bluuebunny/crossref_metadata_2025 huggingface dataset:
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 >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 >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<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<0.05. HF USI: sal 1172±54 vs. cas 758.3±42 kcal, n=9, p<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<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<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<0.01; HF: MM cas 771.8±20 vs. LV-CaSR + cas 1240±89, n=4, p<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)
1384-P: Serum Fibroblast Growth Factor 1 Levels and Its Association with ß-Cell Function and Insulin Sensitivity in Adults with Glucose Intolerance
Authors: KIM JI YOON , CHOI JIMI , KIM SIN GON , KIM NAM HOON
Published: May 2022

Objectives: Beneficial role of Fibroblast growth factor 1 (FGF1) in the regulation of glucose metabolism and adipose tissue remodeling was suggested in rodents. We investigated an association between serum FGF1 levels and metabolic parameters in adults with glucose intolerance.

Research Designs and Methods: Serum FGF1 levels were examined using enzyme-linked immunosorbent assay in 92 individuals with glucose intolerance. Associations between serum FGF1 levels and metabolic parameters including body mass index (BMI) , waist circumference (WC) , glycated hemoglobin (HbA1c) and 75g oral glucose tolerance test-derived parameters including insulinogenic index (IGI) , Matsuda insulin sensitivity index (ISI) , and disposition index (DI) were examined.

Results: Mean age was 49.8 years, and mean BMI was 30.7 kg/m2 of 92 participants. Among them, 87% had type 2 diabetes. There was no significant association between serum FGF1 level and BMI or WC by using censored regression analysis. On the other hand, serum FGF1 level was higher in patients with higher HbA1c (β=0.369, p=0.014) . This association was significant after adjusting for age, sex, and BMI (p=0.005) . Notably, serum FGF1 level was negatively associated with IGI and DI (β=−0.462, p=0.017; β=−0.469, p=0.014, respectively) , but not with ISI. Mean FGF1 concentrations were significantly lower with higher quartiles of IGI and DI (p for trend=0.035 and 0.015 for IGI and DI, respectively) .

Conclusion: Serum concentration of FGF1 was significantly higher in individuals with higher blood glucose and lower insulin secretion, which suggests a possible role of FGF1 in the glucose metabolism, especially in the regulation of β cell function in humans.

Disclosure

J.Kim: None. J.Choi: None. S.Kim: None. N.Kim: None.
1387-P: Impacts of Androgen-Deprivation Therapy on Glucose Metabolism
Authors: GRITSKEVICH ELENA Y. , GRITSKEVICH ALEXANDER , DEMIDOVA TATYANA
Published: May 2022

Study Objective: to assess the impacts of androgen deprivation therapy (ADT) in prostate cancer (PCa) management on glucose metabolism Study Design: follow-up study

Materials and Methods: A total of 99 consecutive patients with PCa who received ADT followed-up at Pletnev and 62th Moscow Hospitals. The mean age was 69±8,64 y.o. Fasting plasma glucose (FPG) , HbA1c, body mass index (BMI) , waist circumference (WC) , were measured at baseline, after 3, 6 and 12 months ADT with gonadotropin releasing hormone agonists (GnRH agonists) . Ambulatory glycemic profiles (AGP) were obtained in patients with elevated glycemia who received ADT with GnRH agonists for at least 6 months by Flash glucose monitoring systems. Glucose variability indices (AUC, CONGA, JINDEX) were calculated.

Study Results: During ADT there were an increase in FPG and HbA1c over 12 months of ADT regardless of baseline age, BMI, WC, with a maximum increase during the first 3 months of treatment, and progressively after 6 months and 12 months. FPG (mmol/l) initially, 3, 6 and 12 months, were respectively 5,18±0,91; 5,67±0,93; 5,77±0,96; 5,90±1,12 (for all differences p ≤ 0.001) . HbA1c (%) 5,36+0,66; 5,66±0,83; 5,77±0,82; 5,89±0,83 (for all differences p ≤ 0.001) . The proportion of individuals with prediabetes were increased, according to ADA criteria (5,6-6.9 mmol/l) after 3 months 36%, after 6 months 41%, and after 12 months 66%. The impact on glucose metabolism ware in also AGP changes, manifested by an increase in the total daily glycemic load (mean AUC 172,49 (p≤0.001) , glycemic variability (mean CONGA 6,817 (p≤0.001) , and an increased in postprandial glycemia (JINDEX 22,945 (p≤0.001) . Conclusion: ADT with GnRH agonists did worsen metabolic parameters: early, progressive, clinically significant impair of glucose metabolism regardless of baseline age, BMI, WC. AGP deteriorations were increased of glucose variability, total glycemic load gained and peak glycemic values rose.

