Insulin Antibodies Research Articles

Exogenous insulin antibodies syndrome: challenges in management

Exogenous insulin antibodies syndrome: challenges in management

Exogenous Insulin Antibody Syndrome (EIAS) Presenting in an Elderly, Long-Term Patient with Type1DiabetesMellitus that Resolved with Low-Cost Outpatient Therapy with Mycophenolate Mofetil and Regular Insulin by Pump.

Exogenous insulin antibody syndrome (EIAS) has until recently been a rarely described complication of exogenous insulin therapy. EIAS results not only in hyperglycemia, but also in hypoglycemia and occasionally in ketoacidosis (DKA). The incidence of EIAS is increasing probably due to an overall increase in autoimmunity associated with the coronavirus disease 2019 (Covid-19) epidemic resulting in increasing binding of insulin by antibodies. Herein, we describe a case of EIAS occurring in an elderly patient with longstanding type 1 diabetes mellitus (T1DM) who had progressive loss of glycemic control. It responded positively, as we have previously described, to oral mycophenolate mofetil and the use of soluble regular insulin delivered by continuous subcutaneous insulin infusion (CSII). Therefore, EIAS is an increasingly frequent cause of hyperglycemia with and without DKA, and hypoglycemia in subjects with T1DM. Once diagnosed, they can be treated with mycophenolate mofetil and soluble insulin in an outpatient setting, which will decrease the rate of hospitalization and lower the expense of therapy.

How should we differentiate hypoglycaemia in non-diabetic patients?

Hypoglycaemic syndromes are rare in apparently healthy individuals and their diagnosis can be a difficult challenge for clinicians as there are no shared guidelines that suggest how to approach patients with a suspect hypoglycaemic disorder. Since hypoglycaemia symptoms are common and nonspecific, it's necessary to document the Whipple Triad (signs and/or symptoms compatible with hypoglycaemia; relief of symptoms following glucose administration; low plasma glucose levels) before starting any procedure. Once the triad is documented, a meticulous anamnesis and laboratory tests (blood glucose, insulin, proinsulin, C-peptide, β-hydroxybutyrate and anti-insulin antibodies) should be performed. Results can guide the physician towards further specific tests, concerning the suspected disease. In this review, we consider all current causes of hypoglycaemia, including rare diseases such as nesidioblastosis and Hirata's syndrome, describe appropriate tests for diagnosis and suggest strategies to differentiate hypoglycaemia aetiology.

The role of GaD65, ZNTS, IA-2, and IAA as predictive biomarkers for type 1 diabetes mellitus in children

Background Type 1 diabetes mellitus (T1DM) is a chronic disorder characterized by immune-mediated harm to the pancreatic β-cells that produce insulin. The four major autoantibodies implicated in the pathophysiology are insulin autoantibodies, glutamic acid decarboxylase antibodies, tyrosine phosphatase antibodies, and zinc transporter 8 antibodies. Objective We examined whether children with T1DM have particular antibodies related to T1DM and their association with clinical features. Materials and methods The study involved 60 Iraqi children who had been diagnosed with T1DM within the last 3 years, as well as a control group of 60 healthy individuals without diabetes or autoimmune diseases. Blood samples were collected from all participants to analyze the levels of serum autoantibodies, specifically insulin (IAA), glutamic acid decarboxylase (GADA), tyrosine phosphatase (IA-2A), and zinc transporter 8 (ZnT8A), using an enzyme-linked immunosorbent assay (Sandwich-ELISA). Results and conclusion The findings revealed that a significant number of patients with diabetes had elevated levels of antibodies against zinc transporter 8 (P<0.001), tyrosine phosphatase (P<0.001), insulin autoantibodies (P<0.001), and glutamic acid decarboxylase (P<0.001). Glutamic acid decarboxylase 65 antibodies were found to be the most prevalent. All four biomarkers showed remarkable effectiveness in distinguishing positive and negative cases. Logistic regression analysis revealed that glutamic acid decarboxylase 65 and insulin antibodies were significantly associated with the outcome, while tyrosine phosphatase and zinc transporter 8 did not show such a relationship. These findings indicate that measurements of anti-zinc transporter 8, tyrosine phosphatase, insulin autoantibodies, and glutamic acid decarboxylase could be important diagnostic markers for identifying patients with T1DM, aiding in early detection and understanding the disease process.

