Adaptive Mechanisms In GRown up ObeSity Study (AMIGROS) (AMIGROS)

Mechanistic Studies in Human Subcutaneous Adipose Tissue

The investigator recently showed that the glycan-binding adipokine galectin-1 increased during overfeeding and that galectin-1 independently could predict type 2 diabetes. Further, the molecules that induce insulin release in the fasting state when blood glucose is normal remain elusive. It is possible that galectin-1 is involved in adaptive mechanisms in adipose tissue in obese subjects.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: Device: Subcutaneous microdialysis

Detailed Description

The investigator will define adaptive mechanisms in adipose tissue associated with galectin-1 in obese insulin-sensitive (Ob-IS) subjects compared with obese insulin-resistant (Ob-IR) subjects and lean healthy controls. Further, the investigator will study molecules secreted from adipose tissue that might trigger insulin secretion when blood glucose is normal.

The investigator hypothesizes that Ob-IS subjects keep fatty acid levels normal through an adaptive response in adipose tissue that involves up-regulation of galectin-1 for dampening of immune cell activity and stimulation of lipolysis.

• Study Type: Observational
• Enrollment (Estimated): 45

Contacts and Locations

• Study Contact: Name: Per-Anders E Jansson, Prof; Phone Number: 46 70 203 30 10; Email: per-anders.jansson@wlab.gu.se
• Study Contact Backup: Name: Vagner R Silva, PhD; Phone Number: 46 76 849 77 03; Email: vagner.silva@wlab.gu.se

Study Locations

• Sweden
  • Region Vastra Gotaland
    • Gothenburg, Region Vastra Gotaland, Sweden, SE-413 46
      • Recruiting
      • Gothia Forum CTC
      • Contact: Anna-Carin Varvne, Manager; Phone Number: 46 70 082 50 91; Email: anna-carin.varvne@vgregion.se
      • Contact: Sari Huusko, Team leader; Phone Number: 46 70 082 34 22; Email: saari.huusko@vgregion.se
      • Sub-Investigator: Emanuel Fryk, MD, PhD
      • Sub-Investigator: Vagner Silva, PhD
      • Sub-Investigator: Jakob Bellman, MD
      • Sub-Investigator: Ingrid Wernstedt Asterholm, Prof
      • Sub-Investigator: Milica Vujicic, PhD
      • Sub-Investigator: Marco Bauza Thorbrügge, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Obese subjects and healthy lean controls will be recruited by advertisements in local newspapers and social media. Catchment area is western Sweden having about 1.5 million inhabitants.

Description

Inclusion Criteria:

1. Men and women of age: 40.0 - 70.0 years
2. BMI: 18.0 - 25.0 kg/m2 (lean subjects) and BMI 30.0 - 38.0 kg/m2 (Ob-IS and Ob-IR)
3. Fasting insulin < 9.0 mU/l (lean and Ob-IS subjects) and fasting insulin > 9.0 mU/l (Ob-IR)
4. Fasting glucose < 6.1 mmol/l
5. Body temperature < 37.5°C
6. First-degree relative with known T2D in Ob-IR
7. Weight stable ± 5 kg < 3 months before screening
8. Fluent in Swedish and can follow given instructions

9. Consent given to participate

   Exclusion Criteria:

10. First-degree relative with known T2D in lean or Ob-IS subjects
11. Alcohol intake > 10 units/week or known high alcohol intake < 10 years back in time
12. Daily use of cigarettes or daily frequent use of smokeless tobacco not enabling the participant to suspend nicotine during a visit at the research center without getting abstinent
13. Regular physical activity corresponding to Saltin-Gimby level 4
14. Special diet eg Atkins or 5:2 for weight reduction. Vegetarian food accepted if duration > 1 year
15. Impaired fasting glucose (IFG) (venous fasting plasma glucose 6.1-6.9 mmol/l)
16. Type 2 diabetes according to ADA criteria
17. Ongoing or previous ischemic heart disease, eg angina pectoris, unstable angina or previous myocardial infarction treated with platelet inhibitors or non vitamin-K oral anticoagulants
18. Heart failure (NYHA II-IV) or cardiac arrhytmia that needs medical treatment
19. Previous cerebral infarction or transitory ischemic episodes (TIA) treated with platelet inhibitors or other anticoagulants
20. Peripheral arterial insufficiency eg claudication
21. Hypertension >170/105 mmHg at screening or more than one class of drugs for treatment of known hypertension
22. Lipid disorder defined as fasting serum triglycerides > 5.0 mmol/l or serum cholesterol > 7.5 mmol/l
23. Hematologic diseases such as anemia not being substituted (Hb < 130 g/l in males and Hv < 120 g/l in females) or disease causing bleeding disorder
24. Renal failure defined as absolute estimated glomerular filtration rate (eGFRcreatinine) < 60 ml/min/1.73 m2
25. Hypothyroidism defined as TSH > 4.0 mIE/l and symptoms
26. Liver disease e.g. hepatitis B, cirrhosis or conditions where AST or ALT are > 2 times UNL
27. Systemic inflammatory disease e.g. rheumatoid arthritis, ulcerative cholitis or Chrons disease. Celiac disease, dyspepsia or IBS are excepted
28. Chronic bronchitis or chronic obstructive pulmonary with disease symptoms
29. Previous pancreatitis or other disease in pancreas that needs treatment
30. Migraine elicited by stress
31. Spinal insufficiency causing inconvenience lying in supine position during the study day
32. Drug addiction interfering with the study procedures
33. Psychiatric insufficiency interfering with the study procedures
34. Medication with potential to affect adipose tissue metabolism that can not be stopped 10 days before the study days
35. Treatment with beta-blockers
36. Less than three months from previous use of antibiotics
37. Cancer disease < 5 years since diagnosis
38. Physical examination or laboratory results indicating that participation in the study is inappropriate
39. Pregnancy or intention to be pregnant during the study
40. Shift work > 1 time per week that might interfere with the circadian rhytm
41. Other reasons that causes the PI to believe that participation is inappropriate

