Prolonged Exposure of Human β-Cells to High Glucose Increases Their Release of Proinsulin during Acute Stimulation with Glucose or Arginine¹

Abstract

The disproportionate hyperproinsulinemia in type 2 diabetes has been attributed to either a primary beta-cell defect or a secondary dysregulation of beta cells under sustained hyperglycemia. This study examines the effect of a 10- to 13-day exposure to 20 mmol/L glucose on subsequent proinsulin and insulin release by human islets isolated from nondiabetic donors. Compared to control preparations kept at 6 mmol/L glucose, the high glucose cultured beta-cells released more proinsulin and less insulin during perifusion at 5, 10, or 20 mmol/L glucose. The lower amounts of secreted insulin resulted from a marked reduction in cellular insulin content (5-fold lower than in controls). The higher amount of secreted proinsulin is attributed to the sustained state of cellular activation that is known to occur after prolonged exposure to high glucose levels. This activated state of the beta-cell population is also held responsible for its higher secretory responsiveness to 5 mmol/L arginine at a submaximal (5 mmol/L) glucose concentration (8-fold higher proinsulin levels than in the control population). It results, together with the reduction in cellular insulin content, in 7- to 10-fold higher proinsulin over insulin ratios in the medium; at 5 mmol/L glucose, this extracellular ratio is similar to that in the cells. These data add direct support to the view that a disproportionate hyperproinsulinemia can result from a sustained activation of human beta-cells after prolonged exposure to elevated glucose levels.

SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells

“…Under a variety of stress and disease conditions, including overnutrition or genetic predisposition, the protein processing capacity within the beta cell secretory compartment is overwhelmed, leading to the accumulation of inadequately processed proinsulin [ 6 – 9 ]. Importantly, aberrant accumulation of proinsulin relative to insulin is observed in islets from pancreatic tissue from human organ donors with autoantibody positivity, type 1 diabetes, and type 2 diabetes [ 7 , 10 – 12 ].…”

“…Clinically, this defect in protein processing and secretion manifests as an elevated ratio of secreted proinsulin/C-peptide or proinsulin/insulin (PI/I), which can be detected in the serum or plasma prior to the onset of both type 1 and type 2 diabetes, with persistence of this phenotype in established disease [ 13 – 19 ]. We and others have shown the presence of impaired proinsulin processing in ex vivo models of diabetes and metabolic stress [ 6 , 8 , 9 , 20 – 22 ]; however, the molecular pathways responsible for defective proinsulin processing in vivo during the development of diabetes remain poorly understood.…”

SERCA2 regulates proinsulin processing and processing enzyme maturation in the pancreatic β cell

“…Under a variety of stress and disease conditions including overnutrition or genetic predisposition, the protein processing capacity within the β cell secretory compartment is overwhelmed, leading to the accumulation of inadequately processed proinsulin (Bollheimer et al, 1998; Hostens et al, 1999; Roomp et al, 2017; Sims et al, 2019b). Importantly, aberrant accumulation of proinsulin relative to insulin is observed in islets within pancreatic tissue from human organ donors with T1D, T2D, and pre-diabetes (Rodriguez-Calvo et al, 2021; Rodriguez-Calvo et al, 2017; Sempoux et al, 2001; Sims et al ., 2019b).…”

“…Clinically, this defect in protein processing and secretion manifests as an elevated ratio of secreted proinsulin:C-peptide or proinsulin:insulin that can be detected in the serum or plasma prior to the onset of both T1D and T2D, with persistence of this phenotype in established disease (Breuer et al, 2010; Egan et al, 2021; Leete et al, 2020; Pfutzner et al, 2015; Sims et al, 2016; Tong et al, 2020; Watkins et al, 2016). We and others have shown impaired proinsulin processing in ex vivo models of diabetes and metabolic stress (Arunagiri et al, 2019; Bollheimer et al ., 1998; Hostens et al ., 1999; Roomp et al ., 2017; Scheuner et al, 2005; Sims et al, 2019a); however, the molecular pathways responsible for defective proinsulin processing in vivo during the development of diabetes remain poorly understood…”