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INTRODUCTION: As treatment agents for diabetes, liraglutide is a long-acting glucagon-like peptide 1 receptor agonist, and dipeptidyl peptidase 4 (DPP4) inhibitors are widely used because of their safety and tolerability. Regular treatment with liraglutide has been reported to significantly reduce blood glucose levels, but the impact of low-dose (0.3 mg) liraglutide on blood glucose levels immediately after treatment switching from a DPP4 inhibitor remains unknown. METHODS: We conducted a single-arm, retrospective, observational study in 55 inpatients with type 2 diabetes (T2D) to investigate the changes (Δ) in their blood glucose levels at six time points (6-point) from the day before (day -1) to the day after (day 1) by switching the antidiabetic treatment from a DPP4 inhibitor to liraglutide 0.3 mg (low-dose liraglutide) once daily. We also attempted to identify factors associated with the blood glucose-lowering effects of liraglutide. RESULTS: The median values of the changes in fasting, preprandial, and postprandial blood glucose levels and the fluctuations in the blood glucose levels expressed as the standard deviation of the 6-point blood glucose levels were significantly lower on day 1 than on day -1 (P < 0.05, P < 0.0001, P < 0.0001, P < 0.01, respectively); there were no cases of severe hypoglycemia. The Δ blood glucose levels were not associated with the baseline serum hemoglobin A1c values or with any markers of the insulin secreting capacity. There were no associations between the previously used blood glucose-lowering drug and the Δ blood glucose levels. CONCLUSION: Switching from a DPP4 inhibitor to low-dose (0.3 mg) liraglutide once daily significantly reduced the blood glucose levels and excursions of the blood glucose levels even from the very day after the treatment switch, with no serious adverse events.
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Imeglimin and metformin act in metabolic organs, including ß-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on ß-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. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased ß-cell mass by enhancing ß-cell proliferation and ameliorating ß-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against ß-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a ß-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of ß-cell mass in db/db mice, probably through direct action on ß-cells, suggesting a potential strategy for protecting ß-cells in the treatment of type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Metformina , Ratones , Animales , Masculino , Metformina/farmacología , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Glucemia/metabolismo , Células Secretoras de Insulina/metabolismo , Glucosa/metabolismo , Ratones Endogámicos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéuticoRESUMEN
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. Injection of S100A8 prolongs the survival of septic mice induced by lethal endotoxemia, Escherichia coli injection, or cecal ligation and puncture. S100A8 decrease the LPS-induced expression of proinflammatory cytokines in peritoneal macrophages by inhibiting TLR4-mediated signals in an autocrine manner. db/db, ob/ob, and western diet-fed mice demonstrate reduced upregulation of S100A8 induced by LPS treatment in both serum and peritoneal cells. These mice also show shorter survival after LPS injection, and S100A8 supplementation prolonged the survival. While myelomonocytic cells-specific S100A8-deficient mice (Lyz2 cre :S100A8 floxed/floxed ) exhibit shorter survival after LPS treatment, S100A8 supplementation prolonged the survival. Thus, myelomonocytic cell-derived S100A8 is crucial for protection from sepsis, and S100A8 supplementation improves sepsis, particularly in mice with obesity and diabetes.
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Plasma and liver SerpinB1 levels are elevated in mice with insulin resistance and promote ß-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. There was no difference in serum SerpinB1 levels between the 2 groups (T2DM, 1.3 ± 0.9 ng/mL vs. NGT, 1.8 ± 1.7 ng/mL; P = 0.146). After adjusting for age and sex, the serum SerpinB1 levels were positively correlated with HOMA2-%S (ß = 0.319, P = 0.036), and negatively correlated with fasting blood glucose (ß = -0.365, P = 0.010), total cholesterol (ß = -0.396, P = 0.006), low-density lipoprotein (LDL) cholesterol (ß = -0.411, P = 0.004), triglycerides (ß = -0.321, P = 0.026), and γGTP (ß = -0.322, P = 0.026) in subjects with T2DM. Thus, circulating SerpinB1 is possibly associated with insulin sensitivity and better blood glucose level in Japanese subjects with T2DM. Trial registration: UMIN Clinical Trials Registry, UMIN000020453.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Serpinas , Humanos , Glucemia , Estudios Transversales , Insulina , JapónRESUMEN
Prevention or amelioration of declining ß cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by ß 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 ß cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks ß-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of ß cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables ß cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote ß cell compensation.
