bluuebunny/crossref_metadata_2025 huggingface dataset:
THU593 Unilaterally Selective Adrenal Vein Sampling For Identification Of Surgically Curable Primary Aldosteronism
Authors: Paolo Rossi Gian , Bagordo Domenico , Amar Laurence , Azizi Michel , Riester Anna , Reincke Martin , Degenhart Christoph , Widimský Jiří , Naruse Mitsuhide , Deinum Jaap , Kocjan Tomaz , Negro Aurelio , Rossi Ermanno , Kline Gregory , Tanabe Akiyo , Satoh Fumitoshi , Christian Rump Lars , Vonend Oliver , Willenberg Holger S , Fuller Peter J , Yang Jun , Nian Chee Nicholas Yong , Magill Steven B , Shafigullina Zulfiya , Quinkler Marcus , Oliveras Anna , Lee Bo-Ching , Chang Chin-Chen , Wu Vin-Cent , Krátká Zuzana , Battistel Michele , Rossitto Giacomo , Seccia Teresa M
Published: October 2023

Disclosure: G. Rossi: None. D. Bagordo: None. L. Amar: None. M. Azizi: None. A. Riester: None. M. Reincke: None. C. Degenhart: None. J. Widimský: None. M. Naruse: None. J. Deinum: None. T. Kocjan: None. A. Negro: None. E. Rossi: None. G. Kline: None. A. Tanabe: None. F. Satoh: None. L. Rump: None. O. Vonend: None. H.S. Willenberg: None. P.J. Fuller: None. J. Yang: None. N. Chee: None. S.B. Magill: None. Z. Shafigullina: None. M. Quinkler: None. A. Oliveras: None. B. Lee: None. C. Chang: None. V. Wu: None. Z. Krátká: None. M. Battistel: None. G. Rossitto: None. T.M. Seccia: None.

Adrenal venous sampling is recommended for the identification of unilateral surgically curable primary aldosteronism, but is often clinically useless, owing to failed bilateral adrenal vein cannulation. Our objective was to investigate if only unilaterally selective adrenal vein sampling studies can allow identification of the responsible adrenal. Among 1625 patients consecutively submitted to adrenal vein sampling in tertiary referral centers, we selected those with selective adrenal vein sampling result in at least on side and surgically cured unilateral primary aldosteronism, used as gold reference. The accuracy of different values of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity, was examined. We found prominent differences of RASI values distribution between patients with and without unilateral primary aldosteronism. The diagnostic accuracy of RASI values estimated by the area under ROC curves (AUROC) was 0.714 and 0.855, respectively, in the responsible and the contralateral side; RASI values >2.55 and ≤0.96 on former and the latter side furnished the highest accuracy for detection of surgically cured unilateral primary aldosteronism. Moreover, in the patients without unilateral primary aldosteronism only 20% and 16% had RASI values ≤0.96 and >2.55. With the strength of large real-life dataset and use of the gold reference entailing an unambiguous diagnosis of unilateral primary aldosteronism, these results indicate the feasibility of identifying unilateral primary aldosteronism using unilaterally selective adrenal vein sampling results.

Presentation: Thursday, June 15, 2023
THU599 Serum And Urinary Free Cortisone As Novel Predictor Of Low-renin Arterial Hypertension
Authors: Tapia-Castillo Alejandra , Perez Jorge , Sandoval Alejandra , Allende Fidel , Solari Sandra , Fardella Carlos E , Carvajal Cristian
Published: October 2023

Disclosure: A. Tapia-Castillo: None. J. Perez: None. A. Sandoval: None. F. Allende: None. S. Solari: None. C.E. Fardella: None. C. Carvajal: None.

A large proportion of low-renin hypertensive (LRH) patients correspond to primary aldosteronism (PA) caused by excessive MR activation mediated by excess of aldosterone. However, some of these LRH patients have low to normal serum aldosterone levels, where is thought the MR activation is aldosterone-independent and more likely due to glucocorticoid-mediated MR activation, as occurs in the nonclassical apparent mineralocorticoid excess (NCAME), which is characterized by high cortisol/cortisone ratio and low cortisone, affecting not only blood pressure (BP) control and urinary potassium excretion but also causing cardiac and renal damage, endothelial dysfunction and subclinical inflammation. Objective: To evaluate cortisone as a predictor of LRH and its association with parameters of kidney and vascular damage. Design: A cross-sectional study was carried out in 206 adult subjects. The subjects were classified according to low-renin phenotype (plasma renin activity (PRA) <1ng/ml*h) and low serum cortisone (<p25th). We measured clinical, biochemical, renal and vascular parameters. Statistical analyses as group comparisons were performed by Mann Whitney, and discriminatory analyses by ROC curves. Results: We identified 43% of subjects with low-renin phenotype. PRA was associated with serum aldosterone (r=0.36; p<0.001) and serum cortisone (r=0.22; p=0.001). A binary logistic regression analysis shows that cortisone predicts low-renin phenotype (OR=0.4 [95% CI, 0.21 – 0.78]). The ROC curves show an AUC for serum cortisone was 0.62 (95% CI: 0.54 to 0.69; p = 0.004) and urinary cortisone 0.6 (95% CI: 0.52 to 0.67; p = 0.02) to discriminate subjects with low-renin from controls. Subjects with low serum cortisone showed a higher albuminuria, PAI-1 and lower sodium renal excretion. Urinary free cortisone was also associated to blood pressure and serum potassium (p<0.05). Conclusion: These findings highlight the concept that the low-renin phenotype is dictated not only by serum aldosterone levels but also by low cortisone, suggesting it should be considered in endocrine arterial hypertension screening, complementary in the diagnosis of primary aldosteronism since it could generate false positives in the calculation of the aldosterone to renin ratio. Moreover, our study suggests that low cortisone levels could be associated with future occurrence of vascular and kidney damage.

Presentation: Thursday, June 15, 2023
FRI102 A Case Of Subclavian Artery Stenosis: Utility Of Lipoprotein (a) In Secondary Prevention Of Atherosclerotic Vascular Disease
Authors: Iqbal Fizzah , Allen Haas Richard
Published: October 2023

Disclosure: F. Iqbal: None. R.A. Haas: None.

