Magnesium in health and disease the role and regulation of magnesiumThis research group examines the role of magnesium in health and disease. Jeroen's team studies the regulation of magnesium handling by the intestine and the kidney, as well as, the role of magnesium in disease including diabetes mellitus type 2 and chronic kidney disease.
Our research group has several aims.
Using next-generation sequencing, we aim to identify the genetic origin of disease in patients with magnesium disturbances.
Magnesium balanceUsing next-generation sequencing, we aim to identify the genetic origin of disease in patients with magnesium disturbances. Using a wide range of molecular, cellular and physiological techniques, we examine new genes or new regulatory pathways in magnesium (re)absorption in the intestine and in the kidney. Identification of new genes that cause hypomagnesemia is essential for the development of new treatments.For Health Care Professionals: We are currently recruiting new patients! Please contact us for genetic testing of patients with hereditary hypomagnesemia.
Supported by NWO Rubicon and Dutch Diabetes Research Foundaiton Grants, my team is examining the role of magnesium in the development of the diabetes mellitus type 2.
Hypomagnesemia in diabetes mellitusSupported by NWO Rubicon and Dutch Diabetes Research Foundaiton Grants, my team is examining the role of magnesium in the development of the diabetes mellitus type 2. As 30% of all type 2 diabetics suffers from hypomagnesemia, we aim to effects of magnesium on lipid and glucose metabolism. By examining the effects of magnesium on insulin secretion and insulin sensitivity, we aim to understand why patients with hypomagnesemia have a worse disease progression.
We examine whether magnesium prevents vascular calcification in the context of chronic kidney disease.
Magnesium treatment for vascular calcificationCardiovascular complications are the main cause of death for patients with chronic kidney disease. In this research project funded by the Dutch Kidney Foundation, we examine whether magnesium prevents vascular calcification in the context of chronic kidney disease. By analysing crystal formation, cellular transdifferentiation and animals models, we aim to reduce vascular calcification.
Several discoveries were made by our research group.
We did three important findings regarding magnesium balance.
- HNF1B was shown to be the transcriptional regulator of the Kir4.1/Kir5.1 K+ channel. This finding explains why HNF1B patients suffer from hypomagnesemia and hypokalemia mimicking Gitelman syndrome. (Kidney Int 2017).
- CNNM2 mutations were identified in patients with hypomagnesemia, intellectual disability and seizures. We showed in cell models and zebrafish that CNNM2 is essential for the Mg2+ balance and brain development (PLOS Genetics 2014).
- Mutations in PCBD1 cause maturity-onset diabetes of the young and hypomagnesemia. PCBD1 was shown to be a co-factor of HNF1B and has an effect on the transcriptional regulation of magnesium reabsorption in the kidney (J Am Soc Nephrol 2013).
We did three important findings regarding hypomagnesemia in diabetes mellitus.
Hypomagnesemia in diabetes mellitus
- Magnesium deficiency abrogates HFD-induced obesity in mice through enhanced eWAT lipolysis and BAT activity. (Diabetologia, 2018).
- Free fatty acid triacylglycerol levels directly reduce the blood magnesium concentration, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. (Diabetelogia, 2019).
- We determined that 30% of patients with diabetes mellitus type 2 has hypomagnesemia. Blood glucose and triglyceride levels were associated with blood magnesium concentration in a cohort of 400 patients. (Eur J Endocrinol Metab., 2017).
We did three important findings regarding magnesium treatment for vascular calcification.
Magnesium treatment for vascular calcification
- Magnesium prevents vascular calcification in Klotho knockout mice, at the expense of osteomalacia. (In press, 2019).
- Magnesium was shown to prevent vascular calcification in vascular smooth muscle cell cultures. Our findings indicate that magnesium inhibits crystal formation and thereby prevents calcification. (Sci reports, 2018).
- Literature research indicates that many studies support an association between serum magnesium and cardiovascular disease risk. A substantial body of in vitro and in vivo studies has identified a protective role for magnesium in vascular calcification. (Arterioscler Thromb Vasc Biol., 2017).
