bluuebunny/crossref_metadata_2025 huggingface dataset:
224-OR: The Efficacy and Safety of HSK 16149 in Chinese with Diabetic Peripheral Neuropathic Pain—A Randomized, Double-Blinded, Placebo and Pregabalin-Controlled Phase II/III Study
Authors: GUO XIAOHUI , ZHANG TINGTING , YUAN GEHENG , YUKUN LI , HUA MA JIAN , HONG-MEI LI
Published: June 2023

Background: Chronic diabetic peripheral neuropathic pain (DPNP) is common and difficult to treat. The recommended medications are either inadequate effective or limited by the side effects. This study aims to evaluate the efficacy and safety of HSK16149, a potent, selective ligand of the a2δ subunit of voltage-gated calcium channels (VGCC), as analgesia treatment for DPNP.

Materials and Methods: This was a randomized, double-blind, placebo and active-controlled phase II/III study of patients aged ≥18 years with diabetic peripheral neuropathy in China. Firstly, the patients with moderate to severe pain were randomized to receive placebo, HSK 16149 40,80 mg/d without titration, and HSK16149 120, 160mg/d, pregabalin 300mg/d with 1 week titration on average. Then more patients were recruited and randomized to placebo and two HSK16149 dose groups, continued the treatment for up to 13 weeks. The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 13. The secondary endpoint was the responder rates as ≥30% and ≥50% improvement in ADPS.

Results: Compared with placebo, the pain was reduced since week 1 in HSK16149 groups. At week 13, the mean ADPS change from baseline was -1.23, -2.24 and -2.16 for placebo (n=177), HSK 16149 40mg/d (n=178) and 80mg/d (n=179), showing statistical significance for both HSK groups versus placebo (P<0.0001). The 30% and 50% responder rate were both significantly greater for two HSK groups versus placebo (≥30%: 57.3%, 51.4% versus 31.6%; ≥50%: 32.0%, 36.3% versus 18.1%) at week 13. Most treatment-emergent adverse events (TEAE) in HSK16149 groups were mild to moderate, and the most frequent TEAEs were dizziness and somnolence, which were always transient and needed no additional treatment.

Conclusions: HSK 16149 rapidly improved analgesia without titration and was efficacious in relieving pain in Chinese DPNP patients, and well tolerated.

Disclosure

X.Guo: None. T.Zhang: None. G.Yuan: None. L.Yukun: None. J.Ma: None. L.Hong-mei: None.
227-OR: Increasing Quarterly Use of Intermittent CGM among Individuals with T2D Is Associated with Improved Glycemic Control over a One-Year Time Frame
Authors: ELLIS ROBERT J. , KOMPALA TEJASWI , BROOKS ROBERT J. , HONE JENNIFER , SALEHI ATOUSA , JAMES ROBERTA
Published: June 2023

Introduction: Continuous glucose monitoring (CGM) is an important tool for biofeedback in diabetes self-management. Intermittent use CGM for T2D users is one approach to address cost and access limitations, but to date only limited evidence supports intermittent use. The objective of this study was to understand the impact of intermittent use CGM in T2D non-intensive insulin users in a real-world setting.

Methods: As part of an ongoing implementation study within the Livongo whole person digital health program, a select population of individuals living with T2D who had not previously used CGM and either used no insulin or basal insulin only were mailed and asked to wear Dexcom G6 CGM sensors for 7-10 days per quarter for 4 consecutive quarters. In this analysis, we examined data from 227 individuals who adhered to wearing CGM for at least 7 days in 2 or more quarters. A multiple linear regression design quantified the impact of the primary variable of interest - the number of quarters with CGM wear (2, 3, or 4) - on changes in glycemic control between the first and latest available sensors, while including additional variables (potential confounds) associated with demographic traits, medication use, and temporal aspects of CGM wear.

Results: Glycemic control at baseline varied widely; 54% of individuals had a Time In Range (TIR) less than the target of 70%. Among the full sample (N = 227), each additional quarter of CGM use (beyond 2) resulted in clinically meaningful average improvements (and significant partial correlations, all p < .05) in mean sensor glucose (11.8 mg/dL decrease), TIR (7.7 point increase), Time Above Range (7.9 point decrease), and the Glycemia Risk Index (9.3 point decrease).

Conclusion: Type 2 non-intensive insulin users who were adherent to quarterly use of intermittent CGM over one year saw meaningful improvements in glycemic control. Providing access to CGM technology may facilitate improvement in outcomes and disease management.

Disclosure

R.J.Ellis: Employee; Teladoc Health. T.Kompala: Employee; Teladoc Health, Stock/Shareholder; Teladoc Health. R.J.Brooks: Employee; Teladoc Health, Stock/Shareholder; Dexcom, Inc. J.Hone: Employee; Teladoc Health, UnitedHealth Group. A.Salehi: Employee; Teladoc Health. R.James: Employee; Teladoc Health.
236-LB: FHL2-/- Perivascular Adipose Tissue Improves Vessel Tone and Insulin-Stimulated Vasodilation by Inhibiting ERK1/2
Authors: HABIBE JAYRON , VAN RAALTE DANIËL , NIEUWDORP MAX , DE VRIES CARLIE , ERINGA ETTO C.
Published: June 2023

Background: Type 2 diabetes, obesity and aging increase risk of developing cardiovascular diseases. Perivascular adipose tissue (PVAT) is a crucial regulator of vascular function. Four and Half Lim domains 2 (FHL2) is a protein upregulated in aging which targets various proteins with established links to adipose tissue growth, potentially regulating metabolic signaling.

Objective: we hypothesized that FHL2 regulates adipose tissue regulation of vascular function.

Methods: Femoral arteries were isolated from Wild type (WT) and FHL2-/- mice and vasoreactivity to insulin and acetylcholine was studied with and without perivascular adipose tissue.

