bluuebunny/crossref_metadata_2025_split huggingface dataset:
1298-P: Metabolic Clearance of Insulin Is Altered after Gastric Bypass and Sleeve Gastrectomy
Authors: RAYAS MARIA S. , DEFRONZO RALPH A. , GASTALDELLI AMALIA , SALEHI MARZIEH 
Published: May 2022

Roux-en-Y gastric bypass (GB) surgery and sleeve gastrectomy (SG) improve glucose tolerance, in part, by enhancing prandial insulin levels. Post-meal hyperinsulinemia after GB is caused by larger insulin secretion and lower metabolic clearance rate of insulin (MCRI) . Reduced prandial MCRI after GB is exaggerated in those with post-GB complication of hypoglycemia, suggesting that altered MCRI is a pathogenic factor. We investigated the role of GB or SG on insulin kinetics in fasting and fed states.
The MCRI were measured during a mixed meal text (MMT) in 9 GB and 7 SG subjects: and during MMT combined with hyperinsulinemic hypoglycemic clamp in 9 GB, 7 SG, and 5 CN. Three groups were matched for age and BMI and surgical groups for time and weight loss since surgery; none had diabetes or liver disease.
Fasting MCRI was greater in GB and SC than CN (p&lt;0.05) . Meal ingestion diminished MCRI to a larger extent in GB subjects compared to SG reaching nadir values in 20-50 min (relative reduction in GB vs. SG: 82±3% vs. 74±3%, p&lt;0.05) . The relative postprandial reduction in MCRI was inversely associated with the glycemic excursion and insulin response. During the clamp hepatic insulin clearance was larger in GB and SG compared to CN (p&lt;0.05) . There was no association between hepatic insulin clearance and peripheral insulin sensitivity (M/I) . Induced hyperinsulinemia approximating 300 µU/ml reduced MCRI in 3 groups despite a larger M/I in surgical subjects. Meal ingestion during hyperinsulinemic hypoglycemia clamp raised MCRI in 3 groups (p&lt;0.05) returning to pre-meal values in an hour. These findings demonstrate that the differences in basal MCRI among GB, SG and CN are mainly attributed to variations in insulin clearance in the liver and independent on peripheral insulin sensitivity. Further, prandial reduction in MCRI is greater after GB than SG in proportion to the rates of nutrient influx.; the effect of nutrient ingestion on insulin kinetics is altered during hyperinsulinemic hypoglycemia.

Disclosure
M.S.Rayas: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk. M.Salehi: None.

Funding
National Institute of Diabetes, Digestive, and Kidney Diseases (DK105379)
1301-P: The Effect of Insulin on α-Aminoadipic Acid Metabolism in Polycystic Ovary Syndrome (PCOS) Patients with Insulin Resistance
Authors: CHANG ALICE Y. , ASOKAN ANEESH K. , SAKRIKAR DHANANJAY , LALIA ANTIGONI , PETTERSON MAI , NAIR K. SREEKUMARAN 
Published: May 2022

Population studies have shown that the α-Aminoadipic Acid (AAA) , a lysine metabolite, predicts future type 2 diabetes and AAA concentrations decrease following administration of insulin sensitizers. To determine whether women with PCOS and insulin resistance have altered lysine and AAA kinetics we compared age-matched 18 women with PCOS to 12 women without PCOS using stable isotopes labeled [α-15N1]-lysine and [13C1]-AAA to measure lysine and AAA kinetics. Baseline levels of AAA flux and lysine concentrations were higher in PCOS compared to women without PCOS. Insulin decreased the concentrations and flux values of lysine and AAA. The conversion of lysine to AAA and AAA-metabolic clearance rates were increased on insulin infusion in both groups (Table) . Insulin sensitivity was negatively correlated with lysine concentration (r = - 0.547, p &lt; 0.05) and AAA flux (r= - 0.587, p &lt; 0.05) . In conclusion, our results indicate that insulin sensitivity is a determinant of AAA metabolism and insulin administration modulate the kinetics thus reducing AAA concentration indicating that altered AAA and lysine metabolism may result from insulin resistance.

Disclosure
A.Y.Chang: None. A.K.Asokan: None. D.Sakrikar: Employee; The Binding Site. A.Lalia: None. M.Petterson: None. K.Nair: None.

