Towards a Better Understanding of Diabetes Distress, Depression and Poor Glycaemic Control in T2DM

Study Overview
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Brief Summary
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DIA-LINK2 is a prospective observational study analysing longitudinal associations and mediating links between diabetes distress (DD), depressive symptoms (DS) and glycaemic outcomes in people with type 2 diabetes (T2DM). A total of 200 people with T2DM with different levels of DD and DS are to be enrolled. At baseline, all participants are assessed for DD and DS, psychological and stress-related variables, self-reported self-management, HbA1c and inflammatory markers. This is followed by a 4-week ambulatory assessment period including continuous glucose monitoring (CGM), continuous activity tracking and daily event sampling regarding sleep, stress levels, mood and diabetes-related issues; additionally, cortisol levels are assessed on four days within this period. Three months after baseline, a follow-up assessment covers DD and DS levels, stress-related variables, self-reported self-management, HbA1c and final CGM assessment. The analyses aim to establish risk factors/protective factors regarding DD and DS, their relative impact on glycaemic outcomes and potential mediation of the associations by behavioural (e.g. self-management, physical activity), physical (e.g. heart rate variability, inflammatory activity) and mental variables (subjective stress level) in T2DM.

Detailed Description
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DIA-LINK2 is a prospective observational study analysing longitudinal associations between diabetes distress (DD), depressive symptoms (DS) and glycaemic outcomes in people with type 2 diabetes (T2DM). A variety of behavioural, physical and mental variables are assessed to analyse the mediating links between DD, DS and glycaemia. A total of 200 people with T2DM are enrolled according to DD (PAID ≥ / < 40) and DS (CES-D ≥ / < 22) scores so that four groups (n = 50 persons each) with varying levels of DD and DS are established: 1. PAID < 40 and CES-D < 22 (no DD, no DS); 2. PAID ≥ 40 and CES-D < 22 (DD, no DS); 3. PAID < 40 and CES-D ≥ 22 (DS, no DD); 4. PAID ≥ 40 and CES-D ≥ 22 (DD and DS). At baseline, all participants are assessed for relevant psychological and stress-related variables (daily hassles, life events, diabetes-related problems and fears, coping styles, resilience, diabetes acceptance, depression) as well as self-reported diabetes self-management using validated self-report scales and interviews; HbA1c and selected markers of inflammation (hsCRP, IL-6, IL-18, IL1Ra) are analysed from venous blood samples. This is followed by a 4-week ambulatory assessment period including continuous glucose monitoring (CGM) (to establish time in range, glucose variability and times in hypo/hyperglycaemia), continuous activity tracking regarding general activity, movement, sleep and heart rate using a wristband as well as event sampling regarding sleep quality, stress levels, mood and diabetes-related issues four times daily using a smartphone app. Additionally, salivary cortisol levels are estimated on four consecutive days (each including a morning, afternoon and night time sample) within this period. Three months after baseline, a follow-up assessment is performed which includes self-report measures of DD and DS, stress-related variables and diabetes self-management, HbA1c estimation from venous blood samples and final CGM assessment over 14 days. The collected data are used to analyse risk factors/protective factors regarding DD and DS, their relative impact on glycaemic outcomes and potential mediation of the associations by behavioural (e.g. self-management, physical activity), physical (e.g. heart rate variability, inflammatory activity) and mental variables (subjective stress level) in T2DM. The findings shall be used to develop personalised interventions for people with diabetes and comorbid mental conditions (DD and DS).

Official Title
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Towards a Better Understanding of Diabetes Distress, Depression and Poor Glycaemic Control Leading to Personalised Interventions for People With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2, Depressive Symptoms, Stress, Psychological, Glucose, High Blood

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes Diabetes duration at least 1 year Age between 18 and 70 years Sufficient German language skills Informed consent Smartphone available Exclusion Criteria: Capacity for consent lacking Illness with significant impairment of cognitive functioning (e.g. dementia) Severe somatic illness or mental disorder which interferes with study participation or might confound the results (dialysis-dependent renal failure; heart failure, i.e. New York Heart Association (NYHA) class III or IV; cancer requiring treatment; schizophrenia/psychotic disorder; bipolar disorder; severe eating disorder F50.0/F50.2; personality disorder) Terminal illness Being bedridden

