Pancreatic α Cells are Resistant to Metabolic Stress-induced Apoptosis in Type 2 Diabetes

• Pancreatic β and α cells show markers of endoplasmic reticulum stress during T2D or metabolic stress.
• Pancreatic β cells, but not α cells, undergo apoptosis secondary to this metabolic stress.
• Resistance of α cells to metabolic stress-induced apoptosis is due to a higher expression of anti-apoptotic Bcl2l1 protein.

Pancreatic α cells are exposed to metabolic stress during the evolution of type 2 diabetes (T2D), but it remains unclear whether this affects their survival. We used electron microscopy to search for markers of apoptosis and endoplasmic reticulum (ER) stress in α and β cells in islets from T2D or non-diabetic individuals. There was a significant increase in apoptotic β cells (from 0.4% in control to 6.0% in T2D), but no α cell apoptosis. We observed, however, similar ER stress in α and β cells from T2D patients. Human islets or fluorescence-activated cell sorting (FACS)-purified rat β and α cells exposed in vitro to the saturated free fatty acid palmitate showed a similar response as the T2D islets, i.e. both cell types showed signs of ER stress but only β cells progressed to apoptosis. Mechanistic experiments indicate that this α cell resistance to palmitate-induced apoptosis is explained, at least in part, by abundant expression of the anti-apoptotic protein Bcl2l1 (also known as Bcl-xL).

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