scholarly journals Insulin resistance and increased pancreatic β-cell proliferation in mice expressing a mutant insulin receptor (P1195L)

2006 ◽  
Vol 190 (3) ◽  
pp. 739-747 ◽  
Author(s):  
J Ogino ◽  
K Sakurai ◽  
K Yoshiwara ◽  
Yoichi Suzuki ◽  
N Ishizuka ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Insulin Receptor ◽  
Plasma Glucose ◽  
Plasma Insulin ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell

Several mutations of the tyrosine kinase domain of insulin receptor (IR) have been clinically reported to lead insulin resistance and insulin hypersecretion in humans. However, it has not been completely clarified how insulin resistance and pancreatic β-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic β-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR β-subunit. Homozygous (IrP1195L/P1195L) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (IrP1195L/wt) mice showed normal levels of plasma glucose, but high levels of plasma insulin in the fasted state and after glucose loading, and a reduced response of plasma glucose lowering effect to exogenously administered insulin compared with wild type (Irwt/wt) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between IrP1195L/wt and Irwt/wt mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in IrP1195L/wt mice. The β-cell mass increased due to the increased numbers of β-cells in IrP1195L/wt mice. More proliferative β-cells were observed in IrP1195L/wt mice, but the number of apoptotic β-cells was almost the same as that in Irwt/wt mice, even after streptozotocin treatment. These data suggest that, in IrP1195L/wt mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of β-cells, which in turn was due to increased β-cell proliferation rather than decreased β-cell apoptosis.

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.

scholarly journals Estimates of Insulin Secretory Function in Apparently Healthy Volunteers Vary as a Function of How the Relevant Variables Are Quantified

2011 ◽  
Vol 57 (4) ◽  
pp. 627-632 ◽  
Author(s):  
Barry R Johns ◽  
Fahim Abbasi ◽  
Gerald M Reaven
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Plasma Glucose ◽  
Insulin Action ◽  
Cell Function ◽  
Model Assessment ◽  
Pancreatic Β Cell ◽  
Homeostasis Model Assessment ◽  
Β Cell ◽  
Β Cell Function

BACKGROUND Several surrogate estimates have been used to define relationships between insulin action and pancreatic β-cell function in healthy individuals. Because it is unclear how conclusions about insulin secretory function depend on specific estimates used, we evaluated the effect of different approaches to measurement of insulin action and secretion on observations of pancreatic β-cell function in individuals whose fasting plasma glucose (FPG) was <7.0 mmol/L (126 mg/dL). METHODS We determined 2 indices of insulin secretion [homeostasis model assessment of β-cell function (HOMA-β) and daylong insulin response to mixed meals], insulin action [homeostasis model assessment of insulin resistance (HOMA-IR) and steady-state plasma glucose (SSPG) concentration during the insulin suppression test], and degree of glycemia [fasting plasma glucose (FPG) and daylong glucose response to mixed meals] in 285 individuals with FPG <7.0 mmol/L. We compared the relationship between the 2 measures of insulin secretion as a function of the measures of insulin action and degree of glycemia. RESULTS Assessment of insulin secretion varied dramatically as a function of which of the 2 methods was used and which measure of insulin resistance or glycemia served as the independent variable. For example, the correlation between insulin secretion (HOMA-β) and insulin resistance varied from an r value of 0.74 (when HOMA-IR was used) to 0.22 (when SSPG concentration was used). CONCLUSIONS Conclusions about β-cell function in nondiabetic individuals depend on the measurements used to assess insulin action and insulin secretion. Viewing estimates of insulin secretion in relationship to measures of insulin resistance and/or degree of glycemia does not mean that an unequivocal measure of pancreatic β-cell function has been obtained.

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 Generation and characterization of a novel mouse model that allows spatiotemporal quantification of pancreatic β-cell proliferation

2020 ◽  
Author(s):  
Ada Admin ◽  
Shinsuke Tokumoto ◽  
Daisuke Yabe ◽  
Hisato Tatsuoka ◽  
Ryota Usui ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Three Dimensional ◽  
Spatiotemporal Analysis ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Partial Pancreatectomy ◽  
Diet Induced Obesity ◽  
Treatment Of Diabetes

