Steven K Malin1, Sangeeta R Kashyap2, Jeff Hammel3, Yoshi Miyazaki4, Ralph A DeFronzo5, John P Kirwan6. 1. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH. 2. Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH. 3. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. 4. University of Texas Health Science Center, Diabetes Division, San Antonio, TX. 5. University of Texas Health Science Center, Diabetes Division, San Antonio, TX kirwanj@ccf.org albarado@uthscsa.edu. 6. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland, OH kirwanj@ccf.org albarado@uthscsa.edu.
Abstract
OBJECTIVE: The hyperbolic relationship between insulin secretion and sensitivity has been used to assess in vivo β-cell function (i.e., the disposition index). The disposition index emphasizes the importance of taking into account both skeletal muscle and hepatic insulin resistance to depict insulin secretion. However, we propose that adipose tissue insulin resistance also needs to be accounted for when characterizing glucose-stimulated insulin secretion (GSIS) because elevated plasma free fatty acids (FFAs) impair β-cell function. RESEARCH DESIGN AND METHODS: To characterize the adipose disposition index, we used [1-(14)C] palmitate infusion to determine basal FFA turnover rate/adipose insulin resistance and an oral glucose tolerance test to characterize the first (i.e., 0-30 min) and second phase (i.e., 60-120 min) of GSIS. We validated a simplified version of the tracer infusion calculation as the product of (1/plasma FFA concentration × plasma insulin concentration) × GSIS in 44 obese insulin-resistant subjects. RESULTS: The plasma FFA and palmitate tracer infusion calculations of the first- and second-phase disposition index were strongly correlated (r = 0.86, P < 0.000001 and r = 0.89, P < 0.000001, respectively). The first- and second-phase adipose disposition index derived from plasma FFA also was tightly associated with fasting hyperglycemia (r = -0.87, P < 0.00001 and r = -0.89, P < 0.00001, respectively) and 2-h glucose concentrations (r = -0.86, P < 0.00001 and r = -0.90, P < 0.00001). CONCLUSIONS: Adjusting GSIS for adipose insulin resistance provides an index of β-cell function in obese subjects across the glucose spectrum. Plasma FFA-derived calculations of β-cell function may provide additional insight into the role of adipose tissue in glucose regulation.
OBJECTIVE: The hyperbolic relationship between insulin secretion and sensitivity has been used to assess in vivo β-cell function (i.e., the disposition index). The disposition index emphasizes the importance of taking into account both skeletal muscle and hepatic insulin resistance to depict insulin secretion. However, we propose that adipose tissue insulin resistance also needs to be accounted for when characterizing glucose-stimulated insulin secretion (GSIS) because elevated plasma free fatty acids (FFAs) impair β-cell function. RESEARCH DESIGN AND METHODS: To characterize the adipose disposition index, we used [1-(14)C] palmitate infusion to determine basal FFA turnover rate/adipose insulin resistance and an oral glucose tolerance test to characterize the first (i.e., 0-30 min) and second phase (i.e., 60-120 min) of GSIS. We validated a simplified version of the tracer infusion calculation as the product of (1/plasma FFA concentration × plasma insulin concentration) × GSIS in 44 obese insulin-resistant subjects. RESULTS: The plasma FFA and palmitate tracer infusion calculations of the first- and second-phase disposition index were strongly correlated (r = 0.86, P < 0.000001 and r = 0.89, P < 0.000001, respectively). The first- and second-phase adipose disposition index derived from plasma FFA also was tightly associated with fasting hyperglycemia (r = -0.87, P < 0.00001 and r = -0.89, P < 0.00001, respectively) and 2-h glucose concentrations (r = -0.86, P < 0.00001 and r = -0.90, P < 0.00001). CONCLUSIONS: Adjusting GSIS for adipose insulin resistance provides an index of β-cell function in obese subjects across the glucose spectrum. Plasma FFA-derived calculations of β-cell function may provide additional insight into the role of adipose tissue in glucose regulation.
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