Loss of postprandial insulin clearance control by Insulin-degrading enzyme drives dysmetabolism traits.

Systemic insulin availability is determined by a balance between beta-cell secretion capacity and insulin clearance (IC). Insulin-degrading enzyme (IDE) is involved in the intracellular mechanisms underlying IC. The liver is a major player in IC control yet the role of hepatic IDE in glucose and lipid homeostasis remains unexplored. We hypothesized that IDE governs postprandial IC and hepatic IDE dysfunction amplifies dysmetabolic responses and prediabetes traits such as hepatic steatosis. In a European/Portuguese population-based cohort, IDE SNPs were strongly associated with postprandial IC in normoglycemic men but to a considerably lesser extent in women or in subjects with prediabetes. Liver-specific knockout-mice (LS-IDE KO) under normal chow diet (NCD), showed reduced postprandial IC with glucose intolerance and under high fat diet (HFD) were more susceptible to hepatic steatosis than control mice. This suggests that regulation of IC by IDE contributes to liver metabolic resilience. In agreement, LS-IDE KO hepatocytes revealed reduction of Glut2 expression levels with consequent impairment of glucose uptake and upregulation of CD36, a major hepatic free fatty acid transporter. Together these findings provide strong evidence that dysfunctional IC due to abnormal IDE regulation directly impairs postprandial hepatic glucose disposal and increases susceptibility to dysmetabolic conditions in the setting of Western diet/lifestyle.

Insulin: Trigger and Target of Renal Functions.

Kidney function in metabolism is often underestimated. Although the word "clearance" is associated to "degradation", at nephron level, proper balance between what is truly degraded and what is redirected to de novo utilization is crucial for the maintenance of electrolytic and acid-basic balance and energy conservation. Insulin is probably one of the best examples of how diverse and heterogeneous kidney response can be. Kidney has a primary role in the degradation of insulin released in the bloodstream, but it is also incredibly susceptible to insulin action throughout the nephron. Fluctuations in insulin levels during fast and fed state add another layer of complexity in the understanding of kidney fine-tuning. This review aims at revisiting renal insulin actions and clearance and to address the association of kidney dysmetabolism with hyperinsulinemia and insulin resistance, both highly prevalent phenomena in modern society.

Data on metabolic profile of insulin-degrading enzyme knockout mice.

Insulin-degrading enzyme (IDE) degrades and inactivates bioactive peptides such as insulin. As insulin is a master regulator of glucose homeostasis, lack of IDE is expected to have a profound impact on both insulin and glucose levels. This article shares data on glucose and insulin homeostasis of control, heterozygous and knockout mice for Ide after 18 weeks of a normal chow diet. This data article is related to a research article entitled "Knockout of insulin-degrading enzyme leads to mice testicular morphological changes and impaired sperm quality" (Meneses et al., 2019).

Knockout of insulin-degrading enzyme leads to mice testicular morphological changes and impaired sperm quality.

Insulin-degrading enzyme (IDE) is a zinc metalloprotease responsible for degrading and inactivating several bioactive peptides, including insulin. Individuals without this enzyme or with a loss-of-function mutation in the gene that codifies it, present hyperinsulinemia. In addition, impairment of IDE-mediated insulin clearance is associated with the development of metabolic diseases, namely prediabetes. Although insulin regulates male fertility, the role of IDE on male reproductive function remains unknown. We proposed to study the influence of IDE in the reproductive potential of males. As insulin mediates key events for the normal occurrence of spermatogenesis, we hypothesized that IDE functioning might be linked with sperm quality. We used C57BL/6N mice that were divided in three groups according to its genotype: wild type (WT), heterozygous and knockout (KO) male mice for Ide. Spermatozoa were collected from the cauda of epididymis and sperm parameters were evaluated. Testicular tissue morphology was assessed through hematoxylin and eosin stain. Mitochondrial complex protein levels and lipid peroxidation were also evaluated in the testicular tissue. Our results show that KO mice present a 50% decrease in testes weight compared to WT mice as well as a decrease in seminiferous tubules diameter. Moreover, KO mice present impaired sperm quality, namely a decrease in both sperm viability and morphology. These results provide evidence that IDE plays an important role in determining the reproductive potential of males.

Differential expression of miRNAs related to angiogenesis and adipogenesis in subcutaneous fat of obese and nonobese women.

To disclose the mechanisms surrounding obesity, we selected microRNAs (miRNAs) that target genes involved in adipogenesis, angiogenesis, and inflammation and compared their expression levels in the subcutaneous adipose tissue of 40 obese and nonobese women. Mature miRNAs were extracted from subcutaneous adipose tissue samples that were collected during surgery and quantified by real-time polymerase chain reaction. miR-16 was overexpressed in the nonobese group (n-expression ratio = - 151.1; P < 0.001). Furthermore, the expression levels of two other miRNAs were significantly correlated with waist circumference in nonobese women (miR-27b, r = 0.453; P = 0.027 and miR-424-5p, r = 0.502, P = 0.014). Central and total subcutaneous adipose tissue thicknesses were correlated with miR-424-5p levels (r = 0.506, P = 0.034 and r = 0.475, P = 0.046, respectively) in the nonobese group. In the obese group, miR-424-5p expression was correlated with body mass index (r = 0.582, P = 0.018). miR-16 and miR-424 have shown correlations with body-fat-mass-related parameters. Because these miRNAs have vascular endothelial growth factor (VEGF) and its receptors as target genes, they may be involved in the alterations of angiogenesis observed in obesity. In addition, higher levels of miR-27 and miR-424 were correlated with higher fat depot measurements in nonobese women. These results highlight the importance of miRNA expression in subcutaneous adipose tissue and encourage further investigation of miRNAs as prognostic markers.