Zinc Transporter 8 Antibody Research Articles

8197 A Captivating Case Report of Teprotumumab Induced Hyperglycemic Hyperosmolar State

Abstract Disclosure: K.M. Tuna: None. J.P. Perdomo Rodriguez: None. Introduction: Teprotumumab, a monoclonal antibody targeting the IGF-1 receptor, is increasingly utilized for moderate to severe thyroid eye disease. Initial trials noted mild hyperglycemia in patients with diabetes, while recent trials revealed a significant elevation in Hemoglobin A1c (HbA1c) among those with diabetes or pre-diabetes post-infusion. Here, we discuss a case of a patient with diet-controlled diabetes who developed hyperglycemic hyperosmolar state (HHS) two months after Teprotumumab infusion. Case Presentation: A 43-year-old male, with class III obesity, obstructive sleep apnea, dyslipidemia, coronary artery disease, and diet-controlled diabetes (HbA1c 6.5%) presented with worsening proptosis, decreased color vision, severe visual field depression. Laboratory evaluation revealed elevated TSH (6.3 mIU/ml), normal free T4 (0.67 ng/dl, ref: 0.60-1.2 ng/dl), and undetectable Thyroid Stimulating Immunoglobulin (<0.1 IU/L). Blood cell count, renal and liver function tests were normal. Due to high clinical suspicion of thyroid eye disease, he was treated with timolol, dorzolamide, brimonidine, and methylprednisolone 1g daily for 3 days. Glycemic control was achieved with 30 units of daily insulin while on pulse steroids. On outpatient ophthalmology follow-up, Teprotumumab was initiated and he received 2 doses. Eight weeks later, the patient was hospitalized with altered mental status caused by HHS (glucose 617 mg/dl, serum osmolality 316 osm). HbA1c was found to be significantly increased to 12% and the patient required 150 units total daily insulin and metformin upon discharge. Of note, the patient did not have significant weight changes during this time. GAD, IA2, and Zinc Transporter-8 antibodies were obtained prior to discharge and results are pending. Discussion: The IGF-1 receptor, a partial homologue of the insulin receptor, plays a pivotal role in glucose homeostasis. Inhibiting this receptor can lead to hyperglycemia. Initial randomized controlled trials (RCTs) reported a 10% incidence of mild hyperglycemia. A recent RCT from a cohort of 42 patients demonstrated a 50% incidence of hyperglycemia, in which two-thirds of the patients remained in a dysglycemic state with one patient with pre-existing prediabetes developing diabetic ketoacidosis (DKA). Our patient mirrored this scenario with no identifiable confounding factors. Conclusion: Teprotumumab-induced hyperglycemia, though rare, can lead to life-threatening complications. Baseline glycemic assessment, identification of high-risk patients, and comprehensive discussions on risks and benefits are crucial before initiating therapy. Close monitoring, especially in those with prediabetes, is recommended. Patient education plays a pivotal role in early symptom recognition, averting delayed diagnoses, and subsequent hospitalization. Presentation: 6/3/2024

6674 Non-Progressive Diabetes Leading to Neurologic Diagnosis

Abstract Disclosure: F.L. Thelmo: None. M. Murugesh: None. B. Simon: None. Introduction: The autoantibody GAD (anti-glutamic acid decarboxylase) is highly associated with Type 1 diabetes (T1DM) and Latent Autoimmune Diabetes in Adulthood (LADA). If GAD is detected before the onset of overt diabetes, typically 80% of patients with abnormal glucose tolerance progress to insulin deficiency and the need for insulin treatment after 5 years.[1] Stiff Person Syndrome (SPS) is also associated with GAD antibodies, but in SPS, the GAD antibodies are believed to be different epitopes that target GABA production in neuromuscular pathways. We present a case of presumed LADA that did not progress for 30 years, with progressive neurologic symptoms leading to a diagnosis of SPS in later adulthood.Case: A 52-year-old female presented for evaluation of T1DM and worsening neuropathies. She had a long history of prediabetes, with mildly elevated glucose values noted on labs since her early twenties. There was no family history of T1DM or autoimmune conditions. Six years ago, she sought endocrine evaluation. HgbA1c values were 6.1 to 6.6%. Intermittent use of continuous glucose monitoring (CGM) revealed post-prandial hyperglycemia up to 180mg/dL, occasionally (but rarely) exceeding 200mg/dL. She recalls being told that she had positive antibodies (unclear which ones tested) and given a diagnosis of T1DM. She declined insulin and maintained glycemic control with carbohydrate restriction and exercise; there were no episodes of diabetic ketoacidosis. She then developed neurologic symptoms: fullness, tightness and bloating in the abdomen (diagnosed with gastroparesis on scanning) and after a COVID 19 booster in 2021, muscle spasms in the legs and back with worsening abdominal tightness. At the time of her current presentation, A1C was 6.4%, glycated albumin was 14.4% (prediabetes range 13.6 - 15.5%) and CGM time in range was 99%. A non-fasting C-peptide was 3.6 ng/mL (1.1- 4.4ng/mL) with glucose of 119 mg/dL. Repeat antibody testing revealed undetectable IA-2 and ZnT8 antibodies, but GAD was grossly elevated at 1,015.3 U/mL. Given the unusually high GAD titer, SPS was suspected, and this diagnosis was confirmed on referral to neurology. The patient was advised to liberalize diet and will be monitored with HgbA1c and serial C-peptide levels to assess progression in the future. Discussion: While high GAD antibody levels are associated with progression to insulin dependence in adults with LADA, in SPS the GAD titers tend to be even higher2. The presence of only one auto-antibody for T1DM (and not multiple), long-standing non-progressive hyperglycemia, and normal C-peptide pointed away from autoimmune diabetes being the etiology for mild glucose intolerance in this patient. If neurologic symptoms are present, high GAD should prompt the evaluation for other syndromes associated with GAD antibody epitopes such as SPS. Presentation: 6/2/2024

8813 Nivolumab-Induced Diabetes: A Hidden Danger

Abstract Disclosure: J. Case: None. R.V. Chemitiganti: None. D. Suravajjala: None. Immunomodulating therapy as utilized in chemotherapy for malignancy may lead to potential adverse events including immune-related adverse events(IRAEs). One such pathway by which this may occur is through alteration of the programmed cell death as affected by drugs such as nivolumab which inhibits appropriate matching of PD-1 and PD-L1 and may lead to a robust immune response with collateral damage to nontumor tissue. Multiple downstream effects may be seen leading to other pathologies including development of autoimmune diabetes as noted in the patient described herein. A 61 year old female presented to establish care for suspected type one diabetes mellitus. She had a history of renal cell cancer diagnosed about one year prior for which she was treated with nivolumab. She was found to have hyperglycemia on routine labwork with further labwork revealing inappropriately low c-peptide as measured at less than 0.10 ng/mL (0.8-3.85ng/mL) with a coincident glucose of 566mg/dL (74-106mg/dL). Further workup revealed no measurable presence of GAD65, antipancreatic islet cell or ZNT8 antibodies. Diagnosis was made of insulinopenic diabetes or otherwise autoimmune diabetes induced as an IRAE subsequent nivolumab use. She was subsequently started on a basal bolus regimen with insulin achieving blood glucose control. IRAEs are an unfortunate, albeit rare consequence of immune checkpoint inhibitors including nivolumab. Depending on the toxicity grade and prognosis the offending agent may be discontinued and steroids initiated to mitigate adverse effects. However sometimes the occurrence of an IRAE may go undetected until too late as noted in the above patient. Her presentation was atypical considering many present with DKA and as well IRAEs are less likely in monotherapy. Education of IRAEs as well as appropriate screening would aid in recognition of potential IRAEs at which time appropriate measures may be taken to alleviate collateral damage. Further elucidation of the mechanism by which this autoimmune response is activated against nontumor tissue may also lead to better understanding of autoimmune diabetes caused by other etiologies. Presentation: 6/2/2024

6370 New-Onset Autoimmune Diabetes Following COVID-19 Infection and its Implications for Identical Twin Siblings

Abstract Disclosure: G. Wintermyer: None. S. Gillis-Funderburk: None. COVID-19 patients face many post-recovery complications,including autoimmune disorders. Late autoimmune diabetes ofadults (LADA) is one such disorder. Studies suggest that SARS-CoV may trigger proinflammatory cytokines that damage beta cellsand impair insulin secretion. Here, we explore a case of new-onsetLADA in a patient after recovery from COVID-19. Further, asidentical twins of LADA patients have a higher risk of developingit, we discuss how we approached the patient’s identical twin.A 29-year-old female with history of obesity (BMI 32.3) presentedto our endocrinology clinic. She complained of difficulty losingweight and fatigue and reported having COVID-19 three monthsearlier. She also mentioned having polyuria. She underwent labtests, including CBC, CMP, TSH, A1C, and a lipid panel. The testresults were within normal limits, except for her A1C of 11.3%.She was started on metformin and weekly Semaglutide injections.Given her recent COVID-19 history, she was assessed for LADA.Anti-GAD-65 and ZNT8 antibodies were 120 U/mL and 150U/mL, respectively. Serum C-peptide and IA-antibodies werewithin normal ranges. The patient informed us of her twin sister’sconcurrent COVID-19 infection. Due to the risk of LADA in hertwin sister, we recommended an evaluation by our clinic. Duringthe sister’s first visit, her BMI was 37.5, and she asked for weightloss medication. Comprehensive testing, including LADAantibodies, was conducted, with results within normal ranges andA1C level of 4.9%. The sister was also started on Semaglutide forweight management.The patient had quarterly follow-up appointments at the clinic.After a year, her A1C and continuous glucose monitoring machine(CGM) readings showed improvement. Her BMI decreased to 24.She never required insulin therapy, as her diabetes was well-managed and her average monthly glucose level on GCM readings were 125, 123 and 119 mg/dL in three different periods. Antibodieswere retested. This time IA-2 antibody was also elevated.Similarly, her twin sister continued to follow-up at our clinic. Thesister achieved significant weight loss without complications. HerLADA antibodies remained negative, and her A1C remainednormal. Clinicians should be vigilant for post-COVID LADA. In this case,Semaglutide aided weight loss, which benefits diabetesmanagement. Ongoing studies explore the potential of GLP-1medications in early-stage LADA. Historically, LADA patientswere started on insulin. However, CGM has enabled close glucosemonitoring, offering management of LADA with non-insulinmedications. It is also important to remember that autoimmunedisease risk is elevated in identical twins. In this case, although thetwin sister did not develop antibodies, the risk remains. Regularevaluation of high-risk patients is crucial for early detection ofantibodies, facilitating timely treatment to prevent adverseoutcomes. Presentation: 6/3/2024

The association of islet autoantibodies with the neural retinal thickness and microcirculation in type 1 diabetes mellitus with no clinical evidence of diabetic retinopathy.