Introduction: Atherosclerosis is the most common cause of upper extremity peripheral arterial disease (PAD). Prevalence of subclavian artery stenosis in the general population is approximately 2% with one study reporting a prevalence of 6.8% in those with diabetes mellitus (DM). We present a case of symptomatic upper extremity PAD in a patient with well controlled Type 1 DM and LDL-cholesterol at goal, but significantly elevated Lp(a). Clinical Case: 57-year-old Caucasian female with Type 1 DM (on CSII), hypothyroidism, obesity (BMI:43), hypertension and hyperlipidemia presented with several month history of left arm pain and cramping worsened by activity. At presentation, HbA1c was 6.1% and TSH 1.036 uIU/mL. She had been on atorvastatin, 40 mg once daily for several years with the addition of ezetimibe two years prior following an elevated coronary calcium score of 63. She underwent a left upper arm arterial duplex which showed 50-99% left subclavian and left axillary artery stenosis along with bilateral ICA stenosis. Lipid profile showed Total-C 112 mg/dL, LDL-C 59 mg/dL and HDL-C 34 mg/dL. She denied any symptoms of TIA or CVA. Vascular surgery recommended medical management with aspirin and risk factor modification. Cardiology advised CT chest-angiogram which showed moderate left subclavian stenosis and mild wall thickening of the great vessels and descending thoracic aorta. Work-up for arteritis was negative. A stress Echocardiogram showed inducible apical wall ischemia however no significant coronary artery disease was seen on angiogram. Her atorvastatin dose was increased to 80 mg once daily but as her diffuse atherosclerosis was out of proportion to her risk factors an Lp(a) level was checked and came back elevated at 356 nmol/L (desirable <75). She was continued on statin therapy, ezetimibe discontinued and Evolocumab (PCSK-9 inhibitor) was commenced. At follow-up (after 6 months of evolucamab treatment), she reported improvement in symptoms and repeat lipid profile was notable for Total-C 90, LDL-C 33, HDL38 and a 41% reduction in Lp(a) to 209. Conclusion: Lipoprotein (a) is an atherogenic, pro-inflammatory LDL-cholesterol like particle, the concentration of which is largely genetically determined. While the association between elevated Lp(a) and coronary artery disease has been well studied, there are few studies describing its relevance in peripheral artery disease. In our patient with symptomatic subclavian stenosis, the high Lp(a) served as marker of her diffuse atherosclerosis and elevated ASCVD risk. Although targeted Lp(a) lowering therapies are currently under investigation with promising initial results, currently the focus of management remains LDL-cholesterol lowering. PCSK9 inhibitors lower Lp(a) by 25%-40% and are a valuable treatment option.

Presentation: Friday, June 16, 2023
FRI114 PUFAs Implicated In Platelet Activation Differ In Receptor Mediated Vs Post-receptor Insulin Resistance
Authors: Klein Rachael , Chung Stephanie T , Brown Rebecca J
Published: October 2023

Disclosure: R. Klein: None. S.T. Chung: None. R.J. Brown: None.

Background: Severe insulin resistance (IR) can be classified as receptor mediated, in which all downstream signaling is blocked, or post receptor IR where some downstream signaling pathways are decreased and others are increased. Receptor-mediated IR occurs in rare mutations of the insulin receptor (INSR), whereas in most forms of IR, including type 2 diabetes (T2DM) and lipodystrophy (LD), IR is post-receptor. LD is a group of syndromes characterized by deficiency of fat depots leading to metabolic dysfunction similar to obesity. Patients with post-receptor IR have increased atherosclerotic cardiovascular disease (ASCVD) risk. Thrombosis underlies pathology of ASCVD and is a result of platelet (PLT) activation. Polyunsaturated fatty acids (PUFAs) are embedded in the PLT membrane and play a key role in thrombosis. During PLT activation, cytosolic phospholipase A2 (cPLA2) hydrolyzes membrane lipids, generating free PUFAs, leading to synthesis of mediators of blood vessel constriction, inflammation, and thrombosis. Methods: This was a cross-sectional study of subjects with INSR (N=30) and LD (N=30) matched for age, sex, HbA1c and pubertal stage. Untargeted metabolomic (848 compounds) and lipidomic (984 compounds) analysis was completed on serum after an 8-12 hour fast. Analyses were conducted by t-test and Mann-Whitney with adjustment for multiplicity. Bonferroni corrected P<0.05 was considered significant. Results: Of 19 long chain PUFAs (ω=3, ω=6) measured, 14 were significantly elevated in LD vs INSR, including arachidonate, docosahexaenoate, docosapentaenoate, stearidonate, and adrenate. There was no difference in linoleate, dihomo-linoleate, tetradecadienoate, linolenate, or docosadienoate levels between LD vs INSR. Among 8 long chain saturated FAs, only 3 were significantly higher in LD, 4 were comparable, and 1 was higher in INSR. All long and medium chain monounsaturated FAs were similar in LD vs INSR. cPLA2 was not different between LD and INSR. Conclusions: Our study shows that liberated PUFAs were higher in the patients with LD compared to INSR. A similar trend was not seen for other FFA such as saturated and monounsaturated FFA, suggesting that higher PUFAs in LD are unlikely to be caused by global differences in FFA metabolism, such as different peripheral uptake of FFA via lipoprotein lipase activity or diet. Instead, our data suggest an increase in PLT membrane ability to store and release PUFAs. These data suggest increased ASCVD risk in post-receptor insulin resistance may be partially mediated through differences in platelet activation.

Presentation: Friday, June 16, 2023
THU246 What’s The Importance of GAD Antibodies In Patients With Stiff Person Syndrome
Authors: Barnett Anne , Elshimy Ghada
Published: October 2023

Disclosure: A. Barnett: None. G. Elshimy: None.

