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Adjusting Glucose-Stimulated Insulin Secretion for Adipose Insulin

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Adjusting Glucose-Stimulated Insulin Secretion for Adipose Insulin Diabetes Care 1 Steven K. Malin,1,2 Sangeeta R. Kashyap,3 Adjusting Glucose-Stimulated Jeff Hammel,1 Yoshi Miyazaki,4 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Ralph A. DeFronzo,4 and Insulin Secretion for Adipose John P. Kirwan1,2,5 Insulin Resistance: An Index of b-Cell Function in Obese Adults DOI: 10.2337/dc13-3011 OBJECTIVE The hyperbolic relationship between insulin secretion and sensitivity has been used to assess in vivo b-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 character- izing glucose-stimulated insulin secretion (GSIS) because elevated plasma free fatty acids (FFAs) impair b-cell function. RESEARCH DESIGN AND METHODS To characterize the adipose disposition index, we used [1-14C] palmitate infusion to determine basal FFA turnover rate/adipose insulin resistance and an oral glu- cose 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 3 plasma insulin con- centration) 3 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 1Department of Pathobiology, Lerner Research index derived from plasma FFA also was tightly associated with fasting hypergly- Institute, Cleveland Clinic, Cleveland, OH 2 cemia (r = 20.87, P < 0.00001 and r = 20.89, P < 0.00001, respectively) and 2-h Department of Nutrition, School of Medicine, r 2 P < r 2 P < Case Western Reserve University, Cleveland, OH glucose concentrations ( = 0.86, 0.00001 and = 0.90, 0.00001). 3Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH CONCLUSIONS 4University of Texas Health Science Center, Di- Adjusting GSIS for adipose insulin resistance provides an index of b-cell function in abetes Division, San Antonio, TX 5 obese subjects across the glucose spectrum. Plasma FFA–derived calculations of Metabolic Translational Research Center, Endo- b crine and Metabolism Institute, Cleveland Clinic, -cell function may provide additional insight into the role of adipose tissue in Cleveland, OH glucose regulation. Corresponding author: John P. Kirwan, kirwanj@ ccf.org, and Ralph A. DeFronzo, albarado@uthscsa .edu. Prevention of b-cell dysfunction is critical for avoiding the development and pro- gression of type 2 diabetes (1). Assessing in vivo insulin secretion is complex because Received 23 December 2013 and accepted 30 July 2014. the release of insulin from the b-cell is influenced by multiple factors including © 2014 by the American Diabetes Association. systemic insulin sensitivity, hepatic insulin extraction, plasma free fatty acid (FFA) Readers may use this article as long as the work concentrations, and glucolipid toxicity (2–4). An important aspect of the regulation is properly cited, the use is educational and not of insulin secretion in healthy adults with normal glucose tolerance is that a for profit, and the work is not altered. Diabetes Care Publish Ahead of Print, published online August 19, 2014 2 Adipose Insulin Resistance and Secretion Diabetes Care reduction in insulin sensitivity is gener- of chronic disease participated in the the duration of the study. During the ally accompanied by a compensatory in- study (14,15). Women were postmeno- last 30 min of tracer equilibration, plasma crease in insulin secretion (5,6). This pausal and were not receiving hor- samples were obtained at 230, 220, relationship typically is curvilinear and mone replacement therapy. Subjects 210, 25, and 0 min for determination has been referred to as the disposition who were being treated with insulin or of plasma [1-14C] palmitate radioactivity index (5). thiazolidinediones were excluded. Sub- and plasma FFA concentration. At 8 A.M. a The disposition index was originally jects were not taking any medications bolus of 3.5 uCi of sodium bicarbonate calculated from insulin sensitivity and known to influence glucose or insulin was given intravenously. Blood samples acute insulin response during the intra- metabolism. The diagnosis of type 2 di- were placed on ice and immediately venous glucose tolerance test (IVGTT) abetes was based on a standard 75-g centrifuged and stored at 2708C until (5,6). Insulin sensitivity measured with oral glucose tolerance test (OGTT): fasting subsequent analysis. Adipose insulin resis- the IVGTT is an aggregate of skeletal plasma glucose .126 mg/dL and/or 2-h tance index (Adipose-IR) was calculated as muscle, hepatic, and adipose insulin glucose .200 mg/dL. Subjects were in the product of the fasting plasma FFA 3 sensitivity. When the disposition index otherwise good health without evidence fasting insulin and compared with the is calculated using the hyperinsulinemic- of renal, hepatic, cardiovascular, or hema- product of basal rate