CD4+ T Cells From Individuals With Type 1 Diabetes Respond to a Novel Class of Deamidated Peptides Formed in Pancreatic Islets.

The β-cell plays a crucial role in the pathogenesis of type 1 diabetes, in part through the posttranslational modification of self-proteins by biochemical processes such as deamidation. These neoantigens are potential triggers for breaking immune tolerance. We report the detection by LC-MS/MS of 16 novel Gln and 27 novel Asn deamidations in 14 disease-related proteins within inflammatory cytokine-stressed human islets of Langerhans. T-cell clones responsive against one Gln and three Asn deamidated peptides could be isolated from peripheral blood of individuals with type 1 diabetes. Ex vivo HLA class II tetramer staining detected higher T-cell frequencies in individuals with the disease compared to control individuals. Furthermore, there was a positive correlation between the frequencies of T cells specific for deamidated peptides, insulin antibody levels at diagnosis, and duration of disease. These results highlight that stressed human islets are prone to enzymatic and biochemical deamidation and suggest that both Gln and Asn deamidated peptides can promote the activation and expansion of autoreactive CD4+ T cells. These findings add to the growing evidence that post-translational modifications undermine tolerance and may open the road for the development of new diagnostic and therapeutic applications for individuals living with type 1 diabetes.

P-23 Insulin autoimmune syndrome possibly induced by Alpha-Lipoic acid

Abstract Introduction Insulin autoimmune syndrome (IAS) is a relative rare cause of hypoglycemia due to the presence of extremely high circulating insulin levels and elevated serum concentrations of autoantibodies to human insulin despite no prior exposure to exogenous insulin, insulin analogues or oral hypoglycemic agents. It is characterized by repeated fasting hypoglycemia or episodes of hypoglycemia late after meals in non-diabetic, non-acutely ill patients. Increasing the titer of insulin autoantibodies and immune reactive insulin occurs owing to both genetic influences and environmental triggers such as medication, genetic instability and other factors. It is associated with the use of drugs comprising sulfhydryl groups, such as methimazole, clopidogrel and alpha lipoic acid, mostly. Insulin autoantibodies appear a few weeks after the exposure of sulfhydryl radicals. Here, we summarize the case of IAS caused by drug administration. Clinical Case A 60-year-old female patient who has a history of migraine for 30 years was referred to our hospital for feeling of hunger, dizziness, sweating, tremor, and palpitations for 1 month. These symptoms had commenced episodically, soon after starting 600 mg/day of alpha lipoic acid. She was diagnosed with hypoglycemia based on a plasma glucose concentration of 31 mg/dL. There was no personal or family history of diabetes mellitus, or previous use of oral hypoglycemic drugs such as sulfonylureas or exogenous insulin. No abnormality was detected in the systemic examination. She had no smoking and alcohol abuse. Her regular medication was tricyclic antidepressant (amitriptyline). Laboratory results are presented in Table 1. On our evalution, the serum levels of insulin, C-peptide, and anti-insulin antibody titers were inappropriately elevated in the presence of hypoglycemia, confirming the diagnosis of hyperinsulinemic hypoglycemia. Thyroid function, human growth hormone, insulin growth factor-1 (IGF-1), and cortisol result were within normal limits. Screening for antinuclear factor, serum protein electrophoresis, serology for viral hepatitis, and other autoimmune diseases were negative. Insulinoma was excluded with computed tomography. In light of the above results, a diagnosis of IAS was made with possible alpha lipoic acid. Because, alpha lipoic acid was the only medication being taken associated with a sulfhydryl group. The patient was prescribed oral methylprednisolone (32 mg once daily), alpha lipoic acid was withdrawn. Hypoglycemia did not occur after methylprednisolone treatment of follow-up. Methylprednisolone treatment was tapered to 4 mg once daily within 2 months. The insulin, and anti-insulin antibody titers had decreased. Conclusion We report a rare case of IAS. Sulfhydryl group containing drugs such as alpha lipoic acid might induce or exacerbate hypoglycemia in patients with a history of IAS. For this reason, the use of alpha lipoic acid should be questioned in patients with IAS. Table 1. Laboratory test results

