Phosphatidylinositol-3,4,5-Triphosphate and Cellular Signaling: Implications for Obesity and Diabetes

Abstract

Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P₃) is one of the most important phosphoinositides and is capable of activating a wide range of proteins through its interaction with their specific binding domains. Localization and activation of these effector proteins regulate a number of cellular functions, including cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism. Phosphoinositides have been investigated as an important agonist-dependent second messenger in the regulation of diverse physiological events depending upon the phosphorylation status of their inositol group. Dysregulation in formation as well as metabolism of phosphoinositides is associated with various pathophysiological disorders such as inflammation, allergy, cardiovascular diseases, cancer, and metabolic diseases. Recent studies have demonstrated that the impaired metabolism of PtdIns(3,4,5)P₃ is a prime mediator of insulin resistance associated with various metabolic diseases including obesity and diabetes. This review examines the current status of the role of PtdIns(3,4,5)P₃ signaling in the regulation of various cellular functions and the implications of dysregulated PtdIns(3,4,5)P₃ signaling in obesity, diabetes, and their associated complications.

The relationship between phospholipids and insulin resistance: From clinical to experimental studies

“…Phosphatidylinositol and its derivatives make up only about 10%‐20% of all phospholipids. Although a minor quantitative portion they are important intracellular second messengers and participate in universal signalling entities in cells, including vesicular trafficking, lipid distribution and metabolism, ion channels, pumps, transporters, and endocytic and exocytic processes . Derangements in phosphatidylinositol and its derivatives are responsible for many human diseases ranging from genetic disorders to the most common cancers and metabolic diseases .…”

“…Insulin treatment of fat and muscle cells results in a rapid increase in glucose transport by controlling the amount of glucose transporter‐4 (GLUT4) translocation from cytoplasm to plasma membrane. In the process of insulin‐stimulated glucose uptake, PIP, PIP2 and PIP3 all play key roles in integrating the insulin receptor‐issued signals with GLUT4 surface translocation and glucose transport activation . PI3K is the key enzyme for generating phosphatidylinositol species.…”

Elevated B Cell Activation is Associated with Type 2 Diabetes Development in Obese Subjects

“…However, despite overwhelmingly strong association of obesity and diabetes in people of European or African descents, in the East Asian population, obesity and diabetes are only moderately associated, with only about 30% of diabetic cases being obese and only about one-third of obese insulin-resistant individuals eventually develop T2D [3]. Genetic and epigenetic factors, as well as immunological correlates, such as previous infection history, diet and intestinal microbe composition, were thought to explain this heterogeneity [2,4].…”

Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

“…Inactivation of the PI3K/AKT signaling has been considered as a hallmark for metabolic diseases9. For the liver, aberrant PI3K/AKT signaling has increasingly emerged as one of the major reasons for liver dysfunction and the metabolic syndrome10. A number of external stimuli and substantial regulators were indicated to regulate the activity of PI3K/ AKT signaling11.…”