title: Impaired glucose-stimulated insulin secretion is coupled with exocrine pancreatic lesions in the Cohen diabetic rat.
abstract: OBJECTIVE
  The Cohen diabetes-sensitive rat develops postprandial hyperglycemia when fed a high-sucrose, copper-poor diet, whereas the Cohen diabetes-resistant rat maintains normoglycemia. The pathophysiological basis of diabetes was studied in the Cohen diabetic rat centering on the interplay between the exocrine and endocrine compartments of the pancreas.
  
  
  METHODS
  Studies used male Cohen diabetes-sensitive and Cohen diabetes-resistant rats fed 1-month high-sucrose, copper-poor diet. Serum insulin and glucose levels were measured during glucose and insulin tolerance tests. The pancreas was evaluated for weight, insulin content, macrophage, and fat infiltration. Glucose-stimulated insulin secretion (GSIS) was determined in isolated perfused pancreas and in islets.
  
  
  RESULTS
  Hyperglycemic Cohen diabetes-sensitive rats exhibited reduced pancreatic weight with lipid deposits and interleukin-1beta-positive macrophage infiltration in the exocrine pancreas. Islet morphology was preserved, and total pancreatic insulin content did not differ from that of Cohen diabetes-resistant rats. Lipids did not accumulate in skeletal muscle, nor was insulin resistance observed in hyperglycemic Cohen diabetes-sensitive rats. Intravenous glucose-tolerance test revealed markedly elevated glucose levels associated with diminished insulin output. Insulin release was induced in vivo by the non-nutrient secretagogues arginine and tolbutamide, suggesting a selective unresponsiveness to glucose. Decreased GSIS was observed in the isolated perfused pancreas of the hyperglycemic Cohen diabetes-sensitive rat, whereas islets isolated from these rats exhibited glucose-dependent insulin secretion and proinsulin biosynthesis.
  
  
  CONCLUSIONS
  The association of the in vivo insulin secretory defect with lipid accumulation and activated macrophage infiltration in the exocrine pancreas suggests that changes in the islet microenvironment are the culprit in the insulin secretory malfunction observed in vivo.
authors.affiliation: The Diabetes Unit, Hadassah-Hebrew University Medical Center, Jerusalem 1200, Israel. sarahz@hadassah.org.il
authors.forename: Sarah
authors.initials: S
authors.lastname: Weksler-Zangen
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Shira
authors.initials: S
authors.lastname: Ehrenfeld
authors.forename: Gail
authors.initials: G
authors.lastname: Amir
authors.forename: Andrei
authors.initials: A
authors.lastname: Oprescu
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
authors.forename: David H
authors.initials: DH
authors.lastname: Zangen
authors.forename: Nurit
authors.initials: N
authors.lastname: Kaiser
mesh_terms: D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002408:Catheters, Indwelling; D003300:Copper / Q000172:deficiency; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003927:Diet, Diabetic; D004040:Dietary Carbohydrates; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000503:physiopathology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000473:pathology*; D019518:Postprandial Period; D051381:Rats; D013395:Sucrose / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D004040:Dietary Carbohydrates; D007328:Insulin; D013395:Sucrose; D003300:Copper