The discovery of insulin 100 years ago opened a door that would lead to life and hope for millions of people with diabetes. Ever since then, insulin, produced in the pancreas, has been considered the primary means of treating conditions characterized by high blood sugar (glucose), such as diabetes. Now, Salk scientists have discovered a second molecule, produced in fat tissue, that, like insulin, also potently and rapidly regulates blood glucose. Their finding could lead to the development of new therapies for treating diabetes, and also lays the foundation for promising new avenues in metabolism research.
The study, which was published in Cell Metabolism on January 4, 2022, shows that a hormone called FGF1 regulates blood glucose by inhibiting fat breakdown (lipolysis). Like insulin, FGF1 controls blood glucose by inhibiting lipolysis, but the two hormones do so in different ways. Importantly, this difference could enable FGF1 to be used to safely and successfully lower blood glucose in people who suffer from insulin resistance.
“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” says co-senior author and Professor Ronald Evans, holder of the March of Dimes Chair in Molecular and Developmental Biology. “We have identified a new player in regulating fat lipolysis that will help us understand how energy stores are managed in the body.”
When we eat, energy-rich fats and glucose enter the bloodstream. Insulin normally shuttles these nutrients to cells in muscles and fat tissue, where they are either used immediately or stored for later use. In people with insulin resistance, glucose is not efficiently removed from the blood, and higher lipolysis increases the fatty acid levels. These extra fatty acids accelerate glucose production from the liver, compounding the already high glucose levels. Moreover, fatty acids accumulate in organs, exacerbating the insulin resistance — characteristics of diabetes and obesity.
Previously, the lab showed that injecting FGF1 dramatically lowered blood glucose in mice and that chronic FGF1 treatment relieved insulin resistance. But how it worked remained a mystery.
In the current work, the team investigated the mechanisms behind these phenomena and how they were linked. First, they showed that FGF1 suppresses lipolysis, as insulin does. Then they showed that FGF1 regulates the production of glucose in the liver, as insulin does. These similarities led the group to wonder if FGF1 and insulin use the same signaling (communication) pathways to regulate blood glucose.
It was already known that insulin suppresses lipolysis through PDE3B, an enzyme that initiates a signaling pathway, so the team tested a full array of similar enzymes, with PDE3B at the top of their list. They were surprised to find that FGF1 uses a different pathway — PDE4.
“This mechanism is basically a second loop, with all the advantages of a parallel pathway. In insulin resistance, insulin signaling is impaired. However, with a different signaling cascade, if one is not working, the other can. That way you still have the control of lipolysis and blood glucose regulation,” says first author Gencer Sancar, a postdoctoral researcher in the Evans lab.
Finding the PDE4 pathway opens new opportunities for drug discovery and basic research focused on high blood glucose (hyperglycemia) and insulin resistance. The scientists are eager to investigate the possibility of modifying FGF1 to improve PDE4 activity. Another route is targeting multiple points in the signaling pathway before PDE4 is activated.
“The unique ability of FGF1 to induce sustained glucose lowering in insulin-resistant diabetic mice is a promising therapeutic route for diabetic patients. We hope that understanding this pathway will lead to better treatments for diabetic patients,” says co-senior author Michael Downes, a senior staff scientist in the Evans lab. “Now that we’ve got a new pathway, we can figure out its role in energy homeostasis in the body and how to manipulate it.”
Other authors included Sihao Liu, Emanuel Gasser, Jacqueline G. Alvarez, Christopher Moutos, Kyeongkyu Kim, Yuhao Wang, Timothy F. Huddy, Brittany Ross, Yang Dai, David Zepeda, Brett Collins, Emma Tilley, Matthew J. Kolar, Ruth T. Yu, Annette R. Atkins and Alan Saghatelian of Salk; Tim van Zutphen, Theo H. van Dijk and Johan W. Jonker of the University of Groningen, in the Netherlands.
The research was supported by the National Institutes of Health, the Nomis Foundation, the March of Dimes, Deutsche Forschungsgemeinschaft (DFG), Netherlands Organization for Scientific Research, the European Foundation for the Study of Diabetes and the Swiss National Science Foundation.
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Elon Musk Places Twitter Deal On Hold
By John Michael OjoW
World richest man, Elon Musk has announced a temporary suspension of his deal with Twitter.
The billionaire, who had earlier disclosed his intention to acquire the micro-blogging platform at an agreed price of $44 billion, on Friday cited issues of spam and fake accounts as the reason for the temporary suspension.
“Twitter deal temporarily on hold pending details supporting calculation that spam/fake accounts do indeed represent less than 5% of users,” Musk tweeted.
