During the pathogenesis of Diabetes Mellitus, whether it be type 1 or 2 diabetes, islet cell heterogeneity becomes apparent. This is most commonly seen as a marked variability between the insulin content of some ß-cells versus others. Indeed, some ß-cells have such low insulin content that they appear to be empty. As such, in using insulin as a marker to estimate ß-cell numbers (as commonly done), one could be under-estimating the actual numbers of ß-cells presented since ‘empty ß-cells’ would not be accounted for. The concept of ‘empty ß-cells’ in the pancreas of diabetic patients could alter current thinking on ß-cell growth and regeneration. And, of course, if ß-cells are present in significant numbers, then it may become an issue of suitably refilling these cells with insulin rather than replacing/regenerating them.

We are interested in further examining the basis of ß-cell heterogeneity and ‘empty ß-cells’. Is this symptomatic of ß-cell dedifferentiation, a degranulated ‘hard working’ ß-cell and/or a stressed ß-cell approaching its end. We have used the transcription factor MafA as an alternative specific marker of adult pancreatic ß-cells, where a MafA+/Insulin- cell would indicate an ‘empty ß-cell’. But MafA is also susceptible to oxidation under oxidative stress conditions (e.g. hyperglycemia) and thus we are interested in examining other markers of ß-cell specificity to complement this analysis. We are also interested in examining adaptive plasticity of ß-cells and what mechanism guides the expansion of the rough endoplasmic reticulum, Golgi apparatus and trans-Golgi network reflective of upregulated insulin production to meet the increased demand in diabetes. Finally, we suspect that oxidative stress is a prime contributor to ß-cell destruction in the pathogenesis of diabetes and want to examine if an ‘empty ß-cell’ marks susceptibility to such stress and/or ß-cell very close to an apoptotic state.