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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.

Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress–activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet–fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.

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.

Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet–induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.

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.

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.

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.

Spring Training is imminent, Opening Day is within sight and the big league season isn't complete for fans without a subscription to MLB.TV. The most comprehensive streaming service in professional sports is now available for the 2019 season.

Here are answers to some of the primary questions you may have as the defending National League East champs prepare to begin Spring Training next week.

The Braves made it clear that, individually, each of their prospects was available in exchange for J.T. Realmuto. But they were not willing to provide the volume of prospects or the MLB-experienced asset sought by the Marlins, who ended an offseason-long saga by dealing the All-Star catcher to the Phillies on Thursday.

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.

Here's a look at 10 stars that you may have forgotten played 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.

At some point over the next six weeks, injuries, improvement or regression will inevitably alter the plan nearly every Major League club brings into Spring Training. The Braves must decide exactly how to round out their rotation and bullpen, but for now it looks like they won't have any position-player battles. Here's the first prediction of how Atlanta's Opening Day roster might look.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

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.

The 30 prospects below all are getting very long looks this spring with an eye toward breaking camp with the parent club. Even if they start the year in the Minors, they all should get the chance to contribute at some point in the very near future.

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.

It didn't come as a surprise to anyone when Dana Brown left the Blue Jays as a special assistant to general manager Ross Atkins to join the Braves as vice president of scouting.

Here is a look at 10 Braves players sure to draw attention during this year's Spring Training.

Brian McCann still laughs about what transpired as he learned the Braves were calling him up to the Majors during the 2005 season. He remembers being summoned to Brian Snitker's room, where he found the then Double-A manager eating pizza while wearing nothing more than his underwear.

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.

When the Braves re-signed Nick Markakis in January, they began leaning toward putting Ender Inciarte in the leadoff spot and moving Ronald Acuna Jr. to the cleanup role. But manager Brian Snitker said Acuna may still get his wish to stay at the top of the lineup.

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.

Who do the Braves have in the pipeline? Get scouting reports, video, stats, projected ETAs and more for Atlanta's Top 30 Prospects on MLBPipeline.com's Prospect Watch.

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.

The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

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.

Having seen what Luiz Gohara had done upon his introduction to the big leagues the previous September, Freddie Freeman told Alex Anthopoulos the big left-hander might immediately became an All-Star. Instead, it became a year of awakening for the young hurler, who remains fueled by last year's disappointments.

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.

The Orioles' restocked farm system might inject some excitement into the club's retooled roster.

Here's an early look at how the Orioles' 25-man roster could shape up on Opening Day.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

The Orioles' crowded outfield mix gained another member on Monday when the team signed veteran Eric Young Jr. to a Minor League contract with an invitation to Spring Training.