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Differences in Plasma Metabolites in Insulin Resistant and Insulin Sensitive Obese Individuals during a Hyperinsulinemic/Euglycemic Clamp
Author(s) -
Casey James L.,
Van Pelt Douglas W.,
Burant Charles,
Horowitz Jeffery,
Evans Charles
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.889.3
Subject(s) - insulin , medicine , clamp , endocrinology , metabolite , glucose clamp technique , insulin resistance , chemistry , metabolism , pancreatic hormone , mechanical engineering , clamping , engineering
Although the vast majority of obese adults are insulin resistant (IR), some obese individuals remain relatively insulin sensitive (IS), though the underlying mechanisms for this difference are unclear. The hyperinsulimemic‐euglycemic clamp (HEC) is the gold standard test for insulin sensitivity. However, it is not clear if the differences in insulin‐mediated changes in glucose metabolism between IS and IR obese individuals extend to other key metabolites. In this study, we monitored the dynamics of 49 metabolites in obese IR vs. IS during a HEC. From an original screening of 28 obese adults, twelve non‐diabetic subjects, matched for age, sex, BMI, fat mass and fat‐free mass were divided into the 6 most IS and 6 most IR women based on glucose uptake during a HEC clamp. Mean glucose uptake during the clamp was 7.4±1.2 vs 15.6±2.47 mg/kg FFM/min for IR and IS, respectively (p <0.0001).Serum metabolite levels were measured at 8 time points during the clamp using liquid chromatography‐mass spectrometry (LC‐MS): 2 samples at baseline, immediately prior to insulin infusion, every 20 minutes during the insulin infusion (4 samples), and 2 samples at steady state glucose levels (after ~2h of insulin infusion).Metabolite levels were quantitated by peak area, with stable‐isotope internal standards used to allow absolute quantitation of select metabolites. Statistical differences between IS and IR groups were assessed using t‐tests. Compared with IS, IR individuals had higher baseline levels of valine (p=0.023) and leucine and isoleucine (LI) (combined peak area) (p=0.006). However, the rate of decline in LI in response to insulin was greater in IS compared with IR. At steady‐state glucose infusion (~2 hr of HEC) most metabolites were either unchanged or fell from baseline levels. LI and valine concentrations fell about 50% in response to insulin in both groups, but LI and valine continued to be 40–100% greater in IR compared with IS (p=0.022 and 0.007, respectively). Likewise, threonine, lysine and glutamate levels were greater in IR than IS (all p<0.019) when glucose reached steady‐state during the HEC. No significant differences between IR and IS were found in various fatty acid, TCA cycle intermediates, or lactate levels at baseline or at steady‐state of the HEC. These findings indicate that obese adults, who are seemingly “protected” against a decline in insulin‐mediated glucose uptake, also demonstrate improved response of insulin to lower BCAA and other amino acids that have been associated with and increase risk of development of type 2 diabetes. These results suggest that changes in the plasma level of metabolites associated with risk of type 2 diabetes is driven by insulin resistance and not obesity per se.