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No DD or DS<br>No diabetes distress or depressive symptoms reported (CES-D < 22, PAID < 40) | |
| DD without DS<br>Diabetes distress but no depressive symptoms reported (CES-D < 22, PAID ≥ 40) | |
| DS without DD<br>Depressive symptoms but no diabetes distress reported (CES-D ≥ 22, PAID < 40) | |
| DD and DS<br>Both diabetes distress and depressive symptoms reported (CES-D ≥ 22, PAID ≥ 40) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depressive symptoms | Depressive symptoms are assessed using the 20-item Center for Epidemiologic Studies Depression Scale (CES-D), covering 20 symptoms of depression. Frequencies of the symptoms during the past week are scored on a 4-point Likert scale (from 0 - rarely or non of the time to 3 - most or all of the time). Item scores are summed to a total score ranging from 0 to 60, whereby higher values reflect higher depressive symptoms. A cut-off point at ≥ 22 points (found to have the best likelihood ratio for detecting depression within the German population) is used to establish elevated depressive symptoms in this study. | 3-month follow-up | 
| Diabetes Distress | Diabetes Distress is assessed as using the 20-item Problem Areas In Diabetes Scale (PAID). 20 potential problems related to living with diabetes are rated on a 5-point Likert scale (from 0 - not a problem to 4 - serious problem). Item scores are summed/transformed to a total score ranging from 0 to 100, whereby higher values reflect higher diabetes distress. A cut-off point at ≥ 40 points is commonly used to establish high diabetes distress, so too in this study. | 3-month follow-up | 
| HbA1c | HbA1c (estimated in %-points; mmol/mol values are calculated thereof) is used as a measure of glycaemic levels during past 3 months. It is estimated from a venous blood sample using high performance liquid chromatography (Tosho G11 analyser; meeting International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) standard) in this study. Higher values indicate less optimal glycaemic control, and values above 7.5% (58 mmol/mol) are considered to indicate glycaemic levels in need of improvement. | 3-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time in range of glucose levels | Percentage of glucose values measured using CGM (FreeStyle Libre 2 glucose monitoring system) during 4-week ambulatory assessment which are between 70 and 180 mg/dl (out of all measured values). Note that although the expression time in range (TIR) suggests a time measure, this is in fact estimated as a percentage score. | Continuous assessment over 4 weeks from baseline | 
| Variability of glucose levels | Estimated by the coefficient of variation (range 0 to 1) of all glucose values measured using CGM (FreeStyle Libre 2 glucose monitoring system) during the 4-week ambulatory assessment phase. | Continuous assessment over 4 weeks from baseline | 
| Time in hypoglycaemia of glucose levels | Percentage of glucose values measured using CGM (FreeStyle Libre 2 glucose monitoring system) during 4-week ambulatory assessment phase which are below 70 mg/dl (out of all measured values). Note that although the expression time in hypoglycaemia suggests a time measure, this is in fact estimated as a percentage score. | Continuous assessment over 4 weeks from baseline | 
| Time in hyperglycaemia of glucose levels | Percentage of glucose values measured using CGM (FreeStyle Libre 2 glucose monitoring system) during 4-week ambulatory assessment phase which are over 180 mg/dl (out of all measured values). Note that although the expression time in hyperglycaemia suggests a time measure, this is in fact estimated as a percentage score. | Continuous assessment over 4 weeks from baseline | 
| Activity time | Activity time (in h/day) is measured continuously during the 4-week ambulatory assessment phase using a wearable health tracker/wristband (Garmin vivosmart 4). | Continuous assessment over 4 weeks from baseline | 
| Sleep time | Sleep time (in h/day) is measured continuously during the 4-week ambulatory assessment phase using a wearable health tracker/wristband (Garmin vivosmart 4). | Continuous assessment over 4 weeks from baseline | 
| Heart rate (variability) | Heart rate (in beats/minute) is measured continuously during the 4-week ambulatory assessment phase using a wearable health tracker/wristband (Garmin vivosmart 4). Heart rate variability is calculated thereof using the coefficient of variation. | Continuous assessment over 4 weeks from baseline | 