Disclosure

E.Y.Gritskevich: None. A.Gritskevich: None. T.Demidova: None.
1397-P: A Cocoa Butter–Based Ketogenic Diet Fails to Improve Glucose Homeostasis and Promote Weight Loss in Obese Mice
Authors: GREENWELL AMANDA A. , SAED CHRISTINA T. , DAKHILI SEYED AMIRHOSSEIN TABATABAEI , HO KIM , GOPAL KESHAV , CHAN JORDAN S.F. , KACZMAR OKSANA , DYER SCOTT A. , EATON FARAH , LOPASCHUK GARY , BATRAN RAMI A. , USSHER JOHN R.
Published: May 2022

Background: High-fat and very low-carbohydrate based ketogenic diets have gained considerable popularity as a non-pharmacological strategy for treating obesity due to their potential to enhance weight loss and improve glucose homeostasis. However, the effectiveness of a ketogenic diet towards metabolic health is equivocal.

Methods: Male and female mice were fed a 60% cocoa butter fat-based high-fat diet for 16-weeks to induce obesity, following which mice were transitioned to either an 85% cocoa butter fat-based ketogenic diet (KD) , a 10% cocoa butter fat-based low-fat diet (LFD) , or maintained on a high-fat diet for an additional 8-weeks. All experimental diets were matched for sucrose and protein content, and contained an identical micronutrient profile, with complex carbohydrates being the primary carbohydrate source in the LFD.

Results: The transition to a KD was ineffective at inducing significant body fat loss, improving glucose homeostasis, or enhancing insulin sensitivity in obese male and female mice. Alternatively, obese male and female mice transitioned to a LFD exhibited a marked decrease in body weight, which was primarily attributed to a loss of adiposity, and an improved glucose tolerance during an intraperitoneal glucose tolerance test. Despite the improvements in glucose tolerance, insulin sensitivity remained impaired in obese male mice transitioned to a LFD, whereas it was improved in obese female mice. These salutary actions attributed to a transition to a LFD resulting in beneficial body composition changes and improved glucose tolerance, may in part be due to the trend to mild reductions and increases in food intake and energy expenditure, respectively.

Conclusions: Our findings suggest that careful consideration should be taken when consuming a KD as a non-pharmacological strategy for treating obesity, whereas consumption of a diet low in saturated fat and rich in complex carbohydrates imparts numerous beneficial actions.

Disclosure

A.A.Greenwell: None. G.Lopaschuk: None. R.A.Batran: None. J.R.Ussher: None. C.T.Saed: None. S.Tabatabaei dakhili: None. K.Ho: None. K.Gopal: None. J.S.F.Chan: None. O.Kaczmar: None. S.A.Dyer: None. F.Eaton: None.
1401-P: Long-Term Metabolic Effects of Noncaloric Sweeteners
Authors: RATHAUS MORAN , AZEM LOZIANA , LIVNE RINAT , RON SOPHIE , RON IDIT , TIROSH AMIR
Published: May 2022

Accumulating evidence link sugar-containing foods and beverages to adverse health outcomes. Non-Caloric Sweeteners (NCSs) are an alternative sugar source that lead to reduction in calories, and may mitigate body weight gain and hyperglycemia, especially in patients with diabetes. Yet, contradicting studies suggest that NCSs may mediate metabolic derangements. Here, we aim to assess long-term metabolic effects of chronic consumption of NCSs. To this aim, mice consuming either regular diet or high fat diet (HFD) were supplemented with NCSs in their drinking water at concentrations consumed by humans. Under HFD, mice consuming reb M or sucralose had significant lower body weight compared to fructose. In comparison to fructose consumption, a significantly lower blood glucose levels were observed in mice under chow diet drinking either sucralose or reb M. Under HFD, a significant decrease in blood glucose levels was found only in mice consuming ace-k. On HFD, all NCSs other than saccharin, resulted in significantly improved insulin sensitivity compared to fructose. A significant decrease in fasting glucose was found only in sucralose and reb M groups under these conditions. A trend towards higher levels of plasma insulin was observed in mice under HFD drinking either fructose or saccharin. None of the interventions caused a decrease in fluid consumption as compared to water, nor were significant differences in daily food intake, daily caloric intake or energy expenditure. RER displayed a normal nocturnal pattern in all groups and no significant change in voluntary physical activity was observed. As compared to fructose, NCS consumption decreased markers of NAFLD in obesity.

In summary, our results suggest that chronic consumption of NCS do not result in any observed metabolic alternations, and may attenuate some of the metabolic derangements associated with fructose and high fat-based diet.

Disclosure

M.Rathaus: None. L.Azem: None. R.Livne: None. S.Ron: None. I.Ron: None. A.Tirosh: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Novo Nordisk, Sanofi, Consultant; Bayer AG, DreaMed Diabetes, Ltd., Research Support; Medtronic, Speaker's Bureau; Eli Lilly and Company.
1403-P: DA-1726, a Balanced GLP1R/GCGR Dual Agonist, Effectively Controls Both Body Weight and Blood Glucose
Authors: KIM TAE-HYOUNG , JUNG IL-HUN , KIM KYUMIN , LEE BORAM , KIM MI-KYUNG , CHAE YUNA
Published: May 2022

DA-1726 is a novel balanced long-acting oxyntomodulin (OXM) analogue, which is under preclinical development for the treatment of obesity. In this study, the pharmacological effects of DA-1726 were evaluated. DA-1726 exhibited a balanced dual action on GLP-1 receptor (GLP1R) and glucagon receptor (GCGR) in CHO-K1 cells transiently overexpressing each human receptor. In high-fat diet-induced obese mice, 3-week treatment of DA-1726 showed more body weight loss (BWL) and increasing energy expenditure than a pair-fed group. This means that the BWL effect of DA-1726 is due to decreased food intake and increased energy metabolism through GLP1R and GCGR action. In comparison with a GLP1R agonist, DA-1726 showed superior BWL, despite eating more food compared to semaglutide (SEMA) after 4-week treatment in obese mice. At the end of the study, DA-1726 significantly increased the expression of thermogenic genes (Ucp-1 and Ppargc1a) in white adipose tissue (WAT) , and increased WAT browning was histologically confirmed. In addition, DA-1726 inhibited adipocyte differentiation in vitro. Taken together, it suggests that the GCGR action of DA-1726 contributes to reduced adiposity by enhancing fat burning and inhibiting adipogenesis. OXM analogue biased to GCGR fails to control blood glucose despite GLP1R agonism. As a balanced analogue, DA-1726 effectively reduced postprandial glucose excursion in acute oral glucose tolerance test in normal mice. Notably, DA-1726 showed similar glycemic control and excellent BWL to SEMA in hyperglycemic and obese FATZO mice after 4-week treatment. Simultaneously, DA-1726 enhanced insulin sensitivity by significantly reducing fasting plasma insulin and glucose levels. Meanwhile, DA-1726 showed no hypoglycemia risk in overnight fasted normal mice unlike SEMA after a single injection, regardless of dose escalation. Our findings suggest that DA-1726 is a balanced GLP1R/GCGR dual agonist that effectively reduces body weight and blood glucose levels.

Disclosure

T.Kim: None. I.Jung: None. K.Kim: None. B.Lee: None. M.Kim: None. Y.Chae: None.
1407-P: Deletion of the Abi3 Immune Gene Locus in Mice Results in Obesity and Systemic Metabolic Disruption
Authors: SMITH DANIEL C. , KARAHAN HANDE , WIJERATNE H.R. SAGARA , AL AMIN MD MAMUN , MCCORD BRIANNE , MOON YOUNGHYE , KIM JUNGSU
Published: May 2022

Obesity is a global epidemic that affects 13% of adults world-wide, and over 40% of adults in the United States. Further, obesity contributes substantially to global morbidity and mortality and acts as a major risk factor for type II diabetes, among many other diseases. Therefore, efforts to understand the pathobiology of obesity and generate novel methods of prevention are paramount.

Recent findings suggest the importance of immune cells in the progression and onset of obesity, prominently including microglia, the immune cells of the central nervous system (CNS) , and peripheral macrophages. To this end, our project proposes to explore the role of these immune cells in the etiology and progression of obesity.

Our laboratory found that deletion of the Abi3 gene locus, which is a gene primarily involved in the regulation of actin dynamics within immune cells, resulted in the induction of obesity in mice. Specifically, mice lacking Abi3 had increased body weight and body fat percentage compared to wild-type mice. Additionally, mice without Abi3 showed impaired glucose tolerance and insulin sensitivity, but no changes in acute energy expenditure or food intake. Further, through RNA-seq analysis, we observed that deletion of the Abi3 gene locus substantially altered the expression of immune genes in both the CNS and peripheral tissue.

Through this study, we aimed to metabolically characterize mice with and without the Abi3 gene locus in order to discover the mechanisms by which this deletion alters central and peripheral immune cells to facilitate the onset of obesity. This and future studies will enable us to understand how perturbations to microglia and peripheral immune cells alter metabolic regulation to mediate susceptibility to metabolic disease.

Disclosure

D.C.Smith: None. H.Karahan: None. H.Wijeratne: None. M.Al amin: None. B.Mccord: None. Y.Moon: None. J.Kim: None.

Funding

Indiana University Diabetes and Obesity Research Training Program, DK064466
141-LB: Targeting Workflow Inefficienes to Improve Continuous Glucose Monitor (CGM) Prescription Rates in Type 1 Diabetes (T1D)
Authors: MAHALI LAKSHMI PRIYANKA , XU SHIMING , AGARWAL SHIVANI , MATHIAS PRIYANKA M.
Published: May 2022

Background: Racial/ethnic disparities exist in CGM prescription rates for people with T1D, and are associated with disparities in glycemic outcomes. We identified healthcare system inefficiencies that may be contributing to inequity and targeted interventions to improve prescription workflow.

Methods: At our large urban diabetes center, we used quality improvement (QI) methodology to implement and test changes in our CGM prescription workflow and examined effect on CGM prescription rates. Since October 2021, we collaborated with a specialty pharmacy to simplify CGM e-prescription for providers to improve device access for patients. We conducted PDSA cycles to add new office workflows for insurance prior authorization, standardize documentation, train support staff, and created change packages for spread across our diabetes practice sites. We examined effects by extracting monthly aggregate CGM prescription data from the electronic medical record and compared CGM prescription rates before and after initiation of the workflow.

Results: We included 717 people with T1D [mean age 38 years; 42.3% Hispanic (n=303) , 29% non-Hispanic Black (n=208) , 14.5% non-Hispanic White (n=104) , 14.3% other (n=102) ; 69% publicly insured]. In the five months since the introduction of the workflow, CGM prescriptions increased by 9.0% (49.4% to 58.4%) . CGM prescription rates in Hispanic and non-Hispanic Black patients were equivalent to White.

Conclusion: Simple, trackable, and iterative changes to CGM prescription workflows are feasible and can effectively increase CGM prescription rates in a short period of time. Further changes to clinic processes using QI methodology may result in meaningful improvements in outcomes.

Disclosure

L. Mahali: None. S. Xu: None. S. Agarwal: Advisory Panel; Medtronic, Consultant; Beta Bionics, Inc. P. M. Mathias: None.
142-OR: Global Extended Polygenic Score Predicts Incident Type 2 Diabetes in Women with History of Gestational Diabetes
Authors: CHOI JAEWON , LEE HYUNSUK , HAN MINSEOK , CHOI DAEHO , JANG HAK CHUL , PARK KYONG SOO , KWAK SOO HEON
Published: May 2022

Around 30-50% of women with history of gestational diabetes (GDM) develop type 2 diabetes (T2D) within years after parturition. However, the role of polygenetic score on prediction of T2D in these women is still unclear. We aimed to investigate the utility of global extended polygenic scores (gePS) in predicting incident T2D using GDM cohorts from 1) UK Biobank (N=941) , 2) Seoul National University Hospital (SNUH, N=357) , and 3) Korean Genome and Epidemiology Study (KoGES, N=379) . We calculated gePS for T2D using Bayesian regression and continuous shrinkage priors, with summary statistics from representative genome-wide association studies in Europeans and East Asians. We performed time-to-event analysis for incident T2D with gePS and assessed improvement of C-statistic when gePS was added to clinical risk factors. In addition, risk of T2D was estimated for those who were in the top percentile of gePS compared to the remainders. The incidence of T2D was 19.8% in UK Biobank, 28.3% in SNUH, and 23.5% in KoGES cohort with median follow-up duration of 28, 4, and 28 years, respectively. The normalized mean PRS for those who developed T2D was higher in each cohort: 0.25±1.vs. -0.06±0.99 in UK Biobank, 0.22±1.vs. -0.09±0.97 in SNUH, and 0.52±0.96 vs. -0.16±0.96 in KoGES (all P<0.01) . When meta-analyzed, adding gePS to clinical risk factors improved the C statistic from 0.715 (95% confidence interval [CI] 0.658-0.766) to 0.743 (95% CI 0.698-0.784) . The standardized gePS was associated with incident T2D in women with history of GDM when the results of the three cohorts were meta-analyzed: hazard ratio 1.68 (95% CI 1.52-1.86, P<0.001) . Furthermore, those who were in the top percentile had 3.52-fold increased risk of T2D: (95% CI 2.68-4.62, P<0.001) . To sum up, genetic information in women with previous GDM pregnancy could be used to identify those who are at high risk of future development of T2D and provide the opportunity for tailored prevention.

Disclosure

J.Choi: None. H.Lee: None. M.Han: None. D.Choi: None. H.Jang: None. K.Park: None. S.Kwak: None.
1426-P: Increased Insulin Secretion and Glucose Effectiveness Result in Improved Glucose Tolerance in Obese Subjects Two Months after Gastric Bypass and Sleeve
Authors: VISENTIN ROBERTO , BRODERSEN KATRINE , RICHELSEN BJØRN , MOLLER NIELS , MAN CHIARA DALLA , NIELSEN MICHAEL F.
Published: May 2022

The early effects of bariatric surgery on insulin secretion and action in obese subjects with type 2 diabetes (T2D) remains poorly investigated. Here we assessed the mechanisms resulting in improved glucose intolerance using the oral minimal model approach. An oral glucose tolerance test was performed before and 2 months after bariatric surgery in 16 obese T2D subjects (9 bypass, 7 gastric sleeve) and in 8 healthy control subjects. For each visit, body mass index (BMI) was measured, and the oral glucose and the insulin and C-peptide minimal models were used to estimate insulin sensitivity (SI) , glucose effectiveness (GE) , total β-cell responsiveness (Φtot) , disposition index (DI) and total hepatic insulin extraction (HE) . Bariatric surgery resulted in a significant reduction (similar between bypass and sleeve groups) in BMI by 14% (from 42±5 to 36±4 kg/m2) . Glucose tolerance increased comparably after bypass and sleeve, but remained impaired compared to the control group (Figure 1) : GE, Φtot, DI and HE were equally increased following bariatric surgery, whereas insulin action (SI) remained unaltered in the two groups. These results suggest that improved glucose tolerance in obese T2D subjects 2 months after bariatric surgery is attributable mainly to an increase in insulin secretion and glucose effectiveness rather than an improvement in insulin action.

Disclosure

R. Visentin: Research Support; Becton, Dickinson and Company, MannKind Corporation, Sanofi-Aventis Deutschland GmbH. K. Brodersen: None. N. Moller: None. C. Dalla Man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. M.F. Nielsen: None.

Funding

Novo Nordisk Foundation
1442-P: Association of Elevated Serum FABP1 with Hyperuricemia in Patients with Obesity and the Alteration after Sleeve Gastrectomy
Authors: QU SHEN , HUI YOU
Published: May 2022

Aims: FABP1’s relationship with obesity-related hyperuricemia remains unknown. We aimed to evaluate FABP1-level changes in patients with obesity-related hyperuricemia and changes after laparoscopic sleeve gastrectomy (LSG) .

Materials and Methods: Participants were categorized according to uric acid (UA) level: normal UA group (NUA, men≤420 μmol/L, women≤360 μmol/L) and high UA group (HUA, men>420 μmol/L, women>360 μmol/L) . The cross-sectional analysis included 123 non-obese individuals (NUA, n=90; HUA, n =33) and 76 patients with obesity (NUA, n =31; HUA, n =45) who underwent LSG. FABP1 levels were measured at baseline and 3, 6, and 12 months post-LSG.

Results: In non-obese individuals, FABP1 did not differ statistically between the NUA and HUA groups (15.52±15.62 ng/mL vs. 18.44±11.47 ng/mL, P=0.330) . However, in patients with obesity, FABP1 was positively correlated with UA and higher in the HUA than in the NUA group (32.47±22.35 ng/mL vs. 22.84±14.54 ng/mL, P<0.05) . Multiple linear regression found a positive correlation between FABP1 and UA (R2=0.101, β=0.317, 95% CI=0.020-0.110, P<0.01) , and binomial logistic regression found that FABP1 could predict HUA in patients with obesity (OR=1.031, 95% CI=1.002-1.061, P<0.05) . UA and FABP1 levels, whether in the NUA or HUA group, decreased at 3, 6, and 12 months postoperatively. But FABP1 decreased faster in the HUA than NUA group, and there was a statistical difference at 12 months.

Conclusions: FABP1 increased in obesity-related hyperuricemia in contrast to only obesity. And FABP1 decreased faster in the HUA than in the NUA group among obesity postoperatively. Key words: FABP1, Obesity, Hyperuricemia, Laparoscopic sleeve gastrectomy

Disclosure

S.Qu: n/a. Y.Hui: None.