O-17 A case of severe and recurrent hypoglycaemia in a healthy patient

Abstract Introduction Hypoglycaemia is a challenging condition for the endocrinologist. Clinical Case A 75 y/o man was admitted to ER due to severe symptoms of hypoglycaemia (weakness, blurring and sweating). His symptoms improved after eating some food and blood glucose was 50 mg/dL. He was treated with oral glucose and referred to our endocrinology clinic. His personal and family history was uneventful (no endocrine, autoimmune or neoplastic disease, no drug) and he did not complain any other symptoms besides hypoglycaemic ones. When going deeply into his medical history, he reported that back pain had occurred 4 weeks before ER access. His GP had thus prescribed supplements containing alpha lipoic acid (ALA) that he had assumed for 3 weeks and then discontinued for the lack of any benefit. He regarded this information as useless as ALA was “just a supplement”. Furthermore, he reported symptoms as shaking, anxiety, dizziness, sweating, and hunger that occurred 5-7 times per day far from meals and faded after eating. A diet was prescribed with frequent eatings, high content of fibers and whole foods. He started flash glucose monitoring (FGM) with the alarm for hypoglycaemia set at 70 mg/dL and was trained for the management of hypoglycaemia. The laboratory alerted us due to the results of oral glucose tolerance test (Table 1). Hypoglycaemic episodes after the test were neither reported nor registered by FGM. The differential diagnosis was among insulinoma, insulin resistance or insulin autoimmune syndrome (Hirata disease). The calculated molar ratio of insulin to C-peptide was 2.68, thus pointing to Hirata disease (to be suspected when the ratio is >1). We opted for watchful waiting while continuing the monitoring. Two weeks later the pending results became available: TSH 1.69 mU/L, HbA1c 5.2%, serum cortisol 14.8 μg/dL, ACTH 18.2 pg/mL, anti-endogenous insulin antibodies 5.8 U/ml (nv <2.4), normal values of transaminases, lipase, and amylase. The patient reported adherence to the diet, two symptomatic hypoglycaemias (in the afternoon, when he couldn't have the snack) as well as asymptomatic FGM alarms once daily, usually early in the morning. We advised to add a snack before bedtime to shorten the fasting period. At the 3-month follow-up he had had no further hypoglycaemias, blood glucose was normal and anti-endogenous insulin antibodies were negative. Conclusion Hypoglycaemia can be a life-threatening condition and differential diagnosis is crucial. It is important to consider even rare conditions, such as Hirata syndrome that can be triggered by several factors and medications, the most common being ALA. Complete medical history is mandatory and tight follow-up essential. Most cases, as the one reported, resolve with a correct diet after the withdrawal of supplements.Table 1.Oral Glucose Tolerance Test

Insulin autoimmunity associated with vitiligo: a rare case presentation.

Insulin autoantibody syndrome (IAS) or Hirata's disease is a rare condition characterized by recurrent fasting hypoglycaemic and postprandial hyperglycaemic episodes. Insulin autoantibodies are diagnostic for the condition. Hirata's disease has been seen to be associated with other autoimmune conditions. Vitiligo is a common depigmentation disorder whose exact cause is unknown but thought to have an autoimmune aetiology. Although autoimmunity plays a role in the pathogenesis of both the diseases, association between the two has not been reported till date. In our case, a 72-year-old Indian woman with vitiligo for the past 30 years presented with recurrent episodes of fasting hypoglycaemia. She was found to have very high levels of fasting insulin, C-peptide, and insulin antibody and was diagnosed with IAS. Thus, we conclude that the clinical spectrum of Hirata's disease has to be taken as more heterogenous than previously assumed. Insulin autoantibody syndrome (IAS) or Hirata's disease is a rare condition characterized by recurrent fasting hypoglycaemic and postprandial hyperglycaemic episodes in which insulin plays a major role. Insulin autoantibodies are diagnostic for IAS. The endocrine insulin and its autoantibodies play a major role in the pathogenesis of the disease. Vitiligo is a common depigmentation disorder whose exact cause is unknown but thought to have an autoimmune aetiology. IAS and vitiligo are two diseases with autoimmune aetiology which has been seen to be associated with each other (the first case to be reported). The clinical spectrum of Hirata's disease has to be taken as more heterogenous than previously assumed. On dealing with autoimmune diseases, we should also keep in mind about other diseases with autoimmune pathogenesis.

IGF-2-mediated hypoglycemia: a case series and review of the medical therapies for refractory hypoglycemia.

Non-islet cell tumour hypoglycemia (NICTH), typically mediated by insulin-like growth factor 2 (IGF-2), is a rare but highly morbid paraneoplastic syndrome associated with tumours of mesenchymal or epithelial origin. Outside of dextrose administration and dietary modification which provide transient relief of hypoglycemia, resection of the underlying tumour is the only known cure for NICTH. Available medical therapies to manage hypoglycemia include glucocorticoids, recombinant growth hormone, and pasireotide. We report two cases of IGF-2 mediated hypoglycemia. The first was managed surgically to good effect, highlighting the importance of a timely diagnosis to maximise the likelihood of a surgical cure. The second patient had unresectable disease and was managed medically, adding to a growing number of cases supporting the efficacy of glucocorticoids and recombinant growth hormone in NICTH. Recurrent fasting hypoglycemia in the setting of a malignancy should raise suspicion of non-islet cell tumour hypoglycemia (NICTH), which is typically mediated by IGF-2. The initial workup for NICTH should include a serum glucose, C-peptide, insulin, insulin antibodies, beta-hydroxybutyrate, IGF-2, IGF-1, and sulphonylurea screen during a spontaneous or induced hypoglycemic episode. An IGF-2/IGF-1 ratio above 10 is highly suggestive of IGF-2-mediated hypoglycemia if the IGF-2 level is normal or elevated. False positives may be seen with sepsis and cachexia as both IGF-2 and IGF-1 are subnormal in these cases. A low IGF binding protein 3 (IGFBP3), such as in renal failure, may also result in a falsely normal or low IGF-2/IGF-1 ratio. Surgical resection of the associated tumour is curative in most NICTH cases. When the tumour is unresectable, moderate-dose glucocorticoids, low-dose glucocorticoids in combination with recombinant growth hormone, and pasireotide are medical therapies with promising results in controlling NICTH.

Insulin-induced Panniculitis in a Child: A Rare Entity

Abstract Insulin-induced panniculitis is a rare entity. It represents the early stage of development of lipoatrophy. The complex of insulin and insulin antibodies leads to the activation of macrophages, which is responsible for the initiation of autoimmune process and leading to panniculitis followed by subsequent development of lipoatrophy. Here, we report the case of insulin-induced panniculitis with lipoatrophy associated with Type 1 diabetes mellitus in an 11-year-old female child.

The Epistemic Value of Gain of Function Experiments.

The phrase "gain of function" (GOF) has recently acquired a negative connotation in experimental biology by its association with risky science. Whereas much of the discussion on the relative merits of GOF-type experiments has focused on their risk-benefit equation, relatively little has been said about their epistemic value. In this article, we recount how GOF experiments were critical for establishing DNA as the genetic material, the identification of cellular receptors, and the role of oncogenes in cancer research. Today, many of the products of the biomedical revolution such as synthetic insulin, growth factors, and monoclonal antibodies are the result of GOF experiments where cells were given the new function of synthesizing medically important products. GOF experiments and complementary loss of function experiments are epistemically powerful tools for establishing causality in biology.

Production of Anti-Recombinant Human Insulin Antibody and Validation by Indirect ELISA

Human insulin potential has become an interest and is important in maintaining the success of therapyin patients with the availability of chemical-based analytical methods, however, only a few have beenusing immunoassays. This study aimed to produce IgG polyclonal antibodies from rabbits immunizedwith 1 mg/mL rhINS subcutaneously and validated by indirect ELISA. Antibody was precipitated andfractioned on a HiTrap® Protein A HP column before being quantified with a UV spectrophotometerat λ 280 nm. The characterization was conducted by Dot Blot test on a BCIP-NBT substrate, as well asSDS-PAGE and Western Blot with polyacrylamide gel concentrations of 7.5% and 17.5%. Validationwas performed using solutions containing glycerol and m-cresol as matrices spiked with rhINS. Thelinearity test in the rhINS concentration range of 80.11-200.28 μg/mL (r = 0.99) showed the linearresult. The accuracy and precision obtained an average of 99.11%±5.01 and 3.91%, while the LODand LOQ were 22.05 μg/mL and 73.51 μg/mL, respectively. Human insulin was stable at 2-8oC for 24hours (α: 0.05, ANOVA). In conclusion, in-house produced IgG polyclonal antibodies and goat anti-IgG peroxidase conjugate can be used for routine testing of human insulin.

