bluuebunny/crossref_metadata_2025_split huggingface dataset:
1782-P: Perinatal Hypoxia Lowers the Glucose Threshold for Insulin Secretion Causing Hypoglycemia and Hyperinsulinism
Authors: JULIANA CHRISTINE , DE LEON DIVA 
Published: June 2023

Perinatal stress-induced hyperinsulinism is a common cause of persistent hypoglycemia in at-risk neonates. The hypoxia-inducible factor-1 (HIF-1) pathway regulates cellular adaptation in hypoxic conditions through hypoxia response elements. We hypothesize that perinatal hypoxia leads to activation of the HIF1 pathway causing increased insulin secretion from neonatal β-cells. We examined glucose homeostasis and insulin secretion in NeuroD1-Cre;VhlLoxp/Loxp(VhlbetaKO) and in hypoxic wild type (WT) mouse pups in the first week of life. In VhlbetaKO pups postnatal day 8 (P8), plasma glucose was significantly lower compared to littermate controls (76 vs 129 mg/dL). Plasma insulin (0.54 vs 0.27 ng/mL) and the insulin to glucose ratio were significantly greater in VhlbetaKO pups indicating a failure to suppress insulin secretion. VhlbetaKO islet perifusion showed the lower plasma glucose level was due to a lower threshold (5 mM) for glucose stimulated insulin secretion (GSIS) compared to controls (10 mM). To assess the consequences of perinatal hypoxia, we exposed WT mouse pups to hypoxia (10% O2) between embryonic day 18 and P6. Islets from the hypoxia exposed pups had a lower GSIS threshold (3 mM) compared to islets from normoxic pups (5 mM) at P6. Hypoxic islets also had a lower insulin secretion threshold when stimulated with BCH, a glutamate dehydrogenase activator, or tolbutamide, a KATP channel inhibitor, suggesting that HIF1 pathway activation leads to a decreased stimulus threshold for secretion at or distal to the KATP channel. Patch clamps revealed that β-cells from hypoxic pups were more depolarized than normoxic controls. Our results show that the HIF1 pathway is critical for setting the GSIS threshold and a potential mediator of PSHI. We posit perinatal hypoxia and the HIF1 pathway at the core of β-cell maturational defects leading to increased risk of diabetes in adult life and the long-sought answer to the cause of perinatal stress-induced hyperinsulinism.

Disclosure
C.Juliana: Research Support; Crinetics Pharmaceuticals, Inc., Twist Bioscience, AmideBio. D.De leon: Consultant; Zealand Pharma A/S, Crinetics Pharmaceuticals, Inc., Eiger BioPharmaceuticals, Hanmi Pharm. Co., Ltd., Research Support; Ultragenix, Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Rezolute, Inc.
188-LB: Association between Age at Diagnosis of Type 2 Diabetes and Hospitalization for Heart Failure (HHF)
Authors: KE CALVIN , SHAH BAIJU R. , ECHOUFFO TCHEUGUI JUSTIN 
Published: June 2023

Background: The relation between age at T2D diagnosis and HHF is unclear. We conducted a population-based cohort study to examine the association between age at diagnosis of T2D and incident HHF in Ontario, Canada.
Methods: Using administrative health databases, we identified people with new-onset T2D between April 1, 2005 and March 31, 2015. We matched each person to 3 other people without diabetes according to birth year and sex. We excluded any people with prior HHF. We used Cox proportional hazards models to estimate adjusted hazard ratios (HR) for the association between age at T2D diagnosis and incident HHF (followed up until March 31, 2020).
Results: Among 743,053 individuals with T2D and 2,199,539 matches, 126,241 incident HHF events occurred (median follow-up 8.9 years). T2D was associated with a greater adjusted hazard of HHF at younger ages (e.g., HR at age 30 years: 5.71, 95% CI: 5.46-5.96; Figure: Model 1) than at older ages (e.g., HR at age 60 years: 2.51, 2.46-2.55). Additional adjustment for recognized mediators (hypertension, coronary artery disease, chronic kidney disease) marginally attenuated this relation (Figure: Model 2).
Conclusion: Younger age at T2D diagnosis is independently associated with a disproportionately elevated risk of HHF relative to age-matched individuals without T2D. This relation may be substantially mediated by novel mechanisms that are inadequately understood.

