bluuebunny/crossref_metadata_2025 huggingface dataset:
THU278 Hidden In The Immune System: Exogenous Insulin Antibody Syndrome In A Patient With Latent Autoimmune Diabetes In Adults
Authors: King Hannah L , Nagappan Raj , Sliwinska Aleksandra
Published: October 2023

Disclosure: H.L. King: None. R. Nagappan: None. A. Sliwinska: None.

Hidden in the Immune System: Exogenous Insulin Antibody Syndrome in a Patient with Latent Autoimmune Diabetes in Adults

Background: Exogenous insulin antibody syndrome (EIAS) is a rare syndrome associated with insulin antibodies induced by exogenous insulin, found predominantly in patients with type 2 diabetes using various insulin formulations. Here, we present a case of young man previously diagnosed with type 2 diabetes, who was found to have severe refractory diabetic ketoacidosis (DKA) due to EIAS. Clinical Case: A 46-year-old man with a history of type 2 diabetes presented to an outside hospital for one week of fever and malaise. Laboratory studies were notable for serum glucose of 600 mg/dL (70-90mg/dL), HCO3 3 mmol/L (22-28mmol/L), and creatinine of 3.9 mg/dL (0.7-1.3mg/dL). He was diagnosed with DKA, shock and renal failure. During hospital stay, he remained on an insulin drip due to multiple unsuccessful attempts of transitioning to subcutaneous insulin, requiring over 1000 Units of insulin daily. This prompted insulin antibody testing that resulted elevated at >50U/mL (0-0.4U/mL), concerning for EIAS. Treatment was initiated with 5 days of IVIG and mycophenolate mofetil. During this treatment, his baseline insulin infusion rate of 30 Units/hr declined to 18 Units/hr, however at day 3, insulin requirements again increased. For better evaluation, quantitative insulin antibody values were requested and resulted as 362.5U/mL, followed by 350.9U/mL post IVIG treatment. After no significant improvement, patient was transferred to our hospital for further management of EIAS. Plasmapheresis was initiated followed by rituximab with plans for long term maintenance therapy. Dexamethasone was trialed but shortly after discontinued due concern of increased insulin resistance and hyperglycemia. Metformin was also started but discontinued due to concern of worsening acidosis in the setting of acute renal failure requiring CRRT. Ultimately, the patient was transitioned to subcutaneous U500 BID 75-150 Units based on scale. At discharge, metformin and pioglitazone were started. Due to the history of early onset insulin-dependent diabetes at age 30, he was tested for GAD-65 which resulted as positive at 0.28 nmol/L (<=0.02 nmol/L) and C peptide of 0.9ng/mL (0.8 - 3.9 ng/mL) consistent with LADA. Conclusion: EIAS is a rare and very challenging entity, increasing risks of severe ketoacidosis, hypoglycemic episodes and numerous other complications. Although mostly reported in type 2 diabetes, EIAS can occur in patients with LADA suggesting that autoimmunity may play a role. There is no FDA approved treatment, however attempts focus on eliminating antibodies by plasmapheresis, IVIG and immunotherapeutic agents.

Presentation: Thursday, June 15, 2023
THU280 Acute Interstitial Nephritis- A Complication Of Semaglutide Use
Authors: Alsayed Hasan Marah , Doroshow Jonathan
Published: October 2023

Disclosure: M. Alsayed Hasan: None. J. Doroshow: None.

Background: With the widespread use of glucagon-like peptide 1 (GLP-1) agonists in diabetes, several cases have been reported of GLP-1 induced acute interstitial nephritis (AIN) with variable recovery in kidney function (1). Although it is a rare side effect, the primary management requires early identification and removal of the offending agent. Clinical Case: A 75-year-old male presented with a week of nausea, vomiting, abdominal pain, and reduced urine output. He was started on semaglutide 4 months prior to admission when his creatinine was 1.16 mg/dL. Initial lab abnormalities included an elevated blood urea nitrogen 119 mg/dL (n 8-20 mg/dL), elevated creatinine 13.8 mg/dL (n 0.7-1.3 mg/dL), anion gap acidosis with a CO2 of 15 mEq/L (n 22-32 mEq/L) and an anion gap of 18 (n<12), lipase 659 U/L (n 20-51 U/L). His urinalysis demonstrated too numerous to count red blood cells, 4-10 white blood cells, rare eosinophils and no casts or crystals. Urine culture was negative. The fractional excretion of sodium and urea were 5.56% and 56% respectively, consistent with intrinsic renal disease. CT of the abdomen and pelvis demonstrated peri-pancreatic inflammation. A follow up renal ultrasound showed normal echotexture with no hydronephrosis or renal calculi. His picture was concerning for pancreatitis and pre-renal/acute tubular necrosis from diuretic use and vomiting. Despite aggressive fluid resuscitation, there was minimal improvement in his creatinine. Further work up for his renal injury was negative for monoclonal antibodies on protein electrophoresis and immunofixation. An autoimmune work up was negative for antinuclear antibody, anti-double stranded DNA, antineutrophil cytoplasmic (ANCA) myeloperoxidase IgG, anti-proteinase 3 ANCA IgG, glomerular basement membrane antibody, hepatitis B and C antibodies, and HIV. Complements and immunoglobin G subclasses were normal. A renal biopsy was performed which showed active interstitial inflammation with eosinophils consistent with allergic interstitial nephritis without an immune complex mediated glomerular lesion. He was started on intravenous methyl prednisone for 3 days followed by a prednisone taper. His home metformin, ramipril and hydrochlorothiazide were discontinued on discharge. He was eventually started on mycophenolate as the creatinine did not return to baseline with steroids. Conclusion: AIN is a rare, yet serious complication of GLP-1 use that requires early identification and discontinuation of the medication. A rapid or unexplained decline in renal function after starting a GLP-1 should be evaluated early on with concern for AIN once volume depletion is ruled out (1).