FRI631 Insulin Antibody Mediated Extremely Insulin Resistant In Pregnancy

Abstract Disclosure: Z. Liu: None. D. James: None. S. Dagogo-Jack: None. Background: Insulin antibodies can rarely complicate diabetes management during pregnancy. Here, we report a patient with extreme insulin resistance during pregnancy associated with positive insulin antibodies. Clinical Case: A 40-year-old primigravida with Type 2 Diabetes (T2DM) was admitted at week 32 for uncontrolled Hypertension (HTN) and extremely high insulin requirement. T2DM was diagnosed 8 years ago and treated with basal insulin 50 units/d, dulaglutide, metformin, and glimepiride. Her HbA1c was 14% one month prior to pregnancy. During pregnancy, patient’s regimen was changed to basal bolus insulin, and oral agents were discontinued. Total daily insulin dose average 740 units (5.6 units/kg/day) at week 32. Patient’s weight was 112 kg at the beginning of pregnancy, increasing to 131 kg in the third trimester. On the high insulin regimen, her HbA1c was 5.6% at week 32. Due to the extreme insulin requirement (indicative of severe insulin resistance), we ordered insulin antibody (IAA), which came back positive at 15 µU/ml (NR <5 µU/ml). Diabetes control remained suboptimal, with frequent post-prandial hyperglycemia followed by hypoglycemia during hospitalization. Insulin regimen was optimized using U-500 in divided doses, starting with 112 units tid. At 34 weeks (hospital day 14), patient underwent cesarean section with delivery of a viable infant (weight 1450 grams, Apgar score 5 and 9 at 1 and 5 minutes). Shortly after delivery, the patient’s insulin requirement plummeted to 62 units daily and she was successfully discharged home. Diabetes control has been stable, with HbA1c ranging between 5.7% and 7% one year after delivery on total insulin dose of 60 units or less per day. Attempts to schedule patient for repeat antibody testing were unsuccessful. Conclusion: Despite the lack of data on repeat antibody testing, this is a compelling case of pregnancy associated extreme insulin resistance likely induced by insulin antibodies. Our conclusion is supported by the dramatic decrease in insulin requirement following postpartum. Presentation: Friday, June 16, 2023

SAT166 Elevated Insulin Autoantibody During COVID19 Illness Associated With Significant Hypoglycemia In A Type 1 Diabetic

Abstract Disclosure: D.A. Shewmon: None. D.C. Preston: None. Background: Insulin antibodies are a rare cause of hypoglycemia in diabetes mellitus type 1 (DM1). Exacerbation of this phenomenon by COVID-19 has not been previously reported. Clinical Case: A 46 year old, 60 kg female with DM1 of 19 year duration with hypoglycemic unawareness and retinopathy, who was admitted for flu-like symptoms, a blood glucose of 600 mg/dL in the absence of DKA, and COVID-19 by RT-PCR test. Hospitalization was complicated by 48 hours of hypoglycemia in the absence of insulin treatment, requiring continuous 10% dextrose infusion. Four months earlier the patient had been admitted for an undiagnosed non-COVID flu-like illness, with hypoglycemia for 60 hours in the absence of insulin treatment. Her glucose control was stable on 5 units of insulin per day at five and nine days after admission, and 25 units per day at 35 days after admission. At both admissions, the workup included a normal cortrosyn stimulation test, an undetectable C-peptide, a normal IGF-2 level, and a careful investigation to rule out evidence for self-administration of insulin. However insulin antibodies were elevated at 1.17 +/- 0.56 U/mL (n=4, normal <0.4) during the non-COVID illness, and 5.0 U/mL and 5.4 U/mL, during and 35 days after the COVID-19 illness, respectively. Thus insulin antibodies were 13 times the upper limit of normal during COVID-19 illness versus 2.9 times the upper limit of normal during the non-COVID-19 illness. Viral infection is one of the most significant environmental factors that may cause overstimulation of the immune system and has been shown to be associated with autoantibody generation and increase, in addition to autoimmune diseases. Known cytokine profiles on COVID-19 infections include IL-1, IL-6, IL-12, IFN-gamma, and TNF-alpha. The presence of IL-1 and TNF-alpha in particular, are known to be key pro-inflammatory cytokines in myriad autoimmune disorders. In vitro data suggest that IL-1 is also an important effector cytokine in DM1, through a number of direct (i.e., beta cell toxicity) and indirect means (i.e., by marking beta cells for Fas-dependent destruction by autoreactive cytotoxic T-lymphocytes). Conclusion: Our data could represent another example of the exacerbation of autoimmunity associated with COVID-19. The increases in the incidence of both autoantibodies and autoimmune diseases seen with COVID-19 suggest one of the conceptual frameworks for creating hypotheses regarding the nature of the Long COVID syndrome. Presentation: Saturday, June 17, 2023