Funding

NSFC 81700752，2021SYPDRC059
1446-P: Sex-Specific Effects of Nr4a1 in the Pancreatic Beta Cell
Authors: TESSEM JEFFERY S. , HERRING JACOB
Published: May 2022

A central aspect of type 2 diabetes disease progression is impaired functional β-cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the β-cell. Nr4a1 expression is decreased in the β-cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetics. Here we demonstrate sex specific effects of β-cell specific Nr4a1 deletion under high fat chow feeding. While female and male βNr4a1-/- mice were no different than wild type controls when fed a standard chow diet, a clear sex dependent difference is observed when fed a high fat diet. High fat fed male βNr4a1-/- have improved fasting and non-fasting blood glucose levels, high fat fed female βNr4a1-/- mice have impaired glucose tolerance as early as two months after beginning high fat feeding. Furthermore, female βNr4a1-/- mice have decreased β-cell mass and improved insulin tolerance. Given the sex specific differences in glucose tolerance, we demonstrated that female mice fed a high fat diet have increased circulating estrogen, and that treatment of INS-1 832/13 cells and primary mouse islets with estradiol resulted in increased expression of Nr4a1 and not the other two Nr4a family members. Our data suggest that Nr4a1 is critical for estrogen mediated maintenance of beta cell function and mass under obesogenic conditions, and that loss of Nr4a1 under conditions of obesity and overnutrition in females results in impaired beta cell compensation and function.

Disclosure

J.S.Tessem: None. J.Herring: None.

Funding

National Institutes of Health (1R15DK124835-01A1)
1449-P: Reducing Ghrelin Levels as a Novel Method to Increase Pancreatic Beta-Cell Mass
Authors: GUPTA DEEPALI , BURSTEIN AVI W. , SHANKAR KRIPA , VARSHNEY SALIL , SINGH OMPRAKASH , PAUL SUBHOJIT , OGDEN SEAN B. , OSBORNE-LAWRENCE SHERRI , METZGER NATHAN , RICHARD CORINE P. , ZIGMAN JEFFREY M.
Published: May 2022

Objective: Exogenous insulin remains the leading therapy for type 1 diabetes mellitus, T1D. However, current insulin formulations and delivery methods do not match the precision of functioning beta-cells, and even intensive monitoring of blood glucose and use of insulin pumps are not enough to halt frequent hypoglycemia, hyperglycemia and morbidity. Thus, regenerating beta-cells has become a major target of diabetes research to treat T1D. While the hormone ghrelin is well known to increase blood glucose, at least in part by inhibiting insulin secretion, ghrelin’s action on beta-cell mass and proliferation has heretofore not been explored in detail. Here, we sought to test the hypothesis that reducing ghrelin levels increases beta-cell mass.

Methods: Using histologic methods, we compared islet anatomy in ghrelin-knockout (ghrelin-KO) mice vs. wildtype littermates at three different ages: newborns (P0-P2) , juveniles (4-week-old) , and adults (10-12-week-old) . We also compared islet anatomy in adult wildtype mice, 4 weeks following conditional ghrelin-cell ablation vs. wildtype mice with intact ghrelin-cells. n= 4-8 mice per group and 33-433 islets per mouse.

Results: Ghrelin gene deletion or ghrelin-cell ablation increased mean islet area and mean islet insulin-immunoreactive (insulin-IR) area by 52-82 % and by 45-51 %, respectively, in juveniles and adults. Increased islet size was driven by an increased % of large islets. Increased insulin-IR area was associated with increased beta-cell number per islet. An increased % of large islets was also observed in newborn ghrelin-KO mice.

Conclusions: In mice, ghrelin plays an important role in controlling beta-cell mass. Reducing ghrelin levels for even short periods can increase islet size by increasing beta-cell numbers.

