Intermittent Fasting to Improve Insulin Secretion

Overview

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.

Interventions

• 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)

Primary outcome measures

• Change in first phase insulin secretion. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]

Secondary outcome measures (8)

• Change in second phase insulin secretion. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in insulin sensitivity. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in BMI. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in liver fat content. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in pancreatic fat content. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in body fat content. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in visceral adipose tissue. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]
• Change in subcutaneous adipose tissue. [Time frame: Before, after 4 weeks and after 24 weeks of lifestyle intervention.]

Eligibility criteria

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 type 2 diabetes mellitus (diagnosed <5 years prior to screening), HbA1c 6.0% - 9.5%, not receiving insulin or thiazolidinediones, and with an appropriate washout period for all other antidiabetic medications)

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 8 centers

• Charité Berlin - Department of Endocrinology and Metabolic Diseases — Berlin
• Universtiy Hospital Carl Gustav Carus — Dresden
• German Diabetes Center — Düsseldorf
• Heidelberg University Hospital - Department of Endocrinology and Metabolism — Heidelberg
• University Hospital Leipzig - Clinic for Endocrinology and Nephrology — Leipzig
• University of Luebeck - Institute of Endocrinology and Diabetes — Lübeck
• Technical University of Munich - Else Kroener-Fresenius-Center for Nutritional Medicine — Munich
• University Hospital Tuebingen - Institute for Diabetes Research and Metabolic Diseases (ID — Tübingen

Publications

• Heilmann G, Trenkamp S, Moser C, Bombrich M, Schon M, Yurchenko I, Strassburger K, Rodriguez MM, Zaharia OP, Burkart V, Wagner R, Roden M. Precise glucose measurement in sodium fluoride-citrate plasma affects estimates of prevalence in diabetes and prediabetes. Clin Chem Lab Med. 2023 Oct 24;62(4):762-769. doi: 10.1515/cclm-2023-0770. Print 2024 Mar 25. PMID 37870928

Identifiers

NCT: NCT04607096 · 596/2020BO1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