Transient Hyperglycemia Alters Pancreatic Function and Peripheral Insulin Signaling in Preterm Baboons

Abstract

Background: Premature infants develop transient hyperglycemia and insulin resistance. Hyperglycemia is not treated by intensivists to avoid caloric restriction and promote growth. Objective: To determine the effects of transient hyperglycemia on endocrine pancreas, skeletal muscle and liver at early stages of development in preterm baboons. Methods: Baboons were delivered prematurely (67% gestation; n=6) via c-section and ventilated for 14 days or sacrificed immediately after birth (n=6). Preterm ventilated animals were randomly assigned to tight glucose control (EUG; serum glucose 50-100mg/dL) or hyperglycemia (HYPER; serum glucose 150-250 mg/dL) from day of life (DOL) 0-5; tight glucose control thereafter. Hyperglycemic (HG) clamps were performed on DOL6 and DOL14. IHC was done for α-β-δ cells in pancreas tissue. Muscle and liver mRNA expression and protein content of key insulin signaling molecules were measured. Results: HYPER baboons had higher serum glucose compared to EUG (183±61 vs. 69±24 mg/dL, p<0.01) from DOL 0-5, and similar glucose from DOL 6-14. During the HG clamps, HYPER baboons had abnormally increased insulin secretion (2.7 fold, p<0.05) on DOL6, but normalized by DOL14. C-peptide was abnormally increased (3.3 fold, p<0.05) on DOL6; by DOL14 the same HYPER animals had a 38% decrease in c-peptide as compared to EUG (p=0.07). The α/β cell area was decreased in HYPER animals. Akt content was increased in the liver of HYPER baboons (2.8 fold, p<0.01) whereas IR/IRS and PEPCK-C didn’t change. Skeletal muscle GLUT1 was 70% decreased in HYPER animals (p<0.01); INSR, IRS-1, Akt and mitochondrial oxygen consumption were similar. Conclusion: Premature baboons exposed to transient hyperglycemia have an initial abnormal increase in insulin/c-peptide secretion followed by a decrease in c-peptide secretion a week later; alterations in α and β cell percent area are found at necropsy. Insulin signaling molecules are altered in liver/skeletal muscle of HYPER preterm baboons. Disclosure C. Blanco: None. A. Quinn: None. L.A. Winter: None. J. Valentine: None. N. Musi: None. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..