bluuebunny/crossref_metadata_2025_split huggingface dataset:
1224-P: Exogenous Secretin Decreases Energy Intake and Exerts a Bimodular Effect on Postprandial Brown Adipose Tissue Activation in Man
Authors: HEIMBÜRGER SEBASTIAN M. NGUYEN , BENTZEN MARIA J. , HARTMANN BOLETTE , HOLST JENS J. , CHRISTENSEN MIKKEL B. , KNOP FILIP K. 
Published: June 2021

Secretin was recently shown to constitute a postprandial satiety signal in mice. This effect was proposed to be mediated by secretin-induced activation of brown adipose tissue (BAT) and subsequent hypothalamic registration of body temperature rise. We investigated the effect of a 5-hour infusion of secretin on appetite sensations, food intake, BAT activity and resting energy expenditure (REE) in man. In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males aged (mean ± SD) 25.7 ± 6.1 years with a BMI of 23.4 ± 1.8 kg/m2 underwent 5-hour infusions of secretin (1 pmol/kg/min) and placebo, respectively, on separate days with an interposed 8-week washout period. During the infusions, before and several times after a liquid mixed meal test, we assessed appetite sensations (by visual analogue scales), REE (by indirect calorimetry) and supraclavicular BAT activity (by thermal imaging). Before terminating the infusions, ad libitum food intake (primary outcome) was assessed. Compared to placebo, secretin did not affect appetite sensations, but it decreased ad libitum food intake by [mean±SEM] 173 ± 88 kcal (P = 0.039). Within the first 15 minutes of infusion, secretin decreased supraclavicular temperature by 0.10 ± 0.02°C (P &lt;0.001), but at 75-90 min and 240-255 min it increased supraclavicular temperature by 0.05 ± 0.01 (P &lt;0.001) and 0.01 ± 0.01 (P &lt;0.001), respectively, compared to placebo. Secretin did not affect REE. During secretin and placebo infusions, 4 and 2 reported headache, 4 and 1 experienced nausea, 2 and 0 participants vomited, and 2 and 0 had diarrhea, respectively.
In conclusion, a 5-hour infusion of secretin in healthy males decreased ad libitum food intake and exhibited a biphasic effect of supraclavicular BAT activity.

Disclosure
S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. M. J. Bentzen: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
1228-P: Cardiovascular Risk of Patients with Overweight and Obesity: A Predictive Model
Authors: TURCHIN ALEXANDER , MORRISON FRITHA J. , SHUBINA MARIA , SHINDE SHRADDHA , AHMAD NADIA , KAN HONG 
Published: June 2021

Obesity is the most common chronic disease in the U.S. Patients with obesity have many cardiovascular risk factors, often modifiable. It is important to identify patients with obesity at high risk of atherosclerotic cardiovascular disease (ASCVD) to be able to appropriately direct treatment and resources.
We conducted an observational study of EMR data of 399,360 adults with BMI ≥ 25 kg/m2 and without baseline ASCVD between 2000 and 2019. We first identified a literature-based pool of risk factors for ASCVD onset and conducted variable selection by applying least absolute shrinkage and selection operator (LASSO) penalized Cox regression with ten-fold cross-validation on an 80% training dataset. We estimated a regular Cox model on the training dataset with selected variables and evaluated model performance on the remaining 20% dataset.
Over the mean of 7.4 years of follow-up, 37,424 (11.7%) of study patients developed ASCVD. The predictive model achieved a Harrell’s C-statistic of 0.81. The greatest risk of ASCVD onset was associated with older age (HR 2.16 per 1 SD = 15.4 years; 95% CI 2.13- 2.20), heart failure (HR 1.85; 95% CI 1.74-1.97), valvular heart disease (HR 1.61; 95% CI 1.53-1.68) and stimulant abuse (HR 1.60; 95% CI 1.41-1.81). Female sex was associated with a lower risk of ASCVD (HR 0.64; 95% CI 0.63-0.65). Patient characteristics found in &gt;5% of patients that carried additional risk included history of smoking (39.9% of patients; HR 1.40; 95% CI 1.37-1.43), proteinuria (5.5%; HR 1.33; 95% CI 1.29-1.38) and hypertension (23.6%; HR 1.29; 95% CI 1.26-1.32). Each standard deviation increase in BMI (5.3 kg/m2) was associated with a 1.15-fold (95% CI 1.14-1.16) increase in the risk of ASCVD onset.
It is feasible to use predictive modeling to identify patients with overweight and obesity at high ASCVD risk. This approach could be utilized to guide population management and clinical treatment decisions.

