Imeglimin enhances glucagon secretion through an indirect mechanism and improves fatty liver in high-fat, high-sucrose diet-fed mice.

AIMS/INTRODUCTION: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic ß-cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α-cells. MATERIALS AND METHODS: Experiments were carried out in high-fat, high-sucrose diet-fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme-linked immunosorbent assay; the latter eliminates cross-reactivities with other proglucagon-derived peptides. RESULTS: Plasma glucagon, insulin and glucagon-like peptide-1 levels were increased by imeglimin administration in high-fat, high-sucrose diet-fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long-term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long-term administration of imeglimin did not alter α-cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein-1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. CONCLUSIONS: Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation.

FGF23-related hypophosphatemic rickets preceding the onset of systemic lupus erythematosus: A juvenile case.

Key Clinical Message: This case report describes the clinical course of a juvenile female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. Our study demonstrates the possibility of hypophosphatemic rickets as an early symptom of SLE. Abstract: Fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets is observed in both genetic and acquired disorders. Various reports describe FGF23-related hypophosphatemia with systemic lupus erythematosus (SLE), although FGF23-related hypophosphatemia preceding the onset of SLE has never been described. Here, we report the case of a 9-year-old female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. The patient presented to us with arthralgia in the lower extremities and abnormality of gait lasting for 8 months. She was diagnosed with FGF23 hypophosphatemic rickets due to the presence of hypophosphatemic rickets symptoms and high serum levels of FGF23. Additional examination excluded hereditary diseases and tumor-induced osteomalacia. Three months after diagnosis of FGF23-related hypophosphatemic rickets, she developed nephritis and was diagnosed with SLE. She was treated with prednisolone, hemodialysis, and disease-modifying drugs, as well as oral sodium phosphate to improve hypophosphatemia. Serum anti-double-stranded DNA antibody (dsDNAab) and plasma tumor necrosis factor-α (TNF-α) were elevated at FGF23-related hypophosphatemic rickets diagnosis. During the clinical course, serum FGF23 correlated with dsDNAab and TNF-α serum levels, which are involved in SLE disease activity. In this case, FGF23-related hypophosphatemic rickets without hereditary diseases or tumor-induced osteomalacia occurred before the appearance of juvenile SLE symptoms, and serum FGF23 represented disease activity in SLE.

Protein Kinase C (Pkc)-δ Mediates Arginine-Induced Glucagon Secretion in Pancreatic α-Cells.

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.