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Aims/Introduction: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐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. [ABSTRACT FROM AUTHOR]

Aim: Clinical trials showed the efficacy of sodium‐glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat‐AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium‐glucose cotransporter 2 inhibitor, ipragliflozin. Methods: Adults with T1D (n = 25) took 50‐mg open‐labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed‐meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C‐peptide, glucagon and β‐hydroxybutyrate. Results: The area under the curve from fasting (0 min) to 120 min (AUC0‐120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial β‐hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0‐120min) from baseline to 12 weeks were significantly correlated with those in β‐hydroxybutyrate levels. Conclusions: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied. [ABSTRACT FROM AUTHOR]

This article discusses the need for specific biomarkers to diagnose and treat diabetes of the exocrine pancreas (DEP), which is a secondary diabetes caused by exocrine pancreatic disorders. The study conducted by Lv and colleagues aimed to identify biomarkers that can distinguish DEP from type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM). The authors found that postacute pancreatitis diabetes mellitus (PPDM-A) showed characteristics of insulin resistance similar to T2DM, while postchronic pancreatitis diabetes mellitus (PPDM-C) showed characteristics of insulin deficiency similar to T1DM. Additionally, lower ghrelin response was found to be a diagnostic marker distinguishing PPDM-C from other types of diabetes, while lower peptide YY (PYY) response was a diagnostic marker distinguishing PPDM-A and PPDM-C from T2DM and T1DM. These biomarkers could potentially contribute to personalized medicine for diabetes in the future. [Extracted from the article]

This commentary discusses the role of G protein-coupled receptors (GPCRs) in regulating glucagon secretion in pancreatic alpha cells. The authors highlight the importance of understanding the signaling pathways in alpha cells for the development of therapeutic drugs targeting glucagon. They discuss recent studies that have identified specific GPCRs, such as the A2A adenosine receptor and the vasopressin 1b receptor, that play a role in glucagon secretion. The findings suggest that targeting these receptors could be a potential strategy for treating metabolic diseases such as diabetes, obesity, and fatty liver. [Extracted from the article]

Forkhead box O (Foxo) transcription factors govern metabolism and cellular differentiation. Unlike Foxo-dependent metabolic pathways and target genes, the mechanisms by which these proteins regulate differentiation have not been explored. [...]

Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism., Author(s): Tadahiro Kitamura [1, 5]; Yun Feng [2, 3, 5]; Yukari Ido Kitamura [1]; Streamson C Chua, Jr [3]; Allison W Xu [4]; Gregory S Barsh [4]; Luciano Rossetti [2, [...]

Research has been conducted on the insulin inhibiting gene expression via the phosphoinositol 3-kinase/Akt pathway. The ability of Akt to phosphorylate different forkhead protein sites in control and insulin receptor-deficient hepatocytes has been investigated and discussed.