bluuebunny/crossref_metadata_2025_split huggingface dataset:
1325-P: Modulation of Overnight Free Fatty Acid and Glucose Concentrations and Their Effect on Postprandial Islet Function and Glucose Metabolism
Authors: WELCH ANDREW A. , SCHEMBRI WISMAYER DANIEL , EGAN AOIFE M. , FARAHANI RAHELE A. , LAURENTI MARCELLO C. , COBELLI CLAUDIO , DALLA MAN CHIARA , VELLA ADRIAN 
Published: May 2022

Individuals with prediabetes can be classified by fasting and glucose tolerance status. Previously we observed that elevated fasting Free Fatty Acids (FFA) are associated with Impaired Glucose Tolerance (IGT) and decreased β-cell function (quantified as Disposition Index (DI)) . Impaired Fasting glucose (IFG) is associated with further decreases in DI. To examine how changes in fasting FFA and glucose alter islet function, we studied subjects with Normal Fasting Glucose (NFG) and Normal Glucose Tolerance (NGT) on 2 occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG / IGT. In addition, we studied 7 subjects with IFG / IGT on 2 occasions. On one occasion insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG / NGT. The 2 groups were matched for Body Mass Index (BMI: 32±3 vs. 31±2 kg/m2, NFG / NGT vs. IFG / IGT respectively, p = 0.87) . The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and β-cell function. Elevation of overnight fasting FFA and glucose in NFG / NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 hrs, Saline vs. Intralipid / glucose, p = 0.55) . In people with IFG / IGT, insulin also did not alter peak and integrated glucose concentrations (2.5 ± 0.1 vs. 2.5 ± 0.2 Mol per 5 hrs, Saline vs. Insulin, p = 0.39) . Changing overnight concentrations of glucose and FFA did not alter postprandial concentrations of insulin and C-peptide in either group. While fasting Endogenous Glucose Production (EGP) differed between groups (14 ± 1 vs. 18 ± 1 μmol/kg/min, NFG / NGT vs. IFG / IGT, p &lt; 0.01) , intervention did not change fasting and nadir EGP. Peak and integrated meal appearance and DI were also unchanged by intervention in either group. We conclude that acute, overnight changes in FFA and glucose concentrations do not alter islet function or glucose metabolism in prediabetes.

Disclosure
A.A.Welch: None. D.Schembri wismayer: None. A.M.Egan: None. R.A.Farahani: None. M.C.Laurenti: None. C.Cobelli: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk.

Funding
NIH DK 078646
1356-P: Investigating the Metabolic Function of an Orphan G Protein–Coupled Receptor in the Intestinal Epithelium
Authors: REN HONGXIA 
Published: May 2022

G protein-coupled receptors (GPCRs) in the gastrointestinal tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We recently identified that an orphan GPCR, Gpr17, was co-expressed in glucagon-like peptide-1 (GLP-1) -expressing EECs in human and rodent intestinal epithelium. However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their glucose metabolism and feeding behavior. We showed that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. We found that acute genetic ablation of Gpr17 in intestinal epithelium (iKO) improved oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) in female and male mice. iKO mice responded to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP) . Intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Furthermore, comprehensive studies including gut morphology, gut epithelium heterogeneity by scRNA-seq, and microbiome analysis were examined but none of them was changed because of intestinal Gpr17 ablation. In addition, male Gpr17 whole body knockout mice have improved intraperitoneal glucose tolerance, and increased insulin sensitivity in hyperinsulinemic-euglycemic clamp studies.
In conclusion, our work showed that ablation of intestinal Gpr17 signaling led to improved neurohormonal regulation to maintain metabolic homeostasis.

Disclosure
H.Ren: None.

