Characterization of signaling pathways associated with pancreatic beta-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice.

The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic beta-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, beta-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic beta-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, beta-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the beta-cell's adaptive flexibility and indicates that therapeutic approaches applied to encourage beta-cell rest are capable of restoring endogenous beta-cell function. However, mechanisms that regulate beta-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying beta-cell adaptive flexibility in db/db beta-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with beta-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking-core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of beta-cell function, providing improved insight into disease pathogenesis of T2D.