Adenylyl cyclase isoform expression in non-diabetic and diabetic Goto-Kakizaki (GK) rat pancreas. Evidence for distinct overexpression of type-8 adenylyl cyclase in diabetic GK rat islets

Glucose-induced insulin release is markedly decreased in the spontaneously diabetic Goto-Kakizaki (GK) rat pancreas. This defect was recently shown to be reversed by forskolin which markedly enhances cAMP generation in GK isl ets, These effects of forskolin were associated with overexpression of type -3 adenylyl cyclase (AC) mRNA due to the presence of two functional point m utations in the promoter region of AC3 gene in GK rat. Nine AC isoforms hav e been described, but their expression pattern in relation to the main panc reatic islet cell types, as well as their involvement in the diabetic state , is still unknown. Using antibodies raised against AC1-8, we have studied by double immunofluorescence the localisation of these AC isoforms in diffe rent endocrine cell types in both normal and diabetic GK rat pancreas, Our results demonstrated a clear immunoreaction (IR) to AC1-4 and 6 in normal a nd GK islet beta-cells, while a smaller number of ACs were expressed in alp ha- and delta-cells. No AC-IR was observed in pancreatic polypeptide cells. Moreover, we have found an increased IR of the Ca2+-stimulated AC1, AC3 an d AC8 in diabetic beta- and alpha-cells, compared with the corresponding IR in control pancreas. Most noticeable was the eliciting of a markedly enhan ced AC8-IR in GK rat beta- and alpha-cells, in contrast to a barely discern ible AC8-IR in corresponding normal cells. In conclusion, AC expression exh ibits a complex pattern in the endocrine pancreas, with specific difference s between the normal and diabetic state.