Funding
National Institute of Health (R01DK120772)
1357-P: Diabetic Hyperglycemia Impairs Intestinal Barrier Function in the Setting of Diet-Induced Obesity
Authors: FRANCIS KENDRA L. , ALONGE KIMBERLY M. , HU SHANNON J.W. , PHAN BAO ANH N. , DOAN TAMMY P. , KRUTZSCH CODY A. , MAAT ZENOURA , SCARLETT JARRAD M. , SCHWARTZ MICHAEL W. 
Published: May 2022

Proper function of the intestinal barrier plays a crucial role to maintain normal health by selectively absorbing nutrients and keeping out pathogens. Increased gut permeability is a feature of several diseases, including metabolic syndrome, but whether it is a cause or a consequence is unknown. We therefore examined the impact on intestinal barrier function of streptozotocin (STZ) -induced diabetes in C57BL/6J mice that were fed either standard chow or high-fat high-sucrose (HFHS) diet for 13wk. Moderate hyperglycemia was induced by low-dose i.p. STZ injection and 12wk later, intestinal tissues were collected and processed for quantification of colonic mucin and tight junction proteins. In both HFHS- and chow-fed mice, STZ treatment resulted in significantly elevated blood glucose levels compared to vehicle-treated controls (HFHS blood glucose 249.1 mg/dL vs. 157.5 mg/dL, p=0.0008; chow 330.2 mg/dL vs. 139.7mg/dL, p=0.0005) . In HFHS-fed mice, STZ hyperglycemia was associated with reductions of both the colonic mucin layer, as measured by Alcian Blue (AB) staining (percent area 52.6 vs. 62.4, p&lt;0.0001) , and the tight junction protein E-cadherin (percent area 34.7 vs. 55.9, p=0.0029) . In non-obese chow-fed mice, however, STZ-induced hyperglycemia had no significant impact on AB mucin staining or E-cadherin protein abundance. Similarly, levels of colonic mucins and E-cadherin were inversely correlated with blood glucose levels in HFHS-fed mice (AB R2=0.43, p=0.0116; E-cadherin R2=0.30, p=0.0439) , but not in chow-fed mice. We conclude that while the combination of hyperglycemia and diet-induced-obesity is sufficient to impair intestinal barrier function, neither obesity nor diabetes in isolation is sufficient to induce this effect. Our additional finding that the magnitude of colonic dysfunction is correlated with the degree of hyperglycemia implicates excess glucose as a potential driver of obesity-associated impairment of intestinal barrier function.

Disclosure
K.L.Francis: None. K.M.Alonge: None. S.J.W.Hu: None. B.N.Phan: None. T.P.Doan: None. C.A.Krutzsch: None. Z.Maat: None. J.M.Scarlett: None. M.W.Schwartz: None.

Funding
National Institutes of Health T32 DK007742
1359-P: Effect of Fat Content on Postprandial Gastric Retention and Glucose Absorption in Subjects with Type 1 Diabetes during Daily Life Conditions: Assessment through a Computational Model
Authors: FAGGIONATO EDOARDO , SCHIAVON MICHELE , BUCKINGHAM BRUCE A. , EKHLASPOUR LAYA , MAN CHIARA DALLA 
Published: May 2022

Understanding the impact of dietary nutrients on postprandial gastric retention (GR) and glucose absorption (GA) is crucial for optimizing both open- and closed-loop therapy in type 1 diabetes (T1D) . Here, we aim to investigate the effect of fat (F) content of a meal on both GR and GA in real life conditions, using a recently developed minimally invasive oral minimal model (MI-OMM) .
Data was collected during an outpatient 5-days clinical trial involving 1patients (age = 3-61 y; M/F = 60/50) wearing a sensor augmented insulin pump. At each meal, the medical staff recorded carbohydrate (C) and F intake. A total of 159 meals were analyzed that included &gt;75% sensor data, C and F contents, no exercise sessions, or other meals/snacks within 2h before and 3h after the meal. Meals were grouped based on F content: high fat (HF, F≥30%) , and Low Fat (LF, F≤15%) .
The model well fitted glucose sensor data and provided estimated GR and GA curves. Fig. 1 shows that model-derived GR was significantly lower from 0.5h onward, and GA was significantly faster from 0.5h to 2.3h after a LF meal compared to a HF.
These findings proved that MI-OMM can be used to estimate GR and GA, using sensor data, in real life meals with different F content and, therefore, it is potentially applicable to optimize insulin therapy in T1D.

