A Rare Case of Insulin-Like Growth Factor (IGF-2) Induced Hypoglycemia Associated With Metastatic Colon Cancer.

The occurrence of hypoglycemia in patients without diabetes is rare, and non-islet cell tumor hypoglycemia (NICTH) accounts for a small portion of these instances. One of the infrequent causes is associated with tumor cell production of Insulin-like growth factor (IGF)-2. Here is a case of a 66-year-old man with stage IV colon cancer who presented to the emergency department with breathlessness during chemotherapy (Bevacizumab plus FOLFOX4 regimen). He had undergone partial colectomy and chemotherapy three years prior but was recently diagnosed with metastatic liver disease. A CT scan revealed a 15 cm hepatic mass occupying the entire right hepatic lobe. Despite receiving dextrose infusions, he experienced persistent hypoglycemia after meals and during fasting. Given that he had no history of diabetes and denied using any oral hypoglycemic agents, the Endocrinology service was consulted for further evaluation. Plasma blood glucose (BG) was measured at 74 mg/dL (reference range 74-106) during dextrose administration. An 8 AM cortisol test yielded a result of 8.08 mcg/dL (4.30-22.40), ruling out adrenal insufficiency. A 72-hour fast was initiated but terminated at eight hours due to symptomatic hypoglycemia with a plasma BG of 48 mg/dL. C-peptide and Insulin levels were both low, measuring <0.05 ng/mL (0.48-5.05) and <1.0 mU/L (3.0-25), respectively, while beta-hydroxybutyrate (BHB) levels were normal at 1.1 mg/dL (0.2-2.8). Administration of 1 mg glucagon during the fast increased BG to 112 mg/dL within 2 hours. IGF-1 levels were undetectable (<1.9 nmol/L), while IGF-2 levels were at 23 nmol/L (44-129 nmol/L), resulting in an IGF2:IGF1 ratio of 12 (>10), confirming IGF-2 mediated NICTH. Treatment with dexamethasone 10 mg daily was initiated, maintaining blood glucose levels above 70 mg/dL without dextrose infusion. In approximately 50% of cases of NICTH, the tumor is detected before the onset of hypoglycemia, yet up to half the patients may remain asymptomatic despite having very low BG. Despite having a known hepatic lesion, our patient exhibited minimal symptoms despite severely low BG levels. The mechanisms underlying NICTH may involve tumor secretion of insulin, replacement of hepatic tissue, increased glucose utilization by the tumor, or, most commonly, secretion of IGF-2. In cases of IGF-2-mediated hypoglycemia, insulin, proinsulin, C-peptide, and ß-hydroxybutyrate levels are typically low. IGF-2 stimulates the insulin receptors resulting in increased glucose uptake by skeletal muscles and suppression of gluconeogenesis, glycogenolysis, and ketogenesis by the liver. Insulin secretion from pancreatic ß-cells is suppressed. IGF-1 levels are usually low, while IGF-2 levels may be high or normal, as many IGF-2omas produce IGF-2 precursors (pro-IGF-2). An elevated IGF-2:IGF-1 ratio (>10) confirms the diagnosis which may be helpful when IGF-2 levels are normal. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated.

Not Just an Accident: A Case of Insulinoma.

