scholarly journals Beneficial effects of lipids and prolactin on insulin secretion and β-cell proliferation: a role for lipids in the adaptation of islets to pregnancy

2008 ◽  
Vol 197 (2) ◽  
pp. 265-276 ◽  
Author(s):  
T Clark Brelje ◽  
Nicholas V Bhagroo ◽  
Laurence E Stout ◽  
Robert L Sorenson
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Cell Division ◽  
Insulin Release ◽  
Post Partum ◽  
Late Pregnancy ◽  
Fold Increase ◽  
Placental Lactogen ◽  
Β Cell

To meet the increased demand for insulin during pregnancy, the pancreatic islets undergo adaptive changes including enhanced insulin secretion and β-cell proliferation. These changes peak in mid-pregnancy and return to control levels by parturition. Because lactogens (placental lactogen and/or prolactin) induce this up-regulation and remain elevated throughout gestation, we examined whether lipids alter the effects of prolactin on islets. In response to prolactin, there was a 2.5-fold increase in insulin secretion when compared with control islets. There was also a 2.5-fold increase in insulin secretion in response to palmitate and a fivefold increase when islets were cultured with a combination of prolactin and palmitate. After culture with prolactin and palmitate, acute stimulation with 10 mM glucose for 1 h showed a suppression of insulin release. However, including palmitate in the stimulation media (a condition similar to late pregnancy in vivo) restored a higher rate of insulin release. This suggests that elevated lipids in late pregnancy lead to enhanced insulin secretion that is increasingly dependent on lipids and less sensitive to glucose. β-Cell proliferation was also increased sixfold by prolactin and threefold with palmitate. The combination of both was slightly more than additive (11-fold). Similar experiments with oleate had no effect on insulin secretion. However, oleate stimulated β-cell division by threefold and was synergistic with prolactin (21-fold). These results were repeated in experiments including normal serum. Interestingly, prolactin also blocked the reduction of glucokinase levels observed with fatty acids. Overall, these results suggest that increased lipids during pregnancy likely contribute to the adaptation of islets to pregnancy by further enhancing β-cell division. In addition, the increase in lipids leads to enhanced insulin secretion that is less sensitive to glucose and more dependent on lipids. This provides a potential mechanism for maintaining elevated insulin secretion until parturition while preparing islets for normal glucose sensitivity post partum.

scholarly journals GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Alba C. Arcones ◽  
Rocío Vila-Bedmar ◽  
Mercedes Mirasierra ◽  
Marta Cruces-Sande ◽  
Mario Vallejo ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
G Protein ◽  
Insulin Release ◽  
Cell Lines ◽  
Early Phase ◽  
G Protein Coupled Receptor ◽  
Β Cell ◽  
Insulin Secretion In Vivo ◽  
G Protein Coupled

Abstract Background Insulin secretion from the pancreatic β-cell is finely modulated by different signals to allow an adequate control of glucose homeostasis. Incretin hormones such as glucagon-like peptide-1 (GLP-1) act as key physiological potentiators of insulin release through binding to the G protein-coupled receptor GLP-1R. Another key regulator of insulin signaling is the Ser/Thr kinase G protein-coupled receptor kinase 2 (GRK2). However, whether GRK2 affects insulin secretion or if GRK2 can control incretin actions in vivo remains to be analyzed. Results Using GRK2 hemizygous mice, isolated pancreatic islets, and model β-cell lines, we have uncovered a relevant physiological role for GRK2 as a regulator of incretin-mediated insulin secretion in vivo. Feeding, oral glucose gavage, or administration of GLP-1R agonists in animals with reduced GRK2 levels (GRK2+/− mice) resulted in enhanced early phase insulin release without affecting late phase secretion. In contrast, intraperitoneal glucose-induced insulin release was not affected. This effect was recapitulated in isolated islets and correlated with the increased size or priming efficacy of the readily releasable pool (RRP) of insulin granules that was observed in GRK2+/− mice. Using nanoBRET in β-cell lines, we found that stimulation of GLP-1R promoted GRK2 association to this receptor and that GRK2 protein and kinase activity were required for subsequent β-arrestin recruitment. Conclusions Overall, our data suggest that GRK2 is an important negative modulator of GLP-1R-mediated insulin secretion and that GRK2-interfering strategies may favor β-cell insulin secretion specifically during the early phase, an effect that may carry interesting therapeutic applications.

scholarly journals Procedure for Seeding Cells on the Disque Platform v1

2021 ◽  
Author(s):  
Peter Anthony Jones* ◽  
Kisuk Yang* ◽  
Jeffrey M Karp
Keyword(s):  
Cell Proliferation ◽  
3D Culture ◽  
Zinc Content ◽  
Fold Increase ◽  
Cell Loss ◽  
High Concentration ◽  
Β Cells ◽  
Β Cell ◽  
Culture Systems

Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes. We previously developed a proliferation-inducing prodrug (ZnPD6) that targets the high concentration of zinc ions in β cells, and which exhibits a 2.4-fold increase in β cell proliferation compared to the DYRK1A inhibitor harmine. These prodrugs were identified through screening on the Disque Platform (DP)—a high-fidelity culture system where stem cell–derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates that mimic in vivo conditions. The Disque Platform allows for the formation of 3D micro-tissues within an automation-friendly design, and is capable of systematically manipulating the cell niche in order to identify chemical and physical cues that enhance β cell proliferation. The Disque Platform better replicates the zinc content of native islets, enabling for the screening of zinc-activated prodrugs whose activity cannot be detected in 2D culture systems, which typically display a markedly lowered zinc content. The Disque Platform is a reliable screening platform that bridges the advantages of 2D and 3D culture systems and responds to interventions when conventional systems cannot produce a clear signal or readout. Here we describe a standard protocol for the formation of 3D micro-tissues in the Disque Platform.

scholarly journals A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells

2020 ◽  
Vol 6 (47) ◽  
pp. eabc3207
Author(s):  
Kisuk Yang ◽  
Miseon Lee ◽  
Peter Anthony Jones ◽  
Sophie S. Liu ◽  
Angela Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
3D Culture ◽  
Zinc Content ◽  
Fold Increase ◽  
High Concentration ◽  
Β Cells ◽  
Β Cell ◽  
Culture Systems ◽  
2D And 3D

Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in β cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)—a high-fidelity culture system where stem cell–derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation—so preferentially in β cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in β cell proliferation compared to harmine.

scholarly journals Glucose Regulates Cyclin D2 Expression in Quiescent and Replicating Pancreatic β-Cells Through Glycolysis and Calcium Channels

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2589-2598 ◽  
Author(s):  
Seth J. Salpeter ◽  
Agnes Klochendler ◽  
Noa Weinberg-Corem ◽  
Shay Porat ◽  
Zvi Granot ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Glucose Metabolism ◽  
Calcium Channels ◽  
Mrna Levels ◽  
Β Cells ◽  
Β Cell ◽  
Cyclin D2 ◽  
Glucose Levels

Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G2-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and β-cell replication.

GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration

2020 ◽  
Vol 12 (530) ◽  
pp. eaaw9996 ◽  
Author(s):  
Courtney Ackeifi ◽  
Peng Wang ◽  
Esra Karakose ◽  
Jocelyn E. Manning Fox ◽  
Bryan J. González ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Blood Glucose Control ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Immunodeficient Mice ◽  
Cell Specificity ◽  
Dipeptidyl Peptidase 4 Inhibitors

Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist–DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist–DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity.

Hormone concentrations, mammary development and milk yield in goats given long-term bromocriptine treatment in pregnancy

1985 ◽  
Vol 104 (1) ◽  
pp. 77-85 ◽  
Author(s):  
I. A. Forsyth ◽  
J. C. Byatt ◽  
S. Iley
Keyword(s):  
Milk Yield ◽  
Post Partum ◽  
Plasma Concentrations ◽  
Late Pregnancy ◽  
Mammary Development ◽  
Stage I ◽  
Placental Lactogen ◽  
Oestrone Sulphate

ABSTRACT Ten British Saanen goats were treated daily with 5 mg bromocriptine intramuscularly from week 8 of pregnancy until week 20 (day 140). By comparison with untreated control goats (n = 8), concentrations of prolactin in plasma were suppressed throughout the treatment period and remained significantly lower until 3 days prepartum, parturition occurring on day 153 ± 0·7 (mean ± s.e.m., n = 10). Growth hormone concentrations were low, but the incidence of levels exceeding 1 μg/l was increased in bromocriptine-treated goats. Plasma concentrations of placental lactogen, progesterone and oestrone sulphate were unaffected. The accumulation of pre-colostrum in the udder (lactogenesis stage I) was not affected by bromocriptine treatment in goats carrying twin fetuses, but in goats with single kids it was delayed by about 4–6 weeks to week 17 of pregnancy. Secretion could not be expressed from the udder and the concentration of α-lactalbumin in plasma remained low. Udder volume was significantly reduced in week 15–16 but not week 20–21 of pregnancy by bromocriptine treatment. Milk yields after 50 or 203 days of lactation were not significantly different from those in control goats. Placental lactogen concentrations in late pregnancy and udder volume in week 20–21 were the only variables measured which correlated with milk yield post partum. It is concluded that in vivo placental lactogen is an effective mammotrophic hormone, although less potent than prolactin as evidenced by the delay in lactogenesis stage I in bromocriptine-treated goats bearing single kids. J. Endocr. (1985) 104, 77–85

scholarly journals Vitamin B6 deficiency disrupts serotonin signaling in pancreatic islets and induces gestational diabetes in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ashley M. Fields ◽  
Kevin Welle ◽  
Elaine S. Ho ◽  
Clementina Mesaros ◽  
Martha Susiarjo
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucose Intolerance ◽  
Vitamin B6 ◽  
Serotonin Receptor ◽  
Dependent Manner ◽  
Β Cell ◽  
Vitamin B6 Deficiency ◽  
Maternal Glucose

AbstractIn pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for β-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased β-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts β-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces β-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent.

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 PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

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.

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