2109-P: Type 2 Diabetic Human Beta Cells Are Characterized by Marked Expression of the Na+-nHCO3- Cotransporter NBCe1 and Intracellular Alkalization

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2109-P
Author(s):  
MATTHEW BROWN ◽  
ALISON STILLER ◽  
MICHAEL F. ROMERO ◽  
ALEKSEY MATVEYENKO
Keyword(s):  
Beta Cells ◽  
Human Beta Cells ◽  
P Type ◽  
Type 2 Diabetic

scholarly journals Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 168 ◽  
Author(s):  
Anne-Françoise Close ◽  
Nidheesh Dadheech ◽  
Hélène Lemieux ◽  
Qian Wang ◽  
Jean Buteau
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Nuclear Receptor ◽  
Pancreatic Beta Cells ◽  
Orphan Nuclear Receptor ◽  
Atp Production ◽  
Human Beta Cells ◽  
Glucose Stimulated Insulin Secretion ◽  
Mitochondrial Networks

Nor1, the third member of the Nr4a subfamily of nuclear receptor, is garnering increased interest in view of its role in the regulation of glucose homeostasis. Our previous study highlighted a proapoptotic role of Nor1 in pancreatic beta cells and showed that Nor1 expression was increased in islets isolated from type 2 diabetic individuals, suggesting that Nor1 could mediate the deterioration of islet function in type 2 diabetes. However, the mechanism remains incompletely understood. We herein investigated the subcellular localization of Nor1 in INS832/13 cells and dispersed human beta cells. We also examined the consequences of Nor1 overexpression on mitochondrial function and morphology. Our results show that, surprisingly, Nor1 is mostly cytoplasmic in beta cells and undergoes mitochondrial translocation upon activation by proinflammatory cytokines. Mitochondrial localization of Nor1 reduced glucose oxidation, lowered ATP production rates, and inhibited glucose-stimulated insulin secretion. Western blot and microscopy images revealed that Nor1 could provoke mitochondrial fragmentation via mitophagy. Our study unveils a new mode of action for Nor1, which affects beta-cell viability and function by disrupting mitochondrial networks.

scholarly journals Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 395-409 ◽  
Author(s):  
Masaya Oshima ◽  
Séverine Pechberty ◽  
Lara Bellini ◽  
Sven O. Göpel ◽  
Mélanie Campana ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Identity ◽  
Human Beta Cells ◽  
Human Beta Cell ◽  
Stearoyl Coa Desaturase

Abstract Aims/hypothesis During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. Methods EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. Results EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. Conclusions/interpretation The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. Data availability Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

scholarly journals Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients

Diabetologia ◽  
2005 ◽  
Vol 48 (2) ◽  
pp. 282-289 ◽  
Author(s):  
M. Anello ◽  
R. Lupi ◽  
D. Spampinato ◽  
S. Piro ◽  
M. Masini ◽  
...  
Keyword(s):  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Morphological Alterations ◽  
Type 2 Diabetic

Zinc ions in beta-cells of obese, insulin-resistant, and type 2 diabetic rats traced by autometallography

Apmis ◽  
2003 ◽  
Vol 111 (12) ◽  
pp. 1147-1154 ◽  
Author(s):  
L. G. SONDERGAARD ◽  
M. STOLTENBERG ◽  
A. FLYVBJERG ◽  
B. BROCK ◽  
O. SCHMITZ ◽  
...  
Keyword(s):  
Beta Cells ◽  
Diabetic Rats ◽  
Zinc Ions ◽  
Insulin Resistant ◽  
Type 2 Diabetic

Niacin receptor GPR109A inhibits insulin secretion and is down-regulated in type 2 diabetic islet beta-cells

2016 ◽  
Vol 237 ◽  
pp. 98-108 ◽  
Author(s):  
Na Wang ◽  
De-yu Guo ◽  
Xiong Tian ◽  
Hao-peng Lin ◽  
Yun-pan Li ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Islet Beta Cells ◽  
Type 2 Diabetic

scholarly journals Thymus praecox subsp. skorpilii var. skorpilii extract attenuates degeneration of beta-cells and reduced insulin levels in type 2 diabetic rats

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO1-5-29
Author(s):  
Ayse Nur Hazar-Yavuz ◽  
Muhammet Emin Cam ◽  
Sila Yildiz ◽  
Turgut Taskin ◽  
Saadet Alan ◽  
...  
Keyword(s):  
Beta Cells ◽  
Diabetic Rats ◽  
Insulin Levels ◽  
Type 2 Diabetic

