bluuebunny/crossref_metadata_2025 huggingface dataset:
1266-P: Random C-Peptide Testing Identified One-Tenth of Thai Adult Patients Misdiagnosed with Type 1 Diabetes Mellitus
Authors: THEWJITCHAROEN YOTSAPON , NAKASATIEN SOONTAREE , BUTADEJ SIRIWAN , WANOTHAYAROJ EKGALUCK , KRITTIYAWONG SIRINATE , HIMATHONGKAM THEP
Published: May 2022

Background: A C-peptide testing carried out several years after a clinical diagnosis of T1DM could uncover a misdiagnosis in some cases. T1DM in Asian population are extremely low in prevalence and display some unique features. This study aims to determine the prevalence and characteristics of Thai adult patients with clinically misdiagnosis with T1DM.

Materials and Methods: A cross-sectional study of Thai patients diagnosed with T1DM registered at the Theptarin Hospital, Thailand was performed. Random plasma C-peptide were measured in all cases and mixed meal tolerance test (MMTT) were performed if random plasma C-peptide was in between 0.1-0.5 ng/mL. Clinically misdiagnosis with T1DM defined by preserved endogenous insulin secretion (random C-peptide ≥ 0.6 ng/mL or stimulated C-peptide after MMTT ≥ 0.6 ng/mL) after at least 3 years after onset of DM.

Results: A total of 73 patients (females 52.1%, mean age 42.2±12.5 years, BMI 23.2±3.3 kg/m2, A1C 7.8±1.3%) with duration of diabetes 20.3±11.3 years were studied. Only 42.5% of patients had measurement of pancreatic auto-antibodies. The prevalence of anti-GAD and anti-IA2 were 53.3% and 20.8%, respectively. Preserved endogenous insulin secretion (random C-peptide ≥ 0.6 ng/mL) were found in 8 patients. The overall prevalence of clinically misdiagnosis with T1DM was 11.0%. When compared with truly T1DM, misdiagnosed patients had higher prevalence of hypertension and diabetic complications. Five were reclassified as having T2DM and 3 patients were suspected to have monogenic diabetes.

Conclusions: Our results were consistent with previous studies from Caucasian patients that about 10-15% of clinically diagnosed T1DM had been wrongly diagnosed. In clinical practice, positivity for pancreatic auto-antibodies was less helpful than a simple random C-peptide measurement. C-peptide testing a few years after a diagnosis of T1DM should be a routine procedure to identify some patients who might have been misdiagnosed.

Disclosure

Y. Thewjitcharoen: None. S. Krittiyawong: None.
1279-P: Caveolin 1 rs1997623 Is Associated with Metabolic Syndrome in Arab Adult Individuals from Kuwait
Authors: MADHOUN ASHRAF AL , HEBBAR PRASHANTHA , NIZAM RASHEEBA , HADDAD DANIA , DASHTI MOHAMMED H. , ABU-FARHA MOHAMED , AHMAD RASHEED , THANGAVEL ALPHONSE T. , ALMULLA FAHD
Published: May 2022

Studies have implicated CAV1 in the pathophysiology of diabetes and obesity. Previously, we demonstrated a potential association between the CAV1 rs1997623 C/A variant and metabolic syndrome (MetS) in Kuwaiti children. In the present study, we substantiate the association of CAV1 with MetS in adult Arab individuals. Method: The CAV1 rs1997623 was genotyped in three cohorts of Arabs (n=479) , South Asians (n=660) and South East Asians (n=362) . MetS status of the individuals was diagnosed using the IDF criteria (i.e., presence of central obesity and of at least two abnormalities of high TG, low HDL, hypertension, or type 2 diabetes) . The quantitative measure of MetS was calculated as siMS=2*WC/Height + FBG/5.6 + TG/1.7 + SBP/130 - HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous traits were assessed using linear and logistic regression, respectively, with and adjustment for age and sex. CAV1 transcripts were quantified in adipose tissues from a cohort of 50 Arab individuals differing in siMS score. Results: The CAV1 variant was significantly associated with MetS status (OR=1.8[1.25-2.61]; P-value=0.0015; Pemp=0.0013) and with siMS (Effect size = 0.206; P-value=0.0035; Pemp=0.0028) in the cohort of Arab individuals. The variant was weakly and insignificantly associated in the cohorts of South Asian and South East Asian individuals (OR= 1.and 1.11; P-values= 0.25 and 0.67, respectively) . siMS scores correlated positively with mRNA levels of CAV1 in adipose tissue. Conclusion: The association of CAV1 rs1997623 C/A with MetS in Arab pediatric is now demonstrated in adults as well. Higher expression levels were seen in individuals poses increasing MetS rates further validates the implication of CAV1 rs1997623 C/A variant in MetS phenotype. Only a weak association signal was seen in the South Asian and South East Asian populations leading us to propose that the CAV1 rs1997623 association with MetS is probably specific to Arab ethnicity.

Disclosure

A.Al madhoun: None. P.Hebbar: None. R.Nizam: None. D.Haddad: None. M.H.Dashti: None. M.Abu-farha: None. R.Ahmad: None. A.T.Thangavel: None. F.Almulla: None.

Funding

Kuwait Foundation for the Advancement of Sciences (KFAS) and Dasman Diabetes Institute, Project RA CB-2021-007
1280-P: Use of Machine Learning to Determine the Relative Influence (RI) of Genetic Risk Scores of Glycemic Traits on Myocardial Infarction and Stroke in 409,633 Participants in the UK Biobank
Authors: DESHMUKH HARSHAL , MILES MARIA , BHAIJI AMIRA , SHAH NAJEEB , AKBAR SHAHZAD , PAPAGEORGIOU MARIA , SATHYAPALAN THOZHUKAT
Published: May 2022

Introduction: Genome-wide association studies have identified numerous glycemic traits-associated SNPs with myocardial infarction (MI) and stroke. However, conventional regression methods combining these large numbers of highly significant SNPs in a weighted genetic risk score (wGRS) have only explained a small proportion of variance in MI and stroke. Therefore, we used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for glycemic traits with MI and stroke in the UK Biobank population.

Methods: We identified 4626 SNPs associated with glycemic traits from the NGHRI catalogue for GWAS studies. wGRS were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on prevalent stroke and MI in the UK Biobank population.

Results: The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m2. The prevalence rates of MI and stroke were 3.6% and 2.3%. In the GBM model, top wGRS associated with MI were type 2 diabetes (RI=14.6) , blood glucose levels adjusted for fasting time (RI=12.2) and beta-cell glucose sensitivity (RI=10.06) . In contrast, the top wGRS associated with stroke were HbA1c (RI=12.13) and fasting insulin levels (RI=10.31) . The addition of wGRS’s to the model comprising the baseline characteristics slightly improved the AUC for predicting stroke and MI.

Conclusion: We showed a differential effect of wGRS for various glycemic traits on the risk of MI and stroke in the UK Biobank population. However, even in machine learning models, these wGRS for various glycemic traits had a limited utility in predicting stroke and MI in the general population.

Disclosure

H.Deshmukh: None. M.Miles: None. A.Bhaiji: None. N.Shah: None. S.Akbar: None. M.Papageorgiou: None. T.Sathyapalan: n/a.

Funding

NIHR Clinical Lectureship
1282-P: Genetic Susceptibility of Dipeptidyl Peptidase-4 Inhibitor–Associated Bullous Pemphigoid in Chinese Patients with Type 2 Diabetes
Authors: SHI MAI , YANG AIMIN , CHOW ELAINE , LAU ERIC S. , TAM CLAUDIA H. , MA RONALD C. , CHEUNG MAN TUNG CHRISTINA , CHAN JULIANA C. , CHAN WAI SZE AGNES
Published: May 2022

Objective: The rare risk association of bullous pemphigoid (BP) with use of dipeptidyl peptidase-4 inhibitors (DPP-4i) had been reported including genetic association with HLA variants. We assessed genetic susceptibility of BP associated with DPP-4i use in patients with type 2 diabetes (T2D) .

Methods: In a prospective cohort of 30,129 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register between 1995 to 2018, we curated multiple case-control cohorts with available genotype data to explore the genetic associations of major histocompatibility complex (MHC) region with DDP-4i-associated BP.

Results: During a median follow period of 9 years, 60 patients developed BP (incidence of 2.cases per 10,000 patient-years) . 20 patient developed BP after DPP-4i use, with median exposure to DPP-4i of 1.7 years (incidence of 4.76 cases per 10,000 patient-years) and an adjusted odds ratio of 1.1 (95% CI 0.5-1.6) . 32 patients developed BP and were not exposed to DPP-4i (incidence of 2.87 cases per 10,000 patient-years) . In 1:2 matched case:control cohort of patients who tolerated DPP-4i and did not develop of BP, multiple variants in the second intron of HLA-DQB1 exhibited strong association with DPP4i-associated BP, including the well-reported HLA-DQB1*03: (OR 12.00; 95% CI 1.99-72.35; P-value 6.71e-03) and a novel single nucleotide polymorphism rs281863580 (OR 11.96; 95% CI 4.14-34.54; P-value 4.53e-06) . We additionally identified variants located in other HLA regions that were associated with BP in non-DPP4i users.

Conclusion: Multiple genetic polymorphisms in the second intron of HLA-DQB1 were associated with increased susceptibility to incident BP in DPP-4i users. Further exploration of the extended MHC region beyond HLA alleles might identify a combination panel for assessing the genetic risk of BP rather than a single HLA allele.

Disclosure

M.Shi: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. E.S.Lau: None. C.H.Tam: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. M.Cheung: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. W.Chan: None.

Funding

The Hong Kong Government Research Grants Committee Theme-based Research Scheme (T12-402/13N) .2) Impact Research Impact Fund (R4012-18) .
1284-P: Genetic and Lifestyle Associations with Cardiometabolic Traits and Diabetes Risk Factors in Ethnically Diverse Africans
Authors: HUI DANIEL , HARRIS DANIEL , MCQUILLAN MICHAEL , HANSEN MATTHEW , RANCIARO ALESSIA , BEGGS WILLIAM , MPOLOKA SUNUNGUKO W. , WOLDEMESKEL DAWIT , NJAMNSHI ALFRED K.K. , NYAMBO THOMAS B. , CHANOCK STEPHEN , TISHKOFF SARAH A.
Published: May 2022

African ancestry populations are underrepresented in human genetic studies, which leaves a knowledge gap about genetic and environmental risk factors for metabolic disease which can bias healthcare treatment. To alleviate these shortcomings, we conducted a series of genome-wide association studies of cardiometabolic traits in a diverse sampling of ∼2,500 (max sample size) ethnically and geographically diverse Africans from populations practicing agriculturalist, hunter-gatherer, and pastoralist subsistence strategies. This study includes the Fulani pastoralists who have a relatively high incidence of adult-onset diabetes, despite having a low average body mass index (BMI) . All individuals in the present study are sampled from rural populations that have relatively homogeneous lifestyles and diet within a community. This unique aspect to the study cohort allows for within- and between- group comparisons to identify trait variation attributable to genetics vs. lifestyle variation. Subjects were genotyped on a new African-focused SNP array from the Human Heredity and Health in Africa (H3 Africa) consortium. Genome-wide data was imputed based on a panel of African whole-genome sequences and data from the 1000 genomes project, resulting in a total of million variants for trait association analysis. Genetic associations were tested for BMI, blood pressure, and blood biomarkers of cardiometabolic health. We checked for replication of genotype/phenotype associations by comparison to large non-African cohorts studied for the same traits. We find that most associations identified in non-African populations do not replicate in the Africans. However, we identified a number of novel loci associated with cardiometabolic traits in the African populations. This study has important implications for identifying genetic risk factors that may play a role in metabolic disease in individuals of African ancestry. Funded by ADA Pathway award 1-19-VSN-02.

Disclosure

D.Hui: None. T.B.Nyambo: None. S.Chanock: None. S.A.Tishkoff: None. D.Harris: None. M.Mcquillan: None. M.Hansen: None. A.Ranciaro: None. W.Beggs: None. S.W.Mpoloka: None. D.Woldemeskel: None. A.K.K.Njamnshi: None.

Funding

American Diabetes Association (1-19-VSN-02) ; National Institutes of Health (R35 GM134957-01, R01AR076241, 5T32DK007314-39, 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154-01)
1291-P: Bioinformatics Analysis of Gene Networks Associated with Glucose Variability and Inflammatory Pathways in Diabetes
Authors: SAIK OLGA V. , KLIMONTOV VADIM
Published: May 2022

Aim: To identify key genes linking glucose variability (GV) and inflammatory pathways in diabetes.

Methods: Text mining-based reconstruction and analysis of the gene networks associated with GV and low-grade inflammation in diabetes were performed by the ANDSystem (www-bionet.sscc.ru/and/cell/) . Key elements of the networks were identified by the highest value of cross-talk centrality (CTC) and cross-talk specificity (CTS) . A comparative analysis of two networks was applied to identify genes that are up- or down-regulated by glucose fluctuations and involve in the inflammatory pathways.

Results: We revealed sixty one genes related to GV and inflammation (Table) . Based on CTC values, TP53, TNF, NFKB1, IL1B, IL6, CASP3, MMP2, MMP9, TGFB1, and VEGFA were identified as the principal hubs in the gene network of inflammation that are regulated by GV. The UCP2, GPX1, SOD2, ANGPT2, GLP1R, HGF, SPP1, MAPK9, TIMP1, and MMP1 genes demonstrated the highest CTS values.

Conclusions: The obtained results improve the understanding of the molecular mechanisms of the proinflammatory effect of GV in diabetes. The role of the identified molecules as key drivers of GV-induced inflammation needs further experimental verification.

Disclosure

O.V.Saik: None. V.Klimontov: None.

Funding

Russian Science Foundation (20-15-00057)
1297-P: Berberine Derivatives as Novel Antidiabetes Agents Targeting Intestinal AMPK and Antimicrobial Peptide-Controlled Gut Microbiome
Authors: ZHANG ERYUN
Published: May 2022

Mammalian 5′-AMP-activated protein kinase (AMPK) is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target for glucose control in type 2 diabetes (T2D) . Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, AMPK functions in the intestine, the first-line organ for nutrient processing, remains largely elusive. We have uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation through modulating the anti-microbial peptide (AMP) -controlled gut microbiota and their metabolites. Therefore, the intestinal AMPK-AMP-microbiota-BAT axis is a potential target for the treatment of T2D. Berberine, a quaternary ammonium protoberberine alkaloid with an isoquinoline scaffold isolated from medicinal herbs, has been used to treat T2D in animal models as well as human trials, while offsetting renal, cardiovascular, hepatic, and respiratory risks. However, its poor bioavailability severely limits its application and development. As such, there is a dire need to explore structural modifications of berberine to obtain better pharmacological properties and elucidate its underlying mechanisms of action. Berberine can activate AMPK indirectly by inhibition of mitochondrial respiration in the adipocyte, myotubes and liver; however, its effects on intestinal AMPK are still unknown. We have successfully synthesized natural and non-natural novel berberine derivatives. We will determine their antidiabetes effects and elucidate the underlying mechanisms of action in targeting the intestinal AMPK-AMP pathways for T2D treatment. Moreover, our study will provide a better structure-activity relationship to guide the future design of berberine derivatives with higher potency and improved bioavailability.

Disclosure

E.Zhang: None.
130-OR: The Association between High Out-of-Pocket Costs and Incidence of Treatment Intensification with an SGLT2 Inhibitor (SGLT2i) or GLP-1 Agonist (GLP-1a) in Patients with Type 2 Diabetes and Established Cardiovascular Disease: A Retrospective Cohort Study
Authors: LUO JING , FELDMAN ROBERT , ROTHENBERGER SCOTT D. , HERNANDEZ INMACULADA , KORYTKOWSKI MARY T. , GELLAD WALID F.
Published: May 2022

The use of SGLT2i and GLP-1RA in patients with T2D remains low despite their known CV benefits. This may be due in part to high drug costs. We sought to assess the association between out-of-pocket (OOP) costs and the likelihood of initiating these two classes in patients with T2D and established CVD. We conducted a cohort study using claims data (Optum) , which included commercial and Medicare Advantage beneficiaries. Adults with T2D on metformin monotherapy between 12/5/17 and 12/31/were eligible. We excluded those:1) not continuously enrolled for ≥1 yr prior to their first metformin dispensing,2) with no evidence of established CVD, or3) whose OOP costs (defined as the sum of copays and deductibles for a 30-day supply) for SGLT2i or GLP-1RA could not be determined. We used Cox proportional hazards models adjusting for demographics, clinical characteristics, insurance plan, provider and laboratory characteristics to estimate hazard ratios (HR) of initiation across quartiles (Q) of OOP costs, with Q1 representing the lowest and Q4 the highest OOP costs. The cohort included 72,743 patients (mean[SD] age 72[9.4], 56% male) followed for a median of 914 days. Most (88%) were covered by a Medicare Advantage plan. The unadjusted incidence of initiating a SGLT2i (or GLP-1RA) was 2.8% (2.1%) in Q4 vs. 3.8% (2.8%) in Q1 of OOP costs. The median time to initiation of a SGLT2i/GLP-1RA was longer in Q4 (418/325 days) vs. Q1 (395/3 days) of OOP costs. In fully adjusted models, the HR for Q4 vs. Q1 of OOP costs was 0.79 (95%CI 0.70 to 0.90) for initiating a SGLT2i and 0.88 (95%CI: 0.77 to 1.01) for a GLP-1RA. In this national cohort of patients w/ T2D and established CVD, beneficiaries enrolled in plans in the highest quartile of OOP costs were significantly less likely to initiate a SGLT2i or GLP-1RA compared to those enrolled in plans in the lower quartile.

Disclosure

J.Luo: None. R.Feldman: None. S.D.Rothenberger: None. I.Hernandez: Consultant; Bristol-Myers Squibb Company, Pfizer Inc. M.T.Korytkowski: None. W.F.Gellad: None.

Funding

NIDDK (K23DK120956) NCATS (KL2TR001856)
1308-P: Role of Medial Amygdala Neurons in Regulating the Metabolic Responses to Homeostatic Challenge
Authors: DEVARAKONDA KAVYA , O’CONNOR RICAHRD , ALVARSSON ALEXANDRA , LI ROSEMARY Y. , GONZALEZ MARIA JIMENEZ , KENNY PAUL , STANLEY SARAH
Published: May 2022

Neural signals play a critical role in metabolic regulation by controlling behavior and coordinating glucose production and uptake in peripheral organs. Physiological and psychological stimuli that disrupt homeostasis - stressors - result in metabolic and behavioral adaptations but our understanding of the precise circuits underlying these adaptations remains incomplete. Here we used in vivo calcium imaging, viral tracing and neural manipulation to determine the contribution of medial amygdala (MeA) circuits to the metabolic responses to stress. Social and psychological stressors result in hyperglycemia. These stressors also rapidly increased fluorescence of genetic calcium indicators (GCamp) in MeA neurons. Chemogenetic activation of MeA neurons significantly increased blood glucose without altering pancreatic hormone release and suppressed feeding. Viral tracing revealed distinct MeA subpopulations projecting to the bed nucleus of the stria terminalis (BNST) and to the ventromedial hypothalamus (VMH) . Chemogenetic stimulation of MeA projections to the VMH but not BNST increased blood glucose during glucose tolerance testing via sympathetic activation of hepatic gluconeogenesis, without effects on pancreatic or adrenal hormones. Conversely, silencing of MeA neurons projecting to the VMH blunted stress-induced hyperglycemia. Together these findings suggest a crucial role for MeA circuits in the metabolic response to stressors with dissociation of sympathetic, hormonal, and behavioral adaptations to homeostatic challenge.

Disclosure

K.Devarakonda: None. R.O’connor: None. A.Alvarsson: None. R.Y.Li: None. M.Jimenez gonzalez: None. P.Kenny: None. S.Stanley: None.

Funding

American Diabetes Association (1-17-ACE-31) ; National Institutes of Health (R01NS097184, OT2OD024912, F31DK129016 and R01DK124461) National Science Foundation (1930163) Department of Defense (W81XWH-20-1-0156, W81XWH-20-1-0345) Naomi Berries Diabetes Center Russell Berrie Foundation AwardRevson Foundation
131-LB: Prevalence of Vitamin B12–Monitoring among Patients Receiving Metformin in a Public Hospital
Authors: GHIYA RONAK D. , FAYFMAN MAYA
Published: May 2022

Background: Metformin reduces intestinal absorption of Vitamin B12 in up to 30% of patients and lowers serum Vitamin B12 concentrations in 5-10%. In 2017, the American Diabetes Association (ADA) updated its guidelines to recommend patients taking metformin undergo regular monitoring of Vitamin B12 levels. To better understand acceptance and application of these guidelines, we undertook an assessment of such monitoring within a single hospital center serving the low-income population in Atlanta, GA to assist in guiding optimal monitoring and patient management.

Methods: Data was collected from a single hospital center using electronic medical records (EMR) and the SlicerDicer tool to identify all outpatients for whom metformin was prescribed either as a single agent or in combination therapy during January 1 - December 31, 2021 and then measure Vitamin B12 prescribing among primary care patients and patients followed by endocrinology and further analyze which patients had neuropathy.

Results: During the period studied, of the total 2,336,914 patients documented in the EMR, 30,803 (0.01%) were outpatients prescribed metformin either as a single agent or in combination therapy. Of these, 816 patients (2.6%) had Vitamin B12 levels ordered and measured. The prevalence of Vitamin B12 levels ordered and measured was 7.5% (674 of 8,975) among patients seen in primary care clinics and 2.3% among those followed in endocrinology (25 of 1,081) (chi-square p<0.0001) . 621 (6.9%) of the metformin-treated primary care patients had neuropathy, and of those 63 had Vitamin B12 levels. 134 (12.4%) of the endocrinology patients had neuropathy, and of those 5 had Vitamin B12 levels. (chi-square p<0.0001)

Conclusion: Among two outpatient cohorts who were prescribed metformin, there was suboptimal adherence to the ADA’s recommendation for regular monitoring of Vitamin B12 levels. Approaches for increasing and optimizing ordering and monitoring Vitamin B12 levels will be developed. Increased awareness of the relationship between metformin and Vitamin B12 deficiency and standardized approaches to monitoring are needed.

