Interplay between birthweight, family history, obesity, and genes in the development of latent autoimmune diabetes in adults (LADA) and type 2 diabetes
Author: Hjort, Rebecka
Date: 2019-08-30
Location: Samuelssonsalen, Tomtebodavägen 6, Karolinska Institutet, Solna
Time: 09.00
Department: Institutet för miljömedicin / Institute of Environmental Medicine
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Thesis (2.509Mb)
Abstract
Diabetes is a chronic and serious public health concern affecting millions of people around the globe. For effective prevention understanding of modifiable risk factors is fundamental. For type 2 diabetes these risk factors are well-described. However, for autoimmune diabetes such as type 1 diabetes, information is essentially missing. LADA, latent autoimmune diabetes in adults is suggested to be a hybrid of type 1 and type 2 diabetes and despite being common, its risk factors are scarcely investigated. Thus, the aim of this thesis was to add new understanding to the aetiology of LADA in relation to birthweight, overweight, obesity, family history of diabetes (FHD) and genes as well as the interaction between these factors in relation to the risk of LADA and how this compares with type 2 diabetes.
The analyses were based on data from two large population based studies: ESTRID, an ongoing case-control study from Sweden including incident cases of diabetes and randomly selected controls (≥35 years of age) and HUNT, a prospective study from Norway with incident cases of diabetes and 22 years of follow-up. LADA was defined by the criteria that age at initial diagnosis is at least ≥35 years old and glutamic acid decarboxylase antibody (GADA) positivity. In ESTRID LADA patients also had C-peptide levels indicating residual insulin secretion. Patients ≥35 years of age with GADA negativity were considered to have type 2 diabetes. Information on birthweight, body mass index (BMI kg/m2) and FHD was self-reported in ESTRID. In HUNT, information on BMI was collected at the baseline medical examination.
Our results indicate that heredity is primarily linked to FHD of type 1 diabetes (Relative risk [RR] 5.75; 95% confidence interval [CI] 3.23-10.25) but is also associated with FHD of type 2 diabetes (RR 1.89; CI 1.45-2.47). Furthermore, our findings suggest that obesity (BMI ≥30) increases the risk of LADA 3-6 fold, although the risk was not as marked as for type 2 diabetes (10-19 fold increased risk). In line with this, the risk of LADA was greater in individuals with low GADA but present also among those with higher degree of autoimmunity. Notably, our analyses indicate that 31-56% of all LADA patients may be prevented by keeping a normal weight (BMI <25). The greatest risk of LADA was seen in those with overweight in combination with HLA genes associated with autoimmunity (RR 7.59, CI 5.27-10.93), with attributable proportion due to interaction (AP) estimated to 0.29 (CI 0.10-0.47). Additionally, type 2 diabetes risk genes interacted with overweight in relation to LADA; TCF7L2 (AP=0.31, CI 0.09-0.52) and FTO (AP=0.38, CI 0.15-0.61). Moreover, low birthweight was associated with a more than 2-fold increased risk of LADA and type 2 diabetes, with the strongest risk in those with low birthweight in combination with adult overweight; LADA, RR 3.26 (CI 1.69, 6.29); and type 2 diabetes, RR 39.93 (CI 19.27, 82.71).
In conclusion, results from this thesis indicate that LADA is associated with risk factors linked to insulin resistance and type 2 diabetes while genetic susceptibility is linked foremost to genes associated with autoimmunity and type 1 diabetes. Importantly, our findings suggest that LADA in part may be prevented by keeping a healthy weight.
The analyses were based on data from two large population based studies: ESTRID, an ongoing case-control study from Sweden including incident cases of diabetes and randomly selected controls (≥35 years of age) and HUNT, a prospective study from Norway with incident cases of diabetes and 22 years of follow-up. LADA was defined by the criteria that age at initial diagnosis is at least ≥35 years old and glutamic acid decarboxylase antibody (GADA) positivity. In ESTRID LADA patients also had C-peptide levels indicating residual insulin secretion. Patients ≥35 years of age with GADA negativity were considered to have type 2 diabetes. Information on birthweight, body mass index (BMI kg/m2) and FHD was self-reported in ESTRID. In HUNT, information on BMI was collected at the baseline medical examination.
