Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Abstract

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

The Effect of Taurine Supplementation on Glucose Homeostasis: The Role of Insulin-Degrading Enzyme

“…On the other hand, female obese mice fed a cafeteria diet exhibited insulin hypersecretion and a decrease in IDE expression in the liver and muscle, which may explain the observed glucose intolerance and the decrease in insulin sensitivity (Brandimarti et al 2013 ). In the present study, we observed that Tau supplementation increased hepatic IDE expression in mice with normal metabolism, indicating that supplementation with this amino acid could modulate glucose homeostasis, even without any previous metabolic disruption.…”

“…Based on our results, it is premature to conclude that increased IDE expression in the liver contributes to improvement in glucose tolerance, and the role of IDE itself in the development and progression of type 2 diabetes is still controversial (Rezende et al 2012 ;Brandimarti et al 2013 ;Matveyenko et al 2008 ;Erdmann et al 2008 ;Goodarzi et al 2011 ;Tamaki et al 2013 ;Lorenzo et al 2013 ). Nevertheless, IDE is certainly a key metabolic enzyme with an important role in the control of glucose homeostasis, and it is affected by Tau supplementation.…”

Interleukin-6 increases the expression and activity of insulin-degrading enzyme

“…Interestingly, IDE knockout (KO) mice display chronic hyperinsulinemia21 that, over time, induces a reduction of insulin receptor expression, leading to insulin resistance22. Also, downregulation of IDE, associated with hyperinsulinemia, is observed in obese and diabetic patients2324, and rodents1325. Therefore, we believe that finding molecules which are able to increase IDE function could be important for the development of new therapeutic strategies against diseases related to hyperinsulinemia, such as obesity and T2DM.…”

Brain pericyte-derived soluble factors enhance insulin sensitivity in GT1-7 hypothalamic neurons

“…Alternatively, these findings raise the possibility that PCM inhibits insulin clearance via insulin-degrading enzyme and/or IRb dephosphorylation by protein tyrosine phosphatase (PTP) 1B. Elevated levels of insulin-degrading enzyme and PTP1B are responsible for hypothalamic neuronal insulin resistance in obese rodents [29,30]. We cannot exclude the possibility that PCM has a direct effect on PI3K and phosphatidylinositol (3,4,5)-trisphosphate downstream of IRS.…”