Temporal Effects of a Viral Peptide on Glucose-Stimulated Insulin Secretion

Impaired glucose homeostasis, often attributed to the destruction of insulin-secreting pancreatic β-cells, results in Type 1 diabetes (T1D). While both genetic and environmental factors have been implicated in the onset of T1D, there is an increase in clinical observations of T1D resulting from or triggered by viral infections. Despite the increase mentioned above, mechanistic insights into viral-induced T1D onset remain scarce. The key question of how viral infections may impact insulin secretion, thereby affecting glucose-stimulated insulin secretion (GSIS), is still unanswered. In this work, we correlate GSIS and viral peptides for the first time. Using the Mouse Insulinoma 6 (MIN6) cell line as a model system for β cells, we studied pituitary adenylate cyclase-activating polypeptide (PACAP) potentiated GSIS. Specifically, we noted that two forms of PACAP, namely, PACAP38 (P38) and PACAP27 (P27) are important in GSIS. From proteomes of chikungunya and dengue viruses (CHIKV and DV, respectively) implicated in triggering T1D, we identified viral peptides that were similar (but not identical) to PACAP. We report that a peptide from CHIKV, termed as CV1, enhances insulin secretion in MIN6 cells along with P38; however, independent treatments with CV1 yield variable outcomes based on duration of incubation. While short-term treatment shows viral peptides outcompeting P38, leading to increased insulin secretion without cytotoxicity, there is a decrease in cell viability with longer incubations under some conditions. Remarkably, long-term CV1 incubation significantly reduces glucose sensitivity of and GSIS by MIN6 cells. We report the first experimental evidence linking viral peptides to GSIS (specifically PACAP-stimulated).