Sargassum fusiforme fucoidan modifies gut microbiota and intestinal metabolites during alleviation of hyperglycemia in type 2 diabetic mice

2021 ◽  
Author(s):  
Qifang Wu ◽  
Siya Wu ◽  
Yang Cheng ◽  
Zhongshan Zhang ◽  
Genxiang Mao ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Biological Activities ◽  
Public Health Problem ◽  
Global Public Health ◽  
Diabetic Mellitus ◽  
Type 2 Diabetic Mellitus ◽  
P Type ◽  
Type 2 Diabetic ◽  
Global Public Health Problem

Type 2 diabetic mellitus (T2DM) is a complicated metabolic disorder that is now considered as a major global public health problem. Fucoidan possesses diverse biological activities, especially preventing metabolic diseases....

scholarly journals Human Islets Contain a Beta Cell Type That Expresses Proinsulin But Not the Enzyme That Converts the Precursor to Insulin

2020 ◽  
Vol 68 (10) ◽  
pp. 691-702
Author(s):  
Gladys Teitelman
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Types ◽  
Human Islets ◽  
Cell Type ◽  
Human Beta Cells ◽  
Human Beta Cell ◽  
Cell Phenotypes

In pancreatic beta cells, proinsulin (ProIN) undergoes folding in endoplasmic reticulum/Golgi system and is translocated to secretory vesicles for processing into insulin and C-peptide by the proprotein convertases (PC)1/3 and PC2, and carboxypeptidase E. Human beta cells show significant variation in the level of expression of PC1/3, the critical proconvertase involved in proinsulin processing. To ascertain whether this heterogeneity is correlated with the level of expression of the prohormone and mature hormone, the expression of proinsulin, insulin, and PC1/3 in human beta cells was examined. This analysis identified a human beta cell type that expressed proinsulin but lacked PC1/3 (ProIN+PC1/3−). This beta cell type is absent in rodent islets and is abundant in human islets of adults but scarce in islets from postnatal donors. Human islets also contained a beta cell type that expressed both proinsulin and variable levels of PC1/3 (ProIN+PC1/3+) and a less abundant cell type that lacked proinsulin but expressed the convertase (ProIN−PC1/3+). These cell phenotypes were altered by type 2 diabetes. These data suggest that these three cell types represent different stages of a dynamic process with proinsulin folding in ProIN+PC1/3− cells, proinsulin conversion into insulin in ProIN+PC1/3+cells, and replenishment of the proinsulin content in ProIN−PC1/3+ cells:

HD-6277, a Novel GPR40 Agonist, Improves Glucose Homeostasis and Enhanced Glucose-Dependent Insulin Secretion in Beta Cells and Type 2 Diabetic Rats

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1202-P
Author(s):  
DAEHOON KIM ◽  
CHUN HWA KIM ◽  
HYO SUN CHOI ◽  
GOEUN YANG ◽  
SEUNG JUN KANG ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Diabetic Rats ◽  
Type 2 Diabetic

scholarly journals Heterogeneous Expression of Proinsulin Processing Enzymes in Beta Cells of Non-diabetic and Type 2 Diabetic Humans

2019 ◽  
Vol 67 (6) ◽  
pp. 385-400 ◽  
Author(s):  
Gladys Teitelman
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cells ◽  
Human Pancreas ◽  
Proprotein Convertase ◽  
Expression Levels ◽  
Processing Enzymes ◽  
Proinsulin Processing ◽  
Heterogeneous Expression ◽  
Human Beta Cells

Although there is evidence indicating transcriptional and functional heterogeneity in human beta cells, it is unclear whether this heterogeneity extends to the expression level of the enzymes that process proinsulin to insulin in beta cells. To address this question, the expression levels of prohormone convertases (PC) 1/3, proprotein convertase 2 (PC2), and carboxypeptidase E (CPE) were determined in immune-stained sections of human pancreas. In non-diabetic donors, the level of proprotein convertase 1/3 (PC1/3) expression varied among beta cells of each islet but the average per islet was similar for all islets of each donor. Although the average PC1/3 expression of all islets examined per sample was unique for each pancreas, donors had similar levels of proinsulin/insulin expression. PC2 expression in beta cells showed less pronounced inter- and intraislet variation while CPE levels were fairly constant. The relationship between PC1/3 and PC2 expression levels was variable among different donors. Type 2 diabetes had an uneven effect on the expression levels of all three enzymes as they decrease only in some islets in a section. These findings suggest the presence of intraislet, but not interislet, variation in the expression of the proinsulin processing enzymes in non-diabetic subjects and a heterogeneous effect of type 2 diabetes on enzyme expression in islets.

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