ResearchPad - diabetes-complications-i https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-632 Involvement of NF-κB-p65 in BAG3 Regulation After Stress Stimuli]]> https://www.researchpad.co/article/elastic_article_8743 We previously identified the limb salvage QTL1 (LSQ-1) on mouse chromosome 7 as a locus that offered protection against ischemic injury following induction of hind limb ischemia (HLI) a model of experimental peripheral arterial disease (PAD) in mice. To better understand the role of the LSQ-1 locus in post ischemic adaptation we characterized several genes within this locus and identified a number of genes that were important in tissue adaptation to ischemia, including BCL2-associated athanogene 3 (BAG3). BAG3 is an anti-apoptotic protein that plays an important role in cell survival through the regulation of autophagy. BAG3 expression is induced in the gastrocnemius muscles of mice after hind limb ischemia but how ischemia regulates BAG3 expression is poorly understood. Additionally, the activation of NF-κB transcription factor is essential for cell survival after stress stimuli. We hypothesized that BAG3 upregulation following stress stimuli is regulated by NF-κB. We determined whether NF-κB is involved in BAG3-mediated survival of primary human skeletal muscle cells (HSMC) during ischemia and diabetic conditions. Within 6 hours of treatment, ischemia induced BAG3 mRNA (no ischemia vs ischemia: 1.0 ±0.09 vs 1.41±0.02; p<0.01) and protein expression (BAG3/total protein, no ischemia vs ischemia 1.0±0.01 vs 1.38±0.06; p<0.01). Knockdown of BAG3 expression by shRNA induced early cell damage in HMSC under ischemic conditions as measured by HMGB1 expression (HMGB1/total protein; control plasmid vs shRNA, 1.0±0.09 vs 1.71±0.04; p<0.01). Knockdown of p65 subunit of the NF-κB by shRNA significantly diminished BAG3 mRNA expression after ischemia (control plasmid vs shRNA: 2.11±0.18 vs 1.48±0.05; p<0.05). Moreover, treatment of HSMC with 750 uM palmitic acid (PA) and 100nM insulin for 3 days to mimic diabetic conditions significantly increased the expression of BAG3 mRNA (control vs PAL+Ins, 1.0±0.14 vs 2.27±0.08; p<0.01) and protein (BAG3/total protein, control vs PAL+Ins, 1.0±0.03 vs 1.39±0.11, p<0.01). Knocking down p65 attenuated these increase in BAG3 mRNA (PAL+Ins vs shRNA+PAL+Ins, 2.27±0.08 vs 1.56±0.02 p<0.01) and protein (BAG3/total protein; PAL+Ins vs shRNA+PAL+Ins, 1.39±0.11 vs 0.99±0.1; p<0.05) Thus, 1) BAG3 expression is important in cell survival under ischemic conditions, and 2) NF-kB plays a key role in upregulating the expression of BAG3 under diabetic and ischemic conditions.

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<![CDATA[SAT-LB110 Sulfonylurea-Induced Hypoglycemia: To Use Octreotide or Not]]> https://www.researchpad.co/article/elastic_article_8611 Background: Sulfonylurea poisoning can cause sustained hypoglycemia refractory to intravenous dextrose. Traditional treatment for sulfonylurea induced hypoglycemia includes intravenous dextrose and glucagon as well as diazoxide in refractory cases. Octreotide is recommended for sulfonylurea poisoning in adult and pediatric patients with laboratory evidence of hypoglycemia.

Clinical Case: An 89 year-old female with chronic kidney disease stage III, hypothyroidism, and diabetes mellitus type II, hypertension who presented with intractable nausea and diarrhea. Patient had been taking cefdinir for an UTI the prior week. On CT scan of the abdomen, colitis was demonstrated. Clostridium Difficile Assay was positive. She was incidentally found to have profound hypoglycemia with a blood glucose level of 30 mg/dL. Patient had hypoglycemia unawareness. Despite receiving 4 ampules of dextrose 50%, glucose level did not significantly improve. In the ED, patient was afebrile and hemodynamically stable. Her labs were significant for a hyponatremia of 125 mmol/L with an acute kidney injury [AKI] (Cr 1.94 mg/dL from 1.5 mg/dL). Patient was placed initially on a dextrose 5% normal saline infusion, but glucose levels continued to decline after brief response. Due to poor IV access, internal jugular central line was placed and patient was placed on D10NS infusion with good glycemic response. Patient had taken sulfonylurea despite not eating appropriately for 2 days. After 24 hours on D10 normal saline infusion, patient was able to maintain normal to slightly hyperglycemic levels with consistent carbohydrate diet. Her nausea and diarrhea had considerably improved after starting vancomycin 125 mg every 6 hours. Sulfonyurea was indefinitely discontinued.

Conclusion: Patients presenting with sulfonylurea induced hypoglycemia complicated by poor PO intake, AKI, and infection can be safely treated with supportive measures like proper hydration, and dextrose infusion medication is appropriately metabolized by body without the need for octreotide infusion.

References:Glatstein M, Scolnik D, Bentur Y. Octreotide forthe treatment of sulfonylurea poisoning.Clin Toxicol (Phila). 2012 Nov;50(9):795-804. doi:10.3109/15563650.2012.734626. Epub 2012 Oct 10.

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<![CDATA[SAT-LB111 Improving Classification of Diabetes Etiology in Electronic Resources Using Phenotype Algorithms and Polygenic Risk Scores]]> https://www.researchpad.co/article/elastic_article_8542 Electronic Health Records (EHR) contain rich data to identify and study diabetes. Many phenotype algorithms have been developed to identify research subjects with type 2 diabetes (T2D), but very few accurately identify type 1 diabetes (T1D) cases or more rare forms of monogenic and atypical metabolic presentations. Polygenetic risk scores (PRS) quantify risk of a disease using common genomic variants well for both T1D and T2D. In this study, we apply validated phenotyping algorithms to EHRs linked to a genomic biobank to understand the independent contribution of PRS to classification of diabetes etiology and generate additional novel markers to distinguish subtypes of diabetes in EHR data. Using a de-identified mirror of medical center’s electronic health record, we applied published algorithms for T1D and T2D to identify cases, and used natural language processing and chart review strategies to identify cases of maturity onset diabetes of the young (MODY) and other more rare presentations. This novel approach included additional data types such as medication sequencing, ratio and temporality of insulin and non-insulin agents, clinical genetic testing, and ratios of diagnostic codes. Chart review was performed to validate etiology. To calculate PRS, we used genome wide genotyping from our BioBank, the de-identified biobank linking EHR to genomic data using coefficients of 65 published T1D SNPS and 76,996 T2D SNPS using PLINK in Caucasian subjects. In the dataset, we identified 82,238 cases of T2D but only 130 cases of T1D using the most cited published algorithms. Adding novel structured elements and natural language processing identified an additional 138 cases of T1D and distinguished 354 cases as MODY. Among over 90,000 subjects with genotyping data available, we included 72,624 Caucasian subjects since PRS coefficients were generated in Caucasian cohorts. Among those subjects, 248, 6,488, and 21 subjects were identified as T1D, T2D, and MODY subjects respectively in our final PRS cohort. The T1D PRS did significantly discriminate well between cases and controls (Mann-Whitney p-value is 3.4 e-17). The PRS for T2D did not significantly discriminate between cases and controls using published algorithms. The atypical case count was too low to calculate PRS discrimination. Calculation of the PRS score was limited by quality inclusion of variants available, and discrimination may improve in larger data sets. Additionally, blinded physician case review is ongoing to validate the novel classification scheme and provide a gold standard for machine learning approaches that can be applied in validation sets.

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<![CDATA[SAT-LB116 Extreme Insulin Resistance: The Diagnostic Challenges When Cost Is a Limitation]]> https://www.researchpad.co/article/elastic_article_7055 Introduction: Insulin resistance occurs most commonly in association with obesity but may result from multiple causes, e.g. medications, lipodystrophy, or antibodies to insulin or insulin receptors. We review a case of an unusual presentation of insulin resistance. We highlight challenges of diagnostic testing and treatment when there are cost limitations. Clinical Case:A 41 year old Hispanic male with T2DM and a history of well-controlled BPD on quetiapine only presents for management of diabetes. His current treatment is metformin and a TDD of 170 U human insulin; A1C is 12.2%. He was diagnosed at age 32 via routine lab tests. At diagnosis BW was 96.4 kg, BMI 29, BP 100/70, CHOL 152, TG 247, HDL 35, LDL 68. Physical exam was unremarkable without acanthosis or lipodystrophy. Anti-GAD, anti-islet cell antibodies, insulin and C-peptide levels were ordered, but not obtained due to cost. He was managed with lifestyle modification for 2 years with maintenance of A1C <7%. At age 35 he developed symptomatic hyperglycemia with A1C 9.4% and was started on metformin and glyburide. At age 36 A1C was >11%, with no change in BW. Glargine 5 U was added, and glyburide was changed to glipizide. Glargine was increased to 40 U without changes in glycemia. At age 37 glipizide was stopped, and he could not afford glargine. He was switched to 70/30 human insulin. Insulin dosages were progressively increased to 220 U a day with no change in glycemia. Liraglutide was tried but not continued due to cost, and quetiapine was switched to trazodone without improvement in A1C. LFTs, CBC, HIV, Hepatitis C and B have been negative. The patient has had multiple visits for education with documented adequate disease understanding and performance of injections. Nonadherence was suspected; for its evaluation, the patient was observed in clinic self-injecting 30 U of regular insulin (brought from home); fasting was confirmed for 3hrs post-injection. BG was 327mg/dL pre-injection and 326mg/dL 3hrs post-injection. Insulin antibodies were requested but not obtained due to cost. Insulin receptor antibodies are not commercially available in the US. Potential empiric strategies, e.g. the NIH protocol for insulin type B resistance (rituximab + dexamethasone + cyclophosphamide) was considered but cost is a limitation. We discussed steroids or methotrexate for possible antibody mediated insulin resistance versus a trial of thiazolidinedione, which has been reported to decrease severe insulin resistance in patients with lipodystrophy. The patient opted to initially try a thiazolidinedione. Conclusion:Although poor adherence has not been excluded, the patient appears to have no response to high doses of injected human insulin, suggesting extreme insulin resistance. Cost limitations preclude optimal diagnostic evaluation. Empiric treatment with low cost options potentially may provide diagnostic information as well as efficacious treatment.

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<![CDATA[SAT-630 Nutritional Influences on One Carbon Metabolism Exacerbate Diabetic Cardiomyopathy and Nephropathy]]> https://www.researchpad.co/article/elastic_article_7028 Choline (Ch) exerts a key role as methyl donor in the one carbon pathway and is an essential nutrient for the optimal development and function of a number of biological systems including the cardiovascular and urinary system. Ch-deprivation has been associated with heart function impairment, insulin resistance, abnormal fat metabolism and acute kidney injury. Diabetes mellitus is a common metabolic disorder with increased prevalence in aging and diabetic patients are of higher risk to develop heart and kidney failure. This study aims to investigate the impact of dietary Ch-deprivation on cardiac and renal function in a streptozotocin (STZ) experimentally induced diabetic setting. Twenty-four male adult Wistar rats, were randomly separated into four groups: control, choline deficient through choline deficient diet (CD), STZ induced diabetic (DM) and diabetic-choline deficient (DM+CD) group. After 5 weeks of dietary intervention, echocardiographic measurements, myocardium and kidney histological examination along with Vascular Endothelial Growth Factor-A (VEGF-A165) and Kidney Injury Molecule-1 (KIM-1) immunohistochemistry expression were performed. DM+CD rats demonstrated an exacerbation of myocardial inflammation and fibrosis accompanied by preserved ejection fraction but with an increased left ventricular (LV) wall tension index and velocity and a decreased LV posterior wall thickness compared to DM group. VEGF-A165 expression both in heart and kidneys was abruptly upregulated in the CD rats with a downward trend under the diabetes mellitus entity reaching significant downregulation in the renal tissue. KIM-1 expression was significantly increased under the insult of both choline deficiency and diabetes mellitus depicting a possible synergistic, though detrimental, effect compared to each condition alone.

In conclusion, five weeks of dietary choline deprivation aggravates the inflammation and fibrosis in the heart and kidneys of diabetic rats leading to organ dysfunction. The structural impairment of the choline deprived diabetic heart with evidence of stiffness and dilation of the left ventricular cavity with preserved systolic function indicates the emergence of a new distinct phenotype of cardiomyopathy that combines features of the restrictive and dilated type at the same time. Moreover, in this setting the kidney injury gets worse implying that diabetic nephropathy might establish earlier and accelerate more quickly in choline deficiency conditions.

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<![CDATA[SAT-631 Increased Incidence of Diabetic Nephropathy in Veterans with Severe Insulin Resistance]]> https://www.researchpad.co/article/elastic_article_7012 Recently, cluster analysis has been used to classify adult onset diabetes based on pathophysiologic profile. Using autoimmunity status, BMI, insulin resistance, and beta cell function, this classification system can predict diabetes associated complications. Individuals with primarily insulin resistant phenotype have been associated with increased incidence of nephropathy while those with insulin deficient phenotype are associated with retinopathy. Clinically, patients with severe insulin resistance can be defined as those who require high doses of insulin to achieve glycemic control, such as patients on U-500 insulin requiring more than 200 units of insulin a day. To characterize the clinical and metabolic phenotype of insulin-resistant patients from a South Texas VA diabetes clinic, we evaluated presence of macro or microvascular complications and beta-cell autoimmunity and function in this population. A retrospective cohort study was completed at the South Texas VA Diabetes Clinic. Charts were reviewed for anthropometric measurements, presence of macro and microvascular complications, anti-diabetic medication, lipid profile and HbA1c over 3 visits, autoimmunity (anti-GADab), and beta-cell function (fasting C-peptide). Patients with insulin doses >200 U/day or on U-500 insulin were categorized as “severe insulin-resistant”. Those with insulin doses < 0.5 U/kg/day were categorized as “mild insulin resistance” as a control group. Out of 120 patients, 30 met criteria for severe insulin resistance (n=30, M/F=29/1 age 61±1.6 years (yr), BMI 41±0.9 kg/m2, duration of diabetes 18.3±0.3 yr, HbA1c -8.4±0.2%, total daily insulin dose (TDD) 301±31U). 30 patients with insulin use <0.5 U/kg/day met criteria for mild insulin resistance (N=30, M/F: 28/2, age 62±2 yr, BMI 30±1 kg/m2, duration of diabetes 12±1.2 yr, HbA1c 7.2±0.2%, TDD 17±2U). Prevalence of nephropathy was higher in the insulin resistant group vs the mild insulin resistant group (76% vs 43%, p<0.05). There was no difference in prevalence of retinopathy (p=0.095) or CAD (p=0.6) between the groups. There was no difference in use of ACE-i or SGLT-2i between the groups. Insulin resistant subjects had a higher plasma triglyceride (325±0.3 vs 202±0.3 mg/dl, p=0.04). Prevalence of GAD ab was not different between the groups (3% vs 0%). Fasting C-peptide concentrations were similar in both groups (5.6±0.3 vs 5.2±0.25 ng/ml, p=0.3). HbA1c in the insulin resistant group improved between visits 1 and 3 (p<0.01). Weight increased over three visits in the severe insulin resistant group as opposed to mild weight loss in the mild insulin resistant group.

Our results support the high prevalence of diabetic nephropathy in patients with severe insulin resistance, although it is unclear that insulin resistance is the etiology. Long-term follow up of these patients may provide insight into the underlying mechanisms of these complications.

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<![CDATA[SAT-LB117 POEMS Syndrome: Rare Presentation of New Onset Diabetes Mellitus]]> https://www.researchpad.co/article/elastic_article_6728 Background: POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is characterized by the presence of a monoclonal plasma cell disorder, peripheral neuropathy, and one or more of the following features: osteosclerotic myeloma, Castleman disease, increased levels of serum vascular endothelial growth factor (VEGF), organomegaly, endocrinopathy, edema, typical skin changes, and papilledema. Clinical Case: 45 year old male with no chronic medical issues presented initially to the orthopedic clinic with right hip pain, pelvic MRI showed a right iliac crest lesion. CT Guided biopsy was done and showed plasmacytoma. SPEP showed elevated IgG lambda level in the gamma zone. In the meantime he was complaining of ascending numbness and weakness in hands and feet and he progressively became wheelchair bound. During his treatment and follow ups with Hematology/Oncology he was noted to have elevated blood sugars in the 500s. Hemoglobin A1C was elevated at 9.5 which confirmed the diagnosis of new onset diabetes. He was also noted to have splenomegaly which confirmed the diagnosis of POEMS syndrome. He was started on insulin and he managed to achieve good diabetes control with insulin and dietary changes. He is currently status post stem cell transplantation with a good response and the weakness and polyneuropathy improved with PT and OT. POEMS syndrome has major and minor criteria for diagnosis, mandatory major criteria includes polyneuropathy, monoclonal plasma cell proliferative disorder (almost always lambda). Additional major criteria are sclerotic bone disease, castleman disease, elevated VEGF. Minor criteria are organomegaly, extravascular volume load, endocrinopathy, and skin changes. In order to diagnose the syndrome, mandatory major criteria, and one major and one minor criteria need to be clinically present. Endocrinopathy includes the adrenal, pituitary, thyroid, gonadal, parathyroid, and pancreatic glands. Two-thirds of patients had at least one endocrine abnormality at presentation. Endocrine abnormalities can also develop later, during the course of the disease. Hypogonadism is the most common endocrine abnormality. Elevated levels of follicle stimulating hormone in the absence of primary hypogonadism levels have been reported, hence history and physical examination is crucial to detect the development of endocrinopathies in POEMS syndrome. There are no current guidelines or recommendations about the frequency of screening for endocrinopathies but it is suggested to obtain a baseline of thyroid function test, pituitary, gonadal, and adrenal axis. In addition to baseline parathyroid hormone level, close monitoring of calcium and blood glucose levels once the diagnosis is confirmed in patients with suggestive symptoms. Conclusion: POEMS syndrome is a rare condition that involves multiple endocrine organs, currently there are no guidelines or recommendations to obtain baseline endocrine labs once the diagnosis is confirmed, but it might be appropriate if there is a high clinical suspicion. References: 1. Castillo JJ (2016). “Plasma Cell Disorders”. Primary Care.43(4): 677-691. doi:10.1016/j.pop.2016.07.002. PMID 27866585. 2. Warsame R, Yanamandra U, Kapoor P (2017). “POEMS Syndrome: an Enigma”. Current Hematologic Malignancy Reports.12(2): 85-95. doi:10.1007/s11899-017-0367-0. PMID 28299525. 3. Dispenzieri A (2017). “POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management”. American Journal of Hematology.92(8): 814-829. doi:10.1002/ajh.24802. PMID 28699668. 4. Kaushik M, Pulido JS, Abreu R, Amselem L, Dispenzieri A (2011). “Ocular findings in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome”. Ophthalmology.118(4): 778-82. doi:10.1016/j.ophtha.2010.08.013. PMID 21035860.

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<![CDATA[SAT-LB112 An Unusual Case of Ipilimumab/Nivolumab Induced Fulminant Diabetic Ketoacidosis (DKA) in a Non Diabetic Patient - a Case Report]]> https://www.researchpad.co/article/elastic_article_6312 INTRODUCTION

Immune Checkpoint Inhibitors (ICIs) have become a revolutionary milestone in the immune-oncology field and have shown a significant improvement in survival rates and outcomes of advanced malignancies. ICIs including: Ipilimumab (1) - monoclonal antibody that inhibits Cytotoxic T Lymphocyte associated Antigen 4 (CTLA4) - Nivolumab (2) - monoclonal antibody that blocks Programmed Cell Death Ligand 1 (PDL1) - and others turn off the tumor mediated immune system inhibition and boost the immune response against tumor cells resulting in decreased tumor growth. However, targeted immunotherapy has a wide spectrum of immune related side effects (3) that can affect various body organs ranging from mild skin rash to a critical immunotherapy induced pneumonitis and severe colitis. We present a case report of Ipilimumab/Nivolumab induced fulminant DKA in a non-diabetic patient.

CASE PRESENTATION

We present a case of a 71 year old male with a history of hypertension, hyperlipidemia, hemorrhagic stroke and stage 4 renal cancer with metastasis to the lungs who presented to the Emergency Department with altered mental status for 1 day and respiratory depression. He was accompanied by his wife who provided most of the history and denied any head trauma, seizure, uncontrolled hypertension, recent infections, arrhythmias, endocrine diseases or alcohol/drug use. Initial blood glucose was 1052, pH 7.11, bicarbonate 6, potassium 6.7, CO2 20.1, anion gap of 29 and WBCs 19.3 without any source of infections. Diabetic ketoacidosis (DKA) protocol was started and patient was intubated for worsening respiratory depression. Patient’s wife denied any personal or family history of diabetes mellitus and stated that his Hemoglobin A1c (HbA1c) has always been below 6% during his follow ups. Upon further questioning about any new medications, she stated that 15 years ago he had renal cell carcinoma treated with left radical nephrectomy and was recently discovered to have pulmonary nodules that were biopsy positive for renal cell carcinoma, to which he recently started Ipilimumab and Nivolumab immunotherapy about 2 month and last received doses was 3 days prior to presentation. She also reported one-month history of lethargy, polyuria and polydipsia. HbA1c was found to be 8.0% and lipase enzyme > 4000 u/L without any pancreatic changes or inflammation on Computed Tomography (CT) scan of the abdomen. Insulin autoantibodies, islet cells antibodies and serum C-peptide were undetectable. During the admission DKA and respiratory depression resolved but the patient continued to have hyperglycemia with blood glucose level of 300-400 and was treated with correctional insulin scale. Patient was discharged on long acting and regular insulin after appropriate education.

DISCUSSION

Ipilimumab and Nivolumab; the novel revolutionary targeted immunotherapy have been approved by the United States Food and Drug Administration in 2011 (4) and 2014 (5) respectively. They enhance the immune response against tumor cells through blocking the immune checkpoints CTLA4 and PDL1 which are activated by the tumor cells as an inhibitory mechanism to interrupt the T lymphocyte - tumor cell destruction pathway (6-7).

Ipilimumab and Nivolumab are used in combination for inoperable or metastatic melanoma (8-9), advanced renal cell carcinoma (10), metastatic squamous non-small cell lung cancer (11) and currently in trials for recurrent small cell lung cancer treatment (12-13). They are also used for primary or metastatic urothelial carcinoma and prostate cancer (14).

As ICIs enhance T lymphocytes immunity by disrupting the inhibitory signaling, they also decrease immune tolerance and, thereby; cause autoimmune toxicities. Yet, ICIs are usually not stopped since their beneficial outcomes seem to outweigh the adverse events. Immunotherapy related adverse events (irAEs) includes: systemic symptoms of fatigue, weakness, muscle and joint pain, dermatological: rash and itchy skin - reported in 10% of patients in trials for melanoma and lung cancer (15) - pneumonitis (16) (4%), gastrointestinal: decreased appetite, abdominal pain, nausea and vomiting, colitis (17) (10%), hepatic toxicity (18) (1-17%), and endocrinopathies: hypothyroidism and hyperthyroidism (19) (8.5% and 3.7% respectively). Severe neurologic disorders including acute demyelination polyneuropathy, ascending motor paralysis and myasthenia gravis have been reported (20). Although there are no guidelines for managing irEAs, most of them are managed with high-dose corticosteroids.

