Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion

Endocrinology ◽  
1992 ◽  
Vol 130 (3) ◽  
pp. 1459-1466 ◽  
Author(s):  
J. A. Parsons
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Islet Cell ◽  
Placental Lactogen

scholarly journals Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells

2019 ◽  
Author(s):  
Hans E. Hohmeier ◽  
Lu Zhang ◽  
Brandon Taylor ◽  
Samuel Stephens ◽  
Peter McNamara ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Small Molecule ◽  
Islet Cell ◽  
Human Islet ◽  
Luciferase Reporter ◽  
Β Cell ◽  
Cytotoxic Stress ◽  
Insulinoma Cells ◽  
Rat Insulinoma

AbstractA key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor Nkx6.1 stimulates β-cell proliferation, while also enhancing GSIS and providing protection against β-cell cytotoxicity through induction of the VGF prohormone. We developed an Nkx6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human β-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. In contrast to recently emergent Dyrk1a inhibitors that stimulate human islet cell proliferation, GNF-9228 does not activate NFAT translocation. These studies have led to identification of a small molecule with pleiotropic positive effects on islet biology, including stimulation of human β-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.

Effect of Silencing Information Regulator on Islet β Cells in High Glucose Environment Through Regulation of Phosphatidylinositol 3 Kinase (PI3K)/Protein Kinase B (AKT)/Nuclear Factor-κ-Gene Binding Pathway

2021 ◽  
Vol 11 (8) ◽  
pp. 1624-1629
Author(s):  
Nali Liu ◽  
Beijing Zhu ◽  
Xin Wei
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
High Glucose ◽  
Islet Cell ◽  
Control Group ◽  
Diabetic Patients ◽  
Phosphatidylinositol 3 Kinase ◽  
Sod Activity ◽  
Sirt1 Expression ◽  
Cell Supernatant

Islet β-cell regeneration is beneficial for treating diabetic patients. Silencing information regulator (SIRT1) has a regulatory role in endocrine diseases. However, SIRT1’s role in islet β cells remains unclear. MIN6 cells were cultured and assigned into control group, high glucose group, and SIRT1 group (treated with SIRT1 agonist, Resveratrol) followed by analysis of SIRT1 expression by Real time PCR and ELISA, cell proliferation by MTT assay, apoptosis activity by Caspase3 activity kit, secretion of TNF-α and IL-2 by ELISA, insulin secretion, ROS and SOD generation and expression of PI3K/Akt/NF-κB signaling by Western blot. SIRT1 mRNA was decreased in high glucose environment and its secretion in cell supernatant was reduced, with inhibited cell proliferation, increased Caspase3 activity and secretion of TNF-α and IL-2, decreased insulin secretion and SOD activity, increased ROS content, pAKT phosphorylation and NF-κB expression. Resveratrol significantly promoted SIRT1 expression and cell proliferation, decreased Caspase3 activity and secretion of TNF-α and IL-2, increased insulin secretion and SOD activity, as well as decreased ROS content, pAKT phosphorylation and NF-κB expression (P <0.05). SIRT1 is decreased in high glucose environment, and SIRT1 expression can inhibit islet cell apoptosis, inhibit oxidative stress and inflammation, and promote islet cell proliferation and insulin secretion by regulating PI3K/Akt/NF-κB signaling.

Pre-diabetes in the spontaneously diabetic BB/E rat: pancreatic infiltration and islet cell proliferation

1987 ◽  
Vol 115 (4) ◽  
pp. 447-454 ◽  
Author(s):  
A. J. Bone ◽  
R. Walker ◽  
B. M. Dean ◽  
J. D. Baird ◽  
A. Cooke
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Cell Surface ◽  
Islet Cell ◽  
Secretory Function ◽  
Cell Replication ◽  
Concomitant Increase ◽  
Low Incidence ◽  
Circulating Autoantibodies ◽  
The Relationship

Abstract. A cohort of BB/E rats derived from litters with a high and low incidence of IDDM was studied prospectively to examine the relationship between circulating autoantibodies, islet insulin secretion, pancreatic infiltration, and islet cell replication during the pre-diabetic period. Although a higher incidence of islet cell surface (ICSA) and insulin autoantibodies (IAA) was detected in the diabetes-prone than in the low diabetic-incidence BB/E rats there was no correlation between the two antibodies in individual animals. Moreover, ICSA, but not IAA, were associated with loss of first phase islet insulin release. Between 75 and 105 days of age the number of diabetes-prone rats with ICSA and impaired islet insulin secretory function increased. Over the same period, there was a concomitant increase in the proportion of diabetes-prone animals with pancreatic infiltration, and increased islet endocrine cell proliferation. All these interrelated phenomena were observed in diabetes-prone BB/E rats at a time when the animals were normoglycaemic.

