Reduced insulin sensitivity and increased β/α cell mass is associated with reduced hepatic insulin-degrading enzyme activity in pregnant rats

Abstract

Aims: Pregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic β-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence of whether insulin clearance contributes to this process. Thus, we investigated some of the hepatic parameters related to insulin clearance during rat pregnancy. We also investigated some molecular parameters in the hypothalamus.

Main methods: We evaluated the body mass and food intake, insulin sensitivity, β- and α-cell masses, insulin clearance based on an exogenous insulin load, hepatic insulin-degrading enzyme (IDE) activity, and hepatic and hypothalamic protein content of IDE and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) in three periods of gestation in Wistar rats.

Key findings: In the first week of pregnancy, both insulin sensitivity and clearance increased, a pattern that inverted in the third week of gestation (reduced insulin sensitivity and clearance). Diminished insulin clearance was associated with lower hepatic IDE activity and higher pancreatic β- and α-cell masses. No alteration in the hepatic IDE and CEACAM protein content was observed throughout pregnancy, but hypothalamic IDE protein content was significantly reduced in the late gestation period.

Significance: In conclusion, elevated insulin demand in the late period of gestation occurs not only as a result of increased β-cell mass and function but also by a potential reduction in hepatic insulin clearance. Knowing this physiological process may be valuable when considering gestational diabetes mellitus results from a failure in insulin supply during pregnancy.

Keywords: Blood glucose; CEACAM; Gestation; Glucose homeostasis; Insulin clearance; Pancreatic islet.