Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Fate of Pancreatic Islets in Type 2 Diabetes

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Related Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 September 2022) | Viewed by 41664

Share This Special Issue

Special Issue Editors

Dr. Shunichiro Asahara

E-Mail Website
Guest Editor

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Interests: diabetes; endocrinology; beta cell viability; insulin signaling; mTORC1; exosome
Special Issues, Collections and Topics in MDPI journals

Dr. Katsuya Tanabe

E-Mail Website
Guest Editor

Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan
Interests: diabetes; insulin; islet; beta cell; cellular plasticity; dedifferentiation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the development of type 2 diabetes, the function and volume of pancreatic β-cells has been known as important factors. In particular, pancreatic β-cell mass is regulated by various factors. Recent studies revealed that dedifferentiation is associated with the regulation of pancreatic β-cell mass in addition to proliferation and apoptosis. This Special Issue of IJMS is focused on the molecular mechanisms of pancreatic β-cell fate, and aims to discuss underlying the mechanisms and downstream pathways involved in the pathogenesis of pancreatic β-cell failure. We welcome unique and creative basic research on the mechanisms of proliferation, apoptosis, transdifferentiation, neogenesis, and dedifferentiation of pancreatic β-cells. We look forward to your contributions.

Dr. Shunichiro Asahara
Dr. Katsuya Tanabe
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pancreatic β-cell
dedifferentiation
apoptosis
proliferation
neogenesis

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Related Special Issue

Fate of Pancreatic Islets in Type 2 Diabetes—2nd Edition in International Journal of Molecular Sciences

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

20 pages, 5057 KiB

Open AccessArticle

PIMT Controls Insulin Synthesis and Secretion through PDX1

by Rahul Sharma, Sujay K. Maity, Partha Chakrabarti, Madhumohan R. Katika, Satyamoorthy Kapettu, Kishore V. L. Parsa and Parimal Misra

Int. J. Mol. Sci. 2023, 24(9), 8084; https://doi.org/10.3390/ijms24098084 - 29 Apr 2023

Cited by 2 | Viewed by 3514

Abstract

Pancreatic beta cell function is an important component of glucose homeostasis. Here, we investigated the function of PIMT (PRIP-interacting protein with methyl transferase domain), a transcriptional co-activator binding protein, in the pancreatic beta cells. We observed that the protein levels of PIMT, along with key beta cell markers such as PDX1 (pancreatic and duodenal homeobox 1) and MafA (MAF bZIP transcription factor A), were reduced in the beta cells exposed to hyperglycemic and hyperlipidemic conditions. Consistently, PIMT levels were reduced in the pancreatic islets isolated from high fat diet (HFD)-fed mice. The RNA sequencing analysis of PIMT knockdown beta cells identified that the expression of key genes involved in insulin secretory pathway, Ins1 (insulin 1), Ins2 (insulin 2), Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Kcnn1 (potassium calcium-activated channel subfamily N member 1), Rab3a (member RAS oncogene family), Gnas (GNAS complex locus), Syt13 (synaptotagmin 13), Pax6 (paired box 6), Klf11 (Kruppel-Like Factor 11), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1) was attenuated due to PIMT depletion. PIMT ablation in the pancreatic beta cells and in the rat pancreatic islets led to decreased protein levels of PDX1 and MafA, resulting in the reduction in glucose-stimulated insulin secretion (GSIS). The results from the immunoprecipitation and ChIP experiments revealed the interaction of PIMT with PDX1 and MafA, and its recruitment to the insulin promoter, respectively. Importantly, PIMT ablation in beta cells resulted in the nuclear translocation of insulin. Surprisingly, forced expression of PIMT in beta cells abrogated GSIS, while Ins1 and Ins2 transcript levels were subtly enhanced. On the other hand, the expression of genes, PRIP/Asc2/Ncoa6 (nuclear receptor coactivator 6), Pax6, Kcnj11, Syt13, Stxbp1 (syntaxin binding protein 1), and Snap25 (synaptosome associated protein 25) associated with insulin secretion, was significantly reduced, providing an explanation for the decreased GSIS upon PIMT overexpression. Our findings highlight the importance of PIMT in the regulation of insulin synthesis and secretion in beta cells. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

18 pages, 4960 KiB

Open AccessArticle

Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells

by Yuko Nagao, Kikuko Amo-Shiinoki, Hiroko Nakabayashi, Masayuki Hatanaka, Manabu Kondo, Kimie Matsunaga, Masahiro Emoto, Shigeru Okuya, Yukio Tanizawa and Katsuya Tanabe

Int. J. Mol. Sci. 2022, 23(21), 13586; https://doi.org/10.3390/ijms232113586 - 5 Nov 2022

Cited by 5 | Viewed by 3992

Abstract

Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3β. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with βTrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2α, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent β-cell death under ER stress conditions. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

13 pages, 10273 KiB

Open AccessArticle

Protein Kinase C (Pkc)-δ Mediates Arginine-Induced Glucagon Secretion in Pancreatic α-Cells

by Norikiyo Honzawa, Kei Fujimoto, Masaki Kobayashi, Daisuke Kohno, Osamu Kikuchi, Hiromi Yokota-Hashimoto, Eri Wada, Yuichi Ikeuchi, Yoko Tabei, Gerald W. Dorn II, Kazunori Utsunomiya, Rimei Nishimura and Tadahiro Kitamura

Int. J. Mol. Sci. 2022, 23(7), 4003; https://doi.org/10.3390/ijms23074003 - 4 Apr 2022

Cited by 3 | Viewed by 2848

Abstract

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine–threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr⁵⁰⁵, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 867 KiB