Disclosure

R. D. Ghiya: None. M. Fayfman: None.
1312-P: Impaired Beta-Cell Function in Older Patients Corresponds to Changes in Salience Network Connectivity
Authors: DEAJON-JACKSON JELANI , LACADIE CHERYL , WATT CHARLES , SCHEINOST DUSTIN , HWANG JANICE J.
Published: May 2022

The salience network (anterior cingulate cortex (ACC) —insula) plays an important role in regulating attention and memory in the context of decision making and has also been shown to be highly responsive to changes in peripheral glucose levels. Increased age is also associated with changes in glucose homeostasis and the salience network. To investigate these relationships, 40 healthy, cognitively normal, non-diabetic subjects (20 Young (age mean 28±1 years, BMI 28.1 ±1.1 kg/m2, HbA1c 5.3±0.1%) and 20 Old (age mean of 73±2 years, BMI 26.9±0.9 kg/m2, HbA1c 5.5±0.1%)) underwent an OGTT, resting state functional connectivity (FC) MRI brain scanning, and cognitive assessments (Cambridge Neuropsychological Test Automated Battery) . Despite similar BMI, HbA1C, and fasting glucose levels, older individuals had lower disposition index (young: 9±2, old: 3.3±0.4, p=0.005) indicating impaired β-cell function. There were no differences in measures of insulin sensitivity (HOMA-IR (p=0.38) or Matsuda index (p=0.70) . A seed-based analysis using a predefined cubic voxel in the ACC showed differences in FC between the ACC and the left insula (Main Effect by group, P<0.001) with lower connectivity values in Old compared to Young subjects. This connectivity value also correlated with errors on the Paired Associate Learning task, which tests attention and memory (r=-0.5, P=0.001) . Moreover, the connectivity values correlated with the disposition index in older subjects (r=0.49, P=0.03) but not younger subjects (P=0.9) . Thus, in our cohort of healthy, cognitively normal older subjects, impairments in beta-cell function are associated with altered functional connectivity within the salience network. These findings highlight the need for future investigations to determine whether mild age-related changes in glycemic control contribute to neurocognitive changes in older patients.

Disclosure

J.Deajon-jackson: None. C.Lacadie: None. C.Watt: None. D.Scheinost: None. J.J.Hwang: None.

Funding

Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342)
1315-P: Optogenetic Activation of Vagal Motor Neurons in Mice Modulates Heart Rate but Not Blood Glucose Levels
Authors: CAMPBELL JOHN , CONLEY NICHOLAS J. , KAUFFMAN LILY S.
Published: May 2022

Parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) control glucose metabolism through the vagus nerve and so are potential targets for diabetes treatment. Yet, little is known about the molecular identity and organization of glucose-regulating DMV neurons. To identify these neurons for further investigation, we optogenetically activated them in mice while measuring blood glucose. We targeted a light-sensitive ion channel, CaTCh, selectively to DMV neurons based on their co-expression of Chat and Phox2b, which resulted in CaTCh expression in most or all DMV neurons but no surrounding neurons. To photostimulate CaTCh+ DMV neurons, we then implanted optical fibers over the DMV in 9 adult Chat::Phox2b::CaTCh mice (4 females, 5 males; mean age ± S.D., 24 ± 13 weeks) . After acclimation we fasted the mice overnight and then delivered pulses of blue laser light (20Hz, 10ms pulse, 3 sec off, 1 sec on) for 15 min to activate DMV neurons. We used a glucometer on tail blood samples drawn every 5 minutes for 1 hour, beginning 20 minutes before and ending 25 minutes after photostimulation. Before, during, and after photostimulation, blood glucose averaged 2± 35 mg/dL, 220 ± 36 mg/dL, and 215 ± 45 mg/dL and did not change significantly with photostimulation (p>0.05, ANOVA) . To rule out stress as a confound, we repeated these studies after anesthetizing 4-hour fasted mice with isoflurane but still did not detect a significant effect of photostimulation on blood glucose. Interestingly, however, heart rate decreased significantly with photostimulation (pre, 5± 23 bpm; during, 429 ± 32 bpm; post, 517 ± 24 bpm; p<0.001, ANOVA) , indicating that the photostimulation parameters were sufficient to activate vagal neurons. Further work is underway to address whether the lack of effect of DMV poststimulation on blood glucose is due to antagonistic signaling (e.g., coincident release of insulin and glucagon) or represents a limitation of the method.

Disclosure

J.Campbell: None. N.J.Conley: None. L.S.Kauffman: None.

Funding

American Diabetes Association (1-18-INI-14) ;
132-LB: Effectiveness of Interventions to Improve Cardiovascular Risk Factors in U.S. Asian Persons with Type 2 Diabetes—A Systematic Review and Meta-analysis
Authors: XIAO JASON , YU JIELU , DECKARD AMBER , WAN WEN , STAAB ERIN M. , RODRIGUEZ ALEX W. , SHETTY RAJ , LAITEERAPONG NEDA
Published: May 2022

Objective: Asian persons have an increased risk of type 2 diabetes (T2D) compared to non-Hispanic white persons, with approximately two in five individuals being diagnosed. The prevalence of T2D among this population has grown in recent years as Asian persons are the fastest growing racial/ethnic group in the US. We conducted a meta-analysis of US randomized controlled trials (RCTs) to evaluate the effectiveness of T2D interventions at improving systolic blood pressure (SBP) , diastolic blood pressure (DBP) , and HbA1c among this population.

Methods: An electronic search of literature in PubMed, Scopus, CINAHL, PsycINFO, and Medline was conducted from 1985 to 2019 for studies evaluating T2D interventions among predominantly minority populations. This analysis was limited to RCTs with an average >6% of total participants identifying as Asian, utilizing the 2020 US Census as standard. Interventions focusing on the efficacy of a drug, device, diet, surgery, or procedure were excluded. A random effects meta-analysis was performed to calculate the pooled effect size of the various outcomes.

