Onset Of Insulin-dependent Diabetes Mellitus Research Articles

Pembrolizumab-induced type 1 diabetes.

Immunotherapy has a crucial role in the current treatment of multiple malignancies. Albeit described as rare, new onset autoimmune diabetes is a potentially life-threatening complication of programmed cell death-1 (PD-1) inhibitors, such as pembrolizumab, and its predisposing factors and pathological mechanism are yet to be clarified. We present a case of a 72-year-old man with a high-grade bladder carcinoma undergoing pembrolizumab treatment. He had no personal or family history of diabetes mellitus but was diagnosed with primary hypothyroidism four months after starting pembrolizumab. Two years after starting pembrolizumab, he presented in the emergency department due to abdominal pain, anorexia, polydipsia, polyuria and vomiting over the preceding five days and he met criteria for severe diabetic ketoacidosis (DKA). Three days prior to his admission, he had received prednisolone therapy for suspected hypersensitivity related to a contrast-enhanced imaging that he performed. Prompt treatment for DKA was started, with transition to insulin basal-bolus therapy after DKA resolution, with progressive glycaemic stabilization. Further investigation revealed low C-peptide levels (0.07 ng/dL, with a fasting blood glucose of 288 mg/dL), HbA1c 9.2% and positive anti-IA2 antibodies, which allowed the diagnosis of new-onset autoimmune diabetes. Pembrolizumab was transiently suspended, and the patient resumed treatment after glycaemic profile optimization under multiple daily insulin administrations two months later. This case highlights the importance of clinical suspicion and glycaemic monitoring as an integral part of treatment protocols in patients on pembrolizumab and other immune checkpoint inhibitors. Additional research and investigation into the underlying mechanisms of this condition are necessary to identify potential screening tests for individuals at higher risk of developing DM and to guide the implementation of management and preventive strategies for ketoacidosis complication.

Diagnostic Dilemmas and Current Treatment Approaches in Latent Onset Autoimmune Diabetes in Adults: A Concise Review.

Latent Onset Autoimmune Diabetes in Adults (LADA) is an autoimmune disorder between T1DM and T2DM and is often misdiagnosed as T2DM due to its late onset. The disease is characterized by β-cell failure and slow progression to insulin dependence. Early diagnosis is significant in limiting disease progression. C-peptide levels and autoantibodies against β-cells are the most critical diagnostic biomarkers in LADA. The review aims to understand the biomarkers used to diagnose LADA, and the treatment approaches followed. We have summarized LADA's pathophysiology and the autoantibodies involved in the condition, diagnostic approaches, and challenges. There are clear shortcomings concerning the feasibility of autoantibody testing. Finally, we explored the treatment strategies involved in the management of LADA. In Conclusion, the usual management includes treatment with metformin and the addition of low doses of insulin. The scope of newer oral hypoglycaemic agents such as GLP-1RA and DPP-4 inhibitors are brought into use. Since the disease is not entirely understood in the research level and clinical practice, we hope to encourage further research in this field to find the prevalence. Large randomized controlled trials are required to compare the efficacy of different treatment options available.

Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment

Simple SummaryWith the growing use of immune checkpoint inhibitors (ICIs), clinicians are increasingly encountering a unique set of adverse events called immune-related adverse events (irAEs) associated with ICIs. In this retrospective study, we tried to analyse the clinical course of endocrine irAEs and determine the factors associated with persistent endocrine dysfunction. We also performed survival analysis of patients with endocrine irAEs compared to those without any irAEs. The clinical course of endocrine irAEs was found to be highly variable. The presentation of some endocrine irAEs could be nonspecific, and sometimes life-threatening if not detected early, e.g., hypocortisolism and diabetic ketoacidosis. Therefore, frequent clinical assessment and laboratory monitoring are recommended. Measuring thyroid antibodies at the start of thyroid dysfunction could be helpful as it was found to be associated with persistent thyroid dysfunction in our study. The presence of endocrine irAEs was found to have survival benefits in our patient population.The exact clinical course and factors associated with persistent endocrine immune-related adverse events (irAEs) are not well-established. Elucidation of these information will aid irAEs screening and follow-up planning for patients on immunotherapy. We analysed the clinical course of endocrine irAEs including thyroid and pituitary dysfunction and insulin-dependent diabetes mellitus (IDDM), identified factors associated with persistent thyroid dysfunction, and determined the association between endocrine irAEs and survival parameters. This retrospective observational study enrolled patients with metastatic cancer who underwent anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 treatment and developed endocrine irAE at the National University Cancer Institute, Singapore, between June 2015 and December 2020. Sixty-six patients with endocrine irAE were evaluated, with a median follow-up time of 15.7 months. The median time to onset of thyroid dysfunction, pituitary dysfunction, and IDDM was 1.8 months (range: 0.3–15.8 months), 6.8 months (range: 1.5–27.3 months), and 7.8 months (range: 1.4–9.1 months), respectively. Positive thyroperoxidase antibodies (TPOAb) and/ or thyroglobulin antibodies (TgAb) status at the time of thyroid dysfunction was associated with persistent thyroid dysfunction (OR 11.6, 95% CI 1.3–570.8, p = 0.02; OR 8.8, 95% CI 1.3–106.9, p = 0.01, respectively). All patients with pituitary irAE had central hypocortisolism. All patients with IDDM had grade 4 irAE. Patients with endocrine irAE had longer median survival times. Endocrine irAEs were associated with non-progressive disease. The screening and follow-up approach for endocrine irAEs should be tailored according to each endocrinopathy’s clinical course. Early screening is imperative given its wide median time to onset.

New onset autoimmune diabetes mellitus and hypothyroidism secondary to pembrolizumab in a patient with metastatic lung cancer.

SummaryImmunotherapy has become an important pillar for the management of advanced cancer. Immune-related adverse events including endocrinopathies have been well described with programmed cell death 1 inhibitors such as pembrolizumab. While thyroid dysfunction is the most common endocrinopathy associated with pembrolizumab, new-onset autoimmune diabetes mellitus (DM) is extremely rare. The authors report a case of pembrolizumab-induced primary hypothyroidism and type 1 diabetes mellitus presenting with diabetic ketoacidosis (DKA). A 59-year-old female patient was treated with pembrolizumab for a stage 4 lung adenocarcinoma. She presented to the emergency department with hyperglycaemia-related signs and symptoms, such as polyuria, polydipsia, weight loss, vomiting, asthenia and dehydration, 3 weeks after her first dose of pembrolizumab. Laboratory evaluation revealed hyperglycaemia, hyperketonaemia and high anion gap metabolic acidaemia consistent with DKA. After prompt and adequate treatment of DKA, she transitioned to s.c. basal-bolus insulin. The diagnose of autoimmune DM was established based on the undetectable C-peptide levels and seropositivity for antiglutamic acid decarboxylase antibodies. Additional hormonal parameters revealed overt hypothyroidism and levothyroxine therapy was initiated. This case highlights the importance of blood glucose and thyroid function monitoring as an integral part of cancer treatment protocols for pembrolizumab and other immune checkpoint inhibitors.Learning pointsProgrammed cell death 1 (PD1) inhibitors such as pembrolizumab can cause endocrine immune-related adverse events (irAE), including thyroid dysfunction and type 1 diabetes mellitus (T1DM).Thyroid dysfunction is the most frequent endocrine irAE secondary to PD1 inhibitors.Autoimmune diabetes and possible resultant diabetic ketoacidosis are rare, but life-threatening adverse events associated with pembrolizumab.Pembrolizumab-induced T1DM often present with relatively low HbAlc levels, reflecting the fulminant onset of β-cell destruction.Patients treated with pembrolizumab and other immune checkpoints inhibitors should be monitored regularly for hyperglycaemia and thyroid dysfunction.

