Masakazu Shiota, DVM, PhD

Masakazu Shiota, DVM, PhD

Associate Professor, Molecular Physiology and Biophysics

762 Robinson Research Building
(615) 936-1092

Hepatic Glucose Flux Regulation in Obesity and Type 2 Diabetes.

Research Description

The liver plays a central role in glucose homeostasis. During the postabsorptive and fasting period, >90% of glucose production is derived from the liver. When glucose enters the blood following feeding, the liver switches from net glucose production to net glucose uptake to lessen the rise in blood glucose. Such switching is regulated by raised blood glucose per se and plasma insulin. Impaired suppression of hepatic glucose production and a defect in hepatic glucose uptake in response to the raise in plasma glucose and insulin are major pathogenesis in fasting and excessive postprandial hyperglycemia that are common feature in obesity and diabetes. Our laboratory is interested in the mechanism of the unresponsiveness of hepatic glucose flux to changes in blood glucose and plasma insulin in obesity and diabetes. 
Glucokinase (GK) plays a critical role in determining net hepatic glucose flux by catalyzing glucose phosphorylation, the first step of glucose utilization by the liver, and by opposing glucose-6-phosphatase, which catalyze glucose de-phosphorylation, the last step of glucose production by the liver. GK activity is regulated allosterically by its regulatory protein (GKRP). GKRP binds to the allosteric site in GK and inhibits GK decreasing the apparent affinity of the enzyme for glucose. We found that in normal rats, GK, but not GKRP, translocated rapidly from the nucleus to the cytoplasm in response to physiological increases in plasma glucose and/or insulin while both proteins co-located in the nucleus in the presence of basal levels of plasma glucose and insulin. We also found that the unresponsiveness of hepatic glucose flux to the rise in plasma glucose and/or insulin seen in Zucker diabetic fatty rats, type 2 diabetes model with obesity, was associated with impaired trasnlocation of GK in the early stage of diabetes and abnormal localization of GKRP in the cytoplasm together with GK in the later stage of diabetes. 
To understand pathogenic role for altered regulation of GK activity by GKRP in impaired hepatic glucose flux in obesity and diabetes, our laboratory focuses on 1) mechanism by which the subcellular localization of GK and GKRP is determined in normal animals, 2) the way in which the GK translocation is impaired in the early stage of diabetes, 3) the relationship between altered distribution of GKRP and impaired glucose phosphorylation by GK in later stage of diabetes, and 4) effect of increasing free (unbound) GK by transfecting GK gene to improve impaired responsiveness of hepatic glucose flux to the rise in plasma glucose and/or insulin and to reduce hyperglycemia in diabetic animals.