Beta-Cell failure is the sine qua non condition for the development and progression of type 2 diabetes. The mechanisms by which Beta-cells fail in type 2 diabetes is not fully clarified. Genome-wide association studies have uncovered several gene variants that are associated with increased risk for diabetes, the majority of the identified genes regulating Beta-cell function, and probably also cell survival. Thus, the capacity of the Beta-cell to respond to the prolonged increased insulin demand created by overnutrition, insulin resistance, and the chronic hyperglycemia of diabetes is very probably under genetic control. Disparity between the demand on the Beta-cell, determined by the chronic nutritional load and the body’s insulin sensitivity, and the capacity of the Beta-cell to increase insulin secretion leads to progressive hyperglycemia. Once hyperglycemia
develops, the Beta-cell is exposed to increased metabolic flux that activates multiple pathways of cellular stress, which in turn further impair Beta-cell function and survival. In type 2 diabetes, hyperglycemia is associated with deregulation of lipid metabolism and elevation of free fatty acids (FFAs), which accentuate the Beta-cell dysfunction, a process called glucolipotoxicity.
Several mechanisms are involved in the induction of metabolic stress by nutrients, including inflammation, oxidative stress, and ER stress. Intricate interactions exist between the various stress pathways, which culminate in impairment of Beta-cell function and survival. In man Beta-cell turnover is slow; however, over the years small but persistent Beta-cell loss may end in decreased Beta-cell mass, an observation verified in most studies of post mortem pancreata from type 2 diabetic patients. Thus hyperglycemia, while itself
the result of Beta-cell dysfunction, is also an important accelerator of Beta-cell malfunction and hence diabetes progression. Indeed a major problem in diabetes treatment is the progressively advancing nature of the disease, which necessitates stepwise increases in the dose and number of therapeutic agents needed to control blood glucose. Over the past decade, important advances have been made in our understanding of the general mechanisms that induce and fight against cellular stress. These conceptual and technical acquisitions have begun to be applied to the Beta-cell and its derangement in type 2 diabetes.
In particular, the endoplasmic reticulum (ER) with its stress is emerging as a main player in the delicate balance between well-being and demise of the overworking Beta-cell. This is not astonishing, since the ER is the site of the correct folding and quality control of export proteins, and since insulin represents almost 50% of the protein production in the Beta-cell, it is clear that the ER is under severe strain in situations where insulin production must be augmented over prolonged time periods.
The XIth Servier-IGIS Symposium dealt with this rapidly developing topic of Beta-cell stress, and the present Digest, masterfully prepared by Dr Stéphanie Migrenne, presents a summary of the topics debated at the meeting. I hope that also physicians not well-versed in the biology of ER or oxidative stress will benefit from this Digest; indeed, cellular stress mechanisms are emerging as the mechanisms responsible for most of the chronic diseases that pose the greatest threat to public health in our century. Future treatments will increasingly target the biological processes discussed in this volume—hence the interest also to the clinician. Those readers with greater interest in the field should read the full proceedings of the XIth Servier-IGIS Symposium, to appear as a supplement to the November issue of Diabetes, Obesity and Metabolism.
Enjoy the read!
“The Stressed Beta-Cell”
I- ER and the canonical unfolded protein response (UPR)
II- When UPR leads to cell death
III- Cellular stress in type 2 diabetes
IV- The mitochondria and cellular stress
V- Therapeutic targeting of ER dysfunction