bluuebunny/crossref_metadata_2025 huggingface dataset:
1108-P: Care Cascade Engagement and Characteristics of Diabetes Awareness in Adult Samoans in 2010 and 2018
Authors: RIVARA ANNA C. , RUSSELL EMILY M. , VIALI SATUPAITEA , REUPENA MUAGUTUTIA SEFUIVA , NASERI TAKE K. , POMER ALYSA , MINSTER RYAN L. , WEEKS DANIEL E. , MCGARVEY STEPHEN T. , HAWLEY NICOLA
Published: June 2021

We describe diabetes care cascade engagement in 2010 and 2018 in adult Samoans and identify the characteristics of diabetes awareness. Participants were from a 2010 study of Samoans (n=2980, 24.5-< 65 years old), n= 500 of whom were followed-up in 2018 (32.5-72.5 years old). At follow-up individuals with a genetic variant associated with lower fasting glucose were oversampled by design. Care cascade components included diabetes prevalence (fasting glucose ≥ 126 mg/dL or diabetes medication use), self-report of doctor’s diagnosis of diabetes (awareness), diabetes medication use, and meets recommended glycemic control (fasting glucose ≤ 130 mg/dL). Percentage loss (proportion of individuals lost from each preceding stage) and unmet need of care (total prevalence - proportion of participants with controlled diabetes) were estimated. Characteristics associated with awareness were examined with logistic regression. In 2010, 469/2980 (15.7%) participants had diabetes, 242 (48.4% loss) were aware, 215 (11.1% loss) reported medication use, and 33 (84.6% loss) met glycemic control (unmet need of 92.9%). In 2018, 146 (29.2%) had diabetes; 61 (57.8% loss) were aware; 48 reported medication use (22.6% loss), and 7 (85.4% loss) met glycemic control (unmet need of 95.2%). Each year of added age (OR 1.07 [1.04-1.10] in 2010 and OR 1.06 [1.01-1.11] in 2018), and higher material lifestyle scores, a proxy for socioeconomic position, (OR 1.16 [1.02-1.33] in 2018) were associated with higher odds of diabetes awareness, and higher BMI (OR 0.93 [0.90-0.96] in 2018) and OR 0.94 [0.89-0.99] in 2018) and smoking (OR 0.49 [0.31-0.78] in 2010) with lower odds of awareness. We observed a very high level of unmet need in diabetes care and a high proportion of participants lost within the care cascade at both time points. Greater odds of disease awareness with increasing socioeconomic position in 2018 suggest that socioeconomic constraints may limit care engagement.

Disclosure

A. C. Rivara: None. N. Hawley: None. E. M. Russell: None. S. Viali: None. M. Reupena: None. T. K. Naseri: None. A. Pomer: None. R. L. Minster: None. D. E. Weeks: None. S. T. Mcgarvey: None.

Funding

National Institutes of Health (R01HL093093, R01HL140570, R01HL133040)
1109-P: The Effect of Neighborhood Food Environment on Diabetes Risk: A Multilevel Analysis of the Veterans Administration Diabetes Risk Cohort
Authors: KANCHI RANIA , LOPEZ PRISCILLA M. , RUMMO PASQUALE E. , LEE DAVID C. , ADHIKARI SAMRACHANA , SCHWARTZ MARK D. , AVRAMOVIC SANJA , SIEGEL KAREN R. , ROLKA DEBORAH B. , IMPERATORE GIUSEPPINA , ELBEL BRIAN , THORPE LORNA
Published: June 2021

Diabetes causes significant morbidity and mortality among adults in the US, yet incidence varies across the country, suggesting that neighborhood factors may contribute to geographic disparities in diabetes. In this longitudinal study, we examined the association between neighborhood food environment and risk of newly diagnosed (“incident”) diabetes in different communities (high density urban, low density urban, suburban, and rural).

We created a retrospective dynamic, national cohort of 6,082,018 diabetes free US veterans identified from the Veterans Affairs electronic health records, enrolled between 2008 and 2016, and followed through 2018. Incident diabetes was defined as: 2 clinical encounters with diabetes ICD codes, a documented prescription for diabetes medication other than metformin or acarbose alone, or 1 clinical encounter with diabetes ICD codes and 2 elevated A1C (≥6.5%). Five-year average counts of fast-food restaurants and supermarkets relative to all other food outlets were used to generate two census tract-level neighborhood measures. We examined the association between food environment and incident diabetes using piecewise exponential survival models with county-level random effects.

The average age of cohort participants was 59 years; the majority were non-Hispanic white (76.3%) and male (92.2%). Relative density of fast-food restaurants was associated with a modest increased risk of diabetes in all community types; adjusted hazard ratios (aHR) in high density urban, low density urban, and suburban communities were each 1.1, in rural communities was 1.2 (p < 0.05 for all). Relative density of supermarkets was associated with lower diabetes risk in suburban and rural communities only (aHR 0.7, 0.8, respectively, p <0.05).

Neighborhood fast food and supermarkets influenced diabetes risk among US veterans in multiple community types, suggesting potential avenues for action to address the diabetes burden.

Disclosure

R. Kanchi: None. G. Imperatore: None. B. Elbel: None. L. Thorpe: None. P. M. Lopez: None. P. E. Rummo: None. D. C. Lee: None. S. Adhikari: Research Support; Self; Johnson & Johnson. M. D. Schwartz: None. S. Avramovic: None. K. R. Siegel: None. D. B. Rolka: None.

Funding

Centers for Disease Control and Prevention
112-LB: Pulsatile Insulin Treatment as a Treatment Option for Patients with Type 2 Diabetes and Stage 3 Kidney Failure
Authors: QUACH SOPHIA , MANESSIS ANASTASIOS
Published: June 2021

In healthy individuals, insulin is secreted by the pancreatic ß-cells in a pulsatile fashion with about 10-12 pulses/hour. Loss of this pulsatility is one of the first indications of ß-cell dysfunction leading to type 2 diabetes. This pulsatility of insulin secretion is considered a trigger mechanism for the regulation of hepatic gluconeogenesis and for maintaining the sensitivity of peripheral metabolic and vascular insulin receptors. Various attempts have been made over the last 30 years to use pulsatile i.v. insulin infusion therapy for treatment of diabetes and secondary complications. The purpose of this prospective randomized pilot study was to investigate the effect of once weekly PIT (2 h vs. 3 h procedures) over a period of 3 months on parameters of kidney function in patients with type 2 diabetes and chronic renal failure. Of the 22 enrolled type 2 patients, 17 performed the trial per protocol. They received a total of 10 PIT procedures. Observation parameters measured at baseline and endpoint were HbA1c, GFR, body weight, blood pressure, creatinine, nerve perception thresholds, and treatment satisfaction. At endpoint, there were no significant differences between the two groups. GFR improved by 10.8 % and creatinine decreased by 6.8 %. Stable results were seen for HbA1c, body weight and blood pressure. No changes were seen in nerve perception thresholds for any of the investigated sensory fiber qualities. The treatments were well tolerated. However, 8 treatment events of muscle cramps were reported for 5 patients during the PIT procedures. In conclusion, an improvement in kidney function and treatment satisfaction was observed after 3 months of PIT in patients with type 2 diabetes and renal failure, irrespective of the duration of the procedure. The results of this pilot trial will now be used to design an appropriate confirmatory study to investigate the effect of PIT when given in addition to standard of care treatment vs. standard of care alone.

Disclosure

S. Quach: None. A. Manessis: Advisory Panel; Self; Medtronic, Research Support; Self; IQVIA, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation, Sanofi US.
1131-P: Clinical Prediction Models for MODY Genetic Testing in the United States Monogenic Diabetes Registry
Authors: MULLIGAN ROBERT P. , LETOURNEAU-FREIBERG LISA R. , BOWDEN TIANA L. , TIAN PERSEPHONE , KANDASAMY BALAMURUGAN , PHILIPSON LOUIS H. , GREELEY SIRI ATMA W. , NAYLOR ROCHELLE N.
Published: June 2021

The University of Chicago National Monogenic Diabetes Registry houses a novel dataset of people presenting with possible or known monogenic diabetes and has over a decade of data points, despite the rarity of the disease relative to T1DM and especially T2DM. Currently, determination of genetic testing, including which specific panel or genes is most appropriate to sequence, is a manual process introducing variability and subjectivity.

Aim: To test and compare performance of several models against the manual process and each other in identifying maturity-onset diabetes of the young (MODY) from available clinical information.

Methods: Statistical models for prediction of monogenic diabetes were applied to clinical data for cases suspected of having MODY. The models tested in the study with this dataset ranged from the traditional methods of regression to more modern approaches of neural nets, classification trees, clustering, and other machine learning algorithms for classification of MODY against type 1 and type 2 and a possible subset of monogenic diabetes subtypes.

Results: Using a sample size of N=330, with 70 testing positive for either GCK, HNF1A, or HNF4A, exploratory data models were able to achieve 75-80% validation accuracy (random validation data set at 10-20% of N) while internal human classification accuracy was roughly 42% over the same samples. The traditional logistic regression and neural net had equivalent performance.

Conclusions: The 3750 participants within the Registry and more than a decade of follow-up presents a unique opportunity to assess which clinical features are most predictive in identifying those with monogenic diabetes. The results of this work will direct future testing efforts within the Registry to assist in efficient diagnosis of these uncommon yet clinically important forms of diabetes.

Disclosure

R. P. Mulligan: None. L. R. Letourneau-freiberg: None. T. L. Bowden: None. P. Tian: None. B. Kandasamy: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. S. W. Greeley: None. R. N. Naylor: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK020595)
1134-P: Polygenic Risk Score of Type 2 Diabetes as a Predictive Factor for Macrovascular Complications: A Prospective Population-Based UK Biobank Study
Authors: JUNG SANGHYUK , KIM DOKYOON , SHIVAKUMAR MANU , WON HONG-HEE , YUN JAE-SEUNG
Published: June 2021

Background: We aimed to investigate the associations between polygenic risk score (PRS) for T2DM and future risk of cardiovascular disease (CVD) in middle-aged UK Biobank participants of European ancestry.

Methods: We used data from UK Biobank participants aged 40-69 years at baseline, registered from 22 assessment centers across the United Kingdom with standardized procedures. Genome-wide PRSs were constructed using >9 million genetic variants, and newly developed myocardial infarction (MI), ischemic stroke, and cardiovascular (CV) mortality were considered as outcomes. Cox proportional hazard models were used to analyze the relationship between PRSs and CV mortality with stratification by age, sex, and lifestyle behavior.

Results: Of 362,405 participants having European ancestry, 8,787 (2.4%) experienced cardiovascular events and 2,414 (0.7%) died due to CVD during a median follow-up of 8.9 years. Risk of CV mortality and of myocardial infarction (MI) were both significantly associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.73 [1.23-2.44] and HR of MI 1.55 [1.24-1.96], P <0.001). By contrast, the risk of ischemic stroke was not associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.24 [0.87-1.79], P =0.232). Adherence to an unfavorable lifestyle in the very high genetic risk group was further associated with a substantially increased risk of CV mortality (HR 6.38 [3.46-11.77]) and with risk of MI (HR 3.28 [2.02-5.32]). There was no evidence of significant interaction between PRS and lifestyle behavior in predicting the risk of CVD.

Conclusion: PRS for T2DM is an independent predictive factor for future CVD and associated mortality in the white, middle-aged population. PRS-based genetic risk assessment could be useful to identify individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CVD.

Disclosure

S. Jung: None. D. Kim: None. M. Shivakumar: None. H. Won: None. J. Yun: None.
115-OR: Microbiome Antigens as a Vaccination Strategy in Type 1 Diabetes
Authors: KOSTIC ALEKSANDAR
Published: June 2021

Type 1 diabetes (T1D) is an autoimmune disorder that results from T cell-mediated destruction of the insulin-producing β cells of the pancreatic islets. Accumulating evidence from both human and animal studies points to the gut microbiome, the 100 trillion microbes inhabiting our intestinal tract, as a key component driving the inflammatory processes leading to T1D. However, the mechanisms therein are poorly understood. We propose that this inflammatory milieu occurs in the pancreas, where microbes or microbial fragments that translocate from their usual luminal, mucosal sites persist and induce the cytokine and chemokine signals needed for destructive, autoimmune cellular and humoral responses that destroy the insulin producing β cells. By controlling this inflammation via vaccination against a highly conserved microbial surface antigen, poly-N-acetyl glucosamine (PNAG), we can decrease the inflammatory response such that vaccination prevents diabetes. In analyses of human and murine pancreatic islets, we have found that PNAG is readily detectable within diabetic, but not healthy, pancreases and associated with both T cells and polymorphonuclear cells (PMNs). This finding suggests that inducing an effective immune response that can clear PNAG-containing microbes or microbial fragments may be critical in counteracting the microbiota-driven inflammation leading to autoimmunity. We report that NOD female mice vaccinated against PNAG exhibited a drastic reduction in diabetes incidence from in 70% of 21 controls to 17% of 18 PNAG-immune mice. Immunophenotyping on these mice indicates that PNAG vaccination dramatically increases Foxp3+ Tregs as well as CD4+ and CD4- IL-10-producing cells. Taken together, our work provides evidence that the translocation of microbial antigens to the pancreas may drive inflammation leading to T1D, and that vaccination against one particular microbial antigen, PNAG, may lead to protection against this disease.

Disclosure

A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-13 to A.K.)
1152-P: Elucidating Protective Mechanisms of Targeting of hOGG1 to Mitochondria on the HFD-Induced Insulin Resistance in Mice Lacking OGG1
Authors: YUZEFOVYCH LARYSA , PASTUKH VIKTOR M. , RACHEK LYUDMILA
Published: June 2021

Ogg1 (8-oxoguanine DNA glycosylase-1) is a DNA glycosylase mediating the first step in the base excision repair which removes 8-oxoguanine and repairs oxidized nuclear and mitochondrial (mtDNA). Obesity-induced mtDNA damage heightens mitochondrial oxidative stress, which leads to the development of insulin resistance. Thus, it is important to understand molecular mechanisms by which mtDNA damage induces insulin resistance and to develop therapies including preventative and treatment strategies. Previously we found that mitochondrial targeting of human OGG1 (mt-hOGG1) ameliorated high fat diet (HFD)-induced insulin resistance in Ogg1 deficient (KO) mice in both genetic model (KO/TG mice) and via TAT-protein delivery using intraperitoneal injections (Diabetes 68, Suppl 1, 2019). As we previously demonstrated that Ogg1 contributed to HFD-induced insulin resistance via hepatic insulin resistance (Diabetes 67, Suppl 1, 2018), the goal of the current study was to elucidate the underlying mechanisms for the protective effect of mt-hOGG1 delivery specifically in liver. In this study we found that targeting of mt-hOGG1 prevented hepatic mtDNA from oxidative damage in both genetic model (KO/TG) and via TAT-protein delivery (TAT-mt-hOGG1) to KO mice. Furthermore, delivery of mt-hOGG1 via TAT-protein transduction significantly increased copy number of mtDNA and expression of VDAC1, a mitochondrial marker in liver isolated from TAT-mt-hOGG1 compared to the vehicle treated mice. Studies are underway which will explore the mechanisms by which TAT-mt-hOGG1 increased mtDNA copy number, including evaluation of mitophagy and mitochondrial biogenesis. Collectively, our findings suggested that mt-hOGG1 is critical to preserve mtDNA integrity in liver and provides strong rationale to use TAT-mediated delivery of DNA repair enzymes into mitochondria as a new translational approach for treatment of obesity-induced insulin resistance.

Disclosure

L. Yuzefovych: None. V. M. Pastukh: None. L. Rachek: None.
1158-P: Genetic Dissection of a Vagal Neurocircuit for Blood Glucose Regulation
Authors: CONLEY NICHOLAS J. , LI CHELSEA , CAMPBELL JOHN
Published: June 2021

Neurons of the hindbrain’s dorsal motor nucleus of the vagus (DMV) in the hindbrain control key physiological functions related to diabetes, including pancreatic hormone secretion and food passage through the GI tract. Different subtypes of DMV neurons, or “functional units,” are thought to mediate distinct physiological roles. However, a lack of definition and access to these subtypes has greatly limited what is known about them. Thus, there is much to learn about the nature of the DMV neurons controlling insulin release and gastric motility, how they function, and how they can be targeted to treat diabetes. To gain traction on this issue, we began by classifying DMV neuron subtypes based on their gene expression, using high-throughput single-nuclei RNA-seq in a mouse model. Our analysis revealed seven, molecularly-distinct subtypes of DMV neurons, two of which were respectively marked by their expression of the genes Calb2 and Grp. Fluorescence in situ hybridization revealed that Calb2 DMV neurons and Grp DMV neurons occupy different subregions of the DMV, suggesting they may innervate different parts of the digestive system. To investigate this, we stained the axons of Calb2 DMV neurons and Grp DMV neurons and imaged them in optically cleared stomach and pancreas from mouse. These studies revealed that Calb2 DMV neurons innervate pancreas but not stomach, whereas Grp DMV neurons innervate neither organ. To then determine whether Calb2 DMV neurons control pancreas endocrine function, we used intersectional optogenetics to stimulate Calb2 DMV neurons while assessing blood glucose levels in vivo. Preliminary data indicate that activating Calb2 DMV neurons causes a rapid and substantial decrease in blood glucose levels. Together our results not only identify Calb2 DMV neurons as pancreas afferents that can lower blood glucose, but reveal a “labeled line” logic to the organization of vagal motor neurons, in which genetically-distinct neuron subtypes innervate different digestive organs to control their function.

Disclosure

N. J. Conley: None. C. Li: None. J. Campbell: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-18-INI-14 to J.C.)
1159-P: One-Hour Glucose during Oral Glucose Tolerance Test Predicts Hyperglycemia Relapse in Black Obese Patients with Hyperglycemic Crises
Authors: JAGANNATHAN RAM , SMILEY-BYRD DAWN , STEFANOVSKI DARKO , UMPIERREZ GUILLERMO E. , VELLANKI PRIYATHAMA
Published: June 2021

Approximately 50% of Black individuals with unprovoked diabetic ketoacidosis (DKA) or severe hyperglycemia (SH, blood glucose [BG]>400 mg/dl without ketosis) at new-onset of diabetes achieve near-normoglycemia remission (FBG < 130 mg/dl, HbA1c < 7%) with intensive insulin treatment. After remission, many patients experience hyperglycemia relapse. Previous studies showed that one-hour post glucose load (1-h PG) correlated with insulin sensitivity (Si) and secretion. We tested whether 1-h PG at remission predicts HR in obese Black individuals presenting with DKA or SH. Seventy-three Black individuals presenting with DKA (n=40) or SH (n=33) underwent a 2-h 75-gm OGTT after achieving remission and followed for a median of 58 weeks until hyperglycemia relapse (FBG>130 mg/dl, random BG>180 mg/dl, or HbA1c> 7%). Si and was calculated from the oral minimal model. Disposition index (DI) was calculated as the product of Si and Area under the curve for insulin. Mean age was 47±10 years, with 36% (n=26) women, mean BMI 36.1±9.5 kg/m2 and 1-h PG 192±48 mg/dl. One-h PG was moderately correlated with Si (r=-0.26; P=0.0294) and DI (r=-0.28; P=0.023). Highest Youden index for 1-h PG was 0.38, corresponding to an optimal cut-point of 199mg/dl with 64% sensitivity and 71% specificity. Cox proportional hazards model adjusted for age, sex and BMI showed that 1-h PG level>199 mg/dl was independently associated with increased hyperglycemia relapse (HR: 2.61 [95% CI:1.13-6.01]). In a multivariate model with fasting BG, adding 1-h PG level improved prediction of hyperglycemia relapse than 2-h PG level, with significant improvements in C index (Δ: +0.07; P=0.04), net reclassification index, and integrated discrimination index. A 1-h PG at the time of remission is a better predictor of hyperglycemia relapse than fasting or 2-h PG among obese Black individuals presenting with DKA or SH. 1-h PG can be used to identify individuals at high risk of developing hyperglycemia relapse.

Disclosure

R. Jagannathan: None. D. Smiley-byrd: Consultant; Self; LifeScan, Other Relationship; Self; Novo Nordisk, Speaker’s Bureau; Self; Merck & Co., Inc. D. Stefanovski: None. G. E. Umpierrez: Research Support; Self; AstraZeneca, Dexcom, Inc., Novo Nordisk. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK11324-01A1, UL1TR002378, K08DK0830361)
1169-P: PNPLA3 148M Is More Susceptible to PA-Induced Endoplasmic Reticulum Stress-Associated Apoptosis in HepG2 Cells
Authors: LIANG HUA
Published: June 2021

PNPLA3 is a major susceptibility gene for MAFLD and its polymorphic locus of rs738409 (I148M) is associated with MAFLD occurrence and progression. Endoplasmic reticulum (ER) stress and hepatocyte apoptosis induced by free fatty acids lipotoxicity in fatty liver cells play an important role in the progression of NAFLD [9]. PNPLA3 is a member of the non-calcium-dependent phospholipase A2 (iPLA2) family, iPLA2ε, and whether PNPLA3 148M has stronger phospholipase activity than 148I to promote apoptosis in hepatocyte is not clear. In this study, we constructed 148I/I knock-in HepG2 cell model by Cas9/sgRNA system on the basis of HepG2 carrying PNPLA3 148M/M. The PNPLA3 148MM and I/I cells were intervened with palmitic acid (PA) for 24 h, and cell lipid deposition was detected using oil red staining, apoptosis was observed by TUNEL, and western blot to detect PNPLA3 expression and ER stress-related CHOP apoptotic signaling pathway molecule expression. The results showed no difference in PNPLA3 expression and hepatocyte lipid deposition between PNPLA3 148M/M and 148I/I cells at baseline. However, after PA intervention, PNPLA3 148M/M cells exhibited more significant lipid deposition and apoptosis than 148I/I, as well as ER-related apoptotic molecules Bip, PERK, p-eIF2α, CHOP PUMA, BAX and cleaved caspase3 expression were more significantly increased.

In conclusion, PNPLA3 148M/M cells were more significantly susceptible to PA-induced lipid deposition and endoplasmic reticulum stress-related apoptosis than 148I/I cells.

Disclosure

H. Liang: None.

Funding

Guangdong Natural Science Foundation (2020A1515010226)
1178-P: Portal Vein Metabolites as Intermediate Regulators of the Gut Microbiome in Insulin Resistance
Authors: MOREAU FRANCOIS , BRANDAO BRUNA B. , AVILA JULIAN , PAN HUI , DREYFUSS JONATHAN , KOSTIC ALEKSANDAR , CLISH CLARY B. , KAHN C. RONALD
Published: June 2021

Previous studies have shown that there is a strong interaction between the diet and the gut microbiome. This is often linked to circulating metabolites, however, in most studies these metabolites are measured in peripheral circulation, after hepatic clearance of intestinal venous drainage. In the present study, we have determined the effects of high fat diet (HFD) and the microbiome on changes in portal and peripheral metabolites and their link to physiology by performing global metabolomics using LC-MS/MS on portal versus systemic (cardiac) blood in C57BL/6 mice on chow diet, HFD or HFD supplemented with either vancomycin or metronidazole in the drinking water to change gut flora.

Among the 644 known metabolites that were identified, 77 were more abundant in cardiac blood whereas 160 were enriched in the portal blood (FC=1.5). In portal blood there was enrichment of secondary bile acids, short-chain fatty acids (butyrate), cinnamoylglycine, indoxylsulfate and hydrocinnamate that are strongly decreased by antibiotics, indicating a direct gut microbial origin. More surprisingly, we also identified several metabolites involved in the TCA cycle, including aconitate, mesaconate and the 2-hydroxyglutarate enriched in portal blood that were not affected by diet but significantly altered by both antibiotics, indicating origin in the gut microbiome. By contrast, some metabolites were enriched in cardiac blood, such as 6, 8 dihydroxypurine, 20-hydroxydocosahexaenoic acid and C46:0 triacylglyercide, were also significantly changed by antibiotics, suggesting they are peripherally produced but depend on precursors coming from gut bacteria.

Thus, the interaction between gut microbiota and circulating metabolites is complex and may affect their production from the small intestine but also from extra intestinal tissues. In addition, the gut microbiome is the source of important circulating metabolites which can enter and modify cellular metabolism at the level of the TCA cycle.

Disclosure

F. Moreau: None. B. B. Brandao: None. J. Avila: None. H. Pan: None. J. Dreyfuss: None. A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. C. B. Clish: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences, Inc., Consultant; Self; Flagship Pioneering, Sana/Cobalt.
1184-P: Return to Normal Glucose Control by Weight Loss in Nonobese People with Type 2 Diabetes: The ReTUNE Study
Authors: AL-MRABEH AHMAD , BARNES ALISON C. , IRVINE KEATON M. , KELLY TARA L. , HOLLINGSWORTH KIEREN G. , ROMERES DAVIDE , COBELLI CLAUDIO , TAYLOR ROY
Published: June 2021

Type 2 diabetes (T2D) in the non-obese has been regarded as etiologically distinct from that in obese people. However, clinical observation suggests that loss of fat mass above a personal fat threshold brings about remission in the same way. ReTUNE aimed to determine what proportion of T2D people with BMI <27kg/m2 could achieve remission, and to assess the fat threshold for this. 25 participants have been studied to date (T2D: 4M/10F, 58.3±2.1years, BMI 24.5±0.6kg/m2; matched nondiabetic controls: n=11). Other types of diabetes were excluded by anti-islet cell antibodies and MODY gene tests (2/14). From baseline, weight loss of 5% was achieved in 2-4 weeks using low calorie diet (800 kcal/day), then 6 weeks of weight maintenance. The cycle of weight loss plus maintenance was repeated 2-3 times until the clinical end point of remission was reached (HbA1c < 6.5%). Only 2 cycles (~10% weight loss) were required in 8/12 participants. The planned decrease in weight (baseline to clinical endpoint: 69.0±3.5 to 60.8±2.9kg, p<0.001) decreased total body fat from 33.1±1.9 to 27.4±2.0% (p<0.001). Fasting plasma glucose decreased from 7.3±0.3 to 6.3±0.3 mmol/l, p<0.05). HbA1c decreased from 7.1±0.2 to 6.5±0.1%, p<0.05 with 8/12 in remission (<6.5%). Fasting plasma insulin decreased (52.2±9.5 to 23.7±3.6 pmol/L, p=0.007) as did plasma triglyceride (1.6±0.2 to 1.0±0.1mmol/L, p=0.002). Liver fat fell from 4.4±0.8 to 1.4±0.1% (p=0.004) becoming similar to 11 matched healthy controls (1.9%). Pancreas fat content in T2D fell (5.1± 0.6 to 4.5±0.6%, p=0.026) towards control levels (3.3±0.3%, p=0.029 vs. T2D at baseline). Post meal insulin sensitivity (Si) and insulin secretion (disposition index and β-cell responsivity Φtot) improved after weight loss.

In conclusion, 2/14 people with BMI <27kg/m2 were found to have other diagnoses, and weight loss brought about remission in 8/12 people accompanied by pathophysiological changes similar to those seen during remission in obesity-associated T2D.

Disclosure

A. Al-mrabeh: None. A. C. Barnes: None. K. M. Irvine: None. T. L. Kelly: Employee; Self; Diabetes Digital Media. K. G. Hollingsworth: None. D. Romeres: None. C. Cobelli: None. R. Taylor: Speaker's Bureau; Self; Novartis AG.

Funding

Diabetes UK (17/0005645)
1188-P: The New Myokine Myonectin Is Significantly Associated with Type 2 Diabetes in Elderly Patients
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , GEIGER KATHRIN , SAELY CHRISTOPH H. , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2021

The novel myokine myonectin is predominantly expressed in skeletal muscle and is involved in the regulation of metabolic homeostasis. A putative association between myonectin and type 2 diabetes mellitus (T2DM) has been discussed controversially in current literature. The association between myonectin and T2DM at different ages is still obscure and thus is addressed in the present study. We measured myonectin in 410 vascular risk patients with a mean age of 66 years. Myonectin did not correlate with age (r=-0.19; p=0.697). Half of our patients (53%) were elderly (≥66 years; n=219) with a mean age of 74 years. The younger ones (≤65 years; n=191) had a mean age of 57 years. 40.6% (n=89) of elderly patients had T2DM and 42.4% (n=81) of the younger ones. Myonectin concentrations were significantly decreased in elderly patients with T2DM compared to nondiabetic ones (1.8 vs, 4.2 ng/ml; p=0.002), whereas no significant difference was seen in younger patients (2.6 vs. 2.3 ng/ml; p=0.183). Regression analysis revealed an unadjusted odds ratio (OR) of 0.24 [0.07-0.81] (p=0.021) for the association between myonectin and T2DM in elderly patients but not in younger patients (OR=1.08 [0.80-1.45]; p=0.609). This association remained significant after adjusting for sex, body mass index, LDL-cholesterol, HDL-cholesterol, current smoking, as well as statin intake in elderly but not in younger patients (OR=0.23 [0.07-0.81]; p=0.021 vs. OR=1.05 [0.76-1.46]; p=0.769). We conclude that plasma myonectin levels are significantly associated with T2DM particularly in elderly vascular risk patients.

Disclosure

A. Leiherer: None. P. Fraunberger: None. H. Drexel: None. A. Muendlein: None. K. Geiger: None. C. H. Saely: None. B. Larcher: None. A. Mader: None. M. Maechler: None. L. Sprenger: None. B. Mutschlechner: None.
1209-P: Profound Metabolic Benefits Observed in an Eight-Week GK Rat Study of a Novel Orally Administered Polymeric Duodenal Exclusion Therapy: Implications for Type 2 Diabetes (T2D) Therapy
Authors: NIMGAONKAR ASHISH , POLOMOSCANIK STEVEN , PASRICHA PANKAJ J. , COLBERT KEVIN , JOZEFIAK THOMAS H. , VORA JITEN , VIEIRA MARCELA , CARLSON TAYLOR , LIU LIANSHENG , KULKARNI SUBHASH , PETERSEN JOHN S.
Published: June 2021

Background: Roux-en-Y gastric bypass surgery produces significant weight loss and improvement in T2D and insulin resistance, attributed predominantly to duodenal exclusion. To mimic this effect non-invasively, we developed an oral, gut-restricted, inert polymer (GLY-POL) that interacts with mucus in the proximal small intestine to form a dynamic barrier excluding the duodenal lining from luminal contents. We therefore hypothesized that such treatment would result in significant improvement in glycemia and weight loss in a rodent model of type 2 diabetes.

Methods: Goto-kakizaki (GK) rats were gavaged daily for 8 weeks. The treatment group (n = 7) received 1.5 ml of GLY-POL (8 wt %) solution and control group (n=7) received saline. Five metabolic responses were evaluated weekly: body weight, food intake, oral glucose (oGTT) and mixed meal tolerance (mMTT) tests, and HOMA-IR.

Results: oGTT performed after chronic GLY-POL therapy produced a profound reduction of post-prandial glycemia (PPG) (incremental area under curve (iAUC)  = 60 – 70%, p<0.0005) compared to control; the PPG reduction amplified with duration of therapy through the study period. Similar robust reduction in PPG iAUC was evident during mMTT (iAUC  > 55%, p < 0.005). Fasting plasma glucose was lower in GLY-POL group (p<0.05) with improvement in HOMA-IR (p<0.005). GLY-POL therapy resulted in 6% weight loss compared to control (p<0.005), without a difference in food intake between the groups.

Conclusion: Our results confirm a key role for chronic duodenal exclusion in improving the systemic metabolic milieu. Chronic once daily oral GLY-POL therapy results in a profound reduction in FPG, PPG, insulin resistance and weight loss. GLY-POL therapy offers the potential for a novel non-invasive approach for glycemic and weight control in T2D patients that mimics the effects of gastric bypass without the adverse effects associated with this surgery.

Disclosure

A. Nimgaonkar: Employee; Self; Glyscend Inc. S. Kulkarni: None. J. S. Petersen: Employee; Self; Glyscend Inc. S. Polomoscanik: Employee; Self; Glyscend Inc. P. J. Pasricha: Stock/Shareholder; Self; Glyscend. K. Colbert: Employee; Self; Glyscend Inc., LifeSprout, Inc. T. H. Jozefiak: Employee; Self; Glyscend Inc., Stock/Shareholder; Self; GLYCOLOGIX LLC. J. Vora: Advisory Panel; Self; Bayer Inc., Other Relationship; Self; AstraZeneca. M. Vieira: Employee; Self; AstraZeneca. T. Carlson: None. L. Liu: None.

Funding

National Science Foundation (1521347)
1224-P: Exogenous Secretin Decreases Energy Intake and Exerts a Bimodular Effect on Postprandial Brown Adipose Tissue Activation in Man
Authors: HEIMBÜRGER SEBASTIAN M. NGUYEN , BENTZEN MARIA J. , HARTMANN BOLETTE , HOLST JENS J. , CHRISTENSEN MIKKEL B. , KNOP FILIP K.
Published: June 2021

Secretin was recently shown to constitute a postprandial satiety signal in mice. This effect was proposed to be mediated by secretin-induced activation of brown adipose tissue (BAT) and subsequent hypothalamic registration of body temperature rise. We investigated the effect of a 5-hour infusion of secretin on appetite sensations, food intake, BAT activity and resting energy expenditure (REE) in man. In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males aged (mean ± SD) 25.7 ± 6.1 years with a BMI of 23.4 ± 1.8 kg/m2 underwent 5-hour infusions of secretin (1 pmol/kg/min) and placebo, respectively, on separate days with an interposed 8-week washout period. During the infusions, before and several times after a liquid mixed meal test, we assessed appetite sensations (by visual analogue scales), REE (by indirect calorimetry) and supraclavicular BAT activity (by thermal imaging). Before terminating the infusions, ad libitum food intake (primary outcome) was assessed. Compared to placebo, secretin did not affect appetite sensations, but it decreased ad libitum food intake by [mean±SEM] 173 ± 88 kcal (P = 0.039). Within the first 15 minutes of infusion, secretin decreased supraclavicular temperature by 0.10 ± 0.02°C (P <0.001), but at 75-90 min and 240-255 min it increased supraclavicular temperature by 0.05 ± 0.01 (P <0.001) and 0.01 ± 0.01 (P <0.001), respectively, compared to placebo. Secretin did not affect REE. During secretin and placebo infusions, 4 and 2 reported headache, 4 and 1 experienced nausea, 2 and 0 participants vomited, and 2 and 0 had diarrhea, respectively.

In conclusion, a 5-hour infusion of secretin in healthy males decreased ad libitum food intake and exhibited a biphasic effect of supraclavicular BAT activity.

Disclosure

S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. M. J. Bentzen: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
1228-P: Cardiovascular Risk of Patients with Overweight and Obesity: A Predictive Model
Authors: TURCHIN ALEXANDER , MORRISON FRITHA J. , SHUBINA MARIA , SHINDE SHRADDHA , AHMAD NADIA , KAN HONG
Published: June 2021

Obesity is the most common chronic disease in the U.S. Patients with obesity have many cardiovascular risk factors, often modifiable. It is important to identify patients with obesity at high risk of atherosclerotic cardiovascular disease (ASCVD) to be able to appropriately direct treatment and resources.

We conducted an observational study of EMR data of 399,360 adults with BMI ≥ 25 kg/m2 and without baseline ASCVD between 2000 and 2019. We first identified a literature-based pool of risk factors for ASCVD onset and conducted variable selection by applying least absolute shrinkage and selection operator (LASSO) penalized Cox regression with ten-fold cross-validation on an 80% training dataset. We estimated a regular Cox model on the training dataset with selected variables and evaluated model performance on the remaining 20% dataset.

Over the mean of 7.4 years of follow-up, 37,424 (11.7%) of study patients developed ASCVD. The predictive model achieved a Harrell’s C-statistic of 0.81. The greatest risk of ASCVD onset was associated with older age (HR 2.16 per 1 SD = 15.4 years; 95% CI 2.13- 2.20), heart failure (HR 1.85; 95% CI 1.74-1.97), valvular heart disease (HR 1.61; 95% CI 1.53-1.68) and stimulant abuse (HR 1.60; 95% CI 1.41-1.81). Female sex was associated with a lower risk of ASCVD (HR 0.64; 95% CI 0.63-0.65). Patient characteristics found in >5% of patients that carried additional risk included history of smoking (39.9% of patients; HR 1.40; 95% CI 1.37-1.43), proteinuria (5.5%; HR 1.33; 95% CI 1.29-1.38) and hypertension (23.6%; HR 1.29; 95% CI 1.26-1.32). Each standard deviation increase in BMI (5.3 kg/m2) was associated with a 1.15-fold (95% CI 1.14-1.16) increase in the risk of ASCVD onset.

It is feasible to use predictive modeling to identify patients with overweight and obesity at high ASCVD risk. This approach could be utilized to guide population management and clinical treatment decisions.

Disclosure

A. Turchin: Consultant; Self; Proteomics International, Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi, Stock/Shareholder; Self; Brio Systems. F. J. Morrison: None. M. Shubina: None. S. Shinde: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. N. Ahmad: Employee; Self; Eli Lilly and Company. H. Kan: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Bristol-Myers Squibb Company, GlaxoSmithKline plc.

Funding

Eli Lilly and Company
123-LB: IDG-16177, a Potent, Orally-Bioavailable GPR40 Agonist, Improves Glycemic Control and Glucose-Stimulated Insulin Secretion in Preclinical Studies
Authors: YOON JONGMIN , LEE DON-GIL , KIM JUNG HO , HONG DAHAE , SHIN CHORONG , JANG EUNHYE , KIM JISU , SONG HAENGJIN , LEE SEOLHEE , JUN YEARIN , AN KYUNGMI , HONG CHANG-HEE , KWAK HYUN-JUNG , JE IN-GYU , SONG HYO-JUNG
Published: June 2021

