The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets

Miwon Ahn, Stephanie M. Yoder, Zhanxiang Wang, Eunjin Oh, Latha Ramalingam, Ragadeepthi Tunduguru, Debbie C. Thurmond

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/interpretation: 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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalDiabetologia
DOIs
StateAccepted/In press - Jul 9 2016

Fingerprint

p21-Activated Kinases
Diet
Survival
Knockout Mice
cdc42 GTP-Binding Protein
Cell Death
Glucose Intolerance
Palmitates
B-Cell Lymphoma
Islets of Langerhans
Caspase 3
Hyperglycemia
Type 2 Diabetes Mellitus
Cultured Cells
Fasting
Phosphotransferases
Fats
Maintenance
Phosphorylation
Cell Proliferation

Keywords

  • Beta cell mass
  • Diet-induced obesity
  • Insulin secretion
  • PAK1
  • Prediabetes
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ahn, M., Yoder, S. M., Wang, Z., Oh, E., Ramalingam, L., Tunduguru, R., & Thurmond, D. C. (Accepted/In press). The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets. Diabetologia, 1-11. https://doi.org/10.1007/s00125-016-4042-0

The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets. / Ahn, Miwon; Yoder, Stephanie M.; Wang, Zhanxiang; Oh, Eunjin; Ramalingam, Latha; Tunduguru, Ragadeepthi; Thurmond, Debbie C.

In: Diabetologia, 09.07.2016, p. 1-11.

Research output: Contribution to journalArticle

Ahn, Miwon ; Yoder, Stephanie M. ; Wang, Zhanxiang ; Oh, Eunjin ; Ramalingam, Latha ; Tunduguru, Ragadeepthi ; Thurmond, Debbie C. / The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets. In: Diabetologia. 2016 ; pp. 1-11.
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