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Aspects of the Pre-Diabetic Period in Type 1 Diabetes
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency, due to immune-mediated destruction of beta cells. Current knowledge regarding the period preceding disease onset comes, to a large extent, from studying risk cohorts based on relatives of T1D-patients, as they have an increased disease risk. Among T1D patients in general, however, few have the disease in their immediate family. It is therefore important to study risk cohorts from the general population as well. An ongoing autoimmune reaction can often be seen in the blood long before disease onset, by detection of autoantibodies directed towards beta cell antigens. By autoantibody screening among participants in the ABIS (All Babies in the South-east of Sweden) cohort, we could identify a group of children from the general population with increased risk for T1D, positive for multiple autoantibodies. They were enrolled in a 2-year prospective follow-up aiming to characterize the prediabetic period and to identify factors indicative of progression/non-progression to T1D. We assessed glucose homeostasis and autoantibody titers over time, and searched for risk-biomarkers by analyzing the expression of immune-related genes (Th1-Th2-Th3) in peripheral blood mononuclear cells (PBMC) from these children, in comparison to healthy children and newly diagnosed T1D patients. In the same groups we also compared serum micro RNA (miRNA) profiles, knowing that miRNA molecules have desirable biomarker properties. We found that two specific autoantibodies, IA2A and ZnT8A, were detected at higher concentrations in risk-individuals who progressed to overt T1D during or after the follow-up period, compared to those who still have not. We also observed disturbed glucose homeostasis long before onset in the progressors, but it was seen among those who remain symptom free as well. Further, we found support for the possible role of insulin resistance as an accelerator of the disease process. For gene expression and serum miRNA, few differences were observed between risk-individuals and healthy children overall. However, for PBMC gene expression and serum miRNA both, there were associations to beta cell function and glucose homeostasis, and for miRNA also to islet autoantibodies. Although specific profiles for prediction of disease onset or identification of risk-individuals could not be found, these results are interesting and deserve to be evaluated further. As part of another sub-study within ABIS, the effects of physical activity on glucose homeostasis were assessed in healthy schoolchildren. The level of physical activity, measured by pedometers, was related to insulin resistance and beta cell-stress, and decreased physical activity was associated with increased insulin resistance and load on the insulin-producing beta cells, already at school-age.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 101 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1529
National Category
Endocrinology and Diabetes Neurology Pediatrics Gastroenterology and Hepatology Rheumatology and Autoimmunity Clinical Science
Identifiers
URN: urn:nbn:se:liu:diva-132171DOI: 10.3384/disss.diva-132171ISBN: 9789176857113 (Print)OAI: oai:DiVA.org:liu-132171DiVA: diva2:1038737
Public defence
2016-11-18, Hasselquistsalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2016-10-19 Created: 2016-10-19 Last updated: 2016-10-24Bibliographically approved
List of papers
1. Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes
Open this publication in new window or tab >>Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes
2013 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 148, no 1Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes (T1D) patients have numeral and functional defects in peripheral immune cells, but the pre-diabetic period is fairly uncharacterized. Our aim was to analyze expression of immunological markers in T1D high risk children and relate it to clinical/immunological parameters. Children from ABIS (All Babies in Southeast Sweden) with greater than= 2 diabetes related autoantibodies were considered at high risk. Age-matched controls and new-onset T1D patients were included. Expression of genes related to immune cell function and different arms of the immune system was assessed in peripheral blood mononuclear cells using PCR array. Risk children had lower TNF and CD45, and although there were few differences between the groups, expression of many genes differed when comparing children with regard to residual insulin secretion. Hence, expression of immune related genes seemed related not only to the autoimmune process but rather to residual beta-cell function, which was decreased already during the pre-diabetic phase.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
Type 1 diabetes; Gene expression; PBMC; T1D high risk; T1D autoantibodies; PCR array
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96458 (URN)10.1016/j.clim.2013.03.011 (DOI)000320427300002 ()
Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2016-10-19
2. Physical Activity, Blood Glucose and C-Peptide in Healthy School-Children, a Longitudinal Study
Open this publication in new window or tab >>Physical Activity, Blood Glucose and C-Peptide in Healthy School-Children, a Longitudinal Study
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, e0156401- p.Article in journal (Refereed) Published
Abstract [en]

Aim To further elucidate the relationship between physical activity and several risk factors for development of diabetes (glucose, C-peptide and obesity) over time. Methods A prospective longitudinal study where physical activity was measured on 199 children from Kalmar and Linkoping at age 8, and the same 107 children from Linkoping again at age 12. Anthropometric data was collected and blood was analyzed for C-peptide and f-glucose. The children in the study were representative for the general Swedish child population, and on an average lean. Results High physical activity was related to lower C-peptide at age 8 and 12. This correlation was especially pronounced in boys, who also were more physically active than girls at both time points. The association seen at 8 years of age was similar at age 12 in most children. Children with higher BMI Z-Score had a higher fasting C-peptide (age 12) but linear regression showed that children with more steps per day were less likely to have a higher fasting C-peptide irrespective of BMI. Longitudinal follow-up showed that a decrease in physical activity increased insulin resistance and beta-cell load. Conclusions Already in young children, physical activity improves insulin sensitivity and decreases the need of C-peptide over time. This seems to become even more pronounced with increasing age when children are followed longitudinally. Low physical activity increases the load on insulin producing beta-cells, might increase the risk for both type 1- and 2 diabetes.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Pediatrics
Identifiers
urn:nbn:se:liu:diva-130132 (URN)10.1371/journal.pone.0156401 (DOI)000377561000012 ()27270732 (PubMedID)
Note

Funding Agencies|Swedish Child Diabetes Foundation (Barndiabetesfonden); Novo Nordisk Foundation; Research Council of South-east Sweden (FORSS); Swedish Research Council [K2005-72X-11242-11A]; ALF/County Council of Ostergotland

Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2016-10-19

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