MItochondrial Diabetes LOw Carb- Diet Study

Study Overview
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Brief Summary
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In daily practice, doctors and dietitians in the clinic receive many questions in general from patients with a Mitochondrial Disease (MD), and more specific whether nutritional changes can alleviate their symptoms. Mitochondrial Inherited Diabetes and Deafness (MIDD) is due to a mitochondrial mutation at the m.3243A>G locus. Nutrition is known to affect disease burden in MIDD. Which diet does this best is unknown. Very low carbohydrate high fat diets improve mitochondrial function in isolated cells and in mice. Whether it does so in people with MIDD is unknown. Therefore, the objective of the study is to explore the effect of a low carbohydrate- high fat diet (LCHF) on clinical symptoms (Goal Attainment Scaling) and gut microbiome in patients with MIDD due to the m.3243A>G mutation. A total of 10 adult patients with the above mentioned characteristics will be randomized to receive first usual care during three months (control period), followed by LCHF dietary intervention for the next three months (intervention period), or vice versa.

Detailed Description
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Mitochondrial disease (MD) is a clinically and genetically heterogenous group of disorders. The dysfunction of the mitochondrial respiratory chain results in ATP shortage and energy depletion resulting in multi system disease. Therapeutic interventions are currently limited and focus on relieving symptoms, since no curative therapies exist. The m.3243A>G related MD is presumably the most frequent MD affecting at least 1 in 5000 people, and the MIDD (Mitochondrial Inherited Diabetes and Deafness) phenotype is its most frequent clinical phenotype. The role of nutrition, providing the essential nutrients for mitochondria to produce energy, is an important disease modifier in MIDD. A ketogenic diet (KD) is a very low-carbohydrate ( ±20 grams a day) high-fat diet that shifts metabolism towards β-oxidation and ketone body production. In cell studies and mice models for MD, ketone bodies or KD significantly affect different dimensions of mitochondrial function. KD has been proven to effectively treat intractable epilepsy in children with MD. The investigators recently performed a 12 week pilot study with KD in 20 adults with different types of mtDNA related MD. The KD improved glucose tolerance, yielded less migraine, and alleviated gastrointestinal symptoms. Despite these positive effects, it proved the KD is a difficult diet to follow and only 8/20 participants finished the 12 week KD intervention. The individuals with m.3243A>G related MD had the longest diet adherence. Because of the positive effects, over half of all participants switched to the more feasible and less restrictive low carbohydrate (± 50-100 gram/dag), high fat (LCHF) diet after completing the study. The positive effect of KD on the subtype of m.3243A>G related MD was very recently confirmed in another study. The LCHF diet however provides no ketone bodies and its effect in mitochondrial disease is not studied properly yet. In irritable bowel syndrome, specific dietary regimens as low-fermentable, oligo-, di-, monosaccharides and polyols (FODMAPs) but also LCHF diets are considered therapeutic. A diet low in fermentable carbohydrates reduces the fermentation by the gut microbiota and is therefore thought to reduce bloating and other gastro intestinal complaints. Based on the results of a previous study from the investigators and the effect of LCHF diets in irritable bowel syndrome, the investigators hypothesize the same positive effect in the cohort of m.3243A>G related MD in which gastro intestinal complaints are very common. An adult diabetes team studied the gut microbiome and observed significant differences in various species and pathways between the faecal stool samples of diabetes patients and healthy controls, and that gut microbiome composition is associated with glycemic control. The gut microbiome is a very promising study field. More insight in patients gut microbiome and the way it can be altered with nutrition could lead to new treatment options and symptom relieve which is very relevant to MD patients. Therefore it is interesting to compare the gut microbiome of MIDD patients with already analysed stool samples of healthy controls and diabetes patients, and study the effect of an LCHF diet intervention. The LCHF diet is an established treatment option in diabetes, with positive effects on glucose homeostasis. The investigators have chosen the subgroup of m.3243A>G related MIDD patients as they hypothesize that the LCHF could help slow down the progression of diabetes severity and reduce the necessity for treatment with insulin in these patients in particular. Studies in the heterogeneous patient population with MD are challenging. By choosing a relatively frequent genotype as well as a defined clinical phenotype the investigators can minimize this problem and study a defined cohort. Additionally the investigators will use a cross over design (patients being their own controls) to further decrease the number of patients needed to be included to achieve robust data. Previous experience with trials in MD including patient consultations has led to an insight that the Goal Attainment Scaling (GAS) is an important individually tailored outcome for this patient group. With the GAS patients choose and score personal goals that they want to achieve with the diet intervention. Taken together, the investigators intend to perform a pilot study to investigate efficacy measured by GAS, diabetes control and gastrointestinal complaints, and influence on the gut microbiome of a low carbohydrate, high fat diet in a group of adult patients with MIDD due to the m.3243A>G mutation.