Several cases of autoimmune diabetes mellitus have been reported (2% of cases) as endocrinologic irEAs, most of them were genetically susceptible to type 1 diabetes mellitus. Less than 1% of cases had diabetes mellitus of rapid onset and complete insulin insufficiency leading to fulminant DKA (19). However, the clinical course of their insulin secretion disruption was not well studied.

To our knowledge, the case that we are presenting here is one of a few cases described in literature of fulminant diabetes/DKA caused by immunotherapy. In fulminant diabetes, patients present with severely elevated blood glucose or DKA; however, their HbA1c is unexpectedly low (7-8%) due to the abrupt onset of presentation. C-peptide and Islet cell autoantibodies levels are low or even undetectable which suggest that pancreatic B-cells are totally destroyed via a process that is not completely understood and not similar to the one causing classic autoimmune type 1 diabetes mellitus. In fulminant diabetes/DKA pancreatic islet cells are attacked by autoreactive T lymphocytes. Thiswas initially thought to be a cell-mediated phenomenon; however, some reported cases had 1 or more islet cell autoantibodies which suggests the implication of a humoral immune response component as well. Diagnosis of such an endocrinopathy should be proper and prompt due to the increased risk of death within the first 24 hours.

CONCLUSION

Identification of rare but serious irAEs like DKA, is very important. This requires a multi-dimensional approach involving effective education about the symptoms of DKA and hyperglycemia in patients receiving immunotherapy along with close monitoring of these patients. More research is needed in this area to clarify the frequency of this entity and its mechanism.

DISCLAIMER

This research was supported (in whole or in part) by HCA Healthcare and/or HCA Healthcare affiliated entity. The views expressed in this publication represent those of author(s) and do not necessarily the official views if HCA Healthcare or any of its affiliated entities.

REFRENCES

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2-Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer. 2017;8(3):410-416. doi: 10.7150/jca.17144.

3-Kadono T. Immune-related adverse events by immune checkpoint inhibitors. Nihon Rinsho Meneki Gakkai Kaishi. (2017) 40:83-9. 10.2177/jsci.40.83

4-Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.

5-“Nivolumab Monograph for Professionals”. Drugs.com. Retrieved 14 November 2019.

6-Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 38, 255 (2019) doi:10.1186/s13046-019-1259-z

7-Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. (2018) 8:86. 10.3389/fonc.2018.00086

8-Johnson DB, Peng C, Sosman JA (March 2015). “Nivolumab in melanoma: latest evidence and clinical potential”. Therapeutic Advances in Medical Oncology. 7 (2): 97-106

9-Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (December 2017). “De-novo and acquired resistance to immune checkpoint targeting”. The Lancet Oncology. 18 (12): e731-e741.

10-Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab vs. sunitinib in first-line treatment for advanced renal cell carcinoma: Extended followup of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol. 2019 Aug 16;

11-Sundar R, Cho BC, Brahmer JR, Soo RA (March 2015). “Nivolumab in NSCLC: latest evidence and clinical potential”. Therapeutic Advances in Medical Oncology. 7 (2): 85-96

12-S.J. Antonia, J.A. Lopez-Martin, J. Bendell, P.A. Ott, M. Taylor, J.P. Eder, et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial, Lancet Oncol., 17 (2016), pp. 883-895

13-Clinical trial number NCT00527735 at ClinicalTrials.gov Phase II Study for Previously Untreated Subjects With Non Small Cell Lung Cancer (NSCLC) or Small Cell Lung Cancer (SCLC)

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16-Tay, Rebecca Y. et al., Checkpoint Inhibitor Pneumonitis — Real-World Incidence and Risk, Journal of Thoracic Oncology, Volume 13, Issue 12, 1812 - 1814

17-Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, Mattar MC. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7(4):405-418. doi: 10.12998/wjcc.v7.i4.405.

18-Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373: 23-34.

19-de Filette J, Andreescu CE, Cools F, Bravenboer B, Velkeniers B (March 2019). “A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors”. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 51(3): 145-156. doi:10.1055/a-0843-3366. PMID 30861560

20-“Two Cases of Myasthenia Gravis Seen With Ipilimumab”. 2014-04-29.

21-Godwin, J.L., Jaggi, S., Sirisena, I. et al. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. j. immunotherapy cancer 5, 40 (2017) doi:10.1186/s40425-017-0245-2

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<![CDATA[SAT-LB128 A Case of Metformin Associated Lactic Acidosis and the Importance of Medication Reconciliation in End-Stage Renal Disease]]> https://www.researchpad.co/article/elastic_article_6103 Background: Metformin is commonly used in the treatment of diabetes mellitus due to its low cost, ease of administration and titration, and favorable side effect profile as it does not cause weight gain and rarely causes overt hypoglycemia. An important yet rare side effect of metformin use is metformin associated lactic acidosis (MALA) which can be seen in patients with significant renal impairment and is associated with high mortality.

