Adaptation of beta cells to fasting at the origin of type 2 diabetes
Upon PKD activation (A), insulin granules generated at the Golgi of pancreatic beta cells are released at the plasma membrane (in yellow in the scheme and in the electron microscopy picture). Upon fasting, PKD1 gets inactivated (B) and insulin granules fuse with lysosomes (in purple) that contain enzymes required for degradation of insulin : in parallel activation of mTOR suppresses autophagy.
Science Feb. 20, 2015
Feb. 20, 2015
Roméo RICCI's team at the IGBMC recently demonstrated that the pancreatic beta cell, responsible for proper insulin secretion, responds in a very distinct way to nutrient withdrawal. The beta cell, in contrast to most other cells, does not digest its own cellular structures (a process known as autophagy) to generate its own nutrients when they are not available from the environment. Instead, autophagy is actively suppressed and replaced through a newly discovered process in beta cells, the specific digestion of freshly made insulin granules. While this cellular process is an important adaptation to fasting, its deregulation may contribute to type 2 diabetes.
This discovery in beta cells may thus open new therapeutic perspectives in the treatment of diabetic patients. This work is published on February 20th 2015 in Science Magazine.
How do cells respond to fasting?
In a period of fasting, the supply of nutrients decreases. To compensate for this deficiency and to maintain cellular functions, mammalian cells usually degrade their own cellular structures that are not absolutely essential for survival, a process called autophagy.
Focusing on pancreatic beta cells, the team of Roméo RICCI (IGBMC) demonstrates for the first time that this specialized secretory cell type does something very distinct in response to fasting. Beta cells suppress autophagy and overcome nutrient deficiency through degradation of newly generated insulin granules.
An optimal strategy of beta cells to adapt to fasting
The researchers also demonstrate that keeping autophagy high in beta cells triggers unwanted insulin secretion upon starvation. High autophagy in beta cells may thus provoke a dramatic reduction in blood glucose levels during fasting, potentially culminating in hypoglycemia and in the most extreme case to loss of consciousness. Specific degradation of insulin granules as opposed to induction of autophagy allows beta cells to generate metabolites and in the same time to eliminate insulin granules to be secreted only in the presence of nutrients.
Starvation-induced granule degradation (SINGD) is caused by deactivation of protein kinase D (PKD). Degradation of insulin granules occurs through direct fusion with lysosomes, structures representing the digestion factory in mammalian cells. This leads to lysosomal activation of another kinase, mTOR, which is responsible for concomitant suppression of autophagy.
Therapeutic implications for diabetic patients
This mechanism is an important evolutionary adaptation of specialized secretory cells to respond to fasting. However, SINGD might be detrimental in diabetes. In fact, diabetes represents a chronic state of fasting even after food intake. The research team thus proposes that SINGD might be very high contributing to suppression of insulin secretion and inhibition of autophagy in beta cells, both representing predominant outcomes contributing to full-blown diabetes.
The results of the team of Roméo Ricci thus offer very interesting therapeutic perspectives in diabetes.