Disclosure
E.Faggionato: None. M.Schiavon: None. B.A.Buckingham: Advisory Panel; Arecor, Lilly Diabetes, Medtronic, Other Relationship; Insulet Corporation, Research Support; Insulet Corporation, Lilly Diabetes, Medtronic. L.Ekhlaspour: Consultant; Tandem Diabetes Care, Inc., Ypsomed AG. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH.

Funding
This work was supported by MIUR (Italian Minister for Education) under the initiative “Departments of Excellence” (Law 232/2016) . Laya Ekhlaspour is funded by NIH (National Institutes of Health) 1K23DK121942.
136-OR: Polygenic Scores Improve the Predictive Accuracy of Type 1 Diabetes Classification Algorithms in a Large Biobank Cohort
Authors: DEUTSCH AARON J. , MAJARIAN TIM , MERCADER JOSEP M. , FLOREZ JOSE C. , UDLER MIRIAM 
Published: May 2022

Introduction: Many biobanks use machine learning algorithms to predict patient phenotypes such as type 1 diabetes (T1D) . It is not known how these algorithms perform in patients with different ancestral backgrounds or whether incorporating genetic data improves phenotypic classification.
Methods: We examined 40,843 patients in the Mass General Brigham (MGB) Biobank, including 34,870 white patients and 4,872 non-white patients. The MGB machine learning algorithm predicted 242 patients to have T1D. After applying a gold standard diagnosis based on chart review, we assessed accuracy of the MGB algorithm in different self-reported races and genetic ancestries. We divided the dataset into separate training and validation cohorts, and we constructed a logistic regression model using the machine learning algorithm and previously published T1D polygenic scores to classify patients as T1D cases or controls.
Results: The MGB machine learning algorithm for T1D had a positive predictive value of 77.8% for white patients, but only 62.2% for non-white patients (p = 0.04) . Among patients with predominantly European genetic ancestry, adding a polygenic score derived from European populations to the MGB classification algorithm improved the area under the receiver operating curve (AUC) from 0.928 to 0.974 (p &lt; 0.05) . Among patients whose predominant genetic ancestry was not European, adding a polygenic score derived from African populations improved the AUC from 0.889 to 0.920 (p &gt; 0.05) . In both cases, the improvement in AUC was less substantial when using non-ancestry-matched polygenic scores.
Conclusions: Automated prediction tools for T1D are imperfect, and performance may differ by patient race. Incorporating ancestry-specific polygenic scores into phenotyping algorithms can improve diagnostic accuracy. This may help reduce healthcare and research disparities by refining the automated classification of T1D in all racial and ancestral groups.

Disclosure
A.J.Deutsch: None. T.Majarian: Employee; Vertex Pharmaceuticals Incorporated. J.M.Mercader: None. J.C.Florez: Consultant; AstraZeneca, Goldfinch Bio, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Novo Nordisk. M.Udler: None.

Funding
National Institutes of Health (K23DK114551, T32DK007028)
1361-P: D-Xylose Test as a Biomarker for Glucose Intestinal Absorption in Humans and Minipigs
Authors: GOUTCHTAT REBECCA , MARCINIAK CAMILLE , CAIAZZO ROBERT , VERKINDT HELENE , QUENON AUDREY , RABIER THIBAUD , LAPIERE SARAH , RAVERDY VIOLETA , HUBERT THOMAS , PATTOU FRANCOIS 
Published: May 2022

