Metabolic health: pathophysiological trajectories and therapy

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Internal Medicine / Endocrinology.


The research of the division of Endocrinology within the department of Internal Medicine is concentrated around the pathophysiology, prevention and  treatment of metabolic disease, including regenerative strategies. The research focuses on three themes: 1) regulation of energy metabolism, 2) beta-cell regeneration, and 3) bone and mineral research, all of which are organized in a multidisciplinary way.
These themes are aligned with several ‘Top Referral Functions’ (TRF) of the division: ‘Endocrine tumours’, ‘Diabetes/Islet transplantation’, and ‘Metabolic bone disease’. More specifically, this concerns TRF expertise in endocrine tumours (i.e. pituitary tumors, (para)thyroid gland tumors, paragangliomas, familial neuroendocrine tumors, and adrenal cancer), diabetes related to cardiovascular disease, islet transplantation, as well as rare (fibrous dysplasia of bone, sterno-costo-clavicular hyperostosis (SCCH), hyperparathyroidism, and Paget’s disease of bone) and common (osteoporosis) diseases of the skeleton. TRF expertise on endocrine tumours is put together within the Center for Endocrine Tumors Leiden (CETL), chaired by Prof. AM Pereira, which is a multi-disciplinary referral center for patients with endocrine tumors, which connects and translates state-of-the art referral care activities with both educational activities and research. TRF expertise in bone diseases in brought together in the Center for Bone Quality, chaired by Dr. N Appelman-Dijkstra.
Endocrine tumors are rare, complex conditions; CETL took care of approx. 2400 patients in 2016. Diabetes is a common disease. The International Diabetes Federation estimates that 425 million people are living with diabetes worldwide (1 in 11 adults has diabetes), which will rise to 629 million by 2045, making it one of the most common chronic diseases, with cardiovascular disease  being the leading cause of death (2.7 million). Rare and common diseases of the skeleton cause high morbidity and mortality, and osteoporotic fractures cause more immobile days in bed than chronic obstructive pulmonary disease, stroke or myocardial infarction. Rare bone diseases serve as a model for the more general condition of osteoporosis. In the Netherlands, 38,666 older individuals have osteoporosis-related fractures, which is expected to increase to 53,993 in 2030.

Theme 1: Regulation of energy metabolism 

The pathogenesis of cardiometabolic disease is still incompletely understood. This theme has two important lines: 1) Prevention and treatment of cardiovascular complications of disturbed energy metabolism as observed in abdominal obesity and type 2 diabetes, with strategies focused on both modulation of energy intake (e.g. very low calorie-mimicking diets, intermittent fasting) and energy expenditure (e.g. activation of brown adipose tissue, modulation of the gut microbiome, and stress circuits). 2) Prevention and treatment of endocrine tumors. Research aims at the dissection of the molecular pathogenesis and the consequences of these disorders, and the development of novel diagnostic and therapeutic strategies. In addition, these disorders, that are usually accompanied by controlled changes in hormone systems, are also studied as models for endocrine regulation (e.g. effects of hypothyroidism or hypercortisolism on metabolism).

Theme 2: Beta-cell regeneration 

The most important activities around the ‘islet transplantation project’ are organized and financed within the division of Nephrology. This theme has two important lines: 1) improvement of islet transplantation and 2) research on stem/progenitor cells for beta-cell therapy in humans, with focus on human cells and applications. Both research lines are closely related to the clinical islet transplantation program that has recently been established at LUMC. The first phase of the construction of the research group consisted of the initiation of a structure in which human cell material (islets and stem/progenitor cells) become available for research on a regular basis. The islet transplantation team is now fully operational with regular availability of cell material for research since 2009. A close collaboration has been initiated with the Hubrecht Institute at which Prof. EJP de Koning is also group leader since 2010.

