The current TZDs are first-generation, non-specific activators of peroxisome proliferator-activated receptor (PPAR) gamma, resulting in a wide array of deleterious side effects that currently limit their use. However, the development of highly targeted selective PPAR gamma modulators (SPPARγMs) and dual PPAR gamma/alpha agonists is on the horizon.

PTU is known to cause severe hepatic failure, particularly in children. Its use in children should be avoided. In adults, it is beneficial to use in the first trimester of pregnancy and thyroid storm. In the rest of the adult population, it should be used with caution. Carbimazole and MMI are associated with less severe hepatic injury and should be preferred when choosing thionamides as a treatment option.

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Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low-or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg ϩ 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazonemetformin combination therapy (8 mg ϩ 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-L␣ expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44. thiazolidinedione; adipocyte; ERp44; Ero1-L␣; chaperone proteins AS THE PREVALENCE OF OBESITY CONTINUES to rise at an alarming rate, so do associated rates of obesity-related metabolic dysfunction; among these are coagulation abnormalities, dyslipidemia, hyperinsulinemia, glucose intolerance, and type 2 diabetes (13, 34). Although long recognized to play a role in fat metabolism, the endocrine role of adipose tissue is a relatively recent and important discovery, potentially providing a link between obesity and disorders of metabolism. Among the growing list of identified adipose endocrine products, adiponectin is uniquely related to changes in insulin sensitivity. Low levels are seen in obesity and insulin-resistant states and are predictive of type 2 diabetes (15), whereas high levels are associated with leanness and greater insulin sensitivity (28, 40) and reduced risk for development of type 2 diabetes (14).Although synthesized as a 32-kDa monomeric protein, adiponectin undergoes extensive posttranslational processing and assembly into low-molecular-weight (LMW) trimers, middlemolecular-weight (MMW) heximers, and high-molecularweight (HMW) complexes prior to secretion (38). In vitro, the HM...

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Background: Calcitonin elevation is a characteristic feature of medullary thyroid carcinoma, but can also be secreted by other neuroendocrine tumors. Pancreatic neuroendocrine tumor is a rare entity, with most functioning tumors secreting insulin and gastrin, while other hormones such as calcitonin are not commonly evaluated. Case: A 63 year old woman with stage 4, well differentiated pancreatic neuroendocrine tumor was referred for evaluation of a thyroid nodule and rising calcitonin level concerning for possible medullary thyroid cancer. She presented with persistent diarrhea and weight loss, and found to have a 10 cm pancreatic mass, liver metastasis and common bile duct obstruction requiring a biliary drain. Pathology showed grade 2, well differentiated neuroendocrine neoplasm with 5/10 mitoses/high power field, immunopositive for chromogranin, synaptophysin and Cam5.2, very faint, rare staining for gastrin and negative for somatostatin. Chromogranin A was 21 (Nl 25-140 ng/mL), serotonin 641 (Nl 56-244 ng/mL), gastrin 16 (Nl <100pg/mL), 24 hr 5HIAA 3.3 (Nl <6mg/24h), pancreatic polypeptide <50 pg/mL (Nl <1823 pg/mL), vasoactive intestinal peptide <5 pg/mL (Nl <75 pg/mL) and somatostatin 33 (Nl <30). She was treated with radioablation of the liver lesions and monthly lanreotide injections. An Octreoscan showed a questionable focus of abnormal uptake within the right thyroid lobe, triggering a calcitonin level that was elevated at 722 pg/mL (Nl <5pg/mL). She was referred for thyroid nodule biopsy to rule out medullary thyroid cancer. Ultrasound of the thyroid gland showed bilateral thyroid nodules with a dominant, right mid thyroid nodule measuring 13.9 x 16. 4 x 18.5 mm, hyperechoic, spongiform with regular, smooth and well defined margins and no calcifications. FNA biopsy of the right mid thyroid nodule was negative for malignant cells, consistent with benign follicular nodule with cystic degeneration, and immunohistochemical staining for calcitonin of the cell block was negative. Immunostaining of the prior pancreatic tumor biopsy for calcitonin was performed and positive. Conclusion: Although elevation in calcitonin raises concern for medullary thyroid cancer, it is rarely secreted by other neuroendocrine tumors. Thus, a, calcitonin-secreting pancreatic neuroendocrine tumor is an important entity to consider as a cause of elevated calcitonin, especially in a patient with benign appearing thyroid nodules. Reference: 1 Jensen, R et al, ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Endocrine Tumor Syndromes. Neuroendocrinology. 2012;95:98-119.

Introduction Diabetes insipidus (DI) is a rare complication of subarachnoid hemorrhage (SAH) and associated with worse prognosis and increased mortality. We present a case of combined nephrogenic and central DI together with osmotic diuresis as a result of SAH and discuss the pathophysiology. Case A 63-year-old female without significant past medical history was found unresponsive. CT head followed by angiography confirmed extensive SAH arising from a saccular anterior communicating artery (Acoma) aneurysm. She underwent emergent coil embolization and right frontal external ventriculostomy drain placement. Postoperatively, she developed polyuria (300-400 mL/hour) and hypernatremia (156 mEq/L) concerning for the development of DI. Serum osmolality was elevated at 316 mOsm/kg, urine osmolality inappropriately low relative to serum osmolality at 289 mOsm/kg but also unexpectedly high for complete DI, serum potassium 2.9 mEq/L and urine potassium elevated urine at 9 mEq/L. Serum copeptin was 6 pmol/L and inappropriately low for nephrogenic DI, suggesting a mixed central and peripheral process as well as contribution from osmotic diuresis. Intravenous (IV) desmopressin (DDAVP) only slightly reduced the polyuria. Management was complicated by adypsia and persistent hypokalemia requiring ongoing replacement. IV fluid, which had initially consisted of high-osmolality Plasma-Lyte (294 mOsm/L), matched to urine output, was switched to D5W, leading to a significant decrease in polyuria. On post-operative day 17, DDAVP was discontinued with normalization of sodium (137 mEq/L), potassium (3.8 mEq/L) and urine output. Three months post-operatively, she was asymptomatic with intact pituitary function and no hypokalemia. Discussion Hypokalemia in patients with SAH is thought due to acute intracellular shift of potassium caused by excessive β2-adrenergic activity generated endogenously by the sympathetic nervous system. In our patient, there was also likely contribution from distal tubular delivery of sodium from osmotic diuresis, leading to increased urinary potassium losses and hypokalemia-induced partial nephrogenic DI which was further complicated by partial central DI as suggested by the inappropriately low copeptin level for nephrogenic DI in face of a high serum osmolality and inappropriately low urine osmolality. As the vascular supply to anterior hypothalamus is derived from the Acoma, rupture may compromise perfusion affecting neuronal populations in the lamina terminalis that regulate thirst and AVP secretion in response to hyperosmolarity. Early detection of DI is critical because hypovolemia can predispose to cerebral vasospasm and worsen outcomes. This case also depicts the importance of careful consideration of sources of osmolar loads such as the composition of administered IV fluids, and aggressive potassium replacement to maintain DDAVP sensitivity. Conclusion DI should be considered in polyuria syndrome with hypernatremia after a neurosurgical event. Nephrogenic and central DI and adypsia can manifest following SAH, with sources of iatrogenic osmolar load further complicating the clinical picture. Early recognition and treatment may reduce morbidity and mortality. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.