title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Department 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.
authors.forename: Ajay
authors.initials: A
authors.lastname: Thankamony
authors.forename: Donatella
authors.initials: D
authors.lastname: Capalbo
authors.forename: M Loredana
authors.initials: ML
authors.lastname: Marcovecchio
authors.forename: Alison
authors.initials: A
authors.lastname: Sleigh
authors.forename: Sine Wanda
authors.initials: SW
authors.lastname: Jørgensen
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Hill
authors.forename: Katrin
authors.initials: K
authors.lastname: Mooslehner
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Les
authors.initials: L
authors.lastname: Bluck
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
mesh_terms: D000293:Adolescent; D000328:Adult; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006262:Health; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism*; D055815:Young Adult
chemical_list: D008055:Lipids; D007334:Insulin-Like Growth Factor I; D005947:Glucose