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Breakthrough In Understanding Development Of Type 1 Diabetes

Scientists 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.

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 Ore¹iè from VTT Technical Research

Centre of Finland and Prof. Olli Simell from University of Turku took part

in

the study, which investigated metabolic profiles of DIPP children

prospectively from birth.

The research team published the results. 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.

Oresic et al. Dysregulation of lipid and amino acid metabolism precedes

islet autoimmunity in children who later progress to type 1 diabetes.

Journal of

Experimental Medicine, Dec. 15, 2008; DOI: