 5) groups (PD: from 18.4 to 10.5 pg/mL, p = 0.037; DP: from 21.0 to 12.1 pg/mL, p = 0.043), whereas postprandial plasma glucagon levels were not changed. In the liquid meal tolerance test after pancreatectomy, 60-min plasma glucagon levels and the area under the curve (AUC) for 0–120 min of PD were significantly higher than those for DP (60-min plasma glucagon: PD 49.0 vs. DP 21.7 pg/mL, p = 0.040; AUC0–120min: PD 4,749 vs. DP 3,564 μg min/mL, p = 0.028). Postoperative plasma glucose, serum insulin, and serum C-peptide levels during the liquid meal tolerance test were not significantly different between the two groups. Although fasting plasma glucagon levels decreased, postprandial glucagon responses were maintained after both PD and DP. The difference in residual meal-stimulated glucagon response between PD and DP suggests that a relative excess of postprandial glucagon is involved in the postoperative nutritional status after PD through its impact on systemic metabolic status.

Aim: To evaluate the pharmacodynamic effects of tirzepatide, a novel dual glucagon‐like peptide‐1 receptor and glucose‐dependent insulinotropic polypeptide receptor agonist, compared with dulaglutide in patients with type 2 diabetes. Materials and Methods: SURPASS J‐mono was a 52‐week, multicentre, randomized, double‐blind, parallel, active‐controlled, Phase 3 study, conducted in Japan. This substudy of SURPASS J‐mono evaluated postprandial metabolic variables and appetite after a meal tolerance test, and body composition measured by bioelectrical impedance analysis. Results: Of 636 participants in SURPASS J‐mono, 48 were included in this substudy and assigned to tirzepatide 5 mg (n = 9), tirzepatide 10 mg (n = 11), tirzepatide 15 mg (n = 9), or dulaglutide 0.75 mg (n = 19). Participants had a mean (standard deviation) age of 58.6 (7.5) years, duration of diabetes of 6.0 (6.3) years, and body mass index of 27.5 (3.5) kg/m ² . Mean glycated haemoglobin at baseline was 66 mmol/mol (8.22%). Following a standardized meal test, statistically significant differences in change from baseline in area under the concentration versus time curve from time zero to 6 h after dose for glucose, insulin, glucagon, C‐peptide and triglycerides were observed in all tirzepatide treatment arms, except triglycerides at 10 mg, compared with dulaglutide at Week 32. For body composition, tirzepatide 10 mg and 15 mg resulted in a significant reduction in body weight, and all doses of tirzepatide resulted in a significant reduction in body fat mass at Week 52. Conclusions: Compared with dulaglutide, tirzepatide showed greater potential for normalizing metabolic factors after a standardized meal. Tirzepatide reduced body weight and body fat mass.

Aims/Introduction: In addition to absolute insulin deficiency, dysregulated glucagon in type 1 diabetes is considered pathophysiologically important. Previously, we confirmed the presence of dysregulated glucagon in Japanese patients with type 1 diabetes, and found a significant correlation between plasma glucagon and blood urea nitrogen levels, suggesting an association between glucagon and amino acid metabolism. In this study, we evaluated plasma amino acid levels in Japanese patients with type 1 diabetes in the context of their functional relationship with glucagon.Materials and Methods: We assessed plasma free amino acid levels using liquid chromatography–mass spectrometry in 77 Japanese patients with type 1 diabetes, and statistically analyzed their characteristics and relationships with clinical parameters, including glucagon.Results: Participants with type 1 diabetes showed a large decrease in glutamate levels together with a characteristic change in plasma free amino acid profiles. The network structural prediction analyses showed correlations between each amino acid and glucagon in type 1 diabetes.Conclusions: Participants with type 1 diabetes showed characteristic changes in plasma glutamate levels and free amino acid profiles compared with controls and type 2 diabetes patients. Glucagon showed a closer correlation with amino acids than with parameters of glucose metabolism, suggesting that type 1 diabetes includes dysregulation in amino acids through dysregulated glucagon from remaining pancreatic α‐cells, together with that in glucose by insulin deficiency.

Incretin‐based therapies were introduced a decade ago in the treatment of diabetes. They have dramatically changed the strategy of diabetes treatments and also re‐iterated the significance of glucagon and α‐cells in the pathophysiology of diabetes. First, glucagon and α‐cells have been extensively studied in the field of basic medical research. For example, our previous studies has provided molecular evidence for the role of insulin signaling in α‐cells in the regulation of glucagon secretion and its involvement in the excessive secretion of glucagon in hyperglycemic state.

Recently, it is widely recognized that microinflammation plays important roles in the pathophysiology of metabolic diseases, especially obesity-related disorders, diabetes and their complications. Lipopolysaccharide-binding protein (LBP) is a liver-derived acute-phase protein responsive to lipopolysaccharides (LPS) produced by gram-negative bacteria, thus reflects the systemic inflammation caused by the infection of those bacteria including gut dysbiosis. In this study, we evaluated the plasma LBP levels and investigated its clinical significance in 67 Japanese patients with type 1 diabetes. Univariable analysis showed that LBP levels were significantly associated with body mass index (BMI; r = 0.43, p < 0.01) and serum high-sensitivity C-reactive protein (hs-CRP; r = 0.64, p < 0.001) levels. However, there was no significant association between plasma LBP levels and diabetic complications. Mediation analysis revealed that LBP had significant mediation effects on the association between hs-CRP and BMI (0.27 [95% confidence interval 0.10–0.48]). These results suggest that the systemic condition where the LBP level increases, such as gut dysbiosis, at least partly, impacts on chronic microinflammation in patients with type 1 diabetes.

Recent progress in research on glucagon and α‐cells highlights their pathophysiological roles in diabetes. We previously showed that plasma glucagon levels measured by newly developed enzyme‐linked immunosorbent assay were dysregulated in patients with type 1 diabetes with respect to plasma glucose levels, suggesting dysregulated secretion. In the current study, the annual change in plasma glucagon levels was assessed in these same patients. We found that the plasma glucagon levels in the 66 Japanese patients involved in the study were significantly correlated between both years. In addition, they were significantly associated with serum blood urea nitrogen (BUN) levels in a multivariate linear regression analysis, as reported in our previous paper. The statistical correlation in glucagon levels between annual checkups and the sustained significant correlation between glucagon and BUN suggest a constant dysregulation of glucagon in association with altered amino acid metabolism in patients with type 1 diabetes.

Glucagon secreted by pancreatic α‐cells plays pivotal roles in the systemic energy homeostasis mainly by regulating systemic glucose mobilization together with another important metabolic hormone, insulin. Recent application of the incretin‐based therapies to clinical diabetes refocused on the central roles of glucagon in the development of diabetic hyperglycemia. This revival of glucagon also enhanced the progress of basic research in α‐cell biology, as targeting glucagon is now expected to be the next therapeutic approach in diabetes treatment.