Welcome to my “Diabetes Series”! Just like my “Cancer Basics” series I’ll be updating this every so often in order to hopefully make the research a little more palatable for the general public. I hope you like it and you continue to tune in!
Scientists from the Salk Institute have unlocked another piece of the diabetes puzzle with their discovery of a mechanism that links endoplasmic reticulum (ER) stress and gluconeogenesis. This is an interesting finding because it identifies a pathway that bridges the gap between obesity and diabetes. Obesity has been shown to be a major factor in the development of diabetes but the picture on why this is so has been fuzzy. Now the picture has become more clear with the discovery of a duel molecular sensor involved in both the ER stress response and gluconeogenesis.
There are two factors in play here I’ll briefly describe each of them.
ER stress is a condition that develops due to a number of conditions, many of which are triggered by obesity (increased demand on cellular machinery, excess lipid accumulation, abnormal intracellular energy flux, and nutrient availability being the main players with obesity). When the cell finds itself in ER stress conditions it activates the unfolded protein response pathway (UPR) which shuts down the translation of proteins. Since obesity is a chronic condition ER stress is almost continual meaning the UPR is activated for long periods of time, leading to long-term downregulation of many proteins.
The second player in this story is gluconeogenesis. This big word just means “making sugar” (glucose to be specific) and it occurs in the liver, normally when blood glucose levels are low. This is an important mechanism to keep blood glucose levels at a steady state in “fasting” conditions (when you are between meals). If the body can’t maintain glucose levels at normal levels then there is a good chance that the body will develop insulin resistance, the hallmark of diabetes.
The paper by the Salk researchers published in Nature identified a key player, CRCT2, in both of these pathways and have proposed a mechanism by which this protein acts as a duel sensor in the cell. The team found that CRCT2 is normally found in the cytoplasm of the cell with a phosphate group attached to it. During acute ER stress this phosphate group is lost and the protein enters the nucleus to bind another protein, activating transcription factor alpha 6 (ATF6α). These combined proteins activate genes that are involved in ER quality control in an attempt to rescue the ER from its stressful conditions.
But CRCT2 has another function as well. It can also enter the nucleus and bind to the cAMP response binding element (CREB). When CRCT2 makes this connection the cell begins the process of gluconeogenesis and glucose starts being produced by the liver. This elevates blood glucose levels in order to keep the rest of the cells in the body well fed.
When the research team knocked the level of ATF6α to a low level in the cell the ER stress response activated gluconeogenesis instead of the ER quality control genes. In contrast, when the team induced adenovirus over-expression of ATF6α the CRCT2-CREB interaction was disrupted and CRCT2 couldn’t interact with the promoter regions for gluconeogensis.
Theorizing that ATF6α levels may be lower in obese mice due to ER stress (remember ER stress leads to lower levels of protein production) the researchers tagged ATF6α expression levels to a GTP reporter. They also created a reported to monitor CRCT2-CREB interactions (this interaction starts the production of glucose) and looked at the different expression between lean mice and those who are chronically obese. This nice little picture is what happened.
The left side of the picture resports the level of ATF6α and you can see in obese mice (bottom row) there is very little to none while in the lean mice there is an observable expression of the protein. On the right side of the picture is the CRCT2-CREB activity and you can see that the obese mice produce a lot of this but the lean mice really show none.
This sealed the deal for the interaction with these two pathways. In chronically obese mice there is not enough ATF6α so when the ER stress response brings CRCT2 into the nucleus it’s only dance partner is CREB, which will activate gluconeogenesis. This leads to elevated levels of glucose in the blood, a piece of the “metabolic syndrome” consistently observed in obese people. Chronically elevated blood glucose levels is one of the factors contributing to insulin resistance and eventually diabetes.
This resarch has implications as the team was able to control the levels of ATF6α by trans-genetic techniques which in the future could be a possible target for helping keep obesity turn into full blown diabetes. I hope you enjoyed part I of my diabetes series, stay tuned for part II in which I’ll steer away from the heavy science for just a bit and focus on some social ills which are contributing to a rise in diabetes.
Wang, Y., Vera, L., Fischer, W., & Montminy, M. (2009). The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis Nature DOI: 10.1038/nature08111