Reference: (1) Chaudhury N., Liarakos A., Gopalakrishnan K., Ayub W., Murthy N., Rao R. Antidiabetic medication-induced acute interstitial nephritis: case report and literature search. British Journal of Diabetes. 2021;21(2);228-32.

Presentation: Thursday, June 15, 2023
THU312 The Type 1 Diabetes Susceptible LEW.1WR1 Rat Develops Insulin Resistance And Severe Non-alcoholic Fatty Liver Disease
Authors: Tahirah Love-Rutledge Sharifa , Wimalarathne Madushika , Mercado Luis D , Smiley Alan , Riley Apperson Christopher , Wilkerson Vidal Quiana C
Published: October 2023

Disclosure: S.T. Love-Rutledge: None. M. Wimalarathne: None. L.D. Mercado: None. A. Smiley: None. C. Apperson: None. Q.C. Vidal: None.

A subpopulation of type 1 diabetes patients develop the pathophysiological parameters to be termed double diabetes. This patient population often develops obesity, non-alcoholic fatty liver disease, and other hallmarks of insulin resistance. The LEW.1WR1 rat is a type 1 diabetes susceptible rodent with hyperinsulinemia that has shown signs of fatty liver infiltration1,2. We hypothesized that LEW.1WR1 rats would develop insulin resistance and severe nonalcoholic fatty liver disease due to its increased circulating insulin and predisposition to autoimmune disease. LEW.1WR1 rats and Wistar Furth rats were used for the 18-week long experiment. Peripheral insulin sensitivity was evaluated using insulin tolerance tests at weeks 11 and 17 showing worsening insulin sensitivity as evidenced by the gradual slope compared to the steep slope of the Wistar Furth rats. HOMA-IR values support LEW.1WR1 rats develop worsening insulin sensitivity and are insulin resistant at week 23 of the experiment (2.613± 0.796, p < 0.0001). Terminal liver mass confirmed increased liver mass normalized to body mass and liver triglyceride levels suggested increased ectopic lid accumulation in the liver (Liver Mass 2.65% ±0.32 p = 0.0005 and triglyceride levels 192.8 ± 21.85 mg/dL, p = 0.034). The H&E-stained digital liver slides were scored for liver ballooning, steatosis, and markers of inflammation. Fibrosis and terminal circulating cytokines were also measured to assess severity of condition. While both groups showed increased steatosis and injury ballooning, trichrome blue staining and inflammatory cytokines verify the severity of disease in the LEW.1WR1 rats. LEW rats have increased fibrosis area and high serum TNF-α, IFN-, MCP-1 levels. As hypothesized, we observed that LEW.1WR1 rats show characteristics of insulin resistance and malignant nonalcoholic fatty liver disease development.

References: (1) Wilkerson-Vidal, et al. Mol. Cell. Endocrinol. 2023; 562:111837. (2) Mordes et al, Diabetes. 2005;54(9):2727-2733.

Presentation: Thursday, June 15, 2023
THU342 Per And Polyfluoroalkyl Substances And Prevalence Of Diabetes Mellitus In Korean Adults
Authors: Kim Shin-Hye
Published: October 2023

Disclosure: S. Kim: None.

Objectives: Recent epidemiologic research has studied the relationship between Per- and polyfluoroalkyl substances (PFAS) and diabetes mellitus (DM), yet the findings have been inconsistent. We examined the association between serum PFAS concentrations and the prevalence of diabetes in the Korean general population. Methods: We analyzed the data of 2,993 participants aged ≥ aged 19 years who participated in the Korean National Environmental Health Survey (KoNEHS) Cycle 4 (2018-2020). Serum concentrations of 5 PFAS [perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDeA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS)] were quantified using using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Individuals with DM were identified by the presence of one or more of the following conditions: (1) self-reported diabetes; (2) use of a glucose-lowering medication; (3) hemoglobin A1c ≥6.5%. Multiple logistic regression models were used to examine the associations between PFAS concentrations and DM after adjusting for age, sex, central obesity, education levels, smoking status, alcohol consumption, physical activity, and frequency of delivery food consumption. Bayesian kernel machine regression (BKMR) was used to investigate the independent and combined relationship between PFAS exposure and DM prevalence. Results: The prevalence of DM was 11.8%. The odds ratios (95% confidence intervals) of DM in the highest quartile relative to the lowest were 0.85 (0.56, 1.32) for PFOA, 1.39 (0.87, 2.23) for PFNA, 0.95 (0.63, 1.43) for PFDeA, 1.52 (1.01, 2.35) for PFHsS, 1.26 (0.77, 2.05) for PFOS and 1.01 (0.66, 1.55) for the sum of PFAS. According to the BKMR model results, PFNA and PFHxS were positively associated with an increased risk of DM, while PFOA and PFDeA were negatively associated. The risk of DM appeared to rise in correlation with the PFAS mixture quartile, but the association was statistically insignificant. Conclusions: Different associations between PFAS concentrations and DM were observed according to the PFAS isomers. Further studies are needed to clarify the mechanism of action of different PFAS isomers on the development of DM.

Presentation: Thursday, June 15, 2023
THU347 Diffusion Tensor Imaging Of The Tibial Nerve Can Detect Peripheral Neuropathy In Type 2 Diabetes
Authors: Park Hyeong-Kyu , Oh Eunsun , Joon Park Sang , Jung Kim Hye , Byun Dongwon
Published: October 2023

Disclosure: H. Park: None. E. Oh: None. S. Park: None. H. Kim: None. D. Byun: None.