Results: Of the articles reviewed, 9 met inclusion criteria. All 9 included HbA1c and 5 included SBP/DBP. Participants were 62.8% Asian and 40.3% female with a mean age of 53.4 years. Interventions included diabetes education programs, utilization of community health workers, bilingual counseling, and cognitive therapy. There was a 0.36% decrease in HbA1c in the experimental group when compared to the control group (95% CI -0.48 to -0.25, p=0.80, I2=0%) . Compared to control, these interventions had minimal effects on SBP (-0.08, 95% CI -0.22 to 0.07, p=0.73, I2=0%) and DBP (0.01, 95% CI -0.22 to 0.25, p=0.23, I2=29%) .

Conclusion: This meta-analysis found that RCTs for T2D in Asian persons modestly lowered HbA1c, with minimal impact on SBP/DBP. Future analysis should include observational studies to evaluate a larger sample and investigate their impact on other markers of health, as well as characterize these effects by level of intervention to inform health policy.

Disclosure

J. Xiao: None. J. Yu: None. A. Deckard: None. W. Wan: n/a. E. M. Staab: None. A. W. Rodriguez: None. R. Shetty: None. N. Laiteerapong: None.
1331-P: Associations between Insulin Resistance and Plasma Lipids and Metabolomics in Women with and without Type 1 Diabetes
Authors: VIGERS TIMOTHY B. , PYLE LAURA , SCHAUER IRENE E. , BERGMAN BRYAN C. , SNELL-BERGEON JANET K.
Published: May 2022

Insulin resistance (IR) increases risk for cardiovascular disease and mortality in people with type 1 diabetes (T1D) . We previously found associations between plasma lipids, metabolites and IR; whether these associations differ in people with and without T1D is not well understood.

We analyzed targeted plasma lipidomics and untargeted plasma metabolomics in 25 premenopausal women aged 18-45 yrs (12 with T1D and 13 without diabetes [non-DM]) who had a hyperinsulinemic euglycemic clamp to measure glucose infusion rate (GIR) . After stratifying by diabetes, women were classified by tertiles of GIR. We used sparse partial least-squares discriminant analysis to predict and moderated t-tests to compare most IR vs. most insulin sensitive (IS) tertile.

Among women with T1D, 3 lipids, 4 amino acids, 3 peptides, 3 xenobiotics, 1 carbohydrate, and 1 nucleotide were lower and 1 lipid and 1 fatty acid were higher in the most IS tertile (Table) . Among non-DM women, 4 lipids, 1 cofactor, 1 fatty acid, and 1 phosphatidylethanolamine were lower and 1 nucleotide and 1 lipid were higher in the most IS tertile. None of the top features were the same in the T1D and non-DM groups.

Plasma lipids and metabolites were differentially associated with IR in women with and without T1D. Future work should validate these findings in a larger sample of women and men, and explore how these biomarkers relate to IR and metabolism in T1D.

Disclosure

T.B.Vigers: None. L.Pyle: None. I.E.Schauer: None. B.C.Bergman: Research Support; Eli Lilly and Company. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc.

Funding

American Diabetes Association (7-13-CD-10) ; National Heart, Lung, and Blood Institute (grant HL61753 and HL113029) , JDRF Diabetes Foundation (grant 17-2013-313) , DERC Clinical Investigation Core (grant P30 DK57516) , NIH-M01-RR00051, NIH P30-DK116073
134-OR: Cost-Effectiveness of a Real-Time Continuous Glucose Monitoring System vs. Self-Monitoring of Blood Glucose in Type 2 Diabetes Patients on Insulin in Canada
Authors: ISITT JOHN J. , ROZE STEPHANE , COGSWELL GREGORY , LYNCH PETER M.
Published: May 2022

A health economic analysis was conducted to determine the cost-effectiveness of a real-time continuous glucose monitoring (rt-CGM) system versus self-monitoring of blood glucose (SMBG) in Type 2 diabetes (T2D) patients treated with insulin. The IQVIA CORE diabetes model was utilized for the analysis. Clinical data were sourced from a US retrospective cohort study of adult T2D patients on insulin and adapted to Canada. The baseline mean age (SD) of the cohort was 61 years (13.2) and proportion of male 49%. Mean baseline HbA1c for the cohort was 8.3% (67 mmol/mol) . Patients using rt-CGM were assumed to have a reduction in HbA1c of -0.56% based on the mean difference between groups after 12-months follow-up. A quality-of-life (QoL) benefit associated with reduced finger-stick testing was applied. The analysis was conducted from the Canadian Agency for Drugs and Technologies in Health perspective over a lifetime horizon. The rt-CGM system was associated with an incremental gain of 0.97 quality-adjusted life years (QALYs) compared with SMBG (mean [SD] 10.35 [3.08] versus 9.375 [2.85] QALYs) . Total mean [SD] lifetime costs were CAN$ 17,223 higher with rt-CGM (CAN$ 206,284 [121,493] versus 189,061 [129.680]) , resulting in an incremental cost-effectiveness ratio of CAN$ 17,652 per QALY gained. Sensitivity analyses demonstrated findings were sensitive to changes in QoL, HbA1c, younger patient cohorts, and rt-CGM cost. Varying rt-CGM cost to -25% of base case yielded an ICER of CAN$ 3,512, and varying rt-CGM cost to -50% of base case the ICER becomes dominant over SMBG. For T2D patients on insulin, rt-CGM was associated with significant clinical outcomes and is a cost-effective management option relative to SMBG based on a willingness-to-pay threshold of CAN$ 50,000 per QALY gained.

