title: Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.
abstract: Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.
authors.affiliation: Department of Pediatrics (C.L.B., L.L.M.-V., S.R.S., D.C.M., M.M.L., D.G.A., M.C.J.), Division of Neonatology, University of Texas Health Science Center at San Antonio, Department of Medicine (A.G., H.L., R.A.D., N.M.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Texas Diabetes Institute (H.L., R.A.D., N.M.), San Antonio, Texas 78207; San Antonio Geriatric, Research and Education Center and Barshop Institute for Longevity and Aging Studies (N.M.), San Antonio, Texas 78245, and Institute of Clinical Physiology, CNR, Pisa, Italy (A.G.).
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Blanco
authors.forename: Lisa L
authors.initials: LL
authors.lastname: McGill-Vargas
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: Steven R
authors.initials: SR
authors.lastname: Seidner
authors.forename: Donald C
authors.initials: DC
authors.lastname: McCurnin
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Leland
authors.forename: Diana G
authors.initials: DG
authors.lastname: Anzueto
authors.forename: Marney C
authors.initials: MC
authors.lastname: Johnson
authors.forename: Hanyu
authors.initials: H
authors.lastname: Liang
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
mesh_terms: D000818:Animals; D001786:Blood Glucose; D005260:Female; D005786:Gene Expression Regulation; D005934:Glucagon; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D010215:Papio / Q000378:metabolism*; D011247:Pregnancy; D047928:Premature Birth; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014715:Vertebrobasilar Insufficiency / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D005934:Glucagon; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose