Diabetes

New discoveries about enzyme’s metabolic role may lead to better diabetes treatments

A photo taken from the research papers shows normal liver tissue on the left and fatty liver tissues on the right. The white areas on the right are accumulated cholesterol. Credit: University of Alabama, Huntsville

The University of Alabama in Huntsville (UAH), has made new discoveries that could lead to a cure for type 2 diabetes.

UAH, a part of University of Alabama System, has characterized for the first time the metabolic function of a poorly understood phosphatase phosphatase enzyme called mitogen -activated protein kinase phosphatase-2.

The research suggests that MKP-2 inhibition could be a possible strategy for treating type 2 diabetes, obesity, or fatty liver disease.

“This opens many possibilities for further research towards the treatment of type 2 diabetes, and other metabolic diseases,” Dr. Ahmed Lawan, assistant professor of biological sciences and principal investigator, said.

Dr. Lawan says that recent work on MKP-5 inhibitors has opened up new strategies for allosteric modulation MKPs that can generally be applied to MKP-2. “However, there is still much work to be done.”

The UAH scientists used mice genetically engineered to be deficient in MKP-2, as well as human liver tissue derived directly from patients with fatty liver disease, to study the physiological role of MKP-2 in whole-body metabolism and determine whether MKP-2 has been altered in obesity and in human fatty liver disease.

The University of Strathclyde provided the mice, while the University of Kansas provided samples of human livers from obese patients with non-alcoholic steatohepatitis. The University of Texas at El Paso was involved in some of the experiments as well as editing the manuscript.

Dr. Lawan says, “We have shown for the first time that MKP-2 expression was upregulated within liver tissue in obese people and fatty liver disease,” “The stress response that contributes towards insulin resistance, type 2 diabetes, and fatty liver disease is MKP-2’s upregulation in the liver during obesity.”

However, the MKP-2-deficient mice had higher activities of proteins that regulate cellular processes in major-insulin sensitive tissues than control mice.

Dr. Lawan reports that MKP-2-deficient mice who are fed a high fat diet are less likely to gain weight. This is due to their reduced food intake. “Mice lacking MKP-2 had a protected liver against the development fatty liver.”

The UAH team found that mice deficient in MKP-2 also have a better balance of blood glucose and insulin sensitivity.

Dr. Lawan says that MKP-2 is upregulated in obesity, which is consistent with lower levels of insulin-like Growth Factor in mice with fatty liver disease or insulin resistance. “These data indicate MKP-2’s upregulation is physiologically relevant. It might be beneficial in hepatic fat utilization during obesity by antagonizing p38, MAPK and JNK signaling modules.”

Dr. Lawan said that UAH investigators could not prove a causal link between MKP-2, type 2 diabetes onset, and their research “is only the beginning of the story” on MKP-2.

He says that the family of phosphatases is a fascinating group of enzymes that does not get enough attention in signaling fields, as they play vital functions in terminating MAP kinase signals. “MKP-2, a poorly understood MKP,” he said.

Savanie Fernando, 2021 biological sciences graduate; Jacob Sellers; Shauri Smith; a graduate student at time of research; Dr. Sarayu Bhogoju; Sadie Junkins; a 2022 graduate in biological sciences with a bachelor’s and has applied to medical school; Nabin Gimire, a biosciences doctoral student; Cassandra Secunda; and Morgan Welch; a master’s student in biological sciences.

Dr. Lawan said that much more research is needed to fully understand the role played by MKP-2 enzymes in liver metabolism.

“The goal of future research is to address MKP-2’s tissue-specific contribution in tissues such the liver, brain, pancreas and brain towards glucose disposal and energy metabolic,” he said. “We will continue to evaluate the translatability our findings in MKP-2-deficient mice using liver and adipose tissues and pancreas samples taken from obese NASH and type-2 diabetes patients.”


A protective factor was found to prevent excess lipid accumulation in obese mice livers. Potential treatment for fatty liver disease


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University of Alabama Huntsville


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New findings about the metabolic role of enzymes may lead to improved diabetes treatments (2022, 26 June 28).
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