title: Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance.
abstract: OBJECTIVE
  Ciliary neurotrophic factor (CNTF) improves metabolic variables of obese animals with characteristics of type 2 diabetes, mainly by reducing insulin resistance. We evaluated whether CNTF was able to improve other metabolic variables in mouse models of type 2 diabetes, such as beta cell mass and insulin clearance, and whether CNTF has any effect on non-obese mice with characteristics of type 2 diabetes.
  
  
  METHODS
  Neonatal mice were treated with 0.1 mg/kg CNTF or citrate buffer via intraperitoneal injections, before injection of 250 mg/kg alloxan. HEPG2 cells were cultured for 3 days in the presence of citrate buffer, 1 nmol/l CNTF or 50 mmol/l alloxan or a combination of CNTF and alloxan. Twenty-one days after treatment, we determined body weight, epididymal fat weight, blood glucose, plasma insulin, NEFA, glucose tolerance, insulin resistance, insulin clearance and beta cell mass. Finally, we assessed insulin receptor and protein kinase B phosphorylation in peripheral organs, as well as insulin-degrading enzyme (IDE) protein production and alternative splicing in the liver and HEPG2 cells.
  
  
  RESULTS
  CNTF improved insulin sensitivity and beta cell mass, while reducing glucose-stimulated insulin secretion and insulin clearance in Swiss mice, improving glucose handling in a non-obese type 2 diabetes model. This effect was associated with lower IDE production and activity in liver cells. All these effects were observed even at 21 days after CNTF treatment.
  
  
  CONCLUSIONS
  CNTF protection against type 2 diabetes is partially independent of the anti-obesity actions of CNTF, requiring a reduction in insulin clearance and increased beta cell mass, besides increased insulin sensitivity. Furthermore, knowledge of the long-term effects of CNTF expands its pharmacological relevance.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, PO Box 6109, Campinas, SP CEP 13083-865, Brazil. luizbio@gmail.com
authors.forename: L F
authors.initials: LF
authors.lastname: Rezende
authors.forename: G J
authors.initials: GJ
authors.lastname: Santos
authors.forename: J C
authors.initials: JC
authors.lastname: Santos-Silva
authors.forename: E M
authors.initials: EM
authors.lastname: Carneiro
authors.forename: A C
authors.initials: AC
authors.lastname: Boschero
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000517:prevention & control*; D004822:Epididymis / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007339:Insulysin / Q000096:biosynthesis; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D011972:Receptor, Insulin / Q000032:analysis
chemical_list: D001786:Blood Glucose; D020934:Ciliary Neurotrophic Factor; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D007339:Insulysin