Dilemma on Classifying Diabetes Mellitus in Adolescence: A Case Report and Review of Literature

Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM) that is prone to occur in children with type 1 DM (T1DM). We report a 17-year-old overweight girl who was treated with multiple oral antihyperglycemic drugs under the initial impression of type 2 DM (T2DM). Nevertheless, severe euglycemic DKA happened after the additional prescription of sodium-glucose cotransporter 2 inhibitors for two months. Consequently, T1DM was diagnosed on the basis of insulinopenic status in glucagon test and the presence of islet autoantibodies. This case highlighted the importance of precise classification before diabetes treatment in adolescence. A literature review is aimed to help clinicians differentiate various types of DM more specifically in clinical practice.


Introduction
The prevalence of diabetic ketoacidosis (DKA) is higher in type 1 diabetes mellitus (T1DM) than type 2 diabetes mellitus (T2DM) [1]. Since DKA is the leading cause of death in children and adolescents with T1DM, early diagnosis and appropriate treatment of diabetes are crucial to avoid life-threatening events [2]. However, the rising incidence of overweight and obesity in adolescents makes an exactly differential diagnosis between T1DM and T2DM become challenging. For example, the previous study reported that approximately 5-10% of patients with autoimmune diabetes were treated as T2DM in the beginning, based on an obese body habitus or age of onset. However, further investigations confirmed the diagnosis as latent autoimmune diabetes in adults (LADA) [3].
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newly-approved oral antihyperglycemic drug (OAD) in T2DM which increase renal glucose excretion to control hyperglycemia. On the other hand, they are associated with increased plasma glucagon level and ketogenesis, then precipitates the development of euglycemic DKA (euDKA) in patients with T1DM [4]. Here we present an overweight girl treated with multiple OADs under the presumed diagnosis of T2DM due to her habitus and family history of T2DM. Nevertheless, severe euDKA developed after the use of SGLT2 inhibitor in two months. Poor β-cell function in response to glucagon test and the presence of glutamic acid decarboxylase antibodies confirmed the diagnosis of T1DM later. This case underscored all newly-onset diabetic adolescents should receive thorough laboratory evaluation to solidify categories of diabetes, in order to provide appropriate therapies and avert the unwarranted complications.

Case Report
A 17-year-old girl presented symptoms of polydipsia, polyphagia, polyuria, and body weight loss two years before. At that time, her height was 165 cm, weight was 70 kg, and body mass index (BMI) was 25.7 kg/m 2 . Laboratory tests revealed fasting blood glucose 311 mg/dL, hemoglobin A1c (HbA1c) 16.5%, and normal lipid profiles (Table 1). Her family history, her grandmother was a patient of T2DM. Glucagon test and serum islet autoantibodies were not evaluated so she was presumed to be a case of T2DM initially. She was treated with multiple OADs including metformin, glimepiride, and pioglitazone by a local medical doctor but the glycemic control was poor. Because the deterioration of her diabetic control with recent HbA1C 16% was noticed, dapagliflozin, a SGLT2 inhibitor, was added as the fourth kind of OAD.
She was noted to have a weight loss of 1.5kg within 2 months after using dapagliflozin. Two days before admission, she suffered from extreme thirst, nausea, and intermittent abdominal pain. No infectious symptom or sign was noted. Because of progressive drowsiness to semi coma, she was sent to our emergency room. Upon arrival, her height was 169 cm (97th percentile), weight was 61.5 kg (85 th -97 th percentile), and BMI was 22.7 kg/m 2 (85 th percentile). The body temperature was 36.7°C, blood pressure was 126/75 mmHg, heart rate was 132 beats/ min, and respiratory rate was 44 breaths/min with Kussmaul pattern. Her abdomen had diffused tenderness without muscle guarding. Her pubertal development was at Tanner Stage V without acanthosis nigricans. Chest X-ray revealed no specific abnormality. Blood tests showed glucose 242 mg/dL, ketone 6.3 mmol/L, pH 6.972, PaCO2 6.6 mmHg, PaO2 139.7 mmHg, HCO3 1.5 mmol/L, base excess -28.3, sodium 138 mmol/L, potassium 4.7 mmol/L, and anion gap 23.5 mmol/L. Urine analysis showed marked glucosuria (4+) and ketonuria (4+). Glucagon test was done at 0 and 6 min showed C-peptide 0.19 and 0.41 ng/ml, respectively. Positive glutamic acid decarboxylase antibodies (GADA) and anti-thyroglobulin antibody (ATA) were detected. She was then diagnosed as T1DM with ketoacidosis based on poor β-cell function and islet autoimmunity.
She was treated with intravenous fluid, electrolytes, and insulin supplement at pediatric intensive care unit for severe ketoacidosis. Her insufficient insulin secretion to overcome glucose dysmetabolism in an early stage. The results of the 6-min glucagon test and islet autoantibodies assessment in our patient provided robust evidence of T1DM as well.
In respect to molecular diagnosis, an increasing validity in candidate genes to predict the type of diabetes has been reported [8,9]. However, only HLA genes were found to have a better odds ratio in predicting T1DM while the predictive value of T2DM by other genetic variants was disappointing [9,10]. Most importantly, the genetic tests to predict and classify diabetes are not always available in clinical practice. To prevent malpractice and severe diabetic complications, we recommended that a detailed history taking with investigations including glucagon test for β-cell function, serum islet autoantibodies, and lipid profiles should be addressed before treatment.
DKA without marked hyperglycemia was referred as euDKA. In addition, partial insulin treatment, intercurrent illness, reduced food and fluid intake, history of alcohol intake or using SGLT2 inhibitors were regarded as potential triggers of euDKA [11]. Currently, SGLT2 inhibitors including canagliflozin, dapagliflozin, and empagliflozin were approved to use in T2DM recently, but not in T1DM. Pharmacologically, the anti-hyperglycemic mechanism of SGLT2 inhibitors was through decreasing glucose reabsorption in proximal renal tubules, subsequently leading to decreased insulin secretion, vicariously increased glucagon levels, and then potentially could exaggerate the process of ketogenesis [4]. As a result, the misuse of SGLT2 inhibitors in autoimmune diabetes can pose a high risk to develop euDKA, as the present case illustrated. Interestingly, our case had severe metabolic acidosis (pH 6.972 and HCO3 1.5 mmol/L) along with borderline hyperglycemia (blood glucose 242 mg/dL) [12][13][14][15]. These extremely discordant data had not been reported in patients with T1DM yet. Likewise, random glucose levels were fallible to determine the severity of DKA, particularly in T1DM patients concomitant with SGLT2 inhibitor treatment.
consciousness gradually recovered and the breathing pattern returned to normal after metabolic acidosis was corrected. She was transferred to our general ward in two days and treatment was shifted to only subcutaneous insulin injection. Her HbA1c was 12% three months later and 5.1 % eight months later during follow-up, respectively.

Discussion
Approximately 10% of patients with autoimmune diabetes could be misclassified as T2DM due to obesity or family history [3]. Regardless of age, metformin monotherapy is the first line pharmacologic agent for T2DM if not contraindicated [5]. When blood glucose is ≥ 300 mg/ dL (16.7 mmol/L) or A1C is ≥ 10% (86 mmol/mol), early insulinization should be considered to prevent glucose toxicity [6]. Reviewing the disease course, insulin therapy should be used in our case at first. Meanwhile, worse diabetic control even under multiple combinations of OADs implied underlying insulinopenia and rapidly deteriorated β-cell function. On the other hand, patients with T2DM tend to have metabolic syndrome rather than those with T1DM ( Table 2). The lack of typical presentations of metabolic syndrome in our patient, such as dyslipidemia and hypertension, also made the diagnosis of T2DM confusing. These discriminations gave us clues to reconsider the possible pathogenesis of autoimmune diabetes in this patient.
Traditionally, LADA belonged to autoimmune diabetes and was considered as a genetic admixture of T1DM and T2DM. Subjects having all of the following three criteria were diagnosed to have LADA: Age at onset more than 30 years, the presence of circulating islet autoantibodies, including GADA, insulin autoantibody (IAA), antibodies to islet cell cytoplasma (ICA) or tyrosine phosphatase like protein(IA-2A), and slow requirement of insulin therapy after diagnosis [7]. Unlike the typical manifestations of LADA, our patient presented with highly elevated HbA1c (16.5 %) in the beginning, which indicated   Characteristics  T1DM  LADA  T2DM  Reference   Risk genotypes  INS VNTR, PTPN22, CTLA4,  IL2RA, STAT4, IFIH1  INS VNTR, PTPN22, TCF7L2  TCF7L2, CAPN10, PPARG, FTO, KCNQ1,  KLF14, CDKAL1, CDKN2A/2B, IGF2BP2, HHEX. [ 8,9] Link of HLA-DQ haplotypes High Low Very low [12] Diabetes-susceptible haplotype In conclusion, this case report highlights the importance of glucagon test and islet autoantibodies detection to achieve a correct diagnosis of adolescents with newly-onset diabetes. Only the correct classification of diabetes leads to appropriate treatment and prevents life-threatening complications. Besides, adolescents with suspected T2DM who have been treated with multiple OADs but still presented with poor glycemic control should always take autoimmune diabetes into consideration [16][17][18][19][20].