UPS and Diabetes: Disrupting the logistics of glucokinase regulation

A decrease in activity of the Ubiquitin Proteasome System (UPS) was recently linked with type 2 diabetes mellitus, an adult-onset form of diabetes characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Following down-regulation of UPS, key players involved in metabolism and/or cell responsiveness to glucose levels can become affected by protein misfolding. In their publication in Biochemical Journal, Dr. Hofmeister-Brix and colleagues from the Institute of Clinical Biochemistry at the Hannover Medical School demonstrated the implication of the glucose sensor enzyme, glucokinase, in this process. Using pancreatic beta cells treated with Enzo’s proteasome selective inhibitor, MG-132, they observed a lack of insulin secretion at basal and stimulating glucose levels, therefore reproducing an ideal model for the study of diabetes. While treatment with MG-132 had a limited effect on the actual viability of these cells, glucokinase activity was significantly decreased and this was accompanied by a significant increase in glucokinase content. Interestingly, this accumulation of misfolded and inactive enzymes correlated with the formation of aggresomes rich in endogenous ubiquitinylated glucokinase in the perinuclear region of the cells as revealed using Enzo's ProteoStat Aggresome detection kit. This study suggests the regulation of glucokinase by the UPS and highlights the ever ongoing need to understand the underlying causes behind type 2 diabetes.

Enzo Life Sciences offers biologists a comprehensive portfolio to study the protein degradation machinery including proteasome inhibitors, antibodies, quantitative and enzymatic assays and live cell analysis tools, some of which are described below:

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