scholarly journals The role of adipokines in β-cell failure of type 2 diabetes

2012 ◽  
Vol 216 (1) ◽  
pp. T37-T45 ◽  
Author(s):  
Simon J Dunmore ◽  
James E P Brown
Keyword(s):  
Type 2 Diabetes ◽  
Β Cells ◽  
Β Cell ◽  
Beneficial Effects ◽  
Published Evidence ◽  
Key Factor ◽  
Excessive Adiposity ◽  
Factor Α

β-Cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review, we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of β-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, tumour necrosis factor α, resistin, visfatin, dipeptidyl peptidase IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to β-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines, which act on the β-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on β-cells.

scholarly journals The pathogenetic role of β-cell mitochondria in type 2 diabetes

2018 ◽  
Vol 236 (3) ◽  
pp. R145-R159 ◽  
Author(s):  
Malin Fex ◽  
Lisa M Nicholas ◽  
Neelanjan Vishnu ◽  
Anya Medina ◽  
Vladimir V Sharoyko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Dysfunction ◽  
Translational Regulation ◽  
Cell Function ◽  
Rare Condition ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.

scholarly journals m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β Cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Yanqiu Wang ◽  
Jiajun Sun ◽  
Zhen Lin ◽  
Weizhen Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Rna Modification ◽  
Β Cells ◽  
Β Cell ◽  
Functional Maturation ◽  
Mass Expansion ◽  
Endocrine Progenitors

<a>m<sup>6</sup>A RNA modification is essential during embryonic development of various organs; however, its role in embryonic and early postnatal islet development remains unknown.</a><a></a><a> </a>Mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3<sup>+</sup> endocrine progenitors (<i>Mettl3/14<sup>nKO</sup></i>) developed hyperglycemia and hypo-insulinemia at 2 weeks after birth. <a></a><a>We found that Mettl3/14 specifically regulated both functional maturation and mass expansion of neonatal</a><a></a><a> β cell</a>s before weaning. Transcriptome and m<sup>6</sup>A methylome analyses provided m<sup>6</sup>A-dependent mechanisms in regulating<a> cell</a> identity, insulin secretion and proliferation in neonatal<a></a><a> </a><a></a><a>β</a> cells.<a></a><a> Importantly, we found that Mettl3/14 were dispensable for β cell differentiation, but directly regulated essential transcriptional factor MafA expression</a><a> at least partially via modulating its mRNA stability and failure to maintain this modification impacted the ability to fulfill β cell functional maturity. </a>In both diabetic <i>db/db</i> mice and type 2 diabetes patients, decreased Mettl3/14 expression in <a></a><a>β</a> cells were observed, suggesting its possible role in type 2 diabetes. Our stud­­­­­­<sub>­­­</sub>y unraveled the essential role of Mettl3/14 in neonatal β cell development and functional maturation, both of which determined functional β cell mass and glycemic control in adulthood.<b></b>

scholarly journals m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β Cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Yanqiu Wang ◽  
Jiajun Sun ◽  
Zhen Lin ◽  
Weizhen Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Rna Modification ◽  
Β Cells ◽  
Β Cell ◽  
Functional Maturation ◽  
Mass Expansion ◽  
Endocrine Progenitors

<a>m<sup>6</sup>A RNA modification is essential during embryonic development of various organs; however, its role in embryonic and early postnatal islet development remains unknown.</a><a></a><a> </a>Mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3<sup>+</sup> endocrine progenitors (<i>Mettl3/14<sup>nKO</sup></i>) developed hyperglycemia and hypo-insulinemia at 2 weeks after birth. <a></a><a>We found that Mettl3/14 specifically regulated both functional maturation and mass expansion of neonatal</a><a></a><a> β cell</a>s before weaning. Transcriptome and m<sup>6</sup>A methylome analyses provided m<sup>6</sup>A-dependent mechanisms in regulating<a> cell</a> identity, insulin secretion and proliferation in neonatal<a></a><a> </a><a></a><a>β</a> cells.<a></a><a> Importantly, we found that Mettl3/14 were dispensable for β cell differentiation, but directly regulated essential transcriptional factor MafA expression</a><a> at least partially via modulating its mRNA stability and failure to maintain this modification impacted the ability to fulfill β cell functional maturity. </a>In both diabetic <i>db/db</i> mice and type 2 diabetes patients, decreased Mettl3/14 expression in <a></a><a>β</a> cells were observed, suggesting its possible role in type 2 diabetes. Our stud­­­­­­<sub>­­­</sub>y unraveled the essential role of Mettl3/14 in neonatal β cell development and functional maturation, both of which determined functional β cell mass and glycemic control in adulthood.<b></b>

