CellR4 2020; 8: e2941 Metabolomics and lipidomics contributions to type 1 diabetes research F. Cesare Marincola Department of Chemical and Geological Sciences, University of Cagliari, University Campus, Monserrato, Cagliari, Italy Corresponding Author: F. Cesare Marincola, PhD; e-mail: [email protected] Keywords: Lipidomics, Metabolomics, Type 1 diabetes, creatic b-cells with consequent insulin deficiency. T1D. Type 2 diabetes (T2D) is the most common form of diabetes (about 90% of cases) and generally occurs ABSTRACT after 30-40 years of age5. T2D is characterized by a Metabolomics is a “omic” science with a focus on progressive loss of adequate b-cell insulin secretion the characterization of metabolome, that is the frequently on the background of insulin resistance. pool of low molecular weight (< 1.5 kDa) metab- Gestational diabetes is one of the most common olites involved in the metabolism of a biological pregnancy complications and usually disappears af- system. When the targets are lipids, metabolomics ter giving birth6. This condition occurs in about 7% is commonly referred to as lipidomics. Since the of pregnancies. The definition is valid regardless of metabolome composition is influenced by several the type of treatment (diet, physical exercise or insu- factors such as environment, disease, drugs, and lin) and the persistence of diabetes even after preg- genetics, metabolomics is extensively used in the nancy. Both World Health Organization (WHO) and biomedical research for the identification of met- American Diabetes Association (ADA) have identi- abolic signatures or novel biomarkers useful in fied an intermediate type of diabetes for individu- diagnosis, prediction, prognosis, and prevention als whose glucose levels do not meet the criteria for of disease. In recent years, both metabolomics diabetes but are too high to be considered normal. and lipidomics have been extensively employed This condition of very high risk of evolving towards in diabetes research to elucidate the molecular the diabetes, especially T2D, is referred to as im- mechanisms triggering this disease and to discov- paired glucose tolerance, also known as pre-diabe- er biomarkers for its prevention, diagnosis, and tes. Finally, there is a form of hybrid diabetes called treatment. In this review, some of the most signifi- “latent autoimmune diabetes in adults” (LADA) that cant findings relative to studies performed on type includes both autoimmune destruction of pancreatic 1 diabetes patients are summarized to provide an b-cells and some degrees of insulin resistance7. Pa- overview of the potential of these approaches. tients with LADA are treated for a short period after diagnosis without insulin injections. Epidemiological data indicate that the number of INTRODUCTION people affected by T1D and T2D is increasing rap- idly worldwide. According to the International Di- The term diabetes mellitus, commonly referred to abetes Federation8, in 2019 approximately 463 mil- as diabetes, is used to define a group of metabolic lion adults (20-79 years) were living with diabetes, disorders characterized by elevated blood glucose and by 2045 this number is estimated to reach 700 levels due to defects in insulin secretion and/or ac- million. More than 1.1 million children and adoles- tion1. Type 1 diabetes (T1D) is an autoimmune dis- cents are living with T1D with the highest incidence ease that represents 5-10% of all cases of diabetes2. in Finland (64.2/100.000)9 followed by the island of It develops at any age but occurs most frequently in Sardinia, Italy (45/100.000)10. These data are further children and adolescents3,4. T1D is characterized by aggravated by the fact that the chronic hyperglyce- a progressive destruction of insulin-producing pan- mia of diabetes is associated with long-term com- This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License 1 2 F. Cesare Marincola plications and comorbidities such as cardiovascular factors such as lifestyle, diet, drug consumption, disease, hypertension, dyslipidemia, diabetic ne- and development of diseases, to name just a few15. phropathy, neuropathy, and retinopathy, becoming The main analytical platforms used in metabolom- one of the top 10 causes of death in adults11. ics are the following: nuclear magnetic resonance The exact etiology of diabetes is unknown. The (NMR) spectroscopy and mass spectrometry (MS) genetic component has an important weight on the combined with gas chromatography (GC-MS), liq- predisposition of diabetes, but it does not have a uid chromatography (LC-MS), high performance direct cause-effect relationship with this disease. liquid chromatography (HPLC-MS), and capillary Indeed, the pathogenetic mechanisms underlying electrophoresis (CE-MS). Basically, NMR offers the clinical phenotype of diabetes are by nature a good reproducibility, is not destructive, and re- complex and arise from a variable interaction be- quires relatively simple and fast preparations of tween genetic and environmental (non-genetic) risk samples. Nevertheless, the low sensitivity of NMR factors. In case of T2D, one of the most significant confines its applications to concentration mea- factors influencing the development of disease is surements in the micromolar to millimolar range. lifestyle, commonly associated with urbanization. MS method is more sensitive than NMR, but it Different studies have established that lifestyle is a destructive technique and requires extensive modification together with physical activity and/or sample preparation, including the derivatization healthy diet can delay or prevent the onset of T2D12. of compounds in case of GC-MS. No one of these Differently, at present, T1D cannot be prevented techniques can provide alone a complete picture yet since the complex molecular network responsi- of metabolome; therefore, a complementary use of ble for the destruction of b-cells is still enigmatic, both technologies is particularly useful to gain a thus slowing down the identification of parameters broader perspective. A detailed description of these with the role of specific T1D indicators13. So, pre- techniques, their advantages and drawbacks are the diction of T1D is done based on the risk assessment subject of various reviews. The reader is referred to defined by a combined use of genetic, immunolog- the literature for further information16-19. ic, and metabolic parameters, while the diagnosis Different types of biofluids can be analyzed in is done when the symptoms are evident. To reduce metabolomics such as blood, urine, faecal extracts the pandemic of T1D and its disastrous social, eco- and saliva. No single biofluid is appropriate for all nomic, and health impacts worldwide, there is an studies; blood20 and urine21 samples can provide sig- urgent need to improve the understanding of the nificant insight into the dysregulation of metabolism molecular network responsible for the destruction at the organ level, while faecal22 and saliva23 metab- of b-cells to identify strategies useful to the pre- olome are specifically informative on microbiota. vention, diagnosis and treatment of this disease. Over the past decades, metabolomics has been successfully applied in medicine and molecular biol- ogy. It has provided useful contributions to the dis- METABOLOmiCS AND LIPIDOmiCS covery of new biochemical pathways in diseases, the understanding of their role in triggering pathologies, Metabolomics is a “omics science” aimed at iden- and the discovery of new therapeutic targets and bio- tifying and quantifying the set of low molecular markers for early diagnosis or monitoring therapeu- weight metabolites (typically < 1500 Da), known tic activities24. More recently, lipidomics, a branch of as metabolome, present in a biological sample metabolomics which studies the complete set of lipids such as biofluids, cells, tissues, and organs14. The (lipidome) produced in a given cell or organism, has metabolome consists of both endogenous and ex- garnered attention, particularly in relation to diseases ogenous components, including amino acids, pep- characterized by dysregulated lipid metabolism. The tides, nucleic acids, organic acids, vitamins, and development of lipidomics has been largely driven by carbohydrates. Since the metabolome composition rapid advances in MS technologies25. can be viewed as a mirror that reflects the glob- Both metabolomics and lipidomics have emerged al assessment of a cellular state, interrogating the as promising approaches also in diabetes research. metabolome enables to investigate the metabolic According to a statistics obtained by searching status of an organism in normal or disruptive phys- “metabolomics, metabolome, lipidomics, or lip- iologic conditions due to altered environmental idome and diabetes” in the “article title, abstract Metabolomics and lipidomics contributions to type 1 diabetes research 3 Figure 1. Research outputs of metabolomics and lipidomics studies in diabetes research. Data were gathered by Scopus26 searching for the terms “metabolomics” or “metabolome” or “lipidomics” or “lipidome” and “diabetes” in “article title, abstract and keywords” field. and keywords” in SCOPUS database26, 2976 con- Within these studies, important contributions to tributions (articles, reviews, books, book chapters, the understanding of T1D pathogenesis have been editorials, notes, and letters) have been published obtained by applying metabolomics and lipidomics since 2002 (Figure 1). Among these, 139 have been