Disclosure

J.J.Isitt: Consultant; Dexcom, Inc. S.Roze: None. G.Cogswell: None. P.M.Lynch: Employee; Dexcom, Inc., Stock/Shareholder; Dexcom, Inc.
1366-P: Examining Central Carbon Metabolic Flux in the Perfused Exocrine Pancreas Using Dissolution Dynamic Nuclear Polarization
Authors: RUSHIN ANNA , MCLEOD MARC , RAGAVAN MUKUNDAN , MERRITT MATTHEW
Published: May 2022

The pancreas functions as both an endocrine and exocrine gland. The endocrine component consists of the islets of Langerhans, whereas the exocrine tissue produces digestive enzymes through the ductal system. Although the majority of Type I Diabetes research has focused on the islets, the exocrine tissue is likely implicated in T1D as well. This research utilizes a novel method to investigate exocrine pancreas metabolism with a pancreas perfusion system. I hypothesized that dissolution dynamic nuclear polarization (dDNP) combined with the pancreas perfusion system would provide real-time measurements of central carbon metabolic turnover in the exocrine pancreas. DNP is a phenomenon in which a transfer of high spin polarization greatly enhances the signal in the resulting nuclear magnetic resonance (NMR) spectra. This research compares dDNP measurements in the exocrine pancreas in C57BL/6 male mice under varying glucose conditions. It also examines central carbon metabolism using this system in the T1D mouse model NOD.Rag1-/-.AI4α/β and the NOD.Rag1-/- control. After cannulation of the common bile duct, the exocrine pancreas was perfused for 30 minutes with perfusate containing either 3mM or 16.7mM glucose. Tissue viability was confirmed throughout the perfusion with oxygen consumption measurements. dDNP was performed using the trityl radical and 4mM [1-13C]pyruvate. NMR spectra were collected on a 600MHz instrument with a 10mm [13C]-optimized cryoprobe and analyzed with Bruker TopSpin. Several metabolites were identified and quantified in all measured spectra, demonstrating the detection of real-time metabolic turnover. Ultimately, this work demonstrates that dissolution dynamic nuclear polarization can be used to evaluate metabolic flux in the pancreas in multiple mouse models. Future will investigate the real-time metabolic response of the exocrine pancreas to insulin concentrations in the T1D disease model.

Disclosure

A.Rushin: None. M.Mcleod: None. M.Ragavan: None. M.Merritt: None.

Funding

National Institutes of Health (T32 DK10876) National Science Foundation (DMR-1644779)
1367-P: A Submembrane Cytoskeleton-Dependent Mechanism Modulates Mitochondrial Homeostasis and Skeletal Muscle Bioenergetics
Authors: VOOS KAYLEIGH , TZENG JOYCE , CHOI HA EUN , PHARR TREVOR , LORENZO DAMARIS
Published: May 2022

Human variants in the ubiquitously expressed cytoskeletal scaffolding protein Ankyrin B (AnkB) , which is enriched in skeletal muscle (SKM) , have been identified as risk factors for diabetes and obesity. Mice harboring pathogenic variants exhibit reductions in levels of the predominant 220-kDa AnkB isoform in several tissues, including SKM and impaired systemic glucose regulation. To understand the specific metabolic role of AnkB in SKM, we developed a conditional knock-out mouse in which 220-kDa AnkB is knocked out only in SKM (SKM-AnkB-KO) . SKM-AnkB-KO mice display glucose mishandling that persists with age, as well as decreases in activity and exercise capacity, measured by indirect calorimetry and voluntary running wheel analysis. Histological evaluations of aged SKM-AnkB-KO mice showed general disorganization of muscle fibers and the presence of centralized nuclei. This is accompanied by increases in lean muscle mass and in the cross-sectional area of mitochondria-rich soleus muscle, suggesting the development of muscle hypertrophy over time. Electron microscopy analysis revealed the presence of hyperfused mitochondria in SKM-AnkB-KO mice. This morphological change was concomitant with up-regulation of transcripts in pathways associated with energetic stress, including AMPK signaling, redox signaling and mTOR signaling, assessed by RNA-seq, and with alterations in mitochondrial respiration in isolated muscle fibers. Interestingly, SKM-AnkB-KO mice mi SKM-AnkB-KO mice also exhibit increases in protein levels of electron transport chain proteins. Through proteomics and biochemical analysis, we uncovered that AnkB directly associates with several mitochondrial proteins and co-fractionates with mitochondrial in SKM. Together, these data suggest a direct role of AnkB in SKM mitochondrial metabolism that is distinct from its previously characterized role in insulin signaling in other tissues and cytoskeletal organization in SKM.

Disclosure

K.Voos: n/a. J.Tzeng: None. H.Choi: None. T.Pharr: None. D.Lorenzo: None.

Funding

American Diabetes Association; National Institutes of Health (1T32GM119999-01A1)
1371-P: Dynamic Mapping of Skeletal Muscle Perfusion and Phosphocreatine with 1H Magnetic Resonance Imaging: A Rest-Exercise Study in Diabetes
Authors: WAHIDI RYAN , LI RAN , ZAYED MOHAMED A. , HASTINGS MARY , ZHENG JIE
Published: May 2022

Aim: Evaluating time and spatially resolved 1H magnetic resonance imaging (MRI) in quantifying muscle tissue phosphocreatine (PCr) kinetics (without extra hardware) and perfusion in healthy individuals and patients with type 2 diabetes mellitus (DM) .

Methods: 18 subjects were imaged in 3 groups using a 3T MRI scanner; young healthy (26y, n= 6) , old healthy (62y, n = 6) , and DM patients (66y, n = 6) . For each subject, a chemical exchange saturation transfer (CEST) MRI scan was performed in the calf every 1 min at rest (3 min) , during exercise (4 min standardized isometric plantarflexion) , and a recovery period (6 min) . Subjects also underwent mapping of skeletal muscle perfusion in a separate exercise protocol. PCr concentration maps were quantified by Bloch-McConnell fitting, and values were obtained in the medial gastrocnemius and soleus muscles.