The role of vitamin D in the development of type 2 diabetes

2021 ◽  
Vol 19 (1) ◽  
pp. 44-52
Author(s):  
A.P. Shumilov ◽  
◽  
M.Yu. Semchenkova ◽  
D.S. Mikhalik ◽  
T.G. Avdeeva ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Vitamin D ◽  
Inverse Relationship ◽  
Biological Mechanisms ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Vitamin D Levels

Vitamin D plays an important role in decreasing the risk of developing type 2 diabetes by influencing calcium metabolism, thereby reducing β-cell dysfunction and preventing insulin resistance. The findings of research works are contradictory enough, although some of them demonstrated an inverse relationship between vitamin D levels and the incidence of type 2 diabetes. The article describes the biological mechanisms of relationships between vitamin D levels and type 2 diabetes, reviews the results of the studies conducted and summarizes the available data. Key words: vitamin D, type 2 diabetes mellitus, insulin resistance

scholarly journals Increased vimentin in human α- and β-cells in type 2 diabetes

2017 ◽  
Vol 233 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Maaike M Roefs ◽  
Françoise Carlotti ◽  
Katherine Jones ◽  
Hannah Wills ◽  
Alexander Hamilton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epithelial To Mesenchymal Transition ◽  
Islet Cells ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

scholarly journals RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

2021 ◽  
Author(s):  
John T Walker ◽  
Diane C Saunders ◽  
Vivek Rai ◽  
Chunhua Dai ◽  
Peter Orchard ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Association Studies ◽  
Critical Role ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Β Cells ◽  
Β Cell ◽  
Gene Regulatory

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

scholarly journals Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3328
Author(s):  
Eloisa Aparecida Vilas-Boas ◽  
Davidson Correa Almeida ◽  
Leticia Prates Roma ◽  
Fernanda Ortis ◽  
Angelo Rafael Carpinelli
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Nadph Oxidase ◽  
Er Stress ◽  
Cell Function ◽  
Caloric Intake ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

scholarly journals An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2475
Author(s):  
Melvin R. Hayden
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cell Injury ◽  
Light And Electron Microscopy ◽  
Β Cell ◽  
Cell Dysfunction

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by the WHO on 19 March 2020. This pandemic is associated with markedly elevated blood glucose levels and a remarkable degree of insulin resistance, which suggests pancreatic islet β-cell dysfunction or apoptosis and insulin’s inability to dispose of glucose into cellular tissues. Diabetes is known to be one of the top pre-existing co-morbidities associated with the severity of COVID-19 along with hypertension, cardiocerebrovascular disease, advanced age, male gender, and recently obesity. This review focuses on how COVID-19 may be responsible for the accelerated development of type 2 diabetes mellitus (T2DM) as one of its acute and suspected long-term complications. These observations implicate an active role of metabolic syndrome, systemic and tissue islet renin–angiotensin–aldosterone system, redox stress, inflammation, islet fibrosis, amyloid deposition along with β-cell dysfunction and apoptosis in those who develop T2DM. Utilizing light and electron microscopy in preclinical rodent models and human islets may help to better understand how COVID-19 accelerates islet and β-cell injury and remodeling to result in the long-term complications of T2DM.

scholarly journals Role of Sodium-Glucose Cotransporter 2 (SGLT 2) Inhibitors in the Treatment of Type 2 Diabetes

2011 ◽  
Vol 32 (4) ◽  
pp. 515-531 ◽  
Author(s):  
Muhammad A. Abdul-Ghani ◽  
Luke Norton ◽  
Ralph A. DeFronzo
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Microvascular Complications ◽  
Tight Glycemic Control ◽  
Β Cell ◽  
Oral Antidiabetic Agents ◽  
Oral Antidiabetic ◽  
Sodium Glucose Cotransporter

Hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus, i.e., glucotoxicity, and it also is the major risk factor for microvascular complications. Thus, effective glycemic control will not only reduce the incidence of microvascular complications but also correct some of the metabolic abnormalities that contribute to the progression of the disease. Achieving durable tight glycemic control is challenging because of progressive β-cell failure and is hampered by increased frequency of side effects, e.g., hypoglycemia and weight gain. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to produce glucosuria and reduce the plasma glucose concentration. These oral antidiabetic agents have the potential to improve glycemic control while avoiding hypoglycemia, to correct the glucotoxicity, and to promote weight loss. In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach.

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