scholarly journals The beneficial effects of a muscarinic agonist on pancreatic β-cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yuzuru Ito ◽  
Mitsuyo Kaji ◽  
Eri Sakamoto ◽  
Yasuo Terauchi
Keyword(s):  
Cell Proliferation ◽  
Oral Administration ◽  
Cell Function ◽  
Cell Mass ◽  
Muscarinic Agonist ◽  
Pancreatic Β Cell ◽  
Wild Type ◽  
Muscarinic Agonists ◽  
Β Cell ◽  
Beneficial Effects

Abstract The brain and nervous system play an important role in pancreatic β-cell function. This study investigated the role of muscarinic agonists or acetylcholine, which is the major neurotransmitter in the vagal nerve, in regulating pancreatic β-cell mass and glucose homeostasis. Administration of the muscarinic agonist bethanechol increased insulin secretion and improved glucose tolerance in insulin-receptor substrate 2 (IRS2)-knockout (IRS-2−/−) mice and diet-induced obesity mice. Oral administration of bethanechol increased β-cell mass and proliferation in wild-type mice, but not IRS-2−/− mice. The muscarinic agonist also increased the incorporation of 5-bromo-2′-deoxyuridine (BrdU) into islets isolated from wild-type mice and pancreatic β-cell line MIN6. The phosphorylation of protein kinase B (Akt) induced by oral administration of bethanechol was observed in wild-type mice, but not IRS-2−/− mice. The secretion of glucagon-like peptide-1 (GLP-1) was also stimulated by bethanechol in wild-type mice, and a GLP-1 antagonist partially inhibited the bethanechol-induced increase in β-cell mass. These results suggest that the muscarinic agonist exerted direct and indirect effects on β-cell proliferation that were dependent on the IRS-2/Akt pathway. The bethanechol-stimulated release of GLP-1 may be indirectly associated with β-cell proliferation.

scholarly journals Lactation improves pancreatic β cell mass and function through serotonin production

2020 ◽  
Vol 12 (541) ◽  
pp. eaay0455
Author(s):  
Joon Ho Moon ◽  
Hyeongseok Kim ◽  
Hyunki Kim ◽  
Jungsun Park ◽  
Wonsuk Choi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Glucose Tolerance ◽  
Serotonin Receptor ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Beneficial Effects

Pregnancy imposes a substantial metabolic burden on women through weight gain and insulin resistance. Lactation reduces the risk of maternal postpartum diabetes, but the mechanisms underlying this benefit are unknown. Here, we identified long-term beneficial effects of lactation on β cell function, which last for years after the cessation of lactation. We analyzed metabolic phenotypes including β cell characteristics in lactating and non-lactating humans and mice. Lactating and non-lactating women showed comparable glucose tolerance at 2 months after delivery, but after a mean of 3.6 years, glucose tolerance in lactated women had improved compared to non-lactated women. In humans, the disposition index, a measure of insulin secretory function of β cells considering the degree of insulin sensitivity, was higher in lactated women at 3.6 years after delivery. In mice, lactation improved glucose tolerance and increased β cell mass at 3 weeks after delivery. Amelioration of glucose tolerance and insulin secretion were maintained up to 4 months after delivery in lactated mice. During lactation, prolactin induced serotonin production in β cells. Secreted serotonin stimulated β cell proliferation through serotonin receptor 2B in an autocrine and paracrine manner. In addition, intracellular serotonin acted as an antioxidant to mitigate oxidative stress and improved β cell survival. Together, our results suggest that serotonin mediates the long-term beneficial effects of lactation on female metabolic health by increasing β cell proliferation and reducing oxidative stress in β cells.

Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic β-cell function and mass through IRS2 in diabetic rats

2007 ◽  
Vol 103 (5) ◽  
pp. 1764-1771 ◽  
Author(s):  
Sunmin Park ◽  
Sang Mee Hong ◽  
Ji Eun Lee ◽  
So Ra Sung
Keyword(s):  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Function ◽  
Cell Mass ◽  
Diabetic Rats ◽  
Pancreatic Β Cell ◽  
High Fat ◽  
Β Cell ◽  
Igf I ◽  
Β Cell Function

In this study, we investigated the effects of a high-fat diet and exercise on pancreatic β-cell function and mass and its molecular mechanism in 90% pancreatectomized male rats. The pancreatectomized diabetic rats were given control diets (20% energy) or a high-fat (HF) diet (45% energy) for 12 wk. Half of each group was given regular exercise on an uphill treadmill at 20 m/min for 30 min 5 days/wk. HF diet lowered first-phase insulin secretion with glucose loading, whereas exercise training reversed this decrease. However, second-phase insulin secretion did not differ among the groups. Exercise increased pancreatic β-cell mass. This resulted from stimulated β-cell proliferation and reduced apoptosis, which is associated with potentiated insulin or IGF-I signaling through insulin receptor substrate-2 (IRS2) induction. Although the HF diet resulted in decreased proliferation and accelerated apoptosis by weakened insulin and IGF-I signaling from reduction of IRS2 protein, β-cell mass was maintained in HF rats just as much as in control rats via increased individual β-cell size and neogenesis from precursor cells. Consistent with the results of β-cell proliferation, pancreas duodenal homeobox-1 expression increased in the islets of rats in the exercise groups, and it was reduced the most in rats fed the HF diet. In conclusion, exercise combined with a moderate fat diet is a good way to maximize β-cell function and mass through IRS2 induction to alleviate the diabetic condition. This study suggests that dietary fat contents and exercise modulate β-cell function and mass to overcome insulin resistance in two different pathways.