THU278 Hidden In The Immune System: Exogenous Insulin Antibody Syndrome In A Patient With Latent Autoimmune Diabetes In Adults

Abstract 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

SAT173 Insulin Autoimmune Syndrome: A Rare Diagnosis With Unique Features

Abstract Disclosure: S. Naqvi: None. S. Syed: None. A.R. Kasireddy: None. S. Alshami: None. D. Edem: None. J.A. Henske: None. Introduction: Insulin Autoimmune Syndrome [IAS], or Hirata’s disease, is a rare cause of hypoglycemia. It is characterized by positive insulin autoantibodies in an insulin naïve patient and should be considered in the differential for post-prandial hypoglycemia. Case: A 48-year-old male presented with postprandial tremors, sweating, palpitations and episodes of incoherent speech and loss of consciousness at least 6 months prior to his presentation. He had no history of diabetes, however, was found to have severe symptomatic documented hypoglycemic episodes, with resolution of hypoglycemic symptoms upon treatment; fulfilling the Whipple’s triad. Outpatient workup for causes of his hypoglycemia ruled out insulinoma, use of diabetes medications or insulin, adrenal insufficiency, severe illness, infections, thyroid, liver or kidney dysfunction. He never had gastrointestinal or bariatric surgery. Given his symptoms and severity of hypoglycemic episodes, he was admitted for observation and 72 hour fast. Lab work during hypoglycemic episode revealed inappropriately elevated insulin and low to normal c-peptide levels, undetectable proinsulin, elevated beta-hydroxybutyrate, normal IGF-1, IGF-2, and a negative sulfonylurea screen. Importantly, his insulin: c-peptide ratio was more than 1 and his insulin antibodies were elevated, consistent with IAS. He denied any history of autoimmune disorders or use of any medications with sulfhydryl group. CGM sensor clearly showed the relationship between high glycemic index foods, glucose spikes, and drops in his blood glucose several hours later. Dietary counselling was provided, without much improvement. Trials of Acarbose and Octreotide were not tolerated due to side effects like rash. Prednisone 20 mg bid was started; Diazoxide was titrated to 200 mg tid with much improvement. He has been followed by our clinic, and tapered to prednisone 10 mg bid and Nifedipine 30 mg daily with resolution of his symptoms. Conclusions: Severe hypoglycemia in non-diabetic patients requires investigation utilizing a broad differential diagnosis and biochemical evaluation. The findings of post-prandial hypoglycemia and inappropriately high insulin, with low to normal c-peptide and proinsulin levels with an insulin: C-peptide [ICP] ratio >1 in a non-diabetic patient is consistent with IAS. An ICP ratio >1 is a clue that the half-life of insulin has been increased by circulating antibodies. Mechanistically, post-prandial hyperglycemia cause insulin secretion, however, circulating insulin antibodies neutralize its effect. Ongoing hyperglycemia leads to further high levels of insulin, followed by intermittent spontaneous decoupling of insulin-antibody complex and subsequent post-prandial hypoglycemia. IAS may spontaneously resolve over time but may require indefinite length of treatment and dietary modification until this occurs. Presentation: Saturday, June 17, 2023

SAT139 Non-insulinoma Pancreatogenous Hypoglycemia Syndrome In A Patient With 1p36 Deletion Syndrome

