A new breakthrough may help scientists better understand the molecular mechanism behind insulin regulation of glucose uptake in fat and muscle cells.
The conserved phospholipid enzyme, PIKfyve, was discovered by Assia Shisheva, Ph.D., professor of physiology in Wayne State University's School of Medicine, lab in 1999.
Based on studies in cultured cells, the lab has implicated PIKfyve in the insulin-regulated glucose transport activation, which led to the development of a unique mouse model with PIKfyve ablation, or removal, in muscle (MPlfKO), the tissue responsible for the majority of postprandial glucose disposal.
Shisheva said that her team found a striking metabolic phenotype in the MPIfKO mice consisting of glucose intolerance and insulin resistance at an early age and on a normal diet.
She said that the study also revealed that PIKfyve is essential for normal insulin signaling to GLUT4/glucose transport in muscle and provided the first in vivo evidence for the central role of PIKfyve in the mechanisms regulating healthy blood glucose levels, or glucose homeostasis.
In addition, the research team found that these metabolic disturbances were followed by increased animal fat (adiposity) and elevated levels of insulin (hyperinsulinemia), but not abnormal amounts of lipids or cholesterol in the blood (dyslipidemia).
Shisheva said that the combined phenotype manifested by the MPlfKO mouse closely recapitulates the cluster of typical features in human prediabetes including systemic glucose intolerance and insulin resistance, hyperinsulinemia and increased visceral obesity without dyslipidemia.
She added that therefore, their mouse model, in addition to providing novel mechanisms of insulin resistance, represents a valuable tool for exploring new preclinical strategies to improve treatments in individuals with prediabetes.
The study has been published online in the American Journal of Physiology - Endocrinology and Metabolism.