Official Title
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The Effect of a Low Carbohydrate- High Fat Diet on Clinical Symptoms and Gut Microbiome in m.3243A>G Related Mitochondrial Diabetes

Conditions
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Mitochondrial Diseases, Diabetes-Deafness Syndrome Maternally Transmitted

Intervention / Treatment
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* Other: LCHF diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: m.3243A>G mutation Diabetes or prediabetes (fasting glucose 6.1-6.9 mmol/L) related to the m.3243A>G mutation BMI ≥ 18.5 kg/m2 Good cognitive health Exclusion Criteria: Kidney failure (MDRD <60 or proteinuria) Use of SGLT2-inhibitors Already on a carbohydrate restricted diet at baseline (carbohydrate intake <100 grams per day) Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCHF diet<br>Participants will adhere to a low-carb high-fat diet for 12 weeks,defined by a carbohydrate intake of 50-100 grams per day. | Other: LCHF diet<br>* Low-carb high-fat (LCHF) diet<br>|
| No Intervention: Control<br>Participants will follow their usual diet for 12 weeks. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Goal Attainment Scaling (GAS) | The Goal Attainment Scale (GAS) is an individualized outcome measure involving goal selection and goal scaling that is standardized in order to calculated the extent to which a patient's goals are met. The scores can range from -2 to +2 with 1-point increments. A score of 0 indicates that the expected level is reached. A negative score means that the level reached was lower than expected, and can be classified as lower (-1) of much lower (-2). A positive score means that the level reached was higher than expected, and can be classified as higher (+1) of much higher (+2). | 12 weeks | 
| Faecal microbiome composition analyses via DNA isolation | The faecal microbiome composition of the participants with their usual diet will be compared the faecal microbiome composition after adhering to the low-carbohydrate high-fat diet. More specifically, DNA will be isolated from the stool samples, and will be compared between the intervention period and the control period. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose monitoring | Blinded glucose monitoring will be performed with a glucose monitoring device that a participant will wear for two time periods of 10 days. One time period will be at the end of the intervention period, and one time period at the end of the control period. The time in range, periods of hypoglycemia and periods of hyperglycemia will be determined. | 12 weeks (home glucose monitoring for two time periods of 10 days) | 
| Gastrointestinal complaints questionnaire | Questionnaire including a numerical score on severity of gastrointestinal complaints (1 = not severe and 10 = very severe), stool frequency, stool type determined via the Bristol stool chart and laxative use. | 12 weeks | 
| Diet adherence | Digital food diary of three days, including one weekend day | 3 days | 
| Checklist Individual Strength (CIS) | The Checklist Individual Strength is a 20-item self-reported questionnaire that captures four domains of fatigue: 1) subjective severity of fatigue 2) reduction in concentration, 3) reduction in motivation and 4) reduction in activity. Respondents will rate the extent to which each statement is true for them in the past two weeks on a seven-point Likert scale. The scores are summed up accordingly. The higher the score, the higher the fatigue level. A score between 27 and 35 suggests an increased risk for fatigue and a score above 35 suggests severe fatigue. | 12 weeks | 
| Newcastle Mitochondrial Disease Adult Scale (NMDAS) | The NMDAS has been introduced to allow evaluation of the progression of mitochondrial disease in adult patients over 16 years. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: Current Function; System Specific Involvement; Current Clinical Assessment and Quality of Life. Each question in the NMDAS has a possible score from 0-5. Each of the first 3 domain scores are calculated by simply summing the scores obtained for each question in that section. The higher the score the more severe the disease. The Quality of Life will be assessed with the Short Form (SF)-12. The SF-12 is a self-reported outcome measure assessing the impact of health on an individual's everyday life. | 12 weeks | 
| Accelerometry | Physical activity measurement to calculate the Physical Activity Level (PAL) | 7 days | 
| Headache diary | Reporting frequency of headaches and use of medication for headaches | 12 weeks | 
| Bodyweight measurements | Bodyweight of participants will be measured | 1 week | 
| Body Mass Index (BMI) | Body Mass Index (BMI) will be determined during every visit | 12 weeks | 
| Bio-electrical Impedance Analysis (BIA) | Body composition will be measured with bioimpedance analysis, with the goal to determine body muscle mass and body fat mass. | 12 weeks | 
| Creatine Kinase (CK) | Creatine Kinase levels in the blood will be measured (physiological parameter) | 12 weeks | 
| Hemoglobin A1c (HbA1c) | Hemoglobin A1c (HbA1c) levels in the blood will be measured (physiological parameter) | 12 weeks | 
| Lipid profile blood test | The lipid profile in the blood will be determined after at least 4 hours of fasting. The lipid profile includes triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total cholesterol (physiological parameters) | 12 weeks | 
| Liver function blood test | The transaminase levels in the blood will be determined to assess liver function. These include the alanine aminotransferase (ALAT) and Aspartate transaminase (ASAT) values (physiological parameters) | 12 weeks | 
| Kidney function blood test | Creatinine levels in the blood will be determined (physiological parameter), which will be used to calculate the Modification of Diet in Renal Disease (MDRD). The MDRD is a measure for glomerular filtration rate (GFR) based on creatinine and patient characteristics. | 12 weeks | 
| Blood lactate concentration | Lactate levels in the blood will be determined (physiological parameter) | 12 weeks | 
| Blood ketone concentration | Ketone levels (specifically beta-hydroxybutyrate) in the blood will be determined with a finger prick (physiological parameter) | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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low carbohydrate high fat diet, gut microbiome, mitochondrial diabetes