scholarly journals Assignment of Functional Relevance to Genes at Type 2 Diabetes-Associated Loci Through Investigation of β-Cell Mass Deficits

2016 ◽  
Vol 30 (4) ◽  
pp. 429-445 ◽  
Author(s):  
Elizabeth A. O'Hare ◽  
Laura M. Yerges-Armstrong ◽  
James A. Perry ◽  
Alan R. Shuldiner ◽  
Norann A. Zaghloul
Keyword(s):  
Type 2 Diabetes ◽  
Candidate Genes ◽  
Age Of Onset ◽  
Cell Mass ◽  
Transgenic Zebrafish ◽  
Potential Contribution ◽  
Β Cells ◽  
Β Cell ◽  
Multiple Genes

Type 2 diabetes (T2D) has been associated with a large number of genomic loci, many of which encompass multiple genes without a definitive causal gene. This complexity has hindered efforts to clearly identify functional candidate genes and interpret their role in mediating susceptibility to disease. Here we examined the relevance of individual genes found at T2D-associated loci by assessing their potential contribution to a phenotype relevant to the disease state: production and maintenance of β-cell mass. Using transgenic zebrafish in which β-cell mass could be rapidly visualized in vivo, we systematically suppressed the expression of orthologs of genes found at T2D-associated genomic loci. Overall, we tested 67 orthologs, many of which had no known relevance to β-cell mass, at 62 human T2D-associated loci, including eight loci with multiple candidate genes. In total we identified 25 genes that were necessary for proper β-cell mass, providing functional evidence for their role in a physiological phenotype directly related to T2D. Of these, 16 had not previously been implicated in the regulation of β-cell mass. Strikingly, we identified single functional candidate genes at the majority of the loci for which multiple genes were analyzed. Further investigation into the contribution of the 25 genes to the adaptive capacity of β-cells suggested that the majority of genes were not required for glucose-induced expansion of β-cell mass but were significantly necessary for the regeneration of β-cells. These findings suggest that genetically programmed deficiencies in β-cell mass may be related to impaired maintenance. Finally, we investigated the relevance of our findings to human T2D onset in diabetic individuals from the Old Order Amish and found that risk alleles in β-cell mass genes were associated with significantly younger age of onset and lower body mass index. Taken together, our study offers a functional approach to assign relevance to genes at T2D-associated loci and offers experimental evidence for the defining role of β-cell mass maintenance in genetic susceptibility to T2D onset.

scholarly journals A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
Author(s):  
Xiao-Ting Huang ◽  
Shao-Jie Yue ◽  
Chen Li ◽  
Yan-Hong Huang ◽  
Qing-Mei Cheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Stimulation Of ◽  
Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

Arachidonic acid fights palmitate: new insights into fatty acid toxicity in β-cells

2010 ◽  
Vol 120 (5) ◽  
pp. 179-181 ◽  
Author(s):  
Henrik Ortsäter
Keyword(s):  
Type 2 Diabetes ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Saturated Fatty Acids ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Self Protection

Saturated fatty acids are toxic to pancreatic β-cells. By inducing apoptosis, they contribute to a decrease in β-cell mass, a hallmark of Type 2 diabetes. In the present issue of Clinical Science, Keane and co-workers show that the polyunsaturated fatty acid arachidonic acid protects the β-cell against the toxic effects of palmitate. As Type 2 diabetes is characterized by subclinical inflammation, and arachidonic acid and metabolites thereof are produced during states of inflammation, it is possible that pancreatic β-cells use arachidonic acid as a compound for self-protection.

scholarly journals Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

2020 ◽  
Vol 21 (5) ◽  
pp. 1770
Author(s):  
Nadia Rachdaoui
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Insulin Resistance

Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

scholarly journals Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

2014 ◽  
Vol 221 (1) ◽  
pp. T43-T61 ◽  
Author(s):  
Benjamin J Lamont ◽  
Sofianos Andrikopoulos
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Preclinical Studies ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors ◽  
Natural Progression ◽  
Glucagon Like Peptide 1

Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet β-cells and an increase in β-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase β-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic β-cells, but may be useful for preserving any remaining β-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

β-Cell compensation concomitant with adaptive endoplasmic reticulum stress and β-cell neogenesis in a diet-induced type 2 diabetes model

2019 ◽  
Vol 44 (12) ◽  
pp. 1355-1366 ◽  
Author(s):  
Hui Huang ◽  
Kaiyuan Yang ◽  
Rennian Wang ◽  
Woo Hyun Han ◽  
Sharee Kuny ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Temporal Association ◽  
Adaptive Responses ◽  
Β Cells ◽  
Β Cell

Insulin-secreting pancreatic β-cells adapt to obesity-related insulin resistance via increases in insulin secretion and β-cell mass. Failed β-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of β-cell compensation are not fully understood. Our previous study reported changes in β-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other β-cell adaptive responses, including glucose metabolism and β-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of β-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in β-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative β-cell growth as a mechanism of β-cell mass adaptation. In contrast, decreased neogenesis and β-cell dedifferentiation were observed in β-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of β-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for β-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. β-Cell neogenesis but not proliferation contributes to β-cell mass adaptation.