Magnetic resonance imaging (MRI) has played little role for the study of peripheral nerve disease. However, recent technological advances in MRI have provided us more information about neural microstructure and higher resolution in peripheral nerves. The aim of this study is to evaluate whether diffusion tensor imaging (DTI) parameters in MRI can detect peripheral neuropathy in type 2 diabetes (T2D). In this prospective, single-center study, eight T2D patients (mean age, 62.1 ± 10.8 yr; 5 M/ 3F) with peripheral neuropathy and seven healthy controls (65.0 ± 3.3 yr, 7 F) were included. All T2D patients underwent Michigan Neuropathy Screening Instrument questionnaire and quantitative sensory testing. MRI including DTI and axial T2-weight Dixon sequence was performed for each participant. Region of interest analysis was independently performed by one radiologist on each side of tibial nerve at two levels: lower margin of adductor magnus muscle insertion (level 1), and quadriceps femoris tendon at patellar attachment (level 2). DTI parameters including cross-sectional areas (CSA), fractional anisotropy (FA), as well as diffusivity (mean (MD), axial (AD), and radial (RD)) were calculated.

FA was significantly lower in T2D patients with peripheral neuropathy than healthy controls at both level 1 (396 ± 74 vs. 541 ± 141, P<0.05) and level 2 (422 ± 65 vs. 565 ± 108, P<0.05). AD was significantly lower in T2D patients with peripheral neuropathy than controls at level 2 (2,207 ± 492 vs. 2,884 ± 497, P<0.05). RD was significantly higher in T2D patients with peripheral neuropathy than controls at level 1 (1,156 ± 313 vs. 867 ± 147, P<0.05). No difference in the CSA of the tibial nerve was seen in both levels between two groups.

Our results have shown that DTI parameters can detect nerve abnormalities of the tibial nerve in T2D patients, suggesting DTI may be useful as a biomarker in diabetic peripheral neuropathy.

Presentation: Thursday, June 15, 2023
THU354 Enfortumab Vedotin Induced Refractory Hyperglycemia
Authors: Hussein Marwah , Makadsi S , Samantray J
Published: October 2023

Disclosure: M. Hussein: None.

Introduction: Immunotherapy has transformed the treatment landscape of cancer therapy and has created promising hope for cancer patients. While immunotherapy has dramatic efficacy it also has unique toxicity profile. A spectrum of adverse events known as endocrinopathies have been reported with immune checkpoint inhibitors. One of the newer medications is Enfortumab Vedotin, an antibody-drug conjugate. This drug is approved for use in advanced urothelial carcinoma. Case: We present a 68-year-old male with advanced urothelial carcinoma who was started on Enfortumab vedotin after he progressed on a different chemotherapy/immunotherapy. His medical history was significant for prediabetes and morbid obesity.2 weeks after the first cycle of treatment he presented to emergency room with worsening dyspnea and fatigue. Vital signs: Temp: 37.3, HR: 90, BP: 122/65, RR 18, SPO2 95% on 3L O2 through nasal canula. BMI 44 kg/m. Biochemical workup revealed elevated Glucose level of 310 and anion gap of 12. He was started on subcutaneous insulin. He continued to be uncontrolled and was transferred to the ICU and switched to intravenous insulin due to hyperglycemia. His total daily insulin dose was close to 900 units to achieve blood glucose <180. It took 48-72 hours of Intravenous insulin use to get controlled blood glucose. Hgba1c was 7.3%. Insulin antibody, GAD65 and Islet cell antibodies were negative, C peptide 38 for a glucose of 428. Unfortunately, the patient developed multiorgan failure, and passed away on day 7 of the admission. Discussion: The mechanism of this drug inducing hyperglycemia is not well understood as of yet. But the presumed theory here is the patient developed severe acute insulin resistance that led to this refractory hyperglycemia, as evident by the high c peptide level. Absence of beta cell antibodies and elevated c peptide go against an autoimmune destructive beta cell pathway. The other theory is that there is a malfunction in the signaling pathway at the cellular level that led to hyperglycemia. Risk of developing hyperglycemia as a side effect to this medication increase with patient’s personal risk factors for developing diabetes mellitus (prediabetes and obesity). In phase 3 trial of Enfortumab vedotinEV301, treatment related hyperglycemia was reported in 6.4 % of patients. Hyperglycemia occurred more frequently in patients with hyperglycemia at baseline or with a body-mass index of 30 or higher. Conclusion: We are in need for further studies to understand the mechanism of refractory hyperglycemia induced by this drug. Patients on this type of therapy should be monitored very closely for developing a new onset of diabetes mellitus or worsening of established diabetes mellitus.

Presentation: Thursday, June 15, 2023
THU372 Finasteride Induced Hyperglycemia
Authors: Bose Vivek , Santos Martinez Dorothy
Published: October 2023

Disclosure: V. Bose: None. D.S. Martinez: None.

Objective: Finasteride is a 5-alpha reductase inhibitor that is often prescribed to treat benign prostatic hyperplasia in men. It prevents the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone has numerous physiological actions including having effects on physiological function of liver and pancreatic β-cells. While the medicine does not have hyperglycemia as an adverse effect on its profile, this is a case presentation of worsening hyperglycemia in a diabetic patient who was started on 5-alpha reductase inhibitor. Methods: The patient’s clinical course with laboratory data is presented. Results: The patient is a 69 year old obese male presented for hyperglycemia management. He had been treated with GLP1 agonist, SGLT2i and NPH. He noted that since starting finasteride in 2018, his fingerstick glucose levels were higher compared to prior readings. His hemoglobin A1c was also noted to have increased from 7% to 8.2%. He also reported some weight gain. Conclusion: In this case, one can see that the use of 5-alpha reductase inhibitor precipitated worsening hyperglycemia. The inhibition of androgens to their various metabolites may result in pathophysiological states that present as hyperglycemia via insulin resistance and liver disturbances. In patients with diabetes, the addition of finasteride or dutasteride should be cautiously monitored and if possible, avoided to limit worsening hyperglycemia and diabetic complications. Reference: Traish AM. Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It's Time to Sound the Alarm. World J Mens Health. 2020 Jul;38(3):323-337. doi: 10.5534/wjmh.200012. Epub 2020 Mar 20. PMID: 32202088; PMCID: PMC7308241.

Presentation: Thursday, June 15, 2023
THU378 Presentation Of Autoimmune Destruction Of Pancreatic Beta Cells By Pembrolizumab In The Setting Of Existing Type 2 Diabetes
Authors: Seidenberg Jacob , Uddin Ansari Mohammad Jamal
Published: October 2023

Disclosure: J. Seidenberg: None. M.J. Ansari: None.

Background: Prembrolizumab, like other immunotherapies, have become a commonplace treatment for certain cancers. Its method of action is binding of the programmed cell death I receptor that blocks the binding of the programmed cell death ligand 1. PD1-1 receptors have been reported to cause autoimmune endocrinopathies including type 1 diabetes. Many patients who present with the adverse reaction of autoimmune diabetes type 1 present with ketoacidosis. However, patients already diagnosed with diabetes type 2 on insulin could have this strong initial presentation masked. Clinical Case: Patient is a 76 year old female who was recently diagnosed with bladder cancer and started on Pembrolizumab. She presented to the endocrinology clinic due to new onset poor blood sugar control with self-tested glucose levels ranging from 300-400. This patient was previously diagnosed with diabetes type II and was taking metformin, Levemir 18 units daily, Humalog 6 units AC. A C peptide level was obtained during euglycemia, which was undetectable, indicating autoimmune destruction of pancreas. Patient was continued on Pembrolizumab due to her clinical response to it and a low probability of pancreatic beta cells functioning again. Patient’s C peptide continued to be undetectable 1 year after her presentation. Conclusion: Autoimmune destruction of pancreatic beta cells from Pembrolizumab is a rare but important adverse effect. Pembrolizumab has been reported to be associated with autoimmune-related pancreatitis leading to type 1 diabetes in only 0.1% of all patients in clinical trials. We present this patient, who was already being treated with insulin for type 2 diabetes and thus was being tested for elevated glucose regularly. She was able to notice a significant change in glucose control prior to onset of symptoms. All patients who take Pembrolizumab, especially those with underlying diabetes, should be regularly evaluated for interference with pancreatic beta cells with regular glucose labs and if hyperglycemia occurs, with a C peptide level should then be ordered.

Presentation: Thursday, June 15, 2023
THU386 Non-diabetic Ketoacidosis As A Rare Complication Of Colitis And Gastritis
Authors: Bosques-Lorenzo Jaymilitte , Irizarry-Garcia Jose J , Baez-Torres Joedali , Colon-Castellano Janet
Published: October 2023

Disclosure: J. Bosques-Lorenzo: None. J.J. Irizarry-Garcia: None. J. Baez-Torres: None. J. Colon-Castellano: None.

Background: Starvation ketoacidosis is a rare cause of metabolic acidosis that is often under-recognized. To our knowledge, no cases of starvation ketoacidosis secondary to colitis and gastritis have been reported. Clinical Case: A 91 y/o male presented to the ER with nausea, vomiting, left lower quadrant abdominal pain, and anorexia that progressed for the previous two days. Physical examination was remarkable for a fragile man, acutely over chronically ill, with reduced skin turgor, dry oral mucosa, but a benign abdominal examination. Vitals signs upon arrival were stable. Basic laboratories showed hypoglycemia at 64 mg/dL (70 - 99 mg/dL), low CO2 17.7 mEq/dL (24 -32 mEq/dL), Na 137 mEq/dL (135 - 145 mEq/dL), Cl 94 mEq/dL (100- 110 mEq/dL). High anion gap metabolic acidosis was demonstrated (25 mEq/L). Renal function was preserved and within the patient's baseline, lactic acidosis was ruled out with normal levels in the laboratory, and CBC was negative for leukocytosis. Patient denied alcohol ingestion upon questioning. There were no suspected infectious foci. Abdomino-pelvic CT scan with oral contrast demonstrated colonic, rectal, and gastric inflammation. Case reevaluation and assessment of the data and history of present illness, led to B-hydroxybutyrate measurement. Surprisingly, ketones levels came back markedly elevated at confirming starvation ketoacidosis in the setting of colitis and gastritis. Patient was treated with aggressive intravenous fluids with normal saline for the first 24 hours, IV glucose to correct hypoglycemia, electrolytes were replaced as needed, and stomach antacids for symptomatic relief of abdominal discomfort. We slowly progressed diet as tolerated and electrolytes were carefully monitored for refeeding syndrome. Few days later the patient was discharged home with full resolution of symptoms. Conclusion: Metabolic acidosis secondary to ketoacidosis is mostly visualized to be exclusive for diabetic patients, leading to under-recognition of starvation ketoacidosis. This is the first case of starvation ketoacidosis secondary to colitis and gastritis. Understanding its association can lead to prompt recognition and treatment, especially in the non-diabetic population.

Presentation: Thursday, June 15, 2023
THU387 Euglycemic Diabetic Ketoacidosis And SGLT-2 Inhibitor Use
Authors: Abrahimi Nora , Abrahimi Aryan , Terrigno Nicole
Published: October 2023

Disclosure: N. Abrahimi: None. A. Abrahimi: None. N. Terrigno: None.