Wolfram syndrome: a case report with severe polyuria and secondary urological abnormalities

Wolfram syndrome is the condition characterized by juvenile onset diabetes mellitus and optic atrophy, which is also known as DIDMOAD. Classical Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in WFS1, a gene involved in endoplasmic reticulum and mitochondrial function. Patients present with type 1 diabetes mellitus followed by optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts as early as in the third decade, and various neurological abnormalities in the early fourth decade. We describe a case report of 14-year-old male child diagnosed as wolfram syndrome with type 1 diabetes mellitus, diabetes insipidus, deafness, optic atrophy and severe urological abnormalities. Patients who present with early onset insulin-dependent diabetes mellitus and optic atrophy together should be evaluated with respect to Wolfram Syndrome. If a patient, who is a known case of diabetes mellitus, presents with persistent polyuria or neurogenic bladder despite good glycemic control, suspicion of wolfram syndrome and further evaluation regarding the same must be made. Recognizing and timely management of this condition will help to improve the quality of life in the patient.

173-LB: Two Cases of Autoimmune Type 1 Diabetes Mellitus (DM) with Prolonged Honeymoon Phase Leading to Partial and Complete Remission following Pregnancy

Background and Purpose: Describe clinical course and outcomes of two cases of autoimmune DM who experienced remission and have remained insulin-free or on significantly reduced doses following pregnancy. Case Description: Case 1: 41 year old female G1P0 at 27w1d presented with diabetic ketoacidosis and was found to have new onset autoimmune diabetes with positive anti-GAD antibodies. She was treated with insulin therapy through the remainder of her pregnancy, and at post-partum follow-up found to be having hypoglycemic episodes. Insulin therapy was titrated down and eventually stopped. She has remained insulin-free with A1C <6% for two and a half years. Case 2: 28 year old female G2P2002 with history of DM 1 since age 8 at 33w6d presented with preeclampsia requiring early induction. Her hospital course was complicated by severe hypoglycemia. She was discharged on 14% of her pre-pregnancy insulin dose and was still hypoglycemic while on only 3 units of glargine. Outcome: Two cases of autoimmune DM with prolonged remission following pregnancy requiring little to no insulin therapy. Discussion: During pregnancy, multiple biological adaptations lead to increased insulin resistance and clearance, and following deliver many of these alterations revert and allow return to pre-pregnancy insulin dosing. These two cases demonstrate prolonged honeymoon phase. In addition to the cases, a literature review of the physiology of honeymoon phase including development of immunologic tolerance and possible mechanisms of resolution of autoimmune DM including suppression of autoimmunity and development of endogenous insulin production is included. Disclosure M.M. Kristan: None. Y. Kim: None. S.E. Thomas: None. K.M. Munir: None.

MON-LB121 New Onset Insulin Dependent Diabetes Mellitus Secondary to Treatment With Immune Checkpoint Inhibitor