To examine the association between islet autoantibodies (IAbs) and the retinal neurovascular changes in type 1 diabetes mellitus (T1DM) with no diabetic retinopathy (NDR). This cross-sectional study measured the neural retinal structure and microvascular density of 118 NDR eyes using spectral-domain optical coherence tomography angiography. Retinal structure parameters included retinal thickness (RT), inner retinal thickness (iRT), retina never fibral layer thickness (RNFL thickness), ganglion cell complex thickness (GCC thickness), and loss volume of GCC. Microvascular parameters included vessel density of superficial capillary plexus (sVD), vessel density of deep capillary plexus, and vessel density of choroid capillary plexus. Comparison and correlation analyses of these OCTA parameters were made with various IAbs, including glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase-related islet antigen 2 antibody (IA2A), and zinc transporter 8 antibody (ZnT8A). A general linear model was used to understand the association of IAbs with the retina parameters. The IAb positive (IAbs +) group, which included 85 patients, had thinner RT (235.20 ± 18.10mm vs. 244.40 ± 19.90mm at fovea, P = 0.021) and thinner iRT (120.10 ± 9.00mm vs. 124.70 ± 6.90mm at parafovea, P = 0.015), compared with the IAb negative (IAbs-) group comprising 33 patients. Furthermore, a more severe reduction of RT was demonstrated in the presence of multiple IAbs. Among the three IAbs, GADA was the most significant independent risk factor of all-round RT decrease (β = -0.20 vs. -0.27 at fovea and parafovea, respectively, P < 0.05), while titers of IA2A negatively affect sVD in the parafovea (β = -0.316, P = 0.003). IAbs are associated with neural retinal thinning and microcirculation reduction in T1DM patients before the clinical onset of diabetic retinopathy.

Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice.

Type 1 diabetes (T1D) is an autoimmune disease where pathogenic lymphocytes target autoantigens expressed in the pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 can home in on the pancreatic islets and prevent autoantibodies from recognizing β-cells. This study demonstrates that mAb43 binds to exocytotic sites on the β-cell surface, masking the antigenic exposure of ZnT8 and insulin following glucosestimulated insulin secretion. In vivo administration of mAb43 to nonobese diabetic (NOD) mice selectively increased the proportion of regulatory T-cells (Tregs) in the islet, resulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation and exhibited no adverse effects during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of β-cells suppresses the immunological cascade from B-cell antigen presentation to T-cell mediated β-cell destruction, providing a novel islet-targeted and antigen-specific immunotherapy to prevent and reverse clinical T1D.

Genetic testing for misclassified monogenic diabetes in Māori and Pacific peoples in Aōtearoa New Zealand with early-onset type 2 diabetes.

Monogenic diabetes accounts for 1-2% of diabetes cases yet is often misdiagnosed as type 2 diabetes. The aim of this study was to examine in Māori and Pacific adults clinically diagnosed with type 2 diabetes within 40 years of age, (a) the prevalence of monogenic diabetes in this population (b) the prevalence of beta-cell autoantibodies and (c) the pre-test probability of monogenic diabetes. Targeted sequencing data of 38 known monogenic diabetes genes was analyzed in 199 Māori and Pacific peoples with BMI of 37.9 ± 8.6 kg/m2 who had been diagnosed with type 2 diabetes between 3 and 40 years of age. A triple-screen combined autoantibody assay was used to test for GAD, IA-2, and ZnT8. MODY probability calculator score was generated in those with sufficient clinical information (55/199). No genetic variants curated as likely pathogenic or pathogenic were found. One individual (1/199) tested positive for GAD/IA-2/ZnT8 antibodies. The pre-test probability of monogenic diabetes was calculated in 55 individuals with 17/55 (31%) scoring above the 20% threshold considered for diagnostic testing referral. Our findings suggest that monogenic diabetes is rare in Māori and Pacific people with clinical age, and the MODY probability calculator likely overestimates the likelihood of a monogenic cause for diabetes in this population.

Clinical Utility and Outcome Prediction of Early ZnT8-IgG Testing and Titer in Type 1 Diabetes

Type 1 diabetes autoantibodies are directed against multiple antigens including: glutamic acid decarboxylase, protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc transporter 8 protein (ZnT8). The aim of our study was to determine if the presence or titer of ZnT8 antibodies (Ab) was predictive for clinical presentation at diagnosis or for the subsequent disease course. Between January, 2003 and May, 2019, 105 patients aged ≤21 years with a clinical diagnosis of type 1 diabetes mellitus had at least 1 autoantibody measured. A retrospective chart review was completed. At diagnosis, we evaluated the body mass index z-score, hemoglobin (HbA1c), and the presence of diabetic ketoacidosis (DKA). Complications analyzed post-diagnosis included episodes of DKA, the diagnosis of autoimmune disease, and the presence of vascular complications. We evaluated cumulative lifetime excess glucose as HbA1c area under the curve (AUC) >6%. Seventy-one patients were ZnT8-Ab(+) (68%), with 19 having low titer ZnT8-Ab and 52 with high titer ZnT8-Ab. Follow-up ranged from 10 days to 15.7 years (median 2.08 years). There were no differences in the characteristics at disease onset or in the subsequent follow-up between those with and those without ZnT8-Ab or those with high or low titers of ZnT8 Ab, except for a small but statistically significant difference in cumulative excess glucose (HbA1c AUC >6%) between those with low and high titers (p=0.0095). Our study adds to the limited literature on the effect of the presence and titer of ZnT8-Ab in pediatric diabetes. The small effect of ZnT8-Ab titer on glucose excess as measured by HbA1c AUC warrants further study.

Autoantibodies against islet cellantigens: Current diagnostic possibilities

In the pathogenesis of type 1 diabetes (T1D) the causative process is the immunological destructionof pancreatic beta cells (-cells) by autoreactive cytotoxic lymphocytes and macrophages.These changes are reflected in the blood of patients as autoantibodies directed against-cell antigens. Antibodies against the following are measured: unidentified cytoplasmic -cells(ICA), glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA-2), endogenous insulin (IAA)and zinc transporter 8 (ZnT8). The complete destruction of pancreatic beta cells stops the productionof autoantibodies. It is therefore believed that the determination of antibodies associatedwith T1D is of major importance in the early stages of the disease. The IAA test must beperformed prior to initiating insulin therapy. As in the case of ICA, GADA and IA-2A, a positiveIAA result in a patient who is not taking insulin confirms the presence of T1D. The latest in T1Ddiagnostics is ZnT8, an ideal complement to the current tests. About 25-30% of patients who donot have GAD, IA2A or ICA antibodies have ZnT8 antibodies. Moreover, in some clinical cases ofT1D with negative specific antibodies, the isolated presence of ICA is observed, which indicatesother, hitherto unknown antigens. Along with routine antibody measurements, optimising samplingand test development in terms of reliability and cost-effectiveness continues. This summarydescribes the present utility and future prospects for T1D prediction and diagnosis using themeasurement of autoantibodies.

PSAT232 Understanding the Duration of Zinc 8 Transporter Antibody Seropositivity

Abstract Background Since their recent discovery of zinc transporter 8 antibodies (ZnT8A) by Wenzlau et al. in 2007, the relevance and clinical utility of this marker has been in question. Some recent reports have shown a wide potential for both diagnostic as well as prognostic clinical applications in T1DM as they can be found years before clinical symptoms appear. Understanding the timing of the seropositivity of antibodies such as ZnT8A can help us understand how to utilize this marker for the diagnosis and prognosis of T1DM. Up to 20% of T1DM patients are reported to have ZnT8A positive with negative GAD-65 and IAA autoantibodies. The duration of seropositivity of ZnT8A is unclear. We describe 2 cases from our endocrine clinic with significant zinc 8 transporter antibody titers over 8 - 26 years after their initial diagnosis. Clinical Cases CASE 1: 34-year-old man diagnosed initially with T2DM 9 years prior and later re-classified as T1DM. He was treated initially with oral agents and switched over to Multiple Daily Injection (MDI) insulin about 3-4 years later. He has no family history of diabetes. Approximately 8 years after his initial diagnosis, his autoantibodies profile showed a positive zinc transporter 8 antibody of 28 U/mL (reference of &amp;lt; 15 U/mL), but negative GAD-65 antibodies (reference &amp;lt;5 IU/mL) and negative Islet cell antibodies. CASE 2: 47-year-old man diagnosed with T2DM in 1995 and was initially started on oral hypoglycemic medications. He was later evaluated at our endocrinology clinic and reclassified as type 1 DM after his serologic testing showed a low C peptide &amp;lt; 0.1 ng/mL, positive zinc transporter 8 antibody of 32 U/mL (reference of &amp;lt; 15 U/mL), and negative islet cell antibody screen negative, and negative GAD-65 antibodies (reference &amp;lt;5 IU/mL). He was transitioned to continuous glucose monitoring and an insulin pump, but was too difficult for the patient to manage. He was ultimately transitioned to a basal-bolus regimen of insulin with MDI. His latest serologic testing showed a HgA1C of 9.2%. Conclusions Zinc 8 transporter antibody can help differentiate type 1 from type 2 diabetes and initiate insulin therapy for better glycemic control as well as aid in prognosis and stratification strategies. The duration of seropositivity of ZnT8A has not been clearly established. Previous reports have shown that ZnT8A can be detected at an age around 3 years of age, but peaks around late adolescence and does not have a significant decline in seropositivity rates in older adults, as does IAA. This emphasizes the use of ZnT8A as a useful marker in adult and elderly patients. We describe 2 case reports which indicate that ZnT8 antibodies can remain positive for at least 8 - 26 years in the absence of other autoantibodies. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSUN269 Suboptimal Sulfonylurea Therapeutic Response in a Patient with MODY-3 with a Rare HNF1A Pathogenic Genetic Variant

Abstract Maturity-onset diabetes of the young (MODY) is a rare non-autoimmune type of diabetes, seen in 1-6% of patients with diabetes, caused by a single gene variant defect that ultimately impairs pancreatic b-cell insulin secretion. MODY-3, caused by mutations in HNF1A gene, accounts for most MODY cases. Misdiagnosis of MODY as type 1 diabetes (T1DM) or young-onset type 2 diabetes (T2DM) due to their overlapping features is common, leading to suboptimal pharmacologic management. When pharmacologic therapy is indicated, patients with MODY-3 typically present an excellent response to sulfonylurea monotherapy. We describe a case of a young adult woman diagnosed with MODY-3, previously treated as T1DM, with an atypical suboptimal response to sulfonylurea therapy possibly attributed to a rare HNF1A pathogenic genetic variant. A 24-year-old female with a BMI of 21, diagnosed with diabetes at age 13 managed as T1DM on insulin, underwent genetic analysis at age 23 after her 14-year-old sister was found to have MODY-3. DNA sequencing revealed heterozygous HNF1A gene with pathogenic variant c.365A&amp;gt;G (p.Tyr122Cys). Sulfonylurea therapy was initiated with the goal to lower the insulin regimen. Additional workup revealed a new HbA1C 12%, new-onset microalbuminuria, positive glutamic acid decarboxylase (GAD) antibody (0.22 nmol/L), negative islet cell antibody, and zinc transporter-8 antibody (ZnT8), in addition to normal C-peptide level of 1.5ng/mL. Upon follow-up visit, sulfonylurea dose was doubled, and basal and pre-prandial insulin were lowered and discontinued, respectively. Although the HbA1C improved to 9.8%, the patient admitted to self-resuming previous basal and pre-prandial insulin regimen after consistently having hyperglycemia 300 mg/dL when following last pharmacologic adjustments. MODY usually has autosomal-dominant inheritance although de novo mutations can occur. The molecular diagnosis aims at tailoring the choice of the most appropriate treatment to improve blood glucose control, reduce the risk of hypoglycemia, and prevent long-term micro and macrovascular complications. Typically, patients with MODY-3 are highly sensitive to monotherapy with sulfonylureas especially when shorter diabetes duration, lower BMI, and lower HbA1C are present at the time of genetic diagnosis. Although our patient's HbA1C level improved once sulfonylurea therapy was initiated, HbA1C remains above the goal level and discontinuation of insulin regimen has not been able to be achieved despite increasing sulfonylurea dose. Similar cases of MODY-3 with atypical sulfonylurea therapeutic response have been reported and attributed to the presence of novel HNF1A genetic variants. Moreover, studies have predicted that about 50% of MODY-3 patients require insulin therapy as the disease progresses. Nonetheless, more research is needed to elucidate possible additional contributing factors to a suboptimal sulfonylurea therapeutic response in MODY-3 cases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSUN267 New-Onset Type 1 Diabetes (T1D) In a Child Presenting With Diabetic Ketoacidosis (DKA) and Severe Hypertriglyceridemia Without Pancreatitis

Abstract Background Hypertriglyceridemia is a rare complication of DKA in children that can prolong hospital course. Case Report A 7-year-old boy with past medical history of autism spectrum disorder presented to an outside hospital with 1 day of abdominal pain and vomiting with "heavy breathing" in the setting of 5 months of weight loss, anorexia, and polyuria/polydipsia with secondary nocturnal enuresis. He had venous pH 6.87, bicarbonate 4.8 mmol/L, and glucose 385 mg/dL consistent with DKA in new onset T1D. He received 10 mL/kg normal saline bolus and regular insulin infusion was then initiated at 0.1 units/kg/hour. Abdominal ultrasound was notable for small bowel-small bowel intussusception. He was transferred to a tertiary care children's hospital. On arrival, labs were notable for pH 7.03, bicarbonate 3 mmol/L, potassium 6.19 mmol/L, glucose 274 mg/dL, beta hydroxybutyric acid 8.90 mmol/L (ref ≤0.29), amylase 20 unit/L (ref 40-220), lipase 10 unit/L (ref 7-60), and HbA1c 9.9%. His blood was noted to be lipemic which prompted lipid evaluation. Direct LDL was 8 mg/dL, HDL was 16.5 mg/dL, and triglycerides (run via dilution) were markedly elevated at 17,675 mg/dL (ref 0-100). Given risk for pancreatitis, triglyceride and lipase levels were trended twice daily. Insulin infusion of 0.1 units/kg/hour did not lead to improvement of acidosis. Infusion rate was increased to 0.15 units/kg/hour and acidosis resolved within 24 hours. He remained NPO and insulin infusion was continued to manage hypertriglyceridemia. Plasmapheresis was considered but given no end-organ dysfunction and down-trending triglycerides, this was not pursued. The insulin infusion rate was decreased to 0.05 units/kg/hour to avoid hypoglycemia. Lipase rose above the upper limit of normal only once to 68 unit/L, on hospital day (HD) 5. The infusion was discontinued on HD 6 with triglycerides 1,290 mg/dL. His appetite improved by HD 5 and, given absence of pancreatitis, he began enteral intake of a low-fat diet. Prior to diagnosis, he had a restrictive diet due to his autism and ate primarily high-fat foods (reportedly 50 breakfast sausages/day), so his diet was liberalized on HD 7 with no increase in triglycerides. One month later, triglycerides normalized to 75 mg/dL. Total cholesterol was elevated at 250, direct LDL 157 mg/dL, and HDL 83 mg/dL. He continues to eat a restrictive, high fat diet which is thought to contribute to his hyperlipidemia. There is no clear family history of hyperlipidemia, but genetic testing for lipid disorders may be obtained. GAD and ZnT8 antibodies were elevated, confirming T1D. Conclusion Hypertriglyceridemia can complicate DKA and require prolonged insulin infusion. Even severe hypertriglyceridemia does not always lead to end-organ dysfunction and can be managed with insulin infusion rather than plasmapheresis. Underlying pathophysiology of hypertriglyceridemia in this case remains incompletely understood. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

LBODP084 Bilateral Cataracts In A 15-year-old Girl With New-onset Type 1 Diabetes Mellitus

Abstract Background Cataracts secondary to Type 1 or Type 2 Diabetes is not uncommon in adults, however, it is a rare finding in pediatrics patients with Type 1 Diabetes. Clinical Case A 15-year-old girl presented with progressively worsened bilateral vision for 6 months, however, vision rapidly deteriorated over the previous month, prompting visit to optometrist. No history of weight loss, however, did report 1.5 years of polydipsia, polyuria, and polyphagia. Outside optometrist reported concerns for cataracts. She presented to our Ophthalmology department one week later, who found bilateral cataracts with haziness in all layers and swollen lenses. Labs were done due to findings, glucose was 668 mg/dL with HbA1C &amp;gt;20%. She presented next day to ER, reported no symptoms other than blurry vision but was found to be in mild DKA with a venous pH of 7.285, Ketones 5.41 mmol/L, Glucose 480 mg/dL, and C-peptide 0.32 pmol/mL. Patient was started on insulin infusion at 0.1u/kg/hour and transitioned quickly to subcutaneous insulin. Pancreatic antibodies were significant for positive GAD65 and ZnT8 antibodies. She had cataract surgery for her left eye 1 week after presentation, found to have intumescent white cataract with "hand motion" vision. Vision in left eye is now 20/20 with plans to operate on the right eye in the near future. Literature Review: The prevalence of early diabetic cataracts in the pediatric population can range from 0.7%- 3.4% (1); and more common in female patients (2). Pathophysiology includes defect in the polyol pathway, combined with oxidative stress, leading to increased fluid retention (3). Treatment involves cataract surgery and improved glycemic control. Current ISPAD guidelines recommend initial evaluation for cataracts, and subsequent surveillance concomitant with diabetic retinopathy monitoring biennially with those with good glycemic control (4). Conclusion Diabetic cataracts are extremely rare in the pediatric population. However, diabetes should be considered as an etiology for juvenile cataracts. Given the rapid formation and severity of onset of bilateral cataracts for this patient, early and frequent ophthalmologic surveillance should be recommended for Type 1 diabetes pediatric population. Reference: 1. Šimunović, M, et al (2018). Cataract as early ocular complication in children and adolescents with type 1 diabetes mellitus. International Journal of Endocrinology, 2018, 1–6. 2. Lu, W. -L, et al (2020). High risk of early cataracts in young type 1 diabetes group: A nationwide cohort study. International Journal of Endocrinology, 2020, 1–8. 3. Pollreisz, A, et al (2010). Diabetic cataract pathogenesis, epidemiology and treatment. Journal of Ophthalmology, 2010, 1–8. 4. Donaghue, KC, et al (2018). ISPAD Clinical Practice Consensus Guidelines 2018: Microvascular and macrovascular complications in children and adolescents. Pediatric Diabetes, 19, 262–274. Presentation: No date and time listed

ODP166 Autoantibody Positivity and Random C-peptide Profile in Young Ethnic South Indian Population with Diabetes Mellitus

Abstract The islet cell autoantibody and beta-cell reserve profiles of young-onset diabetes patients in India are not only heterogeneous but also differ from those in the rest of the world. We sought to assess 3 standard islet cell autoantibodies and random C-peptide in the young ethnic South Indian population with diabetes mellitus attending the Endocrinology OPD of our tertiary care. A total of 190 young diabetes patients aged between 12-30 years were screened for inclusion in the study. Known cases of gestational diabetes and those on diabetogenic drugs were excluded. Additionally, those with clinical features suggestive of pancreatic diabetes or maturity-onset diabetes of young (MODY), or any diabetes-associated syndromic disorders were also excluded. Finally, 138 eligible young diabetes patients were included in the study. The islet cell autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 (IA-2), zinc transporter (ZnT8)was measured by sandwich ELISA technique using a human GAD ELISA kit (Euroimmun, Germany), human IA2 ELISA kit (Euroimmun, Germany), human ZnT8 ELISA kit (RSR diagnostics, USA) respectively. Random C-peptide was measured with chemiluminescence immunoassay analyser Advia Centaur XP. Diagnosis of T1DM was based on the requirement of immediate insulin replacement therapy for hyperglycemia with or without acute-onset ketosis with random C-peptide (&amp;lt;0.6 ng/ml) with /without any of islet cell antibodies. Diagnosis of T2DM is based on the history of control of hyperglycemia with oral hypoglycemic agents with documentation of adequate beta-cell reserve (random C-peptide ≥ 0.6 ng/ml) while maintaining euglycemia. Based on the patient characteristics, treatment profile, islet cell antibody status, and beta-cell reserve as assessed by random C-peptide levels, 82 were classified as T1DM, and 48 were classified as T2DM. The rest 8 patients were categorized as unclassified diabetes. GAD antibody was seen in 54(66%) of 82 T1DM patients. Islet cell autoantibody negativity was documented in 21(26%) of T1DM patients. IA-2 and ZnT8 antibodies contributed to an additional 7(8%) to islet cell antibody positivity in T1DM patients. IA-2 antibody positivity was low and random C-peptide was undetectable in many cases of T1DM in our study and is probably due to prolonged duration of diabetes in many T1DM patients. Autoantibody positivity was seen in 4(8%) T2DM patients. These patients need to be followed up for possible evolution of latent autoimmune diabetes in adults.

Inhibition of PAD4-mediated NET formation by cl-amidine prevents diabetes development in nonobese diabetic mice

Many evidences indicated that neutrophil extracellular traps (NETs) play pathogenic roles in type 1 diabetes (T1D). Peptidylarginine deiminases 4 (PAD4) has been proved to be indispensable for generation of NETs. In the current study, we investigated whether oral administration of cl-amidine, an effective inhibitor of PAD4, protects non-obese diabetic (NOD) mice from T1D development. Female NOD mice were orally administrated with cl-amidine (5 μg/g body weight) from the age of 8 weeks up to 16 weeks. It showed that cl-amidine inhibit NET formation in vitro and in vivo. The onset of T1D was delayed nearly 8 weeks and the incidence of disease was significantly decreased in cl-amidine treated mice compared with the control group. Moreover, cl-amidine decreased the serum levels of anti-citrullinated peptide antibody (ACPA) and anti-neutrophil cytoplasmic antibodies (ANCA) in NOD mice. Also, it decreased generation of T1D autoantibodies such as glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase-related islet antigen-2 antibody (IA2A) and zinc transporter 8 antibody (ZnT8A), which were strongly correlated with the reduced serum PAD4 and MPO-DNA levels. Furthermore, cl-amidine administration inhibited pancreatic inflammation and increased frequency of regulatory T cells in pancreatic lymph nodes (PLNs). In addition, cl-amidine improved gut barrier dysfunction and decreased the serum level of lipopolysaccharide (LPS), which was positively correlated with the NETs markers (PAD4 and MPO-DNA) and T1D autoantibody IA2A. In conclusion, our data showed that orally delivery of cl-amidine effectively prevent T1D development and suggested inhibition of PAD4-dependent NET formation as a potential way of clinical treatment in T1D.

The Unfavorable Impact of DR9/DR9 Genotype on the Frequency and Quality of Partial Remission in Type 1 Diabetes.

Partial remission (PR) is a specific stage in type 1 diabetes (T1D). Although human leukocyte antigen (HLA) class II loci are the strongest genetic determinants in T1D, the relationship between PR and HLA remains unclear. To investigate the association between PR status and HLA genotypes in patients with T1D. A total of 237 patients with T1D were included. PR was defined according to C-peptide ≥300 pmol/L. The frequency of PR and peak C-peptide levels during remission phase were compared according to HLA status. Clinical characteristics including age of onset and diabetes autoantibodies were collected. All analyses were duplicated when subjects were divided into childhood- and adult-onset T1D. The median follow-up time was 24 months, 65.8% (156/237) of patients with T1D went into PR. DR9/DR9 carriers had a lower PR rate (44.2% vs 70.6%, P = .001) and were less likely to enter PR (OR = 0.218, 95% CI 0.098-0.487, P < .001) than the non-DR9/DR9 carriers, observed in both childhood- and adult-onset T1D. Besides, the peak C-peptide level during PR phase was also lower in DR9/DR9 carriers, and more notable in adult-onset T1D. When compared with non-DR9/DR9 carriers, T1D with DR9/DR9 genotype presented an older age of onset and a lower positivity of zinc transporter 8 antibody (ZnT8A), and the lower trend of ZnT8A was only found in adult-onset T1D (P = .049). Patients with T1D carrying susceptible DR9/DR9 are less prone to undergo PR. Additionally, the recovery extent of β-cell function during the PR phase tends to be lower in adults carrying DR9/DR9, which might be associated with ZnT8A.

1143-P: ZnT8 Autoantibody Positivity Does Not Predict Pediatric Diabetes Presentation or Subsequent Clinical Course

Introduction: Type 1 diabetes specific autoantibodies are glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc transporter 8 protein (ZnT8). The aim of our study was to determine if the presence of ZnT8 antibodies(Ab) was predictive of clinical presentation at diagnosis or subsequent disease course. Methods: Between January 2003 and May 2019, 105 patients aged ≤ 21 years with a clinical diagnosis of T1DM had at least 1 diabetes autoantibody measured. For subjects who had less than 4 autoantibodies analyzed initially, residual serum sample was retrieved, and remaining autoantibodies were analyzed. Retrospective chart review was completed. At diagnosis, we evaluated BMI z-score, HbA1c, and the presence and severity of DKA. Complications recorded post diagnosis included episodes of DKA, diagnosis of autoimmune (AI) disease, and the presence of vascular complications. Results: Of the 105 patients, 71 were ZnT8(+) (68%). When comparing ZnT8Ab(+) to (-) patients at diagnosis, there was no difference in age (p=0.94), BMI z-score (p=0.83) or presence of DKA (p=0.26). There was no difference in duration of follow up between ZnT8 Ab (+) and (-) groups (p=0.54). Over follow-up, (0.05-15.7 years), there was no difference in rates of DKA episodes (p=0.71). There were no macrovascular complications recorded and no difference in microvascular complications between the 2 groups (p=0.14). There were more AI conditions in the ZnT8Ab(+) group, 77% compared to 23% in ZnT8Ab(-), but this did not reach statistical significance (p=0.12). Conclusions: Our study, unlike others, suggests that the presence of ZnT8 Ab does not result in a difference in disease course at presentation. This study adds to the literature as it has follow up on patients. Over up to 15 years of follow-up, there is no difference in complications between those with and without ZnT8 Ab’s. This study should be validated with larger numbers and longer follow up. Disclosure A. R. Dahl: None. S. Jenkins: None. J. Zbacnik: None. J. Foster: None. S. Pittock: None.

Accelerated Progression of Prediabetes to Insulin-Dependent Diabetes After 9 Cycles of Nivolumab

Abstract Introduction: Diabetes mellitus have been reported in around 1% of patients receiving immune checkpoint inhibitors (ICI) resultingin immune checkpoint inhibitor induced diabetes mellitus (ICI-DM). 4 phenotypes of ICI-DM exist: acute autoimmuneinsulin-dependent diabetes, decompensation of prediabetes or type 2 diabetes, autoimmune pancreatitis, andautoimmune lipoatrophy. Clinical Case: A 52-year-old man was diagnosed with stage IIIb malignant melanoma. Two months following local excision, he wasstarted on nivolumab every 4 weeks planned for 1 year. His past medical history was significant for prediabetes,hypertension, obesity (BMI 33.27 kg/m²), primary hypogonadism, adult attention deficit disorder, obstructive sleepapnea, gastric ulcer, and gastroesophageal reflux disease. He denied tobacco use but reported semi-daily use ofmarijuana and alcohol. His baseline HbA1c was 6.0%. After the 8th cycle of nivolumab, he reported several bloodglucose readings in the 200 mg/dL range. He was thought to have progressed to type 2 diabetes and metformin wasstarted. Glipizide was added shortly thereafter due to persistent hyperglycemia. At the 9th cycle of nivolumab, hisHbA1c was 8.2%. In 1 week from this time, the patient developed abdominal pain, nausea, and persistent vomiting. Hewas found to be in DKA with blood glucose of 278 mg/dL, bicarbonate of 9.3 mmol/L, anion gap of 21, and arterial pHof 7.22. He was treated in the ICU per standard DKA care. His C-peptide was 0.5 ng/mL (reference 0.8–3.5) withconcomitant plasma glucose of 229 mg/dL. Autoantibody screening was negative including glutamic aciddecarboxylase antibody (anti-GAD), insulin antibody, insulin antigen-2 (IA-2) autoantibody, and zinc transporter 8antibody. The patient was discharged home on multiple daily injections of insulin but he struggled with diabetes carewhich proved to be of brittle nature requiring CGM use. Two months after completion of nivolumab treatment, thepatient reported epigastric abdominal pain with frequent nausea and occasional vomiting of few weeks duration. He wasdiagnosed with subacute pancreatitis based on symptoms and elevated lipase. There was no evidence of gallstones. Although immunotherapy-related pancreatitis was considered, we decided to try alcohol cessation first hoping to avoidthe need to use prednisone. Over several weeks, lipase normalized and his symptoms completely resolved. Conclusion: In this case, nivolumab resulted in progressive beta-cell failure and complete insulin dependence in a person with ahistory of prediabetes. Not all pancreatitis cases in the settings of immunotherapy use are immune-related adverseevents (irAE). Usual causes, e.g. alcohol, should still be considered. With cessation of alcohol, pancreatitis fullyresolved leading to avoidance of prednisone which would likely have worsened diabetes management in this patientwith brittle diabetes.

