High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets

2009 ◽  
Vol 296 (4) ◽  
pp. E681-E689 ◽  
Author(s):  
Alex Rafacho ◽  
Tânia M. Cestari ◽  
Sebastião R. Taboga ◽  
Antonio C. Boschero ◽  
José R. Bosqueiro
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Cell Mass ◽  
Fold Increase ◽  
Insulin Requirement ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Glucose Levels ◽  
Cell Alterations ◽  
High Doses

Activation of insulin signaling and cell cycle intermediates is required for adult β-cell proliferation. Here, we report a model to study β-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of β-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in β-cell proliferation and an increase (17%) in β-cell size, with significant increase in β-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in β-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory β-cell alterations. Augmented β-cell mass involves β-cell hyperplasia and, to a lower extent, β-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for β-cell proliferation in the dexamethasone-induced insulin resistance.

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.

SerpinB1 improves insulin sensitivity

2016 ◽  
Vol 9 (411) ◽  
pp. ec10-ec10
Author(s):  
Annalisa M. VanHook
Keyword(s):  
Cell Proliferation ◽  
Insulin Sensitivity ◽  
Cell Mass ◽  
Dependent Manner ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Link Type ◽  
Proteomic Approach

Pancreatic β cells adjust the secretion of insulin in response to acute changes in plasma glucose concentration. These cells also compensate for long-term changes in insulin sensitivity by adjusting their activity or numbers, or both (see Tarasov and Rorsman). In addition to being insulin resistant, mice lacking the liver insulin receptor (LIRKO mice) also exhibit β cell hyperplasia that depends on factors released from the liver. Using a proteomic approach, El Ouaamari etal. found that the abundance of the protease inhibitor serpinB1 was greater in liver extracts, liver explant–conditioned medium, and serum from LIRKO mice than in those from wild-type mice. SerpinB1 abundance correlated inversely with insulin sensitivity in human patients with risk factors for type 2 diabetes. Recombinant human serpinB1 stimulated the proliferation of β cells in cultured mouse and human islets in a dose-dependent manner. Elastase is a protease inhibited by serpinB1, and forms of serpinB1 that do not inhibit elastase activity did not stimulate proliferation of cultured mouse β cells. Compounds that inhibit elastase also promoted the proliferation of cultured mouse β cells. In mice, elastase inhibitors stimulated the proliferation of both endogenous β cells and the β cells of human islet grafts. Furthermore, overexpression of serpinb1 increased the regeneration of β cells following β cell ablation in zebrafish embryos. In several models of acute and chronic insulin resistance, serpinb1 knockout mice exhibited reduced β cell proliferation compared with wild-type controls. However, β cell proliferation was not abolished in serpinb1 knockouts, indicating that additional factors can induce compensatory proliferation of β cells. Phosphoproteomic analyses demonstrated that treatment of cultured mouse β cells with human serpinB1 stimulated signaling through several pathways that promote cell proliferation and survival. Commentary by Tarasov and Rorsman considers how these findings might be put to clinical use.A. El Ouaamari, E. Dirice, N. Gedeon, J. Hu, J.-Y. Zhou, J. Shirakawa, L. Hou, J. Goodman, C. Karampelias, G. Qiang, J. Boucher, R. Martinez, M. A. Gritsenko, D. F. De Jesus, S. Kahraman, S. Bhatt, R. D. Smith, H.-D. Beer, P. Jungtrakoon, Y. Gong, A. B. Goldfine, C. W. Liew, A. Doria, O. Andersson, W.-J. Qian, E. Remold-O’Donnell, R. N. Kulkarni, SerpinB1 promotes pancreatic β cell proliferation. CellMetab. 23, 194–205 (2016). [PubMed] A. I. Tarasov, P. Rorsman, Dramatis personae in β-cell mass regulation: Enter SerpinB1. CellMetab. 23, 8–10 (2016). [Online Journal]

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 Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring

2014 ◽  
Vol 307 (10) ◽  
pp. E906-E918 ◽  
Author(s):  
Sevim Kahraman ◽  
Ercument Dirice ◽  
Dario F. De Jesus ◽  
Jiang Hu ◽  
Rohit N. Kulkarni
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Blood Glucose ◽  
Endocrine Pancreas ◽  
Cell Mass ◽  
Postnatal Life ◽  
Pancreas Development ◽  
Β Cell ◽  
Early Postnatal Life ◽  
The Impact

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

scholarly journals High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

2015 ◽  
Vol 308 (7) ◽  
pp. E573-E582 ◽  
Author(s):  
Rockann E. Mosser ◽  
Matthew F. Maulis ◽  
Valentine S. Moullé ◽  
Jennifer C. Dunn ◽  
Bethany A. Carboneau ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Mass ◽  
Chow Diet ◽  
High Fat ◽  
Β Cell ◽  
Peripheral Insulin Resistance ◽  
Insulin Tolerance