Background: Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced malignancy like melanoma and lung cancer. Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs). IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Among them is endocrine toxicity, most commonly targeting the thyroid, pituitary, or adrenal glands. New-onset diabetes mellitus has been reported in only around 1% of patients in a recent study.Although rare, fulminant and even fatal toxicities may occur with immune checkpoint inhibitors, and therefore, prompt recognition and management is important. Here we are going to present a patient with new onset Insulin dependent Diabetes mellitus secondary to immunotherapy.It usually presents with diabetic ketoacidosis (DKA) and follows a rapid course. Awareness and prompt management are therefore key. History and investigations:62 year old lady diagnosed with Right Uveal melanoma more than 2 years ago and was treated with Enucleation followed by Rt prosthetic eye. Subsequently patient developed metastatic melanoma with subcutaneous lesion in right paravertebral region, right humoral head and right gluteal muscle. It was unclear whether patient had metastatic uveal or cutaneous melanoma. Other PMH includes were Hypertension and Anxiety.Patient was started on Ipilimumab (CTLA-4 inhibitor) and Nivolumab (PD1 inhibitor) 6 months ago, and Ipilimumab was stopped 8 weeks ago due to side effects but continued with Nivolumab. Other current medications were Amlodipine 10 mg once daily and AmitriptylinePatient was complaining of extreme fatigue last one week and was diagnosed with Hypothyroidism with TSH >100 mIU/L (Normal 0.27-4.2) and FT4 5.4 pmol/L (Normal 12.0-22.0), subsequently patient was started on Levothyroxine 50 mcg once daily.Patient presented to emergency department with polyuria and polydipsia last 5 days and also blurred vision for last 3 weeks. Patient did not notice any recent weight loss and had widespread pain, worse on skin lesions and hip joints but did not had any other specific complaints.Patient was current smoker with more than 40 pack year history and was taking 25 units of Alcohol per week for many years. Patient did not had any significant family history including any history diabetes in the family.On examination, patient was clinically dry with capillary refill time was 5 seconds.Investigations showed-Venous blood gas-Blood Glucose - Hi (mmol/L out of range), later 22.7 mmol/LPh- 7.291, PCO2 6.14 kPa, HCO3 19.3 mmol/L, Lactate 2.2 mmol/LBlood ketones- Hi (mmol/L out of range), later >7 mmol/LOther investigations showed-Na 131 mmol/L (Normal 135-145), K 5.4 mmol/L (Normal 3.5-5.1), Urea 7.1 mmol/L (Normal 1.7-8.3)Creatinine 139 umol/L (Normal 49-92)Bilirubin 12 umol/L (Normal 0-20), ALT 56 IU/L (Normal 10-35), ALP 157 IU/L (Normal 35-104)Amylase 59 IU/L (Normal 28-100), Albumin 48 g/L (Normal 34-50), Adjusted Calcium 2.56 mmol/L (Normal 2.2-2.6)9 am Cortisol 826 nmol/L (Normal 133-537), ACTH 28 ng/l (Normal 7.2-63.3)FSH 78.7 IU/L (Normal 25.8-134.8), LH 37.6 IU/L (Normal 7.7-58.5)IGF1 9.6 nmol/L (Normal 3.5-32.0), Prolactin 476 mIU/L (Normal 102-496)HbA1C 10.6% / 93 mmol/mmol (Normal 20-42)Serum Anti-GAD titre- 5 IU/L (Normal 0-10)Patient was started on treatment for Diabetic Ketoacidosis (DKA) with intravenous fluid and also fixed rate Insulin infusion according to protocol. Patient responded well to treatment and biochemical profile improved with initial treatment, subsequently patient was started on regular basal bolus Insulin regime with the help from the diabetes team. Discussion:Here we have presented a case with new onset Insulin dependent Diabetes Mellitus induced by immune checkpoint inhibitor. This kind of Diabetes progress rapidly to severe insulin deficiency compared to spontaneous Type 1 Diabetes, frequently patient present with DKA and do not go into remission. As this condition can develop rapidly, it is suggested that glucose level is to be monitored regularly and also to check HbA1C prior to initiating the immunotherapy. Their management requires complex Insulin regime to get good glycaemic control and add significant comorbidity along with the underlying cancer. The exact pathophysiologic mechanism and predictive biomarkers have not yet been established. The end result is permanent Insulin dependence. In future better characterization and further study is required to improve diagnosis and management, also to follow the natural history of this condition.Reference:1) Kotwal A, Haddox C, Block M, et alImmune checkpoint inhibitors: an emerging cause of insulin-dependent diabetesBMJ Open Diabetes Research and Care 2019;7:e000591. doi: 10.1136/bmjdrc-2018-0005912) Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.de Filette JMK1, Pen JJ2, Decoster L3, Vissers T4, Bravenboer B1, Van der Auwera BJ5, Gorus FK5, Roep BO6,7, Aspeslagh S3, Neyns B3, Velkeniers B1, Kharagjitsingh AV1,

Null mutations of NEUROG3 are associated with delayed-onset diabetes mellitus.