Jeroen de Baaij The rewards of multiple grants
Jeroen de Baaij from the department of Physiology (theme: Renal disorders) was awarded not one, but three personal grants in 2017, adding up to € 750,000. It not only allows him to continue the research into magnesium deficiencies he started as a PhD candidate but also to set up his own research team. Jeroen is excited that he can shift focus from a rare disease to issues that effect a larger population. It’s no wonder that both the Dutch kidney and diabetes foundations are supporting his research. Summing up, he was awarded the following personal grants in 2017: Veni Grant from the Netherlands Organization for Scientific Research (NWO), a Junior Kolff Fellowship from the Dutch Kidney Foundation and a Junior Fellowship from the Dutch Diabetes Research Foundation. Jeroen is also part of a consortium that was awarded a grant.
Q1 What are you going to research with these funds?
“My research will build on what I studied as a PhD candidate. I looked at the genetic origin of disease in patients with magnesium disturbances. Renal magnesium wasting is often the cause of hypomagnesemia in patients. Magnesium deficiency can cause such things as fatigue, generalized weakness, muscle cramps and abnormal heart rhythms. As a PhD candidate I looked at rare diseases and was so able to concentrate on one defect. Now I turn my attention to a larger population.
Magnesium deficiency, for example, is also connected to diabetes. One in three diabetic patients has a magnesium deficiency. What is the correlation: does diabetes cause the magnesium deficiency or does magnesium deficiency contribute to the development of diabetes?
My current research project 'The magnesium journey through the renal cell: how to get out?' will examine the cells that transport magnesium in the kidney. For fifteen years, it’s been known how magnesium enters these kidney cells, but the mechanism of subsequent extrusion to the blood compartment remains elusive.”
Q2 The received funding allows you to set up your own team. Such a large team is happening sooner than it might otherwise have. Does leading a team make you nervous?
“No, not at all. I get great energy from a team. As a starting postdoc, I also had the funds to get assistance. I got the chance to train people and I really enjoy supervising other researchers. Watching them grow is rewarding. It doesn’t put pressure on me but I’m aware that to continue with a team I’ll need to keep the funds coming in. There’s a time pressure. You cannot slack on finding funding or on getting research results. For example, you can only apply for a Veni, Vidi or Vici grant within a certain amount of years after your PhD. With the current grants I can move forward for a few years, but soon I’ll have to start applying for new grants again.”
Q3 I’m guessing, having to apply for these grants takes a lot of time. Do you think it’s a lot of precious time that’s taken away from research?
“I’ve been very fortunate to have received a number of grants. I can imagine if you’ve spent a lot of time applying but not receiving anything, that it can be frustrating. I do feel, though, that there’s value to applying for grants. It helps shape your ideas. You can easily get distracted by all the small issues and possible paths that a project can take. Grant writing forces you to make clear decisions.
There is, however, a long waiting process which can be tiresome. I might write a proposal in January and not hear until December if I got the grant. In between there are lots of steps that also demand your time and attention.”
Q4 You received two funds from a foundation. Did your research have to have a clear outcome for patients to be applicable for these grants?
“A foundation does want the benefits for their target group to be clear. And that’s fair enough. People have spent lots of time gathering funds for these specific patients. The role of the patient is more important for foundations. The Veni grant, for example, focuses much more on pure scientific issues and academic talent. I will continue in research as long as the questions are interesting and I can get to the next step
But it’s wrong to think that foundations are specifically looking for a new treatment. When applying for these grants I concentrated more on the patients. For one application I even consulted with some patients and took their comments on board. When I had the chance to talk to patients, I realized that for them, finding a treatment is not all they want from research. For them understanding what is happening and why it’s happening is also important. Simply knowing can make a huge difference to them.”
Q5 Was it always clear to you that you wanted to help patients by doing research?
“To be honest, when I began studying Biology, I thought the last thing I’d be doing was research. I guess I had a naïve image of researcher: a pipette in hand, tucked away in a lab. But during my Master’s in France I realized it’s so much more. It’s about solving puzzles. It’s also about working together. Research can be a slow process but it’s also so rewarding.
I will continue in research as long as the questions are interesting and I can get to the next step. I’m really not sure where the questions will take me. We’ll see.”
Regulation of magnesium transport by TRPM6
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