Background and Aim: Increasing evidences suggest that intestinal glucose absorption (IGA) plays a distinct role in pathophysiology of type 2 diabetes (T2D) . However, state of the art IGA measurement with multiple tracers techniques are demanding and . We propose D-xylose, a non metabolized pentose, as a proxy to quantify IGA levels to study IGA involvement in T2D.
Materials and Methods: First (cross sectional studies) , mixed meal tests including D-xylose (MMT) were performed in 165 patients (lean normoglycemic (NG) ; obese NG, glucose intolerant (IGT) or T2D) and 74 healthy adult minipigs. Second (longitudinal studies) , MMT were performed in minipigs before and after 70% intestinal resection (n = 5) , 70% pancreatectomy (n = 15) , and high fat diet for 2 months (HFD) (n = 4) to quantify D-xylose changes after each intervention.
Results: 1h serum D-xylose varied with glucose tolerance status (p&lt;0.005) and was higher in T2D and IGT patients than in obese and lean NG patients In multivariable analysis, 1h postprandial glucose was correlated with D-xylose (r= 0.63; p&lt;0.0001) , independently of insulin secretion (insulinogenic index) and insulin sensitivity (Matsuda index) . In minipigs, D-xylose was also independently correlated with post prandial glucose (r=0.53; p&lt;0.05) . D-xylose appearance was reduced after intestinal resection (p&lt;0.05) , but remained unchanged after pancreatectomy and HFD.
Conclusion and Perspectives: Post prandial glucose was independently correlated with D-xylose in humans and minipigs. Interventional studies in minipigs provided direct evidence that D-xylose is associated with IGA, independently of insulin secretion and sensitivity.

Disclosure
R.Goutchtat: None. F.Pattou: None. C.Marciniak: None. R.Caiazzo: Consultant; Ethicon, Inc., Medtronic. H.Verkindt: None. A.Quenon: None. T.Rabier: None. S.Lapiere: None. V.Raverdy: None. T.Hubert: None.

Funding
ANR
1369-P: The Differential Effects of Estrogen on Determinants of Skeletal Muscle Bioenergetics with a High-Fat, High-Sucrose Diet in Rats
Authors: HULETT NICHOLAS A. , HULL SARA , KNAUB LESLIE , POTT GREGORY , MILLER BENJAMIN F. , REUSCH JANE , SCALZO REBECCA L. 
Published: May 2022

Estrogen is a powerful, beneficial regulator of skeletal muscle mitochondria. Premenopausal women with type 2 diabetes (T2D) have relatively greater complications associated with their T2D compared with the effect of the disease in men. We hypothesize that this impact of T2D in women is in part due to the impairment of estrogen-mediated regulation of skeletal muscle mitochondrial content and function. To explore the interaction between estrogen, diabetes and mitochondrial biogenesis in a rat model, 4-week-old, female Wistar Rats were fed a chow or a high fat/high sugar diet (HFHS) . At 8 weeks all mice underwent an ovariectomy (OVX) and randomized to estradiol (E2) replacement or none. One week prior to sacrifice, deuterium oxide was administered to determine skeletal muscle mitochondrial biogenesis. OVX +/- E2, animals were sacrificed 6 weeks post-randomization. Endpoints: body weight, gonadal fat mass, blood glucose and insulin levels, and gastrocnemius (mitochondrial biogenesis and function) . OVX+E2 rats had lower body mass compared with OVX (P = 0.0028) . HFHS fed rats had greater relative fat mass independent of E2 status (P = 0.0007) , and the OVX+E2 fed the HFHS diet were hyperglycemic (P = 0.00for the diet x E2 interaction) . State 3 mitochondrial respiration with carbohydrate-linked substrates was elevated in chow fed animals with E2, and this response was absent in HFHS animals (P = 0.0138 for the diet x E2 interaction) . Contrary to our hypothesis, there was no effect of diet or E2 on mitochondrial biogenesis measured with deuterium oxide (P &gt; 0.4) . These data support the hypothesis that, in the context of a HFHS diet, the beneficial effect of E2 on skeletal muscle mitochondrial function is impaired. However, mitochondrial biogenesis does not appear to mediate this interaction of diet and E2. Future studies will focus on the E2-mediated regulation of mitochondrial quality to determine their role in the impairment of mitochondrial function.

