Hyperglycemia-induced alteration of ER redox homeostasis delays ER export of proinsulin

Defects in the β-cells secretion system are well-described in Type 2 diabetes (T2D), including reduced insulin storage and impaired proinsulin processing; however, the cellular mechanisms underlying these secretory defects and the contribution of chronic hyperglycemia to this process remain poorly understood. In this study, we provide evidence that oxidative protein folding in the endoplasmic reticulum (ER) is perturbed in models of β-cell dysfunction, leading to delays in proinsulin trafficking and insulin granule formation. Using an in situ fluorescent pulse-chase labeling strategy and APEX2-based proximity labeling, we demonstrate that enriched interactions of proinsulin with ER oxidoreductases coincides with a delay in proinsulin ER export. Furthermore, our data show that proinsulin ER export can be regulated by metabolically-derived NADPH and reducing equivalent (glutathione) availability. Together, these data highlight an emerging role for nutrient metabolism and mitochondrial dysfunction in the maladaptive remodeling of the β-cells secretory pathway during the decline of β-cell function in T2D.

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Furin controls β cell function via mTORC1 signaling

10.1101/2020.04.09.027839 ◽

2020 ◽

Cited By ~ 1

Author(s):

Bas Brouwers ◽

Ilaria Coppola ◽

Katlijn Vints ◽

Bastian Dislich ◽

Nathalie Jouvet ◽

...

Keyword(s):

Secretory Pathway ◽

Cell Function ◽

Mammalian Target Of Rapamycin ◽

Human Islets ◽

Β Cells ◽

Β Cell ◽

Differential Proteomics ◽

Atpase Subunit ◽

Proteolytic Activation ◽

Mtorc1 Signaling

AbstractFurin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific furin knockout (βfurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on βfurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βfurKO cells show impaired cleavage of the essential V-ATPase subunit Ac45, and by blocking this pump in β cells the mTORC1 pathway is activated. Furthermore, βfurKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction.

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Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

Biomolecules ◽

10.3390/biom11121892 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1892

Author(s):

Emily S. Krueger ◽

Joseph L. Beales ◽

Kacie B. Russon ◽

Weston S. Elison ◽

Jordan R. Davis ◽

...

Keyword(s):

Cell Function ◽

Cell Mass ◽

Caloric Intake ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

Granule Formation ◽

Β Cell Function ◽

Molecular Effects ◽

And Function

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

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NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction

Cells ◽

10.3390/cells10071573 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1573

Author(s):

Suma Elumalai ◽

Udayakumar Karunakaran ◽

Jun-Sung Moon ◽

Kyu-Chang Won

Keyword(s):

Nadph Oxidase ◽

Cell Function ◽

Negative Impact ◽

Redox Homeostasis ◽

Metabolic Stress ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Therapeutic Benefits

In type 2 diabetes, metabolic stress has a negative impact on pancreatic β-cell function and survival (T2D). Although the pathogenesis of metabolic stress is complex, an imbalance in redox homeostasis causes abnormal tissue damage and β-cell death due to low endogenous antioxidant expression levels in β-cells. Under diabetogenic conditions, the susceptibility of β-cells to oxidative damage by NADPH oxidase has been related to contributing to β-cell dysfunction. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions by NADPH oxidase, as well as the therapeutic benefits of NOX inhibitors, which may provide clues for understanding the pathomechanisms and developing strategies aimed at the treatment or prevention of metabolic stress associated with β-cell failure.

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The importance of redox shuttles to pancreatic β-cell energy metabolism and function

Biochemical Society Transactions ◽

10.1042/bst0340811 ◽

2006 ◽

Vol 34 (5) ◽

pp. 811-814 ◽

Cited By ~ 41

Author(s):

K. Bender ◽

P. Newsholme ◽

L. Brennan ◽

P. Maechler

Keyword(s):

Insulin Secretion ◽

Energy Metabolism ◽

Electron Transport ◽

Cell Function ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Nutrient Metabolism ◽

Β Cell Function ◽

Malate Aspartate Shuttle

The coupling of cytosolic glycolytic NADH production with the mitochondrial electron transport chain is crucial for pancreatic β-cell function and energy metabolism. The activity of lactate dehydrogenase in the β-cell is low, thus glycolysis-derived electrons are transported towards the mitochondrial matrix by a NADH shuttle system, which in turn regenerates cytosolic NAD+. Mitochondrial electron transport then produces ATP, the main coupling factor for insulin secretion. Aralar1, a Ca2+-sensitive member of the malate–aspartate shuttle expressed in β-cells, has been found to play a significant role in nutrient-stimulated insulin secretion and β-cell function. Increased capacity of Aralar1 enhances the responsiveness of the cell to glucose. Conversely, inhibition of the malate–aspartate shuttle results in impaired glucose metabolism and insulin secretion. Current research investigates potentiating or attenuating activities of various amino acids on insulin secretion, mitochondrial membrane potential and NADH production in Aralar1-overexpressing β-cells. This work may provide evidence for a central role of Aralar1 in the regulation of nutrient metabolism in the β-cells.