Background: Diabetic ketoacidosis (DKA) is a known adverse effect of SGLT-2 inhibitors. (1) Incidences of euglycemic diabetic ketoacidosis in patients on SGLT-2 inhibitors are reported on less. Clinical Case: A 39-year-old male past medical history of uncontrolled, non-insulin dependent diabetes mellitus and pancreatitis who presented with abdominal pain, nausea and coffee ground emesis. On initial work up, basic metabolic panel showed blood glucose level of 175 mg/dL with an elevated anion gap of 22 mmol/L. Initial differentials included suspicion for euglycemic diabetic ketoacidosis or acute intraabdominal pathology. Venous blood gas showed metabolic acidosis, with a pH of 7.21 and bicarbonate of 9.7 mmol/L, beta hydroxybutyrate was elevated at 7.83 mmol/L. CT abdomen pelvis found a small hiatal hernia, gastric wall thickening, likely gastritis, and was negative for other intraabdominal pathology. Home medications of the patient included dapagliflozin, semaglutide, metformin, gabapentin, and pantoprazole. Patient was admitted with the diagnosis of suspected euglycemic diabetic ketoacidosis and was started on an insulin drip along with D5 0.45 normal saline. Patient’s anion gap was monitored with basic metabolic panel orders every two hours. The insulin drip was discontinued once the patient had two consecutive normal anion gaps and the patient was subsequently started on a subcutaneous insulin regimen. Conclusion: SGLT-2 inhibitors may cause euglycemic diabetic ketoacidosis based on the physiology of the SGLT-2 transporter and the pharmacology of the SGLT-2 inhibitors. (2) Clinical importance of this case report is to consider euglycemic diabetic ketoacidosis in patients on SGLT-2 inhibitors presenting with nausea, vomiting with normal blood glucose to not delay in the diagnosis and treatment of this life-threatening condition. References: (1) Liu J, Li L, Li S, Wang Y, Qin X, Deng K, Liu Y, Zou K, Sun X. Sodium-glucose co-transporter-2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2020 Sep;22(9):1619-1627. doi: 10.1111/dom.14075. Epub 2020 May 21. PMID: 32364674. (2) Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849. Epub 2015 Jun 18

Presentation: Thursday, June 15, 2023
THU390 Case Report On Hirata Syndrome: A Rare Cause Of Hypoglycemia
Authors: Pranala Maanasi , Kuttiyil Oommen Varghese Tharakan , Sanker Vivek , Harshitha Vallabhaneni Sree , Ajith Krithika , Thomas Anil
Published: October 2023

Disclosure: M. Pranala: None. V. Kuttiyil Oommen: None. V. Sanker: None. S. Vallabhaneni: None. K. Ajith: None. A. Thomas: None.

Introduction: Hirata's disease, also known as insulin autoimmune syndrome (IAS), is a rare cause of hypoglycemia that is characterized by episodes of spontaneous hypoglycemia and insulin autoantibodies in patients who have not received exogenous insulin. IAS has been associated with rheumatoid arthritis and Graves' disease in 96% of Japanese IAS patients, and it has also been associated with other autoimmune disorders like Graves' disease. Case History: We report a case of 73-year-old male presented with the complaints of episodes of profuse sweating, palpitation and numbness over his head. Patient was initially treated symptomatically and since the symptoms were not resolving further evaluation was done. Two hourly GRBS, c- peptide, insulin levels and serum cortisol of our patient was monitored. Patient had extremely high serum insulin levels. Serum insulin antibodies level was also high (>300 U/ml). CT abdomen ruled out pancreatic pathology. It has been speculated that hypoglycemia occurring in IAS is due to dissociation of insulin from its antibodies in the post absorptive state. Our patient was diagnosed with IAS based on the criteria of Hirata. The age at onset, sex, and duration of hypoglycemic attacks, outcome or treatment, medication taken prior to the onset of IAS and background disease were all taken into consideration. In our patient, hypoglycemia occurred spontaneously in the post-absorptive state 4–6 hours after meal rather than after a 72-hour fast test. Extremely high levels of insulin (>200 µIU/mL) and Serum insulin antibodies found to be >30 U/ml were constructive in the diagnosis of IAS. The patient improved on dietary management alone consisting of frequent small meals. Conclusion: In order to facilitate early recognition and prevent unnecessary investigations, this could be the most significant syndrome in the differential diagnosis of endogenous hyper-insulinemic hypoglycemia (EHH). In such patients with a high index of suspicion, insulin autoantibodies should be examined. IAA prevents insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia

Presentation: Thursday, June 15, 2023
FRI614 Rescuing Aging-associated CD4+ T Cell Dysfunction Via Mitochondrial Transplantation
Authors: Headley Colwyn A
Published: October 2023

Disclosure: C.A. Headley: None.

Mitochondrial dysfunction alters cellular metabolism, increases oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, we investigated whether the transfer of functional mitochondria into CD4+ T cells that were isolated from old mice and elderly humans, could abrogate aging-associated mitochondrial dysfunction and improve the functionality of aged CD4+ T cells. Our results show that the delivery of exogenous mitochondria to aged T cells led to cellular and mitochondrial reprogramming. This was evidenced by significant mitochondrial proteome alterations that coincided with improved aerobic metabolism and decreased mitoROS in non-activated CD4+ T cells from old mice that received healthy mitochondria. Compared to non-manipulated CD4+ T cells, CD4+ T cells that received functional mitochondria (i.e. mito-transferred CD4+ T cells from old mice) showed improvements in activation-induced TCR-signaling kinetics that correlated with increased frequencies of CD4+ T cells that displayed markers of activation (CD25), increased IL-2 production, as well as enhanced proliferation ex vivo. Immunodeficient mouse models (RAG-KO and TCR-KO) showed that the adoptive transfer of mito-transferred naive CD4+ T cells, protected recipient mice from influenza A and M. tuberculosis infections and promoted effector memory T cell differentiation. Further, mito-transfer improved CD4+ T cell activation in human T cells by decreasing activation-induced senescence. These findings support mitochondria as targets of therapeutic intervention in aging.

Presentation: Friday, June 16, 2023
FRI617 Targeting Unc119b For Insulin Sensitization
Authors: Mittal Ayushi , Buscaglia Paul , Sebag Julien A
Published: October 2023

Disclosure: A. Mittal: None. P. Buscaglia: None. J.A. Sebag: None.

