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New scientific knowledge on juvenile diabetes
16.12.2008
Metabolic disturbances indicate progress of the disease even years in advance
Finnish scientists have reported a breakthrough in the attempts to understand
the development of type 1 diabetes. They discovered disturbances in lipid and
amino acid metabolism in children who later progressed to type 1 diabetes,
also known as juvenile diabetes. The alterations preceded the autoimmune
response by months to years. The study may prompt new approaches for
prediction and prevention of type 1 diabetes in pre-autoimmune phase of the
disease.
The results of the Finnish research team, which
consists of scientists from VTT Technical Research Centre of Finland and the
Universities of Turku, Oulu and Tampere, have been published on 15 December
2008, in the Journal of Experimental Medicine.
Type 1 diabetes is an autoimmune disease in which the immune system attacks
the insulin producing pancreatic beta cells. The gradual loss of beta cells
results in life-long dependence on exogenous insulin.
At the
moment, the earliest identifiable process in the pathogenesis of type 1
diabetes has been the development of autoimmunity to pancreatic beta cells in
the measurable form of islet autoantibodies. Although the autoimmunity usually
precedes the clinical disease by months to years, its occurrence may already
be too late for therapeutic approaches aimed at preventing progression to
overt diabetes. The initiators of the autoimmune response have remained
unknown and the mechanisms supporting progression towards beta cell failure
have been poorly understood, making discovery of effective prevention a
challenge. The results of the SYSDIPP project, which was supported by the
Tekes FinnWell Program, bring significant new information for combating the
disease.
The SYSDIPP project has made use of metabolomics.
Metabolomics systematically studies the chemical fingerprints in cells,
tissues and biofluids in a given physiological and environmental context. The
metabolic phenotype is sensitive to subtle factors such as age, lifestyle,
nutrition and the microbe environment of the intestines. Changes in the
concentrations of metabolites may thus reflect both genetic and environmental
factors influencing later susceptibility to chronic diseases.
In
1994, an ongoing birth cohort study (DIPP, the Type 1 Diabetes Prediction and
Prevention study) was launched in Finland, supported by the Juvenile Diabetes
Research Foundation International. Over a period of 14 years, more than
130,000 newborn infants have been screened for genetic risk and over 8000
at-risk children are being regularly followed.
The research
team was led by Prof. Matej Orešič from VTT Technical Research Centre of
Finland and Prof. Olli Simell from University of Turku. Also Professors Mikael
Knip, Jorma Ilonen, and Riitta Lahesmaa together with Dr. Riitta Veijola and
Dr.Tuula Simell took part in the study, which investigated metabolic profiles
of DIPP children prospectively from birth. The research team has published the
results in The Journal of Experimental Medicine on 15 December 2008. The
article reports the discovery of metabolic disturbances that precede the
autoimmune response in children who later progress to type 1 diabetes.
The
investigators found that the individuals who developed diabetes had reduced
serum levels of succinic acid and phosphatidylcholine at birth, reduced levels
of triglycerides and antioxidant ether phospholipids throughout the follow-up
and increased levels of proinflammatory lysophosphatidylcholines several
months prior to autoimmunity to pancreatic beta cells. The metabolic profile
was partially normalized following the autoimmune response, suggesting
autoimmunity may be a relatively late physiological response to the early
metabolic disturbances. The observed lipid changes were not attributable to
HLA-associated genetic risk.
Metabolic profiling at early age
may therefore aid in determining the risk of type 1 diabetes. The reported
findings imply that metabolic or immunomodulatory interventions during the
pre-autoimmune period may be used as a new potential strategy for prevention
of type 1 diabetes.
The incidence of type 1 diabetes among
children and adolescents has increased markedly in the Western countries
during recent decades. The incidence has reached record levels in Finland,
where currently 1 child out of 120 develops type 1 diabetes before the age of
15 years. The annual incidence is increasing at accelerated rate, with the
number of new cases expected to double in the next 15 years.
FIGURE.
The figure shows a case of a girl who was diagnosed with T1D at age 9 years.
During the asympotomatic period, she had unusually high levels of
proinflammatory lysophosphatidylcholine (blue), low level of antioxidant ether
lipid (green), and low levels of ketoleucine. Following the appearance of
first autoantibodies at age of approximately 2 years (GADA), the levels of
these metabolites were normalized.
PHOTO
1: Research Professor Matej Orešič
PHOTO
2: VTTäs Metabolomics team: Research Scientist Marko Sysi-Aho, Senior
Research Scientist Tuulikki Seppänen-Laakso and Research Professor Matej
Orešič.
PHOTO
3: VTT's Metabolomics team: Research Professor Matej Orešič, Senior
Research Scientist Tuulikki Seppänen-Laakso and Research Scientist Marko
Sysi-Aho
PHOTO
4: VTT Metabolomics Laboratory. Senior Research Assistant Annaliisa
Ruskeepää in the photo.
Further information:
VTT
Technical Research Centre of Finland
Prof. Matej
Orešič, Ph.D.
Tel. +358 20 722 4491
Department
of Pediatrics, University of Turku
Prof. Olli
Simell, M.D., Ph.D.
Tel. +358 2 313 2466
http://sysbio.vtt.fi/
Reference
M.
Orešič, S. Simell, M. Sysi-Aho, K. Näntö-Salonen, T. Seppänen-Laakso, V.
Parikka, M. Katajamaa, A. Hekkala, I. Mattila, P. Keskinen, L. Yetukuri, A.
Reinikainen, J. Lähde, T. Suortti, J. Hakalax, T. Simell, H. Hyöty, R.
Veijola, J. Ilonen, R. Lahesmaa, M. Knip, O. Simell, Dysregulation of lipid
and amino acid metabolism precedes islet autoimmunity in children who later
progress to type 1 diabetes, J. Exp. Med. (2008); doi: 10.1084/jem.20081800
Link
to The Journal of Experimental Medicine website presenting the study: http://jem.rupress.org/