| Self-reported sleep quality | Sleep quality of the past night is assessed each morning during the 4-week ambulatory assessment phase using items from the Pittsburgh Sleep Quality Index (PSQI) adapted for ecological momentary assessment (EMA). Subjective sleep quality is rated on a 10-point Likert scale (0-very poor to 10-very good). Further items request total time in bed (How many hours did you stay in bed last night?), sleep latency (How many minutes did it take until you fell asleep?), number of wake-ups (How many times did you wake up last night?) and total time awake (If you woke up, how many minutes did you stay awake in total?). The following aspects are estimated thereof: sleep quality; sleep latency; sleep duration; sleep efficiency (each scored from 0 to 3; higher scores indicate more problems). The scales are summed to a total from 0 to 12; higher scores reflect lower sleep quality. Scoring of the PSQI is explained elsewhere (https://www.dgsm.de/fachinformationen_frageboegen_psqi.php). | Daily assessment over 4 weeks from baseline | 
| Stress level | Stress level is assessed four times daily during the 4-week ambulatory assessment phase assessed using the single item How stressed are you feeling right now? and a Likert scale from 0 - not at all stressed to 10 - very strongly stressed in an ecological momentary assessment (EMA) survey via smartphone. | Daily assessment over 4 weeks from baseline | 
| Mood: Hedonic tone | Mood is assessed twice daily during the 4-week ambulatory assessment phase using selected items from the University of Wales Institute of Science and Technology (UWIST) Mood Adjective Checklist (UMACL) in an ecological momentary assessment (EMA) survey via smartphone. 12 of the 29 UMACL items were selected based on their significant associations with glycaemic outcomes from CGM assessment (own data set); each four of them reflect positive and negative hedonic tone and energetic and tense arousal. Responses are given on a four-point Likert scale (0 - definitely not / 1 - slightly not / 2 - slightly / 3 - definitely) reflecting the presence or absence of each aspects. Item scores are summed/averaged to scale scores (from 0 to 3) reflecting hedonic tone and arousal levels; higher scores reflect higher hedonic tone and arousal levels, respectively. | Daily assessment over 4 weeks from baseline | 
| Mood: Arousal | Mood is assessed twice daily during the 4-week ambulatory assessment phase using selected items from the University of Wales Institute of Science and Technology (UWIST) Mood Adjective Checklist (UMACL) in an ecological momentary assessment (EMA) survey via smartphone. 12 of the 29 UMACL items were selected based on their significant associations with glycaemic outcomes from CGM assessment (own data set); each four of them reflect positive and negative hedonic tone and energetic and tense arousal. Responses are given on a four-point Likert scale (0 - definitely not / 1 - slightly not / 2 - slightly / 3 - definitely) reflecting the presence or absence of each aspects. Item scores are summed/averaged to scale scores (from 0 to 3) reflecting hedonic tone and arousal levels; higher scores reflect higher hedonic tone and arousal levels, respectively. | Daily assessment over 4 weeks from baseline | 
| Diabetes-specific problems | Diabetes-specific problems are assessed daily during the 4-week ambulatory assessment phase using six items adapted from the Problem Areas In Diabetes Scale and additional items in an ecological momentary assessment (EMA) survey via smartphone. Responses are given on a Likert scale from 0 - not at all to 10 - very strong. Item scores are averaged to a scale ranging from 0 to 10, whereby higher scores indicate greater problems. | Daily assessment over 4 weeks from baseline | 
| Cortisol | Cortisol level (in μg/dl) is estimated from saliva samples collected at fixed day times (morning; afternoon; late evening) on four consecutive days (Sat/Sun/Mon/Tue) during ambulatory assessment period. Collection date within 4 week-period is from the beginning of the third week (approx. 2 weeks after baseline). Samples are analysed using electrochemiluminescence (Cobas 6000 analyser). | 2 weeks after baseline | 
| Marker of inflammation #1: high sensitivity C-reactive protein (hsCRP) | Estimated from venous blood sample (fasting blood collection) in mg/dl. | Baseline | 
| Marker of inflammation #2: interleukin-6 (IL-6) | Estimated from venous blood sample (fasting blood collection) in pg/ml. | Baseline | 
| Marker of inflammation #3: interleukin-18 (IL-18) | Estimated from venous blood sample (fasting blood collection) in pg/ml. | Baseline | 
| Marker of inflammation #4: interleukin-1 receptor antagonist (IL-1Ra) | Estimated from venous blood sample (fasting blood collection) in pg/ml. | Baseline |