Abstract Disclosure: E.D. Auckley: None. M.A. Arosemena: None. L. Philipson: None. Background: 1p36 deletion syndrome comprises a phenotypic presentation that includes central nervous system, cardiac, and craniofacial anomalies. There has been no report of associated hypoglycemia with this syndrome. Nesidioblastosis, also known as non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), is understood as a rare condition defined by diffuse pancreatic hypertrophy with subsequent hyperinsulinemic hypoglycemia. Diagnosis requires serologic workup consistent with endogenous hyperinsulinemic hypoglycemia, intraarterial calcium stimulation positive for inappropriately elevated insulin secretion, and imaging studies without identified masses. Clinical Case: A 21-year-old female with 1p36 deletion syndrome (seizure disorder, cerebral palsy, vision loss and heart failure) was admitted to the hospital due to persistent falls. On admission vital signs were within normal limits, and physical exam revealed a thin non-verbal patient without significant other findings. During hospitalization and prolonged fasting periods of approximately 14-18 hours related to poor appetite she developed several episodes of hypoglycemia with serum glucose as low as 57 mg/dl. As patient was non-verbal at baseline, symptoms of hypoglycemia such as sweating, lightheadedness or shakiness were not confirmed. Even when she started to eat, hypoglycemic events continued to occur. Dextrose containing fluids (Dextrose 5% and later 10%) were added to try to maintain blood sugars within the normal range. Nevertheless, she continued to develop hypoglycemia. Endocrinology service was consulted and recommended to obtain a critical sample. A critical sample revealed serum glucose of 59 mg/dl, insulin level of 20.6 mcU/mL, proinsulin of 33 pmol/L, and beta-hydroxybutyrate of <0.10 mmol/L. Insulin antibodies was negative. Adrenal insufficiency was unlikely due to a normal 9 am cortisol level of 13.7 ug/dl. Due to the presence of hyperinsulinemic hypoglycemia further workup was conducted. A CT of the abdomen with a pancreatic protocol and 68Ga-DOTATATE PET/CT scan was negative for a pancreatic mass. Endoscopic ultrasound did not reveal a clear pancreatic mass either. This was followed by a calcium stimulation test which showed a two-fold increase in insulin levels in all 3 catheterized pancreatic territories. In the absence of a discrete mass, non-surgical management was recommended. For hypoglycemia management patient was started on octreotide injections with resolution of hypoglycemia. Prior to discharge she was switched to lanreotide and was discharged to continue monthly lanreotide injections. Conclusion: To our knowledge, this is the first case reported of NIPHS in a patient with a mutation in 1p36 deletion. Hyperinsulinism in the setting of diabetes has been reported in this syndrome1 but to our knowledge no cases of hypoglycemia with NIPHS have been reported. Presentation: Saturday, June 17, 2023

FRI359 Postprandial Hypoglycemia With Elevated Pro-insulin As A Rare Presentation Of Insulinoma

