Obesity, Type 2 Diabetes
Conditions
Keywords
Adipose cells, Fatty acids, Microdialysis, Stromal vascular fraction, Ectopic lipid accumulation, Fasting hyperinsulinemia, Insulin resistance, Amino acids
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.
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.
Interventions
DEVICESubcutaneous 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.
Sponsors
Göteborg University
Vastra Gotaland Region
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Fasting serum galectin-1 concentrations | Three weeks | Comparison between eligible Ob-IS and Ob-IR subjects \< 3 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 |
| 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 |
| Fasting serum neuropilin-1 concentrations | Three weeks | Comparison between eligible Ob-IS and Ob-IR subjects \< 3 weeks after enrolment |
Countries
Sweden
Contacts
Primary ContactPer-Anders E Jansson, Prof
Backup ContactVagner R Silva, PhD
Outcome results
None listed