**7. Future directions**

EGF receptor serine/threonine phosphorylation, thereby enhancing tyrosine phosphorylation. L-PHP receptor activation of Src may have a central role in mediating the effects of L-PHP on the EGF receptor (Fig. 3). The activation of the EGF receptor by L-PHP in multiple circum‐ stances may have important implications for pancreatic β cell biology. Since EGF receptor expression has been found to have a high activity during the embryonic developmental period [4, 36], the possibility exists that L-PHP activation of EGF receptors in pancreatic β cells may

> Fig. (3). The scheme summarized the mechanism of L-PHP (TRH) cross talk with EGF receptor in pancreatic β cells. L-PHP binds to its receptor and dissociates GPCR αβγ complex into α and βγ units. The βγ unit activation of the Src kinase directly results in phosphorylation of EGF receptor Tyr 845. In addition, Src indirectly stimulates Tyr 845 phosphorylation by activation of MMP3 to release heparin-binding EGF. Meanwhile, activation of Src kinase inhibition of PKC results in reducing serine/threonine phosphorylation which blocks off the inhibition of serine/threonine phosphorylation on tyrosine phosphorylation and indirectly activates Tyr 1068 phosphorylation in EGF receptor. LPHP activation of EGF receptor phosphorylation results in the activation of cellular signal pathways such as MAPKs. The activation of Src may have a central role in mediating the effects of L-PHP on the EGF receptor. (R = receptor; \_\_\_\_\_ = activation; ------ = suppression)

**Figure 3.** The scheme summarized the mechanism of L-PHP cross talk with EGF receptor in pancreatic β cells. L-PHP binds to its receptor and dissociates GPCR αβγ complex into α and βγ units. The βγ unit activation of the Src kinase directly results in phosphorylation of EGF receptor Tyr 845. In addition, Src indirectly stimulates Tyr 845 phosphoryla‐ tion by activation of MMP3 to release heparin-binding EGF. Meanwhile, activation of Src kinase inhibition of PKC re‐ sults in reducing serine/threonine phosphorylation which blocks off the inhibition of serine/threonine phosphorylation on tyrosine phosphorylation and indirectly activates Tyr 1068 phosphorylation in EGF receptor. L-PHP activation of EGF receptor phosphorylation results in the activation of cellular signal pathways such as MAPKs. The activation of Src may have a central role in mediating the effects of L-PHP on the EGF receptor. (R=receptor; \_\_\_\_\_=ac‐

The small sized L-PHP neuropeptide may play a significant role in direct regulation of pancreatic β-cell function and, through modulation of pancreatic microenvironment, support β-cell survival. The role of L-PHP may be similar to that of the gut peptide GLP-1, that increases β-cell regeneration, but may also have a role in inducing adult stem cell differentiation into

play a role in β-cell development.

160 Glucose Homeostasis

(From reference #35, with permission).

**6. Conclusions**

tivation;------=suppression) (From reference #35, with permission)

Rat islet cell function can be recovered 90-95% from a pancreatectomy after application of glucagon-like peptide 1(GLP-1) [38]. This β-cell regeneration from damaged rat pancreas has also been mimicked by STZ damaged rat pancreas following administration of L-PHP [39]. However, human islet β-cell regeneration may differ from rat and it may require a totally different microenvironment. In order to initiate human islet β-cell functional recovery from damage or loss, pancreatic stem cells or stem cells from other tissue, such as bone marrow, must be able to in vivo differentiate into multiple types of endocrine cells (αβγ) to reconstitute a new endocrine system in response to glucose challenge. Initiating L-PHP generation *in vivo* or administration from *in vitro* may be a way to approach this goal. Before the application of this peptide, a series of studies must be performed 1) to prove L-PHP can induce stem cells in the pancreatic environment to differentiate into β-cells and 2) L-PHP can induce other islet endocrine cells, such as α and γ cells, to support and regulate β-cell function, even β-cell regeneration. The current evidence from in vivo animal models and in vitro is very promising and encouraging; still multiple steps are needed before L-PHP can be applied in human diabetic therapy.
