Cytochemical Analysis of Pancreatic Islet Lipoapoptosis: Hyperlipidemia-Induced Cytoinvolution following Expression of the Diabetes (db/db) Mutation

Abstract

The diabetes (db/db) genotype mutation induces a hyperglycemic-hyperinsulinemic endometabolic state in C57BL/KsJ mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) associated with intrinsic leptin receptor expression defects. The severity of the DOS-induced premature pancreatic dysfunction and cytoatrophic involution has been linked to the severity of hypercytolipidemia which develops in pancreatic islets following systemic lipoidosis. The current studies define the cytochemical changes associated with pancreatic islet and acinar vesicular degranulation (deproteinization), cytoinvolution and B-cell dysfunction relative to the onset of cellular (nuclear DNA fragmentation) apoptosis in 20- to 26-week-old chronic db/db mutants relative to control (+/?) indices. The db/db mutation induced dramatic increases in body weights, blood glucose as well as serum and tissue triglyceride concentrations relative to +/? parameters. In contrast, pancreatic tissue weights and insulin concentrations were significantly decreased in db/db groups in association with premature islet cytoatrophy relative to +/? indices. Concurrent elevations in db/db tissue triglyceride concentrations and islet cytolipid depositions accompanied the progressive pancreatic cytoatrophic alterations. Diminished B-cell vesicular (insulin) granulation was pronounced in atrophic pancreatic islets, which were also characterized by hyperplasic acinar cellular intrusion and subsequent proteolytic B-cell dissolution coincident with 3′-DNA fragmentation-indexed (TUNEL-labeled) nuclear apoptosis. The chronic expression of the db/db mutation exacerbated these pancreatic islet B-cell atrophy indices, characterized by insulin vesicular degranulation, suppressed systemic insulin concentrations, invasive hypercytolipidemia, progressive cellular atrophy and hyperplasic acinar proteolytic dissolution, culminating in islet volume/mass reduction and chronic db/db-related pancreatic involution. The results of these studies indicate that pancreatic islet B-cell apoptosis is coincident with the progressive hypercytolipidemia component of the type II DOS promoted by the db/db genotypic mutation. These data suggest that the severity of progressive pancreatic lipoapoptosis disrupts regulatory cellular metabolic cascades, resulting in nuclear fragmentation, organelle dissolution and the subsequent promotion of a nonhomeostatic cytochemical milieu which ultimately renders islet B-cell populations susceptible to acinar proteolytic dissolution and progressive pancreatic involution.