Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action.
Recent characterization of the ability of uncoupling protein 2 (UCP2) to reduce ATP production and inhibit insulin secretion by pancreatic beta-cells has placed this mitochondrial protein as a candidate target for therapeutics in diabetes mellitus. In the present study we evaluate the effects of short-term treatment of two animal models of type 2 diabetes mellitus with an antisense oligonucleotide to UCP2. In both models, Swiss mice (made obese and diabetic by a hyperlipidic diet) and ob/ob mice, the treatment resulted in a significant improvement in the hyperglycemic syndrome. This effect was due not only to an improvement of insulin secretion, but also to improved peripheral insulin action. In isolated pancreatic islets, the partial inhibition of UCP2 increased ATP content, followed by increased glucose-stimulated insulin secretion. This was not accompanied by increased expression of enzymes involved in protection against oxidative stress. The evaluation of insulin action in peripheral tissues revealed that the inhibition of UCP2 expression significantly improved insulin signal transduction in adipose tissue. In conclusion, short-term inhibition of UCP2 expression ameliorates the hyperglycemic syndrome in two distinct animal models of obesity and diabetes. Metabolic improvement is due to a combined effect on insulin-producing pancreatic islets and in at least one peripheral tissue that acts as a target for insulin.
De Souza
Cláudio T
CT
Department of Internal Medicine, State University of Campinas, Campinas-SP, Brazil.
Araújo
Eliana P
EP
Stoppiglia
Luiz F
LF
Pauli
José R
JR
Ropelle
Eduardo
E
Rocco
Silvana A
SA
Marin
Rodrigo M
RM
Franchini
Kleber G
KG
Carvalheira
José B
JB
Saad
Mário J
MJ
Boschero
Antonio C
AC
Carneiro
Everardo M
EM
Velloso
Lício A
LA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009765:Obesity / Q000235:genetics*; D015398:Signal Transduction; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate