bluuebunny/crossref_metadata_2025 huggingface dataset:
1333-P: Therapeutic Potential of DA-1726, a Novel Oxyntomodulin Analogue, in a Diet-Induced NASH Mouse Model
Authors: JUNG IL-HUN , KIM TAE-HYOUNG , GOO MOON-JUNG , KIM MI-KYUNG , CHAE YUNA
Published: May 2022

DA-1726 is a novel balanced long-acting GLP-1/glucagon receptor dual agonist, which is under preclinical development for the treatment of obesity. DA-1726 represented a superior efficacy to semaglutide (SEMA) in weight loss in various animal studies. In this study, we evaluated the therapeutic potential of DA-1726 for the treatment of nonalcoholic steatohepatitis (NASH) . To induce NASH, male mice were given a diet containing 40% total fat, 20% fructose, and 2% cholesterol for 30-week. After then DA-1726 and SEMA were subcutaneously injected every three days for 8-week. At the end of treatment, vehicle control, DA-1726 (100 or 200 nmol/kg) and SEMA (250 nmol/kg) significantly reduced body weight compared to baseline (+10.4%, -8.9%, -17.2%, and -12.9%, respectively) . Plasma clinical chemistry parameters (ALT, AST, ALP and T-BIL) and hepatic fat accumulation were significantly decreased by DA-1726. The reduction of plasma glucose and total cholesterol induced by DA-1726 200 nmol/kg was superior to that of SEMA. In a histopathological analysis of steatosis, lobular inflammation, and ballooning in the liver, DA-1726 showed an excellent improvement in NAFLD Activity Score compared to SEMA (NAS: 6.75 for vehicle control, 3.88 and 3.63 for DA-1726, and 5.00 for SEMA) . Liver fibrosis was assessed by Masson Trichrome stain. Improvement of hepatic fibrosis by DA-1726 was also observed (fibrosis score: 1.88 for vehicle control, 1.25 and 1.13 for DA-1726, and 1.50 for SEMA) . In the liver tissue, the expression of inflammatory (Tnfa, Il-1β, and Ccl2) and fibrotic (Acta2, Timp1, Col1a1, Col3a1, and Mmp9) genes were significantly decreased by DA-1726 treatment. In particular, the DA-1726 low-dose group showed a higher efficacy despite lower weight loss compared to SEMA. This is thought to be a result of the dual actions of DA-1726 to GLP-1 and glucagon receptors. Taken together, our findings suggest that DA-1726 has a therapeutic potential for NASH in addition to obesity and type 2 diabetes.

Disclosure

I.Jung: None. T.Kim: None. M.Goo: None. M.Kim: None. Y.Chae: None.
1337-P: Sex-Specific Variation in Lipid Metabolism in Response to Nutritional Stress Is Associated with Differences in NASH Progression
Authors: MOON MACKENZIE , MURALI ANJANA , BELLO FIONA , WANG JIEBIAO , JURCZAK MICHAEL J.
Published: May 2022

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the US, encompassing a disease spectrum defined by steatosis, inflammation (NASH) , and fibrosis. Although the incidence of NASH is less in women compared with men, the mechanistic basis for this phenomenon is unclear. The aim of this study was to use high-resolution LC-MS/MS proteomics to determine sex-specific differences in liver protein abundance in healthy mice and in response to NASH that may contribute to protection in females. Male and female C57BL6J mice were fed regular chow (RC) or fast food (FF) diet (40% fat, 0.15% cholesterol, 42 g/L high-fructose corn syrup drinking water; n=18-20/g) to induce NASH. Liver weight and steatosis were significantly increased in male and female FF mice compared to RC counterparts, and the effects were more pronounced in males versus females. Plasma insulin and ALT followed similar patterns. Label-free differential mass spectrometry identified 2,917 proteins, where 314 and 445 proteins exhibited statistically significant changes in expression associated with sex and diet, and 2proteins showed a significant sex x diet interaction. Unsupervised hierarchical clustering of the 2proteins identified four groups of proteins defined by sex-specific differences in baseline abundance or response to FF-diet. Enrichment analysis of proteins within the four groups identified biological process related to 1) lipid catabolism and synthesis that were upregulated in FF males compared with females; 2) catabolism and oxidation-reduction reactions that were suppressed by FF diet in males but not females and 3) acyl-CoA hydrolase activity and fatty acid oxidation that were higher in RC females than males and induced by FF in males but not females. These data suggest that sex-specific differences in liver lipid metabolism at baseline and in response to nutritional stress may contribute to sexual dimorphism in NASH susceptibility.

Disclosure

M.Moon: None. A.Murali: None. F.Bello: None. J.Wang: None. M.J.Jurczak: None.

Funding

National Institutes of Health (DK114012)
1340-P: The Insulin Sensitivity Index Derived from Euglycemic Clamps Is Correlated to Liver Fat Content Determined by Magnetic Resonance Spectroscopy In Type 1 Diabetes
Authors: MERTENS JONATHAN , BRASPENNING RIE , VANHEVEL FLORIS , SPINHOVEN MAARTEN , FRANCQUE SVEN , DE BLOCK CHRISTOPHE
Published: May 2022

Background: NAFLD is strongly associated with type 2 diabetes. Insulin resistance is proposed as a major contributor. NAFLD is increasingly reported in type 1 diabetes (T1D) , but whether insulin resistance is linked to NAFLD in this population needs elucidation. Furthermore, T1D is an excellent model to investigate insulin resistance in relation to NAFLD without confounding by autologous insulin production.

Aims and Methods: We aimed to assess whether insulin resistance is correlated with liver fat content (LFC) in adults with T1D without causes of secondary liver fat accumulation. A hyperinsulinemic-euglycemic clamp (HEC) was performed according to DeFronzo et al. LFC was measured by magnetic resonance spectroscopy (MRS) and calculated as the mean of three independent regions of interest. NAFLD was diagnosed by LFC > 6.0 % and NAFLD subjects were matched 1:1 to no-NAFLD controls based on age and sex.

Results: 20 subjects with an age of 48 ± 17 y, a BMI of 27.3 ± 4.3 kg/m2, and a HbA1c of 7.3 ± 0.8 % were included. Mean M-index (HEC-derived index of insulin sensitivity) was 5.12 ± 3.03 mg/kg/min. Mean LFC was 15.6 ± 8.3 % (NAFLD) versus 2.8 ± 1.4 % (controls) , p < 0.001. Mean M-index differed significantly (2.88 ± 1.58 [NAFLD] vs. 6.74 ± 2.[controls] mg/kg/min, p < 0.001) . BMI was significantly higher in the NAFLD group (29.6 ± 3.6 vs. 25.1 ± 3.8 kg/m2, p = 0.014) . There was a strong correlation between the M-index and LFC (r = -0.85, p < 0.001) . Linear regression showed a significant association between LFC (dependent) and M-index (B = -1.504, 95% CI: (-2.9to -0.101) , p = 0.037) and BMI (B = 0.879, 95% CI: (0.047 to 1.711) , p = 0.040) but not age or HbA1c level as independent variables.

Conclusion: HEC-derived measures of insulin resistance are strongly correlated to LFC in people with T1D, independently from BMI. These data support the pivotal role of insulin resistance in NAFLD pathophysiology and as a target for NAFLD therapy in T1D.

Disclosure

J.Mertens: None. R.Braspenning: None. F.Vanhevel: None. M.Spinhoven: None. S.Francque: None. C.De block: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk, Research Support; Indigo Diabetes, Speaker’s Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk.
1346-P: Obesity and Type 2 Diabetes in Patients with NAFLD Are Independently Associated with the Risk of Liver Fibrosis, Insulin Resistance, and Atherogenic Dyslipidemia
Authors: MATHEWS APRIL , KALAVALAPALLI SRILAXMI , GODINEZ EDDISON , LOMONACO ROMINA , DILLARD RACHEL E. , GONZALEZ MARIA A. , MARANGI STEPHEN A. , SHETTY SHWETHA S. , SHRESTHA SULAV , MANSOUR LYDIA , CONNELLY MARGERY A. , CHUN KELLY Y. , BARB DIANA , CUSI KENNETH
Published: May 2022

Obesity (OB) and type 2 diabetes (T2D) are associated with NAFLD and a worse cardiometabolic profile. However, their independent contribution to steatosis, fibrosis, insulin resistance (IR) and atherogenic dyslipidemia are controversial. To this end, we examined the prevalence of NAFLD and hepatic fibrosis in 199 patients (64 with T2D, 135 without T2D) screened from outpatient endocrinology and primary care clinics. NAFLD/fibrosis was assessed by transient elastography (liver fat by controlled attenuation parameter/CAP; fibrosis by liver stiffness measurement/LSM) . Patients were divided into groups either with or without obesity (OB) or T2D. Within each group, patients were well matched for age, BMI, A1c and AST/ALT. The impact of obesity was best observed on the prevalence of steatosis, that increased from pts without OB or T2D (controls = C) to OB/no-T2D (OB) and OB/T2D (C: 40% vs. OB: 64% vs. OB/T2D: 86%, both p<0.vs. C) . The impact of T2D was best observed by the increasing prevalence of liver fibrosis (C: 4% vs. OB: 9% vs. OB/T2D: 25%; p=0.30, 0.01, respectively vs. C) . HOMA-IR (primarily hepatic IR, C: 2.5±0.3 vs. OB: 4.3±0.5 vs. OB/T2D: 6.0±0.6, p<0.vs. C) and adipo-IR (adipose tissue IR, C: 2.8±0.3 vs OB: 4.3±0.6 vs. OB/T2D: 5.4±0.6, p<0.vs. C) followed the worsening impact of OB and T2D. Finally, there was an independent, stepped worsening of HDL-C with obesity and T2D (C: 58±18 vs. OB: 50±vs. OB/T2D: 44±mg/dL; p<0.01) and a worsening trend of TG with T2D (C: 110±78 vs. OB: 110±62; p=0.98, and OB/T2D: 148±79 mg/dL; p<0.vs. C) . LDL-C did not follow this pattern as closely.

In conclusion, obesity and T2D increase the prevalence of NAFLD (more driven by OB) and hepatic fibrosis (more driven by T2D) . This is associated with a continuous worsening of IR and of atherogenic dyslipidemia. The clinical implication is that both factors need to be addressed for the prevention of cirrhosis and of cardiovascular disease in NASH.

Disclosure

A.Mathews: None. L.Mansour: None. M.A.Connelly: Employee; LabCorp. K.Y.Chun: None. D.Barb: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. S.Kalavalapalli: None. E.Godinez: None. R.Lomonaco: None. R.E.Dillard: None. M.A.Gonzalez: None. S.A.Marangi: None. S.S.Shetty: None. S.Shrestha: None.

Funding

National Institutes of Health (R01DK120331-01A1 - R01DK120331-02)
1348-P: Roux-en-Y Gastric Bypass Prevents Obesity-Induced Fatty Liver by Modulating Liver Lipocalin Type Prostaglandin D2 Synthase Expression
Authors: SRIVASTAVA ANKITA , STEVENSON MATTHEW , PALAIA THOMAS , HALL CHRIS , LEE JENNY , RAGOLIA LOUIS
Published: May 2022

The obesity epidemic is associated with an increased prevalence and severity of type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) . Bariatric surgery has become a widely accepted treatment for individuals with severe obesity and obesity related health problems. Previous studies from our lab have implicated the role of lipocalin-type prostaglandin D2 synthase (L-PGDS) in adipose tissue dysfunction and NAFLD. Our lab has also shown the effect of Roux-en Y gastric bypass (RYGB) on body weight changes, improvement to insulin sensitivity and adipose tissue physiology. In the current study, we examined the effects of L-PGDS using both diet-induced obesity (DIO) and RYGB models. We found reduced expression of L-PGDS in liver of DIO mice after 14 weeks on high fat diet. We then performed RYGB surgery in DIO mice and compared the effects of diets (normal chow and HFD for 6 weeks) on post-operative outcomes of RYGB. Our results show that both surgery and diet contribute to the substantial improvement in liver weight and HOMA-IR. H&E images of liver sections also demonstrate that both diet and surgery play significant roles in reversal of NAFLD. Interestingly, we only found significant increase to liver L-PGDS expression after RYGB when HFD is administered. We conclude that both surgery and diet plays a significant role in modulating the expression of L-PGDS in liver of obese mice. Thus, our study shows that L-PGDS may serve as a novel therapeutic target in treatment of obesity and NAFLD.

Disclosure

A.Srivastava: None. M.Stevenson: None. T.Palaia: None. C.Hall: None. J.Lee: None. L.Ragolia: None.

Funding

American Heart Association: (#15GRNT22420001) and The George Link Foundation
135-OR: Health Care Utilization among Medicare Beneficiaries with Diabetes during the COVID-Pandemic
Authors: ZHOU XILIN , ROLKA DEBORAH B. , ANDES LINDA J. , IMPERATORE GIUSEPPINA
Published: May 2022

The COVID-pandemic has abruptly impacted health care systems. Using data from Medicare claims we examined the pandemic-related changes in health care utilization among fee-for-service beneficiaries with diabetes. We included persons with diabetes who were aged ≥ 67 and enrolled in both Part A and B programs for all months of the index year and the previous year. Diabetes was identified by having at least one inpatient or two outpatient claims that were diabetes related. We considered utilization by setting (acute inpatient, emergency room, hospital outpatient [HOP], physician office, and ambulatory surgery center [ASC] procedures) and by media (telehealth and in-person) . Utilization was measured as per person use of each type of health care service for each month from Jan. 2018 to Jun. 2021. We quantified the changes in utilization with a fixed-effect model for all post-pandemic months (3/2020-6/2021) and three phases (3/2020-5/2020; 6/2020-12/2020; and 1/2021-6/2021) . We found that health care services usage by setting was 8% to 18% lower than the pre-pandemic level (Table) . Phase 1 had the largest decrease in utilization. In phase 3, utilization was still lower than the pre-pandemic level for most service types, except HOP visits and ASC procedures. We also found a large increase in telehealth visits, although the increase was not large enough to compensate for the decrease in in-person office visits.

Disclosure

X.Zhou: None. D.B.Rolka: None. L.J.Andes: None. G.Imperatore: None.
1353-P: Activation of Brown Adipose Tissue by Low-Protein Diet Ameliorates Hyperglycemia in Lipodystrophic Diabetic Mice Model
Authors: MUNOZ MARCOS D. , ZAMUDIO ALEXA , MCCANN MAXIMILIAN A. , LIEW CHONG WEE
Published: May 2022

Long-term ad libitum dietary restriction such as low-protein diet (LPD) improves metabolic health and extends the life span of mice and possibly humans. However, most studies conducted thus far have focused on the preventive, but not therapeutic, potential of LPDs. Previously we shown that LPD (5.1% kcal from protein) was able to improve postprandial blood glucose values of the lipodystrophic IRFKO (adipose-specific insulin receptor knockout) mice after 14 days with strong activation of interscapular brown adipose tissue (iBAT) and increase energy expenditure. To determine whether iBAT activation was responsible for the hyperglycemia normalization after the LPD treatment, we surgically denervated iBAT of IRFKO mice before LPD treatment. Blood glucose were measured twice a week for up to 4 weeks, at the end of the monitoring mice were subjected to indirect calorimetry assessment (Promethion, Sable Systems) . Our data showed that surgical denervation of iBAT abolished the hyperglycemia normalization effect of LPD in the IRFKO mice. Morphologically, surgical denervation also prevented the ‘browning’ effect of LPD on the whitening iBAT observed in IRFKO mice. In line with the morphological data, LPD failed to induce thermogenic markers including UCP1 and BMP8b in denervated iBAT. In contrast, iBAT denervation has lesser effects on the LPD-induced energy expenditure and circulating FGF21 level, possibly due to compensation by beige fat formation in the inguinal WAT. Together, our data confirms that hyperglycemia normalization caused by LPD on IRFKO is iBAT activation dependent. Our observation suggests that blood glucose could be utilized to fuel LPD-induced iBAT activation as a mechanism for amino acid homeostasis. Further experimentation needs to be done in order to narrow down the mechanism driving this phenomenon. Taken together, our data suggest that short-term LPD could be a potential strategy for the treatment of metabolic syndrome.

Disclosure

M.D.Munoz: None. A.Zamudio: None. M.A.Mccann: None. C.Liew: None.

Funding

NIH RDK109015A1
1365-P: Intermittent Fasting Modifies Pancreatic Glucosensor Mechanism In Diabetic Mice
Authors: VILCHES-FLORES ALONSO , PADILLA-ROMERO YAZMIN
Published: May 2022

Background: A specific feature in type-2 diabetes is beta-cell dysfunction, associated to reduction in glucose-stimulated insulin secretion. This function is high-regulated by the glucose sensor mechanism, conformed by GLUT2 and glucokinase, and their expresión is decreased in type-2 diabetes. Intermittent fasting is a recent option in diet control, with alternate cycles of fasting and feeding. In this study we evaluated intermittent fasting in diabetic mice, and its long-term effect in pancreatic GLUT2 and glucokinase expression.

Methods: C57BL6 mice were fed with high fat diet for eight weeks, and then intermittent fasting cycles among four weeks. Weight, total caloric intake, fasting and glucose tolerance were determinated. Changes in insulin and glucokinase expression were evatualed by immunohistochemistry assays. Glucose-stimulated insulin secretion, and PDX1, insulin, GLUT2 and glucokinase mRNAs were analyzed in isolated islets.

Results: Intermittent fasting caused weight loss, reduction in total caloric intake decrease and enhanced glucose tolerance. In diabetic mice, glucose-stimulated insulin secretion was restored after intermittent fasting, without significant changes in hormone content. Treated groups with fasting increased gene expression of PDX1, insulin and GLUT2, but decreased glucokinase mRNA and localization in beta-cells, but enhanced alpha-cell possitive presence.

Conclusion: Intermittent fasting modifies glucosensor mechanism in pancreatic islets from diabetic mice, through GLUT2, PDX1 and insulin expression, but glucokinase. On future studies we will determine changes glucokinase enzymatic activity, and another transcription factors involved in these effects.

Disclosure

A.Vilches-flores: None. Y.Padilla-romero: None.

Funding

UNAM PAPIIT IN225819
137-LB: Unmet Social Needs and Uptake of Recommended Diabetes Processes of Care in a High-Need, High-Cost Medicaid Population
Authors: DURU O. KENRIK , KLOMHAUS ALEXANDRA M. , MANGIONE CAROL , MOIN TANNAZ
Published: May 2022

Diabetes patients with unmet social needs (e.g., housing instability, food insecurity) may be less able to complete recommended processes of care than patients without these challenges. We examined survey data from a multi-state sample of Medicaid patients with diabetes (n=6,087) identified by UnitedHealthcare as high-cost, high-need based on utilization over the past year, who were enrolled in a comprehensive care coordination intervention by Optum. Before receiving any intervention services, patients reported whether they experienced housing instability, food insecurity, transportation problems, need for help with utilities, or feared for their interpersonal safety at baseline. We used data from administrative claims to measure whether these patients had 4 recommended processes of care completed within the last 18 months: 1) retinal exam, 2) ACE/ARB medication or nephropathy screening, 3) A1c testing, or 4) statin prescription ordered. We examined the cross-sectional association between unmet social needs and processes of care using multivariate logistic regression, controlling for clustering by zip code. The analytic sample was 50% White and 61% female, with 5.6 documented comorbidities on average. Overall, rates of unmet social need varied from 4% for concerns about interpersonal safety to 16% for transportation problems. Only 52% of patients had a retinal exam during the study window, 69% were prescribed a statin, 88% had their A1c checked, and 95% were taking an ACE/ARB medication or had nephropathy screening. In the regression analyses, we did not find statistically significant associations between any of the unmet social needs and the processes of care (all p values >0.05) . In this analysis of high-cost, high-need Medicaid patients, barriers other than unmet social needs may underpin difficulties with achieving recommended processes of care for diabetes, particularly retinal exams and statin use that are completed at lower rates.

Disclosure

O. Duru: None. A. M. Klomhaus: None. C. Mangione: n/a. T. Moin: None.

Funding

Centers for Disease Control and Prevention U18DP006128
137-OR: A Genetic Approach to Detangling the Heterogeneity of Fasting Insulin Levels
Authors: SEVILLA MAGDALENA , GOODARZI MARK O. , DICORPO DANIEL A. , ROTTER JEROME I. , MEIGS JAMES B. , UDLER MIRIAM , MANNING ALISA
Published: May 2022

Fasting insulin (FI) is a heterogeneous trait with high variability between individuals and populations. Increased FI is associated with an increased risk of type 2 diabetes (T2D) and its complications, including coronary artery disease (CAD) and hypertension (HTN) . We hypothesize that we could use a genetic approach to cluster FI-associated variants, characterize the clusters in terms of insulin processes within the Mexican American Cardiovascular Disease Study (MACAD; N=821) , and test for association of polygenic scores (PS) created from these clusters with T2D, CAD and HTN in three cohorts: Mass General Brigham Biobank (MGBB; N=18,127) , Aspirin in Reducing Events in the Elderly (ASPREE; N=13,349) , and Framingham Heart Study (FHS; N=7,145) . We identified six clusters using a soft clustering approach with 446 FI-increasing genetic alleles and 27 FI-related traits. Associations in two of the clusters, allowed us to characterize them and show their impact on T2D and T2D-associated complications. The first cluster had alleles associated with increased subcutaneous and visceral adiposity and was characterized by reduced insulin sensitivity (from euglycemic clamp; P=0.02) , increased insulin secretion (from oral glucose tolerance test [OGTT]; P=0.04) , and increased insulin clearance (from euglycemic clamp; P=0.02) in MACAD. This cluster’s PS was associated with HTN (MGBB Odds ratio (OR) = 1.04, P=0.013) , T2D (MGBB OR = 1.04, P =0.001) and CAD (MGB OR=1.07, P =0.008; ASPREE OR=1.04, P =0.036) The second cluster had alleles associated with a lipodystrophy phenotype and was characterized by increased insulin secretion (from OGTT P =0.019) in MACAD. We observed associations of the PS with T2D (MGBB OR= 1.13, P =2.3x10-10) and HTN (MGBB OR = 1.06, P =0.001) which were replicated in ASPREE and FHS. Our results suggest the presence of two different FI-associated genetic domains and elucidate the deleterious mechanisms by which increased FI is associated with T2D and T2D complications.

Disclosure

M.Sevilla: None. M.O.Goodarzi: None. D.A.Dicorpo: None. J.I.Rotter: None. J.B.Meigs: Consultant; Quest Diagnostics. M.Udler: None. A.Manning: None.

Funding

UM1DK078616
1373-P: Changes in Body Composition Are Associated with Improvement of ß-Cell Function and Insulin Sensitivity after Short-Term Intensive Insulin Therapy in Patients with Newly Diagnosed Type 2 Diabetes
Authors: XU CHANGLIU , LI YANBING , LIU LIEHUA
Published: May 2022

Objective: To investigate the change of muscle strength and body composition during short-term intensive insulin therapy (SIIT) and their association with treatment effects in patients with newly diagnosed type 2 diabetes (T2DM) .

Research Design and Method: Patients with newly diagnosed T2DM were treated with SIIT to normalized blood glucose for at least 1 week. Physical examination including measurement of body diameters (neck circumference, upper arm circumference, waist circumference, hip circumference, thigh circumference, and calf circumference) , muscle strength (grip strength, the five-repetition sit-to-stand test, and the 30-second sit-to-stand test) , and body composition (body fat mass, muscle mass) , were performed. HbA1c and standardized mixed meal challenge tests were performed before and after the therapy.

Results: A total of 53 patients were included. After SIIT, the muscle strength of the lower limbs was significantly enhanced. The average time of the five-repetition sit-to-stand test was shortened from 7.24s±1.58s to 6.15±1.21 (P<0.001) , and the average number of the 30-second sit-to-stand test increased from 24.23±5.56 to 27.69±5.96 (P<0.001) . The HOMA-IR and β-cell function also improved after SIIT. And the baseline thigh circumference was correlated with the change of both HOMA-IR (rs=-0.296 P=0.035) and the insulinogenic index (IGI) (rs=0.373 P=0.006) after SIIT. The fat mass at baseline was also correlated with improvements in both HOMA-IR (rs=-0.368 P=0.021) and the IGI (rs=0.424 P=0.007) after therapy.

Conclusion: The muscle strength of the lower limbs was promoted after SIIT. Improvements in β-cell function and insulin sensitivity after SIIT in newly diagnosed T2DM patients are associated with changes in body composition but there are no relations with muscle strength.

Disclosure

C.Xu: None. Y.Li: None. L.Liu: None.

Funding

the National Natural Science Fund of China (81800716) , the science and technology program of Guangzhou, (202002020053)
1378-P: Chronic Sleep Deprivation Impaired Bone Formation in Growing Rats and Downregulated PI3K/AKT Signaling in Bone Tissues
Authors: DUAN XIAOYE , GUO LIXIN
Published: May 2022

Background: Sleep deprivation (SD) , recognized as a public health epidemic, impaired glucose metabolism, yet little is known about the association between sleep and bone health.

Methods: Twenty 5-week-old male Wistar rats and randomly divided into the CSD and normal control (NC) groups after one-week acclimatization. After a 6-week intervention of sleep deprivation, the distal femurs of both groups were harvested for micro-computed tomography scans and histological analysis. Meanwhile, the femur tissues were measured the mRNA and protein expression via RNA sequencing and immunohistochemical analysis. Serum bone turnover markers were evaluated at 0, 2, 4, and 6 weeks.

Result: CSD impaired the bone growth, showing an imbalance of bone turnover status, dysphasia in the metaphysis growth plate, and deterioration of bone microarchitecture. Further, CSD suppressed bone formation, showing that the expression of osteogenesis-related proteins (col1α1 and osteocalcin) and mRNA (igf1, bglap, runx2, col1α1, pth1r) are down-regulated. Differentially expressed genes were detected, and functional enrichment analyses revealed that the PI3K/AKT pathway was significantly down-regulated in the CSD group. While Diabetic cardiomyopathy, Oxidative phosphorylation, and Neurodegenerative disease-related pathways were up-regulated.

Conclusion: These results suggest that CSD can significantly impaired bone health, and it may exert these effects in part by suppressing bone formation and osteoblast differentiation, and inactivating the PI3K/AKT signaling pathway.

Disclosure

X.Duan: None. L.Guo: None.

Funding

National Natural Science Foundation of China (Grant No. 81670763 and 81471050)
1383-P: Relationship between Body Fat Mass and Insulin Resistance in Nonobese Patients with Idiopathic Hypogonadotropic Hypogonadism and Normal Glucose Tolerance
Authors: XU HUAN , CHEN XUEYAN , YANG XUBIN , XU WEN
Published: May 2022

Objective: The purpose of this study was to investigate the relations between body fat mass and insulin resistance in non-obese patients with idiopathic hypogonadotropic hypogonadism (IHH) and normal glucose tolerance.

Methods: A total of 42 patients with IHH and BMI lower than 28 kg/m2 from January 2013 to October 2017 were recruited. Patients were required to have a normal glucose tolerance test for inclusion in the study. Ten Healthy subjects having a routine physical examination and a normal glucose tolerance test were also recruited as control group. Laboratory studies included fasting insulin, testosterone, and lipids. Waist circumference (WC) , weight, and body fat mass were measured, and waist-to-hip ratio (WHR) , body mass index (BMI) , HOMA-IR, and LogHOMA-B were calculated. Data were compared between groups, and linear regression was used to determine relations.

Results: Blood pressure, fasting glucose, BMI, WHR, and lipids were similar between the groups. Fasting insulin levels (15.61 ± 7.66 mIU/L vs. 7.60 ± 3.84 mIU/L) , logHOMA-B (2.39 ± 0.29 vs. 2.03 ± 0.21) , HOMA-IR (3.38 ± 1.71 vs. 1.64 ± 0.91) , and body fat mass (30.49 ± 9.46% vs. 21.± 4.31%) were significantly greater in the IHH group compared with those in control group (all, P < 0.05) . Multivariable linear regression showed that in IHH patients body fat mass was an independent predictor of fasting insulin level (β = 0.71, 95% confidence interval [CI]: 0.54, 0.88, P < 0.01) , LogHOMA-B (β = 0.02, 95% CI: 0.001, 0.032, P < 0.05) , and HOMA-IR (β = 0.14, 95% CI: 0.09, 0.18, P < 0.05) .

Conclusion: Body fat mass is an independent predictor of insulin resistance in IHH patients with normal glucose tolerance.

