Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice

Introduction: Diabetes mellitus is not just a disease as it is already known, the matter is more complicated, and it is considered as an assembly of metabolic defects with end result of hyperglycemia.verapamil can decrease the expression of thioredoxin-interacting protein (TXNIP), which is recognized as an important factor in pancreatic beta cells.verapamil could enhance beta cell mass and function. Materials and Methods: 160 type 2 diabetes patients in 2 parallel groups. Results: show statistically significant difference in favour of verapamil in increasing c-peptide levels and decreasing hba1c levels. Conclusion: Verapamil could be used as a type 2 diabetes saviour by increasing beta cell mass and function.

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Genetic evidence of the programming of beta cell mass and function by glucocorticoids in mice

Diabetologia ◽

10.1007/s00125-010-1898-2 ◽

2010 ◽

Vol 54 (2) ◽

pp. 350-359 ◽

Cited By ~ 37

Author(s):

B. Valtat ◽

C. Dupuis ◽

D. Zenaty ◽

A. Singh-Estivalet ◽

F. Tronche ◽

...

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Genetic Evidence ◽

And Function

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Role of Ink4a/Arf Locus in Beta Cell Mass Expansion under Physiological and Pathological Conditions

Journal of Diabetes Research ◽

10.1155/2014/873679 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Elisabet Salas ◽

Nabil Rabhi ◽

Philippe Froguel ◽

Jean-Sébastien Annicotte

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Primary Source ◽

Tumour Suppressor Genes ◽

General View ◽

Diabetes Research ◽

And Function ◽

Cdkn2a Locus

The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.

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Aberrant methylation underlies insulin gene expression in human insulinoma

Nature Communications ◽

10.1038/s41467-020-18839-1 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Esra Karakose ◽

Huan Wang ◽

William Inabnet ◽

Rajesh V. Thakker ◽

Steven Libutti ◽

...

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Methylation Pattern ◽

Congenital Hyperinsulinism ◽

Aberrant Methylation ◽

Chromosome 11 ◽

Distal Enhancer ◽

Human Insulinoma ◽

And Function

Abstract Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insulinomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing canonical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the canonical PDX1 enhancer complex, are predicted to drive INS transactivation.

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The Effects of Beta-cell Mass and Function, Intercellular Coupling, and islet Synchrony on Ca2+ Dynamics in Patients with Type 2 Diabetes Mellitus

10.21203/rs.3.rs-132280/v1 ◽

2020 ◽

Author(s):

Maryam Saadati ◽

Yousef Jamali

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Cell Mass ◽

Electrical Coupling ◽

Beta Cell Mass ◽

Intercellular Coupling ◽

And Function

Abstract Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of beta-cell mass via progressive programmed cell death and alteration of beta-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in beta-cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of beta-cell mass to beta-cell function in T2D, we make use of a comprehensive electrophysiological model from human beta-cell clusters. We find that defect in beta-cell mass causes a functional decline in single beta-cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular Ca2+ concentration, which can lead to changes in insulin secretion dynamics and insulin levels. The model demonstrates good correspondence between suppression of synchronizing electrical activity and pulsatile insulin release, and published experimental measurements. We then compare the role of gap junction-mediated electrical coupling with both beta-cell synchronization and metabolic coupling in the behavior of Ca2+ concentration dynamics within human islets. Our results indicate that inter-beta-cellular electrical coupling depicts a more important factor in shaping the physiological regulation of islet function and in human T2D. We further predict that varying the conductance gating of delayed rectifier K+ channels modifies oscillatory activity patterns of the beta-cell population lacking intercellular coupling, which significantly affects Ca2+ concentration and insulin secretion.

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Dual role of the tyrosine kinase GTK and the adaptor protein SHB in beta-cell growth: enhanced beta-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin

Journal of Endocrinology ◽

10.1677/joe.0.1720145 ◽

2002 ◽

Vol 172 (1) ◽

pp. 145-153 ◽

Cited By ~ 14

Author(s):

C Anneren

Keyword(s):

Cell Death ◽

Transgenic Mice ◽

Tyrosine Kinase ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Adaptor Protein ◽

Beta Cell Proliferation ◽

Cell Replication ◽

Beta Cell Replication

Transgenic CBA mice expressing either the tyrosine kinase GTK (gut tyrosine kinase) or the adaptor protein SHB (Src homology 2 protein of beta-cells) under the control of the rat insulin promoter exhibited an increased beta-cell mass, but also elevated cytokine-induced islet cell death compared with control mice. To further investigate the importance of GTK and SHB for beta-cell death and proliferation, these mice were subjected to a 60% partial pancreatectomy (Px) or a sham-operation and beta-cell replication was determined by autoradiographic detection of [(3)H]thymidine incorporation into islet cells positively stained for insulin. The Px-operated control mice exhibited a moderate and insignificant increase in beta-cell replication 4 days after Px compared with the sham-operated mice (0.27+/-0.08% vs 0.08+/-0.02%). In contrast, the Px-induced beta-cell proliferation was significantly increased in both the GTK- and SHB-transgenic mice compared with the corresponding sham-treated animals (0.64+/-0.12% vs 0.11+/-0.04% and 0.44+/-0.11% vs 0.09+/-0.04% respectively). This effect was dependent on intracellular signal transduction pathways activated or enhanced by GTK and SHB overexpression, since the proliferation of acinar cells, located in the vicinity of the islets, was equal in the transgenic and control mice. GTK- and SHB-transgenic mice, treated with a sub-diabetogenic dose of the beta-cell toxin streptozotocin (STZ) on day 0 and subjected to a glucose tolerance test on day 3, exhibited an impaired glucose tolerance in comparison with the STZ-treated control mice. Pretreatment with STZ blunted the regenerative response to Px in the transgenic mice. Furthermore, the SHB-transgenic islets were significantly more damaged with respect to beta-cell loss, compared with the islets of the control mice. Previous and present data suggest a dual role of GTK and SHB for beta-cell growth: whereas these proteins increase the beta-cell mass and induce beta-cell proliferation after 60% Px, SHB and GTK also enhance beta-cell death under certain stressful conditions.

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Glutamine Stimulates Biosynthesis and Secretion of Insulin-like Growth Factor 2 (IGF2), an Autocrine Regulator of Beta Cell Mass and Function

Journal of Biological Chemistry ◽

10.1074/jbc.m114.587733 ◽

2014 ◽

Vol 289 (46) ◽

pp. 31972-31982 ◽

Cited By ~ 22

Author(s):

Honey Modi ◽

Marion Cornu ◽

Bernard Thorens

Keyword(s):

Growth Factor ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Insulin Like Growth Factor ◽

And Function

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Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice

Diabetologia ◽

10.1007/s00125-019-4878-1 ◽

2019 ◽

Vol 62 (7) ◽

pp. 1225-1236 ◽

Cited By ~ 1

Author(s):

Atsushi Obata ◽

Tomohiko Kimura ◽

Yoshiyuki Obata ◽

Masashi Shimoda ◽

Tomoe Kinoshita ◽

...

Keyword(s):

Blood Flow ◽

Beta Cell ◽

Knockout Mice ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Vascular Endothelial ◽

And Function ◽

Pancreatic Beta Cell Mass ◽

Mrna Expression Levels

AbstractAims/hypothesisThe aim of this study was to elucidate the impact of 3′-phosphoinositide-dependent protein kinase-1 (PDPK1) in vascular endothelial cells on the maintenance of pancreatic beta cell mass and function.MethodsMale vascular endothelial cell-specificPdpk1-knockout mice (Tie2+/−/Pdpk1flox/floxmice) and their wild-type littermates (Tie2−/−/Pdpk1flox/floxmice; control) were used for this study. At 12 weeks of age, an IPGTT and OGTT were conducted. Pancreatic blood flow was measured under anaesthesia. Thereafter, islet blood flow was measured by the microsphere method. Mice were killed for islet isolation and further functional study and mRNA was extracted from islets. Pancreases were sampled for immunohistochemical analyses.ResultsDuring the IPGTT, the blood glucose level was comparable between knockout mice and controlfloxmice, although serum insulin level was significantly lower in knockout mice. During the OGTT, glucose tolerance deteriorated slightly in knockout mice, accompanied by a decreased serum insulin level. During an IPGTT after pre-treatment with exendin-4 (Ex-4), glucose tolerance was significantly impaired in knockout mice. In fact, glucose-stimulated insulin secretion of isolated islets from knockout mice was significantly reduced compared with controlfloxmice, and addition of Ex-4 revealed impaired sensitivity to incretin hormones in islets of knockout mice. In immunohistochemical analyses, both alpha and beta cell masses were significantly reduced in knockout mice. In addition, the CD31-positive area was significantly decreased in islets of knockout mice. The proportion of pimonidazole-positive islets was significantly increased in knockout mice. mRNA expression levels related to insulin biosynthesis (Ins1,Ins2,Mafa,Pdx1andNeurod[also known asNeurod1]) and beta cell function (such asGckandSlc2a2) were significantly decreased in islets of knockout mice. Microsphere experiments revealed remarkably reduced islet blood flow. In addition, mRNA expression levels ofHif1α(also known asHif1a) and its downstream factors such asAdm,Eno1,Tpi1(also known asEts1),Hmox1andVegfa, were significantly increased in islets of knockout mice, indicating that islets of knockout mice were in a more hypoxic state than those of controlfloxmice. As a result, mRNA expression levels related to adaptive unfolded protein response and endoplasmic reticulum stress-related apoptotic genes were significantly elevated in islets of knockout mice. In addition, inflammatory cytokine levels were increased in islets of knockout mice. Electron microscopy revealed reduced endothelial fenestration and thickening of basal membrane of vascular endothelium in islets of knockout mice.Conclusions/interpretationVascular endothelial PDPK1 plays an important role in the maintenance of pancreatic beta cell mass and function by maintaining vascularity of pancreas and islets and protecting them from hypoxia, hypoxia-related endoplasmic reticulum stress, inflammation and distortion of capillary structure.

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