Theme 3: Bone and mineral research

The pathogenesis of skeletal diseases and disturbances of bone metabolism are still not completely understood and despite advances in therapeutics, new treatment modalities are needed. The long-term goal of this research programme is the development of improved methods for diagnosis, prevention and treatment of bone diseases. Emphasis is on translational research using patients with rare bone diseases as model for hypo- or hyperfunction of bone cells. Clinical and research activities are mixed within these theme. The group currently is actively involved both in the European Reference Network (ERN) for rare bone diseases (BOND), and in ENDO-ERN, and is one of the key members of the International Fibrous Dysplasia consortium together with the National Institute of Health (NIH) in Bethesda, USA.
All subjects studied belong to the LUMC medical research profile area of Vascular and Regenerative Medicine, which fits well with Regenerative Medicine being one of the three healthcare-related topics that are part of the Dutch National Research Agenda. The overarching goal of our research, innovation in disease prevention, monitoring and therapy is built on strong pillars of basic science programs and ‘state of the art technologies’ in physiology, systems biology, genetics, molecular biology, regenerative biology, and imaging.

Aim and focus

Research in the division of Endocrinology is multidisciplinary and covers clinical, translational and basic areas with the ultimate aim to improve patient care. The division is organized in different subgroups that focus on understanding the pathophysiology, the prevention and cure of:

  • Type 1 diabetes (pancreas and islet transplantation, beta cell function)
  • Type 2 diabetes and associated cardiovascular disease (brown adipose tissue, gut microbiome, stress circuits)
  • Endocrine tumors (pituitary, (para)thyroid gland, familial neuroendocrine, adrenal tumors, and paragangliomas)
  • Bone disease (SCCH, chronic recurrent multifocal osteomyelitis (CRMO), diffuse sclerosing osteomyelitis (DSO) of the mandible; fibrous dysplasia of bone; secondary osteoporosis; Paget’s disease of bone.

Position in international context

Our lead scientists are actively involved in several (scientific advisory) boards and research consortia. Prof Rensen is president of the European Lipoprotein Club (ELC; Prof Pereira is president of the European NeuroEndocrine Association (2016-2018; and coordinator of the European Reference Network (ERN) on Rare Endocrine Conditions (2017-2022). Dr Appelman is actively involved in the ERN on Rare Bone Diseases (BOND), and the ERN on Rare Endocrine Conditions (ENDO-ERN), and key member of the international Fibrous Dysplasia consortium. Prof EJP de Koning coordinates multi-center research programs on improvement of islet transplantation (DCTI), and develops new cell replacement therapies (RegMed XB). Principle Investigators have established collaborations with excellent international research groups on vascular biology (Lüscher, Zurich), energy metabolism (Karpe, Oxford), brown adipose tissue (Heeren, Hamburg), and endocrine tumors (Stratakis, NIH, Bethesda; Melmed, UCLA; Stalla, Max Planck Munich; Lightman, Bristol University; Webb, Barcelona: Johansson, Gothenborg), beta-cells (Dor, Jerusalem; Maedler, Bremen; Wollheim, Geneva; Heimberg, Brussels), fibrous dysplasia (NIH, Bethesda, USA), hyperparathyroidism (University of Barcelona), sclerostin (Mayo Clinic, USA), Paget’s disease (Antwerp University). The group has become out of two European training centers for clinicians and researchers starting with the technique of impact microindentation (IMI), participated in the international phase III trial on the novel anti-osteoporosis drug Romosozumab (completed in 2017), and will be starting the Phase 4 study for a novel drug in the treatment of hypoparathyroidism (2018). The group has attracted international PhD students (e.g. China, Finland, Japan, Mexico) and students within the Erasmus exchange program. To ensure translational relevance and applicability of preclinical research findings, collaborations have been initiated and are ongoing with pharmaceutical partners including MSD, AstraZeneca, Eli Lilly and Corcept. 