palmitate turnover euglycemic clamp technique with supra- tological disease as determined by history, 3 fasting plasma insulin, as previously de- physiological insulin infusion rates (40–80 physical examination, screening blood scribed (12,13). mU z m22 z min21), hepatic glucose pro- chemistries, urinalysis, and electrocardiog- duction and lipolysis are almost com- raphy. The study protocol was approved Insulin Secretion At 8 A.M. on a different day, following a pletely suppressed, and 80–90% of by the institutional review board of the 10- to 12-h overnight fast, blood sam- glucose is disposed in skeletal muscle University of Texas Health Science Center ples were collected from a superficial (7). Therefore, when using the euglyce- at San Antonio and the Cleveland Clinic. antecubital vein to determine fasting mic insulin clamp to calculate the dispo- Subjects gave voluntary written informed plasma glucose, triglyceride, FFA, total sition index, two physiologically relevant consent before their participation. cholesterol, LDL, and HDL concentra- tissues and two physiologically relevant tions. HbA also was measured in pa- processes, that is, hepatic insulin sensitiv- Body Composition 1c tients with type 2 diabetes to further ity (2) and adipose insulin sensitivity (8), Height was measured without shoes characterize glycemic control. Following are not taken into account. Adipose tissue using a wall-mounted stadiometer, and collection of baseline samples, subjects should be considered in the interaction of weight was recorded on a digital platform orally consumed 75 g of glucose, and insulin secretion and insulin action be- scale with minimal clothing. Total body blood samples were obtained at 30, cause fat tissue secretes factors (e.g., fat and fat-free mass were measured by 3 60, 90, and 120 min to determine FFAs and adipokines) that contribute to underwater weighing or use of H-water plasma glucose and insulin concentra- multiorgan insulin resistance (8). These radioactivity, as previously described tions. Whole-body insulin action, which factors may contribute not only to skele- (14,15). reflects the aggregate of skeletal muscle, tal muscle and hepatic insulin resistance Control Period hepatic, and adipose insulin sensitivity, but also to impaired b-cell function in in- Before metabolic testing, subjects were was estimated using the Matsuda Index sulin-resistant states, including impaired instructed to avoid strenuous physical ac- (16). The HOMA of insulin resistance also fasting glucose, impaired glucose toler- tivity for 24 h. All subjects also were in- was calculated as a more reflective surro- ance, type 2 diabetes mellitus, and obe- structed to consume weight-maintenance gate of hepatic insulin resistance (17,18). sity (9,10). Because the fasting plasma meals (;55% carbohydrates, 30% fat, and Glucose and insulin total area under the FFA concentration is influenced by a feed- 15% protein). curve (AUC) during the OGTT were cal- back loop between adipose tissue and the culated using the trapezoidal method. pancreas (11), a valid estimate of adipose Palmitate Turnover First- and second-phase GSIS, that is, the insulin resistance can be obtained from Palmitate turnover, an index of lipolysis, insulinogenic index, was calculated during the product of the basal rate of FFA turn- wasassessedwithanisotopicallyla- the first 30 min and last 60 min of the over and the fasting insulin concentration beled palmitate infusion. After an over- OGTT as insulin AUC divided by plasma glu- (12,13). Relating adipose insulin re- night fast, a polyethylene catheter was cose AUC (i.e., I – /G – and I – – / sistance with glucose-stimulated insulin inserted into an antecubital vein for the 0 30 0 30 0 60 120 G – ). The first- and second-phase ad- secretion (GSIS) could yield a novel index infusion of [1-14C] palmitate. A second 60 120 ipose disposition indices were calculated of b-cell function. In this study we exam- catheter was inserted retrogradely into as follows: I – /G – 3 adipose plasma ine the physiologic relevance of the adi- the distal portion of a vein on the contra- 0 30 0 30 FFA IR and I – /G – 3 adipose pose disposition index as it relates to lateral hand for blood sampling. The hand 60 120 60 120 plasma FFA IR, respectively (19). blood glucose. was kept in a box warmed to ;608Cfor the duration of the study to collect arte- Biochemical Analysis RESEARCH DESIGN AND METHODS rialized blood. A prime (2.5 uCi) and con- Plasma glucose was determined using 14 Subjects tinuous (0.1 uCi/min) infusion of 1- C the glucose oxidase method (YSI 2300 Forty-four obese individuals (Table 1) palmitate was prepared as previously de- STAT Plus; YSI Life Sciences, Yellow who had a stable weight (,2-kg change scribed (14,15) and started at 8 A.M.
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