**4. L-PHP alteration of gene expression modifys microenvironment within the pancreas**

Pancreatic microenvironment alteration by L-PHP has been reported [28]. The findings show that multiple functional genes in rat pancreas were influenced by L-PHP *in vivo*. A total of 60 genes are found to be regulated by L-PHP, 29 genes in the pancreas and 31 genes in rat derived pancreatic β-cell line, INS-1 cells. These genes include Ca2+channel enhancers (Ca2+/calmo‐ dulin-dependent protein kinase, type I and II), G-protein coupling receptor related genes (GPCR kinase 4 and 5, transducin-β 1 subunit,Arrestin-β1, transducin-β1), Protein kinases (serine/threonine kinase-3,PKC β, PCTAIRE-3, v-mos), proliferation or differentiation signal transduction related genes (MAPK3, growth factor receptor-bound protein 2, n-myc, GAP-43) and down-regulated pro-apoptotic Bax gene. Genes relative to insulin secretion are signifi‐ cantly increased by L-PHP including N-methyl-D-aspartate receptor-2A, GABA-A receptor, RAB2, Ras-related GTPase and ADP ribosylation factor 1 and 5. The differential gene expres‐ sion between β-cells and total pancreatic tissue in response to L-PHP shows that of the 36 genes that are initiated and 36 genes that are turned off relative to signal transduction. In rat pancreas 6 genes were initiated and 14 genes were turned off, with one initiating the anti-apoptotic BcLX gene. While in rat INS-1 β cell line only 4 genes were initiated and 4 genes turned off from the 34 signal transduction genes. These significant variations between pure β-cell and entire pancreatic tissue indicate that L-PHP can regulate β-cell function by directly working on βcells or by indirectly altering pancreatic microenvironment to maintain and facilitate β-cell response to glucose resulting in a balance *in vivo* of glucose metabolism.

R1 expression in rat-derived β-cell lines as well as whole pancreas that included nonislet tissue [25]. R1 receptor was also found to associate with EGF receptor function called cross linking

> Fig. (2). In situ hybridization of L-PHP-receptor-1(R1) in rat pancreas A. and D. Dual fluorescent image of rat pancreas. Red indicates insulin immuno-fluorescence; Green indicates R1 in situ hybridization. B. and E show H&E staining for tissue morphology, C and F show dapi for nuclei staining. The large arrows indicate the yellow color, a mixture of green and red represents colocalization of insulin and R1 in islet and the small white arrows indicate the positive staining of R1 in epithelial

**Figure 2.** In situ hybridization of L-PHP-receptor-1(R1) in rat pancreas A. and D. Dual fluorescent image of rat pan‐ creas. Red indicates insulin immuno-fluorescence; Green indicates R1 in situ hybridization. B. and E show H&E staining for tissue morphology, C and F show dapi for nuclei staining. The large arrows indicate the yellow color, a mixture of green and red represents colocalization of insulin and R1 in islet and the small white arrows indicate the positive stain‐

*In vitro* studies have shown that L-PHP is stimulated by glucose and suppressed by insulin release. Cellular cAMP production regulated by somatostatin may involve glucose and insulin regulation of L-PHP [26, 27]. We hypothesize that there is an α-β-γ integrating system, which releases insulin-L-PHP-somatostatin coordinated in respond to glucose challenge in islet. To support this hypothesis, it needs further study but evidence in that tissue cultures of pure β

**4. L-PHP alteration of gene expression modifys microenvironment within**

Pancreatic microenvironment alteration by L-PHP has been reported [28]. The findings show that multiple functional genes in rat pancreas were influenced by L-PHP *in vivo*. A total of 60

A. B. and ductal D. E. (From reference #25, with permission).

**3. Regulation of L-PHP in the pancreas**

**the pancreas**

ing of R1 in epithelial A. B. and ductal D. E. (From reference #25, with permission)

cell do not function as well as an entire islet may be part of the support.

[25] (Fig. 2).

158 Glucose Homeostasis
