STEROID INDUCED DIABETIC KETOACIDOSIS IN PATIENT WITH DIABETES MELLITUS-TYPE 2

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report EP CR STEROID INDUCED DIABETIC KETOACIDOSIS IN PATIENT WITH DIABETES MELLITUS-TYPE 2 Abhinav Tiwari MD 1, Hussain Al-Robeh MD 1, Himani Sharma MD 1, Zaid Ammari, MD 1, Mohammad Saud Khan, MD 1, Juan Jaume, MD 2 From: 1 Department of Internal Medicine, University of Toledo Medical Center; 2 Department of Endocrinology, University of Toledo Medical Center. Running title: Steroid-induced DKA Corresponding address: Dr. Abhinav Tiwari University of Toledo Medical Center 3000 Arlington Ave MS 1150 Toledo, Ohio abhinav.tiwari@utoledo.edu

2 Abstract Objective Diabetic ketoacidosis is usually associated with type 1 diabetes; however, it is increasingly being recognized in patients with type 2 diabetes mellitus. Triggering factors usually involve infections and poor medication adherence. Other potential triggers reported are myocardial infarction, antipsychotic drug usage, malignancy and cerebrovascular accidents. No case of steroid induced diabetic ketoacidosis in a patient with type 2 diabetes mellitus has been reported in the literature. Methods Clinical and laboratory data are presented. Results We present a case of a middle age patient with a history of well-controlled type 2 diabetes on metformin, who was started on oral prednisone for lumbar disc herniation and presented with acute diabetic ketoacidosis. No other trigger for diabetic ketoacidosis but steroid initiation was found. Conclusion We concluded that patients with diabetes who receive glucocorticoids should be monitored carefully, as steroids can precipitate DKA, in the absence of any other triggering factor, even in patients with well-controlled type 2 diabetes. Abbreviations T2D = Type 2 Diabetes Mellitus; DKA = Diabetic Ketoacidosis. Introduction Although diabetic ketoacidosis (DKA) has traditionally been associated with type 1 diabetes, it is increasingly being recognized in patients with type 2 diabetes (T2D). Triggering factors leading to DKA in T2D, although not obvious in many cases, usually involve infections and poor medication adherence. Other reported causes include myocardial infarction, antipsychotic drug usage, malignancy (pancreatic adenocarcinoma) and cerebrovascular accidents [1,2,3]. To our knowledge, there is no specific documented case report of steroid induced DKA in T2D in the literature; however, a retrospective study mentioned one case of steroid-induced DKA in a study population of patients with T2D [4].

3 Steroids can worsen insulin resistance, rendering patients relatively insulin insufficient and unable to maintain a euglycemic state to prevent ketone production. Here we present a case of DKA clearly precipitated by oral prednisone in a 55-year-old female patient with previously well-controlled T2D with oral hypoglycemic agent. Case 55-year-old African American female with a history of well-controlled T2D on metformin, diagnosed five years earlier, presented to primary care physician with left lower extremity pain and weakness for three weeks. Her mother also had T2D, which was well controlled on oral agents. The patient had chronic low back pain, which was controlled by celecoxib. She denied any history of trauma or lifting heavy weight. She also denied any history of bowel or bladder incontinence. Physical exam was significant for tenderness over lumbar spine, 3/5 motor strength in left lower extremity, brisk knee reflexes and positive straight leg raise test. Due to progressive muscle weakness, a magnetic resonance imaging of lumbar spine was performed, which revealed severe left neural foraminal narrowing secondary to focal disc protrusion at L3- L4. The patient was started on 40 mg of prednisone twice daily. One week later she presented to emergency department with one-day duration of lethargy, drowsiness, and confusion. On examination, her body mass index (BMI) was 48 kg/m2 and vital signs included blood pressure of 98/68 mm Hg, heart rate 104/min, respiratory rate of 36/minute and temperature of 36.5 Celsius. Laboratory workup revealed sodium 138 mmol/l, potassium 4.1 mmol/l, creatinine 1.28 mg/dl, bicarbonate 2 mmol/ (Low), glucose 696 mg/dl (High) and anion gap of 29. Arterial blood gas showed ph 7.1 and pco and serum beta hydroxybutyrate was 4.5 mmol/l (normal mmol/l). HbA1c was 13.3 %, which had increased from 7 % one month earlier, reflecting the acutely decompensated hyperglycemic state. She was started on regular insulin infusion and Diabetic Ketoacidosis (DKA) protocol per institution policy. There was no apparent triggering factor for DKA except for the use of steroids. Urine analysis, urine culture, and blood cultures were all negative for infection. Chest x-ray was non-revealing, and troponins remained normal. The patient initially required high doses of intravenous insulin, as high as 240 U/day and needed insulin infusion for three days. The patient recovered uneventfully and was transitioned to subcutaneous basal insulin and metformin. Due to the possibility of Latent autoimmune diabetes of adults (LADA), serum Glutamic Acid Decarboxylase (GAD-65) and insulinoma-associated protein 2 [IA-2] antibodies were measured on follow up visit, which were negative and serum C- peptide was elevated (3.5 nmol/l normal nmol/l).

