Gangliosides modulate insulin secretion by pancreatic beta cells under glucose stress

Abstract In pancreatic beta cells, the entry of glucose and downstream signaling for insulin release is regulated by the glucose transporter 2 (Glut2) in rodents. Dysfunction of the insulin-signaling cascade may lead to diabetes mellitus. Gangliosides, sialic acid-containing glycosphingolipids (GSLs), have been reported to modulate the function of several membrane proteins.Murine islets express predominantly sialylated GSLs, particularly the simple gangliosides GM3 and GD3 having a potential modulatory role in Glut2 activity. Conditional, tamoxifen-inducible gene targeting in pancreatic islets has now shown that mice lacking the glucosylceramide synthase (Ugcg), which represents the rate-limiting enzyme in GSL biosynthesis, displayed impaired glucose uptake and showed reduced insulin secretion. Consequently, mice with pancreatic GSL deficiency had higher blood glucose levels than respective controls after intraperitoneal glucose application. High-fat diet feeding enhanced this effect. GSL-deficient islets did not show apoptosis or ER stress and displayed a normal ultrastructure. Their insulin content, size and number were similar as in control islets. Isolated beta cells from GM3 synthase null mice unable to synthesize GM3 and GD3 also showed lower glucose uptake than respective control cells, corroborating the results obtained from the cell-specific model. We conclude that in particular the negatively charged gangliosides GM3 and GD3 of beta cells positively influence Glut2 function to adequately respond to high glucose loads.

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Effects of Sclerocarya birrea Stem-Bark Extracts on Glucose Uptake, Insulin Synthesis and Expression of Selected Genes Involved in the Synthesis and Secretion of Insulin in Rat Insulinoma Pancreatic Beta Cells

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22693 ◽

2020 ◽

Vol 32 (9) ◽

pp. 2195-2202

Author(s):

A.H. KGOPA ◽

L.J. SHAI ◽

M.A. MOGALE

Keyword(s):

Glucose Uptake ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Glucose Transporter ◽

Stem Bark ◽

Hexane Extract ◽

Insulin Synthesis ◽

Sclerocarya Birrea ◽

Glucose Transporter 2 ◽

Rat Insulinoma

The present study reported the effects of Sclerocarya birrea stem-bark (SBSB) extracts on glucose uptake, insulin synthesis and the expression of glucose transporter 2 (GLUT2), glucokinase, pancreatic duodenal homeobox-1 (PDX-1), musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and pre-proinsulin genes in rat insulinoma (RIN)-m5F pancreatic beta cells. The amount of glucose takenup by RIN-m5F cells was measured using a glucose oxidase-based assay kit. Intracellular and secreted insulin were measured using an enzyme linked immunoassay kit. Pre-proinsulin gene expression was determined using the conventional polymerase chain reaction (PCR) technique, while the expressions of GLUT2, glucokinase, PDX-1 and MafA genes were evaluated using quantitative real-time PCR technique. Of the four SBSB extracts investigated in the study, only the SBSB hexane extract positively affected all the study variables in RIN-m5F cells compared with the DMSO control. Thus, the SBSB hexane extract contains phytochemicals capable of enhancing insulin synthesis partly through up-regulation of the expression of GLUT2, glucokinase, PDX-1, MafA and pre-proinsulin genes.

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The bimodal effect of interleukin 1 on rat pancreatic beta-cells – stimulation followed by inhibition – depends upon dose, duration of exposure, and ambient glucose concentration

Acta Endocrinologica ◽

10.1530/acta.0.1190307 ◽

1988 ◽

Vol 119 (2) ◽

pp. 307-311 ◽

Cited By ~ 71

Author(s):

Giatgen A. Spinas ◽

Jerry P. Palmer ◽

Thomas Mandrup-Poulsen ◽

Henrik Andersen ◽

Jens Høiriis Nielsen ◽

...

Keyword(s):

Beta Cells ◽

Insulin Release ◽

Glucose Concentration ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Interleukin 1 ◽

