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Principal Investigator: Matthew Ng Poy
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $392,998
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Critical to successful innovation in treating diabetes is the development of strategies for promoting insulin
release and preventing pancreatic beta-cell destruction. Chronic demand for insulin production during insulin
resistance and diabetes exacerbates cell dysfunction and this is compounded by ER and oxidative stress. This
results in beta-cell death and loss of insulin production. Recent studies have highlighted defects in insulin
processing, insulin granule maturation, and granule docking that are also linked to all major forms of diabetes;
however conceptual gaps remain in understanding the causes of beta-cell failure and developing methods to
reverse or prevent beta-cell dysfunction.
Our preliminary studies establish Phosphatidylinositol transfer protein alpha (referred to as human
PITPNA and mouse Pitpna), as a major regulator of insulin granule formation and secretion. PITPNA shuttles
phosphatidylinositol (PI) from the endoplasmic reticulum (ER) to the trans-Golgi network (TGN) for
phosphorylation by Phosphatidylinositol 4-kinase (PI4-K) conversion to phosphatidylinositol-4 phosphate
(PtdIns-4-P), an abundant membrane phospholipid involved in insulin granule docking and exocytosis. Our
preliminary data shows: 1) PITPNA expression is dramatically silenced in beta-cells of human T2D subjects, 2)
reduction of PITPNA in human islets both lowered cellular PI4-P levels and insulin granule maturation and
increased accumulation of proinsulin, and 3) conditional beta-cell specific deletion of Pitpna in mice (Ins-Cre;
Pitpnaflox/flox) results in decreased insulin secretion and beta-cell mass, random-fed hyperglycemia, and increased
expression of ER stress proteins in beta cells.
Based on these data, we hypothesize that decreased PITPNA in beta-cells during T2D leads to lower
PI4-P for distribution by the TGN as well as incorporation into insulin granules, thereby disrupting granule
maturation, docking and secretion. We further hypothesize the reduced granule formation results in accumulation
of proinsulin in the ER, leading to ER stress and ultimately beta-cell death. We propose that restoration of
PITPNA in beta-cells of T2D individuals will reverse these aspects of cellular dysfunction. We expect these
studies will demonstrate that promoting PITPNA function and PI4-P formation is a novel strategy for reversing
beta-cell dysfunction in several subcellular compartments including the ER, mitochondria, and the TGN. These
studies aim to highlight restoration of PI4-P between intracellular membranes as an innovative approach for
increasing granule maturation and secretion as well as reversing beta-cell failure in major forms of diabetes.
Terms: <1-Phosphatidylinositol 4-Kinase><Adult-Onset Diabetes Mellitus><B9 endocrine pancreas><Beta Cell><Cell Body><Cell Death><Cell Fractionation><Cell Function><Cell Physiology><Cell Process><Cell membrane><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Cytoplasmic Granules><Cytoplasmic Membrane><Data><Defect><Development><Diabetes Mellitus><Docking><Dysfunction><EC 2.7.1.67><ER stress><Endocrine Pancreas><Endoplasmic Reticulum><Ergastoplasm><Exocytosis><Failure><Functional disorder><Heat shock proteins><Human><Humulin R><Hyperglycemia><Impairment><Individual><Inositide Phospholipids><Inositol Phosphoglycerides><Inositol Phospholipids><Insulin><Insulin Cell><Insulin Resistance><Insulin Secreting Cell><Intracellular Membranes><Islands of Langerhans><Islets of Langerhans><Ketosis-Resistant Diabetes Mellitus><Link><LoxP-flanked allele><Maturity-Onset Diabetes Mellitus><Membrane><Methods><Mice><Mice Mammals><Mitochondria><Modern Man><Morphology><Murine><Mus><NIDDM><NPIK><Nesidioblasts><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Oxidative Stress><PI 4-Kinase><PI Transfer Protein><PI4K92><PI4KBeta><Pancreas><Pancreatic><Pancreatic Islets><Pancreatic beta Cell><Pancreatic β-Cell><Pars endocrina pancreatis><Pathway interactions><Phosphatides><Phosphatidyl Inositol><Phosphatidylinositiol Kinase><Phosphatidylinositol 4-Kinase><Phosphatidylinositol 4-Kinase Beta><Phosphatidylinositol 4-Kinase, Catalytic, Beta><Phosphatidylinositol 4-Kinase, Type III, Beta><Phosphatidylinositol Exchange Protein><Phosphatidylinositol Kinase Type II><Phosphatidylinositol Transfer Protein><Phosphatidylinositols><Phosphoinositide Kinase><Phosphoinositide-4-Kinase Catalytic Beta Polypeptide><Phosphoinositides><Phospholipids><Phosphorylation><Physiopathology><Plasma Membrane><Production><Proinsulin><Protein Phosphorylation><PtdINS4P><PtdIns><PtdIns 4-Kinase><Regular Insulin><Role><Secretory Granules><Secretory Vesicles><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure of beta Cell of islet><Subcellular Process><T2 DM><T2D><T2DM><Testing><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Wortmannin-Sensitive Phosphatidylinositol 4-Kinase><adult onset diabetes><developmental><diabetes><diabetes pathogenesis><endoplasmic reticulum stress><floxed><floxed allele><granule><human subject><hyperglycemic><improved><innovate><innovation><innovative><insulin granule><insulin resistant><insulin secretion><insulin tolerance><islet><islet progenitor><ketosis resistant diabetes><knock-down><knockdown><maturity onset diabetes><membrane structure><mitochondrial><mitochondrial dysfunction><mitochondrial membrane><necrocytosis><new approaches><novel approaches><novel strategies><novel strategy><pancreas beta cell><pancreas β cell><pancreatic b-cell><pathophysiology><pathway><pharmacologic><phosphatidylinositol 4-monophosphate><phosphatidylinositol 4-phosphate><plasmalemma><prevent><preventing><restoration><social role><stress protein><subcellular fractionation><trans-Golgi Network><type 2 DM><type II DM><type two diabetes><β-cell><β-cells><βCell>