The doctoral dissertations of the former Helsinki University of Technology (TKK) and Aalto University Schools of Technology (CHEM, ELEC, ENG, SCI) published in electronic format are available in the electronic publications archive of Aalto University - Aaltodoc.
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Computational Analysis of the Metabolic Phenotypes in Type 1 Diabetes and Their Associations with Mortality and Diabetic Complications

Ville-Petteri Mäkinen

Dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the Faculty of Information and Natural Sciences, Helsinki University of Technology, for public examination and debate in Auditorium of the F- building at Helsinki University of Technology (Espoo, Finland) on the 5th of February, 2010, at 12 o'clock noon.

Overview in PDF format (ISBN 978-952-60-3013-5)   [13235 KB]
Dissertation is also available in print (ISBN 978-952-60-3012-8)

Abstract

Type 1 diabetes is an autoimmune disease that destroys the secretion of insulin (in the pancreas); insulin is a vital hormone for maintaining normal glucose metabolism. Insulin replacement therapy can prevent the acute symptoms, but is not able to fully match the natural regulation, which puts a metabolic stress on tissues. For some patients, the stress manifests as gradual damage to blood vessels and the nervous system over the next few decades after diabetes diagnosis. The aim of the thesis was to describe the metabolic profiles and to investigate their connections with the spectrum of clinical symptoms. Simultaneously, new techniques were applied to measure the profiles (1H NMR spectroscopy) and to visualize the multivariate statistical associations (the self-organizing map). A total of 4,197 patients with type 1 diabetes were recruited for the thesis by the Finnish Diabetic Nephropathy Study. A quarter of the patients exhibited an obesity-related phenotype (high triglycerides, cholesterol, apolipoprotein B-100, low high-density lipoprotein cholesterol, high C-reactive protein). A third of the individuals had a diabetic kidney disease phenotype (high urinary albumin and serum creatinine). The combination of the two was associated with a 10-fold population-adjusted mortality. Nevertheless, there was no discernible metabolic threshold between the phenotype models, nor were there any single variable that could predict the outcomes accurately. These results suggest a need for multifactorial and multidisciplinary paradigms for the research, treatment and prevention of diabetic complications.

This thesis consists of an overview and of the following 5 publications:

  1. Ville-Petteri Mäkinen, Carol Forsblom, Lena M. Thorn, Johan Wadén, Daniel Gordin, Outi Heikkilä, Kustaa Hietala, Laura Kyllönen, Janne Kytö, Milla Rosengård-Bärlund, Markku Saraheimo, Nina Tolonen, Maija Parkkonen, Kimmo Kaski, Mika Ala-Korpela, and Per-Henrik Groop, on behalf of the FinnDiane Study Group. 2008. Metabolic phenotypes, vascular complications, and premature deaths in a population of 4,197 patients with type 1 diabetes. Diabetes, volume 57, number 9, pages 2480-2487.
  2. Ville-Petteri Mäkinen, Pasi Soininen, Carol Forsblom, Maija Parkkonen, Petri Ingman, Kimmo Kaski, Per-Henrik Groop, and Mika Ala-Korpela, on behalf of the FinnDiane Study Group. 2006. Diagnosing diabetic nephropathy by 1H NMR metabonomics of serum. Magnetic Resonance Materials in Physics, Biology and Medicine, volume 19, number 6, pages 281-296.
  3. Ville-Petteri Mäkinen, Pasi Soininen, Carol Forsblom, Maija Parkkonen, Petri Ingman, Kimmo Kaski, Per-Henrik Groop, and Mika Ala-Korpela, on behalf of the FinnDiane Study Group. 2008. 1H NMR metabonomics approach to the disease continuum of diabetic complications and premature death. Molecular Systems Biology, volume 4, 167. © 2008 by authors.
  4. Jaakko Niemi, Ville-Petteri Mäkinen, Jukka Heikkonen, Leena Tenkanen, Yrjö Hiltunen, Minna L. Hannuksela, Matti Jauhiainen, Carol Forsblom, Marja-Riitta Taskinen, Y. Antero Kesäniemi, Markku J. Savolainen, Kimmo Kaski, Per-Henrik Groop, Petri T. Kovanen, and Mika Ala-Korpela. 2009. Estimation of VLDL, IDL, LDL, HDL2, apoA-I, and apoB from the Friedewald inputs—apoB and IDL, but not LDL, are associated with mortality in type 1 diabetes. Annals of Medicine, volume 41, number 6, pages 451-461.
  5. Ville-Petteri Mäkinen, Carol Forsblom, Lena M. Thorn, Johan Wadén, Kimmo Kaski, Mika Ala-Korpela, and Per-Henrik Groop. 2009. Network of vascular diseases, death and biochemical characteristics in a set of 4,197 patients with type 1 diabetes (The FinnDiane Study). Cardiovascular Diabetology, volume 8, 54. © 2009 by authors.

Keywords: type 1 diabetes, kidney disease, NMR spectroscopy, self-organizing map

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Last update 2011-05-26