Using high-throughput screening, we identified a new insulin sensitizer, C59, which enhances insulin-stimulated GLUT4 translocation and glucose uptake in glucose storage tissues. C59 treatment improves glucose tolerance in rodent models of insulin resistance. Using Proteome Integral Stability Assay we identified Unc119B as the molecular target of C59. Interaction of C59 with Unc119 was further confirmed by solving the crystal structure of C59 bound Unc119. Unc119B, a protein involved in intracellular trafficking of lapidated cargos, has not previously been implicated in the regulation of glucose homeostasis. Here, we show that deletion of Unc119B protects mice from high fat diet induced insulin resistance compared to DIO WT mice despite similar weight gain, thus, further suggesting an important role of this protein in glucose handling. To understand the mechanism through which Unc119b may inhibit insulin-stimulated GLUT4 translocation, we tested its interaction with TC10α, a prenylated small G-protein that plays a critical role in GLUT4 translocation. Co-immunoprecipitation in CHO cells revealed that Unc119B forms a complex with TC10α. Our results identify Unc119B as a new important regulator of GLUT4 translocation and suggest that it may be acting through the regulation of TC10α activity. This work also identifies Unc119b as a new promising target for the treatment of pre-diabetes and type II diabetes.

Presentation: Friday, June 16, 2023
FRI623 Beta Cell Primary Cilia Mediate Somatostatin Responsiveness Via SSTR3
Authors: Elizabeth Adamson Samantha , Li Alex , Hughes Jing
Published: October 2023

Disclosure: S.E. Adamson: None. A. Li: None. J. Hughes: None.

Somatostatin is an important modulator of beta cell function, but communication between beta and delta cells is not well-understood. Primary cilia are membrane organelles that act as signaling hubs due to their enrichment in certain G-protein coupled receptors and other signaling proteins. We show that somatostatin modulates insulin secretion via somatostatin receptor 3 (SSTR3) located on beta cell primary cilia in mouse islets. SSTR3 and the presence of primary cilia are required for normal beta cell response to somatostatin. Somatostatin signaling leads to beta cell calcium changes, which we characterize here using a beta cell specific genetically-encoded GCaMP6f calcium reporter. Our findings show that ciliary SSTR3 mediates delta to beta cell paracrine crosstalk.

Presentation: Friday, June 16, 2023
SAT052 Prolonged Nursing Augments Short Chain Fatty Acid Levels And Leads To Amelioration Of Type 1 Diabetes
Authors: Imtiaz rafiqi Shafiya , Zahid Zeeshan , Lamendella Regina , aghogho olomukoro , Gionfriddo Emanuela , Tao Yang , Jaume Juan C , Imam Shahnawaz
Published: October 2023

Disclosure: S. rafiqi: None. Z. Zahid: None. R. Lamendella: None. O. aghogho: None. E. Gionfriddo: None. Y. Tao: None. J.C. Jaume: None. S. Imam: None.

The infant gut microbiome essentially shifts to a diverse and complex microbial system during weaning on separation from the mother and any perturbations lead to pathological imprinting with lifelong implications. Apart from breast milk, the microbiota of the skin and the intimate niche between mother and offspring contribute to gut microbial composition. Gut microbiome dysbiosis has been ascribed in the initiation and/or perpetuation of type 1 diabetes (T1D) in human and animal models. The gut microbial diversification is manifested as change in microbial metabolites particularly short-chain fatty acids (SCFAs) that have direct and indirect roles in immune regulation and epithelial barrier integrity. In this study, we try to decipher the role of prolonged nursing of newborn mice (upto 45 days) in the amelioration of type 1 diabetes in the context of changes in the gut microbiome and microbial metabolites. The humanized T1D mice used in the study spontaneously develop T1D at 3-4 weeks of age and are normally weaned at 21 days. Our results revealed mice subjected to prolonged nursing had consistent increments in levels of butyric acid from 60 to 150 days of age as compared to normal weaned mice, owing to a stable population of SCFA-producing bacteria developed during prolonged nursing with the mother. The normal weaned mice had a transient increase of butyric acid at 60 days but it didn’t sustain till the 150th day. The steady levels of butyrate in prolonged nursed mice exerted immunoregulatory roles which manifested in the enrichment of regulatory T cells (Tregs) in the intestinal mesenteric epithelium, payer’s patches, peri pancreatic lymph nodes (PLN), pancreas (PN) and spleen. The enrichment of Tregs leads to the regulation of diabetogenic Th1, Th17, and interferon gamma-producing CD8 T cells (cytotoxic lymphocytes, CTLs) at PLN, PN, and spleen. This increased immune tolerance was mirrored by improved glucose homeostasis and fasting blood glucose levels in the prolonged nursing group. Prolonged nursing preserved the pancreatic islet architecture and significantly maintained the increased number of islets per pancreas as observed in H&E sections. Also, it could be inferred from the results that SCFA’s promoted intestinal integrity with increased submucosal thickening, longer villi, and shallower crypts in the intestine of prolonged nursed mice. In conclusion, prolonged nursing accounts for gradual and steady gut microbiota succession in infants that augments SCFA production leading to enrichment of T regulatory cells and less aggressive diabetes.

Presentation: Saturday, June 17, 2023
SAT054 LivARKO Female Mice On 1-month Of High Fat Diet (HFD) Did Not Experience Insulin Resistance At The Level Of p-AKT In WAT
Authors: Frenchy Curry Dwight , Bolarinwa Elizabeth , O'neil Hill-Dick Johvan , Young Demarrius , Qutab Rabia , Carr Kiana , Falzarano Claire , Andrisse Stanley
Published: October 2023

Disclosure: D.F. Curry: None. E. Bolarinwa: None. J.O. Hill-Dick: None. D. Young: None. R. Qutab: None. K. Carr: None. C. Falzarano: None. S. Andrisse: None.