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Resistencia a la Insulina , Células Secretoras de Insulina , Animales , Proliferación Celular , Proteína A Centromérica/metabolismo , Factor de Transcripción E2F1/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ratones , Ratones Noqueados , Receptor de Insulina/metabolismoRESUMEN
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 ß-cells and ß-cell failure by using genetically engineered mice and human islets. ß-cell-specific UCP2-overexpressing transgenic mice (ßUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in ßUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of ß-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of ß-cell function.
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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. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models. RESULTS: The AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis-4 (Fib-4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography-diagnosed fatty liver. There was a significant interaction between BMI and Fib-4 index; lower BMI and Fib-4 index >2.67 showed a synergistic association with high AAC grade. CONCLUSIONS: AAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib-4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.
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Enfermedades de la Aorta , Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Calcificación Vascular , Humanos , Calcificación Vascular/complicaciones , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/epidemiología , Estudios Transversales , Índice de Masa Corporal , Aorta Abdominal/diagnóstico por imagen , Aorta Abdominal/patología , Enfermedades de la Aorta/complicaciones , Enfermedades de la Aorta/epidemiología , Estudios Retrospectivos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Factores de Riesgo , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/epidemiología , FibrosisRESUMEN
The effects of imeglimin, a novel antidiabetes agent, on ß-cell function remain unclear. Here, we unveiled the impact of imeglimin on ß-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted ß-cell proliferation, and improved ß-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in ß-cells under ER stress. Imeglimin failed to protect against ER stress-induced ß-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic ß-cells and increased ß-cell mass in Akita mice. Imeglimin also protected against ß-cell apoptosis in both human islets and human pluripotent stem cell-derived ß-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of ß-cell apoptosis both in vitro and in vivo.
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Apoptosis/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Hipoglucemiantes , Células Secretoras de Insulina/fisiología , Triazinas/farmacología , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glucosa/farmacología , Homeostasis/efectos de los fármacos , Humanos , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/ultraestructura , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Células Madre Pluripotentes , Proteína Fosfatasa 1/genética , Proteína Fosfatasa 1/fisiología , Factor de Transcripción CHOP/deficiencia , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/fisiología , Triazinas/uso terapéuticoRESUMEN
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. The changes (Δ) in the blood glucose (BG) levels at six time points (6-point BG levels) from the baseline (day - 1) to the day after the first administration of 0.75 mg of dulaglutide (day 1) were evaluated. The associations of the Δ 6-point BG levels with the patients' characteristics and laboratory data were also analyzed. RESULTS: Significant reduction of the fasting BG, preprandial BG, postprandial BG, and standard deviation (SD) of the 6-point BG levels was observed on day 1 as compared to day - 1 (P < 0.0001) and the reduced BG levels were maintained throughout the remaining observation period of 5 days. The baseline serum hemoglobin A1c and glycoalbumin levels were positively correlated with the reduction of the fasting BG. The Δ BG levels were not related to the parameters of insulin-secreting capacity. Insulin treatment was positively associated with the reduction of the 6-point BG levels. Patients without cerebrovascular disease and patients without diabetic retinopathy showed greater improvements of the fasting BG and SD of the 6-point BG levels, respectively. Urinary microalbumin level was positively correlated with improvements of the 6-point BG levels. Dulaglutide reduced the BG levels, irrespective of the previously used class of antidiabetic medication(s). CONCLUSION: Dulaglutide achieved reduction in glucose level within 24 h of the first injection. The improvement in the BG levels remained stable for a week in the hospitalized clinical setting.
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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. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906.
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Metabolismo Energético , Somatomedinas/metabolismo , Animales , Regulación de la Expresión Génica , Humanos , Insulina/metabolismo , Ratones , Especificidad de Órganos , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal , Somatomedinas/genéticaRESUMEN
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 patient did not complain of headache or photophobia, and showed no signs of meningeal irritation. Positron emission tomography-computed tomography revealed 18F-fluoro-deoxy-glucose accumulation along the cervical spinal cord, based on which the patient was diagnosed as having aseptic meningitis. The hyponatremia was treated successfully by fluid restriction, and optimum plasma sodium concentration was maintained by tolvaptan administration. CONCLUSIONS: This case underscores the need to consider the possibility of mild meningitis as the cause of syndrome of inappropriate antidiuretic hormone secretion in patients without other identifiable cause.
