Type 2 diabetes
The prevalence of obesity and type 2 diabetes is reaching epidemic proportions, and affects people at an ever-younger age. It is estimated that in 2014 more than 250 million people are affected worldwide by type 2 diabetes, especially in countries adopting a Western-type lifestyle. Whereas genetic factors contribute to the development of common late onset diabetes, the sharp increase in disease prevalence can be ascribed to lifestyle factors, like an increased consumption of high-fat food and adoption of a sedentary lifestyle.
Type 2 diabetes is characterized by insulin resistance of peripheral target tissues, in conjunction with a decreased activity of the insulin-producing beta-cells in the pancreatic islets of Langerhans. Our laboratory studies the molecular pathophysiology of type 2 diabetes. We are interested in unravelling insulin action and deregulation of these pathways under conditions of insulin resistance. In addition, we perform genetic association studies for mutations in candidate genes for type 2 diabetes in well-characterized population studies.
Molecular basis of insulin resistance
Insulin is the most anabolic hormone. Following rise in blood glucose levels, for example after a meal, insulin is secreted by the pancreatic beta-cells in the islets of Langerhans. Insulin exerts its action in multiple target tissues, including the liver, skeletal and cardiac muscle, adipose tissue, and the brain. In the liver, insulin suppresses gluconeogenesis through regulation of the expression of key enzymes, and the secretion of VLDL-particles. In skeletal muscle, insulin regulates the uptake of glucose via the insulin-regulated glucose transporter GLUT4, and suppresses the oxidation of fatty acids. In adipose tissue, glucose serves as substrate for triglyceride synthesis, and its uptake is regulated by insulin through GLUT4. Beside, insulin inhibits the release of fatty acids from adipose tissue. The brain and heart have long been neglected as relevant insulin-target tissues. However, recent evidence suggests an important role for the arcuate nucleus in the suppression of hepatic gluconeogenesis and food intake. In the heart, insulin plays a pivotal role in myocardial energy substrate utilization and cell survival.
At the molecular level, insulin action is initiated by the binding of insulin to its receptor at the plasma membrane. The insulin receptor is a member of the tyrosine kinase receptor family, and insulin binding leads to activation of the intracellular tyrosine kinase domain. Next to the insulin receptor itself, also substrates become tyrosine phosphorylated, the most relevant to insulin action being the insulin receptor substrates 1-4 (IRS1-4), and Shc.
Tyrosine phosphorylation of the IRS-proteins recruits and activates the lipid kinase PI 3 Kinase (PI3K), which subsequently phosphorylates inositol lipids at the 3’-position. The phosphorylated 3’-phosphatidylinositol lipids subsequently provide binding sites for proteins with a pleckstrin homology domain, like PDK1 and PKB/Akt. Binding of these proteins leads to phosphorylation and activation of PKB/Akt. The activation of PKB/Akt has been linked to the phosphorylation of multiple substrates, which on their turn regulate fatty acid (FA) and glucose metabolism, gene expression, and cell survival.
Whereas activation of the PI3K/PKB/Akt pathway predominantly regulates the metabolic effects of insulin, phosphorylation of Shc is involved in the regulation of gene expression and DNA synthesis. Tyrosine phosphorylation of Shc recruits and activates the Grb2/mSOS protein complex, the latter being a guanine nucleotide exchange factor for the small GTP-binding protein Ras. GTP-binding to Ras activates multiple Ras-effector pathways, including the Raf-MEK-ERK-pathway and RalGDS-Ral-p38/JNK pathway. Phosphorylation of the MAPkinases ERK1/2, p38 and JNK induces phosphorylation and activation of multiple transcription factors, thus affecting gene expression, and cell proliferation.
Insulin resistance, i.e. an impaired response of target tissues to insulin, is a hallmark of obesity and type 2 diabetes. Recent evidence links mitochondrial dysfunction and intracellular lipid accumulation (lipotoxicity) to the development of insulin resistance and diabetes-related diseases. Accumulation of lipid metabolites, such as triacylglycerol, diacylglycerol and ceramides, leads to activation of serine/threonine kinases, such as PKC isoforms, IKK, and MAPkinases that counteract insulin-mediated activation of the IRS/PI3K/PKB signaling pathway that regulates the metabolic effects of insulin. Interestingly, activation of Ras-mediated signalling pathways seems unaffected.
Genetics of diabetes mellitus or diabetes-related complications
Age-related metabolic and degenerative disorders are rapidly increasing in industrialized countries. Examples of these are Alzheimer's disease, cancer and type 2 diabetes (T2DM). Some of these diseases reach almost epidemic proportions. In most of the common late onset diseases some kind of familial effect is seen suggesting the influence of genetic factors in making a subject susceptible for a certain disease. However, since our genes have not changed very much over the last decades it must be environmental factors, which trigger the large increase in disease prevalence. The exact interplay between genes and diet in enhancing disease risk remains however, mainly unclear. This is largely because of the fact that we simply do not know which genes make us susceptible for the development of age related diseases like common late onset type 2 diabetes.