Funding
National Institutes of Health (RAG62859)
1320-P: Insulin Receptors and Their Signal Transduction Pathways in Choroid Plexus
Authors: MAZUCANTI CAIO , KENNEDY VERNON L. , CHO ANDREW , LIU QING-RONG , O’CONNELL JENNIFER F. , CAMANDOLA SIMONETTA , EGAN JOSEPHINE M. 
Published: May 2022

The insulin receptor (IR) is a tyrosine kinase receptor present in cell membranes. It is highly expressed in hepatocytes (where it promotes glycogenesis and inhibits gluconeogenesis) , and skeletal muscle and fat (where it facilitates glucose uptake by translocation of the glucose transporter GLUT4) . IR expression is also found throughout the brain, both in neurons and all glial cell types, and for decades impaired insulin signaling has been implicated in the onset and development of Alzheimer’s disease. IR expression pattern in the brain parenchyma is heterogeneous, with highest levels of expression found in olfactory bulb, hypothalamus, and hippocampus. However, the choroid plexus (CP) , a structure present in all 4 ventricles of the brain and responsible for the secretion of cerebrospinal fluid, has the highest affinity for insulin binding compared to any other brain region. This work aims to characterize the insulin signaling in the epithelial cells of the choroid plexus (EChP) and its possible implications in diseases of the brain. Relative expression levels of specific splicing variants of the Insr gene in dissected CP of adult mice were evaluated by qPCR and revealed predominant expression of the variant coding for isoform IR-A when compared to isoform IR-B. In vitro stimulation of EChP with insulin elicits a classical tyrosine kinase cascade, with activation of both the mitogenic (ERK) and metabolic (Akt) arms of the insulin signaling pathway, in a time-and concentration-dependent manner. Using pharmacological (S961, an insulin receptor antagonist) and genetic (insulin receptor shRNA, and Insr cre-loxP) approaches, we show that downregulation of IR in these cells not only impairs insulin signaling, but it also decreases IGF2’s ability to activate ERK and Akt, even when IGF1R levels are unaltered. Finally, using a viral vector coding for an IR shRNA, we show that downregulation of Insr expression in CP of adult mice has a profound effect on its structure, as demonstrated by MRI and histological technique.

Disclosure
C.Mazucanti: None. V.L.Kennedy: None. A.Cho: None. Q.Liu: None. J.F.O’connell: None. S.Camandola: None. J.M.Egan: None.
1322-P: Role of Macrophage NOD1 in Fat-Induced ß-Cell Dysfunction
Authors: RAHMAN S.M. NIAZUR , YUNG JUSTIN HOU MING , ZHANG YIHE , GIACCA ADRIA 
Published: May 2022

In individuals with obesity, free fatty acids (FFA) are chronically raised resulting in ß-cell dysfunction, leading to type 2 diabetes (T2D) . Recent data implicate the role of inflammation in developing ß-cell dysfunction, which is in part mediated by nucleotide-oligomerization domain 1 (NOD1) , an intracellular pattern recognition receptor. NOD1 is activated by peptidoglycans of bacterial cell walls; however, in vitro studies have documented that NOD1 can also be activated by saturated FFA.
Previous data from our lab have shown that palmitate-induced ß-cell dysfunction was prevented in whole body and ß-cell specific NOD1 null mice. We have seen earlier reports on increased macrophage infiltration in islets after elevation in circulating palmitate, and much higher expression of NOD1 in macrophages than ß-cells. Hence, we hypothesized that macrophage NOD1 receptors play a pivotal role in FFA-induced ß-cell dysfunction.
We have generated myeloid specific NOD1 null mice to target macrophage NOD1 receptors by crossing NOD1 floxed mice with Lyz2 Cre+ mice. Both knockouts and their controls (floxed and Cre) were infused for 48 h with ethylpalmitate (hydrolyzed to palmitate and ethanol in plasma) , to achieve elevated circulating FFA in a non-toxic manner. Ethanol vehicle was infused as control treatment. To assess in vivo ß-cell function, hyperglycemic clamp was performed following the 48 h infusion, and the disposition index (DI) was calculated.
Ethylpalmitate resulted in elevated plasma FFA compared to vehicle infusion. Ethylpalmitate caused marked reduction in DI in control mice, while knockout mice displayed no significant changes in DI between ethylpalmitate and vehicle infused groups. These results suggest that macrophage NOD1 plays a causal role in palmitate-induced ß-cell dysfunction in vivo. Overall, our data reveal NOD1 as a key factor and a potential therapeutic target for obesity-associated diabetes.

