Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation

Abstract

Aims/hypothesis Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo. Methods We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining. Results Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia. Conclusions/interpretation We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes. Graphical abstract

Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme

“…Closely paralleling the phenotype of constitutive insulin secretion produced by deletion of Ide from β-cells ( 174 ), α-cell specific- Ide deletion resulted in hyperglucagonemia ( 175 ). Two observations could explain, at least in part, this phenotype: (a) high-glucose and insulin levels failed to inhibit glucagon secretion in A-IDE-KO islets, and (b) the α-cell hyperplasia and hypertrophy.…”

“…Unexpectedly, the A-IDE-KO mice showed a-cell hyperplasia (175). Based on published studies, it is plausible to hypothesize that this phenotype might be mediated by an interaction between IDE and the retinoblastoma protein (pRb), a tumor suppressor that inhibits cell-cycle progression at the G 1 /S transition when interacting with E2F transcription factors (216).…”

“…Merino and colleagues developed a mouse model in which Ide was knockout in α-cells (A-IDE-KO) that resulted in metabolic phenotypes consisting of hyperglucagonemia and hyperinsulinemia, but normal glucose tolerance. Importantly, Ide -null α-cells triggers hyperplasia, hypertrophy and impairment in cilia formation ( 175 ). The diversity of phenotypes seen in the A-IDE-KO mouse model indicates that IDE participates directly or indirectly in a number of cellular and physiological processes in α-cells.…”

“…The A-IDE-KO mice also exhibited hyperinsulinemia ( 175 ). This metabolic phenotype could be attributed to an exacerbated paracrine effect wherein excess glucagon release by α-cells stimulates the glucagon receptor on β-cells, leading to the activation of cAMP/PKA/EPAC pathway and thereby stimulating insulin secretion ( 211 – 215 ).…”

“…Genetic depletion of Ide in α-cells (αTC1.9-shRNA-IDE) resulted in cytoskeleton disarrangement and a significant reduction in the number of cilia ( Figure 4A ) ( 175 ). Classically, IDE has been viewed as a protease of insulin and glucagon, but this finding points towards non-proteolytic functions that could be regulating cytoskeleton integrity in pancreatic endocrine cells.…”