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

WNIN/GR-Ob mutant rat is a novel animal model to study metabolic syndrome (obesity, insulin resistance, hyperinsulinemia, impaired glucose tolerance and cardiovascular diseases). We have investigated the islet characteristics of obese mutants at different age groups (1, 6 and 12 months) to assess the islet changes in response to early and chronic metabolic stress. Our data demonstrates altered islet cell morphology and function (hypertrophy, fibrotic lesions, vacuolation, decreased stimulation index, increased TNFα, ROS and TBARS levels) in mutants as compared to controls. Furthermore, network analysis (gene-gene interaction) studied in pancreas demonstrated increased inflammation as a key factor underlying obesity/metabolic syndrome in mutants. These observations pave way to explore this model to understand islet adaptation in response to metabolic syndrome.

Obesity, insulin resistance, and metabolic syndrome: a study in WNIN/Ob rats from a pancreatic perspective.

Alterations in pancreatic milieu to adapt to physiological shifts occurring in conditions of obesity and metabolic syndrome (MS) have been documented, though mechanisms leading to such a state have remained elusive so far. The data presented here tries to look at the gravity of metabolic insult during the early and prolonged phases of obesity/insulin resistance (IR) depicted in WNIN/Ob strain of rats-an obese euglycemic mutant rat model developed indigenously at our institute which is highly vulnerable for a variety of degenerative diseases. The present results in situ show the participation of several confounding factors in the pancreatic milieu that collectively coprecipitates for a state of profound inflammation in the pancreas (among Mutant compared to Lean/Control) which gets worsened with age. These include hypertrophy, macrophage infiltration (CD11b/TNFα/IL6), apoptosis, ß-cell vacuolation, hyperinsulinemia (HI), and stress markers (RL-77/HSP104/TBARS) all of which correlated well with indices for obesity (2-3 fold), IR (1.5-3 fold), and HI (2-3 fold). Further, supportive data was also obtained from in vitro studies using islet cell cultures amongst phenotypes. Taken together, these results advocate that inflammation was the major precipitating factor to cause islet cell dysfunctions (in situ and in vitro) in these Mutant rats compared to their Lean littermates and parental Control.