Disclosure
A. Turchin: Consultant; Self; Proteomics International, Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi, Stock/Shareholder; Self; Brio Systems. F. J. Morrison: None. M. Shubina: None. S. Shinde: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company. H. Kan: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Bristol-Myers Squibb Company, GlaxoSmithKline plc.

Funding
Eli Lilly and Company
123-LB: IDG-16177, a Potent, Orally-Bioavailable GPR40 Agonist, Improves Glycemic Control and Glucose-Stimulated Insulin Secretion in Preclinical Studies
Authors: YOON JONGMIN , LEE DON-GIL , KIM JUNG HO , HONG DAHAE , SHIN CHORONG , JANG EUNHYE , KIM JISU , SONG HAENGJIN , LEE SEOLHEE , JUN YEARIN , AN KYUNGMI , HONG CHANG-HEE , KWAK HYUN-JUNG , JE IN-GYU , SONG HYO-JUNG 
Published: June 2021

GPR40/FFAR1 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. GPR40 agonists are known to stimulate insulin secretion and reduce circulating glucose levels in a glucose-dependent manner. Currently, IDG-16177, as a GPR40 agonist, is being developed by ildong Pharma in first-in-human study. IDG-16177 is a high potency and orally available small molecule agonist. IDG-16177 confirmed linear pharmacokinetic properties and is more potent than fasiglifam from in vivo studies. The oral bioavailability of IDG-16177 was 84.3, 75.4, and 71% in mice, rats, and monkeys, showing high oral absolute bioavailability in preclinical species. The Cmax and AUC values of IDG-16177 increased in a dose-proportional manner in a dose range of 0.3 to 10 mg/kg in mice and rats and 0.3 to 3 mg/kg in monkeys. In vivo long-term glucose-lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a multiple dosing study using SD and OLETF rats. In both in vivo tests, IDG-16177 0.3 mg/kg showed similar effective in glucose tolerance fasiglifam 10 mg/kg, respectively. In addition, IDG-16177 had a positive effect on fasting blood glucose, insulin, and glucagon in the long-term administration of OLETF rats. In these study, Cmax,ss of IDG-16177 showed approximately 60 times lower than those of fasiglifam and AUCss of IDG-16177 showed approximately 170 times lower than those of fasiglifam. In another study, the Glucose-stimulated insulin secretion effect of IDG-16177 was assessed in Male SD rat. IDG-16177 1 mg/kg showed similar effective in insulin secretion fasiglifam 10 mg/kg. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes.

Disclosure
J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. H. Song: None. S. Lee: None.
1239-P: Evidence of Altered Alpha- and Beta-Cell Lysosomes prior to Onset of Type 1 Diabetes
Authors: MURALIDHARAN CHARANYA , CROWDER JUSTIN , LINNEMANN AMELIA K. 
Published: June 2021