Insulin resistance affects up to a third of the US adult population and polycystic ovary syndrome affects up to 10% of reproductive-age adult women. The liver and white adipose tissue play an essential component in the metabolism of insulin and androgen signaling. Hyperandrogenism in females can increase predisposition to insulin resistance. Andrisse et al 2021 showed that deleting the liver androgen receptor (LivARKO) prevented female mice from developing hyperandrogenemia (HA)-induced insulin resistance. The goal of this research was to determine if LivARKO prevents high fat diet (HFD) induced insulin resistance.It was hypothesized that (unlike HA-LivARKO) HFD LivARKO female mice would display impaired insulin action (lowered insulin-stimulated p-AKT) in white adipose tissue in comparison to the Control diet (CD) fed LivARKO female mice, suggesting that AR does not play a significant role in regulating HFD-induced insulin resistance. Female LivARKO mice were placed on two diets for 1 month: CD and HFD. The mice were then sacrificed. Half of the mice were given a dose of 0.5 U/kg insulin before sacrificing to investigate the effects of the diets on insulin signaling. Western blots were used to determine protein expression in tissue from the WAT. BCA assays were used to standardize the protein concentration in each sample. Insulin action can be measured molecularly by examining p-AKT Serine 473 (positive regulator, Santa Cruz sc-514032) and p-IRS1 Serine 306 (negative regulator, Santa Cruz sc-33956). If p-AKT S473 levels increase in the presence of insulin, this indicates that insulin is likely functioning properly in the sample. Whereas if p-IRS1 S306 are elevated, this indicates malfunctioning insulin action or insulin resistance. Following a similar pattern as WT mice on a chow diet (White 2014, Fig. 4), insulin increased p-AKT in WAT of LivARKO female mice fed a CD for 1-month in comparison to LivARKO female mice not given insulin (basal). Following the pattern of WT mice on a HFD (White 2014), LivARKO female mice fed a HFD for 1-month, displayed a similar increase in insulin-stimulated p-AKT in the WAT compared to the Con-Ins group. p-IRS-1 was not detected in the WAT of LivARKO female mice fed a control diet or HFD. In conclusion, LivARKO female mice on 1-month of HFD were not experiencing insulin resistance at the level of p-AKT in WAT. Further studies in different energy storage tissues in this model are warranted.

Presentation: Saturday, June 17, 2023
SAT056 New-onset Autoimmune Diabetes After COVID-19 mRNA Vaccine: A Systematic Review
Authors: Laskova Anna , Syritsa Bohdan
Published: October 2023

Disclosure: A. Laskova: None. B. Syritsa: None.

Background: Vaccination against COVID-19 has become a great tool during the COVID-19 pandemic. Multiple studies have shown that vaccines are safe and effective. However, there have been reports of autoimmune diseases following the vaccination against COVID-19. One of the possible mechanisms is thought to be a reaction to adjuvants in the vaccine (ASIA syndrome). We present a systematic review of the cases of new-onset autoimmune diabetes after the COVID-19 mRNA vaccine. Methods: We included 10 patients from 6 case reports1-6 and 1 case series7 published before December 3, 2022. We analyzed demographics, results, and outcomes using descriptive statistics. Results: 60% were males, and 40% were females. The median age was 51.5 years. 70% received the BNT162b2 vaccine, 20% - the mRNA-1273 vaccine, 10% - an unnamed mRNA vaccine. 70% developed symptoms after the second dose of the vaccine. The onset was distributed from 1 week after the first dose to 8 weeks after the third dose. 30% had either personal or family history of autoimmune diseases. Among other 70%, 57% had HLA DRB1 and/or DQB1 alleles (unknown if HLA was tested in other patients). The disease manifested as diabetic ketoacidosis in 50% of the patients. Anti-GAD antibodies were elevated in 70% of the patients. 30% were weaned off insulin shortly after the diagnosis, meanwhile, the rest required insulin by the time of the articles’ writing. We noted that most of the patients who developed autoimmune diabetes after the COVID-19 vaccine had either personal or family history of autoimmune diseases or tested positive for certain pertinent HLA alleles. However, no causal relationship can be established based on the current cohort, and more research needs to be done.

References:

1. Jano M, Morioka T, Natsuki Y et al. New-onset type 1 diabetes after COVID-19 mRNA vaccination. Intern Med. 2022;61(8):1197-1200

2. Kobayashi T, Yakou F, Saburi M et al. New-onset atypical fulminant type 1 diabetes after COVID-19 vaccination: A case report. Clin Case Rep. 2022;10(10):e6473

3. Kshetree B, Lee J, Acharya S. COVID-19 Vaccine-induced rapid progression of prediabetes to ketosis-prone diabetes mellitus in an elderly male. Cureus. 2022;14(9): e28830

4. Patrizio A, Ferrari SM, Antonelli A et al. A case of Graves' disease and type 1 diabetes mellitus following SARS-CoV-2 vaccination. J Autoimmun. 2021;125:102738

5. Sasaki H, Itoh A, Watanabe Y et al. Newly developed type 1 diabetes after coronavirus disease 2019 vaccination: A case report. J Diabetes Investig. 2022;13(6):1105-1108

6. Sasaki K, Morioka T, Okada N et al. New-onset fulminant type 1 diabetes after severe acute respiratory syndrome coronavirus 2 vaccination: A case report. J Diabetes Investig. 2022;13(7):1286-1289

7. Aydoğan B, Ünlütürk U, Cesur M. Type 1 diabetes mellitus following SARS-CoV-2 mRNA vaccination. Endocrine. 2022;78:42-46

Presentation: Saturday, June 17, 2023
SAT057 Hyperglycemic Emergencies Following Vaccination Against COVID-19: A Descriptive Analysis Of Crude Adverse Event Data
Authors: Laskova Anna , Syritsa Bohdan
Published: October 2023

Disclosure: A. Laskova: None. B. Syritsa: None.

