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Hindrik Mulder

Professor, Leg. läkare

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Personlig profil

Forskning

My scientific work has focused on the insulin-secreting beta-cells in the islets of Langerhans. They release the hormone insulin, which controls whole body metabolism. Insufficient secretion of insulin is required for the development of Type 2 Diabetes, a disease with a soaring incidence. In recent years, my research activities have been devoted to metabolism in islets but I started my scientific career by examining islet hormones other than insulin.

The topic of my first scientific endeavour was the, at that time, newly discovered islet hormone islet amyloid polypeptide (IAPP), also known as amylin. We showed that IAPP is expressed in several islet cell subtypes, as well as in the gastrointestinal tract and the sensory nervous system. A major undertaking for us was to understand how expression of IAPP is regulated in these cell systems and in diabetes.

During my initial postdoctoral years, I became interested in lipid metabolism in beta-cells. We were the first to describe that the hormone-sensitive lipase (HSL) is expressed in beta-cells, controlling break down of triglycerides. This has implications both for normal control of insulin release as well as disease processes in islets, also known as lipotoxicity. Using HSL knock out mice, we were able to demonstrate that the lipase controls insulin secretion.

I also explored the link between neurodegenerative disorders and diabetes. We showed how insulin deficiency in Friedreich’s ataxia is likely to evolve, and that a mouse model for Huntington’s disease develops diabetes due to loss of beta-cells.

It was during my postdoctoral stay in Dallas at Southwestern Medical Center that I really developed my understanding of cellular metabolism. I helped create a novel insulin-producing cell line that has become one of the most widely spread tools to understand beta-cell function. We examined regulation of lipid partioning in beta-cells and its control of insulin secretion. Most importantly, we described the critical role of pyruvate cycling in insulin secretion and how it underlies stimulus-secretion coupling in the beta-cell. This was made possible by a metabolomics approach, using NMR to map metabolic pathway activity in cells.

Exposure to this novel methodology inspired me to establish a metabolomics platform at the Lund University Diabetes Centre. We have acquired several advanced mass spectrometers over the years that permitted analyses of the metabolome in cell extracts and body fluids. The approach has allowed us to further map and understand metabolism in islets and beta-cells.

We have taken a major interest in how mitochondria are genetically regulated, given their pivotal role in cellular energy metabolism and control of insulin secretion from beta-cells. Our identification of a genetic variant of TFB1M, encoding a protein that controls protein synthesis in mitochondria, which is associated with increased risk of Type 2 Diabetes, has been a strong thrust. We have also described the function of TFB2M, a paralogue of TFB1M, and DIMT1, a TFB1M-homologue, in beta-cells. 

We have also taken a strong interest in diurnal control of metabolism. This was prompted by our finding that a variant of the gene encoding the melatonin receptor 1B is strongly associated with impaired insulin release and Type 2 Diabetes. We have shown that risk individuals exhibit reduced insulin secretion due to an enhanced inhibitory effect of melatonin in islets.

Our most recent initiative is having established a platform for induced pluripotent stem cells (iPSC). We procure skin biopsies from patients, reprogram fibroblasts from these into stem cells, i.e., iPSC, which are then differentiated into insulin-producing beta-like cells. Our objective is to identify patients that carry gene variants that mediate risk of developing Type 2 Diabetes; one such gene is TFB1M. The insulin-producing cells that we can make from these patients can then be used to understand the mechanisms by which these risk genes cause dysfunction of beta-cells. An important component of our platform is genome editing by CRISPR-Cas. Using this tool, we can “correct”, i.e., replace the DNA base in or around the risk gene that we believe is underlying the genetic risk. Ultimately, such knowledge can be used to develop new and better drugs to treat Type 2 Diabetes. It is our intention to collect all the iPSC that we make into a biobank – LUNiPS – that will be made available to other researchers.

Samverkan

I have participated in the Almedalen meeting (2015), where we held a workshop about future diabetes research and care. I was invited to the World Diabetes Day event in Malmö 2016, where I talked about the future of diabetes research in Sweden. I have regularly MC’d open seminars on diabetes for the general public in Malmö and Lund.

I chair Metabolic centre (http://www.metaboltcentrum.se/), a collaborative effort on behalf of Region Skåne and Lund University. The objective is to coordinate activities in health care, academia and industry. I am vice-coordinator of EXODIAB, a strategic research environment (SFO; Excellence in diabetes research in Sweden) funded by the government. 

Undervisning

I have authored a book on Diabetes, which was intended for use at the medical programs in Sweden. It is also useful for interns and residents in Internal Medicine, as well as Diabetes nurses and educators. The book is currently available in its 3rd edition (Diabetes mellitus – ett metabolt perspektiv; Studentlitteratur).

For the last 25 years I have been teaching at different levels of the medical program in Lund. I currently lecture on diabetes during the 4th and 5th semester, and serve as a tutor during the 4th and 5th semester. I also lecture for doctoral students on the Publication process as well as on Diabetes.

I have mentored 8 doctoral students and 27 post doctoral fellows. I have served as opponent 21 times. I have given numerous invited lectures at international conferences and symposia in Europe, China, Japan and the United States, including Keystone and Gordon conferences, annual meetings of European Association for the Study of Diabetes and the Scientific Sessions of the American Diabetes Association. 

Yrkesarbete

I am a certified medical doctor in Sweden. My research career has been exclusively academic, so I have not acquired a specialty. Nevertheless, since 2004 I have managed an outpatient clinic at the Department of Endocrinology at Skåne University Hospital. I see adult diabetes patients of all ages and types once a week.  

Ämnesklassifikation (UKÄ)

  • Cell- och molekylärbiologi
  • Endokrinologi och diabetes

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Nätverk

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