Clinical Case: We present a 54-year-old man with hypertension, type 2 diabetes mellitus, and recently diagnosed end-stage renal disease (ESRD) on hemodialysis who presented with shortness of breath and syncope and found to have an elevated lactate to 40.5 mmol/L (reference range: 0.5-2 mmol/L). Notably, the patient was admitted at an outside hospital two and a half weeks prior for a new diagnosis of ESRD and initiated on hemodialysis three times a week. At the time of discharge from his prior hospitalization, he was instructed to continue his diabetes medications: metformin 1g twice a day, glipizide 10 mg twice a day, and pioglitazone 30 mg daily. The patient was admitted to the intensive care unit and found to have MALA. Nephrology was consulted and the patient clinically improved with hemodialysis. Within six hours of presentation, the patient’s clinical course rapidly improved with complete resolution of lactic acidosis and hemodynamic instability within 48 hours.

Conclusion: Although metformin is the most commonly used drug in diabetes mellitus, the side effect of metformin associated lactic acidosis is rarely seen in the inpatient setting. Patients with ESRD are at high risk for complications resulting from poor medication management. However, because metformin is primarily renally cleared, it should be discontinued in those with significant renal impairment. With increased awareness and understanding of MALA, providers can prevent MALA by appropriately stopping or dose reducing metformin in patients with chronic kidney disease. Educating patients on their medications—including their uses, side effects, and drug-drug and drug-food interactions—could help reduce the aforementioned medication-related problems. Clinicians should have a high suspicion of metformin associated lactic acidosis in any patient presenting with multi-organ failure due to its variable clinical presentation. If MALA is suspected, providers should consult nephrology so that patients can be started on hemodialysis.

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<![CDATA[SAT-LB118 Euglycemic Diabetic Ketoacidosis in Type 2 Diabetes Mellitus]]> https://www.researchpad.co/article/elastic_article_5991 Introduction

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes. It is characterized by the triad of hyperglycemia (>250mg/dL), high anion gap metabolic acidosis (HAGMA), and ketonemia. Rarely, it would present with normal or mildly increased glucose levels (<200mg/dL) making it a diagnostic challenge. We present a case of euglycemic DKA in type 2 diabetes mellitus (T2DM).

Case Presentation

A 77-year-old woman living in a nursing home with a history of T2DM treated with insulin glargine, but for the past three days refused medications with decreased caloric intake. There were no new medications or ingestion of alcohol or toxic substances. She then developed worsening altered mental status hence admission to the hospital. Her vital signs were within normal limits. Physical examination revealed no abdominal tenderness. Initial laboratory studies showed glucose 83 mg/dL, bicarbonate 10 mmol/L, and anion gap 23 meq/L. Urinalysis significant with trace ketones. The following day, further work-up was done remarkable with beta-hydroxybutyrate 8.3 mmol/L, lactic acid 0.8 mmol/L, and toxicology panel negative. Arterial blood gas showed pH 7.137, pCO2 14 mmHg, and bicarbonate 4.8 mmol/L. DKA protocol was initiated and she was treated with insulin drip, bicarbonate drip, and intravenous fluid administration with D5W. After two days, DKA resolved and was subsequently transitioned to subcutaneous insulin.

Discussion

Similar to the findings of Burge et al, our case showed that decreased caloric intake predisposes patients with diabetes mellitus to euglycemic DKA during periods of insulin deficiency. A proposed mechanism for the accelerated ketosis is due to the effects of elevated levels of glucagon or catecholamines on lipolysis. Other causes of euglycemic DKA include pregnancy, heavy alcohol use, SGLT2 inhibitors, cocaine abuse, pancreatitis, sepsis, and chronic liver disease. It is also important to rule out other causes of HAGMA. In our case, although she has decreased caloric intake, starvation ketoacidosis usually leads to serum bicarbonate levels >18mmol/L. Management is similar to DKA but important difference is the dextrose administration to prevent hypoglycemia.

Conclusion

Euglycemic DKA is a medical emergency that may be overlooked as patients present without marked hyperglycemia. Physicians should have a high suspicion as this may result in delayed management and potential adverse metabolic consequences.