Results: FHL2-/- vessels with PVAT had increased tone compared to WT vessels with PVAT as well as improved insulin-stimulated vasodilation. Exchange experiments using vessels with PVAT from the opposite genotype showed that FHL2-PVAT enhanced tone and insulin-stimulated vasodilatation compared to WT-PVAT. Gene expression analysis showed downregulation of adiponectin in FHL2-PVAT. Western blot analysis of insulin-stimulated phosphorylation of ERK and Akt in human microvascular endothelial cells (HMECs) stimulated with PVAT-conditioned medium revealed that FHL2-PVAT but not WT-PVAT reduced insulin-stimulated phosphorylation of ERK but not activation of Akt. In line with the effect of FHL2 on insulin-induced vasodilatation and activation of ERK1/2, analysis of publicly available RNA sequencing data of peri-aortic PVAT showed that FHL2 expression in PVAT positively correlates with expression of the endothelial vasoconstrictor peptide endothelin-1 (edn1).

Conclusion: FHL2 regulates vascular function through enhancement of smooth muscle tone, regulation of adipokine secretion affecting insulin-stimulated ERK1/2 activation and Edn1 expression in endothelial cells. These finding provide a new mechanism for vascular dysfunction in type 2 diabetes.

Disclosure

J. Habibe: None. D. van Raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. M. Nieuwdorp: Advisory Panel; caelus health. C. de Vries: None. E. C. Eringa: None.

Funding

Amsterdam Cardiovascular Sciences (ACS201703)
236-OR: Pancreatic ß-Cell TRAPδ Deficiency Reduces Insulin Production but Improves Insulin Sensitivity
Authors: GUO JIYUN , YANG YANSHU , XU NING , YANG YING , FENG WENLI , YE YUANYUAN , LI XIN , XU XIAOXI , CUI JINGQIU , HUANG YUMENG , LIU MING
Published: June 2023

The endoplasmic reticulum (ER) membrane protein translocon-associated protein-δ (TRAPδ, also known as SSR4) is involved in insulin biosynthesis in pancreatic β cell lines. However, its pathophysiological significance for the maintenance of islet β cell function and glucose homeostasis is unclear. Herein, we generated a mouse line with pancreatic β cell-specific deletion of TRAPδ (TRAPδ βKO), and found that TRAPδ βKO led to decreased circulating insulin in mice fed with either normal chow diet or high fat diet. Multiple independent experiments confirmed that, although TRAPδ deletion decreased insulin content in the islets, it did not affect composition of islet cells, insulin gene expression, insulin/proinsulin ratio, nor the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a critical role in the transcription of insulin gene and processing of proinsulin. Importantly, untranslocated preproinsulin was significantly increased when the islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency impaired preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Interestingly, the moderate decrease in the circulating insulin level in TRAPδ βKO mice did not cause impaired glucose tolerance and elevated fasting blood glucose, suggesting that compensatory mechanisms may account for maintaining glucose homeostasis. The insulin tolerance tests confirmed improvement of insulin sensitivity accompanied with upregulation of phosphorylated AKT in the peripheral insulin target tissues of TRAPδ βKO mice. Together, these data uncover a critical role of TRAPδ in preproinsulin translocation and insulin biosynthesis. The moderately decreased circulating insulin promotes insulin sensitivity in the insulin target tissues.

Disclosure

J.Guo: None. Y.Huang: None. M.Liu: None. Y.Yang: None. N.Xu: None. Y.Yang: None. W.Feng: None. Y.Ye: None. X.Li: None. X.Xu: None. J.Cui: None.

Funding

National Natural Science Foundation of China (81830025, 82220108014, 82270864, 82070854); National Key R&D Program of China (2019YFA0802502, 2022YFE0131400); Tianjin Municipal Health and Health Committee (TJWJ2021ZD00); Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-030A)
239-OR: Glycemic Control after Total Pancreatectomy with Islet Autotransplantation—Results from a Single Center with Large Cohort of Patients
Authors: RUB HAKIM MOHAMMED ABDUL , DARDEN CARLY , KIRKLAND JEFFREY , KUNCHA JAYACHANDRA , MATTKE JORDAN D. , LAWRENCE MICHAEL C. , NAZIRUDDIN BASHOO
Published: June 2023

Total pancreatectomy and islet autotransplantation (TPIAT) for refractory chronic pancreatitis has been performed at our center from 2006. We employed anti-inflammatory treatment using IL-1β and TNF-α blockers to improve graft outcomes. We present results on islet characteristics and glycemic control post-TPIAT from this large cohort of patients. Our database of 200 consecutive TPIAT procedures performed were retrospectively reviewed. We collected demographics, pancreas and islet characteristics. Patient follow-ups were performed at 3, 6, 12 m and then annually. Outcomes measures included glycemic control, pain relief and narcotic use. Baseline patient characteristics (age, sex, BMI, etiology, C-peptide and HbA1c, duration of symptoms) and isolation results were shown in Table 1A and post-TPIAT fasting glucose, HbA1c, C-peptide and daily insulin use in Table 1B. The insulin independence rate at 3, 6 and 12 months increased with time from 15%, 24 % and 27%, respectively). At 1 year, pain score was significantly improved (p<0.0001). Narcotic free rate also increased to 47% at 6 months and 56% at 1 year. Most post-TPIAT patients preserved hypoglycemic awareness and good pain relief. A cohort of patients remained normoglycemic without insulin and this group can be further studied to identify the factors that prevent the incidence of T3cDM after TPIAT.

