Intermittent Fasting to Improve Insulin Secretion

Study Overview
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Brief Summary
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Type 2 diabetes (T2D) mellitus is a challenge for health care systems as the numbers increases constantly. In 2014, 422 million people had been living with diabetes worldwide. The absolute numbers of people with prediabetes have also grown substantially over 25 years worldwide. In Germany, about 10% of the population has T2D and another 21 % of the population has prediabetes.Overall, 16% of all deaths in Germany are attributable to type 2 diabetes. Macro- and microvascular complications of diabetes imply a significant threat for the patients and are already present in the prediabetic state. Short term and long term complications, the burden of treatment, and reduced quality of life are major burdens of the disease. Accumulating data indicate that currently recommended therapeutic diet regimens in patients with obesity and diabetes are not sustainable on the long term. Novel concepts are therefore urgently needed. T2D occurs when insulin secretion from pancreatic beta-cells cannot sufficiently be increased to compensate for insulin resistance. Causes of beta-cell dysfunction are heterogeneous. In addition, the most important determinants of diabetes remission are the extend of weight loss and restoration of beta-cell function. In the course of diabetes progression, the inability to recover insulin secretion might identify the state of no return to normal glucose tolerance. It is therefore crucial to improve insulin secretion in treatment and prevention of diabetes. Up to now lifestyle intervention trials in prediabetes or pharmacological intervention trials in diabetes did not show improvement of insulin secretion after intervention. However, one recent small human trial shows that intermittent fasting (early time restricted fasting) is able to improve insulin secretion.Currently, there are no trials that examine the effect of intermittent fasting in individuals with a broad range of impaired glucose metabolism (from prediabetes to diabetes). Recently novel subtypes of diabetes and prediabetes with high risk for the early manifestation of diabetes complications have been identified. Currently, prevention strategies for this high risk individuals have not been examined yet. We will study for the first time the effectiveness of 4 weeks intermittent fasting on changes in insulin secretion capacity in subphenotypes of diabetes and in prediabetes.

Official Title
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Intermittent Fasting to Improve Insulin Secretion

Conditions
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PreDiabetes, Diabetes type2, Intermittent Fasting, Insulin Secretion

Intervention / Treatment
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* Behavioral: Intermittent fasting
* Behavioral: Control diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) between 25 - 40 kg/m² Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. Subjects with prediabetes (IFG and/or IGT, HbA1c 5,4 % - 6,4 %, subphenotype cluster 3 or 5) or Subjects with diabetes mellitus type 2 (diagnosis < 1 year, HbA1c = 6,5 - 9 %, no medical treatment, subphenotype SIDD or SIRD) Exclusion Criteria: Subjects with diabetes mellitus type 1 (GAD-, IA2-AB positive) Women during pregnancy and lactation Treamtent with any medication effecting on glucose metabolism like anti-diabetic drugs or steroids Subjects with a haemoglobin (Hb) ≤ 11.5 g/dl (for males) and Hb ≤ 10.5 g/dl (for females) at screening Any pancreatic disease Medical history of cancer and/or treatment for cancer within the last 5 years. Known current presence or history of severe neurological or psychiatric diseases, schizophrenia, bipolar disorder Known history of bariatric surgery Severe liver or kidney diseases (Alanine Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (AST [SGOT]) above 3 x upper limit of normal (ULN) or Glomerular Filtration Rate (eGFR) ≤ 60 ml/min (MDRD formula) Systemic infection (CRP > 1 mg/dl) Severe diabetic complications like chronic kidney disease (CKD), proliferating retinopathy or symptomatic cardiovascular disease Presence of any contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc. Persons with limited temperature sensation and / or elevated sensitivity to warming of the body Persons with a hearing disorder or a increased sensitivity for loud noises Claustrophobia Participation in other clinical trials or observation period of competing trials up to 30 days prior to this study Refusal to get informed of unexpected detected pathological findings

