Overexpression of protein-tyrosine phosphatase PTP sigma is linked to impaired glucose-induced insulin secretion in hereditary diabetic Goto-Kakizaki rats.
The impaired glucose-induced insulin release in type 2 diabetes mellitus may be accounted for by reduced B-cell ATP/ADP ratio or decreased phosphorylation of proteins regulating exocytosis of insulin. This, in turn, could be due to enhanced phosphatase activity. Using in situ hybridization techniques to assess the expression of 11 different phosphotyrosine phosphatases (PTPases), known to be present in the B-cells, overexpression by approximately 60% of PTP sigma (also known as LAR-PTP2 or PTP NE-3) was demonstrated in pancreatic islets and liver of spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. In agreement with these findings Western blot of islet lysates, using a polyclonal PTP sigma antiserum, showed increased amounts of the protein in GK relative to control rat islets. Exposure of isolated islets for 20 h to 5 muM antisense to PTP sigma, composed of an antisense PNA sequence of 15 bases linked to the cell penetrating peptide transportan, increased glucose-induced insulin secretion from GK rat islets, but not from control islets. In parallel, the amounts of the phosphatase decreased. In conclusion, increased expression of PTP sigma may be of pathogenetic significance for the defective insulin secretion in GK rat islets.
Ostenson
Claes-Göran
CG
Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden. claes-goran.ostenson@ks.se
Sandberg-Nordqvist
Ann-Christine
AC
Chen
Jie
J
Hällbrink
Mattias
M
Rotin
Daniela
D
Langel
Ulo
U
Efendic
Suad
S
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D015533:Transcriptional Activation
D007328:Insulin; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D005947:Glucose