Approaching Type 2 Diabetes Mellitus by Systems Biology

Approaching Type 2 Diabetes Mellitus by Systems Biology

Axel Rasche (Max-Planck-Institute for Molecular Genetics, Germany)
Copyright: © 2009 |Pages: 16
DOI: 10.4018/978-1-60566-076-9.ch022
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Abstract

We acquired new computational and experimental prospects to seek insight and cure for millions of afflicted persons with an ancient malady. Type 2 diabetes mellitus (T2DM) is a complex disease with a network of interactions among several tissues and a multifactorial pathogenesis. Research conducted in human and multiple animal models has strongly focused on genetics so far. High-throughput experimentation technics like microarrays provide new tools at hand to amend current knowledge. By integrating those results the aim is to develop a systems biology model assisting the diagnosis and treatment. Beside experimentation techniques and platforms or rather general concepts for a new term in biology and medicine this chapter joins the conceptions with a rather actual medical challenge. It outlines current results and envisions a possible alley to the comprehension of T2DM.
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Introduction

Type 2 Diabetes mellitus (T2DM) is the most common metabolic disease with more than 170 million patients worldwide. It rapidly increases in the developed and developing countries and is a huge, growing burden for health care systems. In the USA T2DM already accounts for over 130 billion Dollar of the health care costs (Stumvoll, Goldstein, & Haeften, 2005).

In the past, T2DM was rarely seen in young people and thus called age-onset diabetes. But its prevalence increases due to changes in the lifestyle. For babies born in 2000 an estimated chance of 33%-50% to develop T2DM leads to 11 to 18 years reduced life expectancy. Several risk factors account for this prevalence including genetics, nutrition, low physical activity and low birthweight. The genetical prevalence is identified by looking at the offspring of diabetic patients, a positive family history confers for a 2.4 fold increased risk for T2DM. For first-degree relatives to an afflicted person the risk is increased by 15% to 25%. In twin studies the difference of the concordance rate between monozygotic and dizygotic twins returns an estimate of the genetic contribution, as dizygotic twins only share 50% of the genetic code. The concordance rate is 35% to 38% for monozygotic twins and 17% - 20% for dizygotic twins. Prevalence merges with the environment. Increased availability of food combined with reduced physical activity lead to obesity which itself becomes the major influencing factor. In the USA 1991 12% of the population have been classified to be obese, increasing to 20.9% in 2001 and even 30% today resulting in an anticipated epidemic increase of T2DM in the next decades. Physical inactivity is a controllable factor, so 20 minutes exercise per day is enough for a noticeable improvement in treating T2DM. Unhealthy diet with a surplus of fatty acids completes the problem.

Several molecular mechanisms are proposed to link obesity to T2DM. But the connection to the pathophysiology still remains unknown. Less than 10% of the T2DM variants are monogenic disease forms, on the other hand a high number of susceptibility genes is accounted for T2DM. Alterations in an entire network of genes is thought to be responsible for the disease. Most of the costs do not derive directly from diabetes but from its associated complications like macrovascular and microvascular diseases or accelerated atherogenesis. In an unclear pathogenesis, T2DM is preceded by impaired glucose tolerance, where glucose needed for cell energy cannot penetrate the cell wall anymore. Followed by an impairment in insulin action, increased adiposity drives a progression into insulin resistance.

Since available T2DM therapies are of limited effectiveness, new insight into the disease by biomedical research must be sought. The classic genetic approaches have been more successful in monogenic diabetes like maturity-onset diabetes in the young or mitochondrial diabetes. The unknown hereditary mode poses a challenge, so far resulting in a number of candidate genes. Transgenic and knock-out mice are helpful in dissecting the transcriptional regulatory network. With the dawn of high-throughput methods a novel way to tackle these challenges arises. Microarrays allow us:

  • 1.

    To dissect the diversity of the disease primarily on the transcriptomic level.

  • 2.

    To identify transcription factor target sets using ChIP-on-Chip.

  • 3.

    To search for single nucleotide polymorphisms (SNP) using genotyping arrays.

The complex pathophysiological interactions between the tissues fat, muscle, liver, pancreas and brain are captured in distinct expression profiles for different mouse strains and different diets. On the level of proteomics one now knows the secretory proteins in adipose tissue (Chen, 2005), while mass-spectrometry experiments are pursued in several labs.

