title: Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion.
abstract: β-Cell mitochondrial dysfunction as well as proinflammatory cytokines have been suggested to contribute to reduced glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. We recently demonstrated that Cohen diabetic sensitive (CDs) rats fed a high-sucrose, low-copper diet (HSD) developed hyperglycemia and reduced GSIS in association with peri-islet infiltration of fat and interleukin (IL)-1β-expressing macrophages, whereas CD resistant (CDr) rats remained normoglycemic on HSD. We examined: 1) the correlation between copper concentration in the HSD and progression, prevention, and reversion of hyperglycemia in CDs rats, 2) the relationship between activity of the copper-dependent, respiratory-chain enzyme cytochrome c oxidase (COX), infiltration of fat, IL-1β-expressing macrophages, and defective GSIS in hyperglycemic CDs rats. CDs and CDr rats were fed HSD or copper-supplemented HSD before and during hyperglycemia development. Blood glucose and insulin concentrations were measured during glucose tolerance tests. Macrophage infiltration and IL-1β expression were evaluated in pancreatic sections by electron-microscopy and immunostaining. COX activity was measured in pancreatic sections and isolated islets. In CDs rats fed HSD, GSIS and islet COX activity decreased, while blood glucose and infiltration of fat and IL-1β-expressing macrophages increased with time on HSD (P < 0.01 vs. CDr-HSD rats, all parameters, respectively). CDs rats maintained on copper-supplemented HSD did not develop hyperglycemia, and in hyperglycemic CDs rats, copper supplementation restored GSIS and COX activity, reversed hyperglycemia and infiltration of fat and IL-1β-expressing macrophages (P < 0.01 vs. hyperglycemic CDs-HSD rats, all parameters, respectively). We provide novel evidence for a critical role of low dietary copper in diminished GSIS of susceptible CDs rats involving the combined consequence of reduced islet COX activity and pancreatic low-grade inflammation.
authors.affiliation: Diabetes Unit, Hadassah-Hebrew Univ. Medical Center, Jerusalem 12000, Israel 91120. sarahz@hadassah.org.il
authors.forename: Sarah
authors.initials: S
authors.lastname: Weksler-Zangen
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Limor
authors.initials: L
authors.lastname: Tarsi-Chen
authors.forename: Fiona
authors.initials: F
authors.lastname: Vernea
authors.forename: Genya
authors.initials: G
authors.lastname: Aharon-Hananel
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003300:Copper / Q000008:administration & dosage*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D019587:Dietary Supplements; D003576:Electron Transport Complex IV / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D053583:Interleukin-1beta; D014280:Triglycerides; D003300:Copper; D003576:Electron Transport Complex IV
keywords: copper; cytochrome c oxidase; diabetes; interleukin-1β; pancreatic β-cell