Effects of Food Restriction on Glucose Tolerance, Insulin Secretion, and Islet-Cell Proliferation in Pregnant Rats

1998 ◽  
Vol 65 (4-5) ◽  
pp. 671-677 ◽  
Author(s):  
A.G Nieuwenhuizen ◽  
G.A Schuiling ◽  
A.F.J Seijsener ◽  
H Moes ◽  
T.R Koiter
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Islet Cell ◽  
Food Restriction ◽  
Pregnant Rats

scholarly journals Growth-Promoting Effect of Rh(D) Antibody on Human Pancreatic Islet Cells

2008 ◽  
Vol 93 (9) ◽  
pp. 3560-3567
Author(s):  
John M. Feller ◽  
Ann M. Simpson ◽  
Margaret Nelson ◽  
M. Anne Swan ◽  
Philip J. O'Connell ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Islet Cell ◽  
Islet Cells ◽  
Flow Cytometric Analysis ◽  
Antigen Expression ◽  
Immunofluorescent Staining ◽  
Promoting Effect ◽  
Cell Hyperplasia ◽  
Proliferative Effect

Context/Objective: Hyperinsulinism with islet cell hyperplasia is a frequent complication, of unknown cause, in hemolytic disease of the newborn, occurring in Rh(D)-positive infants of Rh-isoimmunized Rh(D)-negative mothers, but not in infants with other hemolytic disorders. We investigated the possibility that trans-placentally acquired anti-D Ig is the cause of both conditions. Design: Monolayer cultures of human islet cells were exposed to sera from Rh-isoimmunized mothers and newborns, where jaundice, hyperinsulinism, and hypoglycemia in the infant had ensued. Parallel cultures with anti-D, specific anti-D monoclonal antibodies, normal human Ig (15 μg/ml), and serum controls were also undertaken. Islet cell proliferation was determined by [3H]thymidine incorporation. Insulin storage and chronic and acute insulin secretion to glucose were analyzed by RIA. Rh(D) surface antigen expression was determined on islet cells by flow cytometric analysis. Results: Islet cell proliferation and insulin secretion were significantly greater in coculture with test sera (P &lt; 0.01; n = 8) and with anti-D (P &lt; 0.001; n = 8), compared with either controls or Ig. After 8 d of growth, the static incubation experiment showed a 3.5-fold response to glucose stimulus in all sera. Rh(D) antigen expression was detected on the islet cell surface by flow cytometry, and islet cell morphology was normal. Colocalization of the proliferation marker Ki67 with insulin by immunofluorescent staining further indicated that Rh(D) antibody promoted islet growth. Conclusions: The anti-Rh(D) islet cell proliferative effect generates neonatal hyperinsulinism in Rh isoimmunization. Anti-Rh(D) may have application for islet cell proliferation in diabetes mellitus treatment for Rh(D)-positive subjects. Further analysis is required.

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 Nutritional regulation of proteases involved in fetal rat insulin secretion and islet cell proliferation

2005 ◽  
Vol 93 (3) ◽  
pp. 309-316 ◽  
Author(s):  
L. Kalbe ◽  
A Leunda ◽  
T Sparre ◽  
C Meulemans ◽  
M.-T Ahn ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Islet Cell ◽  
Epidemiological Studies ◽  
Protein Restriction ◽  
Cathepsin S ◽  
Calpain Inhibitor ◽  
Nutritional Regulation ◽  
Taurine Supplementation ◽  
Maternal Protein Restriction

Epidemiological studies have indicated that malnutrition during early life may programme chronic degenerative disease in adulthood. In an animal model of fetal malnutrition, rats received an isoenergetic, low-protein (LP) diet during gestation. This reduced fetal β-cell proliferation and insulin secretion. Supplementation during gestation with taurine prevented these alterations. Since proteases are involved in secretion and proliferation, we investigated which proteases were associated with these alterations and their restoration in fetal LP islets. Insulin secretion and proliferation of fetal control and LP islets exposed to different protease modulators were measured. Lactacystin and calpain inhibitor I, but not isovaleryl-l-carnitine, raised insulin secretion in control islets, indicating that proteasome and cysteinyl cathepsin(s), but not μ-calpain, are involved in fetal insulin secretion. Insulin secretion from LP islets responded normally to lactacystin but was insensitive to calpain inhibitor I, indicating a loss of cysteinyl cathepsin activity. Taurine supplementation prevented this by restoring the response to calpain inhibitor I. Control islet cell proliferation was reduced by calpain inhibitor I and raised by isovaleryl-l-carnitine, indicating an involvement of calpain. Calpain activity appeared to be lost in LP islets and not restored by taurine. Most modifications in the mRNA expression of cysteinyl cathepsins, calpains and calpastatin due to maternal protein restriction were consistent with reduced protease activity and were restored by taurine. Thus, maternal protein restriction affected cysteinyl cathepsins and the calpain–calpastatin system. Taurine normalised fetal LP insulin secretion by protecting cysteinyl cathepsin(s), but the restoration of LP islet cell proliferation by taurine did not implicate calpains.

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