In this chapter, systems biology is defined as the development of mathematical models by the aggregation of experimental results. In the following we give an overview of the physiology of T2DM to sketch the complexity of the disease. T2DM is under study in several animal models based on different changes in the genomes. These genetic changes have been the most promising approach in the last years, now complemented by high-throughput gene expression, proteomic or metabolic surveys. The results are merged in the discipline of systems biology to generate and validate mathematical models.

Key Terms in this Chapter

Kinetic Model: A mathematical model using differential equations or similar to allow quantitative, continuous predictions for the behavior of a system.

Type 2 Diabetes Mellitus (T2DM): Type 2 Diabetes mellitus is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia.

Protein-Protein Network: The union of undirected pairwise interactions between proteins. Interactions experiments may return large lists of protein-protein-interactions, but do not provide information about the character of the interaction, e.g. transient binding or complex building.

DNA Microarray (microarray, array, DNA chip): A microarray is a collection of microscopic DNA spots, commonly representing sequence extracts of single genes, arrayed on a solid surface by covalent attachment to a chemical matrix. DNA arrays are commonly used for gene expression experiments.

Differential Expression: In a case study experiment comparing two expression states of the same tissue or same cell type.

Mathematical Model: A mathematical model is an abstract model that uses mathematical language to describe the behavior of a system.

Impaired Glucose Tolerance (IGT): Impaired Glucose Tolerance is a pre-diabetic state of dysglycemia, that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years.