Glucose Levels ◽

Lower Glucose ◽

In Vivo Effects

Abstract. To investigate the hypothesis that interleukin 1 initially stimulates and then suppresses beta-cell function and that this sequential effect is directly related to interleukin 1 dose, duration of exposure, and ambient glucose concentration, insulin release was measured from cultured newborn rat islets exposed for 6 h to 6 days to interleukin 1 at doses ranging from 20 to 2000 ng/l at glucose concentrations of 3.3, 5.5 and 11 mmol/l. After 6 h of exposure and at all three glucose levels, all doses of interleukin 1 stimulated insulin release, maximal stimulation (370% of control) being observed at 5.5 mmol/l glucose and 100 ng/l interleukin 1. In contrast, after 6 days, all doses of interleukin 1 were inhibitory irrespective of glucose level, maximal inhibition (90%) being observed at 11 mmol/l glucose and 2000 ng/l interleukin 1. At 24 and 48 h of exposure, the biphasic effect of interleukin 1 was observed: lower doses of interleukin 1 at lower glucose concentrations at 24 h being more stimulatory with transition to inhibition directly related to higher glucose levels, higher interleukin 1 doses, and longer exposure. After 48 h, 200 ng/l of interleukin 1 increased insulin release to 220% at 3.3 mmol/l glucose, but at 11 mmol/l glucose a 60% suppression was seen. On the basis of these data we suggest that interleukin l's effect on beta-cells is bimodal: stimulation followed by inhibition. Increasing interleukin 1 dose and ambient glucose concentration shift this response to the left. Experimental results will, and in vivo effects may, depend upon these three variables.

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The KCNJ11-E23K Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion

10.2337/figshare.13724113 ◽

2021 ◽

Author(s):

Gregor Sachse ◽

Elizabeth Haythorne ◽

Thomas Hill ◽

Peter Proks ◽

Russell Joynson ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Diabetes Risk ◽

Standard Diet ◽

Glucose Levels ◽

Genetically Engineered Mouse Model ◽

Increased Risk ◽

Diabetes Progression

The ATP-sensitive potassium (KATP) channel controls blood glucose levels by coupling glucose metabolism to insulin secretion in pancreatic beta cells. E23K, a common polymorphism in the pore-forming KATP channel subunit (KCNJ11) gene, has been linked to increased risk of type 2 diabetes. Understanding the risk-allele-specific pathogenesis has the potential to improve personalized diabetes treatment, but the underlying mechanism has remained elusive. Using a genetically engineered mouse model, we now show that the K23 variant impairs glucose-induced insulin secretion and increases diabetes risk when combined with a high fat diet (HFD) and obesity. KATP-channels in beta cells with two K23 risk alleles (KK) showed decreased ATP inhibition and the threshold for glucose-stimulated insulin secretion from KK islets was increased. Consequently, the insulin response to glucose and glycaemic control were impaired in KK mice on a standard diet. On a HFD, the effects of the KK genotype were exacerbated, accelerating diet-induced diabetes progression and causing beta cell failure. We conclude that the K23 variant increases diabetes risk by impairing insulin secretion at threshold glucose levels, thus accelerating loss of beta cell function in the early stages of diabetes progression.

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N-glycosylation modulates the membrane sub-domain distribution and activity of glucose transporter 2 in pancreatic beta cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2013.03.076 ◽

2013 ◽

Vol 434 (2) ◽

pp. 346-351 ◽

Cited By ~ 35

Author(s):

Kazuaki Ohtsubo ◽

Shinji Takamatsu ◽

Congxiao Gao ◽

Hiroaki Korekane ◽

Tsutomu M. Kurosawa ◽

...

Keyword(s):

Beta Cells ◽

Pancreatic Beta Cells ◽

Glucose Transporter ◽

Glucose Transporter 2

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Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells

Development ◽

10.1242/dev.125.12.2213 ◽

1998 ◽

Vol 125 (12) ◽

pp. 2213-2221 ◽

Cited By ~ 16

Author(s):

L. Sussel ◽

J. Kalamaras ◽

D.J. Hartigan-O'Connor ◽

J.J. Meneses ◽

R.A. Pedersen ◽

...

Keyword(s):

Transcription Factor ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Glucose Transporter ◽

Large Population ◽

Islet Amyloid ◽

Cell Markers ◽

Glucose Transporter 2 ◽

Alpha Beta

The endocrine pancreas is organized into clusters of cells called islets of Langerhans comprising four well-defined cell types: alpha beta, delta and PP cells. While recent genetic studies indicate that islet development depends on the function of an integrated network of transcription factors, the specific roles of these factors in early cell-type specification and differentiation remain elusive. Nkx2.2 is a member of the mammalian NK2 homeobox transcription factor family that is expressed in the ventral CNS and the pancreas. Within the pancreas, we demonstrate that Nkx2.2 is expressed in alpha, beta and PP cells, but not in delta cells. In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth. Immunohistochemical analysis reveals that the mutant embryos lack insulin-producing beta cells and have fewer glucagon-producing alpha cells and PP cells. Remarkably, in the mutants there remains a large population of islet cells that do not produce any of the four endocrine hormones. These cells express some beta cell markers, such as islet amyloid polypeptide and Pdx1, but lack other definitive beta cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2.2 is required for the final differentiation of pancreatic beta cells, and in its absence, beta cells are trapped in an incompletely differentiated state.

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1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol Attenuates Streptozotocin-Induced Pancreatic Beta Cell Damage by Promoting Glucose Transporter 2 Endocytosis

Molecular and Cellular Biology ◽

10.1128/mcb.00157-19 ◽

2019 ◽

Vol 39 (21) ◽

Author(s):

Jimin Kim ◽

Joo Heon Kim ◽

Ki-Young Sohn ◽

Sun Young Yoon ◽

Jae Wha Kim

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Glucose Transporter ◽

Cell Damage ◽

Serum Insulin ◽

Pancreatic Beta Cell ◽

Ros Generation ◽

Glucose Transporter 2 ◽

Beta Cell Line

ABSTRACT Streptozotocin (STZ) is widely used to induce diabetic rodent models. It is specifically toxic to pancreatic beta cells and causes severe destruction and dysfunction. We investigated the effect of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on an STZ-induced diabetic mouse model. PLAG attenuated the glucose increase and maintained serum insulin at levels similar to those seen with control mice. In pancreatic beta cell line INS-1, STZ-induced cell apoptosis and intracellular reactive oxygen species (ROS) generation were significantly reduced to nearly normal levels after PLAG treatment. Glucose transporter 2 (GLUT2) localization analyses and glucose uptake assays showed that PLAG accelerated GLUT2 internalization, which ameliorated excessive entry of glucose, as well as STZ. STZ-induced cytotoxic effects were significantly reduced in PLAG-treated groups. The biological activity of PLAG was further confirmed in GLUT2-silenced cells, and the specificity of PLAG was verified using its derivative 1-palmitoyl-2-linoleoyl-3-hydroxyl-rac-glycerol (PLH). Our results suggest that PLAG may be a useful agent for protecting beta cells in the setting of excessive glucose influx.

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SEL BETA PANKREAS SINTESIS DAN SEKRESI INSULIN

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.4.3.2012.795 ◽

2013 ◽

Vol 4 (3) ◽

Author(s):

Eka Banjarnahor ◽

Sunny Wangko

Keyword(s):

Insulin Secretion ◽

Blood Glucose ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Plasma Membranes ◽

Secretory Granules ◽

Chromosome 11 ◽

Insulin Synthesis ◽

Glucose Levels ◽

Blood Glucose Levels

Abstract: Insulin synthesis and secretion are done by pancreatic beta cells. Preceding the insulin synthesis, there is a gen translation in chromosome 11 that produces insulin, packed in secretory granules. Insulin secretion is induced by the alteration of blood glucose levels, resulting in the occurence of intracellular reactions preceded by changes of ATP/ADP ratios that trigger the depolarisation of plasma membranes. Furthermore, extracellular Ca2+ ions move inward to beta cells to activate exocytosis. There are still many unknown problems so far in either the synthesis or secretion of insulin that cause unfulfilled insulin needs in the body.Keywords: beta cells, insulin, synthesis, secretionAbstrak: Sintesis dan sekresi insulin dilakukan oleh sel beta pankreas. Sintesis insulin diawali oleh salinan gen pada kromosom 11, yang akan menghasilkan insulin, di kemas di dalam granul-granul sekretorik. Sekresi insulin diinduksi oleh perubahan kadar glukosa, yang berakibat terjadinya reaksi intrasel yang diikuti adanya perbedaan rasio ATP/ADP yang memicu reaksi depolarisasi membran plasma. Sebagai akibat lanjut Ca2+ ekstrasel akan masuk ke dalam sel beta yang berfungsi mengaktifkan eksositosis. Sampai saat ini masih banyak ditemui masalah baik dalam hal sintesis maupun sekresi insulin yang mengakibatkan kebutuhan insulin tubuh tidak terpenuhi.Kata kunci: sel beta, insulin, sintesis, sekresi

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Phosphatases are predicted to govern prolactin-mediated JAK-STAT signaling in pancreatic beta cells

10.1101/2021.10.14.464474 ◽

2021 ◽

Author(s):

Ariella Simoni ◽

Holly Huber ◽

Senta K Georgia ◽

Stacey D Finley

Keyword(s):

Insulin Secretion ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Prolactin Receptor ◽

Potential Method ◽

Least Squares Regression ◽

Biological Targets ◽

Glucose Levels ◽

Stat Signaling ◽

Patients With Diabetes

Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood-glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin. Leveraging this proliferative response to prolactin may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the prolactin-mediated JAK-STAT signaling pathway in pancreatic beta cells. However, this model does not account for variability in protein expression that naturally occurs between cells. Here, we applied the model to understand how heterogeneity affects the dynamics of JAK-STAT signaling. We simulated a sample of 10,000 heterogeneous cells with varying initial protein concentrations responding to prolactin stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing prolactin receptor strengthens negative feedback mediated by the inhibitor SOCS. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes.

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