Intermittent Fasting to Improve Insulin Secretion (IFIS)

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes type2; PreDiabetes; Intermittent Fasting; Insulin Secretion
• Intervention / Treatment: Behavioral: Intermittent fasting; Behavioral: Control diet

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andreas Fritsche, MD; Phone Number: +49 7071 29 80590; Email: andreas.fritsche@med.uni-tuebingen.de
• Study Contact Backup: Name: Michael Roden, MD; Phone Number: +49 211 3382 201; Email: michael.roden@ddz.de

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Not yet recruiting
    • Charité Berlin - Department of Endocrinology and Metabolic Diseases
    • Contact: Joachim Spranger, MD; Phone Number: +49 30 450 514 252; Email: joachim.spranger@charite.de
  • Dresden, Germany, 01307
    • Not yet recruiting
    • Universtiy Hospital Carl Gustav Carus
    • Contact: Peter Schwarz, MD; Phone Number: +49 (0) 351 458271; Email: peter.schwarz@uniklinikum-dresden.de
  • Duesseldorf, Germany, 40225
    • Not yet recruiting
    • German Diabetes Center
    • Contact: Michael Roden, MD; Phone Number: +49 211 3382 201; Email: michael.roden@ddz.de
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • Heidelberg University Hospital - Department of Endocrinology and Metabolism
    • Contact: Julia Szendrödi, MD; Phone Number: +49 (0) 6221 56-8601; Email: Julia.Szendrödi@med.uni-heidelberg.de
  • Leipzig, Germany, 04103
    • Not yet recruiting
    • University Hospital Leipzig - Clinic for Endocrinology and Nephrology
    • Contact: Matthias Blüher, MD; Phone Number: +49 (0)341 - 97 13320; Email: Matthias.blüher@medizin.uni-leipzig.de
  • Luebeck, Germany, 23538
    • Not yet recruiting
    • University of Luebeck - Institute of Endocrinology and Diabetes
    • Contact: Sebastian Schmid, MD; Email: Sebastian.Schmid@uni-luebeck.de
  • Munich, Germany, 80992
    • Not yet recruiting
    • Technical University of Munich - Else Kroener-Fresenius-Center for Nutritional Medicine
    • Contact: Hans Hauner, MD; Phone Number: +49 (0) 8928924911; Email: hans.hauner@tum.de
  • Tuebingen, Germany, 72076
    • Recruiting
    • University Hospital Tuebingen - Institute for Diabetes Research and Metabolic Diseases (IDM)
    • Contact: Andreas Fritsche, MD; Phone Number: +49 7071 29 80590; Email: andreas.fritsche@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prediabetic subjects - cluster 3; Presence of a cluster 3 phenotype will be examined according to the parameters described by Wagner et al.(Nat. Med. 2020).	Behavioral: Intermittent fasting; 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.; Behavioral: Control diet; Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)
Active Comparator: Prediabetic subjects - cluster 5; Presence of a cluster 5 phenotype will be examined according to the parameters described by Wagner et al.(Nat. Med. 2020).	Behavioral: Intermittent fasting; 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.; Behavioral: Control diet; Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)
Active Comparator: Patients with type 2 diabetes - subphenotype: Severe insulin-deficient diabetes (SIDD); 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; 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.; Behavioral: Control diet; Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)
Active Comparator: Patients with type 2 diabetes - subphenotype: Severe insulin-resistant diabetes (SIRD); 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; 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.; Behavioral: Control diet; Control group will be advised to reduce daily caloric intake of 400 kcal below individual requirements (Harris Benedict formula)

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in brain insulin sensitivity.	Effects of intermittent fasting vs. a control diet on brain insulin sensitivity measured by functional magnetic resonance imaging (fMRI) combined with nasal insulin administration.	Before, after 4 weeks and after 24 weeks of lifestyle intervention.
Change in resting energy expenditure (REE).	Effects of intermittent fasting vs. a control diet on resting energy expenditure measured by indirect calorimetry.	Before, after 4 weeks and after 24 weeks of lifestyle intervention.
Change in substrate oxidation.	Effects of intermittent fasting vs. a control diet on substrate oxidation measured by indirect calorimetry.	Before, after 4 weeks and after 24 weeks of lifestyle intervention.
Change in proinsulin processing.	Effect of intermittent fasting vs. a control diet on first phase proinsulin processing during an hyperglycemic clamp.	Before, after 4 weeks and after 24 weeks of lifestyle intervention.
Change in glucagon suppression.	Effect of intermittent fasting vs. a control diet on glucagon suppression during an hyperglycemic clamp.	Before, after 4 weeks and after 24 weeks of lifestyle intervention.
Change in insuin clearance.	Effect of intermittent fasting vs. a control diet on insulin clearance during an hyperglycemic clamp.	Before, after 4 weeks and after 24 weeks of lifestyle intervention.

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: Charite University, Berlin, Germany; Ludwig-Maximilians - University of Munich; University of Leipzig; University of Luebeck; University Hospital Heidelberg; University Hospital Carl Gustav Carus; German Institute of Human Nutrition; German Diabetes-Center, Leibniz-Institut in Düsseldorf; German Center for Diabetes Research

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 28, 2020

Study Record Updates

• Last Update Posted (Actual): May 9, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State
• Other Study ID Numbers: 596/2020BO1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No