Hepatic Insulin Resistance and Altered Gluconeogenic Pathway in Premature Baboons.
Premature infants have altered glucose regulation early in life and increased risk for diabetes in adulthood. Although prematurity leads to an increased risk of diabetes and metabolic syndrome in adult life, the role of hepatic glucose regulation and adaptation to an early extrauterine environment in preterm infants remain unknown. The purpose of this study was to investigate developmental differences in glucose metabolism, hepatic protein content, and gene expression of key insulin-signaling/gluconeogenic molecules. Fetal baboons were delivered at 67%, 75%, and term gestational age and euthanized at birth. Neonatal baboons were delivered prematurely (67% gestation), survived for two weeks, and compared with similar postnatal term animals and underwent serial hyperinsulinemic-euglycemic clamp studies. Premature baboons had decreased endogenous glucose production (EGP) compared with term animals. Consistent with these results, the gluconeogenic molecule, phosphoenolpyruvate carboxykinase messenger RNA, was decreased in preterm baboons compared with terms. Hepatic insulin signaling was altered by preterm birth as evidenced by decreased insulin receptor-β, p85 subunit of phosphoinositide 3-kinase, phosphorylated insulin receptor substrate 1, and Akt-1 under insulin-stimulated conditions. Furthermore, preterm baboons failed to have the normal increase in glycogen synthase kinase-α from fetal to postnatal life. The blunted responses in hepatic insulin signaling may contribute to the hyperglycemia of prematurity, while impaired EGP leads to hypoglycemia of prematurity.
Department of Pediatrics, Neonatology Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Lisa
L
McGill-Vargas
Department of Medicine, Diabetes Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.|Cardiometabolic Risk Unit, Institute of Clinical Physiology, 56100 Pisa, Italy.
Amalia
A
Gastaldelli
Department of Medicine, Diabetes Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Hanyu
H
Liang
Department of Pediatrics, Neonatology Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Diana
D
Anzueto Guerra
Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Teresa
T
Johnson-Pais
Department of Pediatrics, Neonatology Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Steven
S
Seidner
Department of Pediatrics, Neonatology Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Donald
D
McCurnin
Department of Medicine, Diabetes Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Giovanna
G
Muscogiuri
Department of Medicine, Diabetes Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.|Texas Diabetes Institute, San Antonio, Texas 78207.
Ralph
R
DeFronzo
Department of Medicine, Diabetes Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.|Texas Diabetes Institute, San Antonio, Texas 78207.|San Antonio Geriatric, Research, Education and Clinical Center, San Antonio, Texas 78229.|Barshop Institute for Longevity and Aging Studies, San Antonio, Texas 78245.
Nicolas
N
Musi
Department of Pediatrics, Neonatology Division, Texas Health Science Center at San Antonio, San Antonio, Texas 78229.|University Health System, San Antonio, Texas 78229.
Cynthia
C
Blanco
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000151:congenital* / Q000209:etiology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D010215:Papio; D011247:Pregnancy; D047928:Premature Birth / Q000378:metabolism*; D047929:Term Birth / Q000378:metabolism
D007328:Insulin; D005947:Glucose