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 IL1b 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. Key Words" nonhuman primate " insulin resistance " increased islet-associated macrophages " high-fat diet

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

“…Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).…”

Relationship between serum secreted frizzled-related protein 4 levels and the first-phase of glucose-stimulated insulin secretion in individuals with different glucose tolerance

“…There are several morphological and therapeutic intervention studies that indicate a chronic, lowgrade inflammatory state in islets of patients with type 2 diabetes characterized by the presence of cytokines, amyloid deposits, fibrosis, immune cells and β-cell apoptosis [12,[29][30][31]. IL-1β, a prototype proinflamThe deficit of first-phase (acute) insulin secretion is the main characteristic in the early stage of T2DM.…”

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

“…The experiments were carried out both in situ (tissue) and in vitro using the primary islet cell cultures derived from these animals. We hypothesize that the obese mutants portray an altered islet milieu akin to other animal models 10,11 and human subjects 10 with obesity and IR. We have also attempted to construct a genegene interactive network to understand the inflammatory response associated with mutant phenotypes.…”