Disclosure

A.Hakim mohammed: None. C.Darden: None. J.Kirkland: None. J.Kuncha: None. J.D.Mattke: None. M.C.Lawrence: None. B.Naziruddin: None.
24-OR: Augmented Heparanase Secretion in Diabetes Regulates Development of Cardiac Hypertrophy
Authors: SYNG LEE CHAE , SHANG RUI , HUSSEIN BAHIRA , RODRIGUES BRIAN
Published: June 2023

HSPG consist of a core protein to which several linear heparan sulphate (HS) side chains are linked. Heparanase (Hpa) is exceptional in its ability to degrade HS. This property is used to regulate cardiac metabolism by releasing LPL, for its onward movement to the vascular lumen to hydrolyze lipoprotein-TG for FA provision to the heart. We hypothesized that another function of Hpa is its ability to promote cardiac hypertrophy. Hearts from mice with global overexpression of Hpa appeared larger, had higher heart weight/tibia length ratios, and exhibited posterior wall thickening. This evidence of cardiac hypertrophy was not reflected in alterations in cardiac function; ejection fraction, fractional shortening, and stroke volume were largely unaffected. This suggested a physiological rather than pathological hypertrophy, and is linked to a role for Hpa in regulation of arterial structure and mechanics. Hearts from animals with cardiac-specific overexpression of VEGFB also released greater amounts of Hpa, and this coincided with a hypertrophic phenotype. Heart function in these VEGFB-Tg rats remained similar to wild-type, and was likely a consequence of the expanded coronary vasculature and metabolic reprogramming that favoured glucose utilization. Rats made diabetic with STZ did not show any changes in cardiac Hpa gene or protein expression. Nevertheless, immediately after retrograde perfusion, the diabetic hearts released significantly greater amounts of Hpa with evidence of relative cardiac hypertrophy. This cardiac hypertrophy in diabetic rats was pathological with ventricular wall thinning and reduced cardiac function. Our data imply that Hpa can stimulate cardiac hypertrophy that remains physiological when there is associated development of coronary vasculature with metabolic flexibility. With diabetes and the occurrence of microangiopathy along with metabolic inflexibility, hypertrophy progresses towards being pathological, leading to heart failure.

Disclosure

C.Lee: None. R.Shang: None. B.Hussein: None. B.Rodrigues: None.

Funding

Canadian Institutes of Health Research (PJT178134); Heart and Stroke Foundation of Canada (G190026493)
243-OR: A Novel Platform for Genetic Screening of NAFLD-Associated Genes Identifies UBE2G2 and Other Genes That Alter Hepatic Lipid Accumulation
Authors: HU SIQI , ADITI SRI VAISHNAVI KHANDAVILLI SESHA , DIAO RACHEL Y. , RAUM JEFFREY , AZHAR NABIL , BAKAJ IVONA , COWLEY GLENN , RADY BRIAN , REILLY DERMOT F. , MAJITHIA AMIT R.
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver failure that is prevalent in 70% of people with diabetes. Human genetic studies (i.e. GWAS) have identified dozens of potentially causal genes/loci increasing NAFLD susceptibility but translation into actionable drug targets has been impeded by a lack of cellular and molecular mechanistic studies. To address this knowledge gap, we developed a platform for high-throughput genetic perturbation and assessment of fatty acid-triggered lipid accumulation (i.e. hepatic steatosis) in human hepatocytes by combining mechanized cell culture in multi-well plates with high-content microscopy and automated image analysis. We then deployed this platform to screen 106 genes nominated by NAFLD biomarker GWAS, knocking out each gene via CRISPR and scoring the phenotypic changes of the resulting engineered cells in response to oleate treatment. Analysis of over 24,000 images across all gene knockouts revealed 32 genes whose deletion caused significant alterations in cellular lipid droplet (LD) numbers and/or droplet size distribution. Here, we highlight ubiquitin-conjugating enzyme E2 G2 (UBE2G2), whose knockout robustly increases the size of cellular LDs that form in response to oleate stimulation in both the primary screen and subsequent validation. UBE2G2 localizes to the LD surface and is essential for the sterol-induced degradation of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Thus we propose that deletion of UBE2G2 may increase cholesterol derivative content in LDs, thereby increasing LD size. In summary, we demonstrate the successful development and use of a platform for genetic screening of hepatocyte steatosis in vitro and identify multiple NAFLD-associated genes of previously unknown function that likely operate during this early stage of NAFLD pathogenesis. We acknowledge input: Seunghan Lee, Lifeng Wang, David Frederick, Alessandro Pocai

Disclosure

S. Hu: None. S. Khandavilli: None. R.Y. Diao: None. J. Raum: Employee; Janssen Research & Development, LLC. N. Azhar: Employee; Janssen Research & Development, LLC. I. Bakaj: Employee; Janssen Research & Development, LLC. G. Cowley: Employee; Janssen Research & Development, LLC. B. Rady: Employee; Janssen Research & Development, LLC. D.F. Reilly: Employee; Janssen Research & Development, LLC. A.R. Majithia: None.

Funding

National Institutes of Health (RDK01DK123422)
245-LB: Glucagon Infusion into the Mediobasal Hypothalamus Lowers Hepatic Triglyceride Secretion
Authors: GREWAL MANTASH S. , VASILEV BOYAN , SOLTYS CARRIE-LYNN M. , LUM BRYAN , YUE JESSICA T.
Published: June 2023

Diabetes and obesity are associated with dysregulated liver lipid metabolism. Glucagon has an essential role in lipid metabolism, in addition to regulating glucose homeostasis. The brain is a key coordinator of whole-body metabolism. Glucagon signalling in the mediobasal hypothalamus (MBH), a forebrain region that senses hormones and nutrients to regulate metabolism, lowers hepatic glucose production and appetite. However, whether glucagon action in the MBH affects lipid homeostasis in healthy and high-fat diet (HFD)-fed animals remains unknown. We assessed glucagon signaling in the MBH in regulating hepatic TG secretion in chow-fed normolipidemic and HFD-induced hyperlipidemic rats.

Stereotaxic MBH cannulation and vascular catheterizations in Sprague-Dawley rats allowed for direct MBH infusions, intravenous (IV) injections, and blood sampling. Plasma TGs were measured in 10h-fasted rats after IV poloxamer injection with concurrent MBH infusions. MBH glucagon decreased TG secretion compared to MBH vehicle control animals. This hypothalamic effect of glucagon was blocked by a simultaneous MBH co-infusion of an antagonist to the glucagon receptor (GCGR) and by protein kinase A (PKA) inhibition in the MBH in chow-fed rats. Direct MBH infusion of a PKA activator recapitulated the TG-lowering effects of MBH glucagon. Together, this suggests that MBH glucagon signals via a MBH GCGR-PKA pathway. Interestingly, both MBH glucagon and MBH PKA activation lowered TG secretion and plasma FFAs in HFD-induced hyperlipidemic animals. However, MBH glucagon did not affect hepatic TG content or liver lipogenic protein levels of MTP, FAS, or pACC:ACC of RC and HFD rats compared to their MBH vehicle controls.

We demonstrate that hypothalamic glucagon modulates hepatic TG secretion via a MBH GCGR-PKA signalling pathway, and activating MBH glucagon signalling improves lipid metabolism in hyperlipidemic rats. These findings may provide therapeutic insight on lowering lipids in hyperlipidemia.

Disclosure

M. S. Grewal: None. B. Vasilev: None. C. M. Soltys: None. B. Lum: None. J. T. Yue: None.

Funding

Canadian Institutes of Health Research (PJT-378765); Canada Foundation for Innovation (37267); Canada Research Chairs Tier 2 in Brain Regulation of Metabolism
252-OR: Continuous Glucose Monitoring in Patients with Post-bariatric Hypoglycemia Reduces Hypoglycemia and Glycemic Variability
Authors: CUMMINGS CAMERON J. , JIANG ALEX , SHEEHAN AMANDA L. , FERRAZ-BANNITZ RAFAEL , PULEIO ALEXA , SIMONSON DONALD C. , DREYFUSS JONATHAN , PATTI MARY-ELIZABETH
Published: June 2023

Post-bariatric hypoglycemia (PBH) is an increasingly recognized complication of bariatric surgery, with prevalence of up to 36% after gastric bypass. Hypoglycemia typically follows postprandial glycemic spikes. Continuous glucose monitors (CGM) can alert patients to high or low sensor glucose (SG), allowing treatment and prevention of severe hypoglycemia. The aim of this study (NCT03353415) was to determine whether CGM, currently indicated only for diabetes, could reduce hypoglycemia in PBH. In an open label, nonrandomized, pre-post design, sensor glucose data were collected using Dexcom CGM in two sequential phases: (1) masked (no access to SG or alarms); and (2) unmasked (access to SG and alarms for low or rapidly declining SG). Data were available for paired analysis for 22 individuals with PBH (mean±SD age 51.1±13.0 yrs, 20F/2M, BMI 30.6±6.2 kg/m2, 82% with level 3 hypoglycemia and 100% with neuroglycopenia). Participants with PBH spent a lower percentage of time in hypoglycemia with unmasked vs masked CGM (<60 mg/dL, median [MAD]: 0.7 [0.8] vs 1.4 [1.7]%, p=0.03; <70 mg/dL: 2.9 [2.5] vs 4.7 [4.8]%, p=0.04), with similar trends overnight. Likewise, there was more time between 70-180 mg/dL (94.8 [3.9] vs 90.8 [5.2]%, p=0.004), and lower glycemic variability (mean amplitude of glycemic excursion: 74.0 [17.7] vs 79.6 [17.8] mg/dL, p=0.04) during unmasked wear. During the day (6:00 AM-11:59 PM), participants spent more time in normoglycemia with unmasked CGM (94.2 [4.8] vs 90.9 [6.2]%, p=0.005), largely due to reduced hyperglycemia (>180 mg/dL: 1.9 [2.2] vs 3.9 [3.6]%, p=0.02). Availability of real-time CGM data and alarms is associated with reductions in low SG, elevated SG, and glycemic variability. This suggests CGM helps patients detect hyperglycemic peaks and imminent hypoglycemia, allowing dietary modification and self-treatment to reduce hypoglycemia. CGM may thus improve safety in PBH, particularly for patients with hypoglycemia unawareness.

Disclosure

C.J.Cummings: None. A.Jiang: None. A.L.Sheehan: None. R.Ferraz-bannitz: None. A.Puleio: None. D.C.Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows. J.Dreyfuss: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc.

Funding

Diabetes Research Center (P30DK036836)
253-LB: Characterization of Korean Type 2 Diabetes as Hyperinsulinemic, Insulin-Resistant, and miR-10a/b-5p-Deficient Hyperglycemia
Authors: YANG YU TAE , KIM MIN-SEOB , EUN HA SE , SINGH RAJAN , SEON DAHYUN , WOO JEONG JIN , YOUNG LEE MOON , RO SEUNGIL
Published: June 2023

Background: We previously reported that miR-10a-5p and miR-10b-5p are key regulators in the development of type 2 diabetes (T2D). Deficiency of miR-10a-5p or miR-10b-5p triggers the onset of T2D in mice while restoration of their miRNAs remarkably rescues the diabetic symptoms including hyperglycemia by restoration of insulin production and sensitivity. Deficiency of the antidiabetic miR-10a-5p and miR-10b-5p was also observed in T2D patients in the United States. However, the miRNA levels have not been examined in Korean T2D patients.

Method: Plasma samples were obtained from 54 (32 males and 22 females) patients with T2D, 24 (17 males and 7 females) patients with prediabetes, and 38 (21 males and 17 females) healthy donors in South Korea. T2D patients were selected based on the criteria of elevated both fasting glucose (>125 mg/dL), and A1C (>6.5). We examined levels of miR-10a/b-5p and metabolic panels including insulin (INS) and its receptor (INSR) using qPCR, ELISA, and Western blot. For statistics, we used a one-way analysis of variance or the Kruskal-Wallis test.

Results: Plasma samples were grouped into T2D, prediabetes, and healthy controls by levels of both fasting glucose and A1C. Fasting glucose, A1C, C-peptide, and insulin were significantly elevated in the T2D patient group while miR-10a/b-5p and INSR were noticeably reduced compared to the prediabetic group and the healthy control group. The Spearman rank correlation analysis showed significant correlations between miR-10a/b-5p levels and metabolic parameters in T2D patients and. healthy controls. miR-10a/b-5p levels were positively correlated with INSR, but negatively correlated with glucose, INS, C-peptide, BMI, and age in T2D patients.

