scholarly journals VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Frank Chenfei Ning ◽  
Nina Jensen ◽  
Jiarui Mi ◽  
William Lindström ◽  
Mirela Balan ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Glucose Homeostasis ◽  
Lipid Accumulation ◽  
Cell Function ◽  
Lipid Uptake ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Β Cell Function ◽  
Triglyceride Content

AbstractType 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.

scholarly journals Translational factor eIF4G1 regulates glucose homeostasis and pancreatic β-cell function

2020 ◽  
Author(s):  
Ada Admin ◽  
Seokwon Jo ◽  
Amber Lockridge ◽  
Ramkumar Mohan ◽  
Nicholas Esch ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Scaffolding Protein ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Initiation Complex ◽  
Β Cell Function

Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling, is associated with diabetes in both humans and mice. In the present study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells <i>in vivo</i> (βeIF4G1KO). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in both proliferation and apoptosis in β-cells of βeIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca<sup>2+</sup> flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5’-cap binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single β-cells or intact islets of βeIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and β-cell function.

scholarly journals Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

2021 ◽  
Author(s):  
Casey J. Bauchle ◽  
Kristen E. Rohli ◽  
Cierra K. Boyer ◽  
Vidhant Pal ◽  
Jonathan V. Rocheleau ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islet ◽  
Glucose Homeostasis ◽  
Cell Function ◽  
Normal Glucose Tolerance ◽  
Coupling Factor ◽  
Β Cell ◽  
Metabolic Coupling ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC to glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout mice and demonstrate these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme, cytosolic isocitrate dehydrogenase, Idh1, inhibited insulin secretion in wild type islets, but failed to impact β-cell function in β-cell CIC KO islets.<b> </b>Our data demonstrate that the mitochondrial citrate-isocitrate carrier is not required for glucose-stimulated insulin secretion, and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.

scholarly journals Translational factor eIF4G1 regulates glucose homeostasis and pancreatic β-cell function

2020 ◽  
Author(s):  
Ada Admin ◽  
Seokwon Jo ◽  
Amber Lockridge ◽  
Ramkumar Mohan ◽  
Nicholas Esch ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Scaffolding Protein ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Initiation Complex ◽  
Β Cell Function

Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling, is associated with diabetes in both humans and mice. In the present study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells <i>in vivo</i> (βeIF4G1KO). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in both proliferation and apoptosis in β-cells of βeIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca<sup>2+</sup> flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5’-cap binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single β-cells or intact islets of βeIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and β-cell function.

scholarly journals Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

2021 ◽  
Author(s):  
Casey J. Bauchle ◽  
Kristen E. Rohli ◽  
Cierra K. Boyer ◽  
Vidhant Pal ◽  
Jonathan V. Rocheleau ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islet ◽  
Glucose Homeostasis ◽  
Cell Function ◽  
Normal Glucose Tolerance ◽  
Coupling Factor ◽  
Β Cell ◽  
Metabolic Coupling ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC to glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout mice and demonstrate these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme, cytosolic isocitrate dehydrogenase, Idh1, inhibited insulin secretion in wild type islets, but failed to impact β-cell function in β-cell CIC KO islets.<b> </b>Our data demonstrate that the mitochondrial citrate-isocitrate carrier is not required for glucose-stimulated insulin secretion, and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.

scholarly journals TGS1: a novel regulator of β-cell mass and function

2021 ◽  
Author(s):  
Manuel Blandino-Rosano ◽  
Pau Romaguera-Llacer ◽  
Ashley Lin ◽  
Janardan K Reddy ◽  
Ernesto Bernal-Mizrachi
Keyword(s):  
Cell Cycle ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Function ◽  
Cell Mass ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
And Function

Type 2 diabetes (T2D) is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in β-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs (snRNAs and snoRNAs) and is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in β-cells and glucose homeostasis had not been explored. Here we show that TGS1 is upregulated by insulin and upregulated in islets from mice exposed to a high-fat diet and in human β-cells from T2D donors. Using mice with conditional (βTGS1KO and βTGS1Het) and inducible (MIP-CreERT-TGS1KO) TGS1 deletion, we determine that TGS1 regulates β-cell mass and function. Unbiased approaches allowed us to identify a link between TGS1 and ER stress and cell cycle arrest and how TGS1 regulates β-cell apoptosis. Deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2α, and several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating β-cell mass and function as well as playing a role in the adaptive β-cell function to a high-fat diet. These observations can be used as a stepping-stone for the design of novel strategies using TGS1 as a therapeutic target for the treatment of diabetes.

