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Publication in PNAS

Mutation makes TRPM6 "deaf" for insulin

TRPM6 in PNAS 7 Jul 2012

This months in PNAS Anil Nair (not on photo), Sjoerd Verkaart, Femke van Zeeland, RenĂ© Bindels and Joost Hoenderop, together with colleagues from Germany, Switzerland and China demonstrated a vital role of the magnesium channel TRPM6 in Diabetes type 2. The incidence of Diabetes has increased markedly over de last 50 years and in 2010 approximately 285 million people have been diagnosed with the disease. TRPM6 is normally activated by insulin but the channel seems "deaf" for this hormone in pregnant woman who develop type 2 Diabetes leading to disturbances in body magnesium balance. There is a strong association of magnesium shortage and the occurence of Diabetes type 2 but so far the molecular mechanism was not clear. Our study provides the first mechanistic clue to explain this phenomenon.

This weekend the most popular national paper of the Netherlands, the Telegraaf, covers our new publication in an article. Also the popular website nu.nl covers the story about the publication.

To read more info in Dutch go to this website.

Our postdoc Anil Nair is now working in the group of Dennis Brown at Harvard Medical School.

 

Abstract of the study: "There is growing evidence suggesting that Mg2+ deficiency is a significant risk factor for the development of insulin resistance Diabetes Mellitus type 2 (DM2), but the underlying molecular mechanism is unknown. Mg2+ is an essential cofactor for multiple enzymes involved in glucose metabolism including the insulin receptor function. Several cohort studies found an inverse association between Mg2+ intake and risk for diabetes or insulin resistance.   About 5 to 10% of women who have had gestational diabetes go on to develop Type 2 diabetes after pregnancy. Pregnancy represents a unique situation of relative Mg2+ deficiency. We assume that this condition may synergistically increase the risk for impaired glucose tolerance beside the well-known effects of female sex hormones. Our study clearly demonstrates that two genetic variants of the TRPM6 channel (V1393I, K1584E) are associated with high glucose levels. The more frequent genetic variant, TRPM6(K1584E), was associated with a higher likelihood of developing a significant  impairment in glycemic control. We demonstrated that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V1393I) and TRPM6(K1584E) which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T1391)and TRPM6(S1583). These genetic variants of TRPM6 could be used as potential biomarkers to improve diagnosis and identify those at risk for developing DM2-induced hypomagnesemia".

 


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