Protective Effects of Imeglimin and Metformin Combination Therapy on β-Cells in db/db Male Mice.

Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice.

Protective effects of S100A8 on sepsis mortality: Links to sepsis risk in obesity and diabetes.

Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. Here, we examine the role of S100A8 in sepsis of obesity and diabetes models.

Association between circulating SerpinB1 levels and insulin sensitivity in Japanese with type 2 diabetes: A single-center, cross-sectional, observational study.

Plasma and liver SerpinB1 levels are elevated in mice with insulin resistance and promote β-cell proliferation in human islets. We measured serum SerpinB1 levels in Japanese subjects with or without type 2 diabetes (T2DM). We enrolled 12 normal glucose tolerance (NGT) and 51 T2DM subjects.

E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance.

Prevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication.

Abdominal aortic calcification is associated with Fibrosis-4 index and low body mass index in type 2 diabetes patients: A retrospective cross-sectional study.

Aims/introduction: This study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus.

Materials And Methods: This retrospective cross-sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs.

Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca release from the ER.

Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion.

Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway.

The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets.

Immediate Glucose-Lowering Effect After the First Administration of Dulaglutide: A Retrospective, Single-Center, Observational Study.

Introduction: Dulaglutide is a long-acting glucagon-like peptide 1 receptor agonist that is administered once weekly for the treatment of type 2 diabetes. However, the immediate glucose-lowering effect of dulaglutide after the first administration and the factors affecting the efficacy of the drug remain unclear.

Methods: This study was a retrospective and observational study of 80 subjects with type 2 diabetes conducted in a hospitalized setting.

Asymptomatic meningitis diagnosed by positron emission tomography in a patient with syndrome of inappropriate antidiuretic hormone secretion: a case report.

Background: Syndrome of inappropriate antidiuretic hormone secretion can be caused by arginine-vasopressin-producing tumors or enhanced arginine vasopressin secretion from the posterior pituitary gland due to central nervous system disorders and intrathoracic diseases.

Case Presentation: A 53-year-old Asian man was hospitalized with complaints of tremor and hiccups. Laboratory examination revealed findings suggestive of hypotonic hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion.

The Roles of the IGF Axis in the Regulation of the Metabolism: Interaction and Difference between Insulin Receptor Signaling and IGF-I Receptor Signaling.

It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated.

Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes.

Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species and causes endothelial dysfunction. In this study, we evaluated the association of XOR and its substrate with the vascular complications in 94 Japanese inpatients with type 2 diabetes (T2DM).

Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor.

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice.

Soluble EGFR, a hepatokine, and adipsin, an adipokine, are biomarkers correlated with distinct aspects of insulin resistance in type 2 diabetes subjects.

Background: Insulin resistance can occur in all metabolic organs including the liver, adipose tissue, and skeletal muscles. Circulating soluble epidermal growth factor receptor (soluble EGFR) and adipsin levels are altered in obese diabetic mice and are possibly correlated with insulin resistance in both mice and humans. Here, we investigated the significance of soluble EGFR and adipsin as biomarkers for insulin resistance in Japanese subjects with type 2 diabetes.

Effects of liraglutide and empagliflozin added to insulin therapy in patients with type 2 diabetes: A randomized controlled study.

Aims/introduction: Liraglutide and empagliflozin suppress cardiovascular events. However, reports on their long-term combined use with insulin therapy or direct comparisons of these drugs are limited.

Materials And Methods: This open-label, parallel-group, randomized controlled trial compared the effects of liraglutide and empagliflozin combined with insulin therapy in type 2 diabetes patients.

Luseogliflozin increases beta cell proliferation through humoral factors that activate an insulin receptor- and IGF-1 receptor-independent pathway.

Aims/hypothesis: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia.

Influence of Timing of Insulin Initiation on Long-term Glycemic Control in Japanese Patients with Type 2 Diabetes: A Retrospective Cohort Study.

Objective Delays in insulin initiation can lead to the development of complications in the management of type 2 diabetes. Methods In this study, the effects of the timing of insulin initiation on glycemic control in patients with type 2 diabetes were evaluated retrospectively. Changes in the HbA1c levels of 237 patients were analyzed after insulin initiation.

Signaling between pancreatic β cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation.

Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic β cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage-associated molecular pattern molecules (DAMPs), in β-cell inflammation.

Serum Quantitative Proteomic Analysis Reveals Soluble EGFR To Be a Marker of Insulin Resistance in Male Mice and Humans.

To identify circulating factors as candidates involved in type 2 diabetes mellitus (T2DM), we conducted two different quantitative proteomic analyses: (1) db/db mouse sera were compared with db/+ mouse sera obtained at 4, 8, 12, and 24 weeks of age, and (2) db/db mouse sera from animals treated with liraglutide were compared with sera from animals without liraglutide treatment. Twenty proteins were differentially expressed in db/db mouse sera in the first experiment and eight proteins were differentially expressed in db/db mouse sera after liraglutide treatment in the second experiment. Soluble epidermal growth factor receptor (sEGFR) was identified as a common factor, and its protein level was significantly affected in both experiments.

Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic β cell proliferation after the withdrawal of OSI-906.

Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28).

Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets.

Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets.

Effects of metformin on compensatory pancreatic β-cell hyperplasia in mice fed a high-fat diet.

Metformin has been widely used for the treatment of type 2 diabetes. However, the effect of metformin on pancreatic β-cells remains controversial. In this study, we investigated the impacts of treatment with metformin on pancreatic β-cells in a mouse model fed a high-fat diet (HFD), which triggers adaptive β-cell replication.

Evaluation of the appropriateness of using glucometers for measuring the blood glucose levels in mice.

Glucometers are also widely used in diabetes research conducted using animal models. However, the appropriateness of measuring blood glucose levels using glucometers in animal models remains unclear. In this study, we evaluated the consistency between the blood glucose levels measured by 11 models of glucometers and plasma glucose levels measured by a laboratory biochemical test in blood samples collected by retro-orbital sinus puncture or tail-tip amputation.

DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid.

Background: Diabetes therapy that not only lowers glucose levels but also lengthens life spans is required. We previously demonstrated that DPP-4 inhibition ameliorated β cell apoptosis and adipose tissue inflammation in β cell-specific glucokinase haploinsufficient mice fed a diet containing a combination of sucrose and linoleic acid (SL).

Methods: In this study, we investigated the effects of DPP-4 inhibition in obese diabetic db/db mice fed an SL diet or a control diet containing sucrose and oleic acid (SO).