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Obese insulin-sensitive subjects (Ob-IS); Obese Insulin Sensitive subjects (BMI > 30 kg/m2, fasting insulin < 9.0 mU/l and fasting plasma glucose < 6.1 mmol/l) undergoing subcutaneous microdialysis, needle biopsy, glucose clamp and MRI.	Device: Subcutaneous microdialysis; Group with Ob-IS participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Ob-IR participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Leans, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1.
Obese insulin-resistant subjects (Ob-IR); Obese Insulin Resistant subjects (BMI > 30 kg/m2, fasting insulin > 9.0 mU/l and fasting plasma glucose < 6.1 mmol/l) undergoing subcutaneous microdialysis, needle biopsy, glucose clamp and MRI.	Device: Subcutaneous microdialysis; Group with Ob-IS participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Ob-IR participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Leans, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1.
Lean healthy controls (Lean); Lean healthy controls (BMI < 25 kg/m2, fasting insulin < 9.0 mU/l and fasting plasma glucose < 6.1 mmol/l) undergoing subcutaneous microdialysis, needle biopsy, glucose clamp and MRI.	Device: Subcutaneous microdialysis; Group with Ob-IS participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Ob-IR participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Leans, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting galectin-1 concentration in subcutaneous interstitial fluid	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Fasting Neuropilin-1 concentration in subcutaneous interstitial fluid	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting serum galectin-1 concentrations	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Fasting serum neuropilin-1 concentrations	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Fasting fatty acid levels in subcutaneous dialysates	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Fasting plasma fatty acid concentrations	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Fasting amino acid profile in subcutaneous dialysates	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Fasting serum amino acid concentrations	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Circulating metabolome including lipoprotein-related parameters measured by Mass Spectrometry	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Circulating lipidome including lipid derivatives measured by Mass Spectrometry	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Peptides identified by Mass Spectrometry in subcutaneous dialysates	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks
Ectopic lipid accumulation assessed by magnetic resonance imaging in relative measures	Comparison between eligible Ob-IS and Ob-IR subjects < 9 weeks after enrolment	Nine weeks
RNA sequencing results of subcutaneous adipose cells	Comparison between eligible Ob-IS and Ob-IR subjects < 6 weeks after enrolment	Six weeks
Function of immune cells in subcutaneous stromal vascular fraction characterized by Fluorescence Activated Cell Sorting (FACS)	Comparison between eligible Ob-IS and Ob-IR subjects < 6 weeks after enrolment	Six weeks
Activation of insulin signaling proteins in adipose cells assessed by Western blot	Comparison between eligible Ob-IS and Ob-IR subjects < 6 weeks after enrolment	Six weeks
Function of microvascular endothelial cells in subcutaneous stromal vascular fraction	Comparison between eligible Ob-IS and Ob-IR subjects < 6 weeks after enrolment	Six weeks
Messenger RNA expression in whole adipose tissue	Comparison between eligible Ob-IS and Ob-IR subjects < 6 weeks after enrolment	Six weeks
Dysbiosis in faeces assessed by 16S rRNA gene sequencing	Comparison between eligible Ob-IS and Ob-IR subjects < 6 weeks after enrolment	Six weeks
Metabolites in urine including acylcarnitines measured by Mass Spectrometry	Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment	Three weeks

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Collaborators: Göteborg University
• Investigators: Principal Investigator: Per-Anders Jansson, Prof, Region Västra Götaland

Publications and helpful links

General Publications

• Fryk E, Sundelin JP, Strindberg L, Pereira MJ, Federici M, Marx N, Nystrom FH, Schmelz M, Svensson PA, Eriksson JW, Boren J, Jansson PA. Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients. Metabolism. 2016 Jul;65(7):998-1006. doi: 10.1016/j.metabol.2016.04.003. Epub 2016 Apr 13.
• Drake I, Fryk E, Strindberg L, Lundqvist A, Rosengren AH, Groop L, Ahlqvist E, Boren J, Orho-Melander M, Jansson PA. The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses. Diabetologia. 2022 Jan;65(1):128-139. doi: 10.1007/s00125-021-05594-1. Epub 2021 Nov 7.
• Fryk E, Olausson J, Mossberg K, Strindberg L, Schmelz M, Brogren H, Gan LM, Piazza S, Provenzani A, Becattini B, Lind L, Solinas G, Jansson PA. Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study. EBioMedicine. 2021 Mar;65:103264. doi: 10.1016/j.ebiom.2021.103264. Epub 2021 Mar 9.
• Fryk E, Silva VRR, Jansson PA. Galectin-1 in Obesity and Type 2 Diabetes. Metabolites. 2022 Sep 30;12(10):930. doi: 10.3390/metabo12100930.

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 11, 2023
• First Submitted That Met QC Criteria: September 26, 2023
• First Posted (Actual): October 4, 2023

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Insulin resistance; Microdialysis; Fatty acids; Stromal vascular fraction; Amino acids; Ectopic lipid accumulation; Adipose cells; Fasting hyperinsulinemia
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity
• Other Study ID Numbers: 2023-02051-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sensitive personal data will be collected. Results will be shared if possible in the light of GDPR and other regulations, on an individual basis, after contact with the PI.
• IPD Sharing Time Frame: Data analyses and completion of results for the major outcomes of the study will be 2025-2028. Data will be available for 15 years.
• IPD Sharing Access Criteria: Contact on an individual basis with PI of the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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