Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme

Abstract

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE's function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.

Keywords: glucose transporters; insulin receptor; insulin resistance; insulin-degrading enzyme; liver; pancreas.

Figure 1

Cartoon illustrating the primary structure and cleavage products of human insulin. (A) primary structure of insulin showing amino acids that interact with IDE (red color) [63,64,65] and with site 1 (blue color) and site 2 (gold color) of the IR [66,67,68,69]. (B) cleavage products generated by endosomal proteases. At an early time, following insulin endocytosis, endosomal proteases account for major degradation products containing an intact A-chain, and cleavages in the B-chain (green arrows). Purple arrows indicate IDE cleavage sites effected by IDE in vitro [39].

Figure 2

Cartoon illustrating the binding of insulin by IDE. IDE is in an equilibrium between “opened” and “closed” conformational states. In the absence of a substrate (e.g., insulin), IDE is preferentially in the closed conformation. IDE must adopt the open conformation for substrates to enter the internal chamber, whereas the protease must assume the closed conformation for proteolysis to occur. Release of the cleavage products requires a return to the open conformation.

Figure 3

IDE mouse models for the study of insulin proteostasis and insulin sensitivity. In wildtype mice (WT), glucose homeostasis is regulated by insulin secretion out of the pancreas and clearance in the liver. In the fed state, high glucose levels stimulate pancreatic β-cells insulin secretion into portal vein, which is extracted by an insulin receptor-mediated process in hepatic cells. In parallel, insulin promotes glucose utilization and suppresses glucose production in hepatocytes. Pancellular genetic deletion of Ide (IDE-KO mice) causes hyperinsulinemia, hepatic insulin resistance, and glucose intolerance, but isolated islets exhibit reduced insulin secretion. Genetic deletion of Ide in pancreatic β-cells (B-IDE-KO mice) is associated with elevated plasma C-peptide levels, most likely due to constitutive insulin secretion, leading to hepatic insulin resistance, albeit normal glucose tolerance. Genetic deletion of Ide in hepatocytes (L-IDE-KO mice) results in hepatic insulin resistance and glucose intolerance, without altering insulin secretion and clearance. Conversely, IDE overexpression in liver improves hepatic insulin resistance and glucose intolerance, without altering insulin clearance in diet-induced obese mice. Finally, IDE levels are reduced in pancreatic β-cells and the liver of obese patients, which associates with hyperinsulinemia, reduced hepatic insulin clearance, hepatic insulin resistance and glucose intolerance. Each one of the IDE mouse models display hallmarks of the metabolic alterations seen in the setting of obesity. This figure was created using Servier Medical Art (available at https://smart.servier.com/). n.d., not determined.