Diabetes: Partners for life
- Lund University, Sweden
Diabetes is a disease that causes the level of glucose in the blood to become too high. In healthy individuals, two hormones – called insulin and glucagon – work together to keep blood glucose levels within strict limits. Insulin is released when the level of glucose becomes too high, and it stimulates the removal of glucose from the blood so that it can be stored in tissues. On the other hand, glucagon is released when the level of glucose becomes too low, and it triggers the release of glucose from the tissues into the bloodstream.
Many diabetic patients are not able to produce insulin and rely on regular insulin injections to prevent their blood glucose from reaching dangerous levels (insulin-dependent diabetes). Although these injections save lives, they are not sufficient to achieve and maintain the levels of blood glucose that are found in healthy individuals. Even patients considered to have well-controlled diabetes suffer from complications that can damage many tissues in the body. The fact that diabetic patients have too little insulin, as well as uncontrolled levels of glucagon, has led to the hypothesis that diabetes is triggered by inappropriate levels of both hormones, not just insulin alone (Unger and Orci, 1975).
Both insulin and glucagon are produced in the pancreas, within structures called the Islets of Langerhans. Destroying the cells that produce insulin – known as β-cells – causes normal mice to develop diabetes. However, several researchers have recently reported that mice lacking the receptor for glucagon do not develop diabetes when their β-cells are destroyed (Conarello et al., 2007; Lee et al., 2011). These data have attracted a lot of attention since they hold the promise of a new way to treat diabetes, but the conclusions are disputed (Steenberg et al., 2016). Now, in eLife, Pedro Herrera from the University of Geneva and co-workers – including Nicolas Damond as first author – report that inhibiting the action of glucagon to treat diabetes only works if a certain number of β-cells are still present (Damond et al., 2016).
Damond et al. – who are based at the University of Geneva, Eli Lilly, Albert Einstein College of Medicine, Columbia University and Vanderbilt University – made use of mice lacking the glucagon receptor and, in separate experiments, antibodies that can block glucagon signaling. Using these two strategies they were able to elegantly show that if virtually all the β-cells were destroyed, blocking the glucagon signal could not prevent diabetes. However, when the majority, but not all, of the β-cells are destroyed, blocking the glucagon signal could prevent the mice from developing diabetes.
These findings naturally raise the question of whether it is possible to treat diabetes by replacing some of the lost β-cells and administering glucagon inhibitors, instead of giving insulin injections. When faced with severe β-cell loss, the α-cells that normally only produce glucagon can convert to producing both insulin and glucagon (Thorel et al., 2010). Earlier studies show that blocking the glucagon signal increases the number of α-cells (Gelling et al., 2003). Here, Damond et al. show that α-cells are still able to convert to produce both hormones when the glucagon signal is blocked, which results in the Islet of Langerhans having a higher absolute number of α-cells that produce both insulin and glucagon.
How do these findings apply to humans? The experiments make it clear that diabetic patients who cannot produce any insulin would not benefit from a blockade of glucagon signaling. Damond et al. also alert us to the fact that a combination of insulin treatment and blockage of glucagon action might be risky. According to experiments in their laboratories, glucagon signaling is vital to reduce the risk of blood glucose levels becoming too low after insulin injections (unpublished data).
On the other hand, if a patient has enough β-cells to be able to properly respond to changes in blood glucose levels, blocking the glucagon signal might be a useful treatment strategy. Many diabetic patients are not dependent on insulin injections because their β-cells are able to produce some insulin, but not enough to meet the demand. Changes in lifestyle and diet are often effective ways to reduce symptoms in these patients, but it is possible that they could also benefit from receiving drugs that block the glucagon signal.
We know that some patients with insulin-dependent diabetes still have some functional β-cells (Ludvigsson and Heding, 1976). It is not yet clear how many β-cells would be needed for glucagon signal blockers to be an effective alternative to insulin treatment. However, recent advances in understanding how to maintain and/or increase insulin production (Carlsson et al., 2015) provide us with confidence that this milestone will eventually be reached. Although it is not clear what the ideal balance of α-cells and β-cells in the Islets of Langerhans is, the work of Damond et al. tells us that optimal control of blood glucose levels requires these cells to be partners for life.
References
-
Lower blood glucose, hyperglucagonemia, and pancreatic cell hyperplasia in glucagon receptor knockout miceProceedings of the National Academy of Sciences of the United States of America 100:1438–1443.https://doi.org/10.1073/pnas.0237106100
Article and author information
Author details
Publication history
Copyright
© 2016, Eliasson et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 812
- views
-
- 109
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Diabetes: Partners for life
eLife 5:e16798.
https://doi.org/10.7554/eLife.16798
Further reading
-
- Biochemistry and Chemical Biology
- Genetics and Genomics
Yerba mate (YM, Ilex paraguariensis) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here, we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes. Comparative analyses revealed that the large YM genome size is partly due to a whole-genome duplication (Ip-α) during the early evolutionary history of Ilex, in addition to the hexaploidization event (γ) shared by core eudicots. Characterization of the genome allowed us to clone the genes encoding methyltransferase enzymes that catalyse multiple reactions required for caffeine production. To our surprise, this species has converged upon a different biochemical pathway compared to that of coffee and tea. In order to gain insight into the structural basis for the convergent enzyme activities, we obtained a crystal structure for the terminal enzyme in the pathway that forms caffeine. The structure reveals that convergent solutions have evolved for substrate positioning because different amino acid residues facilitate a different substrate orientation such that efficient methylation occurs in the independently evolved enzymes in YM and coffee. While our results show phylogenomic constraint limits the genes coopted for convergence of caffeine biosynthesis, the X-ray diffraction data suggest structural constraints are minimal for the convergent evolution of individual reactions.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The SARS-CoV-2 main protease (Mpro or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that Mpro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. Evolutionary analysis shows the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. TRMT1 proteolysis results in reduced tRNA binding and elimination of tRNA methyltransferase activity. We also determined the structure of an Mpro-TRMT1 peptide complex that shows how TRMT1 engages the Mpro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 Mpro that could help guide future antiviral therapeutic development and show how proteolysis of TRMT1 during SARS-CoV-2 infection impairs both TRMT1 tRNA binding and tRNA modification activity to disrupt host translation and potentially impact COVID-19 pathogenesis or phenotypes.