Abstract Disclosure: S. Kalik: None. S. Dehghani: None. J. Zaidan: None. Background: Insulinoma, a neuroendocrine neoplasm, typically presents with fasting hypoglycemia with abnormally elevated insulin levels but can infrequently present with post-prandial hypoglycemia with elevated pro-insulin levels. Clinical Case: A 49-year-old non-diabetic male, presented with a 3-year history of episodes of blurry vision, sweating, and palpitations associated with low finger stick glucose (45-70mg/dL). Episodes primarily occurred 2-3 hours post-meals particularly after eating a high carbohydrate meal. Symptoms improved after taking glucose tabs consistent with Whipple’s triad. He denied fasting hypoglycemia symptoms. Patient had symptoms at the office 2 hours after eating breakfast and Lab work done at that time showed glucose <35 of mg/dL (70-99 mg/dL), inappropriately high-normal c-peptide level of 3.57 ng/mL (0.81-3.85 ng/mL), elevated pro-insulin level of 12.8 pmol/L (<8.0 pmol/L), and a high insulin level of 29.8 uIU/mL (3-25.0 uIU/mL). Insulin antibodies and Sulfonylurea screen were negative. Review of old imaging revealed unremarkable pancreas on Ct scan done three years ago and a month prior to presentation. Given persistent symptoms and lab results Patient underwent an endoscopic ultrasonography with advanced gastroenterology which showed a 14.2 x 11mm hypoechoic, well circumscribed, regularly shaped and homogenous mass at the pancreatic head that was sampled using fine needle biopsy. Pathology confirmed pancreatic neuroendocrine neoplasm, low grade, consistent with insulinoma. Patient went for MRI of abdomen and pelvis which confirmed a 1.4 x 1.2cm slightly T2 hyperintense, hyper-enhancing lesion in the uncinate process suspicious for islet cell tumor. In addition, a 0.6cm liver lesion was identified although not clearly characterized but small metastatic lesion could not be excluded. PET/CT scan did not reveal any metastatic lesions except the focal uptake at the pancreatic uncinate process. Patient was evaluated by surgery and underwent a successful Whipple procedure for resection of the insulinoma. Discussion: 20% of all insulinomas are misdiagnosed with a seizure disorder or psychiatric disorder before an insulinoma is recognized. This case highlights the fact that insulinoma can be present as post prandial hypoglycemia and the superior imaging modality of EUS and MRI for localizing and identifying smaller functional insulinomas. Conclusion: Insulinoma can present as postprandial hypoglycemia with elevated pro-insulin levels. If high clinical and biochemical suspicion for insulinoma, patient should be evaluated with EUS or MRI even in the setting of a negative CT due to higher diagnostic specificity for insulinoma. Presentation: Friday, June 16, 2023

THU358 A Case Of Latent Autoimmune Diabetes In Adults (LADA) Managed By Lifestyle And Dietary Intervention Alone

Abstract Disclosure: M. Ahmad: None. U. Tarabichi: None. R. Patel: None. B. Arshad: None. A.P. Calimag: None. Introduction: LADA typically presents like Type 2 Diabetes at the time of diagnosis but it slowly progresses to insulin dependence for management. LADA is an autoimmune disease and it is distinguished from Type 2 diabetes by the presence of autoantibody. We present you an interesting case in which patient was diagnosed with LADA and was started on treatment with insulin regimen but over the time patient managed to stay off of insulin and managing his condition exclusively with a high protein ketogenic diet. Case Description: A 57 year old male with past medical history of Hyperlipidemia, gastroparesis, Hypertension and Diabetes. Patient initially diagnosed with diabetes in 2016 with A1C of 11% and was started on Metformin. In 2017, patient was admitted with diabetic ketoacidosis (DKA), had low c peptide on admission. At discharge, patient was started on basal bolus regimen. Patient had a follow up with Endocrinology and autoimmune labs. These were positive for GAD antibody, islet cell antibody and low c-peptide. With subsequent follow ups, lantus dose was decreased and Humalog with meals was discontinued. On further questioning patient reported that he started ketogenic diet along with intermittent fasting in March 2020. With his change of diet, he lost around 100 pounds over 1 year period and his insulin requirements continued to decrease throughout his journey. With time, patient desired to be off of insulin but Endocrinology didn’t recommend given his increased risk of DKA. Patient eventually stopped taking all of his insulin and it was recommended that he continues to use continuous glucose monitoring along with keto testing strips at home to monitor for DKA. Patient has sustained his diet change until this date and he continues to be on ketogenic diet with intermittent fasting 20 hours a day with 4-hour window of eating. He remains off insulin for 2 years, A1C continues to trend down, and with no evidence of DKA. Most recent labs; A1C is 5.5, positive for insulinoma associated antibody 2, negative for Zinc transporter antibody and insulin antibody. Conclusion: There is very little evidence available in the literature that supports treatment of LADA with dietary intervention alone. In our case, there are several fasting cpeptide levels that are less than 1.0, which typically would indicate initiation of insulin therapy. Our patient has managed to control hyperglycemia with dietary changes alone and has not been in diabetic ketoacidosis for greater than 2 years. It is rare for someone to maintain such a restrictive diet which includes 100g of protein, 100g fat and 5g of carbohydrates per day. This case highlights the ability of someone to maintain euglycemia with LADA without need for insulin therapy for greater than 2 years. Most diet studies are not followed that Longterm. Presentation: Thursday, June 15, 2023

THU354 Enfortumab Vedotin Induced Refractory Hyperglycemia

Abstract 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