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Table of Contents
Foreword
Ralf Herwig
Preface
Andriani Daskalaki
Acknowledgment
Andriani Daskalaki
Chapter 1
Peter Ghazal
An increasing number of biological experiments and more recently clinical based studies are being conducted using large-scale genomic, proteomic and... Sample PDF
Pathway Biology Approach to Medicine
$37.50
Chapter 2
Peter Wellstead, Sree Sreenath, Kwang-Hyun Cho
In this chapter the authors describe systems and control theory concepts for systems biology and the corresponding implications for medicine. The... Sample PDF
Systems and Control Theory for Medical Systems Biology
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Chapter 3
S. Nikolov
In this chapter we investigate how the inclusion of time delay alters the dynamic properties of (a) delayed protein cross talk model, (b) time delay... Sample PDF
Mathematical Description of Time Delays in Pathways Cross Talk
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Chapter 4
Elisabeth Maschke-Dutz
In this chapter basic mathematical methods for the deterministic kinetic modeling of biochemical systems are described. Mathematical analysis... Sample PDF
Deterministic Modeling in Medicine
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Chapter 5
Andrew Kuznetsov
Biologists have used a reductionist approach to investigate the essence of life. In the last years, scientific disciplines have merged with the aim... Sample PDF
Synthetic Biology as a Proof of Systems Biology
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Chapter 6
Tuan D. Pham
Computational models have been playing a significant role for the computer-based analysis of biological and biomedical data. Given the recent... Sample PDF
Computational Models for the Analysis of Modern Biological Data
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Chapter 7
Vanathi Gopalakrishnan
This chapter provides a perspective on 3 important collaborative areas in systems biology research. These areas represent biological problems of... Sample PDF
Computer Aided Knowledge Discovery in Biomedicine
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Chapter 8
Thomas Meinel
The function of proteins is a main subject of research in systems biology. Inference of function is now, more than ever, required by the upcoming of... Sample PDF
Function and Homology of Proteins Similar in Sequence: Phylogenetic Profiling
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Chapter 9
Nikolaos G. Sgourakis, Pantelis G. Bagos, Stavros J. Hamodrakas
GPCRs comprise a wide and diverse class of eukaryotic transmembrane proteins with well-established pharmacological significance. As a consequence of... Sample PDF
Computational Methods for the Prediction of GPCRs Coupling Selectivity
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Chapter 10
Pantelis G. Bagos, Stavros J. Hamodrakas
ß-barrel outer membrane proteins constitute the second and less well-studied class of transmembrane proteins. They are present exclusively in the... Sample PDF
Bacterial ß-Barrel Outer Membrane Proteins: A Common Structural Theme Implicated in a Wide Variety of Functional Roles
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Chapter 11
L.K. Flack
Clustering methods are used to place items in natural patterns or convenient groups. They can be used to place genes into clusters to have similar... Sample PDF
Clustering Methods for Gene-Expression Data
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Chapter 12
George Sakellaropoulos, Antonis Daskalakis, George Nikiforidis, Christos Argyropoulos
The presentation and interpretation of microarray-based genome-wide gene expression profiles as complex biological entities are considered to be... Sample PDF
Uncovering Fine Structure in Gene Expression Profile by Maximum Entropy Modeling of cDNA Microarray Images and Kernel Density Methods
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Chapter 13
Wasco Wruck
This chapter describes the application of the BeadArrayTM technology for gene expression profiling. It introduces the BeadArrayTM technology, shows... Sample PDF
Gene Expression Profiling with the BeadArrayTM Platform
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Chapter 14
Djork-Arné Clevert, Axel Rasche
Readers shall find a quick introduction with recommendations into the preprocessing of Affymetrix GeneChip® microarrays. In the rapidly growing... Sample PDF
The Affymetrix GeneChip® Microarray Platform
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Chapter 15
Jacek Majewski
Eukaryotic genes have the ability to produce several distinct products from a single genomic locus. Recent developments in microarray technology... Sample PDF
Alternative Isoform Detection Using Exon Arrays
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Chapter 16
Prerak Desai
The use of systems biology to study complex biological questions is gaining ground due to the ever-increasing amount of genetic tools and genome... Sample PDF
Gene Expression in Microbial Systems for Growth and Metabolism
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Chapter 17
Heike Stier
Alternative splicing is an important part of the regular process of gene expression. It controls time and tissue dependent expression of specific... Sample PDF
Alternative Splicing and Disease
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Chapter 18
Axel Kowald
Aging is a complex biological phenomenon that practically affects all multicellular eukaryotes. It is manifested by an ever increasing mortality... Sample PDF
Mathematical Modeling of the Aging Process
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Chapter 19
Evgenia Makrantonaki
This chapter introduces an in vitro model as a means of studying human hormonal aging. For this purpose, human sebaceous gland cells were maintained... Sample PDF
The Sebaceous Gland: A Model of Hormonal Aging
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Chapter 20
R. Seigneuric, N.A.W. van Riel, M.H.W. Starmans, A. van Erk
Complex diseases such as cancer have multiple origins and are therefore difficult to understand and cure. Highly parallel technologies such as DNA... Sample PDF
Systems Biology Applied to Cancer Research
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Chapter 21
Matej Orešic, Antonio Vidal-Puig
In this chapter the authors report on their experience with the analysis and modeling of data obtained from studies of animal models related to... Sample PDF
Systems Biology Strategies in Studies of Energy Homeostasis In Vivo
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Chapter 22
Axel Rasche
We acquired new computational and experimental prospects to seek insight and cure for millions of afflicted persons with an ancient malady. Type 2... Sample PDF
Approaching Type 2 Diabetes Mellitus by Systems Biology
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Chapter 23
Alia Benkahla, Lamia Guizani-Tabbane, Ines Abdeljaoued-Tej, Slimane Ben Miled, Koussay Dellagi
