Munc18b Increases Insulin Granule Fusion, Restoring Deficient Insulin Secretion in Type-2 Diabetes Human and Goto-Kakizaki Rat Islets with Improvement in Glucose Homeostasis.
Reduced pancreatic islet levels of Munc18a/SNARE complex proteins have been postulated to contribute to the deficient glucose-stimulated insulin secretion (GSIS) in type-2 diabetes (T2D). Whereas much previous work has purported Munc18a/SNARE complex (Syntaxin-1A/VAMP-2/SNAP25) to be primarily involved in predocked secretory granule (SG) fusion, less is known about newcomer SGs that undergo minimal docking time at the plasma membrane before fusion. Newcomer SG fusion has been postulated to involve a distinct SM/SNARE complex (Munc18b/Syntaxin-3/VAMP8/SNAP25), whose levels we find also reduced in islets of T2D humans and T2D Goto-Kakizaki (GK) rats. Munc18b overexpression by adenovirus infection (Ad-Munc18b), by increasing assembly of Munc18b/SNARE complexes, mediated increased fusion of not only newcomer SGs but also predocked SGs in T2D human and GK rat islets, resulting in rescue of the deficient biphasic GSIS. Infusion of Ad-Munc18b into GK rat pancreas led to sustained improvement in glucose homeostasis. However, Munc18b overexpression in normal islets increased only newcomer SG fusion. Therefore, Munc18b could potentially be deployed in human T2D to rescue the deficient GSIS.
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Tairan
T
Qin
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Tao
T
Liang
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Dan
D
Zhu
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Youhou
Y
Kang
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Li
L
Xie
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Subhankar
S
Dolai
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Fundamental Neurobiology, University Health Network, Toronto, ON M5T 2S8, Canada.
Shuzo
S
Sugita
Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University, Shinagawa, Tokyo 142-8501, Japan.
Noriko
N
Takahashi
Department of Molecular Medicine and Surgery, Endocrinology and Diabetology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Claes-Goran
CG
Ostenson
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Comparative Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Kate
K
Banks
Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: herbert.gaisano@utoronto.ca.
Herbert Y
HY
Gaisano
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism*; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050683:R-SNARE Proteins / Q000378:metabolism; D011919:Rats, Inbred Strains; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
D007328:Insulin; D046912:Multiprotein Complexes; D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D050825:Synaptosomal-Associated Protein 25; C112938:VAMP8 protein, human; D005947:Glucose