17q12 Deletion Syndrome. A Rare Association Between Diabetes and Renal/Urogenital Abnormalities

Introduction: Maturity onset diabetes of the young type 5 (MODY 5) is an autosomal dominant, non-autoimmune form of diabetes mellitus caused by HNF1b gene mutations/deletions. Because of a high prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in MODY 5 patients, understanding the extra-pancreatic manifestations of MODY 5 can target genetic testing to provide an earlier diagnosis. Case Description: A 26-year-old male was referred for consultation after his primary care physician found an HbA1c of 11.4% and prescribed metformin 500mg/day. He reported weight loss during the previous weeks and a history of Attention Deficit Hyperactivity Disorder (ADHD). He denied urinary tract infections or renal disease. Family history included diabetes (24-year-old brother (also with ADHD) and both parents). His BMI was 17.07 kg/m2 and labs showed a normal lipid profile, including HDL-C 74 mg/dL; urine albumin 0.8 mg/dL; “inappropriately normal” insulin and c-peptide; and negative GAD65, IA-2, and ZNT8 antibodies. Glimepiride 1mg/day at breakfast was added, with referral to a geneticist to rule out MODY. A follow-up HbA1c was 7.1%; Januvia 100 mg/day was added. Glimepiride was later switched to glipizide 7.5 mg at breakfast and 2.5 mg at supper due to overnight hypoglycemia. Genetic testing revealed a male pathogenic 1.39 Mb deletion of 17q12 containing 20 genes, including HNF1b, consistent with MODY 5. Renal ultrasound showed mild hydronephrosis, increased echogenicity of both kidneys, and bilateral non-obstructing nephrolithiasis. Subsequently, his mother (previously diagnosed with diabetes, fatty liver disease, dyslipidemia, and multiple scattered non-obstructing calculi and cysts in both kidneys) was found to have the same genetic defect. His brother’s diabetes is currently well controlled with glargine 0.3 u/kg and aspart 0.05–0.15 u/kg/meal. Unlike the proband, he has obesity (BMI 30 kg/m2), dyslipidemia, and CKD (GFR 57 ml/min); further workup is pending at this time. Discussion: Because patients with MODY 5 are at high risk for CKD3-4/ESRD, MODY 5 should be considered in young adults with diabetes who have negative islet autoantibodies and extra-pancreatic manifestations including elevated liver enzymes, renal cysts and nephrolithiasis; ADHD and learning difficulties; and pancreatic and hepatic morphological abnormalities. HNF1b-targeted genetic testing should be considered in patients with this clinical presentation.

Immunogenicity and Efficacy of Insulin Glargine Biosimilar Ezelin versus Originator Insulin Glargine in Patients with Type 2 Diabetes.

PurposeTo compare the immunogenicity and efficacy of insulin glargine biosimilar Ezelin (EZL) versus originator insulin glargine Lantus (LAN) as a reference basal insulin in patients with type 2 diabetes (T2D).Patients and MethodsThis was a randomized, multicenter, open-label, 24-week study in insulin-naïve patients with T2D, with HbA1c of >7.0%. We randomly assigned 133 eligible patients to receive either EZL or LAN. Baseline characteristics, including insulin autoantibody (IAA), zinc transporter 8 (ZnT8) antibody, HbA1C, fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2hPPG), AST, ALT, BUN, eGFR, and oral antidiabetic drugs, were obtained before starting insulin treatment. After starting treatment, insulin dose was titrated to achieve FPG target along with oral antidiabetic drugs. Patients were given home glucometer and assisted to record plasma glucose measurement and adverse event (AE). Every month, patients came to the diabetes clinic and performed a regular physical examination and intensifying treatment if needed. Out of the 133 randomized patients, only 122 completed the study and can be examined for their IAA and ZnT8 after 6 months of treatment. The study was registered in clinicaltrials.gov, NCT03352674.ResultsThere is a similar proportion of patients with changes of IAA from baseline: 1 out of 58 (1.7%) patients receiving EZL versus 1 out of 64 (1.6%) patients receiving LAN (p = 1.000). One patient in the EZL group (1.7%) versus none in the LAN group experienced a change of ZnT8 antibody from baseline. Similar glucose control in EZL versus LAN was determined by the change in HbA1c, FPG, and 2hPPG (−2.0%, −67.46 mg/dL, and −76.51 mg/dL in the EZL group versus −1.7%, −58.11 mg/dL, and −70.03 mg/dL in the LAN group). There were six events of documented hypoglycemia in the EZL group versus five events in the LAN group. No patients experienced diabetic ketoacidosis during the study.ConclusionOverall, insulin glargine biosimilar EZL and originator insulin glargine LAN have shown a similar immunogenicity profile, as well as efficacy in providing glucose control and safety findings in T2D populations.