Disclosure

H.Xu: None. X.Chen: None. X.Yang: None. W.Xu: None.

Funding

This study was supported by Natural Science Foundation of Guangdong Province [2018A030313915]; Medical Scientific Research Foundation of Guangdong Province of China [A2018286].
14-LB: Clinical Utility of KidneyIntelX on Patients with Early-Stage Diabetic Kidney Disease—A Real-World Evidence Study
Authors: TOKITA JOJI , DONOVAN MICHAEL J. , FIELDS ROBERT
Published: May 2022

Introduction: KidneyIntelX is a multiplex immunoassay of 3 plasma biomarkers with 7 clinical variables combined using machine-learning to generate a risk score for progressive decline in kidney function over 5 years in individuals with early-stage diabetic kidney disease (DKD) .

Methods: A Population Health defined Mount Sinai approved care pathway for DKD patients informed by the KidneyIntelX test was introduced into the Mount Sinai Health System in New York, NY as part of a Real World Evidence (RWE) study (NCT04802395) . Decision impact of medication management (anti-hypertensives, SGLT2 inhibitors/GLP1 agonists) and specialist referral was tracked. An interim analysis was performed for 1) Assessing comparability between RWE and a published clinical validation cohort based on KidneyIntelX risk score distribution; 2) Determining if necessary EHR clinical fields were captured; 3) Identifying early evidence of KidneyIntelX impact on provider decision-making.

Results: Between Mar-Nov 2021, 1,112 patients had KidneyIntelX test results, with post-test follow up to 36 weeks. The risk breakdown of RWE population was similar to the clinical validation cohort [High 14% vs. 17%, intermediate 40% vs. 37% and low risk 46% vs. 46%]. EHR record review for care changes confirmed ability to meet study objectives. Compared to patients scored low risk, there were changes in anti-hypertensives (OR 3.0; 95% CI 1.6-5.6) , initiation of SGLT2i/GLP-1a (OR 6.4; 95% CI 2.9-14) and increased referrals to nephrologists, endocrinologists, or dieticians (OR 2.8;95% CI 1.7-4.7) in patients scored as high-risk (Figure) .

Conclusions: KidneyIntelX was successfully deployed in a health care system in a comparable population to the validation cohort with high data capture fidelity. Application of guideline-based

therapies and specialist referral increased in the proportion to reported risk level by 3-6 and >2-fold, respectively.

Disclosure

J. Tokita: None. M. J. Donovan: Employee; Renalytix. R. Fields: None.
140-OR: Machine Learning for Metabolite Estimation to Examine Contributors to Glucose Homeostasis and Adiposity: The GUARDIAN Consortium
Authors: ALLRED NICHOLETTE , AINSWORTH HANNAH C. , GUO XIUQING , MACKAY ADRIENNE W. , NYASIMI FESTUS , MELIA OWEN , LIANG YANYU , BOWDEN DONALD W. , TAYLOR KENT , RAFFEL LESLIE J. , BUCHANAN THOMAS A. , WATANABE RICHARD M. , ROTTER JEROME I. , WAGENKNECHT LYNNE E. , LANGEFELD CARL D. , IM HAE K.
Published: May 2022

Diabetes is characterized by metabolic dysregulation. Metabolomics captures interactions of cellular processes and environmental exposures to promote disease and can improve mechanistic understanding to identify clinically relevant targets. However, use is limited by cost and sample availability. To facilitate investigation, machine learning approaches were used in the Insulin Resistance Atherosclerosis Family Study (n=943 Mexican Americans) with empiric metabolites (Metabolon HD4) and GWAS data to generate genetically regulated metabolite estimation models for broad application. 950 metabolites were heritable. Ridge and LASSO regression had cross validated correlation >0.1 for 448 metabolites. In an independent set, LASSO (enforcing sparsity) outperformed Ridge (full polygenic architecture) regression. Estimation was extended to the GUARDIAN Consortium (n∼4377) to assess the association of genetically predicted metabolites with glucose homeostasis and adiposity. Multiple associations (FDR P<0.05) were observed. For glucose homeostasis, mannose, which predicts diabetes development, was inversely associated with glucose effectiveness (P=7.1E-3) . For adiposity, urate was positively associated with BMI and waist circumference, capturing lifestyle contributions. In addition, three uncharacterized metabolites were associated with measures of adiposity (P=0.014-3.1E-6) suggesting this approach could contribute to metabolite characterization.

In conclusion, we have developed algorithms for estimating 448 metabolites using genetic data that had good performance in an independent dataset. Estimation models were used to assess association with glucose homeostasis and adiposity highlighting known and novel associations and demonstrating utility. Future work will expand genetic coverage to include rare variants and phenotypic associations to further characterize metabolic dysregulation.

Disclosure

N.Allred: None. L.J.Raffel: None. T.A.Buchanan: None. R.M.Watanabe: None. J.I.Rotter: None. L.E.Wagenknecht: None. C.D.Langefeld: None. H.K.Im: None. H.C.Ainsworth: None. X.Guo: None. A.W.Mackay: None. F.Nyasimi: None. O.Melia: None. Y.Liang: None. D.W.Bowden: None. K.Taylor: None.