The Tesla CEO, had maintained that one of his objectives would be to remove “spam bots” from Twitter.
Musk, 50, is also expected to serve as a temporary CEO of Twitter for a few months when the deal finally materialises.
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Why I Chose Elon Musk As Twitter’s Buyer – Dorsey
After reaching a deal with Elon Musk on the acquisition of Twitter, the founder of the microblogging app, Jack Dorsey, has given the reason for his decision.
Musk on Monday night reached an agreement to buy Twitter for approximately $44 billion.
The 50-year-old acquired the company at $54.20 a share, the same price named in his initial offer on April 14.
Giving reason for selling Twitter, Dorsey said Elon Musk is the only solution to achieving the purpose of Twitter being run for the public good.
According to him, he trusts Elon’s goal of creating a platform that is “maximally trusted and broadly inclusive”.
READ ALSO: Elon Musk Buys Twitter In $44b Deal
His tweets read, “I love Twitter. Twitter is the closest thing we have to global consciousness. The idea and service is all that matters to me, and I will do whatever it takes to protect both. Twitter as a company has always been my sole issue and my biggest regret. It has been owned by Wall Street and the ad model. Taking it back from Wall Street is the correct first step.
“In principle, I don’t believe anyone should own or run Twitter. It wants to be a public good at a protocol level, not a company. Solving the problem of it being a company, however, Elon is the singular solution I trust. I trust his mission to extend the light of consciousness.
“Elon’s goal of creating a platform that is “maximally trusted and broadly inclusive” is the right one. This is also @paraga’s goal, and why I chose him.
“Thank you both for getting the company out of an impossible situation. This is the right path…I believe it with all my heart.”
Dorsey assured that Twitter would continue to serve the public conversation.
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Elon Musk Buys Twitter In $44b Deal
Elon Musk struck a deal on Monday to buy Twitter for roughly $44 billion, in a victory by the world’s richest man to take over the influential social network frequented by world leaders, celebrities and cultural trendsetters.
Twitter agreed to sell itself to Mr. Musk for $54.20 a share, a 38 percent premium over the company’s share price this month before he revealed he was the firm’s single largest shareholder. It would be the largest deal to take a company private — something Mr. Musk has said he will do with Twitter — in at least two decades, according to data compiled by Dealogic.
“Free speech is the bedrock of a functioning democracy, and Twitter is the digital town square where matters vital to the future of humanity are debated,” Mr. Musk said in a statement announcing the deal. “Twitter has tremendous potential — I look forward to working with the company and the community of users to unlock it.”
The blockbuster agreement caps what had seemed an improbable attempt by the famously mercurial Mr. Musk, 50, to buy the social media company — and immediately raises questions about what he will do with the platform and how his actions will affect online speech globally.
The billionaire, who has more than 83 million followers on Twitter and has romped across the service hurling gibes and memes, has repeatedly said he wants to “transform” the platform by promoting more free speech and giving users more control over what they see on it. By taking the company private, Mr. Musk could work on the service out of sight of the prying eyes of investors, regulators and others.
Yet scrutiny will likely be intense. Twitter is not the biggest social platform — it has more than 217 million daily users, compared with billions for Facebook and Instagram — but it has had an outsized role in shaping narratives around the world. Political leaders have used it as a megaphone, while companies, celebrities and others have employed it for image-making and brand building.
In recent years, Twitter has also become a lightning rod for controversy, as some users spread misinformation and other toxic content on the service. Former President Donald J. Trump frequently turned to Twitter to insult and inflame, before getting barred from the platform after the Jan. 6 riot at the Capitol last year. The company has repeatedly been forced to create policies on the fly to deal with unexpected situations.
In a statement, Bret Taylor, Twitter’s chairman, said the board had “conducted a thoughtful and comprehensive process to assess Elon’s proposal with a deliberate focus on value, certainty, and financing. The proposed transaction will deliver a substantial cash premium, and we believe it is the best path forward for Twitter’s stockholders.”
Mr. Musk himself has had a rocky relationship with online speech. This year, he tried to quash a Twitter account that tracked the movements of his private jet, citing personal and safety reasons. On Monday, he tweeted that he hoped his worst critics would remain on Twitter because “that is what free speech means.”
“Without any conditions for Musk to purchase Twitter, the platform’s community standards and recourse to ban users who violate those standards, Twitter could set a dangerous precedent for other social media companies to follow,” said Bridget Todd, director at UltraViolet, a women’s rights organization. “This is a massively slippery slope.”
Beyond speech issues, Twitter faces questions about its business. For years, the company has struggled to gain new users and to keep people coming back to the service. Its advertising business, which is the main way Twitter makes revenue, has been inconsistent. Twitter has not turned a profit for eight of the last 10 years.