Introduction: Stiff Person Syndrome (SPS) has a strong autoimmune component with positive serology for GAD-65 antibody as one of the diagnostic criteria. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) but is also present in pancreatic beta cells. Hence, insulin-dependent diabetes mellitus (LADA) can develop in patients with SPS. We present two cases that highlight the importance of this association and the difference in the time of onset to ensure appropriate screening. Case: Our first case was a 46-year-old female with systemic sclerosis and SPS that was diagnosed with steroid-induced diabetes in 2012 with HbA1c 8.7% (4.3-6.1%). Her GAD-65 antibody was significantly elevated at 1971 (less than 2nmol/L). For almost 8 years, the patient only required insulin therapy while on high dose steroids, but eventually developed persistent hyperglycemia requiring insulin therapy. Her C-peptide was 0.49 (0.78-5.19ng/mL) with plasma glucose of 201 (74-106mg/dL), consistent with beta-cell dysfunction. The second case was a 60-year-old female with a 20-year history of SPS who was diagnosed with type 2 diabetes in 2014 after receiving high doses of steroids while undergoing chemotherapy for breast cancer. She was initially well-controlled on oral medications until 2 years after her initial diabetes diagnosis where her HbA1c increased rapidly to 8.1% (4.8-5.9%). At that time, she was started on insulin therapy and antibody testing was pursued which showed positive GAD-65 antibody greater than 250 (less than 5IU/mL) consistent with LADA. She had a negative IA-2 antibody undetectable. Due to other autoimmune associations, she was also screened for thyroid disease revealing an elevated TPO-antibody with a normal TSH 4.02 that is being monitored. Discussion: SPS is associated with autoantibodies and other autoimmune disorders including but not limited to type 1 diabetes, anti-thyroglobulin antibodies and anti-parietal cell antibodies. In both cases, the diagnosis of SPS preceded the onset of diabetes then with a latent “honeymoon” phase not requiring long-term insulin therapy for years, most consistent with LADA. However, there are exacerbating factors including high-dose steroids which could be misleading and result in diagnosing these patients with type 2 diabetes initially. It should be taken into consideration that there is variability in the time of onset of beta-cell dysfunction, which varied from 2 to 8 years in our patients. Hence, the recognition of the correlation of autoimmune-mediated diabetes and the variable time course to insulin deficiency is critical for the continued monitoring in patients with SPS. Physicians should be aware of the importance of screening patients with SPS for type 1 diabetes mellitus and differentiate it from steroid-induced type 2 diabetes to avoid developing diabetic ketoacidosis in these patients.

Presentation: Thursday, June 15, 2023
THU252 Can An AI Chatbot, ChatGPT, Help Our Patients with Diabetes And Weight Loss?
Authors: Cheng Emily , Wu Gloria , Zhao Weichen , Wong Adrial , Yong Lee Jae , Tien Katherine
Published: October 2023

Disclosure: E. Cheng: None. G. Wu: None. W. Zhao: None. A. Wong: None. J. Lee: None. K. Tien: None.

Background: ChatGPT, launched 11/30/22, has the newest Artificial Intelligence (AI) software for natural language algorithms to answer questions. It does not use the internet and is current to 2021 level of knowledge. According to the CDC, 37.3M Americans have diabetes, and approximately 70M Americans are overweight or obese (1/3 of all adults). 54% of U.S. adults have a literacy level below 6th grade. Many overweight people are at risk for diabetes. Purpose: To evaluate the newest AI chatbot, ChatGPT, for its answers to questions about diabetes and weight loss. Methods: Questions about diabetes and weight loss were created and typed into ChatGPT and similarly texted to an older AI software-mediated chatbot, Google Assistant. Questions: 1. How can I treat my diabetes and weight problem at the same time? 2. What medications can I use for weight loss? 3. What herbal medicines can I use for weight loss? 4. If I have hypertension and I want to lose weight, what should I do? 5. Where can I obtain reliable information about weight loss? The word count and Flesch-Kincaid Reading Level were the metrics used to assess ChatGPT and Google Assistant responses. The Flesch-Kincaid Reading Level is a mathematical formula used by the U.S. Department of Education that determines a passage’s grade level by the length of a sentence and the number of syllables in the words. Results: Word count: CHAT:Q1=189; Q2=199; Q3=217; Q4=230; Q5=210 vs GOOGLE: Q1=65, Q2=46, Q3=56; Q4=58; Q5=45. CHAT Word Count Avg=209, SD=15.86; GOOGLE Word Count Avg=54, SD=8.46; P-value=0.0000246. Flesch-Kincaid: CHAT: Q1=13.1; Q2=11; Q3=11, Q4=11.7, Q5=15.5 vs. GOOGLE: Q1=5.6, Q2=10.9, Q3=10.2, Q4=12, Q5=1.6. CHAT Flesch-Kincaid Avg=12.46, SD=8.06; GOOGLE Flesh-Kincaid Avg=8.6, SD=4.36; P-value=0.09366. Google Assistant has a lower average grade level of comprehension than ChatGPT. For Q1, ChatGPT is at a 13.1 grade level vs GOOGLE at a 5.6 grade level. This is due to Google Assistant’s use of websites as an answer, whereas ChatGPT is trained using information prior to 2021. Conclusion: ChatGPT uses artificial intelligence to create a natural language and it provides answers which are coherent and understandable for those with a high school education. In the future, as more users use ChatGPT, its internal software for reinforcement will produce responses more geared to the reading level of the lay public.

Presentation: Thursday, June 15, 2023
THU269 Ethnic Differences In Hepatic Insulin Clearance: A Cross-Sectional Study Comparing South Asians And Non-Hispanic Whites
Authors: Ramanathan Amrita L , Fan Hubert , Muniyappa Ranganath
Published: October 2023

Disclosure: A.L. Ramanathan: None. H. Fan: None. R. Muniyappa: None.