scholarly journals Neprilysin Deficiency Is Associated With Expansion of Islet β-Cell Mass in High Fat-Fed Mice

2018 ◽  
Vol 66 (7) ◽  
pp. 523-530 ◽  
Author(s):  
Jacqueline H. Parilla ◽  
Rebecca L. Hull ◽  
Sakeneh Zraika
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Function ◽  
Cell Mass ◽  
Regulatory Peptides ◽  
Wild Type ◽  
High Fat ◽  
Β Cell ◽  
Beneficial Effects ◽  
Β Cell Function

Neprilysin (NEP) is an endopeptidase known to modulate nervous, cardiovascular, and immune systems via inactivation of regulatory peptides. In addition, it may also contribute to impaired glucose homeostasis as observed in type 2 diabetes (T2D). Specifically, we and others have shown that NEP is upregulated under conditions associated with T2D, whereas NEP deficiency and/or inhibition improves glucose homeostasis via enhanced glucose tolerance, insulin sensitivity, and pancreatic β-cell function. Whether increased β-cell mass also occurs with lack of NEP activity is unknown. We sought to determine whether NEP deficiency confers beneficial effects on β- and α-cell mass in a mouse model of impaired glucose homeostasis. Wild-type and NEP−/− mice were fed low- or high-fat diet for 16 weeks, after which pancreatic β- and α-cell mass were assessed by immunostaining for insulin and glucagon, respectively. Following low-fat feeding, NEP−/− mice exhibited lower β- and α-cell mass compared with wild-type controls. A high-fat diet had no effect on these parameters in wild-type mice, but in NEP−/− mice, it resulted in the expansion of β-cell mass. Our findings support a role for NEP in modulating β-cell mass, making it an attractive T2D drug target that acts via multiple mechanisms to affect glucose homeostasis.

scholarly journals Cyclin C stimulates β-cell proliferation in rat and human pancreatic β-cells

2015 ◽  
Vol 308 (6) ◽  
pp. E450-E459 ◽  
Author(s):  
Margarita Jiménez-Palomares ◽  
José Francisco López-Acosta ◽  
Pablo Villa-Pérez ◽  
José Luis Moreno-Amador ◽  
Jennifer Muñoz-Barrera ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Brdu Incorporation ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cyclin C ◽  
Β Cell Function

Activation of pancreatic β-cell proliferation has been proposed as an approach to replace reduced functional β-cell mass in diabetes. Quiescent fibroblasts exit from G0 (quiescence) to G1 through pRb phosphorylation mediated by cyclin C/cdk3 complexes. Overexpression of cyclin D1, D2, D3, or cyclin E induces pancreatic β-cell proliferation. We hypothesized that cyclin C overexpression would induce β-cell proliferation through G0 exit, thus being a potential therapeutic target to recover functional β-cell mass. We used isolated rat and human islets transduced with adenovirus expressing cyclin C. We measured multiple markers of proliferation: [3H]thymidine incorporation, BrdU incorporation and staining, and Ki67 staining. Furthermore, we detected β-cell death by TUNEL, β-cell differentiation by RT-PCR, and β-cell function by glucose-stimulated insulin secretion. Interestingly, we have found that cyclin C increases rat and human β-cell proliferation. This augmented proliferation did not induce β-cell death, dedifferentiation, or dysfunction in rat or human islets. Our results indicate that cyclin C is a potential target for inducing β-cell regeneration.

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 NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Idil I. Aigha ◽  
Essam M. Abdelalim
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Disease Modeling ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Development ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

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 Biphasic Response of Pancreatic β-Cell Mass to Ablation of Tuberous Sclerosis Complex 2 in Mice

2008 ◽  
Vol 28 (9) ◽  
pp. 2971-2979 ◽  
Author(s):  
Yutaka Shigeyama ◽  
Toshiyuki Kobayashi ◽  
Yoshiaki Kido ◽  
Naoko Hashimoto ◽  
Shun-ichiro Asahara ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cell Function ◽  
Cell Mass ◽  
Mammalian Target Of Rapamycin ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass ◽  
Β Cell Function

ABSTRACT Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic β-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on β-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the βTSC2−/− mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of β cells. These results thus indicate that TSC2 regulates pancreatic β-cell mass in a biphasic manner.

scholarly journals Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5200-5211 ◽  
Author(s):  
Céline Zimmermann ◽  
Christopher R. Cederroth ◽  
Lucie Bourgoin ◽  
Michelangelo Foti ◽  
Serge Nef
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Cell Mass ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Levels ◽  
Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

scholarly journals Impact of Small-Molecule Glucokinase Activator on Glucose Metabolism and β-Cell Mass

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1147-1154 ◽  
Author(s):  
Akinobu Nakamura ◽  
Yasuo Terauchi ◽  
Sumika Ohyama ◽  
Junko Kubota ◽  
Hiroko Shimazaki ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Cell Mass ◽  
Isolated Islets ◽  
Brdu Incorporation ◽  
Wild Type ◽  
Β Cell ◽  
Glucokinase Activator ◽  
Insulinoma Cells

We investigated the effect of glucokinase activator (GKA) on glucose metabolism and β-cell mass. We analyzed four mouse groups: wild-type mice and β-cell-specific haploinsufficiency of glucokinase gene (Gck+/−) mice on a high-fat (HF) diet. Each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate β-cell proliferation by GKA. After 20 wk on the above diets, there were no differences in body weight, lipid profiles, and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. β-Cell mass increased in wild-type mice compared with Gck+/− mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to up-regulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 d administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. Although chronic GKA administration failed to cause a further increase in β-cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-d administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment. Glucokinase activator is able to improve glucose metabolism and has an effect on β cell proliferation.

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