Disclosure
S.Rahman: None. J.Yung: None. Y.Zhang: None. A.Giacca: None.
1341-P: Dietary Fat and Fructose Impair Glucagon-Stimulated Liver Glucose Metabolism
Authors: EDGERTON DALE S. , KRAFT GUILLAUME , COATE KATIE C. , FARMER BEN , SMITH MARTA S. , SCOTT MELANIE , HASTINGS JON R. , MOORE MARY C. , CHERRINGTON ALAN D. 
Published: May 2022

High fat and fructose diets (HFFD) disrupt glucose metabolism. The aim of this study was to determine the effect of HFFD on glucagon (GGN) effectiveness. Dogs were fed either chow or HFFD for one month. After a basal sampling period, somatostatin and basal portal vein infusions of insulin and GGN were given for 4h, with the exception of GGN, which was either maintained at basal or increased 6-fold. Glucose was infused in the basal GGN groups (CHOW+GLC & HFFD+GLC) to match the 3-fold increase in plasma glucose that occurred with 6x-GGN (CHOW+GGN & HFFD+GGN) . There were no differences in plasma insulin or glucose and GGN levels were proportional to GGN infusion rates in all groups. 6x-GGN caused an identical increase in net hepatic glucose balance (NHGB) in the chow and HFFD groups (Fig 1A) after which NHGB declined. During the last hour NHGB was 1.8-fold greater in HFHF+GGN compared to Chow+GGN (A) . However, hyperglycemia per se caused a switch from net hepatic glucose output to uptake in Chow+GLC but not HFHF+GLC (there was a 3.7±0.4 vs. 0.3±0.4 mg/kg/min decrease in NHGB over time in the two groups, respectively) (B) . Thus, when expressed relative to each group’s respective glucose control group, the AUC for GGN stimulated NHGB was 1.9-fold greater in the Chow (C) compared to HFHF (D) groups (P&lt;0.05) .
In summary, HFHF feeding reduced hepatic glucagon action indirectly by impairing hepatic glucose effectiveness.

Disclosure
D.S.Edgerton: None. G.Kraft: None. K.C.Coate: None. B.Farmer: None. M.S.Smith: None. M.Scott: None. J.R.Hastings: None. M.C.Moore: None. A.D.Cherrington: Advisory Panel; Biocon, Diakard, Metavention, Sekkei Bio, Sensulin Labs, LLC, vTv Therapeutics, Consultant; Abvance, Fractyl Health, Inc., Novo Nordisk, Research Support; Bristol-Myers Squibb Company.

Funding
NIH R01DK18243
135-LB: Implementation of Depression Screening in a Pediatric Diabetes Clinic with Limited Mental Health Support
Authors: GURNURKAR SHILPA , KULASINGHAM ALICIA Y. , PIERCE JESSICA 
Published: May 2022

Objective: Depression is common in adolescents with type 1 (T1D) and type 2 diabetes (T2D) , and for those with T1D, is associated with suboptimal health outcomes, including higher A1c levels and increased rates of hospitalizations. The ADA standards of care recommend integration of depression screening into routine medical care, but follow-up for positive screens is challenging in settings with limited mental health support. Here, we describe our latest PDSA cycle results from a quality improvement (QI) project for implementing depression screening in adolescents with diabetes.
Methods: This QI project took place in a pediatric diabetes center without access to mental health support as part of routine diabetes care. Our goals were to 1) increase depression screening via the PHQ-9 from 0% to 80% over 2 years in all patients with T1D or T2D &gt;11 yrs old and 2) refer 100% of patients who screened positive to behavioral health by the end of the 2-year period (Dec 2019-Dec 2021) . Our QI project included 4 Plan-Do-Study-Act (PDSA) cycles ranging from trialing PHQ-9 screening with a single provider (Cycle 1) to implementing screening across all providers (Cycle 4) . This abstract focuses on the last 6 months of PDSA Cycle 4 (previous cycles were presented at 2021 ADA Scientific Sessions) .
Results: From July-Dec. 2021, a total of 68% of eligible patients completed PHQ-9 screening. Screening rates ranged from 46-90% across 5 different providers; 2 providers achieved screen rate goal of &gt;80%. Of the 68%, 28% screened positive and 86% of them were referred to behavioral health. Referral rates for positive screens ranged from 83-100% per provider; 2 providers achieved refer rate goal of 100%.
Conclusions: Although we did not achieve our PHQ-9 screen rate goal of 80% or our behavioral health refer rate goal of 100% by the end of 2 years, we found a major discrepancy in rates among providers. This prompted us to add an additional PDSA Cycle 5, which focuses on improving screening and refer rates for all providers.