Conclusion: Korean T2D was defined as miR-10a/b-5p deficiency as well as increased insulin production and resistance through reduction of insulin receptor.

Disclosure

T. Yu: None. M. Kim: None. S. Ha: None. R. Singh: None. D. Seon: None. J. Jeong: None. M. Lee: None. S. Ro: None.
256-OR: Hypoglycemia Effect on Relationship of Renal and/or Retinal Disease with CVD and Vice Versa
Authors: FAHRMANN ELKE R. , DRISCOLL HENRY
Published: June 2023

Baseline microvascular complications have been reported to affect the relationship of severe hypoglycemia (SH: needing assistance) with cardiovascular disease (CVD) in DCCT/EDIC type 1 diabetes (T1D) cohort followed for ~ 30 years. We investigated if this finding holds true considering any presence/absence of renal/retinal disease (any RR: sustained AER >30 mg/24 h and/or eGFR <60 mL/min/1.73 m2, and/or PDR and/or CSME) and whether it is bidirectional during longer follow up of >35 DCCT/EDIC years. DCCT/EDIC data provided by NIDDK CR were evaluated applying time dependent Cox models. Outcome was composite of CV death, myocardial infarct (MI), silent MI, revascularization, congestive heart failure, and angina. Subset SH (sSH) is SH with seizures and or loss of consciousness. Interaction between RR and SH (sSH) was evaluated and probed. During follow up, of 1441 patients (mean baseline age 27 ± 7 years, 47% women) 975 (660) had a SH (sSH) event, 741 experienced RR, and 222 had a CV event. All unadjusted (u) / adjusted (a) interactions (I) were significant: I(SH, RR) with p<0.05 (u) and p~0.01 (a), and I(sSH, RR) with p<0.01 (u) and <0.001 (a). Probing interactions showed: 1) In absence of SH or sSH, hazard ratio (HR) for RR was nonsignificant (ns): p>0.5, p>0.6, respectively. 2) In presence of SH or sSH, HR for RR was 1.74 [1.19, 2.53] p<0.01, 2.40 [1.46, 3.96] p<0.001, respectively. 3) In absence of RR, HR for SH and sSH was ns: p>0.4, p~0.08, respectively. 4) In presence of RR, HR for SH and sSH was 1.78 [1.22, 2.60] p<0.01 and 1.81 [1.28, 2.56] p<0.001, respectively. Subanalyses (stratification by SH (sSH) or RR absence / presence) were consistent. Our analyses provide additional evidence for multifactorial nature of relationship between SH and CVD. We demonstrate that SH increases strengths of association between any RR and CVD during > 35 years of follow up, and vice versa. This bidirectionality in a young cohort should be realized and considered in T1D management to identify individuals at higher CVD risk.

Disclosure

E.R.Fahrmann: None. H.Driscoll: None.
258-LB: Iridoid Glycoside Modulates Gut Microbiota and Ameliorates Nonalcoholic Fatty Liver Disease–Related Metabolic Disorders
Authors: XIE CEN , LIU YAMENG
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease closely associated with glucose and lipid metabolism disturbance. The development of herbal medicine interventions for NAFLD is presently a popular topic in pharmaceutical research. However, although many active natural ingredients have been reported as promising agents for NAFLD, their potential benefits are contrasted by their poor oral absorption. GG-01, an effective iridoid glycoside discovered from a clinical prescription of traditional Chinese medicine (TCM), is exposed first in the intestinal tract, and gut microbes may quickly react to GG-01. Therefore, it is intriguing to explore the role of gut microbiota and microbial metabolites in the beneficial effects of GG-01 on NAFLD-related disorders. Our research intends to commence with the intestinal nutritional characteristics of GG-01. Firstly, the crucial role of intestinal microbiota in the pharmacological effects of GG-01 is confirmed using different animal models. Subsequently, we identify the key microbes by combining high-throughput sequencing and an in vitro culture system of intestinal microbiota. We then focus on one of the key microbes, Akkermansia muciniphila, and elucidate how GG-01 can treat NAFLD-related metabolic disorders by stimulating the bile acid biotransformation of Akkermansia muciniphila based on “TCM-microbiome-host” interaction. Finally, we present a novel therapeutic strategy of the synergistic effect of Akkermansia muciniphila and GG-01 via TGR5 to activate epithelial regeneration, promote GLP-1 production, and further treat NAFLD-related metabolic disorders. We also propose GG-01 as a new type of probiotic for the treatment of NAFLD.

Disclosure

C. Xie: None. Y. Liu: None.
26-OR: A Novel Drug That Normalizes Hyperglycemia in Type 1 Diabetes
Authors: ASADI FARZAD , GUNAWARDANA SUBHADRA C. , PISTON DAVID W.
Published: June 2023