A common feature of age-related metabolic and degenerative disorders is that they are late onset diseases resulting from a gradual accumulation of damage to tissues and organs of an organism. Focusing on type 2 diabetes it is known that insulin resistance and defects in insulin secretion act together in making an individual glucose intolerant. Both develop during aging and are not prominently present during childhood and early adolescence. Research from the past decade has shed some light on the genetic factors involved in both processes showing the involvement of a variety of pathways ranging from transcription factors to mitochondrial functions.
Molecular pathophysiology of type 2 diabetes
The research in our group aims at elucidating insulin signaling pathways and the molecular mechanisms underlying insulin resistance. Furthermore, we are also studying how drugs affect insulin sensitivity. Studies are performed in cultured cell lines as well as animal models of high-fat diet insulin resistance. In tight collaboration with the Leiden Immunoparasitology Group (https://www.lumc.nl/org/parasitologie/research/immunology/) in the Department of Parasitology of LUMC, we recently started of studying the molecular mechanisms underlying the immunometabolic effects of parasitic infection and parasite-derived molecules using both in vitro and in vivo approaches in various rodent models or in humans. This original research line is aimed to identify new metabolically-active molecules and/or potential novel molecular targets involved in tissue-specific regulation of substrate metabolism and insulin sensitivity that can ultimately lead to future therapeutic opportunities for the treatment of metabolic disorders and type 2 diabetes.
Multi-omics studies in type 2 diabetes
We initiated various projects aiming at the identification of novel biomarkers influencing type 2 diabetes risk and response to therapy. In the Diabetes Care System West-Friesland, a diabetes care system including longitudinal information for more than 8000 type 2 diabetes patients and the new Hoorn study, containing data from 2700 healthy subjects, we use a multi-omics approach to investigate and integrate various types of biomarkers (i.e. DNA, RNA, metabolites and classical risk factors). This research identified biomarkers that are associated with beta cell function, type 2 diabetes and also with response to various oral glucose lowering drugs. With our research we aim to identify factors that allow for stratification of subjects at increased risk for type 2 diabetes and or rapid diabetes progression. Together with partners we are developing prediction models based (in part) on our multi-omics studies. This research is performed in collaboration with the section of Molecular Epidemiology at the LUMC and research groups from the Vrije Universiteit Amsterdam and various other national and international partners.
ZonMW-PMO program, the EU Innovative medicines initiative and BBMRI-NL provide financial support for these studies.
- Hussaarts L, Garcia-Tardon N, van Beek L, Heemskerk MM, Haeberlein S, van der Zon GC, Ozir-Fazalalikhan A, Berbee JF, Willems van Dijk K, van Harmelen V, Yazdanbakhsh M, Guigas B. Chronic helminth infection promotes adipose tissue M2 macrophages and improves insulin sensitivity in obese mice. FASEB J. 2015, 29(7):3027-39.
- Geerling JJ, Boon MR, van der Zon GC, van den Berg SAA, van den Hoek AM, Lombes M, Princen HM, Havekes LM, Rensen PCN, Guigas B. Metformin reduces plasma cholesterol and triglyceride levels by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes. 2014, 63(3):880-91.
- Wijngaarden MA, van der Zon GC, Willems van Dijk K, Pijl H, Guigas B. Effects of prolonged fasting on AMP-activated protein kinase signaling, metabolic gene expression and mitochondrial content in skeletal muscle from lean and obese individuals. AJP-Endocrinology & Metabolism. 2013, 304(9):E1012-21.
- ’t Hart LM, Fritsche A, Nijpels G, van LN, Donnelly LA, Dekker JM, Alssema M, Fadista J, Carlotti F, Gjesing AP, Palmer CN, Van Haeften TW, Herzberg-Schafer SA, Simonis-Bik AM, Houwing-Duistermaat JJ, Helmer Q, Deelen J, Guigas B, Hansen T, Machicao F, Willemsen G, Heine RJ, Kramer MH, Holst JJ, de Koning EJ, Haring HU, Pedersen O, Groop L, de Geus EJ, Slagboom PE, Boomsma DI, Eekhoff EM, Pearson ER, Diamant M: The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway. Diabetes 62:3275-3281, 2013.
- van Leeuwen N, Swen JJ, Guchelaar HJ, ’t Hart LM. The role of pharmacogenetics in drug disposition and response of oral glucose-lowering drugs. Clin Pharmacokinet 52:833-854, 2013.
- van Leeuwen N., Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH, Uitterlinden AG, Hofman A, van 't RE, Palmer CN, Guigas B, Slagboom PE, Durrington P, Calle RA, Neil A, Hitman G, Livingstone SJ, Colhoun H, Holman RR, Mccarthy MI, Dekker JM, 't Hart LM, Pearson ER: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia 55:1971-1977, 2012.
- Stephenne X, Foretz M, Taleux N, van der Zon GC, Sokal EM, Hue L, Viollet B, Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia. 2011, 54(12):3101-10.
- Simonis-Bik,AM, Nijpels,G, Van Haeften,TW, Houwing-Duistermaat,JJ, Boomsma,DI, Reiling,E, van Hove,EC, Diamant,M, Kramer,MH, Heine,RJ, Maassen,JA, Slagboom,PE, Willemsen,G, Dekker,JM, Eekhoff,EM, de Geus,EJ, 't Hart,LM: Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A and MTNR1B affect different aspects of pancreatic beta cell function. Diabetes 59:293-301, 2010