Although insulin may be perceived as the most important hormone when it comes to diabetes, glucagon is also essential to maintaining proper glucose homeostasis. Glucagon functions to increase blood glucose levels in a fasted state, by inducing breakdown of glycogen stores and gluconeogenesis, or the synthesis of new glucose molecules in the liver. This pathway describes the mechanisms by which intermittent fasting plays a role in glucagon signaling.
Cyclic AMP response element-binding protein (CREB) is a nuclear transcription factor that mediates hormone activity in response to several types of physiological stress [7]. It has an important role in the glucagon signaling pathway, in which it acts as a secondary messenger that becomes phosphorylated (shown in Figure 1). As mentioned above, glucagon is a pancreatic peptide hormone that works in opposition to insulin action to promote glycogen breakdown during periods of starvation or fasting.
During times of fasting, glucagon binds to a G-coupled protein receptor to activate protein kinase A (PKA), which in turn, phosphorylates CREB at its Serine 133 residue [9]. A simplified diagram of this phosphorylation cascade is shown in Figure 2. By phosphorylating a series of secondary messengers, including CREB, glucagon inactivates glycogen synthase to inhibit glucose molecules from being polymerized. Thus, glucagon induces both glycogenolysis and gluconeogenesis in the liver to release glucose into the bloodstream.
Evidently, the phosphorylation of CREB plays a key role in blood glucose concentration, due to glucagon signaling. CREB phosphorylation is also mediated by the suprachiasmatic nuclei (SCN) of the hypothalamus, the main regulator of the circadian rhythms for mammals. Exposure to light leads to SCN-induced CREB phosphorylation on its Ser133 site [10], which would further promote catabolic glucose metabolism during the daytime.
In patients with type II diabetes, this circadian metabolism is impaired due to a history of an ad libitum, or unrestricted, diet. They exhibit over-phosphorylation of CREB in both the fasting and the fed-state, which causes their cells to continually undergo gluconeogenesis and return glucose into the blood [11]. If these two processes are constantly occurring, blood glucose levels will increase and remain high – despite being in a fasted or fed state.
Intermittent fasting helps regulate the phosphorylation of CREB, thus aiding in blood glucose regulation in patients with type II diabetes. The regulation of this enzyme is essential to maintaining our internal clock through regulating circadian rhythm genes. In short, circadian rhythm genes are responsible for regulating our alertness and sleepiness cycles for the correct times of the day. Time-restricted feeding patterns regulate the transcription of these genes through CREB phosphorylation, and have proven to cause increased sensitivity in phosphorylation when compared to an ad libitum diet [11]. To compare, there is a much greater increase in phosphorylation when entering a period of fasting after eating. Thus, the switch from a fed to a fasted state greatly improves the sensitivity of CREB phosphorylation. Without introducing a fasted state through intermittent fasting, this pathway is desensitized from a constant intake of food, interrupting our bodies’ circadian rhythm.
In the end, intermittent fasting has the potential to restore and help regulate proper glucose metabolism through modulating the internal clock (Figure 3).
In simple terms, this regimen allows your body to sync glucose metabolism to its natural circadian rhythm, through establishing both feeding and fasting periods that correspond to specific times of the day.
This page is excellent too, tons of great information that I didn’t know before. In that final paragraph, I might make it into a tiny summary of what is above, beyond just the mention of internal clock modulation. You have a ton of great information here, and I feel like a small summary of the more complex CREB pathway jargon in a paragraph or two at the end for a less biochemically experienced reader would be great. Good work!
I also don’t have great eyes and have a bit of trouble reading what is in the top orange circle of Figure 1, potentially making the font size a little bigger would be great. Again, super minor detail and this page is awesome.
Hey Ryan! Thank you so much for your kind feedback. I added a sentence at the very end that (hopefully) summarizes things briefly and clearly without any complicated biochem words. Also, I changed figure 1 a bit so the orange circles (glucagon) are a bit easier to read. Hope this helps! 🙂
This page has a lot of good information concerning CREB’s involvement in high blood glucose levels and how targeting this protein could serve as a therapeutic approach in treating Type II diabetes. The diagram concerning the enzymatic cascade of Glucagon receptor binding was also extremely well done, with very clean elements that the reader can easily follow. However, there are areas where further explanation or clarification would be beneficial. The abrupt transition to discussing Glucagon feels a little disorientating provided the previous pages (Question and Background) focuses on Insulin. Maybe providing a little transition could be useful! Additionally, I think there is a need for more clarification on circadian rhythm genes. While the page mentions their role in metabolism, I think a concise explanation of what circadian rhythm genes are and what proteins they express is much needed. However, overall, great work!
Hi Pun! Thank you for your feedback. I added in a little more information on glucagon at the very beginning of the page to introduce the pathway with a bit more context. Additionally, I simplified “circadian rhythm genes” by giving a short explanation on what they do, but didn’t want to make it too complicated for readers.
This was a great chemical pathway explanation overall, I really loved the creative and colorful diagrams to illustrate some complex information! You mention that PKA phosphorylates CREB at its serine 133 residue twice in the paragraph before and after Figure 1. It reads a little repetitive, and I’m still a bit confused about why CREB specifically utilizes the serine 133 residue in its binding site. I know you mention the mechanism of serine 133 in your mechanisms page, so perhaps you can say something like “A more detailed explanation of the advantage of using serine 133 can be accessed here” with the “here” being hyperlinked to the first mechanism.
Really interesting. I had no idea that circadian rhythm was related to type II diabetes. I really like the cartoon-like figure; it is very easy to follow. I liked how detailed the page is, including which residue got phosphorylated, while at the same time explaining simply what is occurring. The figure at the bottom of the page summarizes nicely. Although, maybe some more background on circadian rhythm should be included.
I like the very detailed description of how glucagon acts followed by a comprehensive figure. The transition from how CREB functions under normal conditions to how it is impacted by type II diabetes was well done. I also found the evidence and explanation compelling. While glucagon regulation is introduced in the answer page, I believe that page would benefit from a discussion of glucagon’s role in metabolism. It would make it clear that insulin is not the only factor involved.
Hey Sam, thank you for your comments!! I added a short paragraph at the beginning to introduce glucagon a little more instead of immediately jumping into the pathway. I hope this helps and makes it more clear 🙂