Treatment of hyperglycemia in patients with type 1 diabetes (T1D) depends on insulin injections, which risk hypoglycemia and represent an unfavorable route of administration. Inhibition of EphA4 signaling in α-cells reduces glucagon hypersecretion, which suggests an alternative approach for the treatment of hyperglycemia in T1D. We have designed and synthesized a novel EphA4 agonist (Ki = 0.1 µM), termed WCDD301, that dose-dependently suppresses glucagon secretion (p<0.001) from mouse islets and dispersed α-cells at high glucose levels. Co-treatment of the EphA4 competitive inhibitor, Rhyncophylline (2.5µM) and WCDD301 (2.5µM or 5µM) substantially or partially, respectively, abolishes WCDD301 effects. Further, WCDD301 reduces glucagon secretion from nondiabetic human donor islet cells following 1h (p<0.05), 3h (p<0.01) and 6h (p<0.001) exposure. WCDD301 suppresses glucagon secretion (p<0.001) from isolated islets and dispersed islet cells from T1D subjects, comparable to the natural EphA4 ligand ephrinA5. Similar to ephrinA5 treatment, WCDD301 increases F-actin density in both human and mouse α-cells. WCDD301 exhibits good plasma (>289 and 105 min) and microsomal (>145 and 93.6 min) stability in human and mouse, respectively. In STZ-induced diabetic mice (initial blood glucose <300mg/dL, n=6), oral administration of WCDD301 (daily 10 mg/kg) substantially reduces blood glucose levels (140±31 mg/dL after four weeks). In diabetic NOD mice (initial blood glucose 249.6±13.1 mg/dL; n=7), oral administration of WCDD301 (daily 10 mg/kg) normalizes glucose (105±2.6 mg/dL after 3 weeks), which remains constant for >3 months (experiments on-going) accompanied by reduced plasma glucagon (16.6±7.9 pg/mL) compared to diabetic control (328.5±18.7 pg/ml). The data support our hypothesis that oral administration of WCDD301 suppresses glucagon secretion by an EphA4-dependent pathway. The recovery of euglycemia in T1D mouse models is promising for further evaluation towards potential treatment of T1D.

Disclosure

F. Asadi: None. S.C. Gunawardana: None. D.W. Piston: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (2305-06050); National Institutes of Health (R01DK123301, P30DK020579)
260-LB: The Effect of LXR Activation on Liver Metabolism and Diet-Induced Steatohepatitis in Mice
Authors: BEDNARSKI TOMASZ , RAHIM MOHSIN , WHITTENBARGER NOAH , OLICHWIER ADAM J. , YOUNG JAMEY
Published: June 2023

While nonalcoholic fatty liver disease (NAFLD) affects approx. 30% of the US population, there is currently no approved pharmaceutical treatment to inhibit the progression of NAFLD to its more severe stage of nonalcoholic steatohepatitis (NASH). The liver X receptors (LXRs) are key regulators of cholesterol and fatty acid homeostasis in liver. However, the effects of LXR activation on liver metabolism in NASH pathogenesis are not well understood. We hypothesize that LXR activation might reduce NAFLD progression by augmenting lipid composition and metabolism in hepatocytes. To test this hypothesis, 8-week-old male wild type (WT) or obese, melanocortin-4 receptor knockout (Mc4r-/-) mice were placed on either chow or Western diet (WD) for 8 weeks. Half of the WD-fed mice were given WD supplemented with GW3965 (100mg/kg), a selective, orally active agonist for the LXRs. Animals fed GW3965-supplemented diet had increased gene expression of Abca1 and Lpcat3, both transcriptional targets of LXR action. LXR activation significantly decreased body mass of both WT and Mc4r-/- mice, which was correlated with reduction of subcutaneous fat. GW3965 supplementation greatly improved glucose homeostasis of Mc4r-/-. LXR activation significantly decreased hepatic triglycerides, cholesterol esters and ceramides content which was accompanied by decreased expression of lipogenic factors (Fasn, Dgat1 and 2, Fatp5, Elovl1 and 6) in Mc4r-/-. Contrary expression of genes involved in fatty acid β-oxidation together with pyruvate cycling fluxes (VPC, VPK+ME, VPEPCK) were elevated in Mc4r-/- fed diet supplemented with GW3965. These metabolic changes were related to decrease in hepatic fibrosis, expression of NF-κB pathway genes as well as inflammatory (Itgam, Cd274), oxidative (Sod2), and endoplasmic reticulum stress markers (Chop, Atf4 and 6). Taken together, these data suggest that LXR activation improves phenotype of genetically obese WD-fed animals and inhibits progression from NAFLD to NASH.

Disclosure

T. Bednarski: None. M. Rahim: None. N. Whittenbarger: None. A. J. Olichwier: None. J. Young: Consultant; Pfizer Inc. Stock/Shareholder; Metalytics, Inc. Consultant; Metalytics, Inc. Research Support; Merck Sharp & Dohme Corp.

Funding

National Institutes of Health (R01DK106348); Vanderbilt University; University of Nebraska-Lincoln Nutrition and Health Sciences Fund
261-LB: Hepatocyte Gdf15 Protects against CCL4-Induced Liver Injury Independent of Changes in Feeding and Inflammation
Authors: KASTROLL JAKE , JURCZAK MICHAEL J. , BELLO FIONA , VANDEVENDER AMBER , SIPULA IAN J. , ALDER JONATHAN
Published: June 2023

Growth differentiation factor 15 (GDF15) is a stress-induced secreted protein whose circulating levels increase in obesity and fibrotic liver disease, like NAFLD. GDF15 KO mice develop more severe fibrosis after carbon tetrachloride (CCL4) treatment, suggesting a protective effect of GDF15. Despite this, the tissue specific sites of GDF15 production during liver injury are unknown and the potential for local action is understudied. To determine the hepatocyte specific contribution of Gdf15 to changes in circulating GDF15 and effects on fibrosis, we utilized a Gdf15 KO-first mouse strain where endogenous expression of Gdf15 can be restored in a tissue specific fashion via Flp recombinase (FLP). Gdf15 KO-first mice received AAV8-TBG-Gfp (KO+GFP) or AAV8-TBG-Flp (liver specific Gdf15 expression; KO+FLP) and were treated with CCL4 3X per week for 3 weeks alongside wild type (WT) controls. CCL4 increased circulating GDF15 7X in WT and 3.5X in KO+FLP compared with WT vehicle (VEH), and levels were undetected in KO+GFP mice. CCL4 caused significant BW loss in WT and KO+FLP mice and had no effect on KO+GFP mice. CCL4 reduced feeding similarly in all groups despite marked differences in circulating GDF15. Liver gene expression markers of fibrosis were upregulated in KO+GFP mice compared with WT and KO+FLP mice. Interestingly, despite differences in fibrosis, circulating cytokines and liver expression of inflammatory markers were reduced in KO+GFP and KO+FLP compared with WT mice. These data demonstrate that hepatocyte Gdf15 protects against CCL4-induced fibrotic liver injury independent of feeding and inflammation. They also suggest that GDF15 may have local, GFRAL-independent effects within liver to remodel the extracellular matrix that require further study.