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

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants wil either receive a control diet or join the intermittent fasting group stratified by glycemia (prediabetes/diabetes) as well as by subphenotype.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prediabetic subjects - cluster 3<br>Presence of a cluster 3 phenotype will be examined according to the parameters described by Wagner et al.(Nat. Med. 2020). | Behavioral: Intermittent fasting<br>* The intermittent fasting intervention consists of a decreased daily caloric intake of 400 kcal below individual requirements (Harris Benedict Formula) combined with early time restricted fasting according to the schema 16:8. fasting will be performed over 4 weeks.<br>Behavioral: Control diet<br>* Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)<br>|
| Active Comparator: Prediabetic subjects - cluster 5<br>Presence of a cluster 5 phenotype will be examined according to the parameters described by Wagner et al.(Nat. Med. 2020). | Behavioral: Intermittent fasting<br>* The intermittent fasting intervention consists of a decreased daily caloric intake of 400 kcal below individual requirements (Harris Benedict Formula) combined with early time restricted fasting according to the schema 16:8. fasting will be performed over 4 weeks.<br>Behavioral: Control diet<br>* Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)<br>|
| Active Comparator: Patients with type 2 diabetes - subphenotype: Severe insulin-deficient diabetes (SIDD)<br>Presence of a SIDD phenotype will be examined according to the parameters de-scribed Ahlqvist et al. (Lancet Diabetes Endocrinol. 2018 May;6(5):361-369). | Behavioral: Intermittent fasting<br>* The intermittent fasting intervention consists of a decreased daily caloric intake of 400 kcal below individual requirements (Harris Benedict Formula) combined with early time restricted fasting according to the schema 16:8. fasting will be performed over 4 weeks.<br>Behavioral: Control diet<br>* Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)<br>|
| Active Comparator: Patients with type 2 diabetes - subphenotype: Severe insulin-resistant diabetes (SIRD)<br>Presence of a SIRD phenotype will be examined according to the parameters de-scribed Ahlqvist et al (Lancet Diabetes Endocrinol. 2018 May;6(5):361-369). | Behavioral: Intermittent fasting<br>* The intermittent fasting intervention consists of a decreased daily caloric intake of 400 kcal below individual requirements (Harris Benedict Formula) combined with early time restricted fasting according to the schema 16:8. fasting will be performed over 4 weeks.<br>Behavioral: Control diet<br>* Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in first phase insulin secretion. | Effect of intermittent fasting vs. a control diet on glucose stimulated first phase insulin secretion adjusted for insulin sensitivity during an hyperglycemic clamp. | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in second phase insulin secretion. | Effect of intermittent fasting vs. a control diet on glucose stimulated second phase insulin secretion adjusted for insulin sensitivity during an hyperglycemic clamp. | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in insulin sensitivity. | Effect of intermittent fasting vs. a control diet on insulin sensitivity using insulin sensitivity index during an hyperglycemic clamp. | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in BMI. | Effect of intermittent vs. a control diet fasting on BMI. | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in liver fat content. | Effects of intermittent fasting vs. a control diet on liver fat content (%) measured by magnetic resonance spectroscopy (3 T whole body imaging). | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in pancreatic fat content. | Effects of intermittent fasting on pancreatic fat content (%) measured by magnetic resonance spectroscopy (3 T whole body imaging). | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in body fat content. | Effects of intermittent fasting vs. a control diet on total adipose tissue (TAT) measured by magnetic resonance tomography (3 T whole body imaging). | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in visceral adipose tissue. | Effects of intermittent fasting vs. a control diet on visceral adipose tissue (VAT) measured by by magnetic resonance tomography (3 T whole body imaging) | Before, after 4 weeks and after 24 weeks of lifestyle intervention. | 
| Change in subcutaneous adipose tissue. | Effects of intermittent fasting vs. a control diet on subcutaneous adipose tissue (SCAT) measured by by magnetic resonance tomography (3 T whole body imaging) | Before, after 4 weeks and after 24 weeks of lifestyle intervention. |