Autophagic degradation is a dynamic recycling process that contributes to cellular homeostasis and mitigation of cellular stress. While there are multiple forms of -phagic degradation processes, a common endpoint is the final degradation step in the lumen of the acidic lysosomes. Post-mitotic cells, including beta cells, can accumulate tertiary lysosomes called telolysosomes which contain oxidized proteins and lipids that are not completely digested. We recently found that autophagy is impaired in the beta cells of individuals with T1D and also in islets of diabetic NOD mice. We also observed a significant increase in the number of autophagosomes, and telolysosomes in the beta cells of autoantibody positive organ donors when compared to nondiabetic organ donors. We now also find a 1.5-fold increase in the number of telolysosomes in the alpha cells of autoantibody positive donors when compared to nondiabetic organ donors (p=0.03). This was mirrored by our previous observation of globally increased lysosome numbers across the islets of pre-diabetic NOD mice, suggesting that these lysosomes may be dysfunctional. To test this, we performed a lysosomal enzyme activity assay to analyze the lysosomal cysteine protease Cathepsin H (a T1D susceptibility locus). Interestingly, we found that the activity of Cathepsin H was increased by ~2-fold in islets of pre-diabetic NOD mice when compared to NOR controls (p=0.02). Taken together, these data suggest a compensatory hyperactivation of the lysosomal enzyme Cathepsin H in the islets of pre-diabetic NOD mice, potentially as a mechanism to rid the cell of degradation-resistant oxidized proteins and lipids whose accumulation in lysosomes might lead to the presence of telolysosomes.

Disclosure
C. Muralidharan: None. J. Crowder: None. A. K. Linnemann: None.

Funding
Network for Pancreatic Organ Donors with Diabetes (nPOD; RRID:SCR_014641); JDRF (nPOD: 5-SRA-2018-557-Q-R); The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D053)
1243-P: The Chd4 Helicase Regulates Pdx1-Controlled Genes Involved in ß-Cell Function
Authors: DAVIDSON REBECCA K. , CASEY NOLAN , KANOJIA SUKRATI , SPAETH JASON 
Published: June 2021

Diabetes progression is partly characterized by a loss of key transcription factors (TFs) in a subset of failing β-cells. Among these TFs is Pdx1, which coordinates the expression of numerous genes related to β-cell function (MafA, Ins2, Ucn3), mitochondrial function (Tfam), and calcium signaling (Cacna1d, Camkk2, Atp2a2). Pdx1 requires the recruitment of transcriptional coregulators to modulate its activity and has recently been shown to interact with the Chd4 ATPase subunit of the Nucleosome Remodeling and Deacetylase complex. In other cellular contexts, Chd4 is required to maintain cellular identity and mitochondrial function; however, the contribution of Chd4 in controlling Pdx1-target genes in the β-cell has yet to be explored. Here, we confirmed the Pdx1:Chd4 interaction using co-IP in mouse β-cell lines and proximity ligation assay in mouse and human β-cell lines and tissue. We found, by ChIP-Sequencing, that Chd4 binds to 4796 genes in β-cell lines, 4463 of which are also bound by Pdx1, including MafA, Cacna1d, and Atp2a2. Transient siRNA knockdown of Chd4 in the βTC-3 murine insulinoma cell line led to a reduction of MafA at the transcript (41% ± 3, p &lt; 0.05) and protein level, as well as reduced expression of mitochondrial TF Tfam (39% ± 8, p &lt;0.05) and calcium regulators Camkk2 (53% ± 6, p &lt;0.05) and Serca2b (51% ± 13, p &lt;0.05). Furthermore, glucose-stimulated insulin secretion in the INS1 832/13 rat insulinoma cell line was impaired (p = 0.0504) in Chd4 knockdown cells. We next generated a tamoxifen-inducible, β-cell-specific (MIP-CreERT) mouse knockout line of Chd4 and found significant impairment in glucose tolerance in male mice 2 weeks post-tamoxifen. Together, these data indicate Chd4 is required for the expression of numerous Pdx1-controlled genes important for β-cell function and whole-body glucose homeostasis. Future efforts are focused on defining the contributions of Chd4 in regulating gene expression and chromatin accessibility in β-cells using our β-cell-specific Chd4 knockout model.

