Molecular Nexus between Insulin-like peptides and Downstream Kinases Regulate Glucose Homeostasis, Cell Survival and Growth in Drosophila

Abstract

Drosophila is a versatile model organism to study metabolic disorders, one such being diabetes mellitus. Eight insulin-like peptides (ILPs) have been identified in Drosophila . ILPs are produced from paired Insulin-producing cells present in brain ganglia. Another protein called adipokinetic hormone (AKH) is homologous to mammalian glucagon and is released from the corpora cardiaca. Synergistic action of ILP and AKH maintains sugar homeostasis in Drosophila . ILP binds with insulin receptors on the adipocytes and trigger autophosphorylation and dimerization. The activated receptors then initiate a downstream signaling by various modulators to phosphorylate Akt (protein kinase B, a serine-threonine-specific protein kinase). Akt, when activated, targets multiple signaling molecules including Target of Rapamycin (TOR) that participates in glucose metabolism, protein synthesis, cell proliferation, neuroendocrine signaling, and stress response. Akt also phosphorylates transcription factor FOXO that promotes cell survival by up-regulating TRAIL, a pro-apoptotic protein. High lipid accumulation in the fat body is linked with insulin resistance in Drosophila . Drosophila reared on high lipid diet shows up-regulation in protein kinase C (PKC). PKC is known to antagonize insulin signaling in fruit flies. A clear concept regarding the complex process of glucose homeostasis can be generated through further investigations. Since Drosophila has several advantages over vertebrate models, it can be used to identify additional modulators of insulin biology and metabolism.