Depressie en cognitie bij type 2 diabetes Miranda Schram afdeling Interne Geneeskunde MUMC+
Disclosure potential conflicts of interest Geen (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties: Bedrijfsnamen Sponsoring of onderzoeksgeld - Honorarium of andere (financiële) vergoeding - Aandeelhouder - Andere relatie, namelijk -
Eén derde van de volwassen Limburgers heeft (pre)diabetes 2 van 6 vakken met publiek
Type 2 diabetes and depression Risk of depression in type 2 diabetes is doubled QoL, societal costs Mortality risk : OR for mortality 1.46 * OR for cvd mortality 1.39 * * F. van Dooren et al, Plos One 2013; 8(3):e57058
Course of depression in type 2 diabetes
Course of depression in type 2 diabetes Paucity of data Probably a chronic course Under reported, under recognised, under treatment Treatment resistance, ineffective treatment? Different etiology than early life depression Biology largely unknown
Mechanisms Psychosocial variables Lifestyle factors Biological mechanisms
Mechanisms Psychosocial variables Lifestyle factors Biological mechanisms
Mechanisms Psychosocial variables Inflammation Lifestyle factors Biological mechanisms Endothelial dysfunction
Research questions We investigated the associations between markers of - Hyperglycemia (glucose, AGEs) - Inflammation, and - Endothelial dysfunction with depressive symptoms and depressive disorder in a population-based study
Mechanisms Psychosocial variables Inflammation Lifestyle factors Biological mechanisms Endothelial dysfunction
The Maastricht Study 10,000 participants, 40-75 years From the Maastricht area Oversampling of type 2 diabetes Advanced deep phenotyping Survey I: 2010-2018 Dataset n~3400 (Nov 10-Sept 13) Eur J Epidemiology (2014) 29:439-451
Extremely detailed phenotyping
Depression PHQ-9, MINI diagnostic interview (gold standard) Diabetes Oral glucose tolerance test Methods Glycemic control (fasting gluc, HbA1c, AGEs: SAF, Pentosidine, CEL, CML) Inflammation (hscrp, SAA, sicam-1, IL-6, IL-8, TNF-α) Endothelial function (svcam-1, sicam-1, se-selectin, vwf) MRI (brain atrophy and cerebral small vessel disease) Lifestyle (physical activity, sedentary time, nutrition)
General characteristics No type 2 diabetes (n=2349) Type 2 diabetes (n=918) Age, years 58.7 ± 8.2 62.6 ± 7.6 Female sex, n (%) 1291 (55%) 298 (33%) Partner, n (%) 1972 (85%) 731 (82%) Educational level, % low/middle/high 28/28/44 46/28/26 HbA1c, % 5.5 ± 0.4 6.9 ± 1.0 Smoking, % never/former/current 37/50/12 28/56/16 Body mass index, kg/m 2 26.0 ± 3.9 29.9 ± 5.0 Blood pressure, mmhg 132 ± 17 / 76 ± 10 142 ± 18 / 77 ± 10 Total cholesterol, mmol/l 5.5 ± 1.1 4.5 ± 1.0 HDL cholesterol, mmol/l 1.61 ± 0.47 1.27 ± 0.37 N= 3267
Prevalence of depression prevalence in % 10 9 8 7 6 5 4 3 2 3,4 * 6,2 * 2,7 2,7 * 6,3 4,0 * 9,0 Non-DM DM2 1 0 1,4 PHQ-9 score > 10 Minor depression Major depression Major and minor depression
Association of depression with T2DM Depressive symptoms Odds ratio 95% CI p-value PHQ-9 score (continuous) 1.06 (1.02-1.09) < 0.001 PHQ-9 10 1.94 (1.20-3.13) 0.007 Depressive disorder Minor depressive disorder (MINI) 1.81 (0.90-3.64) 0.097 Major depressive disorder (MINI) 1.99 (1.24-3.19) 0.005 Adjusted for age, sex, educational level, bmi, smoking, partner status, systolic blood pressure, prior CVD, total cholesterol and HDL cholesterol
Hyperglycemia and depression Independent variables Fasting glucose per SD HbA1c per SD Skin Autofluoresence per SD Hyperglycemia sum score per SD Major depression OR (95%CI) P-value 1.30 (1.09-1.55) 0.003 1.37 (1.15-1.63) 0.001 1.28 (1.02-1.62) 0.036 1.54 (1.22-1.96) <0.001 adjusted for age, sex, smoking, alcohol consumption, hypertension, cholesterol ratio, physical activity, and BMI
Advanced Glycation Endproducts (AGEs) * Adjusted for age, sex, type 2 diabetes, bmi, smoking, egfr Van Dooren et al, Depression and Anxiety, 2016 Jun 6
Insuline resistance and depression Independent variables Major depression OR (95%CI) P-value Fasting insulin per SD HOMA per SD Insulin resistance markers sum score per SD 0.97 (0.8-1.18) 0.740 1.04 (0.83-1.29) 0.756 1.01 (0.78-1.13) 0.923 adjusted for age, sex, smoking, alcohol consumption, hypertension, cholesterol ratio, physical activity, and BMI
Hyperglycemia, IR and depression
Conclusie Type 2 diabetes is geassocieerd met meer depressie Verschillende maten van hyperglycemie zijn geassocieerd met depressie Insuline resistentie is niet geassocieerd met depressie
Mechanisms Psychosocial variables Inflammation Lifestyle factors Biological mechanisms Endothelial dysfunction
Depression PHQ-9, MINI diagnostic interview (gold standard) Diabetes Oral glucose tolerance test Methods Glycemic control (fasting gluc, HbA1c, AGEs: SAF, Pentosidine, CEL, CML) Inflammation (hscrp, SAA, sicam-1, IL-6, IL-8, TNF-α) Endothelial function (svcam-1, sicam-1, se-selectin, vwf) MRI (brain atrophy and cerebral small vessel disease) Lifestyle (physical activity, sedentary time, nutrition)
Low grade inflammation * * * * * OR was 1,54 (1,18-2,02) for LGI sumscore after adjustment for age, sex, DM2, egfr, prior CVD Van Dooren et al, Brain Behaviour and Immunity, 2016 Aug;56:390-6.