Disclosure
C. Ke: Advisory Panel; Sanofi, Speaker's Bureau; AstraZeneca, Abbott. B. R. Shah: None. J. Echouffo tcheugui: None.

Funding
National Heart, Lung, and Blood Institute (K23HL153774 to J.E.T.); University of Toronto (to B.R.S.)
19-OR: Monitoring Stage 2 to Stage 3 Transition in Type 1 Diabetes Using Continuous Glucose Monitoring (CGM)
Authors: FROHNERT BRIGITTE I. , SEPULVEDA FLOR , STOUGHTON JESSICA E. , STECK ANDREA , SIMMONS KIMBER M. 
Published: June 2023

Introduction: CGM can be used to monitor evolution of dysglycemia in presymptomatic, stage 2 type 1 diabetes (T1D) and to target early initiation of insulin upon reaching stage 3 T1D.
Methods: Participants (N=31) with dysglycemia by A1c, OGTT, CGM and/or home glucose testing (HGT) measures (Table 1) were randomized 2:1 into 6 months unblinded CGM-guided education intervention vs blinded CGM and monitoring only. Surveys included PHQ8, PedsQLFamilyImpact, Tolerance of Uncertainty and Diabetes Knowledge (30 point scale).
Results: Intervention and control group were similar in baseline characteristics (Table), except younger age and significantly higher 2-hour OGTT glucose level in the intervention group. Diabetes knowledge was not significantly different between intervention and control at baseline (22±6 vs 20±7, p=0.61) or 3-month follow-up (23±6 vs 20±4, p=0.28). There were no differences between groups for PHQ8, PedsQLFamilyImpact or Tolerance of Uncertainty at baseline or follow-up to date. Of those diagnosed with stage 3 T1D, CGM average sensor glucose and time &gt;140 mg/dL were higher than at study entry. All participants met ADA stage 3 diagnostic criteria; however, none had A1c≥6.5%.
Conclusion: CGM facilitates early recognition of stage 3 T1D before elevation in HbA1c and metabolic decompensation. Unblinded CGM does not appear to negatively impact quality of life.

Disclosure
B.I.Frohnert: Advisory Panel; Provention Bio, Inc. F.Sepulveda: None. J.E.Stoughton: None. A.Steck: None. K.M.Simmons: Advisory Panel; Provention Bio, Inc., Consultant; Dexcom, Inc., Provention Bio, Inc., Research Support; Novartis.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (G-1911-03463)
190-OR: Lrtm1, a Novel Regulator of Insulin Signaling and Metabolism
Authors: WANG GUOXIAO , YU YINGYING , CHEN WENQIANG , CAI WEIKANG , LIU XIANGYU , RONALD KAHN C. 
Published: June 2023