Background: There have been case reports in the literature describing the onset of hyperglycemic emergencies after receiving the COVID-19 vaccine. One of the potential mechanisms includes hypercytokinemia leading to pancreatic damage [1]. We present a summary of cases reported to the vaccine adverse events reporting system (VAERS).

Objectives: To summarize the existent crude data about the frequency of hyperglycemic emergencies reported to the VAERS. Methods: We accessed the VAERS and searched for reports of hyperglycemic emergencies in patients who received vaccination against COVID-19 as of 12/30/2022. We manually reviewed reports and applied descriptive statistics. Results: We chose the symptoms “DIABETIC COMA; DIABETIC HYPERGLYCAEMIC COMA; DIABETIC HYPEROSMOLAR COMA; DIABETIC KETOACIDOSIS; DIABETIC KETOACIDOTIC HYPERGLYCAEMIC COMA; HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME; HYPERGLYCAEMIC UNCONSCIOUSNESS” as well as “COVID19 VACCINE”, and our search returned 455 reports. Among them, the keyword “DIABETIC KETOACIDOSIS” was used in 90% of reports, “HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME” - in 4% of reports. Pfizer-Biontech was the vaccine manufacturer in 62% of reports, Moderna - in 27%, Janssen - in 10%, and other manufacturers - in 1% of reports. In 42% of cases, the event developed after the first dose of the vaccine, 47% - after two doses, and 10% - after three doses. Males were affected in 46% of reports, females - in 54%. The onset of the symptoms was unknown in 15% of the cases. 38% of the remaining cases reported an onset within 7 days of the vaccine administration. 87% of events were categorized as “serious”. 79% of patients were hospitalized. Death was reported in 16% of cases. We reviewed the available records, and 11% of them contained no details. Among the others, 60% mentioned either history of diabetes or antidiabetic medications in the description part. About 5% of the reports contained the words “new diagnosis of diabetes” or “new-onset diabetes”. Conclusions: Our analysis of crude data reported to VAERS showed that the majority of the cases of hyperglycemic emergencies occurred in patients with a known history of diabetes. More than half of the cases occurred later than within 1 week of the vaccine administration. We would like to speculate that the later the onset is, the less likely it is associated with the vaccine. During the manual review of the records, we found that 5% of cases describe a potential new-onset diabetes event. Anyone can report to VAERS, and for any event, no causality has been established [2].

References:

1. Samuel SM, Varghese E, Triggle CR et al. COVID-19 Vaccines and Hyperglycemia-Is There a Need for Postvaccination Surveillance?. Vaccines (Basel). 2022;10(3):454.

2. https://vaers.hhs.gov/data/dataguide.html

Presentation: Saturday, June 17, 2023
SAT074 Induction Of Insulin Hypersecretion Uncovers Distinctions Between Adaptive And Maladaptive Endoplasmic Reticulum Stress Response In Beta Cells
Authors: Roy Gitanjali , dos Santos Karina Rodrigues , Kwakye Michael B , Tan Zhiyong , Johnson Travis S , Kalwat Michael A
Published: October 2023

Disclosure: G. Roy: None. K. Rodrigues dos Santos: None. M.B. Kwakye: None. Z. Tan: None. T.S. Johnson: None. M.A. Kalwat: None.

Pancreatic islet β-cells release insulin to maintain glucose homeostasis. β-cells must translate, package, and secrete large amounts of insulin. During this process the unfolded protein response of the endoplasmic reticulum (UPRER) is induced to maintain these functions. However, stimuli that force β-cell to secrete insulin at enhanced rates and for prolonged durations risk inducing the terminal UPRER and eventual apoptosis. In a chemical screen for insulin secretion modulators, we discovered SW016789 which caused hypersecretion of insulin and led to a transient induction of the UPRER, but not apoptosis. In contrast, SERCA2 ER Ca2+ pump inhibitor thapsigargin induces the terminal UPRER. We hypothesized that SW016789 can be used as a tool compound to discover genes involved in β-cell adaptation to hypersecretion-induced stress. We performed time course transcriptomics in MIN6 β-cells exposed to SW016789 (5 µM) or thapsigargin (100 nM) from 0-24 h. Unbiased analyses using a Dirichlet process Gaussian process (DPGP) method revealed clusters of genes temporally co-regulated and the genes within these clusters were distinct between SW016789 and thapsigargin treatments. In particular, after 6 h of SW016789-induced hypersecretion we found a highly induced cluster of genes (SW cluster 3) enriched in adaptive UPRER factors (e.g. Manf). Conversely, most of the thapsigargin-induced genes clustered at 24 h and were enriched for terminal UPRER factors (e.g. Txnip). Pathway analysis of SW cluster 3 indicated that genes involved in in regulation of mRNA methylation and ER-associated degradation were also induced by SW016789 sooner and with greater amplitude than by thapsigargin, suggesting distinct differences in the handling of protein translation and degradation. From the SW cluster 3 genes we selected proteins known to be ER-associated or secreted and generated stable transgenic or CRISPR knockout MIN6 β-cell lines for each. Our data suggest altered expression of these factors may impair glucose-stimulated insulin secretion responses and alter cell viability in presence or absence of ER stressors including cytokines, thapsigargin, and tunicamycin. In conclusion, we have successfully shown that pharmacological induction of insulin hypersecretion can induce a distinct transcriptional outcome from that of canonically-induced UPRER and that we can take advantage of this property to discover new β-cell regulatory pathways and targets. We envision this dataset as a resource for the secretory biology and islet biology communities.

Presentation: Saturday, June 17, 2023