GPR40/FFAR1 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. GPR40 agonists are known to stimulate insulin secretion and reduce circulating glucose levels in a glucose-dependent manner. Currently, IDG-16177, as a GPR40 agonist, is being developed by ildong Pharma in first-in-human study. IDG-16177 is a high potency and orally available small molecule agonist. IDG-16177 confirmed linear pharmacokinetic properties and is more potent than fasiglifam from in vivo studies. The oral bioavailability of IDG-16177 was 84.3, 75.4, and 71% in mice, rats, and monkeys, showing high oral absolute bioavailability in preclinical species. The Cmax and AUC values of IDG-16177 increased in a dose-proportional manner in a dose range of 0.3 to 10 mg/kg in mice and rats and 0.3 to 3 mg/kg in monkeys. In vivo long-term glucose-lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a multiple dosing study using SD and OLETF rats. In both in vivo tests, IDG-16177 0.3 mg/kg showed similar effective in glucose tolerance fasiglifam 10 mg/kg, respectively. In addition, IDG-16177 had a positive effect on fasting blood glucose, insulin, and glucagon in the long-term administration of OLETF rats. In these study, Cmax,ss of IDG-16177 showed approximately 60 times lower than those of fasiglifam and AUCss of IDG-16177 showed approximately 170 times lower than those of fasiglifam. In another study, the Glucose-stimulated insulin secretion effect of IDG-16177 was assessed in Male SD rat. IDG-16177 1 mg/kg showed similar effective in insulin secretion fasiglifam 10 mg/kg. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes.

Disclosure

J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. H. Song: None. S. Lee: None.
1239-P: Evidence of Altered Alpha- and Beta-Cell Lysosomes prior to Onset of Type 1 Diabetes
Authors: MURALIDHARAN CHARANYA , CROWDER JUSTIN , LINNEMANN AMELIA K.
Published: June 2021

Autophagic degradation is a dynamic recycling process that contributes to cellular homeostasis and mitigation of cellular stress. While there are multiple forms of -phagic degradation processes, a common endpoint is the final degradation step in the lumen of the acidic lysosomes. Post-mitotic cells, including beta cells, can accumulate tertiary lysosomes called telolysosomes which contain oxidized proteins and lipids that are not completely digested. We recently found that autophagy is impaired in the beta cells of individuals with T1D and also in islets of diabetic NOD mice. We also observed a significant increase in the number of autophagosomes, and telolysosomes in the beta cells of autoantibody positive organ donors when compared to nondiabetic organ donors. We now also find a 1.5-fold increase in the number of telolysosomes in the alpha cells of autoantibody positive donors when compared to nondiabetic organ donors (p=0.03). This was mirrored by our previous observation of globally increased lysosome numbers across the islets of pre-diabetic NOD mice, suggesting that these lysosomes may be dysfunctional. To test this, we performed a lysosomal enzyme activity assay to analyze the lysosomal cysteine protease Cathepsin H (a T1D susceptibility locus). Interestingly, we found that the activity of Cathepsin H was increased by ~2-fold in islets of pre-diabetic NOD mice when compared to NOR controls (p=0.02). Taken together, these data suggest a compensatory hyperactivation of the lysosomal enzyme Cathepsin H in the islets of pre-diabetic NOD mice, potentially as a mechanism to rid the cell of degradation-resistant oxidized proteins and lipids whose accumulation in lysosomes might lead to the presence of telolysosomes.

Disclosure

C. Muralidharan: None. J. Crowder: None. A. K. Linnemann: None.

Funding

Network for Pancreatic Organ Donors with Diabetes (nPOD; RRID:SCR_014641); JDRF (nPOD: 5-SRA-2018-557-Q-R); The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D053)
1243-P: The Chd4 Helicase Regulates Pdx1-Controlled Genes Involved in ß-Cell Function
Authors: DAVIDSON REBECCA K. , CASEY NOLAN , KANOJIA SUKRATI , SPAETH JASON
Published: June 2021

Diabetes progression is partly characterized by a loss of key transcription factors (TFs) in a subset of failing β-cells. Among these TFs is Pdx1, which coordinates the expression of numerous genes related to β-cell function (MafA, Ins2, Ucn3), mitochondrial function (Tfam), and calcium signaling (Cacna1d, Camkk2, Atp2a2). Pdx1 requires the recruitment of transcriptional coregulators to modulate its activity and has recently been shown to interact with the Chd4 ATPase subunit of the Nucleosome Remodeling and Deacetylase complex. In other cellular contexts, Chd4 is required to maintain cellular identity and mitochondrial function; however, the contribution of Chd4 in controlling Pdx1-target genes in the β-cell has yet to be explored. Here, we confirmed the Pdx1:Chd4 interaction using co-IP in mouse β-cell lines and proximity ligation assay in mouse and human β-cell lines and tissue. We found, by ChIP-Sequencing, that Chd4 binds to 4796 genes in β-cell lines, 4463 of which are also bound by Pdx1, including MafA, Cacna1d, and Atp2a2. Transient siRNA knockdown of Chd4 in the βTC-3 murine insulinoma cell line led to a reduction of MafA at the transcript (41% ± 3, p < 0.05) and protein level, as well as reduced expression of mitochondrial TF Tfam (39% ± 8, p <0.05) and calcium regulators Camkk2 (53% ± 6, p <0.05) and Serca2b (51% ± 13, p <0.05). Furthermore, glucose-stimulated insulin secretion in the INS1 832/13 rat insulinoma cell line was impaired (p = 0.0504) in Chd4 knockdown cells. We next generated a tamoxifen-inducible, β-cell-specific (MIP-CreERT) mouse knockout line of Chd4 and found significant impairment in glucose tolerance in male mice 2 weeks post-tamoxifen. Together, these data indicate Chd4 is required for the expression of numerous Pdx1-controlled genes important for β-cell function and whole-body glucose homeostasis. Future efforts are focused on defining the contributions of Chd4 in regulating gene expression and chromatin accessibility in β-cells using our β-cell-specific Chd4 knockout model.

Disclosure

R. K. Davidson: None. N. Casey: None. S. Kanojia: None. J. Spaeth: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115633)