Patients with obesity and metabolic syndrome, as well as individuals with pre-type 2 diabetes, exhibit hyperinsulinemia prior to development of hyperglycemia due to underlying skeletal muscle insulin resistance. To mimic the effect of chronic hyperstimulation of the insulin receptor (IR), we overexpressed the IR specifically in skeletal muscle (IRMOE). This led to skeletal muscle post-receptor desensitization, with increased IR and IRS-1(Tyr) phosphorylation but decreased phosphorylation of Akt Ser473 and Thr308. To identify the regulators involved in this post-receptor insulin resistance, we performed RNA sequencing of IRMOE muscle. Among the most upregulated genes was Lrtm1, a poorly characterized leucine rich repeat transmembrane molecule while highly expressed in the heart and skeletal muscle. Overexpression of Lrtm1 in C2C12 myoblasts led to increased phosphorylation of early insulin signaling molecules (the insulin receptor, IRS-1, and Shc), but reduced phosphorylation of the downstream molecules Akt (at both Ser473 and Thr308) and Erk Thr202/204 following insulin stimulation. Mice with knockout of Lrtm1 (Lrtm1KO) showed significant increases in percent lean mass and decreases in percent fat mass, as well as a slight reduction in overall body weight. In addition, Lrtm1KO mice were more active than controls in both metabolic cages and an open field behavioral tests. Lrtm1KO mice also exhibited improved glucose tolerance and insulin sensitivity, especially in males, even on normal chow diet. Most importantly, Lrtm1KO mice were protected from high fat diet induced obesity and metabolic syndrome, with the knockouts showing 18% less body weight gain, 30% lower fat mass, significantly improved glucose tolerance and improved insulin sensitivity. Thus, Lrtm1 is a novel regulator of post-receptor insulin signaling and glucose metabolism that may provide a new target for therapy insulin resistant prediabetes and type 2 diabetes.

Disclosure
G. Wang: Employee; Agilent. Y. Yu: None. W. Chen: None. W. Cai: None. X. Liu: None. C. Kahn: None.
192-LB: Temporal Relationship of New Pediatric Diabetes Diagnoses and COVID-19
Authors: REDDY NEHA , JOHNSON STEVE , MOFFITT RICHARD A. , EVANS MICHAEL , YEH HSIN-CHIEH , REUSCH JANE E.B. , WONG RACHEL , BUSE JOHN B. , BRAMANTE CAROLYN , HARPER JEREMY 
Published: June 2023

SARS-CoV-2 infection may increase the incidence of diabetes mellitus (DM) in children.1-3 Mechanisms are incompletely understood and likely vary between type 1 and type 2 DM. All children may be at greater risk regardless of infection due to pandemic control measures increasing sedentary time and disrupting primary care.4,5 This cross sectional analysis examined the percentage of new DM diagnoses in children across 60-day calendar-time intervals relative to SARS-CoV-2 infection in a nationwide database, the National COVID Cohort Collaborative. The percentage of new type 1 and 2 DM diagnoses was highest in the acute period, within 60 days of infection. After acute infection, the percentage of new diagnoses appears lower than pre-infection percentages. Further study of this nuanced relationship is needed to inform screening and treatment.

Disclosure
N. Reddy: None. J. Harper: None. S. Johnson: None. R. A. Moffitt: None. M. Evans: None. H. Yeh: None. J. E. B. Reusch: Advisory Panel; Medtronic. R. Wong: None. J. B. Buse: Consultant; Alkahest, Anji Pharmaceuticals, AstraZeneca, Bayer Inc., Biomea Fusion, Inc., Boehringer Ingelheim International GmbH, CeQur SA, Cirius Therapeutics, Inc., Corcept Therapeutics, Eli Lilly and Company, GentiBio, Glycadia, Glyscend Inc., Janssen Pharmaceuticals, Inc., Mellitus Health, Pendulum Therapeutics, Praetego, LLC, Stability Health, Terns, Inc, Valo, Other Relationship; Novo Nordisk, Research Support; Dexcom, Inc., Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend Inc., Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. C. Bramante: None.

Funding
National Center for Advancing Translational Sciences (U24TR002306); Clinical and Translational Science Institute, University of Minnesota (UL1TR002494); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK124654); National Institutes of Health (3R01DK130351-02S1)
193-OR: Muscle α-Parvin Deletion Results in Insulin Resistance by Impairing GLUT4 Translocation and Hexokinase II Association with Mitochondria in Mice
Authors: CAPPEL DAVID A. , DEAVER JOHN W. , COZZANI LUCIANO , BRACY DEANNA , LANTIER LOUISE , DONG XINYU , PRINTZ RICHARD , ZENT ROY , POZZI AMBRA , WASSERMAN DAVID H. 
Published: June 2023

