J Mol Endo

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Abstract

Type 2 diabetes (T2D) is characterized by chronic insulin resistance and a progressive decline in beta-cell function. Although rigorous glucose control can reduce morbidity and mortality associated with diabetes, achieving optimal long- term glycemic control remains to be accomplished in many diabetic patients. As beta-cell mass and function inevitably decline in T2D, exogenous insulin administration is almost unavoidable as a final outcome despite the use of oral antihyperglycemic agents in many diabetic patients. Pancreatic islet cell death, but not the defect in new islet formation or beta-cell replication, has been blamed for the decrease in beta-cell mass observed in T2D patients. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve the management of T2D, because of its potential to reverse diabetes not just ameliorate glycemia. Therefore, an ideal beta-cell-preserving agent is expected to protect beta cells from apoptosis and stimulate postprandial insulin secretion along with increasing beta-cell replication and/or islet neogenesis. One such potential agent, the islet endocrine neuropeptide vasoactive intestinal peptide (VIP) strongly stimulates postprandial insulin secretion. Because of its broad spectrum of biological functions such as acting as a potent anti-inflammatory factor through suppression of Th1 immune response, and induction of immune tolerance via regulatory T cells, VIP has emerged as a promising therapeutic agent for the treatment of many autoimmune diseases including diabetes.

Figure 1 Mechanism of VIP-augmented glucose-induced insulin secretion. While VPAC1 and VPAC2 receptors can be activated by both VIP and PACAP, PAC1 can only selectively interact with PACAP. G protein-coupled receptors stimulate G proteins resulting in the activation of AC, a cAMP-producing enzyme from ATP. Binding of cAMP to PKA results in dissociation of catalytic subunits of PKA from regulatory subunits phosphorylating several cytoplasmic proteins involved in exocytosis of insulin. However, VIP-induced insulin secretion takes place only in the presence of glucose. VIP and PACAP have insulinotropic effects on pancreatic beta cells.

Figure 2 Potential functional roles of VIP on pancreatic beta cells. VIP treatment augments glucose-induced insulin secretion lowering blood glucose of diabetics. Although ectopic PACAP expression has been shown to enhance proliferation of pancreatic beta cells in STZ-induced diabetes, whether or not VIP overexpression in pancreatic beta cells would result in a similar phenotype has not been tested yet.

Figure 3 VIP-induced immune tolerance. VIP has two different ways of generating regulatory T cells (Tregs) that are crucial for the maintenance of immune tolerance. Under the influence of VIP, monocytes and dendritic cells originating from bone marrow yield immature dendritic cells (DCs) characterized by low-level co-stimulatory molecule expression, such as CD40, CD80, and/or CD86. These immature DCs also display enhanced expression of IL10 (shown as spherical substances in figure) while TNFa, IL12, and IL6 expressions are reduced.Alternatively, VIP can generate CD4+CD25+FoxP3+ cells directly from the peripheral naive CD4+CD25+ T cells. These cells express high levels of CTLA4 and produce substantial levels of IL10/TGFb. VIP-induced Tregs can block autoreactive Th1 cells to prevent autoimmunity favoring Th2 type response. Arrows in the figure indicate a decrease or an increase in the expression levels of molecules of interest while arrowheads show the direction of cell differentiation process.

In conclusion, despite the presence of numerous novel therapeutic agents developed against T2D, a rare disease of the past became a modern day pandemic. Hence, discovery of novel therapeutic interventions with the potential to rejuvenate beta-cell function and mass will be very crucial in bringing a modern day pandemic disease down to its original rare status.