Biallelic mutations of the gene encoding the transcription factor NEUROG3 are associated with a rare disorder that presents in neonates as generalized malabsorption - due to a complete absence of enteroendocrine cells - followed, in early childhood or beyond, by insulin-dependent diabetes mellitus (IDDM). The commonly delayed onset of IDDM suggests a differential requirement for NEUROG3 in endocrine cell generation in the human pancreas versus the intestine. However, previously identified human mutations were hypomorphic and, hence, may have had residual function in pancreas. We report 2 patients with biallelic functionally null variants of the NEUROG3 gene who nonetheless did not present with IDDM during infancy but instead developed permanent IDDM during middle childhood ages. The variants showed no evidence of function in traditional promoter-based assays of NEUROG3 function and also failed to exhibit function in a variety of potentially novel in vitro and in vivo molecular assays designed to discern residual NEUROG3 function. These findings imply that, unlike in mice, pancreatic endocrine cell generation in humans is not entirely dependent on NEUROG3 expression and, hence, suggest the presence of unidentified redundant in vivo pathways in human pancreas capable of yielding β cell mass sufficient to maintain euglycemia until early childhood.

SUN-LB036 Diabetic Ketoacidosis: A Rare Side Effect of Nivolumab Induced Insulin Dependent Diabetes Mellitus

Introduction: Nivolumab, is a monoclonal antibody directed against programmed cell death-1 receptor (anti PD-1), and is used in adjuvant treatment of melanoma. With the widespread use of immunotherapies, the incidence of autoimmune diseases referred to as immune related adverse events (irAE) is also increasing. Our case highlights a rare side effect of autoimmune insulin dependent diabetes mellitus (IDDM) related to immunotherapy, in a patient with no detectable diabetes related antibodies. We also review management of this rare side effect. Clinical Case: A 52-year-old woman with a diagnosis of stage IIIC malignant melanoma and no previous history of diabetes mellitus presented with abdominal pain and nausea. She had received 10 doses of Nivolumab as adjuvant therapy for melanoma. She denied any family history of diabetes or autoimmune disorders. Physical exam including vital signs was normal. Lab work up was significant for blood glucose of 280 mg/dl and glycated hemoglobin (HbA1c) was 7.4%, and additional blood work up showed low serum C-peptide 0.5 ng/ml (normal range 1.1-4.4 ng/mL) and negative results were obtained for all islet cell autoantibodies. Arterial blood gas (ABG) revealed high anion gap metabolic acidemia with pH 7.11, pCO2 25 mm Hg, bicarbonate (HCO3) 12 mmol/L, high anion gap 22 and serum lactate 0.8 mmol/L, consistent with diabetic ketoacidosis (DKA). Prior to initiation of Nivolumab, her HbA1c was 5.7%. The patient was diagnosed with DKA due to autoimmune-mediated IDDM secondary to Nivolumab therapy. She was treated with an insulin drip and intravenous fluids after which the anion gap and her symptoms resolved. She was discharged home with a subcutaneous basal bolus insulin regimen. Conclusion: Immunotherapies such as Nivolumab can cause new onset IDDM by inducing autoimmune response. Most likely mechanism of developing IDDM in patients treated with Nivolumab is inappropriate activation of T cells leading to destruction of pancreatic islet cells. Our patient had low serum C-peptide level which correlates with low insulin secretion suggestive of islet cell destruction. Median time of onset of IDDM is 4.4 months after starting Nivolumab. Most common endocrinopathies associated with Nivolumab are hypophysitis, thyroiditis or primary adrenal insufficiency. New onset IDDM is very uncommon irAE, and so far it has been reported in less than 1% of patients. In contrast to other irAE such as colitis there is limited data regarding role of high dose steroids in autoimmune diabetes and it can even exacerbate hyperglycemia and DKA.

Bihemispheric Cerebral Oximetry Monitoring's Functionality in Suspected Cerebral Edema Diabetic Ketoacidosis With Therapeutic 3% Hyperosmolar Therapy in a Pediatric Emergency Department.

Suspected cerebral edema diabetic ketoacidosis (SCEDKA) is more common than perceived with symptoms including altered mentation, headache with vomiting, depressed Glasgow coma scale (GCS), abnormal motor or verbal responses, combativeness, and neurological depression. Suspected cerebral edema diabetic ketoacidosis has been associated with initial diabetic ketoacidosis (DKA) presentation and at start of DKA therapy.Cerebral oximetry (bihemispheric regional cerebral oxygen saturation [rcSO2] and cerebral blood volume index [CBVI]) can detect increased intracranial pressure (ICP)-induced altered bihemispheric cerebral physiology (rcSO2) (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700). In pediatrics, rcSO2 of less than 60% or rcSO2 of greater than 85% reflects increased ICP and cerebral edema (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700). Cerebral oximetry can detect increased ICP-induced altered bihemispheric cerebral physiology (rcSO2, CBVI) and cerebral physiological changes (rcSO2, CBVI changes) during therapeutic mechanical cerebral spinal fluid removal to decrease increased ICP (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700).In the pediatric intensive care units, SCEDKA patients with nonbihemispheric cerebral oximetry showed an initial rcSO2 of greater than 90%. Bihemispheric rcSO2 with CBVI in SCEDKA patients has the potential to detect the abnormal cerebral physiology and disruptive autoregulation while detecting 3% hypertonic saline solution (HTS) effects on the SCEDKA altered cerebral physiology (rcSO2). The purposes of this study were to analyze and compare 3% HTS effect on bihemispheric rcSO2 readings, neurological and biochemical parameters in SCEDKA with 3% HTS infusion to non-SCEDKA patients in pediatric emergency department (PED). An observational retrospective comparative analysis study of bihemispheric rcSO2 readings, neurological and biochemical parameters in 2 groups of PED DKA patients were performed: PED DKA patients with SCEDKA +3% HTS infusions versus non-SCEDKA without 3% HTS infusions. From 2008 to 2013, of the 1899 PED DKA patients, 60 SCEDKA patients received 3% HTS (5 mL/kg via peripheral intravenous) infusion (median age of 5 years [range, 3.7-7 years]), with 42 new DKA insulin dependent diabetes mellitus onset. Suspected cerebral edema diabetic ketoacidosis patients had GCS of 11 (range, 11-12), with consistent SCEDKA signs and symptoms (severe headaches with vomiting, confusion, blurred vision, altered speech, lethargy, and combativeness). Suspected cerebral edema diabetic ketoacidosis patients' initial (0-5 minutes) left rcSO2 readings were 91.4% (range, 88.4%-94.1%) and right was 90.3% (range, 88.6%-94.1%) compared with non-SCEDKA patients' left rcSO2 readings of 73.2% (range, 69.7%-77.8%) and right of 73.2% (range, 67.6%-77%) (P < 0.0001). The rcSO2 monitoring time before 3% HTS infusion was 54.9 minutes (range, 48.3-66.8 minutes) with 3% HTS time effect change: pre-3% HTS (54.9 minutes [range, 48.3-66.8 minutes]). Before 3% HTS infusion, the left rcSO2 readings were 90.0% (range, 89%-95%) and right was 91% (range, 86%-95%). The 30 to 45 minutes post-3% HTS showed that left was 64% (range, 62%-69%) and right was 65.4% (range, 63%-70%) (P < 0.0001). rcSO2 Δ change for post-3% HTS (0-20 minutes) to pre-3% HTS was as follows: left, -26.58 (-29.5 to -23.7) (P < 0.0001); right, -25.2 (-27.7 to -22.6) (P < 0.0001). Post-3% HTS GCS (14,15) and biochemistry compared with pre-3% HTS infusions all improved (P < 0.001). In PED SCEDKA patients, the pre-3% HTS bihemispheric rcSO2 readings were greater than 90% and had lower GCS than non-SCEDKA patients. The post-3% HTS infusion rcSO2 readings showed within minutes a substantial reduction compared with non-SCEDKA patients, with no complications. Changes in rcSO2 readings after 3% HTS correlated with improved SCEDKA indicators (improved mental status, headache, and GCS) without any complications. We showed that cerebral oximetry in PED SCEDKA patients has shown an initial bihemispheric of greater than 90% readings signifying abnormal bihemispheric cerebral physiology. We also showed the cerebral oximetry's functionality in detecting 3% HTS therapeutic effects on SCEDKA's abnormal cerebral physiology and the beneficial therapeutic effects of 3% HTS infusion in SCEDKA patients. Using cerebral oximetry in pediatric DKA patients' initial cerebral assessment could have a significant impact in detecting SCEDKA patients. Further SCEDKA research using cerebral oximetry should be considered.

Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes.

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

Diabetic Ketoacidosis With Acute Necrotizing Pancreatitis as First Presentation in Latent Autoimmune Diabetes in Adult

This case describes delayed diagnosis of acute necrotizing pancreatitis in the setting of diabetic ketoacidosis (DKA) as the first presentation of late onset autoimmune diabetes of adulthood (LADA). Possible presentation of DKA with LADA and acute pancreatitis (AP) are explored in this paper, with an emphasis on early diagnosis of pancreatitis for appropriate management. This case is a critical reminder that although DKA can non-specifically elevate pancreatic enzymes, LADA and AP can present concurrently, and pancreatic pathology should still be considered in the differential. J Med Cases. 2017;8(11):356-358 doi: https://doi.org/10.14740/jmc2881w

Enhanced Vascular Collateralization Through the Pancreaticoduodenal Arcade Secondary to Median Arcuate Ligament Compression of the Celiac Axis in the Setting of Pancreatic Body Adenocarcinoma: The Ideal Scenario for the Modified Appleby Procedure

Abstract Background: A modified Appleby procedure for pancreatic body tumors relies upon collateral vessels maintaining blood flow to the proper hepatic artery (PHA) through the pancreaticoduodenal arcade (PDA) off of the superior mesenteric artery (SMA). Compression of the celiac axis by the median arcuate ligament (MAL) promotes the expansion of collateral vessels without preoperative intervention. Case Presentation: A 51-year-old male with asymptomatic compression of the celiac artery presented with new onset insulin-dependent diabetes mellitus. He underwent imaging that demonstrated a locally advanced pancreatic body tumor that encased the superior mesenteric vein and portal vein confluence and involved the common hepatic artery. He had an adequate response to neoadjuvant FOLFIRINOX chemotherapy and underwent an uncomplicated modified Appleby procedure with a margin negative resection. Hepatic blood flow was adequate through the PHA as a result of collateralization of blood flow through the PDA off th...

Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer

BackgroundAdvances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM.Case PresentationA 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy.ConclusionNew onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM.

Diabetic ketoacidosis as first presentation of latent autoimmune diabetes in adult.

A 54-year-old white female with hypothyroidism presented with abdominal pain, nausea, vomiting, and diarrhea. She was found to have diabetic ketoacidosis (DKA) and admitted to our hospital for treatment. Laboratory workup revealed positive antiglutamic acid decarboxylase antibodies and subsequently she was diagnosed with latent onset autoimmune diabetes in adult (LADA). She was successfully treated with insulin with clinical and laboratory improvement. Diagnosis of LADA has been based on three criteria as given by The Immunology of Diabetes Society: (1) adult age of onset (>30 years of age); (2) presence of at least one circulating autoantibody (GADA/ICA/IAA/IA-2); and (3) initial insulin independence for the first six months. The importance of this case is the unlikely presentation of LADA. We believe that more research is needed to determine the exact proportion of LADA patients who first present with DKA, since similar cases have only been seen in case reports. Adult patients who are obese and have high blood sugar may deserve screening for LADA, especially in the presence of other autoimmune diseases. Those patients once diagnosed with LADA need extensive diabetic education including potentially serious events such as diabetic ketoacidosis.