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Hiponatremia , Síndrome de Secreción Inadecuada de ADH , Meningitis , Antagonistas de los Receptores de Hormonas Antidiuréticas , Humanos , Hiponatremia/etiología , Síndrome de Secreción Inadecuada de ADH/complicaciones , Síndrome de Secreción Inadecuada de ADH/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
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). The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the high density lipoprotein cholesterol. The plasma XOR activity also showed a positive correlation with the serum triglyceride. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. The plasma XOR activity negatively correlated with the duration of diabetes, and positively correlated with the coefficient of variation of the R-R interval and sensory nerve conduction velocity. Furthermore, the plasma XOR activity was significantly decreased in patients with coronary artery disease. Thus, the plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in T2DM.Trial registration: This study is registered at the UMIN Clinical Trials Registry (UMIN000029970; https://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from Nov 15, 2017.
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Diabetes Mellitus Tipo 2/metabolismo , Xantina Deshidrogenasa/análisis , Anciano , Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/metabolismo , Biomarcadores/sangre , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Japón/epidemiología , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Xantina/sangre , Xantina/metabolismo , Xantina Deshidrogenasa/sangre , gamma-Glutamiltransferasa/metabolismoRESUMEN
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. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.
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Imidazoles/efectos adversos , Linagliptina/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pirazinas/efectos adversos , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Glucemia/metabolismo , Familia 2 del Citocromo P450/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Imidazoles/farmacología , Insulina/sangre , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Perilipina-2/metabolismo , Pirazinas/farmacología , Esteroide Hidroxilasas/metabolismo , Triglicéridos/sangreRESUMEN
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. METHODS: We measured the soluble EGFR and adipsin levels in sera from 47 non-diabetic subjects and 106 subjects with type 2 diabetes using enzyme-linked immunosorbent assays (ELISAs) and analyzed the correlations between the soluble EGFR or adipsin levels and metabolic parameters in type 2 diabetes subjects. We also measured the gene expression levels of Egfr and Cfd (adipsin) in the liver, adipose tissue, and skeletal muscle in mice with/without obesity or diabetes. RESULTS: The soluble EGFR levels were correlated with the fasting blood glucose level (P = 0.010), HOMA-IR (P = 0.035), HbA1c level (P = 0.007), HDL-cholesterol level (P = 0.044), and FIB-4 index (P = 0.017) after adjustments for age, sex, and total cholesterol levels. These factors are known to be related to hepatic insulin resistance. The serum adipsin levels were correlated with BMI (P < 0.001), waist circumference (P < 0.001), fasting serum insulin level (P = 0.001), HOMA-IR (P = 0.009), CPR-index (P = 0.045), and FIB-4 index (P = 0.007) after adjustments for age, sex and eGFR levels. Abdominal adiposity leads to the potentiation of these factors. The expression of Egfr was abundant in the liver, while Cfd was predominantly expressed in adipose tissue in mice. CONCLUSIONS: Soluble EGFR, a hepatokine, is correlated with insulin resistance in the liver, while adipsin, an adipokine, is associated with adipose insulin resistance.Trial registration: UMIN Clinical Trials Registry (www.umin.ac.jp), UMIN000020474. Registered 8 January 2016.
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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. Adult type 2 diabetes outpatients undergoing stable insulin therapy with glycated hemoglobin levels of 7.0-9.5% were enrolled. Participants received 0.9 mg/day liraglutide or 10 mg/day empagliflozin for 24 weeks. The primary end-point was the change in glycated hemoglobin levels from week 0 to 24. Body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: A total of 64 insulin-treated patients were randomized to receive liraglutide or empagliflozin. We analyzed 61 patients (30 liraglutide and 31 empagliflozin) who could be followed up. Liraglutide induced greater changes in glycated hemoglobin and glycated albumin than empagliflozin (glycated hemoglobin -1.24 ± 0.15% vs -0.35 ± 0.11%, P < 0.0001; glycated albumin -4.4 ± 0.6% vs -2.4 ± 0.5%, P < 0.01). Bodyweight (-1.3 ± 0.4 kg vs -1.5 ± 0.3 kg, P = 0.69) or body fat mass/lean tissue mass; urinary albumin excretion (median -5.3 mg/g-creatinine [interquartile range -60.6, 9.9 mg/g-creatinine] vs -12.9 mg/g-creatinine [interquartile range -70.8, -2.0 mg/g-creatinine], P = 0.23); and frequency of hypoglycemia did not differ significantly between the groups over a period of 24 weeks. There were no cases of study discontinuation owing to adverse effects. CONCLUSIONS: Liraglutide addition to ongoing insulin therapy more effectively reduced glycated hemoglobin and glycated albumin levels than empagliflozin in patients with inadequately controlled type 2 diabetes.
