Patients in this group will receive oral supplementation with EPA+DHA (3.9grams/day) for 6 months.

Patients in this group will be supplemented with placebo capsules containing ethyl oleate.

Omega-3

Placebo

Total

Sex: Female, Male

Region of Enrollment

A 2-stage insulin clamp will be performed with titration of dextrose to maintain euglycemia. D2 glucose will be infused to evaluate hepatic glucose production at baseline and in response to insulin. Hyperinsulinemic-euglycemic clamp technique: The plasma insulin concentration is acutely raised and maintained by a continuous infusion of insulin. Meanwhile, the plasma glucose concentration is held constant at basal levels by a variable glucose infusion. When the steady-state is achieved, the glucose infusion rate (GIR) equals glucose uptake by all the tissues in the body and is therefore a measure of tissue insulin sensitivity.

Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp at Baseline and 6 Month Follow up

Following consumption of a mixed meal, beta cell function will be evaluated from serial measurements of C-peptide. C-peptide was measured using a two-side immunometric assay using electrochemiluminescence detection.

Beta Cell Function From Insulin Secretion Following Ingestion of a Mixed Meal at Baseline and 6 Month Follow up

Measurements of oxygen consumption in isolated mitochondria will be performed using a polarographic oxygen electrode.

Mitochondrial Function Determined by Muscle Biopsy at Baseline and 6 Month Follow up

Sensitivity of adipose tissue lipolysis to insulin suppression, was calculated as the insulin concentration needed to suppress palmitate appearance rates (ie, flux) by 50% (IC50(palmitate)f).

Insulin Concentration Needed to Suppress Palmitate Appearance Rates (IC50(Palmitate)f)

Tissue burden of senescent cells, which was measured by staining for senescence-associated B-galactosidase activity and expressed as the number per 100 nucleated positive cells.

Senescent Cells

One week after the pancreatic clamp study, participants were provided a standardized meal before an overnight fast. The next morning an abdominal adipose tissue biopsy was collected, and the samples were analyzed for adipocyte size. Immunohistochemistry was used to assess macrophage burden (total (CD68), M1 (CD14) and M2 (CD206) macrophages per 100 adipocytes).

Immunohistochemistry Assessments of Macrophage Burden

Macrophages surrounding dying or dead adipocytes form crown-like structures (CLSs). One week after the pancreatic clamp study, participants were provided a standardized meal before an overnight fast. The next morning an abdominal adipose tissue biopsy was collected, and the samples were analyzed for adipocyte size. Immunohistochemistry was used to assess the number of crown-like structures per 10 images.

Macrophage Crown-like Structures

Post hoc analyses were conducted to test whether EPA and DHA concentrations in plasma in response to intervention explained variation in outcome measures of adipose tissue lipolysis insulin sensitivity and inflammatory markers post-intervention.

EPA and DHA Concentrations in Plasma

Post hoc analyses were conducted to test whether EPA and DHA concentrations in subcutaneous abdominal adipose tissue in response to intervention explained variation in outcome measures of adipose tissue lipolysis insulin sensitivity and inflammatory markers post-intervention.

EPA and DHA Concentrations in Adipose Tissue

Patients in this group will receive oral supplementation with EPA + Docosahexaenoic acid (DHA) (3.9grams/day) for 6 months.

3 beta galactosidase/inflamação

Omega-3 Fatty Acids and Insulin Sensitivity

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