Clinical trial NCT01477957: The Effect of Bariatric Surgery on Insulin Sensitivity and Energy Metabolism
Official title: The Effect of Bariatric Surgery on Insulin Sensitivity and Energy Metabolism in Obesity Grade 2 -3
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Obesity
Diabetes Mellitus, Type 2
Keywords: weight loss after bariatric surgery
Insulin sensitivity
insulin resistance
Lead sponsor: German Diabetes Center
Sponsor class: OTHER
Collaborators: name: Dep.of General-, Visceral- and Pediatric Surgery, HHU, Duesseldorf, Germany
name: Dep.for Metabolic Diseases, HHU, Duesseldorf, Germany
name: Hospital Neuwerk, Mönchengladbach, Duesseldorf, Germany
First posted: 2011-11-23
Enrollment: 450
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: People with obesity and various stages of MASLD, that qualify for bariatric surgery.

Brief summary: The purpose of this study is:

1. To explore to what extent insulin sensitivity, energy metabolism and ectopic lipid storage can be improved by bariatric surgery
2. To explore to what extent hepatic and muscular disorders of energy metabolism occur in patients with obesity (degree 2-3)
3. To explore whether the steato liver occurring in patients with obesity (degree 2-3) is associated with the degree of liver inflammation

Detailed description: Insulin resistance strongly relates to ectopic lipid deposition in skeletal muscle and the liver, which correlate with insulin resistance. Lipid metabolites accumulating in skeletal muscle and the liver are thought to impair insulin signalling and thereby reduce glucose uptake and glycogen storage. Insulin resistant humans frequently present with decreased mitochondrial function in skeletal muscle which might contribute to lipid accumulation and the development of insulin resistance. Metabolic dysfunction-associated steatotic liver disease comprises steatosis, steatohepatitis and cirrhosis. MASLD correlates with insulin resistance, increased risk for cardiovascular diseases and type 2 diabetes. The mechanisms leading from steatosis to steatohepatitis and insulin resistance in the liver are yet unclear. Bariatric surgery aims at profound reduction of body weight. Also, it frequently and rapidly leads to normalization of glucose tolerance even before the onset of body weight reduction. The underlying mechanisms are yet unclear. In this study we aim to explore the mechanisms underlying the onset of insulin resistance and steatohepatitis in patients with steatosis and to identify the mechanisms leading to improved glucose tolerance in humans after bariatric surgery. We test the following hypotheses: increased lipid availability leads to (i) increased lipid oxidation and oxidative stress (ii) accumulation of lipid metabolites that impair insulin signalling (iii) bariatric surgery improves insulin sensitivity by increasing lipid oxidation.

This study will contribute to the understanding of MASLD and will help to identify new targets for the therapy of diabetes.

Eligibility criteria: Inclusion Criteria:

* Aged ≥ 20 years- ≤ 70 years
* BMI 20- 25 kg/m 2 normal- weight group
* BMI 35- 39,9 kg/m 2 (Obesity grade 2)
* BMI \>40 kg/m 2 (Obesity grade 3)

Exclusion Criteria:

* Acute illness 2 weeks before start of examination
* Autoimmune or Immune disorder diseases (Leukozyten \< 5000/µl
* Renal insufficiency (Kreatin \> 1,5 mg/dl)
* Heart disease, condition after heart attack
* Anemia (Hb \<12g/l, controlled before every day of examination) or blood donations 4weeks before examination.
* Participation in another trial within the last 2 weeks
* Pharmacological- immunotherapy (Cortisol, Antihistaminika, ASS)
* Thyroid disorders
* Glitazone Therapy
* Pregnancy, Lactation, Menstruation
* Smoking cigarettes, Alcohol- and drug abuse
* Psychiatric disorders
* Risk for/ or diagnosed HIV/ AIDS or Hepatitis B/C
* Liver disease, which are not caused by non- alcoholic steato- hepatitis
* Working on night shifts or irregular rhythm of night- day
* Impaired wound healing or clotting disorders
* Allergic reaction to local anesthetics
* Malignant cancer

Primary outcomes:
measure: Energy metabolism
timeFrame: 5 years
Secondary outcomes:
measure: weight loss
timeFrame: 5 years
measure: Insulin sensitivity
timeFrame: 5 years
Other outcomes:
Locations:
city: Düsseldorf
country: Germany
facility: German Diabetes Center
state: NRW
Study officials:
affiliation: German Diabetes Center
name: Michael Roden, Prof., MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, Herder C, Carstensen M, Krausch M, Knoefel WT, Schlensak M, Roden M. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015 May 5;21(5):739-46. doi: 10.1016/j.cmet.2015.04.004.
citation: Pafili K, Kahl S, Mastrototaro L, Strassburger K, Pesta D, Herder C, Putzer J, Dewidar B, Hendlinger M, Granata C, Saatmann N, Yavas A, Gancheva S, Heilmann G, Esposito I, Schlensak M, Roden M. Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease. J Hepatol. 2022 Dec;77(6):1504-1514. doi: 10.1016/j.jhep.2022.08.010. Epub 2022 Aug 19.
citation: Apostolopoulou M, Gordillo R, Koliaki C, Gancheva S, Jelenik T, De Filippo E, Herder C, Markgraf D, Jankowiak F, Esposito I, Schlensak M, Scherer PE, Roden M. Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis. Diabetes Care. 2018 Jun;41(6):1235-1243. doi: 10.2337/dc17-1318. Epub 2018 Mar 30.