Content / highlights / achievements

  • Important role of brown adipose tissue was confirmed in energy metabolism in humans and mice (Nat Commun 2015; Sci Transl Med 2016; Nat Commun 2017; Gut 2018) and various strategies to activate brown adipose tissue have been elucidated (Diabetes 2015; Diabetologia 2015), based on which phase I studies were initiated (MSD, AstraZeneca).
  • Disturbance in circadian rhythmicity was identified as causal factor for decreased energy expenditure (PNAS USA 2015).
  • Biomarker for non-alcoholic steatohepatitis (NASH), a prominent CVD risk factor, was discovered (Hepatology 2015).
  • Role of the NLRP3 inflammasome in energy metabolism and insulin resistance has been discovered (PNAS USA 2011).  
  • Mechanisms underlying the disadvantageous metabolic phenotype of the South Asian population were partly dissected (Lancet Diab Endocrinol 2014).
  • The futility of raising HDL-C to prevent cardiovascular disease has been demonstrated (Eur Heart J 2015). 
  • Loss-of-function mutations in IGSF-1 were discovered to cause an X-linked syndrome of central hypothyroidism (Nat Genet 2012)
  • Discovery of brain abnormalities in patients considered cured after treatment for Cushing’s disease, and new effective stepwise medical therapy for Cushing’s disease was established (N Engl J Med 2010)
  • Clinical islet transplantation program has been established.
  • A novel modulator of the glucocorticoid receptor that is effective in brain stress circuits and metabolic disease has been discovered (PNAS USA 2013l Br J Pharmacol 2015), and has been taken to phase I clinical studies for fatty liver disease.
  • A comprehensive approach to understand regional selectivity of glucocorticoid receptor effects was developed, and proof of principle for functional interference was established (PNAS USA 2016).
  • Common and rare genetic variations associated with circulating metabolites were identified and the role of metabolites as risk factors for metabolic syndrome and associated pathology were determined (Nat Commun 2015).
  • Micro Indentation technique (J Clin Endocrinol Metab 2015) has been CE-marked and will be FDA approved soon.
  • Mechanism of action of sclerostin has been elucidated in general and specifically in patients suffering from congenitally decreased sclerostin (i.e. sclerosteosis and Van Buchems Disease).
  • Clinical and psychological phenotyping of patients with fibrous dysplasia, especially linking the disease to breast cancer (J Bone Miner Rees 2018).
  • Genotypic-phenotypic relationships in familial Paget’s diseases of bone have been established (Nat Genet 2011).
Research financing (2011-2016; alphabetical order)
BBMRI-NL, Bontius Foundation (‘Beter bot’), CHAFEA (EU), Chinese Scholarship Council (CSC), Conacyt (Mexico), COST action (EU), CTMM, CVON (GENIUS, IN-CONTROL, ENERGISE), Dutch Heart Foundation (e.g. Established Investigator, Dekker Junior Postdoc), Dutch Diabetes Research Foundation (e.g. Junior Fellow), European Federation for the Study of Diabetes (EFSD), Innovation Funds Health Insurances, Lilly Research Award Program (LRAP), National Institute for Public Health and the Environment (RIVM), NWO-ALW, Parelsnoer, Pharmaceutical partners (e.g. Amgen, AstraZeneca, Corcept Therapeutics, Eli Lilly, MSD, Retrotope, Unilever), Rembrandt Institute for Cardiovascular Science (RICS), Resolve (EU), Dutch Arthritis Foundation (‘Reumafonds’), ZonMW (Rubicon, VENI, Profidys, PTO).

