| Title |
The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets
|
|---|---|
| Published in |
Diabetologia, July 2016
|
| DOI | 10.1007/s00125-016-4042-0 |
| Pubmed ID | |
| Authors |
Miwon Ahn, Stephanie M. Yoder, Zhanxiang Wang, Eunjin Oh, Latha Ramalingam, Ragadeepthi Tunduguru, Debbie C. Thurmond |
| Abstract |
Human islets from type 2 diabetic donors are reportedly 80% deficient in the p21 (Cdc42/Rac)-activated kinase, PAK1. PAK1 is implicated in beta cell function and maintenance of beta cell mass. We questioned the mechanism(s) by which PAK1 deficiency potentially contributes to increased susceptibility to type 2 diabetes. Non-diabetic human islets and INS 832/13 beta cells cultured under diabetogenic conditions (i.e. with specific cytokines or under glucolipotoxic [GLT] conditions) were evaluated for changes to PAK1 signalling. Combined effects of PAK1 deficiency with GLT stress were assessed using classic knockout (Pak1 (-/-) ) mice fed a 45% energy from fat/palmitate-based, 'western' diet (WD). INS 832/13 cells overexpressing or depleted of PAK1 were also assessed for apoptosis and signalling changes. Exposure of non-diabetic human islets to diabetic stressors attenuated PAK1 protein levels, concurrent with increased caspase 3 cleavage. WD-fed Pak1 knockout mice exhibited fasting hyperglycaemia and severe glucose intolerance. These mice also failed to mount an insulin secretory response following acute glucose challenge, coinciding with a 43% loss of beta cell mass when compared with WD-fed wild-type mice. Pak1 knockout mice had fewer total beta cells per islet, coincident with decreased beta cell proliferation. In INS 832/13 beta cells, PAK1 deficiency combined with GLT exposure heightened beta cell death relative to either condition alone; PAK1 deficiency resulted in decreased extracellular signal-related kinase (ERK) and B cell lymphoma 2 (Bcl2) phosphorylation levels. Conversely, PAK1 overexpression prevented GLT-induced cell death. These findings suggest that PAK1 deficiency may underlie an increased diabetic susceptibility. Discovery of ways to remediate glycaemic dysregulation via altering PAK1 or its downstream effectors offers promising opportunities for disease intervention. |
X Demographics
The data shown below were collected from the profiles of 5 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 20% |
| Unknown | 4 | 80% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 4 | 80% |
| Science communicators (journalists, bloggers, editors) | 1 | 20% |
Mendeley readers
The data shown below were compiled from readership statistics for 34 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 34 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 6 | 18% |
| Student > Master | 5 | 15% |
| Researcher | 5 | 15% |
| Student > Bachelor | 2 | 6% |
| Lecturer | 1 | 3% |
| Other | 5 | 15% |
| Unknown | 10 | 29% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 9 | 26% |
| Biochemistry, Genetics and Molecular Biology | 4 | 12% |
| Nursing and Health Professions | 2 | 6% |
| Chemical Engineering | 2 | 6% |
| Agricultural and Biological Sciences | 2 | 6% |
| Other | 5 | 15% |
| Unknown | 10 | 29% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 October 2016.
All research outputs
#12,844,183
of 22,880,691 outputs
Outputs from Diabetologia
#4,103
of 5,038 outputs
Outputs of similar age
#178,135
of 354,628 outputs
Outputs of similar age from Diabetologia
#54
of 77 outputs
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