scholarly journals Offspring of Mice Exposed to a Low-Protein Diet in Utero Demonstrate Changes in mTOR Signaling in Pancreatic Islets of Langerhans, Associated with Altered Glucagon and Insulin Expression and a Lower β-Cell Mass

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 605 ◽  
Author(s):  
Renee King ◽  
Jessica Hill ◽  
Bibek Saha ◽  
Yuzhen Tong ◽  
Brenda Strutt ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
In Utero ◽  
Mtor Signaling ◽  
Mrna Levels ◽  
Β Cells ◽  
Β Cell ◽  
Low Protein ◽  
Glucagon And Insulin

Low birth weight is a risk factor for gestational and type 2 diabetes (T2D). Since mammalian target of rapamycin (mTOR) controls pancreatic β-cell mass and hormone release, we hypothesized that nutritional insult in utero might permanently alter mTOR signaling. Mice were fed a low-protein (LP, 8%) or control (C, 20%) diet throughout pregnancy, and offspring examined until 130 days age. Mice receiving LP were born 12% smaller and β-cell mass was significantly reduced throughout life. Islet mTOR levels were lower in LP-exposed mice and localized predominantly to α-rather than β-cells. Incubation of isolated mouse islets with rapamycin significantly reduced cell proliferation while increasing apoptosis. mRNA levels for mTORC complex genes mTOR, Rictor and Raptor were elevated at 7 days in LP mice, as were the mTOR and Raptor proteins. Proglucagon gene expression was similarly increased, but not insulin or the immune/metabolic defense protein STING. In human and mouse pancreas STING was strongly associated with islet β-cells. Results support long-term changes in islet mTOR signaling in response to nutritional insult in utero, with altered expression of glucagon and insulin and a reduced β-cell mass. This may contribute to an increased risk of gestational or type 2 diabetes.

scholarly journals Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion

2015 ◽  
Vol 112 (9) ◽  
pp. 2888-2893 ◽  
Author(s):  
Miles Berger ◽  
David W. Scheel ◽  
Hector Macias ◽  
Takeshi Miyatsuka ◽  
Hail Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Perinatal Period ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Gpcr Signaling

Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

scholarly journals DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

2012 ◽  
Vol 49 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Shinobu Shimizu ◽  
Tetsuya Hosooka ◽  
Tomokazu Matsuda ◽  
Shun-ichiro Asahara ◽  
Maki Koyanagi-Kimura ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Serum Concentration ◽  
Er Stress ◽  
Cell Mass ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4

The development of type 2 diabetes is accompanied by a progressive decline in β-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on β cells was studied in diabetic mice. Diabetic pancreatic β cell-specific C/EBPB transgenic (TG) mice exhibit decreased β-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on β cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased β-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in β cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in β cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic β cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.

scholarly journals A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

2007 ◽  
Vol 40 (2) ◽  
pp. 37-45 ◽  
Author(s):  
Thierry Brun ◽  
Benoit R Gauthier
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Pancreatic Islet ◽  
Cell Expansion ◽  
Cell Mass ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell

Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet β- and α-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet β-cells. Autoimmune destruction of β-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of β-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs β-cell mass plasticity may provide a means to develop strategies to countera,ct β-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the β-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature β-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet β-cell physiology and its contribution to pathophysiology when deregulated.

scholarly journals PANCREATIC AND EXTRA-PANCREATIC EFFECTS OF INCRETINS AND PERSPECTIVES FOR STUDYING ENTEROINSULIN HORMONAL SYSTEM DURING GESTATIONAL DISORDER OF CARBOHYDRATE METABOLISM

2013 ◽  
Vol 12 (3) ◽  
pp. 132-147
Author(s):  
T. V. Saprina ◽  
Ye. S. Timokhina ◽  
N. N. Musina ◽  
T. S. Prokhorenko ◽  
L. A. Tashireva ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Carbohydrate Metabolism ◽  
Negative Impact ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Hormonal System ◽  
Glucagon Like Peptide 1 ◽  
The Brain

The absence of an ideal medicine for the treatment of patients with type 2 diabetes, that would be able to provide not only high quality and constant monitoring of glycemia without increasing body weight, with no risk of hypoglycemia, with no negative impact on the heart, kidneys, liver, but could also ensure the preservation of the secretory function of β-cells, makes scientists continue to search for new opportunities to influence the occurrence and progression of T2D.Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β-cells. Within the pancreas, GIP and GLP-1 together promote β-cell proliferation and inhibit apoptosis, thereby expanding pancreatic β-cell mass, while GIP enhances postprandial glucagon response and GLP-1 suppresses it. In adipose tissues, GIP but not GLP-1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP-1 inhibits bone absorption. In the brain, both GIP and GLP-1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP-1 and their insulinotropic effects on β-cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects.Enteroinsulin hormones' role in the development of gestational disorder of carbohydrate metabolism is poorly understood.In a review article we analyze the publications that summarize what is known about the pancreatic and extra-pancreatic GIP and GLP-1-effects compared with healthy subjects and type 2 diabetes patients. The aspects of gestational diabetes pathophysiology and the perspectives for studying enteroinsulin hormonal system during pregnancy are also discussed in the article.

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