Future themes

The strategy for the coming years involves continuation of the current research lines within the Einthoven Laboratory for Vascular and Regenerative Medicine ( In addition, we will further elucidate the relevance of brown adipose tissue (BAT) in cardiometabolic disease, optimize visualisation and quantitation procedures for BAT in humans, identify biomarkers for BAT and perform human intervention studies ultimately aimed to explore the feasibility of BAT as a pharmacological target. In addition, we will further elucidate the tissue-specific molecular mechanisms involved in the interaction between the central nervous system, inflammatory pathways, stress hormones, and metabolism, including interaction between bone(marrow), glucocorticoids and insulin resistance. Besides focusing on energy expenditure through BAT activation, we will also address the impact of nutrition on aging-associated chronic disease. The recently completed genotyping of the Netherlands Epidemiology of Obesity (NEO) cohort allows us to assess causality of genes in the pathophysiology of obesity and its complications using Mendelian Randomization approaches. In addition, we will assess disease-specific consequences of protocolled treatment of functioning and non-functioning pituitary adenomas on morbidity and quality of life, as well as epigenetic consequences of chronic glucocorticoid effects on the brain, and potential reversal by mifepristone. We will expand translational research, using patients with rare bone diseases such as van Buchems disease, to define the functional role of osteocytes and its secreted protein sclerostin on bone strength, in patients with fibrous dysplasia to further unravel the underlying mechanisms of their bone and extra skeletal diseases, patients with SCCH, DSO and CRMO for further genetic, clinical and psychological phenotyping, We will further explore the use of IMI in the assessment and follow up of bone diseases and osteoporosis, including combining IMI with bone histomorphometry and imaging. We will implement new imaging techniques in metabolic bone diseases, such as NaF-PET-scanning and HRqCT-scanning. We will assess the use of known and new bone markers/diagnostic tools in metabolic bone diseases, including transplant related bone disease, and osteoporosis, and elucidate the functional significance of mutated genes identified in patients with Paget’s disease of bone. We will address disease burden and optimal approach of patients with hyperparathyroidism. Finally, we will increase our efforts to offer contract research services centered around metabolic research and cardiovascular complications through the recently established ‘Leiden Metabolic Research Services’ (LMRS).

Cohesion within LUMC

Our research program is performed in the context of the LUMC research theme ‘Vascular and Regenerative Medicine’ in the context of the Einthoven Laboratory for Vascular and Regenerative Medicine. Through this framework we closely collaborate within the Dept. Medicine with Divs. Gerontology, Nephrology, Vascular Medicine and Thrombosis and Haemostasis; and with Depts. Cardiology, Clinical Epidemiology, Human Genetics and Neurosurgery. In addition, we have active collaborations with the departments of (in alphabetical order) Cardiology (atherosclerosis/human populations), Center for Proteomics and Metabolomics (lipidomics), Clinical Epidemiology (NEO), Clinical Genetics (genetics of (familial) endocrine tumors), Clinical Oncology (mitotane in adrenal cancer, iodine-refractory thyroid cancer, calorie restriction and chemotherapy, RANK-L and tumorigenesis, breast cancer and bone), Computational Biology Center (bioinformatics), Endocrine Surgery and Clinical Decision Making (hyperparathyroidism and methodology of thyroid cancer research), Gerontology and Geriatrics (metabolism in elderly), Human Genetics (stress and chromatin remodelling; exon skipping in stress and metabolic disease, bioinformatics, SCCH, CRMO, DSO), Infectious Disease (immunometabolism), Medical Statistics (nutrition and aging), Molecular Cell Biology (biological clock, cellular mechanisms), Neurosurgery (fibrous dysplasia, sclerosing bone disorders), Nuclear Medicine (BAT/thyroid nodules imaging by PET-CT, NaF-PET-scanning in metabolic bone diseases, DXA/VFA in diagnosis of osteoporosis), Oncology, Ophthalmology (stress and retinopathy, fibrous dysplasia), Oral and Maxillary Surgery (DSO, osteoporosis, fibrous dysplasia), Orthopedics (fibrous dysplasia), Pediatric Rheumatology (CRMO, DSO), Parasitology (immunometabolism), Pathology (molecular targets for diagnosis/treatment of (para)thyroid and neuroendocrine tumors, role RANKL in breast cancer in fibrous dysplasia); Pediatrics (genetics of growth disorders, IGSF-1 consortium), Psychiatry/LIBC (fMRI, stress, and mood disorders), Psychology (SCCH and fibrous dysplasia), Pulmonology (lung inflammation and metabolic disease), Radiology (body fat imaging by MRI, Allen Brain Atlas in endocrine research, rodent neuroimaging), Traumatology (osteoporosis), and Urology (cell and tissue cultures of fibrous dysplasia).