This chapter reports a variety of molecular biology informatics and mathematical methods that model the cell response to pathogens. The authors... Sample PDF
Systems Biology and Infectious Diseases
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Chapter 24
Daniela Albrecht, Reinhard Guthke
This chapter describes a holistic approach to understand the molecular biology and infection process of human-pathogenic fungi. It comprises the... Sample PDF
Systems Biology of Human-Pathogenic Fungi
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Chapter 25
Jessica Ahmed
Secretases are aspartic proteases, which specifically trim important, medically relevant targets such as the amyloid-precursor protein (APP) or the... Sample PDF
Development of Specific Gamma Secretase Inhibitors
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Chapter 26
Paul Wrede
Peptides fulfill many tasks in controlling and regulating cellular functions and are key molecules in systems biology. There is a great demand in... Sample PDF
In Machina Systems for the Rational De Novo Peptide Design
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Chapter 27
Ferda Mavituna, Raul Munoz-Hernandez, Ana Katerine de Carvalho Lima Lobato
This chapter summarizes the fundamentals of metabolic flux balancing as a computational tool of metabolic engineering and systems biology. It also... Sample PDF
Applications of Metabolic Flux Balancing in Medicine
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Chapter 28
Roberta Alfieri, Luciano Milanesi
This chapter aims to describe data integration and data mining techniques in the context of systems biology studies. It argues that the different... Sample PDF
Multi-Level Data Integration and Data Mining in Systems Biology
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Chapter 29
Hendrik Hache
In this chapter, different methods and applications for reverse engineering of gene regulatory networks that have been developed in recent years are... Sample PDF
Methods for Reverse Engineering of Gene Regulatory Networks
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Chapter 30
Alok Mishra
This chapter introduces the techniques that have been used to identify the genetic regulatory modules by integrating data from various sources. Data... Sample PDF
Data Integration for Regulatory Gene Module Discovery
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Chapter 31
Elizabeth Santiago-Cortés
Biological systems are composed of multiple interacting elements; in particular, genetic regulatory networks are formed by genes and their... Sample PDF
Discrete Networks as a Suitable Approach for the Analysis of Genetic Regulation
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Chapter 32
A. Maffezzoli
In this chapter, authors review main methods, approaches, and models for the analysis of neuronal network data. In particular, the analysis concerns... Sample PDF
Investigating the Collective Behavior of Neural Networks: A Review of Signal Processing Approaches
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Chapter 33
Paolo Vicini
This chapter describes the System for Population Kinetics (SPK), a novel Web service for performing population kinetic analysis. Population kinetic... Sample PDF
The System for Population Kinetics: Open Source Software for Population Analysis
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Chapter 34
Julia Adolphs
This chapter introduces the theory of optical spectra and excitation energy transfer of light harvesting complexes in photosynthesis. The light... Sample PDF
Photosynthesis: How Proteins Control Excitation Energy Transfer
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Chapter 35
Michael R. Hamblin
Photodynamic therapy (PDT) is a rapidly advancing treatment for multiple diseases. PDT involves the administration of a nontoxic drug or dye known... Sample PDF
Photodynamic Therapy: A Systems Biology Approach
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Chapter 36
Andriani Daskalaki
Photodynamic Therapy (PDT) involves administration of a photosensitizer (PS) either systemically or locally, followed by illumination of the lesion... Sample PDF
Modeling of Porphyrin Metabolism with PyBioS
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Chapter 37
Alexey R. Brazhe, Nadezda A. Brazhe, Alexey N. Pavlov, Georgy V. Maksimov
This chapter describes the application of interference microscopy and double-wavelet analysis to noninvasive study of cell structure and function.... Sample PDF
Interference Microscopy for Cellular Studies
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Chapter 38
Cathrin Dressler, Olaf Minet, Urszula Zabarylo, Jürgen Beuthan
This chapter deals with the mitochondrias’ stress response to heat, which is the central agent of thermotherapy. Thermotherapies function by... Sample PDF
Fluorescence Imaging of Mitochondrial Long-Term Depolarization in Cancer Cells Exposed to Heat-Stress
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Chapter 39
Athina Theodosiou, Charalampos Moschopoulos, Marc Baumann, Sophia Kossida
In previous years, scientists have begun understanding the significance of proteins and protein interactions. The direct connection of those with... Sample PDF
Protein Interactions and Diseases
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Chapter 40
Bernard de Bono
From a genetic perspective, disease can be interpreted in terms of a variation in molecular sequence or expression (dose) that impairs normal... Sample PDF
The Breadth and Depth of BioMedical Molecular Networks: The Reactome Perspective
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Chapter 41
Jorge Numata
Thermodynamics is one of the best established notions in science. Some recent work in biomolecular modeling has sacrificed its rigor in favor of... Sample PDF
Entropy and Thermodynamics in Biomolecular Simulation
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Chapter 42
Isabel Reinecke, Peter Deuflhard
In this chapter some model development concepts can be used for the mathematical modeling in physiology as well as a graph theoretical approach for... Sample PDF
Model Development and Decomposition in Physiology
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Chapter 43
Mohamed Derouich
Throughout the world, seasonal outbreaks of influenza affect millions of people, killing about 500,000 individuals every year. Human influenza... Sample PDF
A Pandemic Avian Influenza Mathematical Model
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Chapter 44
Mohamed Derouich
Dengue fever is a re-emergent disease affecting more than 100 countries. Its incidence rate has increased fourfold since 1970 with nearly half the... Sample PDF
Dengue Fever: A Mathematical Model with Immunization Program
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Chapter 45
Ross Foley
The field of histopathology has encountered a key transition point with the progressive move towards use of digital slides and automated image... Sample PDF
Automated Image Analysis Approaches in Histopathology
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