title: Pancreatic inflammation and increased islet macrophages in insulin-resistant juvenile primates.
abstract: Chronic high caloric intake has contributed to the increased prevalence of pediatric obesity and related morbidities. Most overweight or obese children, however, do not present with frank metabolic disease but rather insulin resistance or subclinical precursors. The innate immune system plays a role in the pathophysiology of type 2 diabetes but how it contributes to early metabolic dysfunction in children on chronic high-fat diet (HFD) is unclear. We hypothesize that such inflammation is present in the pancreas of children and is associated with early insulin resistance. We used nonhuman primate (NHP) juveniles exposed to chronic HFD as a model of early pediatric metabolic disease to demonstrate increased pancreatic inflammatory markers before the onset of significant obesity or glucose dysregulation. Pancreata from 13-month-old Japanese macaques exposed to a HFD from in utero to necropsy were analyzed for expression of cytokines and islet-associated macrophages. Parameters from an intravenous glucose tolerance test were correlated with cytokine expression. Before significant glucose dysregulation, the HFD cohort had a twofold increase in interleukin 6 (IL6), associated with decreased first-phase insulin response and a sexually dimorphic (male) increase in IL1β correlating with increased fasting glucose levels. The number of islet-associated macrophages was also increased. Pancreata from juvenile NHP exposed to HFD have increased inflammatory markers and evidence of innate immune infiltration before the onset of significant obesity or glucose dysregulation. Given the parallel development of metabolic disease between humans and NHPs, these findings have strong relevance to the early metabolic disease driven by a chronic HFD in children.
authors: Pediatrics, Division of Neurosciences, Oregon National Primate Research Center Pape Pediatric Research Institute, Oregon Health and Science University, CDRCP, 707 SW Gaines Street, Portland, Oregon 97239-3098, USA. nicol@ohsu.edu
authors: L E
authors: LE
authors: Nicol
authors: W F
authors: WF
authors: Grant
authors: W R
authors: WR
authors: Grant
authors: S M
authors: SM
authors: Comstock
authors: M L
authors: ML
authors: Nguyen
authors: M S
authors: MS
authors: Smith
authors: K L
authors: KL
authors: Grove
authors: D L
authors: DL
authors: Marks
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D007333:Insulin Resistance / Q000502:physiology*; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology*; D008251:Macaca; D008264:Macrophages / Q000473:pathology*; D008297:Male; D010195:Pancreatitis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D053583:Interleukin-1beta; D015850:Interleukin-6