Disclosure
R. K. Davidson: None. N. Casey: None. S. Kanojia: None. J. Spaeth: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115633)
1247-P: The SND1 Coregulator Controls ß-Cell Function and Identity
Authors: KANOJIA SUKRATI , DAVIDSON REBECCA K. , CASEY NOLAN , SPAETH JASON 
Published: June 2021

Pancreatic β-cells are crucial for glucose-stimulated insulin secretion (GSIS) and whole-body glucose homeostasis. Dysfunctional β-cell mass results in diabetes mellitus (DM), a growing pandemic causing global economic burden. Pancreas-enriched transcription factors (TFs) highly expressed in the β-cell that coordinate expression of genes essential for normal β-cell function, are commonly disrupted in β-cells from diabetic individuals. Therefore, it is of considerable importance to understand how TFs function normally and the mechanisms driving their dysfunction in settings of diabetes. Pdx1, an essential TF involved in β-cell function and identity, recruits transcriptional coregulators to coordinate expression of gene expression programs throughout the β-cell. Here we focus on the Staphylococcal Nuclease and Tudor domain containing protein (SND1) coregulator, which has been shown in other cellular contexts to facilitate transcriptional control through the recruitment of chromatin modifying enzymes. By co-immunoprecipitation and proximity ligation assays, we have found Pdx1 and SND1 interact in rodent and human β-cell lines and tissues. We generated SND1 CRISPR/Cas9 knockout cell lines in the Min6 mouse β-cells (SND1-KO) and performed mRNA-sequencing. Genes linked to insulin secretion, (vitamin D receptor (VDR)), and maintenance of β-cell identity (SIX2) were found to be differentially expressed in SND1-KO cells. Glucose-stimulated insulin secretion (GSIS) in INS1 832/13 rat insulinoma cell lines is trending down following Snd1 knockdown (p = 0.15). Future studies include measuring GSIS under different stimulatory conditions in following knockdown of SND1 in primary mouse and human islets. Moreover, we will define the chromatin occupancy footprint of SND1 and explore if chromatin accessibility is altered in SND1-KO β-cell lines. Lastly, we will explore how interactions between Pdx1 and SND1 are altered in models of diabetes and human donor tissues.

Disclosure
S. Kanojia: None. R. K. Davidson: None. N. Casey: None. J. Spaeth: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115633, P30DK097512)
1248-P: Histone Deacetylase Inhibition Improves Store-Operated Calcium Entry and Glucose-Stimulated Insulin Secretion in Cytokine-Stressed Pancreatic ß-Cells
Authors: LEE CHIH-CHUN , KONO TATSUYOSHI , WEAVER STACI A. , SOHN PAUL , EVANS-MOLINA CARMELLA 
Published: June 2021

Store-operated calcium entry (SOCE) functions to refill endoplasmic reticulum (ER) Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai channels by the ER Ca2+ sensor STIM1. Dysfunctional β cell SOCE has been observed in response to cytokine-mediated stress, whereas select histone deacetylase (HDAC) inhibitors are able to protect against cytokine-mediated β cell death and have been shown to improve glucose homeostasis in diabetic mice. Here, we tested the relationship between HDAC inhibition and SOCE in the pancreatic β cell. To this end, we investigated the effects of the HDAC inhibitor sodium butyrate (NaB) on Ca2+ signaling, insulin secretion, and gene expression in cytokine-treated mouse islets, human islets, and STIM1 knockout (KO) 832/13 INS-1 β cells. In mouse islets treated with IL-1β, IFN-γ and TNF-⍺, NaB increased glucose-induced phase Ca2+ responses and restored Ca2+ oscillations. In IL-1β-treated INS-1 β cells, NaB rescued SOCE and ER Ca2+ store depletion, and increased glucose-stimulated insulin secretion (GSIS), while additionally improving cell viability and reducing apoptosis. Chronic (24hrs) but not acute (8hrs) NaB treatment prevented IL-1β-mediated reduction in the SOCE response, suggesting changes in gene expression may underlie these effects. To test this, RT-qPCR for SOCE molecular components was performed and revealed increased STIM1 expression in cytokine-treated mouse islets and INS-1 cells, while no change was observed in Orai1/2 levels. Consistent with these results, NaB was unable to restore SOCE in IL-1β-treated STIM1 KO INS-1 cells. Lastly, NaB treatment in human islets from donors with type 2 diabetes significantly increased levels of GSIS. Taken together, these data suggest that HDAC inhibition restores insulin secretion under pro-inflammatory conditions through improved SOCE and STIM1 upregulation.

