Hedgehog signaling regulation of insulin production by pancreatic beta-cells

Hedgehogs (Hhs) are intercellular signaling molecules that regulate tissue patterning in mammalian development. Mammalian Hhs include Sonic hedgehog ( Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). The absence of Shh expression is required for the early development of the endocrine and exocr ine pancreas, but whether Hh signaling functions in the fully developed adu lt endocrine pancreas is unknown. Here we report that Hhs Ihh and Dhh and t heir receptors patched (Ptc) and smoothened are expressed in the endocrine islets of Langerhans of the fully developed rat pancreas and in the clonal beta -cell line INS-1. We demonstrate the coexpression of Ptc with insulin in p-cells of mouse pancreatic islets, indicating that beta -cells are targ ets of active Hh signaling. The administration of cyclopamine, a Hh signali ng inhibitor, decreases both insulin secretion from and insulin content of INS-1 cells. The effects of Hh signaling on insulin production occur at the transcriptional level because activation of Hh signal transduction by ecto pic expression of Shh increases rat insulin I promoter activation in a dose -dependent manner in transient transfections of INS-1 and MIN6 beta -cell l ines. In contrast, inhibition of Hh signaling with increasing concentration s of cyclopamine progressively reduces insulin promoter activity. Furthermo re, the treatment of INS-1 cells with cyclopamine diminishes endogenous ins ulin mRNA expression. We propose that Hh signaling is not restricted to pat terning in early pancreas development but also continues to signal in diffe rentiated beta -cells of the endocrine pancreas in regulating insulin produ ction. Thus, defective Hh signaling in the pancreas should be considered as a potential factor in the pathogenesis of type 2 diabetes.