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Diabetes Mellitus at the Time for Diagnosis: Studies on Prognostic Factors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.ORCID iD: 0000-0002-6060-6229
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim for this thesis was to identify prognostic factors for chronic diabetes complications that exist at the time of diabetes diagnosis.

Low level of education (<12 years) and low income (<60% of median) was found to increase the risk to have high (>70 mmol/mol) HbA1c at the time of diagnosis with 34 % and 35 %, respectively.

Prevalence of diabetic retinopathy (DR) was 12% in a cohort of patients newly diagnosed with diabetes. Diabetic macular edema was present in 11% of patients with type 2 diabetes (T2D) and 13% of those with Latent Autoimmune Diabetes in Adults (LADA). Low beta cell function and low level of education increased the risk for DR with 110% and 43%, respectively. For every unit of increase in body mass index, the risk for DR was reduced by 3%.

The cellular immunology of LADA patients was a mixture of that observed in both type 1 (T1D) and T2D patients. Compared to patients with T1D, LADA patients had more B-regulatory lymphocytes and antigen presenting cells capable of producing interleukine-35. This indicates a higher anti-inflammatory capacity in LADA patients compared to type T1D patients.

By imputing age, body mass index, HbA1c at diagnosis, beta cell function and insulin resistance in a cluster analysis, five distinct diabetes clusters were identified. The four clusters representing T2D patients differed in incidence of DR, nephropathy and non-alcoholic fatty liver disease. This was replicated with similar results in three geographically separate populations.

By studying socioeconomic background and factors present at the time of diagnosis we can better predict prognosis for chronic diabetes complications. These findings may facilitate better-targeted diabetes screening programs and more individually tailored treatment regimes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , p. 87
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1361
Keywords [en]
New-onset Diabetes Mellitus, socioeconomic position, epidemiology, diabetes complications, diabetic retinopathy, cellular immunology, diabetes classification, type 2 diabetes, latent autoimmune diabetes in adults (LADA), type 1 diabetes
National Category
General Practice
Research subject
Family Medicine; Endocrinology and Diabetology
Identifiers
URN: urn:nbn:se:uu:diva-328382ISBN: 978-91-513-0047-4 (print)OAI: oai:DiVA.org:uu-328382DiVA, id: diva2:1135323
Public defence
2017-10-13, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Funder
EXODIAB - Excellence of Diabetes Research in Sweden, 2009-1039Available from: 2017-09-21 Created: 2017-08-22 Last updated: 2018-01-13
List of papers
1. Education, immigration and income as risk factors for hemoglobin A1c >70 mmol/mol when diagnosed with type 2 diabetes or latent autoimmune diabetes in adult: a population-based cohort study
Open this publication in new window or tab >>Education, immigration and income as risk factors for hemoglobin A1c >70 mmol/mol when diagnosed with type 2 diabetes or latent autoimmune diabetes in adult: a population-based cohort study
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2017 (English)In: BMJ Open Diabetes Research and Care, Vol. 5, no 1Article in journal (Refereed) Published
Abstract [en]

Objectives The aim of this research is to study education, income and immigration as risk factors for high hemoglobin A1c (HbA1c &gt;70 mmol/mol (8.6%)) when diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA).Research design and methods Patients were included from the All New Diabetics in Scania study (2008-2013). Level of education, disposable income and immigration year were retrieved from the longitudinal integrated database for labour market research (LISA) register compiled by Statistics Sweden. Logistic regression models were used to estimate ORs for HbA1c &gt;70 mmol/mol (8.6%) at diagnosis.Results A total of 3794 patients with incident T2D (n=3 525) or LADA (n=269) were included. Patients with T2D with a low (<=9 years) or medium (10-12 years) levels of education were more likely to have high HbA1c at diagnosis compared with patients with T2D with a high (&gt;12 years) level of education (OR 1.34, 95% CI 1.08 to1.66, OR 1.26, 95% CI 1.03 to 1.54). Low-income patients with T2D (&lt;60% of median) were more likely to have high HbA1c at diagnosis compared with high-income patients withT2D (&gt;150% of median) (OR 1.35, 95% CI 1.02 to 1.79).Conclusions Patients with lower levels of education or low income and are more likely to have HbA1c is &gt;70 mmol/mol (8.6%) when diagnosed with T2D. An understanding of how socioeconomic position influences the clinical presentation at diagnosis may facilitate screening programs designed to target populations at risk for delayed diagnosis.

Place, publisher, year, edition, pages
BMJ Specialist Journals, 2017
National Category
Public Health, Global Health, Social Medicine and Epidemiology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-321637 (URN)10.1136/bmjdrc-2016-000346 (DOI)
Available from: 2017-05-18 Created: 2017-05-18 Last updated: 2017-08-22
2. Prevalence and risk factors for diabetic retinopathy at diagnosis (DRAD) in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA)
Open this publication in new window or tab >>Prevalence and risk factors for diabetic retinopathy at diagnosis (DRAD) in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA)
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2016 (English)In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 30, no 8, p. 1456-1461Article in journal (Refereed) Published
Abstract [en]

PURPOSE: 

To study prevalence of diabetic retinopathy (DR) at diagnosis (DRAD) and to estimate contributing risk by sociodemographic, cardiovascular and metabolic characteristics present in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA).