Disclosure

D.Gupta: None. C.P.Richard: None. J.M.Zigman: Research Support; Novo Nordisk Research Center Indianapolis, Novo Nordisk Research Center Indianapolis, Stock/Shareholder; Medtronic, Medtronic. A.W.Burstein: None. K.Shankar: None. S.Varshney: None. O.Singh: None. S.Paul: None. S.B.Ogden: None. S.Osborne-lawrence: None. N.Metzger: None.
1452-P: PDX1 and CKas Markers of Cell Maturation in the Human Pancreas
Authors: PROSHCHINA ALEXANDRA , KRIVOVA YULIYA , OTLYGA DMITRY , SAVELIEV SERGEY
Published: May 2022

Regeneration of beta-cell mass is one of the fundamental problems in diabetology. Embryonic source of all pancreatic cell types is the epithelial cells of the primitive ducts. During pancreas development, epithelial progenitors differentiate in three directions, which is accompanied by changes in cell phenotype, including the expression of various types of cytokeratins, transcription factors, as well as hormones and some other antigens. The early markers of pancreatic epithelial progenitors are the homeodomain transcription factor Pdx 1 (pancreatic and duodenal homeobox 1) and an intermediate filament protein cytokeratin (CK19) . The aim of our work was to analyze the distribution of Pdx1 and CKduring endocrine pancreas development in humans. The study was performed on the pancreatic samples from 27 fetuses (gestational age 14-40 weeks) using double and triple immunohistochemistry with antibodies to Pdx1, CK19, and insulin or glucagon. During human prenatal development, the co-expression of CKand Pdx1 was detected in several cell types. Firstly, it was observed in the epithelial cells of the pancreatic ducts. During the branching of pancreatic ducts, CKexpression decreased in outgrows, while the Pdx1 expression was lowered in large ducts. Secondly, co-expression of CKand Pdx1 was detected in endocrine cells (mainly in alpha) . However, the intensity of the reaction to both markers in these cells was low. Phenotype of beta cells was Pdx1+/ CK19−. At the same time, during development, some cells with an intense reaction to CKand Pdx1 were detected in the forming islets. Apparently, an intense reaction to CK19/Pdx1 may characterized low-differentiated (progenitor) cells that are present in the epithelium of ducts and in the forming islets during the development of the human pancreas.

Disclosure

A.Proshchina: n/a. Y.Krivova: None. D.Otlyga: None. S.Saveliev: None.
1454-P: A Transcriptomic Signature of Pancreatic Islet Leader Beta Cells
Authors: CHABOSSEAU PAULINE L. , YONG SU WERN FIONA , LOPEZ LIVIA , LECLERC ISABELLE , ALI YUSUF , MARTINEZ-SANCHEZ AIDA , RUTTER GUY A.
Published: May 2022

Pulsatile increases in Ca2+ within beta cells underlie the stimulation of insulin secretion at elevated glucose concentrations. Recent data obtained by imaging these transients in intact islets have revealed the existence of subpopulations of beta cells (“leaders”) which initiate Ca2+ waves across the syncytium and are critical for these dynamics. Whether leader cells possess unique transcriptional features is unknown. By combining Ca2+ imaging with cell labelling and isolation, we sought to address this question.

Method: Islets were isolated from C57BL6/J mice expressing the Ca2+ probe GCaMP6f selectively in beta cells. After infection with an adenovirus expressing photo-activable- (PA) mCherry, Ca2+ imaging was performed at 11mM glucose at 5 Hz. Leader (or follower) cells were identified and photopainted by PA-mCherry activation at 405nm. After islet dispersal, cell sorting was used to isolate single cells. cDNA libraries were obtained using NEBNext Single cell kit and used for sequencing (Illumina HiSeq 4000) . Reads were aligned to the mmtranscriptome with Salmon v1.3 and differential expression analysis performed with DESeq2. Differentially expressed genes were subjected to Gene Ontology analysis.

Results: cDNA was obtained from 13 leader cells, identified as those exhibiting the first Ca2+ signal increase during Ca2+ waves, and 9 follower cells. Of 96 differentially expressed genes, the most strongly affected included cell adhesion proteins (Cdh22; Scarf2) and the calcium sensor Mctp1. Other genes identified were involved in mitochondrial Ca2+ uptake (Mcub) , cytochrome assembly (Tmem177) and type 2 diabetes risk (Tcf7l2) . GO analysis identified 9 enriched functional clusters, including protein ubiquitination and metal ion binding.

Conclusion: Leader cells possess a stably altered transcriptome, and the affected genes include several which may regulate cell adhesion. The extent to which the identified genes reflect the contribution of these cells to Ca2+ wave initiation requires further study.

