Long-term Metabolic Effects of Cafestol

Study Overview
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Brief Summary
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Twelve-week double-blinded, placebo-controlled, parallel intervention study on 40 participants with a large waist circumference who will ingest cafestol or placebo capsules twice daily. Insulin resistance is measured before and after the twelve-week intervention.

Detailed Description
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Participants are randomly allocated to the cafestol intervention group or placebo group. Before and after the twelve-week intervention the participants partake in: A modified two-stage Insulin Suppression Test to determine insulin mediated glucose uptake. Fasting participants receive body-surface-area-adjusted octreotide, insulin and glucose infusions for 240 minutes. Octreotide is infused with the same rate throughout the test. Insulin and glucose infusions are slow for the initial 120-minute stage and increased the final 120-minute stage, simulating fasting and post-postprandial conditions, respectively. Steady state measurements of plasma glucose are acquired the final 30 minutes of each stage, at time points 100, 110, 120, 220, 230 and 240 minutes. A mixed meal test. Fasting participants consume 75 g. white bread, 10 g. butter, 30 g. cheese and 200 ml. orange juice. Blood samples are drawn at time points -15, 0, 15, 30, 60, 90, 120, 180 and 240 min for glucose-, insulin-, glucagon- and triglyceride measurements. A Magnetic Resonance Imaging (MRI) scan. Participants undergo dixon-sequences scanning the abdomen, assessing visceral and sub-cutaneous fat volume and liver fat content. Magnetic Resonance (MR) spectroscopy is also used to determine fat percentage of the liver. 24-hour ambulatory blood pressure measurement, every 20 minutes during daytime and every 30 minutes during nighttime. 1-week continuous glucose measurement using blinded continuous glucose monitor/sensor on upper arm. Fecal and urine sampling 72-hour food-diary Fasting blood samples: Insulin, c-peptide, HbA1c and glucose Total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides Thyroid-stimulating hormone (TSH) Alanine aminotransferase, creatinine, sodium and potassium High sensitivity C reactive protein (CRP) and alpha-hydroxybutyrate C-terminal telopeptide (CTX) and Procollagen type 1 N-terminal propeptide (P1NP) Parathyroid hormone (PTH), Vitamin D and Ionized calcium Monocyte Chemoattractant Protein-1 (MCP-1) Interleukin 1 & 8 (IL-1α, IL-1β, IL-8) Gastric inhibitory polypeptide (GIP), Glucagon-like peptide-1 (GLP-1) and Glucagon- like peptide-2 (GLP-2) Growth/differentiation factor 15 (GDF-15) Tumor necrosis factor (TNFα) Fasting assessment of insulin resistance (Homeostatic Model Assessment for Insulin Resistance by C-peptide). Pre-intervention and end-intervention test results will be compared using repeated-measures ANOVA / mixed models.

Official Title
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Does the Bioactive Substance in Coffee, Cafestol, Have Preventive Properties on Type-2-diabetes? (Long-term Substudy)

Conditions
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Obesity, Abdominal

Intervention / Treatment
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* Dietary Supplement: Placebo
* Dietary Supplement: Cafestol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Waist circumference > 102 cm (men) / 88 cm (women) Exclusion Criteria: Type 2 diabetes (HbA1c > 48 mmol/mol) or in treatment with antidiabetic drugs Pregnancy Planned pregnancy Breastfeeding Significant comorbidity expected to unable the subject from completing visits

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cafestol<br>Participants in this arm ingest 6 mg cafestol capsules twice daily with breakfast and dinner. | Dietary Supplement: Cafestol<br>* Capsule with 6 mg cafestol twice daily<br>|
| Placebo Comparator: Placebo<br>Participants in this arm ingest placebo capsules twice daily with breakfast and dinner. | Dietary Supplement: Placebo<br>* Capsule without cafestol twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady state plasma glucose during stage 2 of insulin suppression test (mmol/L) | Subjects are administered a 25 μg octreotide bolus at time-point 0 minutes and subsequently infused with 0.27 μg octreotide / m2 • minute, 6 milliunits (mU) insulin / m2 • minute, and 50 mg glucose / m2 • minute. At time-point 120 minutes, infusion speeds were increased to to 32 mU insulin / m2 • minute and 267 mg glucose / m2 • minute. | 220, 230 and 240 minutes after test-start. Comparison between pre-intervention and end-intervention steady state plasma glucose. | 
| Steady state plasma glucose during stage 1 of insulin suppression test (mmol/L) | Subjects are administered a 25 μg octreotide bolus at time-point 0 minutes and subsequently infused with 0.27 μg octreotide / m2 • minute, 6 mU insulin / m2 • minute, and 50 mg glucose / m2 • min. | 100, 110 and 120 minutes after test-start. Comparison between pre-intervention and end-intervention steady state plasma glucose. | 
| Area under the curve for glucose during mixed meal test (mmol/L*min) | Area under the curve for glucose during a mixed meal test. | -15 to 240 minutes from ingestion of standardized meal at time point 0 minutes. Comparison between pre-intervention and end-intervention area under the curves. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve for insulin during mixed meal test (pmol/L*min) | Area under the curve for insulin during a mixed meal test. | -15 to 240 minutes from ingestion of standardized meal at time point 0 minutes. Comparison between pre-intervention and end-intervention area under the curves. | 
| Area under the curve for glucagon during mixed meal test (pmol/L*min) | Area under the curve for glucagon during a mixed meal test. | -15 to 240 minutes from ingestion of standardized meal at time point 0 minutes. Comparison between pre-intervention and end-intervention area under the curves. | 
| Area under the curve for triglycerides during mixed meal test (mmol/L*min) | Area under the curve for triglycerides during a mixed meal test. | -15 to 240 minutes from ingestion of standardized meal at time point 0 minutes. Comparison between pre-intervention and end-intervention area under the curves. | 
| Glycated hemoglobin (HbA1c) (mmol/mol) | Glycated hemoglobin (HbA1c) (mmol/mol) | 12-week change. Comparison between pre-intervention and end-intervention glycated hemoglobin levels. | 
| Liver fat content (%) | Measured with dixon-sequences scanning the abdomen and MR-Spectroscopy. | 12-week change. Comparison between pre-intervention scan and end-intervention scan. | 
| Visceral fat content (ml) | Measured with dixon-sequences scanning the abdomen | 12-week change. Comparison between pre-intervention scan and end-intervention scan. | 
| Subcutaneous fat content (ml) | Measured with dixon-sequences scanning the abdomen | 12-week change. Comparison between pre-intervention scan and end-intervention scan. | 
| One-week continuous glucose measurement | One-week continuous glucose measurement data. | Average glucose measured every 15 minutes for one week prior to study day 1 and 3. 12-week change. Comparison between pre-intervention measurement and end-intervention measurement. | 
| Blood pressure (mmHg) | Average daytime and night-time ambulatory blood pressure. 24-hour ambulatory blood pressure measurement, measured every 20 minutes during daytime and every 30 minutes during nighttime. | 12-week change. Comparison between pre-intervention average ambulatory blood pressure and end-intervention average ambulatory blood pressure. | 
| Food consumption in kilocalories (kcal) | Food consumption is registered for 72-hours prior to study day 1 and 3. Food consumption is measured in kilocalories (kcal). | 12-week change. Comparison between pre-intervention food consumption and end-intervention food consumption. |