Adipose Tissue Dysfunction in Type 2 Diabetes and Its Reversibility by Bariatric Surgery (ADIDYS)

ABSTRACT Background: Insulin resistance (IR) plays a major role in the pathogenesis of type 2 diabetes (T2D). Adipose tissue (AT) dysfunction leading to systemic low-grade inflammation and ectopic lipid deposition plays an important role in obesity-induced IR, but its role in T2D pathogenesis and to what extent insulin-sensitizing interventions can reverse AT dysfunction remain to be clarified.

Hypothesis/aims: To test the hypotheses 1) that T2D is associated with exaggerated AT dysfunction compared with obesity alone, 2) that increased insulin sensitivity and remission of T2D after bariatric surgery is in part explained by improved AT function Research plan: Novel markers of exaggerated AT dysfunction will be identified and studied together with known markers of AT dysfunction in patients with T2D compared with non-diabetic obese and lean individuals. Then the effects of bariatric surgery on all these markers of AT dysfunction in obesity and T2D will be studied. Adipose tissue and skeletal muscle biopsies and blood samples will be used for 1) next generation RNA sequencing, 2) targeted analysis of mRNA and protein content/activities, 3) metabolomics, 4) morphological analysis and 5) analysis of adipokines/myokines. Abnormalities in T2D and changes in response to bariatric surgery will be related to substrate metabolism, insulin sensitivity and secretion and insulin signalling in muscle.

Perspectives: This project provides novel insight into the role of AT dysfunction in T2D pathogenesis in humans and the potential of bariatric surgery to reverse AT dysfunction and improve insulin sensitivity. We ultimately expect that this will help us to identify novel pharmaceutical targets for the treatment of IR.

Study Overview

• Status: Recruiting
• Conditions: Adipose Tissue Dysfunction Type 2 Diabetes Mellitus Bariatric Surgery
• Intervention / Treatment: Procedure: Gastric byspass

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kristoffer Jensen Kolnes, MD, PhD-student; Phone Number: +4593988934; Email: kristoffer.jensen.kolnes@rsyd.dk
• Study Contact Backup: Name: Kurt Højlund, Professor, consultant doctor; Email: Kurt.Hoejlund@rsyd.dk

Study Locations

• Denmark
  • Odense, Denmark, 5000
    • Recruiting
    • Kristoffer Jensen Kolnes
    • Contact: Kristoffer J Kolnes, Doctor; Phone Number: 93988934; Email: kristoffer.jensen.kolnes@rsyd.dk
    • Contact: Tine Hylle, secretary; Phone Number: +4523741691; Email: tine.hylle@rsyd.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• GAD65 antibody negative patients with T2D
• Treated with either diet alone or diet in combination with metformin, DPP-4 inhibitors, sulphonylureas, GLP1-analogs or insulin (maximum 40 IE long - or intermediate acting insulin).
• HbA1c < 70 mmol/l for diabetics and <48 mmol/l for obese.
• Do not have any known diabetic complication (macroalbuminuria, proliferative retinopathy, neuropathy or cardiovascular disease).
• The use of up to two antihypertensive drugs and one cholesterol lowering drug is allowed in patients with T2D and obese individuals.
• Both patients with T2D and obese individuals should be eligible for bariatric surgery, and should be able and willing to discontinue all drugs for 1 week prior to the clamp studies
• Except for the conditions mentioned above, the patients with T2D and the obese individuals should be healthy.
• Lean controls should be healthy, lean and drug naive.
• Obese and lean controls should have no first degree family history of diabetes.
• All participants should be 30-65 years old.
• All participants should be able to provide informed written consent.

Exclusion Criteria:

• Any unknown disease or need for medication that occurs after inclusion.
• Abnormal ECG, screening blood tests and/or severe hypertension (>160/100 mmHg).
• Impaired glucose tolerance (IGT) or impaired fasting glucose in lean, healthy participants (2-hour plasma glucose > 7.8 mmol/l or fasting plasma glucose > 5.6 mmol/l).
• Known pregnancy or positive beta-HCG in blood during screening.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group
Experimental: Gastric bypass with T2DM	Procedure: Gastric byspass; Test will be before and 9-12 month after gastric bypass
Experimental: Gastric bypass without T2DM	Procedure: Gastric byspass; Test will be before and 9-12 month after gastric bypass

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Markers in adipose tissue dysfunction	Changes in morphology of adipocytes, mRNA expression and protein abundance in adipocytes	3 year
Muscular insulin sensitivity	Changes in muscle mRNA expression and protein abundance	3 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of disposal	Changes in rate of disposal	3 year
Body composition	Changes in body composition	3 year
Metabolomics	Changes in metabolomics	3 year

Collaborators and Investigators

• Sponsor: Odense University Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2022
• Primary Completion (Anticipated): April 30, 2023
• Study Completion (Anticipated): April 30, 2023

Study Registration Dates

• First Submitted: March 14, 2022
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 22, 2022

Study Record Updates

• Last Update Posted (Actual): March 22, 2022
• Last Update Submitted That Met QC Criteria: March 14, 2022
• Last Verified: March 1, 2022

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
• Other Study ID Numbers: S-20190162

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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