Background: Hepatic insulin clearance homeostaticallyregulates peripheral plasma insulin concentration. Reduced or impaired insulinclearance promotes insulin resistance and hyperinsulinemia, which increase therisk of type 2 diabetes mellitus (T2DM). South Asians (SA) have an elevatedrisk and prevalence of T2DM compared to other ethnic groups, but insulinclearance by ethnicity has not yet been investigated. Our cross-sectional studyexamines insulin clearance in SA compared to non-Hispanic whites (NHW) todetermine ethnic differences in hepatic extraction in both the fasting andpostprandial states. Methods: Thirty healthy SA (age: 39.1 ± 9.4; female: n=12;BMI: 27.7 ± 4.8 kg/m2) and thirty healthy NHW (age: 39.2 ± 11.4;female: n=12; BMI: 26.7 ± 5.3 kg/m2) underwent mixed meal tolerancetests (MMTT) to determine plasma glucose, insulin, and C-peptide levels. Wederived parameters of hepatic clearance using a C-peptide kinetics model, aninsulin secretion model, and an insulin kinetics three-compartmental model. Model parameters included distribution volume of insulin (Vp), control ofplasma glucose on hepatic extraction (aG), basal hepatic extraction levels(HEb), and total hepatic extraction levels (HEtot). Differences by ethnicity werecalculated using an unpaired t-test for parametric variables and a Mann-Whitneytest for nonparametric data. Results: Fasting glucose (93.7 ± 9.77 vs. 89.0 ± 6.96 mg/dL,p=0.06) and fasting insulin (13.30 ± 8.04 vs. 6.58 ± 6.61 mu/mL, p<0.001)were higher in SA. Insulin area under the curve during MMTT was also elevatedin SA (12608 ± 6031 vs. 5892 ± 3533 min*mU/mL, p<0.001). Calculated mean Vp(0.0365 ± 0.0133 vs. 0.0564 ± 0.0130 kg-1, p<0.0001), mean aG(0.2001 ± 0.0409 vs. 0.2285 ± 0.0556 mmol-1, p=0.03), and basalhepatic extraction (54.9 ± 22.6 vs. 65.6 ± 18.8%, p=0.04) were lower in SA.Total hepatic extraction during MMTT was not different between SA and NHW(p=0.33). Conclusions: SA have reduced basal hepatic clearancecompared to NHW, although total extraction remained similar between the twogroups during MMTT. Further investigations are needed to derive accurateinsulin clearance parameters for ethnic groups with elevated T2DM risk.

Presentation: Thursday, June 15, 2023
THU272 Early Time Restricted Feeding As a Weight Neutral Approach To Improved Glycemic Variation
Authors: Nasserifar Shabnam , Bruno Joanne , Vanegas Sally , Popp Collin , Walker Jeanne M , Aleman Diaz Jose Orlando
Published: October 2023

Disclosure: S. Nasserifar: None. J. Bruno: None. S. Vanegas: None. C. Popp: None. J.M. Walker: None. J.O. Aleman Diaz: None.

Abstract: Early time-restricted feeding (eTRF) is a type of intermittent fasting that involves restricting caloric intake to the first 6-8 hours of the day. Various studies suggest that eTRF improves cardiometabolic health and glycemic variation. However, it is unclear whether these effects are a consequence of weight loss that frequently accompanies this dietary intervention or due to the metabolic effects of the feeding strategy itself. To address this, we conducted a randomized 7-day isocaloric crossover supervised feeding study comparing eTRF (80% of calories consumed before 1 pm) to a usual feeding pattern (UFP, 50% of calories consumed after 4 pm) among 10 participants with prediabetes and obesity in a metabolic ward. Participants were randomized 1:1 to eTRF or UFP for days 1-7, and then subsequently crossed over to the alternate arm on days 8-14. In order to determine the weight-independent effects of this intervention, food was provided to meet participants’ calculated caloric needs for weight maintenance. To assess glycemia, continuous glucose monitoring was utilized throughout the study period and OGTTs were performed at baseline, crossover point (day 7), and at the end of the study (day 14). Subjects’ weights were stable across the study duration. Compared to the control (UFP), eTRF resulted in decreased mean amplitude of glycemic excursion (MAGE) of 2.5 mmol/L ± 0.2 vs 2.9 mmol/L ± 0.3 (p<0.05) and decreased time above range of 3.1 % ± 1.3 vs 6.7 % ± 1.7 (p= 0.02). Time in range was similar between the two groups (eTRF 75.4 % ± 4.7 vs UFP 74.9 % ± 4.8 (p=0.88)). There was no significant difference in AUC of OGTT between the study groups (eTRF 16391 ± 1595 vs UFP 1586 ± 1586). In conclusion, our study findings suggest that eTRF can improve glycemic variation and decrease time above range in a weight independent manner. Ongoing studies will elucidate the signaling and metabolomic implications of the observed glycemic improvement.

Presentation: Thursday, June 15, 2023
THU273 Sixteen Years Of Insulin Independence In A Patient With Type 1 Diabetes Mellitus Following Single-Donor Islet Cell Transplantation
Authors: Kachhadia Palak , Khan Shaza , Aldasouqi Saleh , Donley Christina , Abu Limon Ahmad
Published: October 2023

Disclosure: P. Kachhadia: None. S. Khan: None. S. Aldasouqi: None. C. Donley: None. A. Abu Limon: None.

Introduction: Patients with Type 1 Diabetes Mellitus (T1DM) require treatment with long term insulin unless they undergo whole organ pancreatic transplant, or they undergo islet cell transplantation. Due to paucity of donors, there is a trend towards single rather double-donor islet cell transplant. There is about 50% long term viability with single-donor transplants. We are not aware of islet cells viability over 15 years. We present the case of a patient with T1DM who received single-donor islet cell transplant 16 years ago, and she is still insulin independent. Case Presentation: The patient is a 52-year-old female with T1DM who received single-donor islet cell transplantation at the University of Illinois at Chicago Hospital. She was diagnosed with T1DM at age 9 and was using an insulin pump till she received the transplant in May of 2006. She is currently not on insulin therapy and is only taking sitagliptin 100mg once daily (as a beta-cell preservative). To our knowledge, she has the longest islet cell viability from a single-donor transplant (over 16 years). Long term immunosuppressive therapy includes mycophenolate 720mg BID and Tacrolimus 1mg BID. Most recent Hemoglobin A1C is 6.6%. She only has diabetic retinopathy that she developed prior to transplant. Retinopathy has been stable and she has received laser treatments by ophthalmology. Discussion: In this procedure, islets are taken from the pancreas of a deceased organ donor. A patient often receives transplantation of around 500 000 islet cells through the use of a percutaneous catheter into the portal vein of the liver or through mini-laparotomy. Though pancreatic transplantation itself carries a higher rate of insulin independence as compared to islet cell transplantation (75% vs 57%), it is associated with higher risks of infections and hospitalizations. As per the Collaborative Islet Transplant Registry, greater than 90% of those who were experiencing hypoglycemia prior to transplantation were free of such events at follow up of 5 years. In addition, 60% of patients were able to maintain glycemic control at A1C less than 6.5%. Conclusion: In conclusion, physicians should consider islet cell transplant as a viable option for long term treatment of patients who have T1DM with difficulties of achieving glycemic control or with severe or refractory hypoglycemia.

Presentation: Thursday, June 15, 2023
THU284 BCG Clinical Trial Programs In Advanced Type 1 Diabetes - 2023 Update
Authors: Kühtreiber Willem M , Hostetter Emma , Lee Amanda H , Ng Nathan , Wolfe Grace , Aristarkhova Anna , Braley Joan , Zheng Hui , Faustman Denise L
Published: October 2023

Disclosure: W.M. Kühtreiber: None. E. Hostetter: None. A.H. Lee: None. N. Ng: None. G. Wolfe: None. A. Aristarkhova: None. J. Braley: None. H. Zheng: None. D.L. Faustman: None.

The bacillus Calmette-Guerin (BCG) vaccine, first introduced a century ago for tuberculosis prevention, is today being tested in double-blinded, randomized clinical trials for treatment of diverse forms of autoimmunity, including type 1 diabetes (T1D) and multiple sclerosis (MS). There are multiple clinical protocols underway at our institution testing various aspects of BCG’s ability to lower HbA1c, reduce insulin requirements and change day-to-day fluctuations in blood sugars, including: 1) Ten-year follow up of a Phase I study of BCG vaccination in longstanding T1D to study the durability of lowered HbA1c values after BCG treatment; 2) Randomized, double-blinded Phase II clinical trial testing the BCG vaccine in adults with longstanding T1D to demonstrate the reproducibility of BCG’s effects seen in the Phase I trial; 3) Radiologic study to quantify and identify through FDG-CAT scans the organs and organ systems that utilize more sugar after BCG treatment; 4) Study in adults with longstanding T1D to evaluate the effects of two doses of BCG compared to 6 doses of BCG over 5 years of observation; and 5) A multi-center clinical trial of adolescents with > 2 years since T1D diagnosis to evaluate the potential benefits of BCG vaccination. To date, we have enrolled 295 patients as part of a planned enrollment of 500, including 272 BCG-vaccinated patients. Global studies on the effects of BCG on the immune system show that the impact of multi-dose vaccination in MS and T1D is optimized by at least 2 years of follow up and that the effects appear durable without further treatment in both MS and T1D to 5+ years. BCG vaccine therapy may provide a safe and affordable medical intervention in individuals with longstanding autoimmunity.

Presentation: Thursday, June 15, 2023
THU291 Successful Reversal Of Glucose Toxicity After DKA Precipitated By SGLT2 Inhibitor
Authors: Abdelrahman Houda , DeMoranville Beatriz
Published: October 2023

Disclosure: H. Abdelrahman: None. B. DeMoranville: None.

Case: A 40 year old man with history of NAFLD and type 2 diabetes mellitus with HbA1c 12.2% on metformin 750 mg daily, presented with diabetic ketoacidosis (DKA) with blood glucose 275 mg/dL and anion gap 24 (AG 10-12). He had been started on empagliflozin 25 mg daily four days prior as outpatient. He was treated with IV insulin and hydration per DKA protocol. Labs showed C-peptide 3.0 ng/mL (1.1-4.4 ng/mL), Anti-GAD Ab 0.01 nmol/L (<0.02 mol/L), negative anti-insulin cell Ab. He was discharged on glargine 10u qHS, lispro 2u AC plus corrective scale, and metformin 750 mg BID. On outpatient follow-up, pre-meal glucose remained under 130 mg/dL, not requiring corrective insulin. He was started on semaglutide 0.5mg weekly and insulin was discontinued. At 3 months, his HbA1c improved to 5.8%. Self-monitoring glucose levels were at goal.

Discussion: This case illustrates glucotoxicity due to significant hyperglycemia causing beta-cell apoptosis and resulting in insulin deficiency. The initiation of SGLT2 inhibitors (SGLT2i) when insulin deficiency and peripheral resistance are at their peak increases risk of DKA. This patient with type 2 diabetes presented with blood glucose 275 mg/dL in DKA four days after starting empagliflozin, a SGLT2i. SGLT2i increase risk of DKA due to dehydration from glucosuria, inhibiting ketone body excretion by the kidneys, causing a state of carbohydrate deficit and hypovolemia that promotes glucagon release from alpha-cells, an increased glucagon-to-insulin ratio, and thus triggers ketogenesis.1

In glucose toxicity, intra-cellular hyperglycemia-induced molecular dysfunction results in beta-cell apoptosis. Islet cells cultured in a glucotoxic environment (20 mmol/l) had suppressed insulin content, but fully reversed the intra-cellular calcium response after one week of culturing in a euglycemic environment, demonstrating recovery of the molecular steps promoting insulin release. 2

Treatment with insulin close to euglycemic goals promotes the reversal of glucose toxicity. Our patient recovered beta-cell function several weeks after the glucotoxic episode and was able to discontinue insulin therapy.

With the addition of semaglutide, a GLP-1 receptor agonist, which potentiates glucose-dependent insulin release to control post-prandial hyperglycemia, he was able to maintain euglycemia and an HbA1c 5.8%.

Conclusion Patients with type 2 diabetes mellitus may present in diabetic ketoacidosis due to glucose toxicity which can be reversed with short-term insulin therapy.