Our results indicate that heredity is primarily linked to FHD of type 1 diabetes (Relative risk [RR] 5.75; 95% confidence interval [CI] 3.23-10.25) but is also associated with FHD of type 2 diabetes (RR 1.89; CI 1.45-2.47). Furthermore, our findings suggest that obesity (BMI ≥30) increases the risk of LADA 3-6 fold, although the risk was not as marked as for type 2 diabetes (10-19 fold increased risk). In line with this, the risk of LADA was greater in individuals with low GADA but present also among those with higher degree of autoimmunity. Notably, our analyses indicate that 31-56% of all LADA patients may be prevented by keeping a normal weight (BMI <25). The greatest risk of LADA was seen in those with overweight in combination with HLA genes associated with autoimmunity (RR 7.59, CI 5.27-10.93), with attributable proportion due to interaction (AP) estimated to 0.29 (CI 0.10-0.47). Additionally, type 2 diabetes risk genes interacted with overweight in relation to LADA; TCF7L2 (AP=0.31, CI 0.09-0.52) and FTO (AP=0.38, CI 0.15-0.61). Moreover, low birthweight was associated with a more than 2-fold increased risk of LADA and type 2 diabetes, with the strongest risk in those with low birthweight in combination with adult overweight; LADA, RR 3.26 (CI 1.69, 6.29); and type 2 diabetes, RR 39.93 (CI 19.27, 82.71).
In conclusion, results from this thesis indicate that LADA is associated with risk factors linked to insulin resistance and type 2 diabetes while genetic susceptibility is linked foremost to genes associated with autoimmunity and type 1 diabetes. Importantly, our findings suggest that LADA in part may be prevented by keeping a healthy weight.
List of papers:
I. Hjort R, Alfredsson L, Carlsson P-O, Groop L, Martinell M, Storm P, Tuomi T, Carlsson S. Low birthweight is associated with an increased risk of LADA and type 2 diabetes: results from a Swedish case–control study. Diabetologia. 2015, 58:2525–2532.
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II. Hjort R, Alfredsson L, Andersson T, Carlsson P-O, Grill V, Groop L, Martinell M, Rasouli B, Storm P, Tuomi T, Carlsson S. Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA). Diabetes & Metabolism. 2017, 43:536-542.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Hjort R, Ahlqvist E, Carlsson P-O, Grill V, Groop L, Martinell M, Rasouli B, Rosengren A, Tuomi T, Åsvold BO, Carlsson S. Overweight, obesity and the risk of LADA: results from a Swedish case–control study and the Norwegian HUNT Study. Diabetologia. 2018, 61(6):1333-1343.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Hjort R, Löfvenborg JE, Ahlqvist E, Alfredsson L, Andersson T, Grill V, Groop L, Sørgjerd EP, Tuomi T, Åsvold BO, Carlsson S. Interaction between overweight and genotypes of HLA, TCF7L2, and FTO in relation to the risk of Latent Autoimmune Diabetes in Adults and type 2 diabetes. J Clin Endocrinol Metab. 2019 May 24. pii: jc.2019-00183.
Fulltext (DOI)
Pubmed
I. Hjort R, Alfredsson L, Carlsson P-O, Groop L, Martinell M, Storm P, Tuomi T, Carlsson S. Low birthweight is associated with an increased risk of LADA and type 2 diabetes: results from a Swedish case–control study. Diabetologia. 2015, 58:2525–2532.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Hjort R, Alfredsson L, Andersson T, Carlsson P-O, Grill V, Groop L, Martinell M, Rasouli B, Storm P, Tuomi T, Carlsson S. Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA). Diabetes & Metabolism. 2017, 43:536-542.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Hjort R, Ahlqvist E, Carlsson P-O, Grill V, Groop L, Martinell M, Rasouli B, Rosengren A, Tuomi T, Åsvold BO, Carlsson S. Overweight, obesity and the risk of LADA: results from a Swedish case–control study and the Norwegian HUNT Study. Diabetologia. 2018, 61(6):1333-1343.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Hjort R, Löfvenborg JE, Ahlqvist E, Alfredsson L, Andersson T, Grill V, Groop L, Sørgjerd EP, Tuomi T, Åsvold BO, Carlsson S. Interaction between overweight and genotypes of HLA, TCF7L2, and FTO in relation to the risk of Latent Autoimmune Diabetes in Adults and type 2 diabetes. J Clin Endocrinol Metab. 2019 May 24. pii: jc.2019-00183.
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Carlsson, Sofia
Co-supervisor: Alfredsson, Lars; Tuomi, Tiinamaija
Issue date: 2019-08-07
Rights:
Publication year: 2019
ISBN: 978-91-7831-520-8
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