Adaptive Mechanisms In GRown up ObeSity Study (AMIGROS)

Sponsor

Vastra Gotaland Region (Other)

Overall Status

Recruiting

CT.gov ID

NCT06065930

Collaborator

Göteborg University (Other)

Enrollment

Location

67.9

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Obesity Type 2 Diabetes	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 Design

Study Type:

Observational

Anticipated Enrollment :

45 participants

Observational Model:

Case-Control

Time Perspective:

Cross-Sectional

Official Title:

Mechanistic Studies in Human Subcutaneous Adipose Tissue

Actual Study Start Date :

May 5, 2023

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2028

Arms and Interventions

Arm	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.

Arm

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

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

Outcome Measures

Primary Outcome Measures

Fasting galectin-1 concentration in subcutaneous interstitial fluid [Three weeks]
Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment
Fasting Neuropilin-1 concentration in subcutaneous interstitial fluid [Three weeks]
Comparison between eligible Ob-IS and Ob-IR subjects < 3 weeks after enrolment

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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

Exclusion Criteria:

First-degree relative with known T2D in lean or Ob-IS subjects
Alcohol intake > 10 units/week or known high alcohol intake < 10 years back in time
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
Regular physical activity corresponding to Saltin-Gimby level 4
Special diet eg Atkins or 5:2 for weight reduction. Vegetarian food accepted if duration > 1 year
Impaired fasting glucose (IFG) (venous fasting plasma glucose 6.1-6.9 mmol/l)
Type 2 diabetes according to ADA criteria
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
Heart failure (NYHA II-IV) or cardiac arrhytmia that needs medical treatment
Previous cerebral infarction or transitory ischemic episodes (TIA) treated with platelet inhibitors or other anticoagulants
Peripheral arterial insufficiency eg claudication
Hypertension >170/105 mmHg at screening or more than one class of drugs for treatment of known hypertension
Lipid disorder defined as fasting serum triglycerides > 5.0 mmol/l or serum cholesterol > 7.5 mmol/l
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
Renal failure defined as absolute estimated glomerular filtration rate (eGFRcreatinine) < 60 ml/min/1.73 m2
Hypothyroidism defined as TSH > 4.0 mIE/l and symptoms
Liver disease e.g. hepatitis B, cirrhosis or conditions where AST or ALT are > 2 times UNL
Systemic inflammatory disease e.g. rheumatoid arthritis, ulcerative cholitis or Chrons disease. Celiac disease, dyspepsia or IBS are excepted
Chronic bronchitis or chronic obstructive pulmonary with disease symptoms
Previous pancreatitis or other disease in pancreas that needs treatment
Migraine elicited by stress
Spinal insufficiency causing inconvenience lying in supine position during the study day
Drug addiction interfering with the study procedures
Psychiatric insufficiency interfering with the study procedures
Medication with potential to affect adipose tissue metabolism that can not be stopped 10 days before the study days
Treatment with beta-blockers
Less than three months from previous use of antibiotics
Cancer disease < 5 years since diagnosis
Physical examination or laboratory results indicating that participation in the study is inappropriate
Pregnancy or intention to be pregnant during the study
Shift work > 1 time per week that might interfere with the circadian rhytm
Other reasons that causes the PI to believe that participation is inappropriate