Genetic deletions of specific integrin receptor a-subunits and the integrin-like kinase (ILK) have no effect on insulin action in lean C57Bl/6J mice but are required for insulin resistance in diet-induced obese (DIO) mice. ILK binds to a-parvin through which it controls the rho kinase pathway and cytoskeleton thereby altering cellular compartmentation and dynamics. The hypothesis tested was that integrin signaling is required for insulin resistance in DIO mice due to disruption of the critical interaction between ILK and a-parvin. We predicted that preventing this interaction in lean mice would recapitulate the insulin resistance observed in DIO mice. Lean and DIO mice with muscle-specific a-parvin (mPar) knockout (KO) and wild type littermates (WT) were studied. Insulin clamps were performed in mPar KO and WT mice. A muscle-specific index of glucose uptake (Rg) was measured isotopically during insulin clamps. Lean mPar KO had a 50% reduction in muscle Rg that was associated with a similar deficit in GLUT4 translocation to the cell membrane and a decrease in hexokinase II-associated with mitochondria. Mitochondria oxidative capacity was reduced by 50% in lean mPar KO mice compared to lean WT mice. The insulin resistance in DIO WT mice was no worse in DIO mPar KO mice. Insulin signaling was not impaired by mPar KO in lean mice. However, lean mPar KO had impaired a-actinin, Rac1, p-cofilin/cofilin, and p-MLC/MLC compared to lean WT mice during insulin stimulation. These changes affect cytoskeletal dynamics and provide a basis for the reduction in GLUT4 translocation, hexokinase II localization to mitochondria, and impaired mitochondria oxidation. In conclusion, a-parvin is a key node in coupling integrin signaling as it causes muscle insulin resistance in otherwise healthy lean mice. Deletion of muscle a-parvin does not affect insulin signaling but rather attenuates insulin-stimulated glucose uptake by impairing cytoskeletal dynamics.

Disclosure
D.A.Cappel: None. D.H.Wasserman: None. J.W.Deaver: None. L.Cozzani: None. D.Bracy: None. L.Lantier: None. X.Dong: None. R.Printz: None. R.Zent: None. A.Pozzi: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050277, R01DK054902, R24DK059637)
194-OR: Lower Insulin Sensitivity before the Onset of Type 2 Diabetes Is Associated with Increased Risk of Albuminuria after Diabetes Onset
Authors: WILLIG MEEAH R. , STINSON EMMA J. , LOOKER HELEN C. , MITCHELL CASSIE M. , HANSON ROBERT L. , NELSON ROBERT G. , KRAKOFF JONATHAN , CHANG DOUGLAS C. 
Published: June 2023

Background: Reduced renal insulin signaling is implicated in the pathogenesis of albuminuria, a marker of kidney failure, cardiovascular disease, and mortality. We sought to investigate whether insulin action and secretion, measured prior to diabetes onset, are associated with development of albuminuria after diabetes onset.
Methods: Baseline body composition, insulin sensitivity by hyperinsulinemic-euglycemic clamp at submaximal and max insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test (acute insulin response, AIR) were measured in 166 Indigenous American adults who subsequently developed diabetes. After diabetes onset and during median follow-up of 12.3 years, 44 participants (27%) developed albuminuria. The separate associations of M-low, M-high, and AIR (per 1-SD change) with risk of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) were identified by Cox regression models adjusted for age, sex, and body fat (%).
Results: Participants who developed albuminuria were of similar age (26.8 ± 5.6 vs. 27.1 ± 6.0 years), sex distribution (50% vs. 46% male), body fat (36.6 ± 6.0 vs. 35.8 ± 8.0%), and AIR (3.1 ± 0.3 vs. 3.0 ± 0.3, pmol/L [log]) as those who did not develop albuminuria, but had lower insulin sensitivity (M-low: 0.32 ± 0.06 vs. 0.36 ± 0.11, p = 0.007, M-high: 0.85 ± 0.11 vs. 0.90 ± 0.12, p = 0.03; mg/kg-metabolic body size/min [log]). In separate adjusted models, lower M-low and M-high (i.e., lower insulin sensitivity) were both associated with increased risk for albuminuria (HR 1.67, 95% CI 1.12, 2.50, p = 0.01; HR 1.35, 95% CI 1.03, 1.79, p = 0.03), whereas AIR was not (HR 1.18, 95% CI 0.79, 1.75, p = 0.42).
Conclusion: Lower insulin sensitivity is associated with development of albuminuria, suggesting a role for insulin signaling in the pathogenesis of proteinuria and is a potential therapeutic target for prevention of cardiovascular and kidney disease.