Funding

R01DK118062
1408-P: Acute Aerobic Exercise Unveils Serum Metabolomics Markers That Distinguish Overweight and Healthy Weight Individuals
Authors: NELSON ALISA B. , CHOW LISA S. , HUGHEY CURTIS C. , MYERS CHAD , HAN XIANLIN , CRAWFORD PETER A. , PUCHALSKA PATRYCJA
Published: May 2022

Exercise confers metabolic benefits to both normal weight and overweight populations. Responses of the metabolome to acute aerobic exercise may predict cardiovascular fitness and longer-term outcomes, including the development of diabetes and its complications. We applied an LC-MS based untargeted metabolomics platform to evaluate the effect of acute exercise on the serum metabolome of overweight trained (OWT, n = 11, HOMA-IR 1.6 ± 0.1) and normal weight trained (NWT, n = 14, HOMA-IR, 0.9 ± 0.2, p < 0.01) runners. Trained individuals were studied to limit the effects of a deconditioned acute stress response. While NWT and OWT metabolic profiles shared increased circulating acylcarnitines and free fatty acids (FFAs) with exercise, intermediates of adenine metabolism, inosine and hypoxanthine, were strongly correlated with body fat percentage (R = 0.67) and VO2max (R = 0.70) . Untargeted metabolomics-guided follow-up quantitative lipidomic analysis revealed that, as expected, baseline levels of fatty acid esters of hydroxy fatty acids (FAHFAs) were generally diminished in the OWT group. FAHFAs negatively correlated with visceral fat mass and HOMA-IR. Strikingly, a 4-fold decrease in FAHFAs was provoked by acute aerobic running in NWT, an effect that negatively correlated with circulating IL-6 (R ≤ -0.7) . These effects of exercise were not observed in the OWT group. Machine learning models based on a profile including FAHFAs, FFAs, and adenine intermediates predicted 53% of the variation in cardiovascular fitness. Taken together, these findings in relatively insulin resistant overweight human participants and healthy controls have implications for metabolic crosstalk between adipose tissue and skeletal muscle and support the notion that FAHFAs could modulate the inflammatory response, fuel utilization, and insulin resistance.

Disclosure

A.B.Nelson: None. L.S.Chow: Other Relationship; Dexcom, Inc. C.C.Hughey: None. C.Myers: None. X.Han: None. P.A.Crawford: Advisory Panel; Abbott Diabetes, Johnson & Johnson Global Services. P.Puchalska: None.

Funding

NIH (DK091538, AG069781, DK098203, TR000114, UL1TR002494)
141-OR: Associations between Type 2 Diabetes Partitioned/Process-Specific Polygenic Scores and Metabolic Traits
Authors: WEDEKIND LAUREN E. , HSUEH WEN-CHI , KOBES SAYUKO , BAIER LESLIE , BOGARDUS, III CLIFTON , KNOWLER WILLIAM C. , MAHAJAN ANUBHA , MCCARTHY MARK , HANSON ROBERT L.
Published: May 2022

Polygenic scores (PS) for type 2 diabetes (T2D) associate strongly with disease status. Since T2D is heterogenous, using “partitioned” PS (pPS) that capture distinct etiological processes may improve clinical utility. A previous study in Europeans identified 6 pPS from genetic clusters (GCs) based on association patterns across traits, among 3T2D-associated variants: adiposity (GC1) , lipids (GC2) , insulin action (GC3) , beta cell function (GC4, GC5) , and mixed features (GC6) . Few data exist on how pPS associate with T2D and subphenotypes in non-European populations.

The current analysis reconstructed these pPS using genotypes for 245 of the 3variants captured in a genome-wide association study in an Indigenous study population from the Southwest US. pPS associations were analyzed with T2D (N=7659) , % body fat (PFAT, non-diabetic only, n=557) , insulin action from hyperinsulinemic-euglycemic “clamp” (logM, non-diabetic only, n=557) , and acute insulin response from an IVGTT (lgAIR, normal glucose tolerance only, n=404) . Results (table) show that T2D pPS strongly associate with the subphenotype corresponding to the putative etiologic mechanism.

These results demonstrate transferability of the phenotypic classifications of the T2D pPS and suggest that genetic influences on adiposity, insulin action, and insulin secretion contribute to development of T2D in this population.

Disclosure

L.E.Wedekind: None. W.Hsueh: None. S.Kobes: None. L.Baier: None. C.Bogardus: None. W.C.Knowler: None. A.Mahajan: Employee; Genentech, Inc. M.Mccarthy: Employee; Genentech, Inc. R.L.Hanson: None.
1414-P: Dapagliflozin Protects Human Cardiac Progenitor Cells from Deleterious Effects of the Secretome from Visceral Adipose Cells of Obese Subjects
Authors: PALMA GIUSEPPE , CACCIOPPOLI CRISTINA , DORIA ROSSELLA , GENCHI VALENTINA ANNAMARIA , SANTARPINO GIUSEPPE , CIGNARELLI ANGELO , NATALICCHIO ANNALISA , LAVIOLA LUIGI , PEZZOLLA ANGELA , GIORGINO FRANCESCO , PERRINI SEBASTIO
Published: May 2022

Dysfunction of visceral and epicardial adipose tissue may alter heart performance and promote adverse cardiovascular outcomes in obesity and diabetes. We assessed whether the secretome from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes might affect the viability of human cardiac progenitor cells (hCPC) in human obesity, and the effects of dapagliflozin (DAPA) , a selective SGLT-2 inhibitor. ASC and mature adipocytes were isolated from AV and E adipose tissue biopsies of obese (Ob) and non-obese subjects, respectively. hCPC were isolated from right auricle biopsies of non-Ob, non-diabetic donors. hCPC were pretreated with uM DAPA for 24 h or left untreated, and then exposed to the conditioned media (CM) of AV-ASC, E-ASC, and AV mature adipocytes. The CM of AV-ASC, E-ASC, and AV mature adipocytes induced apoptosis, assessed by ELISA for cytoplasmic oligonucleosomes, in hCPC after 24 h (p<0.05) . Exposure of hCPC to the CM of AV-ASC, E-ASC, and AV mature adipocytes for 24 h also resulted in impaired organization of the hCPC actin filaments, assessed by indirect immunofluorescence (p<0.05) . In addition, the CM of AV-ASC, E-ASC, and AV mature adipocytes induced c-Jun phosphorylation, a measure of JNK activation, after 4 h and 8 h (p<0.05) . Importantly, these effects were not observed when the hCPC were exposed to the CM of AV-ASC, E-ASC, and AV mature adipocytes from non-Ob subjects. Pretreatment of hCPC with DAPA resulted in reduced apoptosis and less impairment of actin filaments following exposure to the CM of AV-ASC, E-ASC, and AV mature adipocytes (p<0.05) , as well as in reduced c-Jun phosphorylation (p<0.05) .