References

1) Nasa P, et al. Euglycemic diabetic ketoacidosis: A missed diagnosis. World J Diabetes. 2021 May 15;12(5):514-523.

2) Tariq M, et al. Prolonged culture of human pancreatic islets under glucotoxic conditions changes their acute beta cell calcium and insulin secretion glucose response curves from sigmoid to bell-shaped. Diabetologia. 2022 Dec 2. Epub ahead of print. PMID: 36459178.

Presentation: Thursday, June 15, 2023
THU294 Glucagon Like Peptide-1 Analogue Therapy In Obese Patients With Cystic Fibrosis Related Diabetes
Authors: Reddy Ankireddypalli Anvitha , Moheet Amir
Published: October 2023

Disclosure: A.R. Ankireddypalli: None. A. Moheet: None.

Introduction: Cystic fibrosis (CF) has classically been associated with malnutrition and being underweight. Intense emphasis on nutritional augmentation and advancement in medical therapies including recent introduction of CFTR modulators have significantly reduced the prevalence of malnutrition in CF. However, this success has been accompanied by a significant rise in overweight/obesity in CF. Recent studies have reported that one-third of all adult CF patients are overweight or obese. Glucagon like peptide receptor-1 agonists (GLP-1RA) therapy is an effective treatment for type 2 diabetes mellitus (T2DM) and obesity. Current guidelines for CF related diabetes (CFRD), recommend insulin as the mainstay of treatment. However, with increase in prevalence of obesity, there is increased interest in examining the role of incretin-based therapies in CFRD. Gastrointestinal (GI) symptoms like abdominal pain, steatorrhea, gastroparesis are common in CF. Concerns about the potential GI side effects had previously dampened the enthusiasm for these drugs in CF.The objective of this case series is to demonstrate impact on glycemic control and weight, and tolerability of GLP1-RA treatment in obese patients with CFRD and pancreatic insufficiency (PI) after 1 year of therapy. Case 1: A 21-year-old female with CF (delta F508 homozygote) and PI, was diagnosed with CRFD at 15 years. She was initially on lantus 14 units daily with HbA1c of 6.7%. She was started on CFTR modulator therapy and with increase in BMI from 37 to 45 in 1 year with HbA1c of 8.9%. She was started on semaglutide and tolerated the medication well with no GI side effects. 1 year later her BMI reduced to 42 and HbA1c was 8.2%. Case 2: A 62-year-old male with CF (delta F508 heterozygote) and PI, diagnosed with CFRD at age 44 years. He was on lantus 66 units and aspart 1 unit per 5 grams carbohydrate coverage. He was started on CFTR modulator and in 1 year BMI increased from 53 to 57. He was started on semalglutide, which he tolerated well with no GI symptoms. 1 year later his Hba1c improved to 7% with a BMI of 54. Discussion: In this era of CFTR modulator therapy, CF patients are faced with changing metabolic parameters, including weight gain and developing T2DM phenotype with insulin resistance. There is one previous case report of short duration of GLP-1RA use in CFRD. We report > 1 year of clinical experience of GLP-1RA use in 2 patients. GLP-1RA was well tolerated in these patients with improvement in glycemic control and weight loss. GLP-1 RA should be considered in obese, PI patients with CFRD as an add-on therapy to insulin. However, larger studies with long-term follow up are required to study the full impact of GLP-1RA to establish it as a treatment option in CFRD.

Presentation: Thursday, June 15, 2023
THU315 Sleep And Circadian Regulation, And Intrinsically Photosensitive Retinal Ganglion Cells Function In Diabetic Retinopathy
Authors: Reutrakul Sirimon , McAnany J Jason , Park Jason C , Chau Felix Y , Danielson Kirstie K , Bharati Prasad , Pannain Silvana , Van Cauter Eve , Hanlon Erin C
Published: October 2023

Disclosure: S. Reutrakul: None. J.J. McAnany: None. J.C. Park: None. F.Y. Chau: None. K.K. Danielson: None. P. Bharati: None. S. Pannain: None. E. Van Cauter: None. E.C. Hanlon: None.

Background: Diabetic retinopathy (DR) is associated with a dysfunction of intrinsically photosensitive retinal ganglion cells (ipRGCs), a crucial component of the entrainment of the circadian system and of the photic entrainment of melatonin secretion. We explored ipRGC function, sleep, 24-h melatonin and cortisol profiles in patients with and without DR. Methods: Type 2 diabetes patients with DR (n=10) and without DR (n=7,) participated. ipRGC function was inferred from the post illumination pupil response (PIPR). Sleep was assessed by 14-day actigraphy. Serum was sampled at hourly intervals for 24hrs for melatonin and cortisol measurement. Results: Mean (SD) age (53.8 (8.1) vs (54.0 (8.6) yr) and mean A1C (7.5 (1.7) vs. 7.1 (0.9)%) did not differ between DR and no-DR patients. PIPR was significantly smaller in DR than no-DR patients (0.14 (0.16) vs. 0.33 (0.10), p=0.001). Nightly sleep duration and efficiency were similar, but sleep variability (standard deviation of daily sleep duration over 7 nights) tended to be larger in DR than no-DR patients (84.1 (29.8) vs. 59.5 (21.8) minutes), p=0.08. Twenty four-hour serum melatonin output was significantly lower in DR than no-DR patients (103.1 (95.4) pg/ml vs. 231.1 (131.3) pg/ml, p=0.034). All no-DR patients exhibited the classical 24-h profile of melatonin with consistently low levels during the day time and a clear nocturnal rise peaking around the middle of the night. In contrast, a normal melatonin rhythm was observed only in 3 of the 10 patients with DR. Six DR patients had 24-h mean melatonin level under 3 pg/ml, five without any evident day-night pattern. One DR patient had a shift in melatonin timing. There was a significant correlation between PIPR and 24-h melatonin output, r= 0.726, p<0.001, but not with sleep variability. In contrast, mean 24-h cortisol profiles and levels, however, were not significantly different between the two groups (mean levels DR 6.18 (1.23) vs no-DR 6.18 (0.73) μg/dL), Conclusion: DR is associated with ipRCGs dysfunction, irregular sleep, and with major disruptions of the 24-hour melatonin rhythm while cortisol rhythm was maintained, suggesting circadian dysfunction in those with type 2 diabetes and retinopathy. Whether melatonin supplementation is beneficial in type 2 diabetes with DR should be explored.

