We have developed a non-human primate (NHP) model of impaired pancreatic islet development. Pancreatic islets of fetuses (F) of nutrient restricted (NR) pregnant baboons fed 70% of ad libitum fed controls (CTR) show normal IGF-I, IGF-II and insulin (INS) content at 0.5 gestation (G - 90 days gestation - term 185 days). However, at 0.9G, islet size and content of all three growth promoting peptides is reduced 50%. We propose post-natal studies in 24 CTR offspring (OFF - 12 of each sex) and 24 NR OFF (12 of each sex) to determine the extent to which these marked fetal changes persist in post-natal life and alter INS secretion and peripheral INS resistance (IR) in juvenile NHP. Hypothesis 1, Juvenile OFF of NR mothers show decreased in vivo INS secretion in response to glucose and amino acid (AA) stimulation compared to CTR OFF. Hypothesis 2, Pre-puberty OFF of NR mothers develop peripheral IR. Hypothesis 3. The IR demonstrated by OFF of MNR mothers is due in part to decreased INS signaling in OFF skeletal muscle (SM). APPROACH: We will use our unique NHP cohort to evaluate: Experiment 1 (addressing Hypothesis 1): pancreatic INS secretion in response to a hyperglycemic clamp and AA infusion;Experiment 2 (addressing Hypothesis 2): peripheral IR using a hyperinsulinemic euglycemic clamp;Experiment 3 (addressing Hypothesis 3): INS signaling in peripheral SM. We will evaluate differences between male and female OFF. INNOVATION: The last fifteen years has seen an explosion of interest and activity in Developmental programming (DP) defined as a response to a specific challenge to the mammalian organism during a critical developmental time window that alters the trajectory of development with persistent effects on OFF phenotype. Extensive evidence exists for DP into post-natal life from rodent and sheep studies and human epidemiology, but no NHP data exist on effects of MNR. The R21 mechanism to which we are responding is designed to encourage novel and high risk studies. The high risk in this project comes from the need to demonstrate post- natal effects in an NHP model that has never before been done and is an indispensible prerequisite for future studies that would not be funded without this initial demonstration. The studies that we propose will rectify lack of relevant NHP data in relation to DP of OFF pancreatic development and IR. NHP studies are expensive and extensive preliminary data cannot be obtained with internal funds. These are high risk NHP studies that will provide the preliminary data for more extensive future R01 applications and thus we hope they are appropriate for the R21 mechanism. In addition performing preliminary studies on some, but not all, animals in the cohort at a younger age than the others will weaken its overall strength as all animals must maintain the same history. Certainly the rationale from rodent and human studies is strong and no one else in the world is in a position to conduct these NHP studies. ENVIRONMENT: We have all the facilities and the required cohorts. INVESTIGATORS have extensive experience with studying unanesthetized NHP using a tether system to study metabolism without anesthetic confounds.
Poor nutrition during development alters pancreatic development in rodents and sheep, predisposing OFF to type 2 diabetes. Identification of early, causative mechanisms in NHP will enable translation to sub-optimal human development and the development of diagnostic, preventative and therapeutic strategies.
| Choi, Jaehyek; Li, Cun; McDonald, Thomas J et al. (2011) Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction. Am J Physiol Regul Integr Comp Physiol 301:R757-62 |