Both short- (1 wk) and long-term (2–12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.

scholarly journals TCTP Is Essential for β-Cell Proliferation and Mass Expansion During Development and β-Cell Adaptation in Response to Insulin Resistance

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 392-404 ◽  
Author(s):  
Ming-Jen Tsai ◽  
Hsin-Fang Yang-Yen ◽  
Ming-Ko Chiang ◽  
Mei-Jen Wang ◽  
Shiou-Shian Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Cell Mass ◽  
Perinatal Period ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Insulin Resistant ◽  
Mass Expansion

The perinatal period is critical for β-cell mass establishment, which is characterized by a transient burst in proliferation to increase β-cell mass in response to the need for glucose homeostasis throughout life. In adulthood, the ability of β-cells to grow, proliferate, and expand their mass is also characteristic of pathological states of insulin resistance. Translationally controlled tumor-associated protein (TCTP), an evolutionarily highly conserved protein that is implicated in cell growth and proliferation, has been identified as a novel glucose-regulated survival-supporting protein in pancreatic β-cells. In this study, the enhanced β-cell proliferation detected both during the perinatal developmental period and in insulin-resistant states in high-fat diet-fed mice was found to parallel the expression of TCTP in pancreatic β-cells. Specific knockout of TCTP in β-cells led to increased expression of total and nuclear Forkhead box protein O1 and tumor suppressor protein 53, and decreased expression of p70S6 kinase phosphorylation and cyclin D2 and cyclin-dependent kinase 2. This resulted in decreased β-cell proliferation and growth, reduced β-cell mass, and insulin secretion. Together, these effects led to hyperglycemia. These observations suggest that TCTP is essential for β-cell mass expansion during development and β-cell adaptation in response to insulin resistance.

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 NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dror Sever ◽  
Anat Hershko-Moshe ◽  
Rohit Srivastava ◽  
Roy Eldor ◽  
Daniel Hibsher ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Developmental Stages ◽  
Cell Mass ◽  
Diabetes Incidence ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Regulatory Circuit ◽  
Proliferation And Apoptosis

AbstractNF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in β-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIβ and NOD/ToIβ mice, in which NF-κB activation is specifically and conditionally inhibited in β-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet β-cell development. Interestingly, inhibiting the NF-κB pathway in β-cells during embryogenesis, but not after birth, in both ToIβ and NOD/ToIβ mice, increased β-cell turnover, ultimately resulting in a reduced β-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal β-cells, significant activation was not detected in β-cells of either adult NOD/ToIβ mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIβ mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or β-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of β-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating β-cell mass and the development of diabetes in the mouse model of T1D.

scholarly journals Insulin Stimulates Primary β-Cell Proliferation via Raf-1 Kinase

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2251-2260 ◽  
Author(s):  
Jennifer L. Beith ◽  
Emilyn U. Alejandro ◽  
James D. Johnson
Keyword(s):  
Cell Proliferation ◽  
Dominant Role ◽  
Cell Mass ◽  
Diabetes Type 2 ◽  
Dominant Negative ◽  
Cell Replication ◽  
Β Cell ◽  
Physiological Control ◽  
Primary Mouse

A relative decrease in β-cell mass is key in the pathogenesis of type 1 diabetes, type 2 diabetes, and in the failure of transplanted islet grafts. It is now clear that β-cell duplication plays a dominant role in the regulation of adult β-cell mass. Therefore, knowledge of the endogenous regulators of β-cell replication is critical for understanding the physiological control of β-cell mass and for harnessing this process therapeutically. We have shown that concentrations of insulin known to exist in vivo act directly on β-cells to promote survival. Whether insulin stimulates adult β-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double labeled with 5-bromo-2-deoxyuridine and insulin antisera. Treating cells with 200-pm insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating glucose from 5–15 mm did not significantly increase β-cell replication. β-Cell proliferation was inhibited by somatostatin as well as inhibitors of insulin signaling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by low, but not high (superphysiological), insulin doses. Insulin-stimulated mouse insulinoma cell proliferation was dependent on both phosphatidylinositol 3-kinase/Akt and Raf-1/MAPK kinase pathways. Overexpression of Raf-1 was sufficient to increase proliferation in the absence of insulin, whereas a dominant-negative Raf-1 reduced proliferation in the presence of 200-pm insulin. Together, these results demonstrate for the first time that insulin, at levels that have been measured in vivo, can directly stimulate β-cell proliferation and that Raf-1 kinase is involved in this process. These findings have significant implications for the understanding of the regulation of β-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes.

scholarly journals Development of a Nongenetic Mouse Model of Type 2 Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Elizabeth R. Gilbert ◽  
Zhuo Fu ◽  
Dongmin Liu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Serum Insulin ◽  
Cell Mass ◽  
Low Fat ◽  
Β Cell ◽  
Islet Mass ◽  
Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

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