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Compuestos de Bencidrilo/uso terapéutico , Biomarcadores/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Liraglutida/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/análisis , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Adulto JovenRESUMEN
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. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice. METHODS: We treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets. RESULTS: SGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (ßIRKO) beta cells with serum from both luseogliflozin- and OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets. CONCLUSIONS/INTERPRETATION: These results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.
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Proliferación Celular/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/fisiología , Sorbitol/análogos & derivados , Animales , Medios de Cultivo Condicionados/metabolismo , Medios de Cultivo Condicionados/farmacología , Sinergismo Farmacológico , Técnicas de Inactivación de Genes , Humanos , Imidazoles/farmacología , Proteínas Sustrato del Receptor de Insulina/genética , Células Secretoras de Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Pirazinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/fisiología , Receptor de Insulina/antagonistas & inhibidores , Receptor de Insulina/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sorbitol/farmacologíaRESUMEN
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. Results The patients were divided into 4 groups according to the duration of diabetes at the time of insulin initiation: ≤3 years, 4 to 6 years, 7 to 9 years, or ≥10 years. Patients with a diabetes duration of ≤3 years were more frequently hospitalized at the time of insulin initiation, had a higher HbA1c level before insulin initiation and a lower HbA1c level at 1 year after insulin initiation and exhibited significant decreases in HbA1c at 1, 3, or 5 years after insulin initiation than those in the other 3 groups with longer durations of diabetes. In the group receiving 4 insulin injections per day, the reduction in HbA1c after 5 years of treatment was larger in patients with a diabetes duration at the time of insulin initiation of ≤3 years than in those with a duration of 7 to 9 years or ≥10 years. Conclusion Our results suggested that an earlier initiation of insulin therapy was crucial for sustaining glycemic control in Japanese patients with type 2 diabetes, particularly in those with a history of obesity or receiving multiple insulin injections daily.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Esquema de Medicación , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de TiempoRESUMEN
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 ß 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 ß-cell inflammation. Co-cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet-produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8-mediated interaction between islets and macrophages evoked ß-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives ß-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent ß-cell loss in patients with diabetes.
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Apoptosis , Calgranulina A/inmunología , Inflamación/inmunología , Células Secretoras de Insulina/inmunología , Macrófagos/inmunología , Animales , Línea Celular , Células Cultivadas , Glucosa/inmunología , Humanos , Células Secretoras de Insulina/citología , Macrófagos/citología , Masculino , Ratones Endogámicos C57BL , Palmitatos/inmunología , Transducción de Señal , Receptor Toll-Like 4/inmunologíaRESUMEN
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. An enzyme-linked immunosorbent assay confirmed that the relatively low serum sEGFR levels in db/db mice were restored by liraglutide treatment. The serum sEGFR levels were elevated in diabetic mice with impaired insulin secretion and decreased in high-fat diet-fed mice and ob/ob mice. The serum sEGFR levels increased after the administration of a dual inhibitor of IGF-1/insulin receptor or streptozotocin. In humans with normal glucose tolerance or T2DM, the serum sEGFR levels were correlated with the fasting blood glucose, fasting serum insulin, homeostatic model assessment of insulin resistance, HbA1c, total cholesterol, low-density lipoprotein cholesterol, and triglycerides levels. These findings suggest that sEGFR might be a biomarker for evaluating insulin resistance or a therapeutic target of liraglutide.
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Biomarcadores/sangre , Receptores ErbB/sangre , Resistencia a la Insulina , Proteoma/metabolismo , Proteómica/métodos , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ensayo de Inmunoadsorción Enzimática , Receptores ErbB/antagonistas & inhibidores , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Lípidos/sangre , Liraglutida/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
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). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and ß cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.