METHODS: 

Patients (n=2174) recently diagnosed T2D (93%) or LADA (7%) were included upon arrival for their baseline DR screening. Fundus photographs of 4902 eyes were graded by a senior ophthalmologist according to the International Diabetic Retinopathy Disease Severity Scale. Official registers held by Statistics Sweden provided sociodemographic variables. The National Patient Register and Swedish Prescribed Drug Register were used to assess cardiovascular risk. Beta cell function (HOMA2%b) and insulin sensitivity (HOMA2%s) were estimated from fasting (f) C-Peptide using the homeostasis model assessment (HOMA) 2 calculator. Odds ratios (OR) for DRAD were estimated using generalized estimating equation models.

RESULTS: 

The prevalence of DRAD was 12% (7% mild and 5% moderate) and of diabetic macular edema it was 11% (all within vascular arch). The prevalence did not significantly differ between T2D and LADA. Due to sample size, the regression analysis of LADA patients did not yield any significant estimates. In T2D low educational level (≤9years) increased risk for DRAD by 44% (OR 1.44; 95% CI 1.07-1.93) and <50% beta-cell function adjusted for HbA1c and insulin sensitivity at diagnosis increased the risk by 77% (OR 1.77; 95% CI 1.28-2.44). For every unit increase in BMI, risk for DRAD decreased by 3% (OR 0.97; 95% CI 0.95-0.99).

CONCLUSIONS: 

DRAD prevalence in patients recently diagnosed with T2D or is 12%. Low educational level and low beta cell function at diagnosis are risk factors for DRAD. Estimation of beta cell function from (f)C-Peptide and (f)P-Glucose may be a valuable tool in identifying patients at risk for DRAD.

Keywords
Diabetes, Diabetic macular edema, Diabetic retinopathy, Diabetic retinopathy at diagnosis (DRAD), Latent autoimmune diabetes in the adult (LADA), Type 2 diabetes (T2D)
National Category
Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-319750 (URN)10.1016/j.jdiacomp.2016.08.009 (DOI)000399434900009 ()27593902 (PubMedID)
Available from: 2017-04-08 Created: 2017-04-08 Last updated: 2017-08-22Bibliographically approved
3. Characterization of Cellular Immunology in LADA Patients
Open this publication in new window or tab >>Characterization of Cellular Immunology in LADA Patients
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: Patients with latent autoimmune diabetes mellitus in adults (LADA) have antibodies against the insulin-producing b-cells but at disease onset they are not insulin-dependent. This study presents cellular immunological differences between LADA, type 1, type 2 diabetes and healthy controls.

Research Design and Methods: All patients and matched (by age, gender and body mass index) healthy controls were recruited from the County of Uppsala, Sweden. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine proportions of innate, adaptive and regulatory immune cells by using flow cytometry.

Results: Included were 14 patients with LADA, 16 with type 1 diabetes, 16 with type 2 diabetes and 13 healthy controls. The proportion of CD11c+CD123- antigen presenting cells (APCs) was lower, whilst proportions of CD11c+CD123+ APCs and Interleukin (IL)-35+ tolerogenic APCs were higher in LADA patients compared to patients with type 1 diabetes. The proportion of CD3-CD56highCD16+ Natural Killer (NK) cells was higher in LADA patients than in both healthy controls and type 2 diabetes patients. IL-35+ Treg cell numbers were similar to those observed in both type 1 diabetes and type 2 diabetes patients, but a lower frequency of IL-35+ regulatory T (Treg) cells was observed in LADA patients than in healthy controls. The proportion of regulatory B (Breg) cells in LADA patients was higher than in healthy controls, type 1 and type 2 diabetes patients and IL-35+ Breg cell numbers were higher than in type 1 diabetes patients.

Conclusions: LADA patients present a mixed cellular immunological pattern compared to type 1 and type 2 diabetes patients. Numbers of APCs, IL-35+ tolerogenic APCs and IL-35+ Breg cells in LADA patients are similar to those observed in type 2 diabetes patients, whereas the changes in NK cells are similar to those observed in type 1 diabetes patients. 

Keywords
Cellular immunology, latent autoimmun diabetes in adults, diabetes, type 1 diabetes, type 2 diabetes, interleukin 35
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-328352 (URN)
Projects
Diabetes Mellitus at the Time of Diagnosis - Studies on Prognostic Factors
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2017-08-22 Created: 2017-08-22 Last updated: 2018-01-13Bibliographically approved
4. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables
Open this publication in new window or tab >>Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables
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2018 (English)In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 6, no 5, p. 361-369Article in journal (Refereed) Published
Abstract [en]

 Background

Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.

Methods

We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.

Findings

We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.

Interpretation

We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.

National Category
Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-328355 (URN)10.1016/S2213-8587(18)30051-2 (DOI)000430631600013 ()
Projects
Diabetes Mellitus at the Time for Diagnosis, Studies on Prognostic Factors
Funder
EXODIAB - Excellence of Diabetes Research in Sweden, 2009-1039Swedish Research Council, 521-2010-3490Swedish Research Council, 2010-5983Linnaeus research environment CADICS, 349-2006-237
Note

Tredjeförfattarskapet delas av tredje och fjärde författaren.

Available from: 2017-08-22 Created: 2017-08-22 Last updated: 2018-07-20Bibliographically approved

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