Disclosure
N.A.Hulett: None. S.Hull: None. L.Knaub: None. G.Pott: None. B.F.Miller: None. J.Reusch: Advisory Panel; Medtronic. R.L.Scalzo: None.

Funding
Veterans Affairs (BX004533)
1376-P: Comparison of a-Cell Response to Intravenous or Oral Glucose in Nondiabetic Humans
Authors: LAURENTI MARCELLO C. , MANDUCA ARMANDO , COBELLI CLAUDIO , MAN CHIARA DALLA , VELLA ADRIAN 
Published: May 2022

Type 2 Diabetes (T2DM) and prediabetes are characterized by β-cell and α-cell dysfunction which can occur independently. Defects in α-cell response to rising glucose can be evaluated with an oral or intravenous challenge: the former reflects normal physiology, the latter is unaffected by incretins or gut motility. We compared Glucagon Secretion Rate (GSR) in response to rising glucose during a Graded Glucose Infusion (GGI) and an Oral Glucose Tolerance Test (OGTT) . We studied 39 non-diabetic, weight-stable subjects (53 ± 2 yrs, 29 ± 1 Kg/M2) , with different fasting and glucose tolerance status. All subjects underwent a 75g OGTT and a GGI, with glucose infusion doubling every hour for 4 hours. GSR was calculated by deconvolution from plasma concentrations of glucagon on both study days (GSRGGI and GSROGTT) . The suppression of GSRGGI could be described with a single-exponential relationship between GSR and glucose concentrations. The slope of the log-transformed secretion line allows estimation of the change in glucose necessary to suppress GSR by 50% (G50) . This index of suppressibility is elevated in people with impaired fasting glucose compared to normal fasting glucose (2.7 ± 0.2 vs. 3.8 ± 0.4 mmol/L, p=0.01) . Intriguingly, GSROGTT, exhibited a delayed response to rising glucose (compared to GSRGGI) , during the early part of the OGTT. However, the relationship of GSROGTT to glucose did not differ from that of GSRGGI during the fasting state and at the time of peak postprandial suppression. This allowed the calculation of G50 during the OGTT, which was similar to that observed during the GGI (R2=0.66) and correlated with weight, age and fasting glucose (R2=0.49) . These data demonstrate the ability of a novel index (G50) , to reproducibly quantify α-cell suppression by oral or intravenous glucose in non-diabetic subjects. Future studies will be necessary to determine if this relationship also applies to T2DM and how gastrointestinal and other factors alter the rate of GSR suppression during an OGTT.

Disclosure
M.C.Laurenti: None. A.Manduca: None. C.Cobelli: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk.

Funding
National Institutes of Health (DK078646, DK116231)
1385-P: Impact of Preanalytical and Analytical Factors on Glucagon and GLP-1 Levels in Humans
Authors: RASMUSSEN CHRISTINE , KJELDSEN SASHA , JENSEN NICOLE J. , HEINZ NIKLAS , HARTMANN BOLETTE , HOLST JENS J. , ALBRECHTSEN NICOLAI J. WEWER 
Published: May 2022

Glucagon and glucagon-like peptide-1 (GLP-1) have important roles in the development and treatment of diabetes. Their plasma concentrations are currently being measured in more than 500 clinical studies according to clinicaltrial.gov. As glucagon and total GLP-1 (reflecting the secretion and action of GLP-1 and is analytically independent of DPP-4 activity) circulate in the low picomolar range it has been troublesome to accurately measure their plasma concentrations. Equally important are so-called preanalytical considerations including the use of enzyme inhibitors. The latter may also depend on the analytical approach, for example single-antibody assay versus sandwich ELISA. To provide guidelines for measurement of glucagon and GLP-1 in clinical trials we obtained blood samples using four different blood-containers (with either neprilysin inhibitor: sacubitrilat 25 µg/mL; trasylol 500KIU/mL; P800 tubes; or vehicle) from healthy individuals (male/female; 7/4; mean ± SD; age: 32 ± 12 years, BMI; 26 ± 4 kg/m2) after an overnight fast and following an intravenous amino acid (AA) infusion (14 g/L; 331 mg/min/kg body weight. Plasma concentrations of glucagon increased significantly during the AA-infusion independent of blood containers and assays. The sandwich ELISA showed significant lower levels of glucagon with addition of neprilysin inhibitor whereas both trasylol and P800 tubes resulted in increased levels during the AA-infusion. Glucagon levels measured by the two radioimmunoassays (RIA) did not depend on the containers. Levels of total GLP-1 did not depend on the containers using a sandwich ELISA (Mercodia) but increased by a factor of a 2.5 when plasma from P800 containers was assayed using a C-terminal specific RIA.
In summary, levels of glucagon and GLP-1 depend on both preanalytical and analytical factors that should be standardized for future clinical studies.

Disclosure
S. Kjeldsen: None. N.J. Jensen: None. N. Heinz: None. B. Hartmann: Board Member; Bainan Biotech. J.J. Holst: Advisory Panel; Novo Nordisk. Board Member; Antag Therapeutics, Bainan Biotech. N.J. Wewer Albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc. Speaker's Bureau; Merck & Co., Inc., Mercodia AB.

Funding
Nicolai J. Wewer Albrechtsen were financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.
1390-P: FOXO1 Promotes Sexually Dimorphic Effects on Energy Balance in the Preoptic Anterior Hypothalamus
Authors: LUO PEI , IRIZARRY VALERIA C. TORRES , YE HUI , IBRAHIMI LUCAS , SCHAUL SARAH , PATEL NIRALI , CARRILLO-SÁENZ LESLIE , ANTONY NIMISHA , DIXIT DEVIN , KOTA MAYA , UNTERMAN TERRY , XU PINGWEN 
Published: May 2022

The preoptic anterior hypothalamus (POAH) , known as a thermointegrative center, modulates metabolic adaptation in response to temperature change, thus making it relevant for body weight homeostasis. Forkhead transcription factor O1 (FoxO1) plays an important role in mediating effects of leptin and insulin on metabolic homeostasis in the hypothalamus. However, the homeostatic role of FoxO1 in POAH has not been investigated. We found that FoxO1 specific deletion in the POAH neurons (FoxO1POAH-KO) prevented high fat diet-induced obesity (DIO) in female but not male mice. This female-specific protection was associated with increased lean mass, decreased fat mass, and upregulated thermogenesis in adipose tissues. The female FoxO1POAH-KO mice also showed improved insulin sensitivity and increased energy expenditure when exposed at room temperature (22 °C) or cold (6 °C) . Moreover, the FoxO1POAH-KO-induced protection against DIO in females was blunted by ovariectomy (OVX) , while 17β-estradiol supplementation after OVX failed to restore this protection, suggesting an estrogen-independent mechanism. Finally, mice with FoxO1 constitutively activated in the POAH neurons (FoxO1POAH-CA) significantly increased DIO in both sexes, further supporting an essential metabolic role of FoxO1POAH. Together, these findings indicate that FoxO1POAH is a crucial transcription factor that directs and coordinates control of energy balance, thermogenesis, and glucose homeostasis in female mice.
Key words: FoxO1, POAH, sex difference.

Disclosure
P. Luo: None. H. Ye: None. T. Unterman: None. P. Xu: None.

Funding
P. Xu is supported by National Institutes of Health (R00DK1070 and R01DK123098) , Department of Defense (Innovative Grant W81XWH-19-PRMRP-DA) , and The University of Chicago Diabetes Research and Training Center (The Pilot and Feasibility Award DK020595) .