Disclosure
M.R.Willig: None. E.J.Stinson: None. H.C.Looker: None. C.M.Mitchell: None. R.L.Hanson: None. R.G.Nelson: None. J.Krakoff: None. D.C.Chang: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK069015-36)
196-LB: Heterogeneity in Elevated Glucose and A1C as Predictors of the Prediabetes-to-Diabetes Transition—Framingham Heart Study, Multiethnic Study on Atherosclerosis, Jackson Heart Study, and Atherosclerosis Risk In Communities
Authors: PATEL CHIRAG 
Published: June 2023

The clinical utility of the elevated altered glucose tolerance and prediabetes, and novel phenotypes of diabetes risk is a hotly debated. The heterogeneity of risk and incidence across diverse cohorts needs to be considered when developing new approaches for screening and when communicating the uncertainty in the transition rate. How the definition of prediabetes relates to cohort-level sources of variation and predicts the transition from prediabetes to overt diabetes has not been well characterized. Here, we study the range and heterogeneity in the absolute incidence and the relative risk for diabetes across competing definitions of prediabetes in participants from four large US cohorts, the Framingham Heart Study (FHS), Multi-Ethnic Study on Atherosclerosis (MESA), Jackson Heart Study (JHS), and Atherosclerosis Risk in Communities (ARIC). We computed the incidence rates across prediabetes (fasting glucose, A1C%; ADA or WHO), outcome definition (elevated glucose or overt T2D), body mass index, blood pressure, age, race, sex and cohort. The cross-cohort meta-analytic estimate rate for transition to diabetes for FBG 100-125 mg/dL, 110-125 mg/dL, and A1C 5.7-6.4% were 4.2, 8.2, 2.8 cases per 100 person-years, respectively. This contrasts with incidence rates of 0.6, 1.0, and 0.6 for the individuals with FBG less than 100, FBG less than 110, and A1C% less than 5.7% respectively. All the meta-analytic estimates had I2 greater than 93%. The between-cohort range FBG 110-125 mg/dL was 4 (FHS Generation 3), 5 (FHS Generation 2), 5.5 (ARIC), 12.5 (JHS), and 14.8 (MESA). In contrast, the range of the incidence rate for A1C 5.7-6.4% was 1.6 (ARIC) to 5.2 (JHS). We found that these inter-cohort differences cannot be explained by body mass index or ethnic differences and reporting of rates need to consider the wide prediction interval between cohorts.

Disclosure
C. Patel: None.

Funding
National Institutes of Health (R01ES032470)
197-OR: Dynorphin, a Novel Paracrine Factor That Regulates Insulin Secretion
Authors: BLANDINO-ROSANO MANUEL , PANZER JULIA , BERNAL-MIZRACHI ERNESTO 
Published: June 2023

