IDE (Insulin Degrading Enzyme): Insulin & Glucose

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

This was an in vitro study done with human liver cells (HepG2 cell line).  The cells were incubated with either a normal glucose solution (1g/L = 100 mg/dL common units for blood glucose) or a high glucose solution (4.5g/L = 450 mg/dL) and treated with insulin for 24 hours vs. untreated cells.  The activity of insulin degrading enzyme, IDE, was measured.  (For those not familiar with IDE, here's the Wikipedia entry on it)

Here are the results for one insulin concentration studied: (as always you can click to enlarge)

Note:  cytosol = fluid inside the cells

So we see that at normal glucose levels insulin markedly stimulates IDE inside the cells while mildly suppressing it in the membrane.  The total effect is a marked stimulation of IDE by insulin.  This effect is almost nullified by hyperglycemia with an insignificant uptick in cytosolic activity and an uptick in membrane activity for only a small total stimulatory effect.
The observed increase in IDE activity after insulin treatment in human hepatoma cells under normal glucose concentration obviously switches off the action of insulin:  insulin induces an increase in IDE activity which leads to increased insulin degradation and decreased insulin signalling.

Insulin stimulates its own proper degradation and disposal under normal conditions.  
Sustained hyperglycemia (which is what culturing in a medium simulates) blunts it.  In the discussion the authors mention a possible proposed mechanism of interference with insulin binding to IDE, but go on to state that insulin binding was not disrupted therefore this mechanism is not supported by their findings.  Perhaps the need for the insulin at the membrane to assist in glucose transport is the mechanism?  
Under conditions of high glucose, we observed a loss of insulin-induced changes in IDE activity accompanied by an increase in IDE gene expression.

The cells are "trying"?

Next, the researchers tested the in vivo IDE activity by taking biopsies of subQ fat from human subjects (17 healthy male non-diabetics) before and after 4 hours of hyperinsulinemic infusion with euglycemic (normal BG = 4.4 mmol/L ~ 80 mg/dL) or hyperglycemic (high BG = 7.8 mmol/L ~ 140 mg/dL) clamps.  

Here are the results:

The gray = before, the black = after;  (a) glucose, (b) insulin, (c) IDE mRNA; left to right:  saline infusion, insulin + normal glucose,  insulin + high glucose

The effect seems much less pronounced perhaps due to the relatively low glucose levels tested, but is statistically significant nonetheless.  
In the NaCl infusion test, no alterations in IDE expression were observed. However, in EC a trend towards an increase in IDE mRNA levels at the end of the clamp test was observed (increase of 17.1%, p=0.097) and the increase was more pronounced in HC (increase of 45.6%, p=0.091)
I feel compelled to remind everyone that the insulin infusion and the glucose levels were sustained "artificially" for 4 hours  so this is not analogous to normal postprandial responses.

This observation [that in the Hep cells: Under conditions of high glucose, we observed a loss of insulin-induced changes in IDE activity accompanied by an increase in IDE gene] supported by data from a hyperglycaemic–hyperinsulinaemic clamp study, in which there were similar changes in IDE mRNA levels in subcutaneous fat tissue in vivo. It is possible that the deficit in IDE activity at a high glucose concentration may lead to a compensatory increase in IDE expression.
The center graphic seems to support a conclusion that hyperglycemia can sustain hyperinsulinemia.

Our findings suggest that hyperglycaemia itself provokes the known disturbance of IDE activity in type 2 diabetes.
Results of the present study suggest that the increase in IDE activity after insulin treatment and the disturbance of this regulation at a high glucose concentration cannot be explained by observed changes in IDE gene expression.