Abstract:
Background: Myricetin (MyR), a bioflavonoid known for its broad therapeutic spectrum, has
shown promising anti-diabetic potential, making it a viable candidate for managing Type 2
Diabetes Mellitus (T2DM). While numerous in-vitro and in-vivo studies support its role in glucose
homeostasis, the precise molecular mechanisms underlying its action remain inadequately
explored.
Objective: To identify the intracellular signaling pathways involved in MyR-induced insulin
secretion in INS-1 β-cells, with a focus on identifying key molecular effectors and their
pharmacological modulation
Methods: A rigorous experimental approach was used, incorporating the MTT assay (50,000 INS-
1 cells/well) to assess cell viability, and a static glucose-stimulated insulin secretion (GSIS) assay
(100,000 INS-1 cells/well) under 2 mM and 20 mM glucose to quantify insulin secretion after
exposure to MyR (5-160 μM). Pharmacological inhibitors, including H-89 (PKA inhibitor, 50μM),
KN-62 (CaMKII inhibitor, 10 μM), GO6976 (PKC inhibitor, 1μM), U0126 (MEK inhibitor, 10
mM), Nifedipine (L-type VGCC blocker, 10 μM), EGTA (extracellular Ca²⁺chelator, 2 mM), and
Diazoxide (K_ATP channel opener, 50 μM) were used to dissect the signaling pathways
modulated by MyR.
Results: MyR significantly enhanced insulin secretion in a glucose-dependent manner, with
peaking at a non-toxic dose of 80 μM (7.652±0.3315% μg/100,000 INS-1cells/hour) in 20 mM
glucose. Insulin secretion levels remained unchanged in the presence of L-type VGCC and
K_ATP channel inhibitors, indicating that MyR’s insulinotropic effect is independent of these
pathways. In contrast, the response was markedly reduced upon inhibition of PKA, CaMKII, PKC,
and MEK pathways, indicating their pivotal roles in MyR-mediated β-cell signaling.
Conclusions: MyR induces insulin secretion in a glucose-dependent manner and activating
multiple kinase pathways. Further investigations using β-cells and animal models are warranted to
fully elucidate the physiological relevance of these mechanisms. These insights could pave the
way for uncovering MyR-based therapies that are both effective and affordable for managing
T2DM.
