Aristea Sideri

Context. Numerous reports suggest an association between SGLT2 inhibitors and DKA. Since the use of these drugs for diabetes has increased dramatically, identification of patients at greatest risk of this life-threatening complication is essential. Objective. To describe the clinical and biochemical characteristics of all reported cases of DKA associated with SGLT2 inhibitor use in patients with type 2 diabetes mellitus and to identify potential risk factors. Design. A retrospective case series was conducted between March 2013 and August 2019 using an electronic medical record search algorithm. Results. 25 patients met the criteria for DKA associated with SGLT2i use (total of 29 cases), 15 were female, average age was 54.24years, and mean diabetes duration was 8.76years. The majority of the patients (23 patients) had no history of prior DKA. Average blood glucose concentrations at presentation were 298.9152.7mg/dl. Interestingly, nearly half of the episodes (14) met the criteria of euglycemic DKA (glucose Conclusions. The majority of SGLT2i-associated DKA cases occurred in patients with T2DM without prior episodes of DKA. The most common presenting symptoms were nausea, vomiting, and abdominal pain, while poor food intake and infection were the main precipitants. Clinicians should consider the possibility of DKA in SGLT2i-treated patients presenting with these symptoms, even in absence of marked hyperglycemia.

Context Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive. Objective We investigated biomarkers associated with use of lorcaserin, a 5HT_2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, in order to identify predictors of clinical efficacy. Methods Thirty subjects with obesity were treated with 7-days of placebo and lorcaserin in a randomized crossover study. Nineteen subjects continued on lorcaserin for 6-months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin and food intake during a meal were also studied. Results Lorcaserin induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide β-endorphin after 7-days; β-endorphin/POMC increased by 30% (p < 0.001). This was accompanied by a substantial decrease in insulin, glucose and HOMA-IR prior to WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6-months that were distinct from prior reports after diet alone. Changes in POMC, food intake or other hormones did not predicted WL. However, baseline CSF POMC correlated negatively with WL (p = 0.07) and a cutoff level of CSF POMC was identified that predicted > 10% WL. Conclusions Our results provide evidence that lorcaserin impacts the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT_2cR agonists.

Delayed diagnosis of Cushing syndrome (CS) results in advanced disease, treatment delays, and poor outcomes. We present a patient with ectopic ACTH syndrome (EAS) from a pancreatic neuroendocrine tumor (NET) whose care posed diagnostic and therapeutic challenges. A 59-year-old female with classic Cushing stigmata, biochemical evidence of ACTH-dependent hypercortisolism, and a 5-mm pituitary lesion presented for inferior petrosal sinus sampling, which was contraindicated due to non-ST elevation myocardial infarction and acute/subacute strokes. Whole-body computed tomography (CT) scan was unrevealing, but elevations in chromogranin A and proopiomelanocortin (POMC) concentrations suggested EAS. Positron emission tomography-CT with gallium 68-DOTATATE demonstrated a 7-mm pancreatic tail lesion, suspicious for a pancreatic NET. The patient was not a surgical candidate and treatment with ketoconazole was complicated by hepatoxicity. Endoscopic ultrasound-guided biopsy and radiofrequency ablation of the lesion was pursued. Pathology confirmed ACTH immunoreactive low-grade pancreatic NET. Post procedure, sustained normalization of ACTH and cortisol was achieved. This case supports the utility of POMC measurements in the differential diagnosis of CS and the use of advanced nuclear imaging for tumor localization. For patients with functional pancreatic NET who are poor surgical candidates or intolerant of pharmacotherapy, novel endoscopic ablation may offer a low-risk therapeutic option and should be further investigated.

Background and objectives: Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis. Materials and methods: Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay. Results: Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects. Conclusions: Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.