Biomarkers for type 2 diabetes Laakso, Markku
Molecular metabolism (Germany),
09/2019, Letnik:
27, Številka:
Suppl
Journal Article
Recenzirano
Odprti dostop
The prevalence and incidence of type 2 diabetes (T2D), representing >90% of all cases of diabetes, are increasing rapidly worldwide. Identification of individuals at high risk of developing diabetes ...is of great importance as early interventions might delay or even prevent full-blown disease. T2D is a complex disease caused by multiple genetic loci in interplay with lifestyle and environmental factors. Recently over 400 distinct association signals were published; these explain 18% of the risk of T2D.
In this review there is a major focus on risk factors and genetic and non-genetic biomarkers for the risk of T2D identified especially in large prospective population-based studies, and studies testing causality of the biomarkers for T2D in Mendelian randomization studies. Another focus is on understanding genome-phenome interplay in the classification of individuals with T2D into subgroups.
Several recent large population-based studies and their meta-analyses have identified multiple potential genetic and non-genetic biomarkers for the risk of T2D. Combination of genetic variants and physiologically characterized pathways improves the classification of individuals with T2D into subgroups, and is also paving the way to a precision medicine approach, in T2D.
The prevalence of diabetes mellitus will likely increase globally from 371 million individuals in 2013 to 552 million individuals in 2030. This epidemic is mainly attributable to type 2 diabetes ...mellitus (T2DM), which represents about 90-95% of all cases. Cardiovascular disease is the leading cause of mortality among individuals with diabetes mellitus, and >50% of patients will die from a cardiovascular event-especially coronary artery disease, but also stroke and peripheral vascular disease. Classic risk factors such as elevated levels of LDL cholesterol and blood pressure, as well as smoking, are risk factors for adverse cardiovascular events in patients with type 1 diabetes mellitus (T1DM) and T2DM to a similar degree as they are in healthy individuals. Patients with T1DM develop insulin resistance in the months after diabetes mellitus diagnosis, and patients with T2DM typically develop insulin resistance before hyperglycaemia occurs. Insulin resistance and hyperglycaemia, in turn, further increase the risk of adverse cardiovascular events. This Review discusses the mechanisms by which T1DM and T2DM can lead to cardiovascular disease and how these relate to the risk factors for coronary artery disease.
The two major pathophysiological abnormalities in type 2 diabetes are insulin resistance and impaired insulin secretion. Insulin resistance is a general term meaning that insulin does not exert its ...normal effects in insulin-sensitive target tissues, such as skeletal muscle, adipose tissue, and liver, the major target tissues for insulin action in glucose metabolism. Insulin resistance (IR) promotes cardiovascular disease via multiple mechanisms, including changes in classic cardiovascular risk factors and downregulation of the insulin signaling pathways in different tissues. This review presents evidence for the association of insulin resistance with cardiovascular disease from clinical and population-based studies. The causality of the association of insulin resistance with cardiovascular disease is discussed on the basis of recent findings from the Mendelian randomization studies.
The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005–2010. The aim of the study is to investigate nongenetic and genetic factors ...associated with the risk of T2D and CVD, and with cardiovascular risk factors. The protocol includes a detailed phenotyping of the participants, an oral glucose tolerance test, fasting laboratory measurements including proton NMR measurements, mass spectometry metabolomics, adipose tissue biopsies from 1,400 participants, and a stool sample. In our ongoing follow-up study, we have, to date, reexamined 6,496 participants. Extensive genotyping and exome sequencing have been performed for essentially all METSIM participants, and >2,000 METSIM participants have been whole-genome sequenced. We have identified several nongenetic markers associated with the development of diabetes and cardiovascular events, and participated in several genetic association studies to identify gene variants associated with diabetes, hyperglycemia, and cardiovascular risk factors. The generation of a phenotype and genotype resource in the METSIM study allows us to proceed toward a "systems genetics" approach, which includes statistical methods to quantitate and integrate intermediate phenotypes, such as transcript, protein, or metabolite levels, to provide a global view of the molecular architecture of complex traits.
Diabetes has reached epidemic proportions worldwide. Currently, approximately 537 million adults (20–79 years) have diabetes, and the total number of people with diabetes is continuously increasing. ...Diabetes includes several subtypes. About 80% of all cases of diabetes are type 2 diabetes (T2D). T2D is a polygenic disease with an inheritance ranging from 30 to 70%. Genetic and environment/lifestyle factors, especially obesity and sedentary lifestyle, increase the risk of T2D. In this review, we discuss how studies on the genetics of diabetes started, how they expanded when genome-wide association studies and exome and whole-genome sequencing became available, and the current challenges in genetic studies of diabetes. T2D is heterogeneous with respect to clinical presentation, disease course, and response to treatment, and has several subgroups which differ in pathophysiology and risk of micro- and macrovascular complications. Currently, genetic studies of T2D focus on these subgroups to find the best diagnoses and treatments for these patients according to the principles of precision medicine.
Statins are widely used to prevent cardiovascular disease events. Cardiovascular diseases and type 2 diabetes are tightly connected since type 2 diabetes is a major risk factor for cardiovascular ...diseases. Additionally, cardiovascular diseases often precede the development of type 2 diabetes. These two diseases have common genetic and environmental antecedents. Statins are effective in the lowering of cardiovascular disease events. However, they have also important side effects, including an increased risk of type 2 diabetes. The first study reporting an association of statin treatment with the risk of type 2 diabetes was the WOSCOPS trial (West of Scotland Coronary Prevention Study) in 2001. Other primary and secondary cardiovascular disease prevention studies as well as population-based studies have confirmed original findings. The purpose of our review is to examine and summarize the most important findings of these studies as well as to describe the mechanisms how statins increase the risk of type 2 diabetes.
The gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 ...well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study.
We investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota-metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state.
Our study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host-gut microbiota relationships.
Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, ...germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D.
In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index BMI and waist circumference WC), "lipodystrophy-like" fat distribution (low BMI, adiponectin, and high-density lipoprotein HDL cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study METSIM, N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank UKBB, N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry.
Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management.
The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the ...associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, ...but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.
Display omitted
•HK2 deletion exerts resistance to oncogenic transformation•HK2 deletion selectively targets cancer cells•Systemic deletion of HK2 is well tolerated and therapeutic for cancer l•HK2 is required for glucose-derived and glutamine in utilization in anaplerosis
PDF