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Stevioside improves pancreatic β-cell function during glucotoxicity via regulation of acetyl-CoA carboxylase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00356.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1906-E1916 ◽

Cited By ~ 9

Author(s):

Jianguo Chen ◽

Per Bendix Jeppesen ◽

Iver Nordentoft ◽

Kjeld Hermansen

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Cell Function ◽

Acetyl Coa Carboxylase ◽

Negative Effects ◽

Β Cells ◽

Β Cell ◽

Acetyl Coa ◽

Chronic Hyperglycemia ◽

Mouse Islets

Chronic hyperglycemia is detrimental to pancreatic β-cells, causing impaired insulin secretion and β-cell turnover. The characteristic secretory defects are increased basal insulin secretion (BIS) and a selective loss of glucose-stimulated insulin secretion (GSIS). Several recent studies support the view that the acetyl-CoA carboxylase (ACC) plays a pivotal role for GSIS. We have shown that stevioside (SVS) enhances insulin secretion and ACC gene expression. Whether glucotoxicity influences ACC and whether this action can be counteracted by SVS are not known. To investigate this, we exposed isolated mouse islets as well as clonal INS-1E β-cells for 48 h to 27 or 16.7 mM glucose, respectively. We found that 48-h exposure to high glucose impairs GSIS from mouse islets and INS-1E cells, an effect that is partly counteracted by SVS. The ACC dephosphorylation inhibitor okadaic acid (OKA, 10−8 M), and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, 10−4 M), an activator of 5′-AMP protein kinase that phosphorylates ACC, eliminated the beneficial effect of SVS. 5-Tetrade-cyloxy-2-furancarboxylic acid (TOFA), the specific ACC inhibitor, blocked the effect of SVS as well. During glucotoxity, ACC gene expression, ACC protein, and phosphorylated ACC protein were increased in INS-1E β-cells. SVS pretreatment further increased ACC gene expression with strikingly elevated ACC activity and increased glucose uptake accompanied by enhanced GSIS. Our studies show that glucose is a potent stimulator of ACC and that SVS to some extent counteracts glucotoxicity via increased ACC activity. SVS possesses the potential to alleviate negative effects of glucotoxicity in β-cells via a unique mechanism of action.

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Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

Antioxidants ◽

10.3390/antiox10040526 ◽

2021 ◽

Vol 10 (4) ◽

pp. 526

Author(s):

Štěpánka Benáková ◽

Blanka Holendová ◽

Lydie Plecitá-Hlavatá

Keyword(s):

Secretory Pathway ◽

Cell Metabolism ◽

Redox Homeostasis ◽

Cell Communication ◽

Redox Signaling ◽

Β Cells ◽

Β Cell ◽

Peripheral Tissues ◽

Insulin Synthesis ◽

Wide Range

Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.

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An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

Nature Communications ◽

10.1038/s41467-020-20454-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jinyoung Kim ◽

Kihyoun Park ◽

Min Jung Kim ◽

Hyejin Lim ◽

Kook Hwan Kim ◽

...

Keyword(s):

Cell Death ◽

Cell Function ◽

Therapeutic Potential ◽

Therapeutic Modality ◽

Protective Effects ◽

Β Cells ◽

Β Cell ◽

Islet Amyloid ◽

Amyloid Accumulation ◽

Human Diabetes

AbstractWe have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

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

Scientific Reports ◽

10.1038/s41598-021-81774-8 ◽

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.

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Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

International Journal of Molecular Sciences ◽

10.3390/ijms22157917 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7917

Author(s):

Hideaki Kaneto ◽

Tomohiko Kimura ◽

Masashi Shimoda ◽

Atsushi Obata ◽

Junpei Sanada ◽

...

Keyword(s):

Large Scale ◽

Cell Function ◽

Apoptotic Cell ◽

Early Stage ◽

Insulin Biosynthesis ◽

Protective Effects ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Toxicity

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/2920530 ◽

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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