title: Abnormal expression of pancreatic islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptors in Goto-Kakizaki rats is partially restored by phlorizin treatment and accentuated by high glucose treatment.
abstract: The role of glucotoxicity in dysregulation of islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex proteins and insulin response was explored in the hyperglycemic Goto-Kakizaki (GK) rat. Syntaxin-1A and vesicle-associated membrane protein isoform 2, which drive insulin granule exocytotic fusion, and the associated nSec1, which modulates the SNARE complex assembly, were diminished in GK pancreatic islets to approximately 40% of the levels in control Wistar rat islets. Phlorizin treatment (12 d) induced normoglycemic control in GK rats, resulting in partial restoration of the insulin response to glucose. Furthermore, islet SNARE complex and nSec1 proteins increased by about 40%. Phlorizin treatment did not affect levels of islet SNARE proteins in controls or on the same SNARE complex proteins in GK rat brain. To examine the role of hyperglycemia per se, GK and control rat islets were exposed for 5 d in culture to 5.5 and 16.7 mM glucose. High glucose treatment greatly increased the levels of synaptosomal-associated membrane protein of 25 kDa and, less markedly, the levels of syntaxin-1A and nSec1 in control islets more than in GK rat islets, whereas levels were reduced in both. This was accompanied by sustained impairment of the insulin response to glucose in GK islets and a normal response in control islets. Thus, GK islets demonstrate dysregulation of SNARE protein expression, and their compensatory increase by high glucose exposure is abrogated. Conversely, normoglycemic control results in partial replenishment of these critical components of the insulin exocytotic machinery and improvement in the insulin response. We propose that dysregulation of SNARE proteins is an important mechanism behind glucotoxicity-mediated impairment of the insulin response to glucose.
authors.affiliation: Department of Medicine and Physiology, University of Toronto, Ontario, Canada M5S 1A8. herbert.gaisano@utoronto.ca
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Claes-Goran
authors.initials: CG
authors.lastname: Ostenson
authors.forename: Laura
authors.initials: L
authors.lastname: Sheu
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D046508:Culture Techniques; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D052066:N-Ethylmaleimide-Sensitive Proteins; D010695:Phlorhizin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D008565:Membrane Proteins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D033921:Vesicular Transport Proteins; D010695:Phlorhizin; D052066:N-Ethylmaleimide-Sensitive Proteins; C498737:Nsf protein, rat; D005947:Glucose