Results: DM patients show a longer PCr recovery time τ during recovery compared to both healthy groups: young healthy τ = 47.1 ± 18.2s, old healthy τ = 41.9 ± 15.1s, and DM τ =122.2 ± 58.6s, p = 0.02 (Figure) . There is a negative correlation between PCr and perfusion during exercise in healthy groups (r = 0.38, p = 0.034) that is not significant in the DM group.

Conclusion: Dynamic PCr mapping by proton MRI in calf muscle reveals impaired energetics that is uncoupled from muscle perfusion in DM compared to healthy controls.

Disclosure

R.Wahidi: None. R.Li: None. M.A.Zayed: None. M.Hastings: None. J.Zheng: None.
1382-P: Novel Mechanisms to Reconvert Glucocorticoids into Pro-Metabolic Agents through Adiponectin
Authors: WINTZINGER MICHELLE , MIZ KAREN , PANTA MANOJ , DURUMUTLA HIMA BINDU , PRAGASAM ASHOK DANIEL PRABAKARAN , QUATTROCELLI MATTIA
Published: May 2022

Adiponectin is the most abundant adipokine in our circulation and regulates inter-tissue communication like the adipose-muscle axis. Pharmacological modulation of this crosstalk is beneficial in promoting exercise tolerance in metabolic stress conditions like obesity. Endogenous glucocorticoids regulate metabolic function and stress response, but chronic daily intake of exogenous glucocorticoids produces or exacerbates metabolic stress. However, in stark contrast to daily intake, we discovered that intermittent regimens of glucocorticoids, e.g. once-weekly, improves exercise tolerance. However, the mechanisms underlying the differential regimen-specific effects of glucocorticoids in obesity remain unknown. Here we investigated the mechanisms differentiating once-weekly versus once-daily regimens of the same glucocorticoid prednisone in obesity. In mice with diet-induced obesity, once-weekly prednisone stimulated total and high-molecular weight adiponectin levels, improving exercise tolerance and energy expenditure. These effects were dependent upon adiponectin and were blocked by genetic ablation of the adipokine. Upregulation of Adipoq occurred through the adipose-specific glucocorticoid receptor (GR) , as this effect was blocked in mice with inducible GR ablation in adipose tissue. In contrast, once-daily prednisone decreased adiponectin levels through upregulation of known repressors of adiponectin expression in adipose tissue. The drug regimens remodeled in opposite ways also transcriptome and function in skeletal muscle after onset of obesity. Particularly, once-weekly prednisone treatment increased the muscle metabolic response to adiponectin through the CAMKK2-AMPK cascade. Our study demonstrates that intermittent glucocorticoids produce healthful metabolic remodeling in diet-induced obesity through direct upregulation of adiponectin expression in adipose tissue and adiponectin-dependent signaling in skeletal muscle.

Disclosure

M.Wintzinger: Employee; Cincinnati Children's Hospital. K.Miz: None. M.Panta: None. H.Durumutla: None. A.Pragasam: None. M.Quattrocelli: None.

Funding

National Institutes of Health grant DK121875National Institutes of Health grant HL158531CCHMC Trustee AwardCCHMC Heart Institute Translational Grant
1386-P: Confirmation of the Criteria for Insulin Administration at the Start of Steroid Therapy
Authors: KANEKO SHIZUKA , MOTOHASHI KAZUYA , MINAMI TOMOKO , UEBA YOKO , OSUGI TOMOAKI , TOKUMOTO SHINSUKE
Published: May 2022

Blood glucose elevates at initial high-dose steroid (HDS) administration and is prolonged by persistent amplification of glucagon-induced glycogenesis. Insulin (INS) administration at initial dose of HDS will avoid this. However, INS administration criteria regarding BS elevation are not defined. HDS were given based on COVID-treatment guidelines. HDS administration circumstances in clinical settings may clarify these criteria. The necessity of INS therapy at initial HDS administration is studied. COVID-inpatients receiving HDS, regarding a COVID-period in Japan comprising 5 waves, were sub-grouped into those requiring INS therapy and those not, and analyzed with respect to age, BMI, fasting blood glucose (FBS) , A1c, C-peptide (CPR) index, CPR/glucagon (GCG) . INS was administered, target BS level 200 mg/dL or less at 14:00, depending on BS level after HDS administration. From 396 patients, 257 received HDS as follows, 1of the 154 patients in Wave 1-3 (69.5 ± 16.7 years, BMI 23.9 ± 4.8%, A1c 6.3 ± 1.1%) , 79 of the 83 patients in Wave 4 (64.5 ± 14.6 years, BMI 24.9 ± 4.78, A1c 6.6 ± 1.1%) , and 73 of the 117 patients in Wave 5 (54.4 ± 15.2 years, BMI 25.2 ± 5.1, A1c 6.2 ± 0.8%) . Of the 257 patients above, 145 were treated with INS. In all Waves, only FBS and A1c differed significantly between INS-treated and non-INS-treated patients. ROC analysis in Wave 1-3, Wave 4 and Wave 5 showed cut-off values of A1c (sensitivity/specificity) and FBS (sensitivity/specificity) measuring 6.1% (0.85/0.62) and 121.5 mg/dL (1.00/ 0.62) , 6.5% (0.44/0.83) and133.5 mg/dL (0.40/0.93) , and 6.4% (0.49/1.0) and 112.5 mg/dL (0.81/0.85) , respectively. In patients with FBS levels of 112.5 mg/dL or higher or A1c levels of 6.3% or higher, the use of INS from the initial HDS administration reduced prolongation of hyperglycemia. Variables BMI, CPR, and GCG secretion cannot determine the need for INS therapy. It is important to use FBS and A1c levels, according to conventional practice, to ascertain if INS administration is necessary.

Disclosure

S.Kaneko: None. K.Motohashi: None. T.Minami: None. Y.Ueba: None. T.Osugi: None. S.Tokumoto: None.

Funding

Reiwa 2nd year cookie test clinical research grant