scholarly journals Pericytes contribute to the islet basement membranes to promote beta-cell gene expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lina Sakhneny ◽  
Alona Epshtein ◽  
Limor Landsman
Keyword(s):  
Gene Expression ◽  
Cell Function ◽  
Basement Membranes ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Cell Clustering ◽  
Β Cell Function ◽  
Cell Gene Expression ◽  
Glucose Stimulated Insulin Secretion

Abstractβ-Cells depend on the islet basement membrane (BM). While some islet BM components are produced by endothelial cells (ECs), the source of others remains unknown. Pancreatic pericytes directly support β-cells through mostly unidentified secreted factors. Thus, we hypothesized that pericytes regulate β-cells through the production of BM components. Here, we show that pericytes produce multiple components of the mouse pancreatic and islet interstitial and BM matrices. Several of the pericyte-produced ECM components were previously implicated in β-cell physiology, including collagen IV, laminins, proteoglycans, fibronectin, nidogen, and hyaluronan. Compared to ECs, pancreatic pericytes produce significantly higher levels of α2 and α4 laminin chains, which constitute the peri-islet and vascular BM. We further found that the pericytic laminin isoforms differentially regulate mouse β-cells. Whereas α2 laminins promoted islet cell clustering, they did not affect gene expression. In contrast, culturing on Laminin-421 induced the expression of β-cell genes, including Ins1, MafA, and Glut2, and significantly improved glucose-stimulated insulin secretion. Thus, alongside ECs, pericytes are a significant source of the islet BM, which is essential for proper β-cell function.

scholarly journals Herbal Medicines Targeting the Improved β-Cell Functions and β-Cell Regeneration for the Management of Diabetes Mellitus

2021 ◽  
Vol 2021 ◽  
pp. 1-32
Author(s):  
Akurange Sujeevi Dammadinna Wickramasinghe ◽  
Pabasara Kalansuriya ◽  
Anoja Priyadarshani Attanayake
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Herbal Medicines ◽  
Cell Regeneration ◽  
Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
Glucose Transporter 2 ◽  
Β Cell Function

There is an increasing trend of investigating natural bioactive compounds targeting pancreatic β-cells for the prevention/treatment of diabetes mellitus (DM). With the exploration of multiple mechanisms by which β-cells involve in the pathogenesis of DM, herbal medicines are gaining attention due to their multitasking ability as evidenced by traditional medicine practices. This review attempts to summarize herbal medicines with the potential for improvement of β-cell functions and regeneration as scientifically proven by in vivo/in vitro investigations. Furthermore, attempts have been made to identify the mechanisms of improving the function and regeneration of β-cells by herbal medicines. Relevant data published from January 2009 to March 2020 were collected by searching electronic databases “PubMed,” “ScienceDirect,” and “Google Scholar” and studied for this review. Single herbal extracts, polyherbal mixtures, and isolated compounds derived from approximately 110 medicinal plants belonging to 51 different plant families had been investigated in recent years and found to be targeting β-cells. Many herbal medicines showed improvement of β-cell function as observed through homeostatic model assessment-β-cell function (HOMA-β). Pancreatic β-cell regeneration as observed in histopathological and immunohistochemical studies in terms of increase of size and number of functional β-cells was also prominent. Increasing β-cell mass via expression of genes/proteins related to antiapoptotic actions and β-cell neogenesis/proliferation, increasing glucose-stimulated insulin secretion via activating glucose transporter-2 (GLUT-2) receptors, and/or increasing intracellular Ca2+ levels were observed upon treatment of some herbal medicines. Some herbal medicines acted on various insulin signaling pathways. Furthermore, many herbal medicines showed protective effects on β-cells via reduction of oxidative stress and inflammation. However, there are many unexplored avenues. Thus, further investigations are warranted in elucidating mechanisms of improving β-cell function and mass by herbal medicines, their structure-activity relationship (SAR), and toxicities of these herbal medicines.

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