Presentation: Thursday, June 15, 2023
THU351 Reduced Total Antixoxidant Capacity In Type 1 DM Without Chronic Complications
Authors: Oliveira Sara C , Oliveira Claudia Rafaella S , Stein Carolina S , Lauria Marcio W , Moresco Rafael N , Comim Fabio V , Premaor Melissa O
Published: October 2023

Disclosure: S.C. Oliveira: None. C.S. Oliveira: None. C.S. Stein: None. M.W. Lauria: None. R.N. Moresco: None. F.V. Comim: None. M.O. Premaor: None.

Type 1 diabetes mellitus (T1DM) is a condition associated with chronic inflammation and disturbances in the oxidative stress balance, which may be related to its complications. Our study aimed to investigate some REDOX markers ( TOS=total oxidant status ; TAC= total antioxidant capacity; FRAP =ferric reducing ability of plasma; AOPP=advanced oxidation protein products) in subjects with type 1 diabetes and controls. The local ethics committee approved this study. Overall, 51 subjects with T1DM and 106 controls were evaluated in an outpatient clinic. The age in T1DM group was (mean +− SD) 43.7 +− 17 years versus 43.1 +− 13.5 years in controls (NS).The proportion of smokers (17% vs. 15%) and ethnic composition were comparable between the groups. The mean +− SD HbA1c was 8.15 +− 1.65 % in diabetic patients. Concerning REDOX markers, we could observe a significant reduction in the TAC in T1DM (mean +− SD ) of 1.32 +− 0.17 against 1.47 +− 0.16 mmol Trolox equiv/ L(p<0.001) but not other oxidative stress markers. In the sequence, we proceed with the analysis of four subgroups: group 1: T1DM without any diabetic complication or high blood pressure and BMI <25kg/m2; group 2: T1DM with any diabetic complication, high blood pressure or BMI >= 25 kg/m2; group 3: normal controls without the high blood pressure and BMI <25kg/m2; group 4: controls with metabolic disease(excluding T2DM)and high blood pressure or BMI >= 25 kg/m2. Analyzing the profile of groups 1,(T1DM without complications) against group 3(normal controls), we noted a reduced TAC (mean +− SD) of 1.34 +− 0.2 in G1 versus 1.47 +− 0.16 mmol Trolox equiv/ L in G3 ( p=0.006). No significant differences were perceived in relation to TOS ( mean +− SD) of 102.33 +− 43 in G1 vs. 88.57 +− 48.7 micromol H2O2 equiv/L in G3, FRAP 287 +− 64.5 in G1 vs 306.6 +− 72 micromol/L in G3, or AOPP 252.11 +− 127 in G1 vs 260.38 +− 152 micromol/L in G3. Our results suggest that a reduction in the total antioxidant capacity is present in normal blood pressure T1DM even without chronic complications.

Presentation: Thursday, June 15, 2023
THU368 A Rare Case Of Glycogenic Hepatopathy With Persistent Lactic Acidosis
Authors: Shah Mauli , Challagulla Sabita
Published: October 2023

Disclosure: M. Shah: None. S. Challagulla: None.

Background: Glycogenic hepatopathy (GH) is an under-recognized complication of poorly controlled diabetes. It is caused by abnormal glycogen accumulation in hepatocytes leading to hepatomegaly and transient elevation of liver transaminases. Diagnosis is often delayed as liver biopsy is needed to distinguish it from other causes of liver injury. Complete resolution can be achieved with intensive glucose control. We present a case of GH diagnosed in a patient who developed increasing liver transaminases and persistent lactic acidosis after resolution of DKA. Clinical Case: We present a 21-year-old female with uncontrolled Type 1 diabetes who presented with fatigue, nausea, and generalized body aches. Patient was hemodynamically stable. Laboratory work up on admission showed a serum glucose of 834 mg/dL, serum bicarbonate less than 5 mEq/L, beta hydroxybutyrate was elevated to 8.7 mmol/L (normal <0.4 mmol/L), lactic acid was also elevated to 7.9 mmol/L (normal <2.0 mmol/L). She was diagnosed with DKA and treated with IV fluids and insulin drip. Over the next five days the patient’s symptoms improved and DKA resolved with beta hydroxybutyrate falling to <0.1 mmol/L. Her lactic acidosis however persisted, she had no apparent infection and no episodes of hypotension to explain this finding. CT scan of the abdomen revealed hepatomegaly not compatible with steatosis. Liver enzymes on admission were mildly elevated AST 57 IU/L and ALT 61 IU/L however values continued to rise and peaked at AST 2372 IU/L and ALT 681 IU/L five days later. Further laboratory studies revealed no evidence of viral hepatitis, no presence of drugs or toxins. Chronic liver disease work up revealed normal ANA, AMA, SPEP, ceruloplasmin, and iron levels. Patient ultimately underwent liver biopsy which revealed glycogenic hepatopathy, mild steatosis, and mild fibrosis. Patient’s lactic acidosis eventually improved with supportive care, and she was discharged. On follow up 3 months later the patient's liver enzymes had returned to normal. Discussion: Glycogenic hepatopathy is a rare diagnosis usually seen in patients with uncontrolled diabetes and elevated liver transaminases. It is hypothesized that pathogenesis of GH involves insulin increasing glycogen synthesis in the liver resulting in congested hepatocytes. Persistent lactic acidosis can also be seen; it has been proposed that increased insulin and dextrose administration prevents gluconeogenesis in the liver, therefore decreased conversion of pyruvate to glucose and increased lactate production. GH is important to understand and differentiate from other causes of liver injury and disease as treatment and prognosis is unique. Prompt liver biopsy should be pursued to elucidate diagnosis of GH. If patients are treated with aggressive glycemic control, hepatopathy can completely resolve.

