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J Clin Endocrinol Metab. 2014 Jun;99(6):2198-207. doi: 10.1210/jc.2013-4542. Epub 2014 Mar 11.

Low circulating levels of IGF-1 in healthy adults are associated with reduced β-cell function, increased intramyocellular lipid, and enhanced fat utilization during fasting.

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  • 1Department of Paediatrics (A.T., D.C., M.L.M., K.M., D.B.D.) and Wolfson Brain Imaging Centre (A.S.), University of Cambridge, CB2 0QQ, Cambridge, United Kingdom; Medical Research Council (MRC) Metabolic Diseases Unit (G.S.H.Y.), University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom; MRC Human Nutrition Research of Growth and Reproduction (L.B.); and National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre (D.B.D.), Cambridge, CB1 9NL, United Kingdom; Department of Endocrinology (S.W.J., A.V.), Rigshospitalet and Copenhagen University, DK-2100 Denmark; Oxford Centre for Diabetes, Endocrinology, and Metabolism (N.R.H.), University of Oxford, Oxford, OX3 7LE, United Kingdom; and Department of Growth and Reproduction (A.J.), Rigshospitalet, Faculty of Health and Medical Sciences, DK-2100 Denmark.

Abstract

CONTEXT:

Low serum IGF-1 levels have been linked to increased risk for development of type 2 diabetes. However, the physiological role of IGF-1 in glucose metabolism is not well characterized.

OBJECTIVE:

Our objective was to explore glucose and lipid metabolism associated with variations in serum IGF-1 levels.

DESIGN, SETTING AND PARTICIPANTS:

IGF-1 levels were measured in healthy, nonobese male volunteers aged 18 to 50 years from a biobank (n = 275) to select 24 subjects (age 34.8 ± 8.9 years), 12 each in the lowest (low-IGF) and highest (high-IGF) quartiles of age-specific IGF-1 SD scores. Evaluations were undertaken after a 24-hour fast and included glucose and glycerol turnover rates using tracers, iv glucose tolerance test to estimate peripheral insulin sensitivity (IS) and acute insulin and C-peptide responses (indices of insulin secretion), magnetic resonance spectroscopy to measure intramyocellular lipids (IMCLs), calorimetry, and gene expression studies in a muscle biopsy.

MAIN OUTCOME MEASURES:

Acute insulin and C-peptide responses, IS, and glucose and glycerol rate of appearance (Ra) were evaluated.

RESULTS:

Fasting insulin and C-peptide levels and glucose Ra were reduced (all P < .05) in low-IGF compared with high-IGF subjects, indicating increased hepatic IS. Acute insulin and C-peptide responses were lower (both P < .05), but similar peripheral IS resulted in reduced insulin secretion adjusted for IS in low-IGF subjects (P = 0.044). Low-IGF subjects had higher overnight levels of free fatty acids (P = .028) and β-hydroxybutyrate (P = .014), increased accumulation of IMCLs in tibialis anterior muscle (P = .008), and a tendency for elevated fat oxidation rates (P = .058); however, glycerol Ra values were similar. Gene expression of the fatty acid metabolism pathway (P = .0014) was upregulated, whereas the GLUT1 gene was downregulated (P = .005) in the skeletal muscle in low-IGF subjects.

CONCLUSIONS:

These data suggest that serum IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.

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