4 Discussion DKA, for a long time, had been considered a hallmark of type 1 diabetes presentation; however, more recently, this condition has been increasingly recognized in patients with T2D and ketosis-prone diabetes. The occurrence of DKA is due to relative or complete insulin deficiency, which is not sufficient to prevent ketosis in the presence of excess counterregulatory hormone [5]. Insulin inhibits gluconeogenesis and glycogenolysis; however, insulin is unable to effectively control glucogenic enzymes in insulin resistant states, leading to increased glucose output from the liver [6]. It was thought that patients with T2D do not develop ketoacidosis as there is almost always, some residual beta-cell function in the pancreas, which could produce sufficient amounts of insulin to prevent ketogenesis, but inadequate to control blood glucose [7]. The occurrence of DKA in T2D has been related to the presence of co-existing stressors such as infections, cardiovascular or cerebrovascular events, or due to sudden discontinuation of insulin [1]. Although not due to steroids, DKA has been reported to be the initial presentation of T2D in adolescents [8]. Other triggering factors have been reported including, antipsychotic drug usage, pregnancy, alcohol consumption and malignancy (pancreatic adenocarcinoma) [1,2,3]. Several medications have also been known to trigger DKA including high-dose thiazide diuretics, and second-generation antipsychotic agents, sympathomimetic agents (eg, dobutamine and terbutaline) [9,10]. Furthermore, there have been reports of ketoacidosis associated with Sodium-Glucose Trasporter-2 (SGLT-2) inhibitors [11]. However, a recent (2017) meta-analysis compared 72 trials on SGLT-2 inhibitors reporting information on DKA, found no signal of increased risk for ketoacidosis for SGLT2 inhibitors as a class (MH-OR [95% CI] 1.14 [ ], p = 0.78) or as individual molecule [12]. Steroids, although being the main cause of drug-induced hyperglycemia [13], have not been specifically reported to induce DKA in T2D. However, a retrospective study by Jabbar, et al. (2003) has mentioned one case of steroid-induced DKA in a study population with T2D [4]. Our patient received prednisone, which is classified as intermediate-potency glucocorticoid, with a peak of action 4-6 hours after administration. When administered in a single dose in the morning, it causes glucose elevation predominantly in the evening and night, without much effect on fasting glucose 24 hours after. However, multiple divided doses can cause persistent hyperglycemia [14]. Steroids induce hyperglycemia by multiple mechanisms. Steroids interfere with signaling cascades (mainly GLUT4 transporter) in muscle cells, leading to the reduction in insulin-mediated glucose uptake and reduction in insulin-mediated glycogen synthesis [15,16].

5 Steroids also induce lipolysis and proteolysis and enhance the effects of counterregulatory hormones, such as glucagon and epinephrine, and also induce insulin resistance via the nuclear peroxisome proliferator-activated receptor (PPAR) [16,17]. In response to insulin resistance, usually there is increased insulin secretion by pancreatic beta cells to maintain glucose homeostasis, but at times this increase is insufficient to compensate for insulin resistance resulting in hyperglycemia [16,17,18]. Therefore, steroids cause hyperinsulinism in a state of insulin resistance. In non-diabetic subjects, this mechanism is compensated by an increase in endogenous insulin secretion, thereby preventing hyperglycemia [18]. However, in patients with T2D, who may already have insulin resistance and low rate of insulin production, this compensation is inadequate to offset the metabolic effects of steroids [17]. These effects result in hyperglycemia and in extreme settings, like in our case, the anti-lipolytic effect of insulin is lost, resulting in DKA. Although DKA in patients with T2D tends to have less severe acidosis [19,20], our patient had severe acidosis. Our patient also had high insulin requirement, which is not unusual for DKA in T2D, as patients may require larger amounts of insulin to correct hyperglycemia [21]. It has been reported that DKA associated 30-day mortality is higher in T2D as compared to type 1 diabetes (11.9% vs. 2.4%) [23]. Studies have shown that about % patient with T2D who were admitted to the hospital due to DKA and required insulin on discharge, were able to stop insulin at some point [4,21,22]. This may reflect recovery of betacell function after resolution of the acute hyperglycemic episode (glucotoxicity). Therefore, need for continuation of insulin should be assessed in such individuals at each follow-up visit. In conclusion, we present a case report of DKA precipitated by steroid use in T2D which to our knowledge has not been previously reported as the sole cause. Patients with T2D who receive glucocorticoids should be monitored carefully, as steroids can precipitate DKA, in the absence of any other triggering factor, even in patients with well-controlled T2D. Conflict of Interest All authors have no conflict of interest to declare.. References: 1. Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. International textbook of diabetes mellitus. 2004

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