Endothelial dysfunction Odds ratio 1,8 1,7 1,6 1,5 1,4 1,3 1,2 1,1 1 Endothelial function is associated with depressive disorder * 1,25 * * 1,35 1,36 1,19 1,64 svcam-1 sicam-1 E-selectine vwf ED sumscore * OR was 1,40 (1,10-1,77) for ED sumscore after adjustment for age, sex, DM2, egfr, prior CVD Van Dooren et al, Brain Behaviour and Immunity, 2016 Aug;56:390-6.
Inflammation and incident depression Longitudinal associations of low-grade inflammation sum score with incident depression Odds ratio 95% CI p value Model 1: crude + demographics 1.81 1.37-2.38 <0.001 Model 2: model 1 + cardiovascular risk factors Model 3: model 2 + lifestyle risk factors 1.44 1.05-1.97 0.022 1.34 0.95-1.88 0.096 Model 1 included age, sex, education status and partner status; model 2 additionally incorporated cardiovascular risk factors as type 2 diabetes status, history of cardiovascular disorder, kidney function and HbA1c; model 3 added modifiable lifestyle risk factors as body mass index (BMI), blood pressure, smoking and physical activity.
Endothelial dysfunction and incident depression Longitudinal associations of endothelial dysfunction sum score with incident depression Odds ratio 95% CI p value Model 1: crude + demographics 1.80 1.43-2.26 <0.001 Model 2: model 1 + cardiovascular risk factors 1.48 1.14-1.92 0.004 Model 3: model 2 + lifestyle risk factors 1.40 1.07-1.84 0.014 Model 1 included age, sex, education status and partner status; model 2 additionally incorporated cardiovascular risk factors as type 2 diabetes status, history of cardiovascular disorder, kidney function and HbA1c; model 3 added modifiable lifestyle risk factors as body mass index (BMI), blood pressure, smoking and physical activity.
LGI, ED and incident depression 55% 45%
Inflammation, endothelial dysfunction and chronic depression Remission Resistant or recurrent LGI Odds ratio 95% CI p value Odds ratio 95% CI p value Model 1: demographics 1.75 1.17; 2.62 0.007 2.72 1.89; 3.93 0.000 Model 2: model 1 + cardiovascular risk factors Model 3: model 2 + lifestyle risk factors 1.82 1.17; 2.83 0.008 1.86 1.21; 2.86 0.005 1.62 0.99; 2.69 0.057 1.69 1.03; 2.77 0.039 ED Model 1: demographics 1.06 0.67; 1.68 0.818 2.18 1.59; 3.00 0.000 Model 2: model 1 + cardiovascular risk factors Model 3: model 2 + lifestyle risk factors 1.01 0.61; 1.67 0.967 1.51 1.04; 2.21 0.032 0.74 0.42; 1.31 0.302 1.37 0.89; 2.09 0.150 Model 1 included age, sex, education status and partner status; model 2 additionally incorporated cardiovascular risk factors as type 2 diabetes status, history of cardiovascular disorder, kidney function and HbA1c; model 3 added modifiable lifestyle risk factors as body mass index (BMI), blood pressure, smoking and physical activity.
Depressie als gevolg van vaatschade ORs = 1.14 1.58 Agtmaal et al JAMA Psychiatry 2017 Jul 1;74(7):729-739.
Conclusie Inflammatie en endotheel dysfunctie zijn geassocieerd met incidente depressie, mogelijk causaal verband Inflammatie en endotheel dysfunctie samen kunnen chronische depressie voorspellen
Mechanisms Psychosocial variables Inflammation Lifestyle factors Biological mechanisms Endothelial dysfunction
Type 2 diabetes and dementia 2x greater risk of dementia in type 2 diabetes Via hyperglycaemia? Via vascular brain damage?
Type 2 diabetes and cognitieve functie
White matter hyperintensities
Brain tissue volumes
Vaatschade in het brein Vaatschade op MRI Geen diabetes Pre-diabetes Diabetes Van Agtmaal et al, submitted
White matter volume Geen diabetes Pre-diabetes Diabetes Van Agtmaal et al, submitted
Grey matter volume Geen diabetes Pre-diabetes Diabetes Van Agtmaal et al, submitted
Cerebrospinal fluid Geen diabetes Pre-diabetes Diabetes Van Agtmaal et al, submitted
Conclusion Prediabetes is associated with White matter hyperintensities Lower white matter volume 4 years of aging T2DM is associated with White matter hyperintensities Lower white matter volume Higher CSF volume 8.5 years of aging
Take home message Depressie en dementie komen 2x zo veel voor bij type 2 diabetes Verklarende mechanismen hiervoor zijn: Hyperglycemie Inflammatie Endotheel dysfunctie Vasculaire brein schade Zowel prediabetes als type 2 diabetes zijn geassocieerd met versnelde veroudering van het brein weefsel vergelijkbaar met 4 vs 8 jaar veroudering
Eén derde van de volwassen Limburgers heeft (pre)diabetes 2 van 6 vakken met publiek
17 PhD theses on The Maastricht Study A further 20 PhD theses in preparation