scholarly journals Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

2021 ◽  
Vol 22 (12) ◽  
pp. 6344
Author(s):  
Ilaria Coppola ◽  
Bas Brouwers ◽  
Sandra Meulemans ◽  
Bruno Ramos-Molina ◽  
John W. M. Creemers
Keyword(s):  
Insulin Receptor ◽  
Glucose Homeostasis ◽  
Glucose Control ◽  
Proteolytic Cleavage ◽  
Proprotein Convertase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Proprotein Convertases ◽  
Essential Step

The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific Furin knockout (βFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in βFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis.

scholarly journals Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ionel Sandovici ◽  
Constanze M. Hammerle ◽  
Sam Virtue ◽  
Yurena Vivas-Garcia ◽  
Adriana Izquierdo-Lahuerta ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Chow Diet ◽  
Genome Wide Association Studies ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

AbstractWhen exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

scholarly journals ROCK1 regulates insulin secretion from β-cells

2021 ◽  
Author(s):  
Byung-Jun Sung ◽  
Sung-Bin Lim ◽  
Jae Hyeon Kim ◽  
Won-Mo Yang ◽  
Rohit N Kulkarni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pyruvate Kinase ◽  
Glucose Homeostasis ◽  
Isolated Islets ◽  
Whole Body ◽  
Proximity Ligation Assay ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Objective: The endocrine pancreatic β-cells play a pivotal role in the maintenance of whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate b-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis. Methods: Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1loxP/loxP, β-ROCK1-/-) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. Insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1-/- mice or β-cell lines with knockdown of ROCK1 were also evaluated. Proximity ligation assay was performed to determine the physical interactions between PK and ROCK1. Results: Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1-/- mice displayed progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS was markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium levels, ATP levels, and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that ROCK1 binding to PK is greatly enhanced by glucose stimulation in β-cells. Conclusions: Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and maintenance of glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

scholarly journals Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

2009 ◽  
Vol 44 (3) ◽  
pp. 171-178 ◽  
Author(s):  
James E P Brown ◽  
David J Onyango ◽  
Manjunath Ramanjaneya ◽  
Alex C Conner ◽  
Snehal T Patel ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Receptor ◽  
Mrna Expression ◽  
Fold Increase ◽  
Receptor Activation ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Nicotinamide Phosphoribosyltransferase

The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic β-cell-specific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic β-cells. β-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1β (32-fold increase), HNF4α (16-fold increase) and nuclear factor κB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (−3.73-fold) and UCP2 (−1.3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of β-cell function-associated genes in mouse β-cells.

scholarly journals Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion

2015 ◽  
Vol 112 (9) ◽  
pp. 2888-2893 ◽  
Author(s):  
Miles Berger ◽  
David W. Scheel ◽  
Hector Macias ◽  
Takeshi Miyatsuka ◽  
Hail Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Perinatal Period ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Gpcr Signaling

Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

scholarly journals Loss of the voltage-gated proton channel Hv1 decreases insulin secretion and leads to hyperglycemia and glucose intolerance in mice

2020 ◽  
Vol 295 (11) ◽  
pp. 3601-3613 ◽  
Author(s):  
Huimin Pang ◽  
Xudong Wang ◽  
Shiqun Zhao ◽  
Wang Xi ◽  
Jili Lv ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Glucose Homeostasis ◽  
Membrane Depolarization ◽  
Proton Channel ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Voltage Gated ◽  
Deficient Mice

Insulin secretion by pancreatic islet β-cells is regulated by glucose levels and is accompanied by proton generation. The voltage-gated proton channel Hv1 is present in pancreatic β-cells and extremely selective for protons. However, whether Hv1 is involved in insulin secretion is unclear. Here we demonstrate that Hv1 promotes insulin secretion of pancreatic β-cells and glucose homeostasis. Hv1-deficient mice displayed hyperglycemia and glucose intolerance because of reduced insulin secretion but retained normal peripheral insulin sensitivity. Moreover, Hv1 loss contributed much more to severe glucose intolerance as the mice got older. Islets of Hv1-deficient and heterozygous mice were markedly deficient in glucose- and K+-induced insulin secretion. In perifusion assays, Hv1 deletion dramatically reduced the first and second phase of glucose-stimulated insulin secretion. Islet insulin and proinsulin content was reduced, and histological analysis of pancreas slices revealed an accompanying modest reduction of β-cell mass in Hv1 knockout mice. EM observations also indicated a reduction in insulin granule size, but not granule number or granule docking, in Hv1-deficient mice. Mechanistically, Hv1 loss limited the capacity for glucose-induced membrane depolarization, accompanied by a reduced ability of glucose to raise Ca2+ levels in islets, as evidenced by decreased durations of individual calcium oscillations. Moreover, Hv1 expression was significantly reduced in pancreatic β-cells from streptozotocin-induced diabetic mice, indicating that Hv1 deficiency is associated with β-cell dysfunction and diabetes. We conclude that Hv1 regulates insulin secretion and glucose homeostasis through a mechanism that depends on intracellular Ca2+ levels and membrane depolarization.

scholarly journals Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR‐29 family

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Jing Li ◽  
Yujing Zhang ◽  
Yangyang Ye ◽  
Dameng Li ◽  
Yuchen Liu ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Pancreatic β-cells express hepcidin, an iron-uptake regulatory peptide

2008 ◽  
Vol 197 (2) ◽  
pp. 241-249 ◽  
Author(s):  
Hasan Kulaksiz ◽  
Evelyn Fein ◽  
Peter Redecker ◽  
Wolfgang Stremmel ◽  
Guido Adler ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Secretory Granules ◽  
Rinm5f Cells ◽  
Β Cells ◽  
Additional Source ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Vital Functions ◽  
Immunohistochemical Studies ◽  
Insight Into

Body iron is involved in various vital functions. Its uptake in the intestine is regulated by hepcidin, a bioactive peptide originally identified in plasma and urine and subsequently in the liver. In the present study, we provide evidence at the transcriptional and translational levels that hepcidin is also expressed in the pancreas of rat and man. Immunohistochemical studies localized the peptide exclusively to β-cells of the islets of Langerhans. Immunoelectron microscopical analyses revealed that hepcidin is confined to the insulin-storing β-cell secretory granules. As demonstrated in insulinoma-derived RINm5F cells, the expression of hepcidin in β-cells is regulated by iron. Based on the present findings we conclude that pancreatic islets are an additional source of the peptide hepcidin. The localization of this peptide to β-cells suggests that pancreatic β-cells may be involved in iron metabolism in addition to their genuine function in blood glucose regulation. In view of the various linked iron/glucose disorders in the pancreas, the present findings may provide an insight into the phenomenology of intriguing mutual relationships between iron and glucose metabolisms.

Chlorogenic acid and β-glucan from highland barley grain ameliorate β cell dysfunction via inhibiting apoptosis and improving cell proliferation

2021 ◽  
Author(s):  
Zehua Liu ◽  
Bo Li
Keyword(s):  
Cell Proliferation ◽  
Chlorogenic Acid ◽  
Barley Grain ◽  
Whole Grain ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Active Compounds ◽  
Cell Dysfunction ◽  
Highland Barley

Recent studies support the view that highland barley as whole grain diet showed anti-hyperglycemic effects, while little information is available about the active compounds that could ameliorate pancreatic β cells...

Sign in / Sign up

Export Citation Format

Share Document