Phosphatidylinositol-4-phosphate-5-kinase α deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice

Ping Huang, Oladapo Yeku, Haihong Zong, Phyllis Tsang, Wenjuan Su, Xiao Yu, Shuzhi Teng, Mary Osisami, Yasunori Kanaho, Jeffrey E. Pessin, Michael A. Frohman

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

OBJECTIVE - Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP2). We sought to examine the role of the α isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS - The response of PI4P5Kα-/- mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kα-/- pancreatic islets and β-cells were characterized in culture. RESULTS - We show that PI4P5Kα -/- mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kα-/- pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP2 depletion occurred on the plasma membrane of the PI4P5Kα-/- pancreatic β-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kα-/- β-cells under resting conditions. CONCLUSIONS - Our findings suggest that PI4P5Kα plays a complex role in restricting insulin release from pancreatic β-cells through helping to maintain plasma membrane PIP2 levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems.

Original languageEnglish (US)
Pages (from-to)454-463
Number of pages10
JournalDiabetes
Volume60
Issue number2
DOIs
StatePublished - Feb 2011

Fingerprint

Obesity
Insulin
Glucose
Islets of Langerhans
Type 2 Diabetes Mellitus
Cell Membrane
High Fat Diet
1-phosphatidylinositol-4-phosphate 5-kinase
Exocytosis
Phosphatidylinositols
Actin Cytoskeleton
Actins
Protein Isoforms
Research Design
Diet
Serum

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Phosphatidylinositol-4-phosphate-5-kinase α deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice. / Huang, Ping; Yeku, Oladapo; Zong, Haihong; Tsang, Phyllis; Su, Wenjuan; Yu, Xiao; Teng, Shuzhi; Osisami, Mary; Kanaho, Yasunori; Pessin, Jeffrey E.; Frohman, Michael A.

In: Diabetes, Vol. 60, No. 2, 02.2011, p. 454-463.

Research output: Contribution to journalArticle

Huang, Ping ; Yeku, Oladapo ; Zong, Haihong ; Tsang, Phyllis ; Su, Wenjuan ; Yu, Xiao ; Teng, Shuzhi ; Osisami, Mary ; Kanaho, Yasunori ; Pessin, Jeffrey E. ; Frohman, Michael A. / Phosphatidylinositol-4-phosphate-5-kinase α deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice. In: Diabetes. 2011 ; Vol. 60, No. 2. pp. 454-463.
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abstract = "OBJECTIVE - Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP2). We sought to examine the role of the α isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS - The response of PI4P5Kα-/- mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kα-/- pancreatic islets and β-cells were characterized in culture. RESULTS - We show that PI4P5Kα -/- mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kα-/- pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP2 depletion occurred on the plasma membrane of the PI4P5Kα-/- pancreatic β-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kα-/- β-cells under resting conditions. CONCLUSIONS - Our findings suggest that PI4P5Kα plays a complex role in restricting insulin release from pancreatic β-cells through helping to maintain plasma membrane PIP2 levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems.",
author = "Ping Huang and Oladapo Yeku and Haihong Zong and Phyllis Tsang and Wenjuan Su and Xiao Yu and Shuzhi Teng and Mary Osisami and Yasunori Kanaho and Pessin, {Jeffrey E.} and Frohman, {Michael A.}",
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T1 - Phosphatidylinositol-4-phosphate-5-kinase α deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice

AU - Huang, Ping

AU - Yeku, Oladapo

AU - Zong, Haihong

AU - Tsang, Phyllis

AU - Su, Wenjuan

AU - Yu, Xiao

AU - Teng, Shuzhi

AU - Osisami, Mary

AU - Kanaho, Yasunori

AU - Pessin, Jeffrey E.

AU - Frohman, Michael A.

PY - 2011/2

Y1 - 2011/2

N2 - OBJECTIVE - Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP2). We sought to examine the role of the α isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS - The response of PI4P5Kα-/- mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kα-/- pancreatic islets and β-cells were characterized in culture. RESULTS - We show that PI4P5Kα -/- mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kα-/- pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP2 depletion occurred on the plasma membrane of the PI4P5Kα-/- pancreatic β-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kα-/- β-cells under resting conditions. CONCLUSIONS - Our findings suggest that PI4P5Kα plays a complex role in restricting insulin release from pancreatic β-cells through helping to maintain plasma membrane PIP2 levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems.

AB - OBJECTIVE - Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP2). We sought to examine the role of the α isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS - The response of PI4P5Kα-/- mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kα-/- pancreatic islets and β-cells were characterized in culture. RESULTS - We show that PI4P5Kα -/- mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kα-/- pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP2 depletion occurred on the plasma membrane of the PI4P5Kα-/- pancreatic β-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kα-/- β-cells under resting conditions. CONCLUSIONS - Our findings suggest that PI4P5Kα plays a complex role in restricting insulin release from pancreatic β-cells through helping to maintain plasma membrane PIP2 levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems.

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DO - 10.2337/db10-0614

M3 - Article

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