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<![CDATA[SAT-634 The Effect of Continine Verified Smoking on the Development of Diabetes]]> https://www.researchpad.co/article/N3352158e-bd0e-48cc-897d-c30090b3b246 50 ng/mL were defined as cotinine-verified current smokers. Results: Among the total participants without diabetes at baseline, 605 (3.4%) participants had diabetes after 6 years. The risk for diabetes was lower in nonsmokers than in current smokers and quittters after adjusting for confounding factors (OR 0.71; 95% confidence interval (CI)0.56-0.89) with current smokers as the reference group. The risks of diabetes were gradually increased with amount of smoking in both quitters and current smokers. When the participants were analyzed in subgroups according to the urinary cotinine levels, those with high urinary cotinine levels >500ng/mL showed the higher risk for the development of diabetes (OR 1.57; 95% CI 1.27 – 1.93). Conclusions: This study showed that cotinine-verified smoking was associated with the development of diabetes. Furthermore, there was a potential association between smoking amounts and the development of diabetes regardless of smoking cessation. We also found that those with high urinary cotinine levels showed an increased risk for diabetes compared with participants with low urinary cotinine levels. ]]> <![CDATA[SAT-LB114 Metabolic Profile Changes in Patients With Diabetes Mellitus After Hurricane Maria: A Retrospective Case Series]]> https://www.researchpad.co/article/N813c58f3-9526-4b3d-bf91-5ef9e3f73622 <![CDATA[SAT-LB109 Implementation of a Quality Improvement Initiative for Advanced Ketone Management in Children With Recently Diagnosed Type 1 Diabetes]]> https://www.researchpad.co/article/N8512aac5-23bb-4ba0-b064-19fa4aff561c <![CDATA[SAT-628 Risk Factors Associated with 30-Day and 90-Day Readmission in Persons with Diabetic Foot Ulcers]]> https://www.researchpad.co/article/N35c26d83-a562-4f78-b621-bda543a232cb

Abstract

Diabetic foot ulcers (DFU) are the leading cause of lower-extremity amputations among patients with diabetes (DM)

. 15% of patients with DM develop DFU, with the potential for progression to osteomyelitis or gangrene with suboptimal glycemic control. Repeated readmissions are not only a negative prognostic indicator for these patients, but also contributes to increasing healthcare costs.

Previous studies have examined associations among demographics, comorbidities and DFU, and the value of Hemoglobin A1c (HbA1c) and C-reactive protein (CRP) as a prognostic indicator and monitoring tool for progression and regression, respectively

. However, no studies to date have examined medical or pharmaceutical factors contributing to 30-day and 90-day readmission.

A retrospective chart review was conducted examining 397 patients with type 2 diabetes readmitted for DFU between 2014 and 2019. Variables were summarized using descriptive statistics, t-tests, chi-square, and logistic regressions.

Majority of patients were white males with a BMI over 30 and HbA1c >7%. Patients with 30-day readmission were more likely to be using anticoagulants (30.00% vs. 17.24%, p= 0.0493). Patients with 90-day readmission were more likely to be discharged home with healthcare services (55.67% vs. 39.85%, p=0.0341) or to a skilled nursing facility (7.22% vs. 6.02%, p=0.0341). Although not statistically significant, patients with both 30-day and 90-day readmissions were also more likely to have HbA1c >7, while those with a 90-day readmission had higher CRP levels.

DFU patients with suboptimal glycemic control were more likely to experience a 30-day and 90-day readmission. Predicators for readmission in this population include: anticoagulation use, discharge to a skilled nursing facility or discharge home with healthcare services. As a result, patients not on anticoagulation, as well as those discharged home without services or to rehabilitation facilities have a reduced risk of readmission.

1.

Lazzarini PA, Clark D, Derhy PH. What are the major causes of lower limb amputations in a major Australian teaching hospital? The Queensland Diabetic Foot Innovation Project, 2006 – 2007. 2011;4(1):O24. doi:10.1186/1757-1146-4-S1-O24

2.

Vella L, Gatt A, Formosa C. Does Baseline Hemoglobin A1c Level Predict Diabetic Foot Ulcer Outcome or Wound Healing Time? Journal of the American Podiatric Medical Association.

. Published July 2017. Accessed September 28, 2019.

3.

King DE, Mainous AG, Buchanan TA, Pearson WS. C-Reactive Protein and Glycemic Control in Adults With Diabetes. Diabetes Care.

. Published May 1, 2003. Accessed September 28, 2019.

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<![CDATA[SAT-LB115 Metformin-Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes Mellitus: The Sydney Memory and Ageing Study]]> https://www.researchpad.co/article/Nb8cea6b0-52e8-425b-aa1a-d60b42ec9f01 <![CDATA[SAT-LB113 Psychosocial Benefits of Using Basal-IQ® Predictive Low Glucose Suspend Technology in a Real-World Setting: Results From Pediatric Patients With Type 1 Diabetes]]> https://www.researchpad.co/article/N90fc4431-82ac-4dd6-9a92-3f80382c056b <![CDATA[SAT-633 Features of Vitamin B12 and Vitamin D Homeostasis in Patients with Type 2 Diabetes Mellitus Associated with Tuberculosis]]> https://www.researchpad.co/article/N6f62e839-e76e-403c-9281-a41aa40cc650