Disclosure

J. Kastroll: None. M. J. Jurczak: None. F. Bello: None. A. Vandevender: None. I. J. Sipula: None. J. Alder: None.
264-LB: Aerobic Exercise Training Reorganizes Skeletal Muscle Mitochondrial and Lipid Droplet Architecture
Authors: PARRY HAILEY A. , AXELROD CHRISTOPHER L. , BAENA VALENTINA , DANTAS WAGNER S. , KIRWAN JOHN P. , GLANCY BRIAN
Published: June 2023

Exercise is a known intervention to alleviate insulin resistance. This study investigated how a 12-week endurance exercise intervention changes skeletal muscle mitochondrial and lipid droplet architecture in patients with type 2 diabetes. Participants completed 12 weeks of endurance exercise at 70% of their VO2 max five days a week at one hour a day. Muscle biopsies were taken before and 72 hours after the last exercise session. A subset of these muscle biopsies from two participants (58±0 years, 42.3±3.3 BMI, 2.5±0.7 medications, 8.2±0.1% HbA1c) was imaged using focused ion-beam scanning electron microscopy. Due to these results being preliminary, general trends are discussed. A deep-learning model segmented 14,197 mitochondria and 4,400 lipid droplets to assess individual mitochondrial and lipid droplet 3D structures, and mitochondria-to-lipid interactions. Surprisingly, exercise did not change individual mitochondrial and lipid droplet volume, surface area to volume ratio, or sphericity. There was an increase in mitochondria-to-mitochondria and mitochondria-to-lipid droplet interactions after endurance training. These preliminary data suggest that exercise may relieve insulin-resistant skeletal muscle by increasing the connectivity among mitochondria and lipid droplets prior to changing individual organelle morphology. Further analyses are ongoing to confirm these findings.

Disclosure

H. A. Parry: None. C. L. Axelrod: None. V. Baena: None. W. S. Dantas: None. J. P. Kirwan: None. B. Glancy: None.
268-LB: Dietary Resistant Starch Supplementation Upregulates Deoxycholic Acid Production in Mice
Authors: REUTER MELANIE , TUCKER MADELYNN , MARFORI ZARA , SHISHANI RAHAF , BUSTAMANTE JESSICA M. , MORENO ROSALINDA , CUMMINGS BETHANY
Published: June 2023

The gut microbiome plays an important role in the regulation of metabolic health, largely through the metabolites it produces, making it an important target for management and prevention of diabetes. Some of the most abundant metabolites produced by the gut microbiome are bile acids. Primary bile acids produced in the liver are converted into secondary bile acids by bacteria in the gut via 7-ɑ-dehydroxylation. These secondary bile acids are strong ligands for bile acid receptors known to improve glycemic regulation. However, the bacteria and enzymatic pathways involved in 7-ɑ-dehydroxylation have not been fully defined. Therefore, we are developing tools with which to study the dynamic regulation of gut bacterial 7-ɑ-dehydroxylation. In this study, we hypothesized that feeding mice a diet rich in resistant starch (RS) would alter the gut microbiome to favor bacteria capable of executing 7-ɑ-dehydroxylation. To test this, mice were fed a diet supplemented with RS or an isocaloric (IC) control diet. Profiling of gut luminal bile acids shows that RS supplementation proportionally increases the production of the secondary bile acid, deoxycholic acid (DCA) (DCA as a proportion of total bile acids in gut luminal contents: IC = 0.16 ± 0.03 RS = 0.55 ± 0.08, P = 0.001). RS tended to decrease unconjugated cholic acid (CA) concentrations, the substrate for 7-ɑ-dehydroxylation in DCA production, compared to IC-fed controls. Hepatic expression of the enzyme required for production of CA, Cyp8b1, did not differ between groups. Therefore, these data suggest that RS-induced increases in DCA are due to increased gut bacterial conversion of CA to DCA. Determining which bacteria can carry out 7-ɑ-dehydroxylation is critical to targeting gut bacterial bile acid metabolism. This study demonstrates that RS supplementation upregulates DCA production, identifying RS supplementation as a tool with which to define the dynamic regulation of 7-ɑ-dehydroxylation by gut bacteria.

Disclosure

M. Reuter: None. M. Tucker: None. Z. Marfori: None. R. Shishani: None. J. M. Bustamante: None. R. Moreno: None. B. Cummings: None.
270-OR: Health Care Utilization and Cost Associated with Empagliflozin in Older Adults with Type 2 Diabetes—Results from the EMPRISE study
Authors: HTOO PHYO T. , TESFAYE HELEN , SCHNEEWEISS SEBASTIAN , WEXLER DEBORAH J. , GLYNN ROBERT , SCHMEDT NIKLAS , DERUAZ-LUYET ANOUK , KOENEMAN LISETTE , PAIK JULIE M. , PATORNO ELISABETTA
Published: June 2023

Within the EMPRISE study program, we compared the cost and healthcare utilization of empagliflozin (EMPA) vs. dipeptidyl peptidase-4 inhibitors (DPP-4i) using Medicare data (2014-18). We identified 23,335 pairs of 1:1 propensity score-matched patients aged ≥65 years with type 2 diabetes (T2D) initiating EMPA or a DPP-4i, overall and stratified by baseline cardiovascular disease (CVD). We estimated ratios and differences in rates of healthcare utilization per 1,000 person-years, and costs per member per year (PMPY) for EMPA vs. DPP-4i using zero-inflated negative binomial or gamma models. Compared to DPP-4i, EMPA was associated with lower rates of hospital days [rate ratio (RR) (95% CI) 0.89 (0.82, 0.97); rate difference (RD) -557 (-587, -528)], number of hospitalizations [RR 0.86 (0.79, 0.93); RD -73 (-84, -61)], and number of emergency visits [RR 0.86 (0.82, 0.91); RD -128 (-145, -111)]. Estimates were similar when stratified by baseline CVD. Relative to DPP-4i, EMPA was associated with lower total costs in USD [RR 0.94 (0.92, 0.96); PMPY -1109 (-1478, -739)], and inpatient costs [RR 0.84 (0.81, 0.87); PMPY -713 (-847, -579)], and nearly-similar pharmacy costs [RR 1.04 (1.02, 1.06); PMPY 355 (177, 532)]. RRs in baseline CVD subgroups were similar, but absolute RDs were larger in those with CVD. Relative to DPP-4i, EMPA reduced healthcare utilization and costs in routine care.