Presentation: Thursday, June 15, 2023
THU369 A Rare Case Of IgG4-related Autoimmune Pancreatitis And Diabetes Mellitus
Authors: Zahid Maleeha , Shakil Jawairia
Published: October 2023

Disclosure: M. Zahid: None. J. Shakil: None.

Introduction: IgG4 related disease (IgG4-RD) is a rare multiorgan inflammatory condition characterized by dense lymphoplasmacytic infiltrates, presence of IgG4+ plasma cells and fibrosis. Here we present a case of young male with painless jaundice and hyperglycemia diagnosed with IgG4 related autoimmune pancreatitis and DM. Clinical Case: 46-year-old male with no significant history presented to outpatient clinic for pruritis and dark-colored urine of 2-week onset. He reported 17-pounds weight loss in the preceding month. While undergoing outpatient workup, patient developed epigastric pain prompting visit to the hospital. On examination, patient was afebrile, tachycardiac, icteric and had epigastric tenderness. Labs revealed normal electrolytes and renal function. LFTs were significant for total protein 7.6 g/dl (n=6.3-8.3 g/dl), AST 77 U/L (n = 10-50 U/L), ALT 127 U/L (n = 5-50 U/L), alkaline phosphatase 458 U/L (n = 40-129 U/L) and direct bilirubin >10.0 (n = 0-0.3 mg/dl). Lipase was 99 U/L (n - 13-60 U/L), blood glucose was 292 mg/dl and A1C was 6.5% (n = 4.0-5.6%). US abdomen revealed diffuse gallbladder wall thickening with moderate sludge and intrahepatic and extrahepatic distal biliary obstruction and dilatation. MRCP showed common bile duct and intrahepatic biliary ductal dilation. Pancreas was diffusely irregular with areas of hemorrhagic pancreatitis. ERCP showed dilatation of upper and middle third of main bile duct, left and right hepatic ducts and all intrahepatic branches with a stricture in distal bile duct. Biliary sphincterotomy and placement of temporary plastic biliary stent was performed and ampullary biopsies were taken. IgG4 level was checked due to suspicion for IgG4-RD and was 293 mg/dl (n: 1-123 mg/dl). Pathology revealed mucosa with epithelial reactive changes. CD138 stain showed several mature plasma cells within the inflammatory infiltrate. In addition, immunostain for IgG4 shows several IgG4 positive plasma cells forming small clusters confirming diagnosis of IgG4-RD. Post procedure, his abdominal pain and LFTs started improving. Patient was started on prednisone for IgG4-RD and insulin for persistent hyperglycemia. His prednisone dose was later tapered after starting methotrexate. Patient’s most recent LFTs have normalized except mildly elevated ALT and A1C improved to 6.2%. Conclusion: Autoimmune pancreatitis and cholangiopathy are the pancreatobiliary manifestation of IgG4-RD and most often present as painless jaundice mimicking pancreatic cancer. Endocrine insufficiency usually manifests as diabetes mellitus/pre-diabetes and may also lead to autoimmune hypophysitis and Reidel’s fibrosis. Other organ systems that may also get involved include lacrimal and salivary glands, lungs, kidneys, nervous system, and lymphatic/vascular system. Early recognition and ongoing surveillance are key to appropriate management of this condition.

Presentation: Thursday, June 15, 2023
FRI636 Sleep Architecture In Diabetic Patients With Sleep Apnea On Metformin
Authors: Varma Madhu , Eghbali Mason , Hung Derek , Sahai Anurag
Published: October 2023

Disclosure: M. Varma: None. M. Eghbali: None. D. Hung: None. A. Sahai: None.

Background: Metformin, commonly used medication to treat Type II Diabetes Mellitus (DM) improves insulin sensitivity, reduces glucose production in liver and absorption by intestines. Type II DM patients often have higher BMI with increased incidence of sleep apnea. Metformin consuming patients sometimes report insomnia. Blood glucose levels affect sleep duration; therefore Metformin-related changes in blood glucose levels may affect sleep. Metformin prescriptions grew from 40 million in 2004 to 90 million in 2020. This has improved long term vascular complications outcomes in diabetics. Coincidentally the number of patients using sleeping aids has increased. Melatonin sales have doubled since 2004, approximating 821 million USD in sales in 2020. With diabetes and Metformin each causing significant changes in sleep, we aimed to examine sleep architecture in known diabetic patients on Metformin presenting with excessive daytime sleepiness and fatigue. Hypothesis: We hypothesize that Metformin affects sleep and influences sleep architecture in diabetic patients. Methods: Sleep architecture in 29 Type II DM patients taking Metformin, with symptoms of excessive daytime sleepiness, snoring, and fatigue was examined. Patients underwent overnight polysomnography which included six channel EEG, Electrooculogram, Electromyogram EKG, and pulse oximetry, respiratory and flow monitoring in a sleep lab. Sleep staging done using AASM guidelines. Data on age, gender, BMI, medications and sleep stages N1, N2, N3 and REM was collected. Data analyzed and shown as mean + SD, t test p<0.05 significant. Results: All patients had OSA diagnoses per AASM guidelines. The average age of patients with DM and OSA on Metformin therapy was 63 years, average BMI was 36. AASM stage distribution was N1 2.69 % + 0.02, N2 59.31% + 0.15, N3 12.22 % + 0.09, (Normal 25%) with 5.71% +0.06 REM sleep (normal 25%). All stages of sleep were reduced with significant reduction in deep sleep (N3) and REM sleep. Conclusion: Diabetic patients on Metformin had alterations in sleep architecture with significantly reduced restorative phases of deep and REM sleep. Sleep apnea reduces N3 and REM sleep, but diabetic pts had a more significant decrease. Although Metformin improves long term outcomes in diabetes associated complications, it alters sleep patterns. Altered sleep patterns further modify insulin release and over prolonged periods worsen glycemic control. Often patients on Metformin need additional medication like insulin for metabolic control. In part the progression of insulin resistance can be from altered sleep. Better understanding the effects of Metformin on sleep is needed to prevent long-term deteriorating effects on sleep while maintaining effective metabolic control.

Presentation: Friday, June 16, 2023