Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

Aims/hypothesis 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 ce...

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Bibliographic Details
Published in:Diabetologia 2012-05, Vol.55 (5), p.1495-1504
Main Authors: Rezende, L. F., Santos, G. J., Santos-Silva, J. C., Carneiro, E. M., Boschero, A. C.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biological and medical sciences
Blood Glucose - drug effects
Body Weight - drug effects
Ciliary Neurotrophic Factor - pharmacology
Diabetes
Diabetes Mellitus, Experimental - prevention & control
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - prevention & control
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Enzymes
Epididymis - drug effects
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Fatty Acids, Nonesterified - blood
Glucose
Hep G2 Cells
Human Physiology
Humans
Hyperglycemia
Insulin - blood
Insulin - metabolism
Insulin Resistance
Insulin Secretion
Insulin-Secreting Cells - drug effects
Insulysin - biosynthesis
Internal Medicine
Kinases
Liver
Male
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Metabolism
Mice
Obesity
Phosphorylation
Proteins
Proto-Oncogene Proteins c-akt - analysis
Receptor, Insulin - analysis
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Summary:Aims/hypothesis 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/interpretation 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.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-012-2493-5