In conclusion, in human obesity, the secretome of both AV and E ASC and mature adipocytes induces stress kinase activation in hCPC and impairs their viability and functionality, and these effects can be counteracted by SGLT-2 inhibitors directly acting on the hCPC.

Disclosure

G.Palma: None. 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. S.Perrini: None. C.Caccioppoli: None. R.Doria: None. V.Genchi: None. G.Santarpino: None. A.Cignarelli: None. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. A.Pezzolla: None.
1418-P: Effect of Eight-Hour Time-Restricted Eating vs. Daily Calorie Restriction on Cardiovascular Disease Risk Factors in Adults with Obesity
Authors: LIN SHUHAO , CIENFUEGOS SOFIA , GABEL KELSEY , EZPELETA MARK , VARADY KRISTA , CHAKOS KAITLIN , MCSTAY MARA , MULAS ANDREA
Published: May 2022

Background: Time restricted eating (TRE) is a form of intermittent fasting that involves confining the period of eating to 8-h and fasting with zero-calorie beverages for 16-h. Short-term studies (2-3 month) suggest that 8-h TRE produces moderate weight loss and improves blood pressure and plasma lipids. What remains unknown is whether these improvements by TRE would become more pronounced over longer periods of time (6-months) , and whether these benefits are comparable to that of daily calorie restriction (CR) .

Objective: Accordingly, this study compared the effects of 8-h TRE versus CR and a no-intervention control group on body weight and cardiovascular disease risk factors in adults with obesity over 6-months.

Design: Adults with obesity (n = 63) were randomized to 1 of 3 interventions for 6-months: 8-h TRE (ad libitum eating between 12:00 to 8:00 pm, fasting between 8:00 to 12:00 pm) ; CR (25% energy restriction daily) ; or control (ad libitum food intake with no meal timing restrictions) .

Results: By month 6, body weight decreased (P = 0.02) by CR (-4.9 ± 1.4%) but not TRE (-3.4 ± 0.7%) , versus controls (-0.7 ± 1.1%) . Diastolic blood pressure was significantly (P = 0.04) reduced by TRE (-4.0 ± 1.4 mm Hg) , but not CR (-0.1 ± 1.7 mm Hg) , versus controls (1.6 ± 1.5 mm Hg) . Changes in systolic blood pressure, fat mass, visceral fat mass, lean mass, LDL cholesterol, HDL cholesterol, triglycerides, and heart rate did not differ between groups at month 6. Adherence to 8-h TRE remained high throughout the trial, i.e. subjects adhered to the 8-h eating window on 6 ± 0.1 days/week.

Conclusions: These preliminary findings suggest CR may produce greater weight loss compared to TRE over 6-months. While TRE did not produce significant weight loss, the diet did lower diastolic blood pressure. This would suggest that this intermittent fasting regimen may produce improvements in cardiovascular parameters in the absence of body weight reductions.

Disclosure

S. Lin: None. S. Cienfuegos: None. K. Gabel: None. K. Varady: None. A. Mulas: None.

Funding

NIH-NIDDK (1R01DK128180 - 01A1)
1422-P: The Potential of Semaglutide Once-Weekly in Patients without Type 2 Diabetes with Weight Regain or Insufficient Weight Loss after Bariatric Surgery
Authors: LAUTENBACH ANNE , WERNECKE MARIE , STOLL FABIAN D. , MEYHÖFER SEBASTIAN M. , MEYHÖFER SVENJA , ABEREL JENS
Published: May 2022

Background: About 20-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after bariatric surgery (BS) associated with relapse of obesity-related comorbidities. Therefore, we aimed to assess the effectiveness of Semaglutide once-weekly as synthetic analogue of the hormone GLP-1 in patients without type 2 diabetes (T2D) with WR or IWL after BS.

Methods: Post-bariatric surgery patients without T2D with WR or IWL (n=48) were included in the analysis. The primary endpoint was weight loss 3 and 6 months after initiation of add-on treatment with Semaglutide. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP, pancreatic lipase and liver enzymes.

Results: Patients initiated Semaglutide approximately 64.4 months [interquartile range (IQR) 27-97 months] after BS. Mean postoperative weight regain after reaching weight nadir following surgery to initiation of Semaglutide was 11.5kg and 12.9%, respectively. Over 3.2 (IQR 3.0-3.5 months) (n=36) and 5.8 months (IQR 5.8-6.4 months) (n=14) taking Semaglutide, mean total weight loss was 6.2% (IQR 3.5-8.6%) and 9.8% (IQR 5.8-13.3%) , respectively. Categorical weight loss data indicate that 64% of patients reached more than 5% weight loss, 17% more than 10% weight loss and 6% more than 15% weight loss at visit 2. With regard to type of surgery, there were no significant differences in drug-induced total weight loss (p=0.8) .

Discussion and Conclusion: Weight loss options for excess weight management in post-bariatric surgery patients are limited. Our results suggest that post-bariatric patients with WR or IWL may benefit from add-on treatment with Semaglutide once-weekly. Our results might be the basis for a prospective randomized-controlled trial to evaluate larger cohorts of patients to determine if Semaglutide once-weekly may close the gap between lifestyle intervention and revision surgery to treat weight recidivism or IWL after BS.

Disclosure

A.Lautenbach: Advisory Panel; Novo Nordisk, Speaker's Bureau; Boehringer Ingelheim International GmbH, Novo Nordisk. M.Wernecke: None. F.D.Stoll: None. S.M.Meyhöfer: None. S.Meyhöfer: None. J.Aberel: Advisory Panel; Novo Nordisk, Speaker's Bureau; Novo Nordisk.