Abstract
Histomorphological and functional alterations in pancreatic islet composition directly correlate with hyperglycemia severity. Progressive deterioration of metabolic control in subjects suffering from type 2 diabetes is predominantly caused by impaired beta-cell functionality. The glutaredoxin system is supposed to wield protective properties for beta-cells. Therefore, we sought to identify a correlation between the structural changes observed in diabetic pancreatic islets with altered glutaredoxin 5 expression, in order to determine an underlying mechanism of beta-cell impairment. Islets of db/db mice presenting with uncontrolled diabetes were assessed in terms of morphological structure and insulin, glucagon, and glutaredoxin 5 expression. MIN6 cell function and glutaredoxin 5 expression were analyzed after exposure to oleic acid and hypoxia. Islets of diabese mice were marked by typical remodeling and distinct reduction of, and shifts, in localization of glutaredoxin 5-positive cells. These islets featured decreased glutaredoxin 5 as well as insulin and glucagon content. In beta-cell culture, glutaredoxin 5 protein and mRNA expression were decreased by hypoxia and oleic acid but not by leptin treatment. Our study demonstrates that glutaredoxin 5 expression patterns are distinctively altered in islets of rodents presenting with uncontrolled diabesity. In vitro, reduction of islet-cell glutaredoxin 5 expression was mediated by hypoxia and oleic acid. Thus, glutaredoxin 5-deficiency in islets during diabetes may be caused by lipotoxicity and hypoxia.
Highlights
Type 2 diabetes mellitus is hallmarked by deprivation of the microarchitecture of pancreatic islets and progressive loss of beta-cells due to gluco- and lipotoxicity as well as a chronic state of inflammation [1]
The aim of this study was to determine whether; (I) islets of db/db mice presenting with uncontrolled diabetes differ qualitatively and quantitatively from lean, leptin-susceptible wild types in terms of Grx5 expression, (II) changes in islet Grx5 protein pattern correlate with structural alterations and shifts in the cellular composition of the islets of Langerhans, (III) leptin action can be delineated from changes in glutaredoxin expression in vitro, and (IV) hypoxia and lipotoxicity have an effect on beta-cell Grx5 expression
Obese homozygous leptin-resistant db/db mice were utilized for comparison with lean wild-type C57BL/6 animals as the db strain is typically presenting a strong phenotype of diabesity
Summary
Type 2 diabetes mellitus is hallmarked by deprivation of the microarchitecture of pancreatic islets and progressive loss of beta-cells due to gluco- and lipotoxicity as well as a chronic state of inflammation [1]. Lipotoxicity, as mediated by free fatty acids, is a pivotal pathogenetic factor in type 2 diabetes as it induces pronounced insulin resistance [2] concomitant with significant impairment of insulin secretion [3]. Free fatty acids mediate beta-cell death by induction of ER stress [4] and ROS production [5]. The islets of Langerhans broadly express members of the glutaredoxin (Grx) system [8]. These proteins are mainly involved in redox regulation of cellular processes and biogenesis of iron–sulfur proteins.
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