05 Jul Study Detects Mechanism That Keeps Insulin Receptors on Cell Surface
MedicalResearch.com Interview with:
Dr. Eunhee Choi
Research scientist in the Yu laboratory and lead author of the study
UT SouthWestern
Dr. Hongtao Yu, Professor of Pharmacology at UT Southwestern and
Investigator with the Howard Hughes Medical Institute (HHMI).
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Diabetes is a metabolic disease. High blood sugar is a common symptom of diabetes, and over time it can lead to serious damage to multiple organs. Insulin, a hormone made by the pancreas, regulates blood sugar. Diabetes can occur either when the pancreas does not produce enough insulin (type 1 diabetes) or when the cells in our body cannot efficiently respond to insulin (type 2 diabetes). Diabetes is now a major global epidemic. The World Health Organization (WHO) estimates that more than 400 million people worldwide have diabetes.
Insulin binds the insulin receptor (IR) at the cell surface. The insulin-bound IR can send signals inside the cell and instruct the cell to take up sugar from the blood, thus maintaining healthy blood sugar levels. After insulin has done its job, insulin-bound IR is packaged into small vesicles with a protein coat and dragged into the cell, thus terminating the signals. An adequate level of IR on the cell surface is crucial for insulin signaling and blood sugar metabolism. We have found a new mechanism that keeps IR at the cell surface. Without such a mechanism, IR is prematurely dragged inside the cell before it encounters insulin.
Our discovery is quite unexpected. A main interest of our lab is to study the molecular control of cell division. During each cell division, the duplicated sister chromosomes are evenly separated into two daughter cells. A cellular surveillance system called the spindle checkpoint ensures the accuracy of sister-chromosome separation. Three checkpoint proteins, p31comet, MAD2 and BUBR1, are critical for accurate chromosome segregation. In the process of studying this checkpoint, we have unexpectedly discovered that mice lacking p31comet in the liver develop diabetes. Liver cells lacking p31comet do not have IR on the cell surface, and thus cannot respond to insulin. We have further shown that MAD2 directly binds to IR, and along with BUBR1, helps to drag IR inside the cell. p31comet prevents BUBR1 from interacting with IR-bound MAD2, thus keeping IR at the cell surface. In cells lacking p31comet, MAD2 and BUBR1 gain the upper hand and remove IR from the cell surface. Thus, the dynamic tug-of-war between p31comet and MAD2-BUBR1 determines the status of IR at the cell surface.
MedicalResearch.com: What should readers take away from your report?
Response: We have shown that the mitotic checkpoint regulators control insulin signaling through modulating IR levels on the cell surface. This is a fine example of how an entire branch of key regulators in one cellular pathway can be used for another. The crosstalk between two pathways might allow extracellular hormones to regulate chromosome segregation during cell division.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Type 2 diabetes is the most common form of diabetes. Unlike type 1 diabetes, patients with type 2 diabetes produce insulin but their body cannot respond properly to insulin. Our study suggests the premature loss of IR from the cell surface as a potential cause of type 2 diabetes. In the future, it will be interesting to examine and compare the IR levels on cellular surface in the liver biopsies of healthy people versus type 2 diabetes patients.
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Citation:
Eunhee Choi, Xiangli Zhang, Chao Xing, Hongtao Yu.Mitotic Checkpoint Regulators Control Insulin Signaling and Metabolic Homeostasis. Cell, 2016; DOI:10.1016/j.cell.2016.05.074
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
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Last Updated on July 5, 2016 by Marie Benz MD FAAD