Within the pancreatic islet, the crosstalk between different islet cells through paracrine signals orchestrates a hormonal response that controls glucose levels. The dysregulation of these signals contributes to impaired glucose homeostasis and diabetes. Therefore, understanding intra-islet communication is imperative for developing new strategies for diabetes management. Here, we show that intra-islet dynorphin (Dyn) stimulates somatostatin (SST) secretion and is a novel factor regulating islet function and insulin secretion in human and mouse islets. Dyn, an opioid peptide involved in stress response, pain, and addiction is synthesized in human and mouse β-cells and secreted in response to glucose. Dyn acts mainly through the k-opioid receptor (KOR) expressed in all islet cells with the highest expression in δ-cells. Using perifusion and static incubation studies, we show that Dyn induces SST secretion and decreases insulin secretion in mouse and human islets and that Dyn fails to induce SST secretion in islets from mice with KOR deletion in δ-cells, thereby providing a mechanism for feedback control of insulin secretion (β- to δ-cell Dyn/KOR negative feedback loop). Our data also show that Dyn is increased in islets from HFD-fed mice (8-fold) and in human β-cells from T2D donors. Remarkably, dynorphin mRNA is one of the top ten most upregulated genes in islets from HFD-fed mice, higher than several critical β-cell genes, including pdx1 or ucn3. We demonstrate that the β- to δ-cell Dyn/KOR negative feedback loop is upregulated in diabetes and pharmacological inhibition or genetic deletion of KOR in δ-cells improves glucose homeostasis in high-fat diet (HFD)-fed mice, demonstrating the therapeutic potential of this system. The novel role of the Dyn/KOR axis in islet function in healthy and diabetogenic conditions can have profound implications for glucose homeostasis and serve to develop potential targets for T2D.

Disclosure
M.Blandino-rosano: None. J.Panzer: None. E.Bernal-mizrachi: None.
198-OR: Pancreatic Elastase Regulates Human Beta-Cell Viability by Impairing the PAR2 Pathway
Authors: BASILE GIORGIO , VETERE AMEDEO , HU JIANG , DE JESUS DARIO F. , CHOUDHARY AMIT , WAGNER BRIDGET , KULKARNI ROHIT 
Published: June 2023

The discovery of SerpinB1 pointed to acinar cell-derived proteases such as pancreatic elastase (PE) being involved in regulating human β-cell viability. Indeed, we observed that expression of a major form of PE, namely CELA3B, was increased in acinar cells from donors with type 2 diabetes (T2D) compared to samples from nondiabetic (ND) donors. Surprisingly, CELA3B protein levels were higher in T2D vs. ND islets, although its gene expression levels were virtually undetectable. We confirmed that increasing doses of exogenous PE is able to decrease viability and function of EndoC-βH3 (βH3) cells in vitro. To evaluate the effects of PE inhibition on β-cell survival, we used telaprevir, an FDA-approved drug, that we identified as a potent PE blocker using a High-Throughput Screening assays with an IC50 of 15.6 nM to inhibit PE activity. Consistent with the effects of SerpinB1 on β-cells, telaprevir also increased human β-cell viability in in vitro and in vivo systems. By performing phospho-antibody microarrays and single-cell RNA-Seq in human islets treated with vehicle or telaprevir, we identified the Protease-Activated Receptor 2 (PAR2) pathway as a candidate pathway linking PE inhibition to β-cell viability. We validated the results by treating EndoC-βH1 (βH1) cells with a PAR2 inactivating peptide (FSLLRY-NH2) in addition to PE +/- telaprevir. We observed that PE impaired the PAR2 cascade, and these effects were reversed by telaprevir in control β-cells, but not in cells treated with the PAR2 inhibitor. Furthermore, telaprevir was able to reverse PE effects and improve viability of control human primary β-cells, but not of those in which the PAR2 pathway was pharmacologically impaired. These data point to novel pathways reflecting acinar-β-cell crosstalk that has therapeutic potential to resolve diabetes in patients.

Disclosure
G. Basile: None. A. Vetere: None. J. Hu: None. D.F. De Jesus: None. A. Choudhary: None. B. Wagner: Research Support; Novo Nordisk. Stock/Shareholder; Pfizer Inc., Provention Bio, Inc. Research Support; Japan Tobacco Inc. Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd. Stock/Shareholder; Curis, Inc. Consultant; Fresh Tracks Therapeutics. R. Kulkarni: Advisory Panel; Novo Nordisk, Inversago. Research Support; Inversago. Advisory Panel; Biomea Fusion, Inc., REDD Pharma.