Pancreatic β-cell proliferation has been gaining much attention as a therapeutic target for prevention and treatment of diabetes. In order to evaluate potential β-cell mitogens, accurate and reliable methods for detection and quantification of the β-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating β cells as mVenus<sup>+</sup> cells by using RIP-Cre;R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in β cells. In response to β-cell proliferation stimuli such as insulin receptor antagonist S961 and diet-induced obesity (DIO), the number of EdU<sup>+</sup> insulin<sup>+ </sup>cells per insulin<sup>+ </sup>cells and the number of mVenus<sup>+ </sup>cells per <a>mCherry<sup>+ </sup>mVenus<sup>-</sup> cells + mCherry<sup>- </sup>mVenus<sup>+</sup> cells</a> were similarly increased in these mice. Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled quantification of replicating β cells in the islets and morphometric analysis of the islets following known mitogenic interventions such as S961, DIO, pregnancy and partial pancreatectomy. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis and quantification of β-cell proliferation in response to mitogenic stimulation.

scholarly journals Hyperinsulinemia Precedes Insulin Resistance in Mice Lacking Pancreatic β-Cell Leptin Signaling

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4178-4186 ◽  
Author(s):  
Sarah L. Gray ◽  
Christine Donald ◽  
Arif Jetha ◽  
Scott D. Covey ◽  
Timothy J. Kieffer
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Leptin Receptor ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Primary Defect ◽  
Insulin Sensitizer ◽  
Leptin Signaling ◽  
Deficient Mice

The adipocyte hormone leptin acts centrally and peripherally to regulate body weight and glucose homeostasis. The pancreatic β-cell has been shown to be a key peripheral target of leptin, with leptin suppressing insulin synthesis and secretion from β-cells both in vitro and in vivo. Mice with disrupted leptin signaling in β-cells (leprflox/flox RIPcre tg+ mice) display hyperinsulinemia, insulin resistance, glucose intolerance, obesity, and reduced fasting blood glucose. We hypothesized that hyperinsulinemia precedes the development of insulin resistance and increased adiposity in these mice with a defective adipoinsular axis. To determine the primary defect after impaired β-cell leptin signaling, we treated leprflox/flox RIPcre tg+ mice with the insulin sensitizer metformin or the insulin-lowering agent diazoxide with the rationale that pharmacological improvement of the primary defect would alleviate the secondary symptoms. We show that improving insulin sensitivity with metformin does not normalize hyperinsulinemia, whereas lowering insulin levels with diazoxide improves insulin sensitivity. Taken together, these results suggest that hyperinsulinemia precedes insulin resistance in β-cell leptin receptor-deficient mice, with insulin resistance developing as a secondary consequence of excessive insulin secretion. Therefore, pancreatic β-cell leptin receptor-deficient mice may represent a model of obesity-associated insulin resistance that is initiated by hyperinsulinemia.

scholarly journals Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e108693 ◽  
Author(s):  
Karyn J. Catalano ◽  
Betty A. Maddux ◽  
Jaroslaw Szary ◽  
Jack F. Youngren ◽  
Ira D. Goldfine ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Insulin Receptor Tyrosine Kinase

A Mutation in the Tyrosine Kinase Domain of the Insulin Receptor Associated with Insulin Resistance in an Obese Woman*

1991 ◽  
Vol 73 (4) ◽  
pp. 894-901 ◽  
Author(s):  
ALESSANDRO CAMA ◽  
MARIA DE LA LUZ SIERRA ◽  
LAURA OTTINI ◽  
TAKASHI KADOWAKI ◽  
PHILLIP GORDEN ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Obese Woman ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain

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

2017 ◽  
Vol 313 (3) ◽  
pp. E367-E380 ◽  
Author(s):  
Kazuki Tajima ◽  
Jun Shirakawa ◽  
Tomoko Okuyama ◽  
Mayu Kyohara ◽  
Shunsuke Yamazaki ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Mass ◽  
Mammalian Target Of Rapamycin ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Hyperplasia

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. An 8-wk treatment with metformin improved insulin resistance and suppressed the compensatory β-cell hyperplasia induced by HFD-feeding. In contrast, the increment in β-cell mass arising from 60 wk of HFD feeding was similar in mice treated with and those treated without metformin. Interestingly, metformin suppressed β-cell proliferation induced by 1 wk of HFD feeding without any changes in insulin resistance. Metformin directly suppressed glucose-induced β-cell proliferation in islets and INS-1 cells in accordance with a reduction in mammalian target of rapamycin phosphorylation. Taken together, metformin suppressed HFD-induced β-cell proliferation independent of the improvement of insulin resistance, partly via direct actions.

scholarly journals Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

2016 ◽  
Vol 229 (2) ◽  
pp. 73-83 ◽  
Author(s):  
Binbin Guan ◽  
Wenyi Li ◽  
Fengying Li ◽  
Yun Xie ◽  
Qicheng Ni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Akt Pathway ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Promote Cell Proliferation

The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucose-stimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation.

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