Disclosure
C. Lee: None. T. Kono: None. S. A. Weaver: None. P. Sohn: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.
126-OR: MIR192-5p Is a Novel Regulator of GLP-1R and Insulin Secretion That May Contribute to Risk of Statin-Induced Diabetes
Authors: KUANG YU-LIN , MUNOZ ANTONIO , QIN YUANYUAN , DOSÉ ANDRÉA , NALULA GILBERT , THEUSCH ELIZABETH , SANCHEZ GABRIELA , IRIBARREN CARLOS , KRAUSS RONALD M. , MEDINA MARISA W. 
Published: June 2021

Statins are a commonly prescribed cardiovascular disease drug class that can increase risk of type 2 diabetes (T2D). To investigate molecular mechanisms underlying this effect, we created induced pluripotent stem cells (iPSCs) from normoglycemic patients identified from electronic health records of Kaiser Permanente of Northern California who developed T2D after statin initiation or controls who maintained normal fasting glucose on statin treatment (24 per group). RNAseq analysis of iPSCs incubated with 250nM atorvastatin, 500nM simvastatin or mock buffer for 24h identified MIR194-2HG as one of the transcripts exhibiting the greatest differential change between cases vs. controls. Both statins increased MIR194-2HG in the controls but decreased levels in cases. This long non-coding RNA encompasses two microRNAs: MIR-192 and MIR-194. MIR192-5p is predicted to bind the 3’ UTR of the glucagon like peptide 1 receptor gene (GLP1R), and we found that transfection of a rat insulinoma cell line (INS-1) with a MIR192-5p mimic caused increased Glp1r transcript (1.4-fold) and protein (2.1-fold) levels compared to a scrambled control. Using a luciferase reporter containing human GLP1R 3’ UTR, we observed similar increases in signal; however, this elevation remained even after disruption of the predicted MIR192-5p binding site demonstrating that MIR192-5p upregulates GLP1R through an indirect mechanism. GLP1R augments glucose-stimulated insulin secretion, and we found that the MIR192-5p mimic increased insulin levels in media of glucose-stimulated INS-1 cells (1.4-fold). Reduction in media insulin in INS-1 cells treated with 1 μM simvastatin was rescued by MIR192-5p overexpression, while a MIR192-5p antisense inhibitor abolished this effect. These findings implicate MIR192-5p in statin-induced impairment of glucose stimulated insulin secretion through the regulation of GLP1R, an effect that may contribute to the increased risk of T2D in statin users.

Disclosure
Y. Kuang: None. M. W. Medina: None. A. Munoz: None. Y. Qin: None. A. Dosé: None. G. Nalula: None. E. Theusch: None. G. Sanchez: None. C. Iribarren: None. R. M. Krauss: Advisory Panel; Self; Virta Health Corp.

