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

TY - JOUR

T1 - 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

AU - Thankamony, Ajay

AU - Capalbo, Donatella

AU - Marcovecchio, M Loredana

AU - Sleigh, Alison

AU - Jørgensen, Sine Wanda

AU - Hill, Nathan R

AU - Mooslehner, Katrin

AU - Yeo, Giles S H

AU - Bluck, Les

AU - Juul, Anders

AU - Vaag, Allan

AU - Dunger, David B

PY - 2014/6

Y1 - 2014/6

N2 - 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 comparedwithhigh-IGFsubjects, indicatingincreasedhepaticIS.AcuteinsulinandC- peptideresponses 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=-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 =-cell function and glucose as well as lipid metabolic responses during fasting.

AB - 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 comparedwithhigh-IGFsubjects, indicatingincreasedhepaticIS.AcuteinsulinandC- peptideresponses 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=-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 =-cell function and glucose as well as lipid metabolic responses during fasting.

KW - Adolescent

KW - Adult

KW - Fasting

KW - Glucose

KW - Health

KW - Humans

KW - Insulin-Like Growth Factor I

KW - Insulin-Secreting Cells

KW - Lipid Metabolism

KW - Lipids

KW - Male

KW - Middle Aged

KW - Muscle Fibers, Skeletal

KW - Young Adult

U2 - 10.1210/jc.2013-4542

DO - 10.1210/jc.2013-4542

M3 - Journal article

C2 - 24617714

SN - 0013-7227

VL - 99

SP - 2198

EP - 2207

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 6

ER -