Early presentation of gait impairment in Wolfram Syndrome

BackgroundClassically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease.MethodsGait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups.ResultsAcross all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs= 0.564, p = 0.045) and dual task forward walking (rs= 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = −0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = −0.64, p = 0.03).ConclusionsQuantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and/or brainstem abnormalities. Effective patient-centered treatment paradigms could benefit from a more complete understanding of the progression of motor and other neurological symptom presentation in individuals with WFS.

Reliability and validity of the Wolfram Unified Rating Scale (WURS)

BackgroundWolfram syndrome (WFS) is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS) to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS).MethodsA rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease). WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age). Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated.ResultsThe WURS had high inter-rater reliability (ICCs>.93), moderate to high internal consistency reliability (Cronbach’s α = 0.78-0.91) and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (rs>.67, p<.03), between the WURS Behavioral Scale and reports of mood and behavior (rs>.76, p<.04) and between WURS Total scores and quality of life (rs=-.86, p=.001). The WURS demonstrated acceptable content validity (Scale-Content Validity Index=0.83).ConclusionsThese preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS.

Balance impairment in individuals with Wolfram syndrome

AimWolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test. MethodBalance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals. ResultsA significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age. InterpretationImpairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms.

Acetylcholinesterase is associated with apoptosis in &amp;beta; cells and contributes to insulin-dependent diabetes mellitus pathogenesis

Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic β-cell apoptosis. Here, we investigated the role of AChE in the development of IDDM and analyzed protective effects of AChE inhibitors. Multiple low-dose streptozotocin (MLD-STZ) administration resulted in IDDM in a mouse model. Western blot analysis, cytochemical staining, and immunofluorescence staining were used to detect AChE expression in MIN6 cells, primary β cells, and apoptotic pancreatic β cells of MLD-STZ-treated mice. AChE inhibitors were administered intraperitoneally to the MLD-STZ mice for 30 days. Blood glucose, plasma insulin, and creatine levels were measured, and glucose tolerance tests were performed. The effects of AChE inhibitors on MIN6 cells were also evaluated. AChE expression was induced in the apoptotic MIN6 cells and primary β cells in vitro and pancreatic islets in vivo when treated with STZ. Induction and progressive accumulation of AChE in the pancreatic islets were associated with apoptotic β cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels and plasma creatine clearance in the MLD-STZ mice. AChE inhibitors partially protected MIN6 cells from the damage caused by STZ treatment. Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM.

Clinico-pathological findings in a patient with progressive cerebellar ataxia, autoimmune polyendocrine syndrome, hepatocellular carcinoma and anti-GAD autoantibodies

Objective To report clinical and pathological findings of a patient with late onset insulin-dependent diabetes mellitus (IDDM), progressive cerebellar ataxia (PCA) and hepatocellular carcinoma (HCC). Patient A 64-year-old woman, with a long lasting IDDM, progressively developed a severe cerebellar syndrome and died 2 years after the onset of the symptoms for a systemic infection. Autoantibodies to antigastric parietal cell and anti-pancreatic islet cell resulted positive. Autopsy showed a selective loss of Purkinje cells in the cerebellum, with an increase of Bergmann glia and variable microglial proliferation; furthermore, it disclosed an HCC. GAD-Abs were detected both in serum and CSF. Conclusions Clinical and experimental reports suggest a possible role of neoplastic cells in producing GAD-Abs. We postulate, in our case, that HCC could have been responsible for an overproduction of GAD-Abs, leading to the onset of PCA. Thus, GAD-Abs could be considered as a paraneoplastic marker in a subgroup of patients with PCA.