Disclosure

P.L.Chabosseau: n/a. S.Yong: None. L.Lopez: None. I.Leclerc: None. Y.Ali: n/a. A.Martinez-sanchez: None. G.A.Rutter: Advisory Panel; Sun Pharmaceutical Industries Ltd., Research Support; Sun Pharmaceutical Industries Ltd.
1456-P: Molecular Architecture of AR Action in Insulin Secretion in Male Pancreatic ß-Cells
Authors: MOTA DE SA PAULA , QADIR MIRZA MUHAMMAD FAHD , BLANDINO-ROSANO MANUEL , FAN JIA , XU WEIWEI , BERNAL-MIZRACHI ERNESTO , MAUVAIS-JARVIS FRANCK
Published: May 2022

Male mice lacking the androgen receptor (AR) in islet β cells exhibit blunted glucose-stimulated insulin secretion (GSIS) , leading to hypoinsulinemia and hyperglycemia. We showed that dihydrotestosterone (DHT) activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of GLP-1 in mouse and human islets. To gain information on DHT-stimulated signaling networks promoting GSIS, we combined functional proteomics with highly selective pharmacological inhibitors in male human islets, and islets from genetic mouse models. We found that DHT-stimulated GSIS in human islets involved a signaling cascade including focal adhesion kinases, the nonreceptor tyrosine kinase SRC, phosphoinositide 3-kinase, and the activation of mTOR complex 2. To define the early network of AR interacting proteins, we performed DHT-stimulated AR immunoprecipitation in INS1 832/3 cells followed by mass spectrometry-based proteomics. We will discuss the AR interactome including: 1) adenylate cyclase-modulating G proteins Gαs and Gαi, cAMP-dependent PKA, and the cAMP-dependent protein LASP1 regulating actin-based cytoskeletal activities; 2) Actin cytoskeleton remodeling proteins promoting actin depolymerization, and 3) Vesicular maturation including the lysosomal vacuolar-type ATPase acidifying insulin secretory granules and the prohormone convertase 2 involved in proinsulin processing. Notably, GLP-1 addition to DHT decreased AR interaction with all these proteins and promoted AR interaction with microtubule motor proteins promoting vesicular transport, proteins involved in exocytic vesicle docking to the plasma membrane, as well as small GTPase activating proteins and guanine nucleotide exchange factors involved in actin remodeling, as well as vesicle trafficking. Together these experiments provide novel insights into the architecture of AR action in enhancing GSIS.

Disclosure

P.Mota de sa: None. M.Qadir: None. M.Blandino-rosano: None. J.Fan: None. W.Xu: None. E.Bernal-mizrachi: None. F.Mauvais-jarvis: Consultant; Mithra Pharmaceutical.

Funding

National Institutes of Health (DK107444 and DK074970) U.S. Department of Veterans Affairs Merit Award (BX003725)
146-OR: Loss of Hydroxycarboxylic Acid Receptor 2 (HCA2) Affects Adipose Tissue Homeostasis in a Sex-Specific Manner during Prolonged Fasting
Authors: MCCAFFERTY KAYLEEN J. , BRINKER EMILY , GRAFF EMILY , STEURY TODD D. , GREENE MICHAEL W. , JUDD ROBERT L.
Published: May 2022

Hydroxycarboxylic acid receptor 2 (HCA2) , formally known as GPR109A, is a metabolite-sensing receptor expressed predominately on adipocytes, immune cells and intestinal epithelial cells. The primary endogenous ligand of HCA2 is β-hydroxybutyrate (βOHB) , which is elevated during periods of nutrient deprivation including fasting. Previous in vitro studies have suggested that βOHB activation of HCA2 on adipocytes inhibits lipolysis and serves as a negative feedback mechanism to prevent excess fat loss during fasting. However, the metabolic implications of this feedback mechanism have not been tested in vivo during a prolonged fast. To address this question, male and female C57BL/6J (WT) and HCA2 knockout (KO) mice were fasted in metabolic cages for 36 hours. No significant differences were observed for genotype or sex in RER, EE, or VO2. Following the fast, KO males exhibited a significant decrease in body weight compared to their WT counterparts. However, body weight was not significantly different between female WT and KO mice after fasting. Gonadal white adipose tissue (gWAT) depot weights were significantly lower in KO male mice compared to WT male mice, with no significant difference in gWAT weight between female WT and KO mice. Inguinal white adipose tissue (iWAT) depot weights were significantly lower for both sexes in KO mice compared to WT mice. KO males displayed significantly lower levels of circulating NEFAs compared to WT males. However, no differences in NEFAs were observed between female WT and KO mice. No significant differences were shown between groups for glucose, insulin, or βOHB. Therefore, this study demonstrates that mice lacking HCA2 possess a diminished capacity to regulate body and adipose tissue weight during a fast, which is observed to a greater extent in male mice.

Disclosure

K.J.Mccafferty: None. E.Brinker: None. E.Graff: None. T.D.Steury: None. M.W.Greene: None. R.L.Judd: None.