scholarly journals ERRATUM FOR “WITHDRAWN AS DUPLICATE: Noninvasive Evaluation of GPR119 Agonist Effects on β-Cell Mass in Diabetic Male Mice Using 111In-Exendin-4 SPECT/CT”

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Keyword(s):  
Cell Mass ◽  
Noninvasive Evaluation ◽  
Male Mice ◽  
Β Cell ◽  
Gpr119 Agonist

scholarly journals Effects of the Antitumor Drug OSI-906, a Dual Inhibitor of IGF-1 Receptor and Insulin Receptor, on the Glycemic Control, β-Cell Functions, and β-Cell Proliferation in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2102-2111 ◽  
Author(s):  
Jun Shirakawa ◽  
Tomoko Okuyama ◽  
Eiko Yoshida ◽  
Mari Shimizu ◽  
Yuka Horigome ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glycemic Control ◽  
Insulin Receptor ◽  
Cell Mass ◽  
Male Mice ◽  
Β Cell ◽  
Dual Inhibitor ◽  
Cell Functions

The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

scholarly journals Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion

2020 ◽  
Author(s):  
Søs Skovsø ◽  
Evgeniy Panzhinskiy ◽  
Jelena Kolic ◽  
Derek A. Dionne ◽  
Xiao-Qing Dai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Whole Body ◽  
Calcium Oscillation ◽  
Male Mice ◽  
Β Cells ◽  
Β Cell ◽  
Specific Insulin

AbstractInsulin receptor (Insr) protein can be found at higher levels in pancreatic β-cells than in most other cell types, but the consequences of β-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in β-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined β-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFκB signaling. Male, but not female, βInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout β-cells from female, but not male mice. Female βInsrKO and βInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce β-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include β-cell insulin resistance, which predicted that β-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female βInsrKO and βInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of β-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

scholarly journals Incretin Therapies Do Not Expand β-Cell Mass or Alter Pancreatic Histology in Young Male Mice

Endocrinology ◽  
2017 ◽  
Vol 158 (6) ◽  
pp. 1701-1714 ◽  
Author(s):  
Aaron R. Cox ◽  
Carol J. Lam ◽  
Matthew M. Rankin ◽  
Jacqueline S. Rios ◽  
Julia Chavez ◽  
...  
Keyword(s):  
Cell Mass ◽  
Young Male ◽  
Male Mice ◽  
Β Cell ◽  
Incretin Therapies

scholarly journals Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis

2014 ◽  
Vol 306 (11) ◽  
pp. E1305-E1314 ◽  
Author(s):  
Marianna Sadagurski ◽  
Taylor Landeryou ◽  
Manuel Blandino-Rosano ◽  
Gillian Cady ◽  
Lynda Elghazi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Early Life ◽  
Energy Homeostasis ◽  
Cell Mass ◽  
Adult Life ◽  
Postnatal Growth ◽  
Male Mice ◽  
Β Cell ◽  
Female Mice ◽  
The Impact

The action of nutrients on early postnatal growth can influence mammalian aging and longevity. Recent work has demonstrated that limiting nutrient availability in the first 3 wk of life [by increasing the number of pups in the crowded-litter (CL) model] leads to extension of mean and maximal lifespan in genetically normal mice. In this study, we aimed to characterize the impact of early-life nutrient intervention on glucose metabolism and energy homeostasis in CL mice. In our study, we used mice from litters supplemented to 12 or 15 pups and compared those to control litters limited to eight pups. At weaning and then throughout adult life, CL mice are significantly leaner and consume more oxygen relative to control mice. At 6 mo of age, CL mice had low fasting leptin concentrations, and low-dose leptin injections reduced body weight and food intake more in CL female mice than in controls. At 22 mo, CL female mice also have smaller adipocytes compared with controls. Glucose and insulin tolerance tests show an increase in insulin sensitivity in 6 mo old CL male mice, and females become more insulin sensitive later in life. Furthermore, β-cell mass was significantly reduced in the CL male mice and was associated with reduction in β-cell proliferation rate in these mice. Together, these data show that early-life nutrient intervention has a significant lifelong effect on metabolic characteristics that may contribute to the increased lifespan of CL mice.

scholarly journals Long- But Not Short-Term Adult-Onset, Isolated GH Deficiency in Male Mice Leads to Deterioration of β-Cell Function, Which Cannot Be Accounted for by Changes in β-Cell Mass

Endocrinology ◽  
2014 ◽  
Vol 155 (3) ◽  
pp. 726-735 ◽  
Author(s):  
Jose Cordoba-Chacon ◽  
Manuel D. Gahete ◽  
Naveen K. Pokala ◽  
David Geldermann ◽  
Maria Alba ◽  
...  
Keyword(s):  
Cell Function ◽  
Gh Deficiency ◽  
Cell Mass ◽  
Adult Onset ◽  
Male Mice ◽  
Β Cell ◽  
Short Term ◽  
Β Cell Function

InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation

2020 ◽  
Author(s):  
Ada Admin ◽  
Fabio Russo ◽  
Antonio Citro ◽  
Giorgia Squeri ◽  
Francesca Sanvito ◽  
...  
Keyword(s):  
T Regulatory Cells ◽  
Lentiviral Vector ◽  
Autoimmune Diabetes ◽  
Therapeutic Option ◽  
Combined Therapy ◽  
Cell Mass ◽  
Nod Mice ◽  
Β Cell ◽  
Suboptimal Dose ◽  
Islets Transplantation

The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of lentiviral vector enabling expression of insulinB9-23 (LV.InsB) in hepatocytes, arrests β cell destruction in pre-diabetic NOD mice, by generating InsB9-23-specific FoxP3+T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 mAb (combined therapy, 1X5µg CT5) reverts diabetes and prevents recurrence of autoimmunity following islets transplantation in ~50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, allo-islets were transplanted after optimized CT tolerogenic conditioning (1X25µg CT25). Diabetic NOD mice conditioned with CT25 when glycaemia was <500mg/dL, remained normoglycaemic for 100 days after allo-islets transplantation, displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T cell unresponsiveness to InsB9-23 stimulation and increased Tregs frequency in islets infiltration and pancreatic LN. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 co-stimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before allo-islets transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous β cell mass.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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