Loss of MANF Causes Childhood Onset Syndromic Diabetes due to Increased Endoplasmic Reticulum Stress

MANF is an endoplasmic reticulum resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse beta cells, its precise role in human beta cell development and function is unknown. Herein, we show that lack of MANF in humans results in diabetes due to increased ER stress leading to impaired beta cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human beta cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin processing capacity of beta cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in diabetic recipients. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human beta cell function and demonstrate the crucial role of MANF in this process.

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A Triple Threat? The Role of Diet, Nutrition, and the Microbiota in T1D Pathogenesis

Frontiers in Nutrition ◽

10.3389/fnut.2021.600756 ◽

2021 ◽

Vol 8 ◽

Author(s):

Emma E. Hamilton-Williams ◽

Graciela L. Lorca ◽

Jill M. Norris ◽

Jessica L. Dunne

Keyword(s):

Beta Cell ◽

Intestinal Microbiota ◽

Beta Cell Function ◽

Cell Function ◽

The Body ◽

Islet Autoimmunity ◽

Potential Mechanism ◽

Modifiable Factors ◽

And Function

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.

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ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.012721 ◽

2020 ◽

Vol 295 (17) ◽

pp. 5685-5700

Author(s):

Irina X. Zhang ◽

Jianhua Ren ◽

Suryakiran Vadrevu ◽

Malini Raghavan ◽

Leslie S. Satin

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Beta Cell ◽

Er Stress ◽

Beta Cells ◽

Beta Cell Function ◽

Cell Function ◽

Critical Role ◽

Beta Cell Apoptosis

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

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Imaging Beta-Cell Function in the Pancreas of Non-Human Primates Using a Zinc-Sensitive MRI Contrast Agent

Frontiers in Endocrinology ◽

10.3389/fendo.2021.641722 ◽

2021 ◽

Vol 12 ◽

Author(s):

Veronica Clavijo Jordan ◽

Catherine D. G. Hines ◽

Liza T. Gantert ◽

Shubing Wang ◽

Stacey Conarello ◽

...

Keyword(s):

Beta Cell ◽

Contrast Agent ◽

Contrast Enhancement ◽

Beta Cells ◽

Beta Cell Function ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Mri Contrast Agent ◽

C Peptide

Non-invasive beta cell function measurements may provide valuable information for improving diabetes diagnostics and disease management as the integrity and function of pancreatic beta cells have been found to be compromised in Type-1 and Type-2 diabetes. Currently, available diabetes assays either lack functional information or spatial identification of beta cells. In this work, we introduce a method to assess the function of beta cells in the non-human primate pancreas non-invasively with MRI using a Gd-based zinc(II) sensor as a contrast agent, Gd-CP027. Additionally, we highlight the role of zinc(II) ions in the paracrine signaling of the endocrine pancreas via serological measurements of insulin and c-peptide. Non-human primates underwent MRI exams with simultaneous blood sampling during a Graded Glucose Infusion (GGI) with Gd-CP027 or with a non-zinc(II) sensitive contrast agent, gadofosveset. Contrast enhancement of the pancreas resulting from co-release of zinc(II) ion with insulin was observed focally when using the zinc(II)-specific agent, Gd-CP027, whereas little enhancement was detected when using gadofosveset. The contrast enhancement detected by Gd-CP027 increased in parallel with an increased dose of infused glucose. Serological measurements of C-peptide and insulin indicate that Gd-CP027, a high affinity zinc(II) contrast agent, potentiates their secretion only as a function of glucose stimulation. Taken in concert, this assay offers the possibility of detecting beta cell function in vivo non-invasively with MRI and underscores the role of zinc(II) in endocrine glucose metabolism.

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Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

Journal of Diabetes Research ◽

10.1155/2014/618652 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 23

Author(s):

Valérie Plaisance ◽

Gérard Waeber ◽

Romano Regazzi ◽

Amar Abderrahmani

Keyword(s):

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Oxidized Ldl ◽

Cell Mass ◽

Beta Cell Mass ◽

Beta Cell Proliferation ◽

Beta Cell Compensation ◽

And Function

Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

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NKX6.1 Transcription Factor: A Crucial Regulator of Pancreatic β-Cell Development, Identity, and Proliferation

10.20944/preprints202006.0277.v1 ◽

2020 ◽

Author(s):

Idil I. Aigha ◽

Essam M. Abdelalim

Keyword(s):

Transcription Factor ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Cell Function ◽

Disease Modeling ◽

Critical Role ◽

Cell Mass ◽

Cell Development ◽

Beta Cell Development

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

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NKX6.1 Transcription Factor: A Crucial Regulator of Pancreatic β-Cell Development, Identity, and Proliferation

10.20944/preprints202006.0277.v2 ◽

2020 ◽

Author(s):

Idil Aigha ◽

Essam Abdelalim

Keyword(s):

Transcription Factor ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Cell Function ◽

Disease Modeling ◽

Critical Role ◽

Cell Mass ◽

Cell Development ◽

Beta Cell Development

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

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Effects of Extra Virgin Olive Oil Polyphenols on Beta-Cell Function and Survival

Plants ◽

10.3390/plants10020286 ◽

2021 ◽

Vol 10 (2) ◽

pp. 286

Author(s):

Nicola Marrano ◽

Rosaria Spagnuolo ◽

Giuseppina Biondi ◽

Angelo Cignarelli ◽

Sebastio Perrini ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Olive Oil ◽

Beta Cells ◽

Intracellular Signaling ◽

Beta Cell Function ◽

Cell Function ◽

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Insulin Biosynthesis

Extra virgin olive oil (EVOO) is a major component of the Mediterranean diet and is appreciated worldwide because of its nutritional benefits in metabolic diseases, including type 2 diabetes (T2D). EVOO contains significant amounts of secondary metabolites, such as phenolic compounds (PCs), that may positively influence the metabolic status. In this study, we investigated for the first time the effects of several PCs on beta-cell function and survival. To this aim, INS-1E cells were exposed to 10 μM of the main EVOO PCs for up to 24 h. Under these conditions, survival, insulin biosynthesis, glucose-stimulated insulin secretion (GSIS), and intracellular signaling activation (protein kinase B (AKT) and cAMP response element-binding protein (CREB)) were evaluated. Hydroxytyrosol, tyrosol, and apigenin augmented beta-cell proliferation and insulin biosynthesis, and apigenin and luteolin enhanced the GSIS. Conversely, vanillic acid and vanillin were pro-apoptotic for beta-cells, even if they increased the GSIS. In addition, oleuropein, p-coumaric, ferulic and sinapic acids significantly worsened the GSIS. Finally, a mixture of hydroxytyrosol, tyrosol, and apigenin promoted the GSIS in human pancreatic islets. Apigenin was the most effective compound and was also able to activate beneficial intracellular signaling. In conclusion, this study shows that hydroxytyrosol, tyrosol, and apigenin foster beta-cells’ health, suggesting that EVOO or supplements enriched with these compounds may improve insulin secretion and promote glycemic control in T2D patients.

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