How hands-on Mr. Musk plans to be at Twitter is unclear. Among the unanswered issues are who he might pick to lead the company and how involved he would be in running the service. In addition to running Tesla and SpaceX, Mr. Musk also has other companies, such as Neuralink, which aims to build a computer interface for the human brain, and the Boring Company, which makes tunnels.
Elon Musk has said he doesn’t trust Twitter’s current leadership to make necessary changes to promote free speech on the platform.
Elon Musk can at times be inscrutable, and his politics are elusive, which has made it somewhat difficult to determine exactly what the billionaire would do if he successfully acquired Twitter. But over the past weeks and months, as he neared Monday’s deal with the company, Mr. Musk has given more hints about what he would change about Twitter — in interviews, regulatory filings and, of course, on his personal Twitter account.
READ ALSO: Elon Musk Offers To Buy Twitter For $43b
Here are the main areas Mr. Musk could seek to address:
Free speech and content moderators. Mr. Musk has frequently expressed concern that Twitter’s content moderators go too far and intervene too much on the platform, which he sees as the internet’s “de facto town square.”
In the regulatory filing in which he announced his bid to buy Twitter, he wrote: “I invested in Twitter as I believe in its potential to be the platform for free speech around the globe, and I believe free speech is a societal imperative for a functioning democracy.”
He added that he didn’t trust the company’s current leadership to make the changes he saw as necessary and prioritize his ideas about free speech on the platform. “Since making my investment, I now realize the company will neither thrive nor serve this societal imperative in its current form,” he wrote.
In a tweet on Monday, ahead of the announcement of his agreement with Twitter, Mr. Musk said he hoped even his “worst critics” continued to use the platform “because that is what free speech means.”
The Trump question. Mr. Musk has not commented publicly on how he would handle the former President Donald Trump’s banned Twitter account. But his free speech comments have stoked speculation that Twitter under his ownership might reinstate Mr. Trump, who was barred from the platform last year. After the Jan. 6 riot at the Capitol, Twitter said Mr. Trump had violated its policies by inciting violence among his supporters. Facebook also banned Mr. Trump for the same reason.
The former president, who was known for tweets that criticized opponents and sometimes announced policy changes, is also trying to get his own social media site off the ground. His start-up, Truth Social, has struggled to attract users, and the problem could get worse now that Mr. Musk has suggested changing content moderation rules on Twitter. Mr. Trump said in a recent interview that he probably wouldn’t rejoin Twitter if he could.
The algorithm. At a TED conference this month, he elaborated on his plans to make the company’s algorithm an open-source model, which would allow users to see the code showing how certain posts came up in their timelines.
He said the open-source method would be better than “having tweets sort of be mysteriously promoted and demoted with no insight into what’s going on.”
Mr. Musk has also pointed to the politicization of the platform before, and recently tweeted that any social media platform’s policies “are good if the most extreme 10 percent on left and right are equally unhappy.”
Who uses the platform and how. Before Mr. Musk offered to buy Twitter this month, he expressed concern about the relevance of the platform.
When an account posted a list of the 10 most followed Twitter accounts, including former President Barack Obama and the pop stars Justin Bieber and Katy Perry, Mr. Musk responded and wrote: “Most of these ‘top’ accounts tweet rarely and post very little content. Is Twitter dying?”
More recently, the Tesla chief executive promised in a tweet Thursday that he would “defeat the spam bots or die trying!”
Less moderation could conflict with new European regulations.
The European Union headquarters in Brussels. Under a new law, Twitter and other social media companies with more than 45 million users in the E.U. will be required to conduct annual risk assessments about the spread of harmful content on their platforms.
Elon Musk made a centerpiece of his bid for Twitter the need to restrain what he sees as overly aggressive content moderation policies that limit what people can say on the site. He may face a major challenge fulfilling such a dream in Europe.
On Saturday, European policymakers reached an agreement on landmark new legislation, called the Digital Services Act, which requires social media platforms like Twitter to more aggressively police their services for hate speech, misinformation and illicit content.
Under the new law, Twitter and other social media companies with more than 45 million users in the E.U. will be required to conduct annual risk assessments about the spread of harmful content on their platforms and outline plans to combat the problem. If they are not seen as doing enough, the companies can be fined up to 6 percent of global revenue, or even be banned from the E.U. for repeat offenses.
The shifting laws in Europe illustrate the broader legal challenges Mr. Musk would inherit if he closes a deal to buy Twitter. Rather than having a single unified approach to policing its platform, the company has had to adjust based on the different laws where it operates. In Germany, Twitter removes flagged hate speech, racism and references to Nazism. In countries like Turkey, the company faces pressure to remove content critical of the ruling government. In Russia, the service has been largely blocked.
Tweets about Bill Gates may hint at Musk’s leadership style.
Over the weekend, as negotiations for his takeover of Twitter were approaching their final stages, Elon Musk took a shot at fellow billionaire Bill Gates in a series of high-profile tweets. The messages were a reflection of Mr. Musk’s freewheeling style on the social network, where he has more than 80 million followers, mixing serious messages and more sophomoric material.
Mr. Musk said Mr. Gates had taken a short position in Tesla’s stock, betting that it would fall. Mr. Musk was responding to a tweet that included screenshots of texts he apparently exchanged with Mr. Gates about potential philanthropic projects. Minutes later, he mocked Mr. Gates’s physical appearance in a tweet that got 1.1 million “likes.”
On Sunday, before a pivotal meeting between him and Twitter’s board, Mr. Musk tweeted that he was “moving on” from “making fun of Gates for shorting Tesla while claiming to support climate change action.”
The DealBook newsletter notes that the tweets may be a glimpse at how Twitter would run under Mr. Musk’s ownership. Critics say they were just the latest example of Mr. Musk using the platform, and his enormous following on it, as a bully pulpit, whether directed at billionaires or others.
Mr. Musk has said he wants Twitter to fulfill its “societal imperative” as a platform for free speech. But as DealBook has reported, that raises questions about what will happen to Twitter under his watch, given the tone he is setting and the problems that plagued the network’s previous chief executive, Jack Dorsey, before he embraced a more rules-based approach to content moderation.
Mr. Dorsey had said that he “didn’t fully predict or understand the real-world negative consequences” of a more unfettered service.
The deal could be a threat to Trump’s social media venture.
The launch of Truth Social, former President Donald J. Trump’s social media project, has been marred by outages, long wait lists and underwhelming enthusiasm from users.
Truth Social is slow and clunky. Its audience participation remains low. Two top executives have left. And the merger that could bring $1.3 billion in desperately needed cash to former President Donald J. Trump’s social media project seems far from completion.
And that was before Elon Musk entered the picture, The Times’s Matthew Goldstein, Kenneth P. Vogel and Ryan Mac report.
Mr. Musk’s acquisition of Twitter is the latest challenge for Trump Media & Technology Group’s flagship Truth Social app, which Mr. Trump has positioned as Twitter’s freewheeling conservative counterpart. Truth Social, which is available only for Apple devices, has 1.3 million installs, Sensor Tower, an app insights company, estimated. By comparison, Twitter has more than 200 million active users.
Mr. Musk announced a deal with Twitter Monday morning after announcing that he had lined up $46.5 billion in financing for his takeover bid. In recent weeks, Mr. Musk has said he would loosen the Twitter moderation policies that he has chafed under — and that famously led the service to bar Mr. Trump for inciting violence over the outcome of the 2020 presidential election.
Although Mr. Musk has not said if he would allow Mr. Trump to return to the platform, his ideas for easing Twitter’s rules would further sap the appeal of Mr. Trump’s beleaguered start-up as it faces a regulatory investigation that could decide its future.
Trump Media declined to comment on Mr. Musk’s Twitter bid. Liz Harrington, a spokeswoman for Mr. Trump, pointed to a recent interview with Americano Media in which the former president said he “probably wouldn’t rejoin Twitter if he could.”
How Twitter employees are reacting to the potential Musk deal.
Twitter employees are searching for answers about how Elon Musk’s potential takeover could impact them and the company.
They said they were frustrated because they weren’t hearing much from management about what was going on with the takeover fight and what it meant for them, even as Twitter closed in on a deal with Mr. Musk on Monday. They asked their chief executive, Parag Agrawal. They asked Mr. Musk himself in questions sent on Twitter. Some even went to Charles Schwab, the financial firm that manages their stock options, for clarity about the impact a sale of the company would have on them.
But they were not getting very many answers, even as it became clear that they could soon find themselves reporting to Mr. Musk. This is according to 11 Twitter employees who asked to not be named in interviews with The Times’s Kate Conger because they were not authorized to speak publicly. Some employees vented their frustrations on Twitter on Monday, while others commiserated in private chats.
Employees said they worried that Mr. Musk would undo the years of work they have put into cleaning up the toxic corners of the platform, upend their stock compensation in the process of taking the company private, and disrupt Twitter’s culture with his unpredictable management style and abrupt proclamations.
But Mr. Musk also has fans among Twitter’s rank-and-file, and some employees have welcomed his bid.
. The New York Times
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