Disclosure

P.T.Htoo: Employee; Johnson & Johnson. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration. H.Tesfaye: None. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; UCB, Inc., Boehringer Ingelheim International GmbH, Stock/Shareholder; Aetion, Inc. D.J.Wexler: Other Relationship; Novo Nordisk A/S. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis, Pfizer Inc. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Paik: None.

Funding

Boehringer Ingelheim (116283)
271-LB: Assessment of P311's Influence on Key Genetic Signatures within Brown Adipose Tissue
Authors: MORETON STEVEN L. , ALURU MANEESHA R. , BADRI KAMESWARA R.
Published: June 2023

The dramatic ascent in global obesity levels > 40% has ushered in an alarming increase in chronic metabolic illnesses such as insulin resistance, type 2 diabetes, and cardiovascular disease all for which obesity is a major risk factor. This development has created a need for a deeper understanding of the molecular underpinnings which regulate this interplay between obesity and metabolic homeostasis. Our studies show that P311 can modulate adipocyte development, plasticity and there by regulating metabolic function. Novel single cell RNA technology using the 10X platform was performed to assess key adipogenic and metabolic gene signatures. Single cells collected from brown adipose tissue of C57BL/6 control mice (WT) and P311 KO mice were used for RNA sequencing. Bioinformatic analysis using the Seurat package in R evaluated the cellular heterogeneity found in brown adipose tissue, including immune cells, preadipocytes, and beige adipocytes. Marker genes were employed to identify and characterize these distinct cell populations. Visualization using UMAP showed the significant alteration of cluster identities between WT and P311 KO tissue. Our findings showed a significant decrease (p<0.01) in key brown adipocyte signatures in P311 KO brown adipocytes compared to WT brown adipocytes. We observed a tremendous decrease of browning in brown adipocytes switching them to more whitish brown adipocytes in P311KOs compared to WT that could be responsible for deranged metabolic alterations in P311KOs. We conclude that P311 regulates browning of adipocytes there by regulating metabolic homeostasis.

Disclosure

S. L. Moreton: None. M. R. Aluru: None. K. R. Badri: None.

Funding

National Institute of General Medical Sciences (SC1GM141937 to K.R.B.)
273-OR: Hybrid Closed-Loop Therapy vs. Other Modalities of Therapy during Ramadan Intermittent Fasting in Adults and Adolescents with Type 1 Diabetes
Authors: AL-SOFIANI MOHAMMED , ALHARTHI SAHAR , ALBUNYAN SARAH , ALZAMAN NAWEED , KLONOFF DAVID C. , ALGUWAIHES ABDULLAH M.
Published: June 2023

Introduction: Most people with type 1 diabetes (PwT1D) are considered high risk to fast during the month of Ramadan. Yet, many of them attempt to fast and abstain from eating and drinking from dawn to dusk. Here, we evaluate the association between the sociodemographic indicators, modality of T1D treatment, and number of days when fasting is broken due to diabetes among PwT1D.

Methods: We surveyed 294 PwT1D who attempted to fast during Ramadan 2022, were seen at our Endocrine clinics during the month preceding Ramadan, and who agreed to share their health information and fasting experience. Participants were categorized into 5 groups based on their treatment modality: a) Pump + CGM [Hybrid closed loop (HCL)] (n=62); b) Pump + CGM [Conventional open loop] (n=37); c) Pump + Self-monitoring of blood glucose (SMBG) (n=8); d) Multiple daily injections (MDI) + CGM (n=155); e) MDI + SMBG (n=32). Predictors for fasting most days of Ramadan (i.e. breaking fast ≤ 2 days) were analyzed using uni- and multi-variable logistic regression.

Results: Private health insurance rates were highest among pump users (82%, 63%, and 41% for HCL, Pump + SMBG, and conventional open loop, respectively); whereas, MDI users had the lowest insurance rates (25% and 21% for MDI + SMBG and MDI + CGM, respectively). The median numbers of days when fasting was broken due to diabetes were 2, 5, 3, 3.5, and 2.5 days among the HCL, conventional open loop, MDI + CGM, Pump + SMBG, and MDI + SMBG groups, respectively (p=.047). Users of HCL therapy were two times as likely to complete fasting most days of Ramadan (i.e. breaking fast ≤2 days) compared to MDI + CGM users [odds ratio (95% CI): 2.37 (1.14, 4.90)] after adjusting for age, sex, educational level, employment status, insurance status, and diabetes duration.

Conclusion: Among the common treatment modalities of T1D, the use of HCL pump therapy is associated with the highest rates of fasting most days of Ramadan after adjusting for potential confounders.

Disclosure

M.Al-sofiani: Consultant; Eli Lilly and Company, Speaker's Bureau; Sanofi, Medtronic, Vitalair. S.Alharthi: None. S.Albunyan: Employee; ProMedEx, Medtronic. N.Alzaman: None. D.C.Klonoff: Consultant; EOFlow Co., Ltd., Fractyl Health, Inc., Integrity, Lifecare, Inc., Rockley Photonics, Thirdwayv Inc. A.M.Alguwaihes: Consultant; Eli Lilly and Company, Research Support; AstraZeneca, Novo Nordisk, Speaker's Bureau; Novo Nordisk, Sanofi.