scholarly journals The Phosphatase PHLPP2 Plays a Key Role in the Regulation of Pancreatic Beta-Cell Survival

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Marta Letizia Hribal ◽  
Elettra Mancuso ◽  
Gaetano Paride Arcidiacono ◽  
Annalisa Greco ◽  
Donatella Musca ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Cell Survival ◽  
High Glucose ◽  
Chronic Exposure ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Pleckstrin Homology Domain ◽  
Causative Role

Currently available antidiabetic treatments fail to halt, and may even exacerbate, pancreatic β-cell exhaustion, a key feature of type 2 diabetes pathogenesis; thus, strategies to prevent, or reverse, β-cell failure should be actively sought. The serine threonine kinase Akt has a key role in the regulation of β-cell homeostasis; among Akt modulators, a central role is played by pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) family. Here, taking advantage of an in vitro model of chronic exposure to high glucose, we demonstrated that PHLPPs, particularly the second family member called PHLPP2, are implicated in the ability of pancreatic β cells to deal with glucose toxicity. We observed that INS-1 rat pancreatic β cell line maintained for 12–15 passages at high (30 mM) glucose concentrations (INS-1 HG) showed increased expression of PHLPP2 and PHLPP1 both at mRNA and protein level as compared to INS-1 maintained for the same number of passages in the presence of normal glucose levels (INS-1 NG). These changes were paralleled by decreased phosphorylation of Akt and by increased expression of apoptotic and autophagic markers. To investigate if PHLPPs had a casual role in the alteration of INS-1 homeostasis observed upon chronic exposure to high glucose concentrations, we took advantage of shRNA technology to specifically knock-down PHLPPs. We obtained proof-of-concept evidence that modulating PHLPPs expression may help to restore a healthy β cell mass, as the reduced expression of PHLPP2/1 was accompanied by a recovered balance between pro- and antiapoptotic factor levels. In conclusion, our data provide initial support for future studies aimed to identify pharmacological PHLPPs modulator to treat beta-cell survival impairment. They also contribute to shed some light on β-cell dysfunction, a complex and unsatisfactorily characterized phenomenon that has a central causative role in the pathogenesis of type 2 diabetes.

scholarly journals The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

2015 ◽  
Vol 21 (6) ◽  
pp. 619-627 ◽  
Author(s):  
Bengt-Frederik Belgardt ◽  
Kashan Ahmed ◽  
Martina Spranger ◽  
Mathieu Latreille ◽  
Remy Denzler ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Cell Survival ◽  
Pancreatic Beta Cell

The Incretin System and Type 2 Diabetes

2009 ◽  
Vol 05 (01) ◽  
pp. 57 ◽  
Author(s):  
Anthony H Barnett ◽  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Pancreatic Islet Cell ◽  
Receptor Agonists

While antidiabetes therapies target glycemic control, most do not address the underlying problems of excess bodyweight and deteriorating pancreatic beta-cell function. Some therapies also provoke hypoglycemia and/or weight gain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the gut in response to nutrient intake and has a major role in the post-prandial insulin response in healthy individuals. The incretin response is, however, impaired in individuals with type 2 diabetes. There are two therapeutic approaches that target the incretin system: GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1 receptor agonists provide pharmacological levels of GLP-1 activity, while DPP-4 inhibitors restore physiological levels. The pharmacological levels of GLP-1 induced by GLP-1 receptor agonists provide effective glycemic control and weight reduction. The DPP-4 inhibitors also improve glycemic control but are weight-neutral. Pre-clinical studies in animal models andin vitrosystems suggest that incretin-based therapies have the potential to preserve beta-cell mass and improve their function. Initial clinical data show improvements in beta-cell function in patients treated with incretin-based therapies, supporting the pre-clinical observations. A further benefit of incretin-based therapies is that they provide glucose-dependent glucose control, which means that they have a low inherent risk of inducing hypoglycemia. These agents therefore look extremely promising in the management of type 2 diabetes, being efficacious and having positive benefits on weight, low risk of hypoglycemia, and the potential to improve pancreatic islet cell function in the long term.

Is Defective Pancreatic Beta-cell Mass Environmentally Programmed in Goto-Kakizaki Rat Model of Type 2 Diabetes?

Pancreas ◽  
2006 ◽  
Vol 33 (4) ◽  
pp. 412-417 ◽  
Author(s):  
Sophie Calderari ◽  
Marie-No??lle Gangnerau ◽  
Marie-Jos?? Meile ◽  
Bernard Portha ◽  
Patricia Serradas
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Rat Model ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Pancreatic Beta Cell Mass

scholarly journals Reduced beta cell number rather than size is a major contributor to beta cell loss in type 2 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Hironobu Sasaki ◽  
Yoshifumi Saisho ◽  
Jun Inaishi ◽  
Yuusuke Watanabe ◽  
Tami Tsuchiya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Cell Size ◽  
Cell Mass ◽  
Cell Number ◽  
Relative Reduction ◽  
Major Contributor ◽  
Islet Morphology ◽  
The Impact

Abstract Aims/hypothesis Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. Methods Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. Results Both beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 μm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA1c (r = −0.45, p < 0.01). Conclusions/interpretation Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes. Graphical abstract

scholarly journals A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell

2014 ◽  
Vol 94 (2) ◽  
pp. 186-197 ◽  
Author(s):  
Jennifer R. Kulzer ◽  
Michael L. Stitzel ◽  
Mario A. Morken ◽  
Jeroen R. Huyghe ◽  
Christian Fuchsberger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Regulatory Variant

scholarly journals A role for pancreatic beta-cell secretory hyperresponsiveness in catch-up growth hyperinsulinemia: Relevance to thrifty catch-up fat phenotype and risks for type 2 diabetes

2011 ◽  
Vol 8 (1) ◽  
pp. 2 ◽  
Author(s):  
Marina Casimir ◽  
Paula B de Andrade ◽  
Asllan Gjinovci ◽  
Jean-Pierre Montani ◽  
Pierre Maechler ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
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