Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.

Download Full-text

Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

Mediators of Inflammation ◽

10.1155/2013/750540 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 14

Author(s):

Alessandra Puddu ◽

Roberta Sanguineti ◽

François Mach ◽

Franco Dallegri ◽

Giorgio Luciano Viviani ◽

...

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Beta Cell Dysfunction ◽

Molecular Pathways ◽

Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

Download Full-text

JOE DOUPE LECTURE: Emerging Strategies for the Preservation of Pancreatic Beta-cell Function in early Type 2 Diabetes

Clinical & Investigative Medicine ◽

10.25011/cim.v37i6.22247 ◽

2014 ◽

Vol 37 (6) ◽

pp. 414 ◽

Cited By ~ 4

Author(s):

Ravi Retnakaran

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Fundamental Problem ◽

Pancreatic Beta Cell ◽

Beta Cell Dysfunction ◽

Cell Dysfunction ◽

Pancreatic Beta Cell Function

A fundamental problem in the clinical management of type 2 diabetes is the inability to prevent the ongoing deterioration of pancreatic beta-cell function over time that underlies the chronic progressive nature of this condition. Importantly, beta-cell dysfunction has both reversible and irreversible components. Furthermore, the amelioration of reversible beta-cell dysfunction through the early institution of short-term insulin-based therapy has emerged as a strategy that can yield temporary remission of type 2 diabetes. In this context, we have forwarded a novel therapeutic paradigm consisting of initial induction therapy to improve beta-cell function early in the course of diabetes followed by maintenance therapy aimed at preserving this beneficial beta-cell effect. Ultimately, this approach may yield an optimized therapeutic strategy for the durable preservation of beta-cell function and consequent modification of the natural history of type 2 diabetes.

Download Full-text

The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

Journal of Population Therapeutics and Clinical Pharmacology ◽

10.15586/jptcp.v27isp2.744 ◽

2020 ◽

Vol 27 (SP2) ◽

pp. e22-e38

Author(s):

Maximilian Andreas Storz

Keyword(s):

Type 2 Diabetes ◽

Fatty Acids ◽

Fatty Acid ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Cell Function ◽

Beta Cell Dysfunction ◽

Cell Dysfunction

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood. The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function. Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction. Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels. All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

Download Full-text

GLIS3 binds pancreatic beta cell regulatory regions alongside other islet transcription factors

Journal of Endocrinology ◽

10.1530/joe-19-0182 ◽

2019 ◽

Vol 243 (1) ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

David W Scoville ◽

Kristin Lichti-Kaiser ◽

Sara A Grimm ◽

Anton M Jetten

Keyword(s):

Transcription Factors ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Critical Role ◽

Regulatory Regions ◽

Insulin Expression

The Krüppel-like zinc finger transcription factor Gli-similar 3 (GLIS3) plays a critical role in the regulation of pancreatic beta cells, with global Glis3-knockout mice suffering from severe hyperglycemia and dying by post-natal day 11. In addition, GLIS3 has been shown to directly regulate the early endocrine marker Ngn3, as well as Ins2 gene expression in mature beta cells. We hypothesize that GLIS3 regulates several other genes critical to beta cell function, in addition to Ins2, by directly binding to regulatory regions. We therefore generated a pancreas-specific Glis3 deletion mouse model (Glis3Δ panc ) using a Pdx1-driven Cre mouse line. Roughly 20% of these mice develop hyperglycemia by 8 weeks and lose most of their insulin expression. However, this did not appear to be due to loss of the beta cells themselves, as no change in cell death was observed. Indeed, presumptive beta cells appeared to persist as PDX1+/INS−/MAFA−/GLUT2− cells. Islet RNA-seq analysis combined with GLIS3 ChIP-seq analysis revealed apparent direct regulation of a variety of diabetes-related genes, including Slc2a2 and Mafa. GLIS3 binding near these genes coincided with binding for other islet-enriched transcription factors, indicating these are distinct regulatory hubs. Our data indicate that GLIS3 regulates not only insulin expression, but also several additional genes critical for beta cell function.

Download Full-text

Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

Journal of Biological Chemistry ◽

10.1074/jbc.m116.748335 ◽

2017 ◽

Vol 292 (8) ◽

pp. 3466-3480 ◽

Cited By ~ 24

Author(s):

Jonàs Juan-Mateu ◽

Tatiana H. Rech ◽

Olatz Villate ◽

Esther Lizarraga-Mollinedo ◽

Anna Wendt ◽

...

Keyword(s):

Alternative Splicing ◽

Beta Cell ◽

Beta Cells ◽

Insulin Release ◽

Beta Cell Function ◽

Rna Binding ◽

Cell Function ◽

Rna Binding Proteins ◽

Pancreatic Beta Cell ◽

Splicing Regulators

Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuron-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function, and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain, and other human tissues, and we identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1, and Rbfox2, were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, whereas silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival, and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.

Download Full-text

AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet

Journal of Endocrinology ◽

10.1530/joe-18-0287 ◽

2019 ◽

Vol 240 (2) ◽

pp. 123-132 ◽

Cited By ~ 4

Author(s):

Niels L Mulder ◽

Rick Havinga ◽

Joost Kluiver ◽

Albert K Groen ◽

Janine K Kruit

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Gene Transfer ◽

Beta Cell ◽

Beta Cells ◽

High Fat Diet ◽

Beta Cell Function ◽

Cell Function ◽

Beta Cell Proliferation ◽

High Fat

MicroRNAs have emerged as essential regulators of beta cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta cell function in vivo. To overexpress miR-132 specifically in beta cells, we employed adeno-associated virus (AAV8)-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow-fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet-fed mice. Furthermore, miR-132 overexpression increased beta cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta cells improves beta cell function in mice in response to a high-fat diet. This suggests that increased miR-132 expression is beneficial for beta cell function during hyperglycemia and obesity.

Download Full-text

Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells

Biomolecules ◽

10.3390/biom11101474 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1474

Author(s):

Shiau-Mei Chen ◽

Siow-Wey Hee ◽

Shih-Yun Chou ◽

Meng-Wei Liu ◽

Che-Hong Chen ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cells ◽

Aldehyde Dehydrogenase ◽

Mitochondrial Function ◽

Beta Cell Function ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Aldehyde Dehydrogenase 2 ◽

Min6 Cells

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.

Download Full-text

Arginase 2 and Polyamines in Human Pancreatic Beta Cells: Possible Role in the Pathogenesis of Type 2 Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms222212099 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12099

Author(s):

Lorella Marselli ◽

Emanuele Bosi ◽

Carmela De Luca ◽

Silvia Del Guerra ◽

Marta Tesi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Pancreas Development ◽

Tissue Specific

Arginase 2 (ARG2) is a manganese metalloenzyme involved in several tissue specific processes, from physiology to pathophysiology. It is variably expressed in extra-hepatic tissues and is located in the mitochondria. In human pancreatic beta cells, ARG2 is downregulated in type 2 diabetes. The enzyme regulates the synthesis of polyamines, that are involved in pancreas development and regulation of beta cell function. Here, we discuss several features of ARG2 and polyamines, which can be relevant to the pathophysiology of type 2 diabetes.

Download Full-text

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.

Download Full-text