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Insulin Resistance: Causes, biomarkers and consequences
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. (Molecular Epidemiology (Tove Fall / Erik Ingelsson))ORCID-id: 0000-0001-8435-3978
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.

The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.

In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.

In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. , s. 54
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1316
Nyckelord [en]
insulin resistance, diabetes, insulin secretion, cardiovascular, mendelian randomization, proteomics, metabolomics, genomics, molecular epidemiology, complex disease, risk prediction, coronary heart disease, stroke, hyperglycemia
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper Klinisk medicin Cell- och molekylärbiologi Endokrinologi och diabetes Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi Fysiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-316891ISBN: 978-91-554-9856-6 (tryckt)OAI: oai:DiVA.org:uu-316891DiVA, id: diva2:1081351
Disputation
2017-05-22, Room E10:1309 (BMC Navet), Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-04-28 Skapad: 2017-03-14 Senast uppdaterad: 2018-01-13
Delarbeten
1. Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts
Öppna denna publikation i ny flik eller fönster >>Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts
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2016 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 1, s. 276-284Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.

Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-270825 (URN)10.2337/db15-0881 (DOI)000367424900029 ()26420861 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2012-1397Hjärt-Lungfonden, 20140422Diabetesförbundet, 2013-024Knut och Alice Wallenbergs StiftelseEU, Europeiska forskningsrådet
Tillgänglig från: 2016-01-04 Skapad: 2016-01-04 Senast uppdaterad: 2017-12-01Bibliografiskt granskad
2. Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study
Öppna denna publikation i ny flik eller fönster >>Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study
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2016 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, nr 10, artikel-id e1006379Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-310027 (URN)10.1371/journal.pgen.1006379 (DOI)000386683300041 ()27768686 (PubMedID)
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, 2015.0327Diabetesförbundet, DIA 2013-024Göran Gustafssons Stiftelse för främjande av vetenskaplig forskning vid Uppsala universitet och Kungl tekniska högskolan (UU/KTH)Hjärt-Lungfonden, 20120197 20150429 20070481EU, Europeiska forskningsrådet, 33595 HEALTH-2009-2.2.1-3/242114 HEALTH-2013-2.4.2-1/602936Vetenskapsrådet, 2012-1397 2015-03477 M-2005-1112 2016-00250Karolinska Institutets ForskningsstiftelseNIH (National Institute of Health), DK U01-066134Stiftelsen för strategisk forskning (SSF)
Tillgänglig från: 2016-12-12 Skapad: 2016-12-09 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
3. Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
Öppna denna publikation i ny flik eller fönster >>Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.

Nationell ämneskategori
Cell- och molekylärbiologi Fysiologi Endokrinologi och diabetes Annan medicinsk bioteknologi
Identifikatorer
urn:nbn:se:uu:diva-316886 (URN)
Anmärkning

Tove Fall and Erik Ingelsson has contributed equally to this work.

Tillgänglig från: 2017-03-08 Skapad: 2017-03-08 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
4. Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization study
Öppna denna publikation i ny flik eller fönster >>Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization study
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Type 2 diabetes (T2D) and its hallmarks insulin resistance, impaired insulin secretion, and hyperglycaemia affect over 400 million persons worldwide and are associated with raised cardiovascular risk, but their causal role has been difficult to dissect due to overlap between risk factors. We used Mendelian randomization analysis, which utilises genetic polymorphisms associated with a risk factor, to assess causal effects of T2D, insulin resistance, insulin secretion, and fasting glucose on mortality, ischaemic stroke, and coronary artery disease (CAD) risk in 120,091 adults in the UK Biobank and in the CARDIoGRAMplusC4D consortium (63,746 cases of CAD and 130,681 controls). We found evidence for a causal effect of T2D on raised CAD risk (odds ratio (OR) per doubling in the odds of T2D, 1.07, 95% confidence interval (CI) 1.05 – 1.09, P = 1.2 x 10-9) and for a causal effect of impaired insulin secretion on the risk of CAD (OR per SD-unit decrease, 1.14, 95% CI 1.06 – 1.22, P = 0.002). The genetic score for insulin resistance was associated with increased coronary artery disease risk; however, sensitivity analysis indicated that the instrument might not be appropriate to use for robust causal inference testing. Our results support previous reports of a causal role of T2D and impaired insulin secretion in coronary artery disease and point to a complex relationship between variants affecting insulin resistance and cardiovascular outcomes.

Nyckelord
diabetes, insulin resistance, mendelian randomization, uk biobank, heart disease, cardiovascular disease
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper Klinisk medicin
Identifikatorer
urn:nbn:se:uu:diva-316888 (URN)
Tillgänglig från: 2017-03-08 Skapad: 2017-03-08 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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