Abstract
Environmental pollutants have recently emerged as potential risk factors for metabolic diseases, urging systematic investigation of pollutant effects on metabolic disease processes. To enable risk assessment of these so-called metabolic disruptors the use of stable, robust and well-defined cell based screening systems has recently been encouraged. Since beta-cell (dys)functionality is central in diabetes pathophysiology, the need to develop beta-cell based pollutant screening systems is evident. In this context, the present research evaluated the strengths and weaknesses of the INS-1 832/13 pancreatic beta-cell line as diabetogenic pollutant screening system with a focus on beta-cell function. After optimization of exposure conditions, positive (exendin-4, glibenclamide) and negative (diazoxide) control compounds for acute insulin secretion responses were tested and those with the most profound effects were selected to allow potency estimations and ranking of pollutants. This was followed by a first explorative screening of acute bisphenol A and bis(2-ethylhexyl)phthalate effects. The same approach was applied for chronic exposures, focusing primarily on evaluation of acknowledged chronic stimulators (diazoxide, T0901317, exendin-4) or inhibitors (glibenclamide) of insulin secretion responses to select the most responsive ones for use as control compounds in a chronic pollutant testing framework. Our results showed that INS-1 832/13 cells responded conform previous observations regarding acute effects of control compounds on insulin secretion, while bisphenol A and bis(2-ethylhexyl)phthalate had limited acute effects. Furthermore, chronic exposure to known beta-cell reactive compounds resulted in deviating insulin secretion and insulin content profiles compared to previous reports. In conclusion, this INS-1 subclone appears to lack certain characteristics needed to respond appropriately to acute pollutant exposure or long term exposure to known beta-cell reactive compounds and thus seems to be, in our setting, inadequate as a diabetogenic pollutant screening system.
Highlights
One of the hypotheses recently postulated with regard to the current diabetes pandemic is the ‘‘metabolic disruptor’’ hypothesis, referring to the involvement of environmental pollutants in the development of metabolic diseases [1,2,3,4,5]
To obtain a condition with robust glucose responsiveness and insulin secretion induction, insulin secretion was compared at two different seeding densities and at different time points
We evaluated if the INS-1 832/13 cell line could be used as a beta-cell based system to assess pollutant effects on insulin secretion
Summary
One of the hypotheses recently postulated with regard to the current diabetes pandemic is the ‘‘metabolic disruptor’’ hypothesis, referring to the involvement of environmental pollutants in the development of metabolic diseases [1,2,3,4,5]. Systematic investigation of the metabolic disruptor potency of thousands of pollutants by means of animal testing would be time consuming, very expensive and ethically questionable. Alternative approaches such as first line cell based screening for identification and prioritization of high risk pollutants are highly encouraged [13,14,15,16]. The development and evaluation of physiological relevant in vitro systems to enable metabolic disruptor screening is crucial [17]
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