Disclosure
S. Gurnurkar: None. A. Y. Kulasingham: None. J. Pierce: None.
1351-P: Molecular Pathogenesis of NASH through the Dysregulation of Metabolic Organ Network in the NASH-HCC Model Mouse Treated with Streptozotocin, High-Fat Diet
Authors: BUI LINH P. , SAKAKIBARA YUKI , TANAKA RYUTO , PIGNEY ELIZABETH H. , HASHIGUCHI TAISHI 
Published: May 2022

Introduction: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease, often associated with type II diabetes, which sometimes progresses to hepatocellular carcinoma (HCC) . NASH has become a health problem worldwide, but therapeutic agents for NASH have not yet been approved. Although the mechanism of NASH progression has not been fully elucidated, the multiple parallel hits hypothesis suggests abnormalities in adipocytokines, endotoxins, etc could contribute to the development of NASH. The STAM™ model is a clinically-correlated murine NASH model which shows the same pathological progression as human patients. Diabetes is a well-known comorbidity of NASH, and it is evident in the STAM™ model but analysis has focused mostly on the liver. Considering organ crosstalk interactions between the liver, and the gut and adipose tissue in the model should be clarified.
Methods: NASH was induced by injection of 200 µg streptozotocin solution 2 days after birth and feeding with HFD after 4 weeks of age. The mice were sacrificed at NASH stage. Colon samples were snap frozen in liquid nitrogen and stored at -80°C for tight junction-related protein analysis. Adipose tissue was prepared into paraffin blocks for HE staining. Blood adiponectin was analyzed to confirm changes in adipocytokine profile.
Results: Tight junction-related proteins in the intestine of STAM™ showed that expression of ZO-1 decreased with the progression of disease. Increased expression of endotoxin in the blood and decreased expression of adiponectin were also observed. HE staining of adipose tissue revealed hypertrophy of adipocytes.
Conclusion: The data suggested the occurrence of leaky gut, and abnormalities in adipocytokine secretion. Together with the liver, phenotypes in these organs are highly similar to human NASH patients, and might be involved in the pathogenesis of NASH.

Disclosure
L.P.Bui: None. Y.Sakakibara: None. R.Tanaka: None. E.H.Pigney: None. T.Hashiguchi: None.
1358-P: Small Intestinal Casein Sensing Regulates Food Intake and Glucose Tolerance in Rats
Authors: LI ROSA J.W. , BARROS DANIEL , LIM YUMI , ZHANG SONGYANG , GAO ANNA , LAM TONY K. 
Published: May 2022

High protein diet reduces food intake and improves glucose homeostasis in rodents and humans with obesity and diabetes, but the mechanistic site (s) of action remain unclear. Small intestinal lipid and glucose sensing regulates energy and glucose homeostasis, but the metabolic role of gut protein sensing remains elusive. In this study, we infused 8% casein hydrolysate as protein source into the upper small intestine (USI) and performed fasting-refeeding studies. We found that USI casein infusion (1.28 kcal/min) suppressed food intake up to 6h in chow but not high fat (HF) - fed rats (chow USI: sal 47±2 vs. cas 36±2 kcal, n=18, p&lt;0.01. HF USI: sal 39±3 vs. cas 40±3 kcal, n=11) . Interestingly, we discovered USI casein infusion instead improved intravenous glucose tolerance effectively in both chow and HF rats (AUC, chow USI: sal 1152±112 vs. cas 850.2±37, n=7, p&lt;0.05. HF USI: sal 1172±54 vs. cas 758.3±42 kcal, n=9, p&lt;0.05) . Next, we evaluated whether small intestinal calcium sensing receptor (CaSR) mediates protein sensing and first discovered that CaSR was expressed in the small intestine with higher expression in the ileum vs. USI (USI 1.0±0.1 vs. ileum 5.8±1, n=8, p&lt;0.01) . Next, we inhibited CaSR with CaSR inhibitor NPS2143 (56 µM) and found that its USI co-infusion with casein prevented the effects on glucose tolerance in both chow and HF rats. Finally, we injected lentivirus expressing shRNA of CaSR or mismatch sequence into the USI and CaSR expression was reduced by ˜40% (n=6, p&lt;0.001) . Importantly, USI casein effect in both chow and HF rats on glucose tolerance were lost (chow: MM cas 799.2±51 vs. LV-CaSR cas 1069±64, n=6, p&lt;0.01; HF: MM cas 771.8±20 vs. LV-CaSR + cas 1240±89, n=4, p&lt;0.05) .
In summary, these data illustrate that USI protein sensing increases glucose tolerance in chow and HF rats via CaSR, and lowers feeding in chow but not HF rats. Future studies are needed to dissect the metabolic role of CaSR not only for USI but also ileal protein sensing in energy balance and glucose homeostasis in obesity and diabetes.