Funding
National Institutes of Health (P50GM115318)
1261-PUB: Type 2 Diabetes Mellitus Is an Independent Predictor of Hand Grip Strength in Patients with Established Cardiovascular Disease
Authors: LARCHER BARBARA , VONBANK ALEXANDER , MADER ARTHUR , MAECHLER MAXIMILIAN , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2021

Low hand grips strength (HGS), a validated parameter for poor skeletal muscular function, has been shown to be a predictor for mortality and cardiovascular events. Patients with established cardiovascular disease are at an increased risk of death and cardiovascular events, especially those who also have type 2 diabetes (T2DM). Factors predicting HGS in this important population are unclear and are therefore addressed in the present study. We investigated a high-risk cohort of 874 patients with established cardiovascular disease, including 670 patients with angiographically verified coronary artery disease and 204 patients with sonographically verified peripheral artery disease. From our patients, 274 (31.4%) had T2DM according to ADA criteria. In analysis of covariance, the presence of T2DM significantly predicted higher HGS (F 8.8; p=0.003); further predictors of higher HGS were younger age (F=206.8; p&lt;0.001), male sex (F 176.7; p&lt;0.001), and greater body height (F= 77.1; p&lt;0.001). We conclude that the presence of T2DM is a predictor of higher HGS in high-risk patients with established CVD.

Disclosure
B. Larcher: None. C. H. Saely: None. A. Vonbank: None. A. Mader: None. M. Maechler: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
127-OR: In Vivo Genetic Evidence That the Pyruvate Kinase Isoforms PKM1 and PKM2 Differentially Control Beta-Cell Fuel Sensing
Authors: FOSTER HANNAH R. , HO THUONG , POTAPENKO EVGENIY , LEWANDOWSKI SOPHIE L. , SDAO SOPHIA , VANDEUSEN HALENA R. , CARDONE REBECCA L. , KIBBEY RICHARD , MERRINS MATTHEW J. 
Published: June 2021

Pancreatic β-cells couple nutrient metabolism with appropriate insulin secretion. Here, we examined the requirements of pyruvate kinase (PK) isoforms in fuel sensing through the β-cell specific deletion of consititutively active PKM1 and allosterically recruitable PKM2 (PKM1- βKO, PKM2-βKO). β-cell deletion of PEP carboxykinase (PCK2-βKO) was used to block mitochondrial PEP production, leaving glycolytic PEP production intact. In vivo, only the PKM1-βKO mice showed glucose intolerance, and ex vivo insulin secretion was correspondingly reduced. Glucose-dependent Ca2+ oscillations were comparable in PKM1 βKO and PKM2-βKO islets, while the oscillatory frequency and duty cycle in PCK2-βKO islets increased relative to controls, suggesting redundancy in the PK response to glycolytic but not mitochondrial PEP. Using direct single-channel measurements of KATP in intact β-cells, amino acids were sufficient to stimulate KATP closure in control and PKM2-βKO cells, but failed to do so in the PCK2-βKO and PKM1-βKO models. PK activators (PKa) rescued KATP closure in PKM1- but not PCK2-deficient β-cells, arguing that PKM1 and PCK2 mediate membrane depolarization in response to mitochondrial fuels. The dependence of PKM2 on glucose was confirmed by the ability of PKa to rescue KATP closure in excised membrane patches from PKM1-βKO mice. Consistently, calcium influx stimulated by amino acids at low glucose was deficient in islets from PKM1-βKO and PCK2-βKO mice. PKa was sufficient to rescue the calcium defect in the PKM1-βKO islets but did not fully rescue the PCK2-βKO. Our findings provide strong genetic and electrophysiological evidence that the PCK2-PKM1 pathway is uniquely suited to direct the active (secretory) phase of calcium oscillations through direct effects on KATP, when FBP is low and PKM2 is inactive. While more limited in function, PKM2 can be therapeutically targeted, endowing it with the ability to respond to mitochondrial PEP and boost insulin secretion.

Disclosure
H. R. Foster: None. T. Ho: None. E. Potapenko: None. S. L. Lewandowski: None. S. Sdao: None. H. R. Vandeusen: None. R. L. Cardone: None. R. Kibbey: Research Support; Self; Agios, Inc. M. J. Merrins: None.

Funding
Health Resources and Services Administration (T32HP10010); National Institute on Aging (T32AG000213); National Institutes of Health (R01DK113103)