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      Relationships Between Circulating Metabolic Intermediates and Insulin Action in Overweight to Obese, Inactive Men and Women

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          Abstract

          OBJECTIVE

          To determine whether circulating metabolic intermediates are related to insulin resistance and β-cell dysfunction in individuals at risk for type 2 diabetes.

          RESEARCH DESIGN AND METHODS

          In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry–based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates.

          RESULTS

          The 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity ( S I) ( R 2 = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose ( R 2 = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) ( R 2 = 0.39). Sex differences were found for metabolic predictors of S I and DI.

          CONCLUSIONS

          In addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.

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          Most cited references21

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          Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.

          Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
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            Plasma amino acid levels and insulin secretion in obesity.

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              Effect of the volume and intensity of exercise training on insulin sensitivity.

              Physical activity enhances insulin action in obese/overweight individuals. However, the exercise prescription required for the optimal enhancement is not known. The purpose of this study was to test the hypothesis that exercise training consisting of vigorous-intensity activity would enhance insulin sensitivity more substantially than moderate-intensity activity. Sedentary, overweight/obese subjects (n = 154) were randomly assigned to either control or an exercise group for 6 mo: 1) low-volume/moderate-intensity group [ approximately 12 miles walking/wk at 40-55% peak O2 consumption (Vo2 peak)], 2) low-volume/high-intensity group ( approximately 12 miles jogging/wk at 65-80% Vo2 peak), and 3) high-volume/high-intensity group ( approximately 20 miles jogging/wk at 65-80% Vo2 peak). Training volume (miles/wk) was achieved by exercising approximately 115 min/wk (low-volume/high-intensity group) or approximately 170 min/wk (low-volume/moderate-intensity and high-volume/high-intensity groups). Insulin action was measured with an insulin sensitivity index (SI) from an intravenous glucose tolerance test. In the control group, there was a decrement (P < 0.05) in SI. In contrast, all the exercise groups significantly (P < 0.05) increased SI; the relative increment in the low-volume/moderate-intensity and high-volume/high-intensity groups ( approximately 85%) were greater than in the low-volume/high-intensity group ( approximately 40%). In conclusion, physical activity encompassing a wide range of intensity and volume minimizes the insulin resistance that develops with a sedentary lifestyle. However, an exercise prescription that incorporated approximately 170 min of exercise/wk improved insulin sensitivity more substantially than a program utilizing approximately 115 min of exercise/wk, regardless of exercise intensity and volume. Total exercise duration should thus be considered when designing training programs with the intent of improving insulin action.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                September 2009
                5 June 2009
                : 32
                : 9
                : 1678-1683
                Affiliations
                [1] 1Physical Medicine and Rehabilitation, Veterans Affairs Medical Center, Durham, North Carolina;
                [2] 2Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
                [3] 3Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina;
                [4] 4Department of Exercise and Sports Science and the Human Performance Laboratory, East Carolina University, Greenville, North Carolina;
                [5] 5Division of Geriatrics, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
                [6] 6Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
                Author notes
                Corresponding author: Kim M. Huffman, huffm007@ 123456mc.duke.edu .
                Article
                2075
                10.2337/dc08-2075
                2732163
                19502541
                843d90ec-39a5-4901-be38-34e62f9adade
                © 2009 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 13 January 2009
                : 25 May 2009
                Funding
                Funded by: National Institutes of Health
                Award ID: R01HL-57354
                Categories
                Original Research
                Pathophysiology/Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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