Disclosure
R.J.W.Li: None. D.Barros: None. Y.Lim: None. S.Zhang: None. A.Gao: None. T.K.Lam: None.
1375-P: Effects of Irisin Administration on Pancreatic Islets of Diabetic Mice
Authors: MARRANO NICOLA , BIONDI GIUSEPPINA , BORRELLI ANNA , ROBERTO LUCA , CIGNARELLI ANGELO , PERRINI SEBASTIO , LAVIOLA LUIGI , GIORGINO FRANCESCO , NATALICCHIO ANNALISA 
Published: May 2022

Irisin is a hormone secreted by skeletal muscle following exercise or excess of saturated fatty acids (SFAs) , able to improve metabolic homeostasis and promote energy expenditure. Serum irisin levels are reduced in type 2 diabetes (T2D) , while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin protects human and rodent β-cells and pancreatic islets from SFAs-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) , and promotes β-cell proliferation, both in vitro and in vivo in healthy wild-type mice. Irisin may also restore the defective GSIS and reduce the high rate of apoptosis that are characteristic of islets from T2D patients. However, the β-cellular effects of irisin administration to diabetic mice are still unknown. 6 weeks-old C57Bl/6 mice (n = 8) were fed a high-fat diet (HFD, 60% of energy deriving from fat) for weeks and then intraperitoneally injected with streptozotocin (STZ, 100 mg/Kg) to induce diabetes. 4 standard diet (SD) -fed mice were used as control. HFD/STZ mice were then treated with 0.5 μg/g irisin (n = 4) or vehicle (n = 4) for 14 days. Glucose tolerance, glycemia, insulinemia, body weight, pancreatic islet architecture and function were assessed throughout the study. As expected, compared to SD mice, HFD/STZ mice showed higher glycemia and body weight, glucose intolerance, and reduced GSIS; in addition, HFD/STZ mice showed reduced islet volume (-78%) , β-cell area (-35%) , and insulin content (-60%) , while increased α-cell area (+54%) . Irisin administration significantly restored glycemia (-31%) , body weight (-13%) , glucose tolerance (-27%, AUC) , GSIS (+23%, AUC) , islet volume (+61%) , β-cell (+34%) and α-cell (-49%) areas, and insulin content (+36%) . Of note, irisin treatment induced a 9-fold increase in β-cell proliferation rate. These results show for the first time that irisin can restore β-cell functional mass when administered in vivo to diabetic mice.

Disclosure
N.Marrano: None. G.Biondi: None. A.Borrelli: None. L.Roberto: None. A.Cignarelli: None. S.Perrini: None. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi.

Funding
EU – ESF PON R&I 2014-20, AIM
1379-P: Combination of FGF21 and ß3-Adrenergic Treatment in Obese Mice
Authors: ZOUHAR PETR 
Published: May 2022

An induction of lipolysis by β3-adrenergic agonist CL316,243 (CL) increases plasma free fatty acid (FFA) level resulting later in ectopic lipid accumulation in liver. The peak of FFA stimulates insulin secretion and causes acute drop of blood glucose (BG) in chow-fed mice. This glucose-lowering effect is attenuated in insulin-resistant dietary obese (DIO) mice. Fibroblast growth factor 21 (FGF21) treatment increases insulin sensitivity while inhibiting lipolysis. Both FGF21 and CL induce uncoupling protein 1 (UCP1) in brown adipose tissue, increasing capacity for combustion of glucose. Thus, the FGF21 treatment has a potential to modulate the glucoregulatory action of CL. Here we aim to characterize the effect of the CL+FGF21 combination and to investigate the role of UCP1 in this effect. DIO C57Bl/6 mice were housed at 30 °C in order to minimize basal adrenergic tone. Animals were treated 2x daily with 65 μg FGF21 or its vehicle for 8 days. This treatment lowered insulin (increased insulin sensitivity) . Subsequently, the mice were injected with 35 μg CL or with saline. CL increased FFA and insulin in control mice, but did not affect BG (probably because of impaired insulin sensitivity) . The day after CL injection, 4-fold rise in ectopic lipid content in liver was observed in comparison to saline-treated group. In FGF21-treated mice, the CL-induced rise of NEFA and insulin was only transient, but sufficient to cause a drop of BG. The hepatic lipid accumulation after CL was completely preveted by FGF21. The same experimental set-up was repeated in DIO UCP1+/+ and -/- mice. Although the BG-lowering effect of the CL+FGF21combination was observed in both genotypes, the effect was significantly stronger in UCP1+/+. Thus, FGF21 sensitizes DIO mice to the BG-lowering effect of adrenergic stimulation while it prevents ectopic lipid accummulation. The drop of BG is observed even in the absence of UCP1, but UCP1 activity is required to reach the maximal BG-lowering effect of the combination.

Disclosure
P.Zouhar: None.

Funding
Czech Science Foundation (19-05356Y)