Open AccessReview

The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome

by Shuntaro Morikawa and Fumihiko Urano

Int. J. Mol. Sci. 2023, 24(1), 230; https://doi.org/10.3390/ijms24010230 - 23 Dec 2022

Cited by 12 | Viewed by 3721

Abstract

The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of “poorly folded proteins”, namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

15 pages, 1221 KiB

Open AccessReview

Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting

by Suma Elumalai, Udayakumar Karunakaran, Jun-Sung Moon and Kyu-Chang Won

Int. J. Mol. Sci. 2022, 23(22), 13679; https://doi.org/10.3390/ijms232213679 - 8 Nov 2022

Cited by 3 | Viewed by 2394

Abstract

Metabolic stress impairs pancreatic β-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and β-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in β-cells. The vulnerability of β-cells to oxidative damage caused by iron accumulation has been linked to contributory β-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic β-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by β-cell failure. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

11 pages, 1084 KiB

Open AccessReview

Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Pancreatic β-Cell Mass and Function

by Akinobu Nakamura

Int. J. Mol. Sci. 2022, 23(9), 5104; https://doi.org/10.3390/ijms23095104 - 4 May 2022

Cited by 9 | Viewed by 2724

Abstract

Sodium-glucose co-transporter-2 inhibitors (SGLT2is) not only have antihyperglycemic effects and are associated with a low risk of hypoglycemia but also have protective effects in organs, including the heart and kidneys. The pathophysiology of diabetes involves chronic hyperglycemia, which causes excessive demands on pancreatic β-cells, ultimately leading to decreases in β-cell mass and function. Because SGLT2is ameliorate hyperglycemia without acting directly on β-cells, they are thought to prevent β-cell failure by reducing glucose overload in this cell type. Several studies have shown that treatment with an SGLT2i increases β-cell proliferation and/or reduces β-cell apoptosis, resulting in the preservation of β-cell mass in animal models of diabetes. In addition, many clinical trials have shown that that SGLT2is improve β-cell function in individuals with type 2 diabetes. In this review, the preclinical and clinical data regarding the effects of SGLT2is on pancreatic β-cell mass and function are summarized and the protective effect of SGLT2is in β-cells is discussed. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

19 pages, 693 KiB

Open AccessReview

Stem Cell-Derived Islets for Type 2 Diabetes

by Andrew Salib, Fritz Cayabyab and Eiji Yoshihara

Int. J. Mol. Sci. 2022, 23(9), 5099; https://doi.org/10.3390/ijms23095099 - 4 May 2022

Cited by 8 | Viewed by 4619

Abstract

Since the discovery of insulin a century ago, insulin injection has been a primary treatment for both type 1 (T1D) and type 2 diabetes (T2D). T2D is a complicated disea se that is triggered by the dysfunction of insulin-producing β cells and insulin resistance in peripheral tissues. Insulin injection partially compensates for the role of endogenous insulin which promotes glucose uptake, lipid synthesis and organ growth. However, lacking the continuous, rapid, and accurate glucose regulation by endogenous functional β cells, the current insulin injection therapy is unable to treat the root causes of the disease. Thus, new technologies such as human pluripotent stem cell (hPSC)-derived islets are needed for both identifying the key molecular and genetic causes of T2D and for achieving a long-term treatment. This perspective review will provide insight into the efficacy of hPSC-derived human islets for treating and understanding T2D. We discuss the evidence that β cells should be the primary target for T2D treatment, the use of stem cells for the modeling of T2D and the potential use of hPSC-derived islet transplantation for treating T2D. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

14 pages, 345 KiB

Open AccessReview

Role of the Transcription Factor MAFA in the Maintenance of Pancreatic β-Cells

by Wataru Nishimura, Hiroaki Iwasa and Munkhtuya Tumurkhuu

Int. J. Mol. Sci. 2022, 23(9), 4478; https://doi.org/10.3390/ijms23094478 - 19 Apr 2022

Cited by 18 | Viewed by 3853

Abstract

Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

16 pages, 772 KiB

Open AccessReview

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

by Yasutaka Miyachi, Takashi Miyazawa and Yoshihiro Ogawa

Int. J. Mol. Sci. 2022, 23(6), 3222; https://doi.org/10.3390/ijms23063222 - 16 Mar 2022

Cited by 25 | Viewed by 7833

Abstract

Understanding the genetic factors of diabetes is essential for addressing the global increase in type 2 diabetes. HNF1A mutations cause a monogenic form of diabetes called maturity-onset diabetes of the young (MODY), and HNF1A single-nucleotide polymorphisms are associated with the development of type 2 diabetes. Numerous studies have been conducted, mainly using genetically modified mice, to explore the molecular basis for the development of diabetes caused by HNF1A mutations, and to reveal the roles of HNF1A in multiple organs, including insulin secretion from pancreatic beta cells, lipid metabolism and protein synthesis in the liver, and urinary glucose reabsorption in the kidneys. Recent studies using human stem cells that mimic MODY have provided new insights into beta cell dysfunction. In this article, we discuss the involvement of HNF1A in beta cell dysfunction by reviewing previous studies using genetically modified mice and recent findings in human stem cell-derived beta cells. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Figure 1

31 pages, 1743 KiB

Open AccessReview

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

by Alberto Bartolomé

Int. J. Mol. Sci. 2022, 23(1), 501; https://doi.org/10.3390/ijms23010501 - 2 Jan 2022

Cited by 4 | Viewed by 4133

Abstract

Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research. Full article

(This article belongs to the Special Issue Fate of Pancreatic Islets in Type 2 Diabetes)

► Show Figures

Journal Menu

Journal Browser

Fate of Pancreatic Islets in Type 2 Diabetes

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI