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A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult Tph1 βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of Htr2b in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell–derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.

Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity, and diabetes remain unclear. Lamin A, lamin C, and progerin, products of the Lmna gene, have antagonistic functions on energy metabolism and life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because β-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to β-cell function in physiopathological conditions. We demonstrate that aged lamin C only–expressing mice (Lmna^LCS/LCS) become obese but remain glucose tolerant due to adaptive mechanisms including increased β-cell mass and insulin secretion. Triggering diabetes in young mice revealed that Lmna^LCS/LCS animals normalize their fasting glycemia by both increasing insulin secretion and regenerating β-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in Lmna^LCS/LCS islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time that the sole expression of lamin C protects from glucose intolerance through a β-cell–adaptive transcriptional program during metabolic stresses, highlighting Lmna gene processing as a new therapeutic target for diabetes treatment.

The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A⁺ NK6 homeobox 1⁺ cells and very few INS⁺ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells.

Henry "Hank" Aaron was born in Alabama three years after Willie Mays, 85 years ago Tuesday. Now, all this time later, Aaron is as much the conscience and the soul of baseball as any man alive. But we don't just celebrate a great baseball life today. We celebrate a great American life.

As the Mets, Nationals and Phillies have made multiple upgrades, Braves GM Alex Anthopoulos has thus far limited his offseason activity to giving Josh Donaldson a record one-year deal and bringing to fruition the desires of Brian McCann and Nick Markakis to play for the Braves.

Reporter Mark Bowman addresses the Braves' offseason as a whole, as well as identifying a Minor League who has a chance at making the club out of Spring Training.

When the Braves open Spring Training next week, their bid to defend their National League East crown will be significantly influenced by whether Josh Donaldson is capable of reestablishing himself as one of baseball's elite superstars.

Fans and analysts spend the entire offseason speculating where the top free agents could go, but sometimes an under-the-radar pickup can end up making a world of difference. As positional competitions begin to heat up at Spring Training camps this month, MLB.com's beat writers were asked to identify one potentially overlooked acquisition for each of the 30 clubs. Here's who they came up with.

Here are the top players in each league who could get the opportunity to show what they can do at the highest level this year, perhaps even contending for Rookie of the Year honors

Those hoping to watch Ronald Acuna Jr. extend last season's incredible post-All-Star break production should remember that his pace would have equated to 45 homers and 33 stolen bases over 162 games.

We're reluctant to finalize our list of offseason winners because, as you may have heard, there are some prominent unsigned free agents. Not just Bryce Harper and Manny Machado, either.

As the Braves open camp, they'll provide a glimpse of how much they have progressed since claiming an unexpected division crown last year. Freddie Freeman, Ronald Acuna Jr. and Ozzie Albies will once again be in a lineup that has been enriched by the addition of Josh Donaldson, the former American League MVP Award winner who thus far arguably ranks as baseball's top free-agent signee.

Freddie Freeman spent the offseason sharing excitement about the possibility that Josh Donaldson would not end up being the Braves' only significant offseason addition.

On this opening week of Spring Training, all 30 Major League teams have one thing in common: optimism. Here's an optimism cheat sheet for each of them.

As Braves manager Brian Snitker evaluates who might serve as his closer, A.J. Minter has made it clear he wants to be the guy who is consistently called upon to handle high-leverage threats that develop in late innings.

While playing close to his Alabama home and enjoying a chance to once again work with Atlanta general manager Alex Anthopoulos, the former American League MVP Award winner Josh Donaldson also understands the importance of rejuvenating his career with his deal.

It could be argued that Ender Inciarte stands as the X-factor in regard to the Braves' bid to defend last year's National League East crown and experience a successful postseason.

Braves manager Brian Snitker joked that he could almost detect a smile as he shared a phone conversation with Nick Markakis after the stoic outfielder re-signed with the club in January. Snitker and others actually saw that smile on Tuesday morning, when Markakis reported to Spring Training to begin his fifth season with the Braves and attempt to push the club past the rebuild he positively enriched through his leadership.

Sean Newcomb entered last June as an All-Star candidate and exited the regular season wondering if he had done enough to earn a spot on Atlanta's postseason roster. The inconsistent nature of his first full Major League season enhances the difficulty of projecting how valuable he might be to the Braves from both an immediate and long-term perspective.

To those of a certain age, Frank Robinson was the definition of greatness, leadership and toughness. Well into his 70's and 80's, he carried himself with the confidence and unmistakable gait of a great athlete.

In outlining their plans to rebuild the Orioles following the least successful season in franchise history, new club officials routinely point to experience: They just did the same thing elsewhere.

Frank Robinson, a trailblazing figure who was Major League Baseball's first African-American manager and one of its greatest players during a career that spanned 21 seasons, died Thursday after a prolonged illness. He was 83.

Fans and analysts spend the entire offseason speculating where the top free agents could go, but sometimes an under-the-radar pickup can end up making a world of difference. As positional competitions begin to heat up at Spring Training camps this month, MLB.com's beat writers were asked to identify one potentially overlooked acquisition for each of the 30 clubs. Here's who they came up with.

Since the Rays debuted "the opener" last May, no fewer than eight teams have helped transform the concept from a fad into a mini-movement. Consider the Orioles a candidate to dive in next.

A year ago, Danny Farquhar was not going to be in the middle of a spring storyline. That's going to change this spring as he tries to win a spot in the Yankees' bullpen

On this opening week of Spring Training, all 30 Major League teams have one thing in common: optimism. Here's an optimism cheat sheet for each of them.

Steve Wilkerson enters Orioles camp competing for a super-utility role after a brief big league cameo last year. He isn't traveling light, as Wilkerson has 10 gloves on display.

Like so many pitchers in Major League camps, Orioles hurlers have extra sets of eyes on them this spring. The Edgertronic cameras, perched on tripods, are set about a stride's length beyond the backfield bullpen mounds at the club's Ed Smith Stadium complex, as conspicuous as the coaches standing cross-armed behind them.

Orioles right-hander Hunter Harvey had hopped off a backfield mound at the club's Spring Training complex and exhaled. He was one of 14 pitchers scheduled to face hitters as part of the club's first full-squad workout on Monday, and now that he had, Harvey was asked to recall when was the last time he threw competitive pitches.

The Orioles will honor late icon Frank Robinson during Grapefruit League play and will continue to do so throughout the season, with a patch on the sleeves of their uniforms. The patch features Robinson's No. 20 in orange against a black background.

The whitening and loss of brown adipose tissue (BAT) during obesity and aging promote metabolic disorders and related diseases. The imbalance of Ca²⁺ homeostasis accounts for the dysfunction and clearance of mitochondria during BAT whitening. Capsaicin, a dietary factor activating TRPV1, can inhibit obesity induced by high-fat diet (HFD), but whether capsaicin inhibits BAT loss and the underlying mechanism remain unclear. In this study, we determined that the inhibitory effects of capsaicin on HFD-induced obesity and BAT whitening were dependent on the participation of SIRT3, a critical mitochondrial deacetylase. SIRT3 also mediated all of the beneficial effects of capsaicin on alleviating reactive oxygen species generation, elevating mitochondrial activity, and restricting mitochondrial calcium overload induced by HFD. Mechanistically, SIRT3 inhibits mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium overload by reducing the H3K27ac level on the MCU promoter in an AMPK-dependent manner. In addition, HFD also inhibits AMPK activity to reduce SIRT3 expression, which could be reversed by capsaicin. Capsaicin intervention also inhibited aging-induced BAT whitening through this mechanism. In conclusion, this study emphasizes a critical role of the AMPK/SIRT3 pathway in the maintenance of BAT morphology and function and suggests that intervention in this pathway may be an effective target for preventing obesity- or age-related metabolic diseases.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcr^m–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr^m–/m– mice than in control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m–/m– and Hmgcr^fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Fans and analysts spend the entire offseason speculating where the top free agents could go, but sometimes an under-the-radar pickup can end up making a world of difference. As positional competitions begin to heat up at Spring Training camps this month, MLB.com's beat writers were asked to identify one potentially overlooked acquisition for each of the 30 clubs. Here's who they came up with.

All-Star right-hander Gerrit Cole won his arbitration case against the Astros on Wednesday, meaning he will make $13.5 million this season. The team offerred $11.425 million, a difference of $2,075,000.

The Astros logo outside the Ballpark of the Palm Beaches really is something to see, all the way from Haverhill Rd. The closer you get the bigger it gets, the white "H" right there in front of the huge orange star. Underneath the "H" is the following message, white against orange: "2017 World Champions." It would have been a simple matter to put "2018" down there, too. There was room.

Spring Training is underway. Players around the league are stepping back onto the baseball field as they get ready for the 2019 season. MLB.com's beat reporters have you covered with the action from every team's training camp. Keep track of the latest highlights of Spring Training right here.

We're reluctant to finalize our list of offseason winners because, as you may have heard, there are some prominent unsigned free agents. Not just Bryce Harper and Manny Machado, either.

The 2019 MLB season feels so close now. Spring Training has begun. Players are taking the field. So it's time to rank the best of the best.

With Dallas Keuchel and Charlie Morton leaving in free agency and Lance McCullers Jr. on the mend following Tommy John surgery, Collin McHugh is returning to his roots this year and is back in the Houston rotation. He said his experience as a reliever will only help him evolve as a starter.

All eyes were on right-hander Forrest Whitley, MLB Pipeline's top pitching prospect, when he threw in the bullpen for the first time Friday in Major League camp. Astros manager AJ Hinch, assistant general manager Brandon Taubman and director of player development Pete Putila were all watching intently as Whitley threw 21 pitches -- fastballs, changeups and cutters.

Gerrit Cole and Justin Verlander are not fans of the "opener" and explained why it's not a long-term option.

On this opening week of Spring Training, all 30 Major League teams have one thing in common: optimism. Here's an optimism cheat sheet for each of them.

The question would come shortly after Cy Sneed would write his name on the chalkboard. A young hand would rise into the air, and Sneed would brace himself for the chuckles that were sure to soon fill the classroom. "Are you a lumberjack?"

Astros outfielder Josh Reddick vows to start hitting to the opposite field more this year, which is something he did well in 2017, but not '18. Reddick hit .242 with 17 homers and 47 RBIs last year after hitting .314 with 13 homers and 82 RBIs to help the Astros to the World Series title in '17.

They wrestled with the decision to start a family for five years. It's something most young couples discuss at some point. Timing is important, and considering their busy lives, even more so for Astros pitcher Joe Smith and his wife, TV sports reporter Allie LaForce. The issue facing the couple is far more momentous than most others have to deal with -- one that's a matter of life and death.

UNITED NATIONS (AP) — The United Nation’s leader said Wednesday the world’s one billion people living with disabilities are among the hardest hit by the coronavirus and called for them to have equal access to prevention and...

HARRISBURG, Pennsylvania (AP) — A Pennsylvania inmate whose dreadlocks violated a jail’s haircut policy has been released from solitary confinement after more than a year, although his federal lawsuit is still pending. A federal...