Insulinomas are a rare cause of recurrent hypoglycemia in non-diabetic patients. Diagnosis requires hypoglycemia (plasma glucose <50 mg/dL), neuroglycopenic symptoms, and prompt relief of symptoms following the administration of glucose, known as Whipple's triad. The gold standard diagnostic tests are measuring insulin, C-peptide, and glucose during a 72-hour fast. In the preoperative period and in patients with unresectable or metastatic tumors, medical management with diazoxide and octreotide can be considered for recurrent hypoglycemia. We present a case of insulinoma in a 37-year-old woman who initially presented after a seizure-related motor vehicle accident. Upon admission, her initial glucose level was 32 mg/dL, indicating a likely hypoglycemic seizure. During her hospitalization, she had recurrent episodes of fasting and postprandial hypoglycemia, ranging from 32-70 mg/dL. She exhibited the characteristics of Whipple's triad when values dropped below 50 mg/dL. These episodes necessitated continuous infusions of 10% dextrose. Tests for insulin autoantibodies, sulfonylurea screens, and thyroid function yielded unremarkable results. A 72-hour fasting test was initiated to investigate potential endogenous causes of excessive insulin production. Laboratory results from a venous glucose level of 46 mg/dL indicated a notable rise in C peptide and insulin levels, alongside beta hydroxybutyrate suppression, all of which fulfilled the diagnostic criteria for insulinoma. An abdominal magnetic resonance imaging (MRI) unveiled a 1.3 cm mass in the pancreatic tail. This case emphasizes the importance of employing a focused approach when evaluating non-diabetic individuals displaying hypoglycemia with positive Whipple's triad. This targeted method not only enables early detection of this rare condition but also assists in eliminating other common causes of recurrent hypoglycemia in non-diabetic individuals. Moreover, in addition to this diagnosis being rare, it is important to note that patients with insulinomas typically do not exhibit a glucose level low enough to induce seizures during their initial presentation.

Exogenous Cushing Syndrome and Hip Fracture Due to Over-the-Counter Supplement (Artri King).

The most common cause of Cushing syndrome (CS) is exposure to exogenous glucocorticoids. There is an increasing incidence of adulterated over-the-counter (OTC) supplements containing steroids. We present a case of Artri King (AK)-induced CS in a 40-year-old woman who presented with an intertrochanteric fracture of her right femur. Laboratory testing revealed suppressed cortisol and adrenocorticotropic hormone, which was consistent with suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Following the cessation of the AK supplement, the patient's HPA axis recovered, and the clinical manifestations of CS improved. This case emphasizes the need for better regulation of OTC supplements and the need for cautious use.

Congenital Adrenal Hyperplasia Causing Poor Response to Androgen Deprivation Therapy in Prostate Cancer.

Androgen deprivation therapy (ADT) is recommended for the treatment of advanced prostate cancer. Inadequate suppression of testosterone while on ADT poses a clinical challenge and requires evaluation of multiple potential causes, including adrenal virilizing disorders. We present 2 cases of elderly patients with prostate cancer who had undiagnosed congenital adrenal hyperplasia (CAH) driving persistent testosterone elevation during ADT. The first patient is a 73-year-old man who underwent radical prostatectomy on initial diagnosis and was later started on ADT with leuprolide following tumor recurrence. He had a testosterone level of 294.4 ng/dL and prostate-specific antigen (PSA) level of 17.7 ng/mL despite leuprolide use. Additional workup revealed adrenal nodular hyperplasia, elevated 17-hydroxyprogesterone (19 910 ng/dL) and dehydroepiandrosterone sulfate (378 mcg/dL), and 2 mutations of the CYP21A2 gene consistent with simple virilizing CAH. The second patient is an 82-year-old man who received stereotactic radiation therapy at time of diagnosis. He had insufficient suppression of testosterone with evidence of metastatic disease despite treatment with leuprolide and subsequently degarelix. Laboratory workup revealed elevated 17-hydroxyprogesterone (4910 ng/dL) and dehydroepiandrosterone sulfate (312 mcg/dL). Based on clinical, radiographic and biochemical findings, the patient was diagnosed with nonclassic CAH. The first patient initiated glucocorticoid therapy, and the second patient was treated with the CYP17 inhibitor abiraterone in combination with glucocorticoids. Both patients experienced rapid decline in testosterone and PSA levels. Inadequate testosterone suppression during ADT should trigger evaluation for causes of persistent hyperandrogenemia. CAH can lead to hyperandrogenemia and pose challenges when treating patients with prostate cancer.

A Primary Adrenal Epithelioid Angiomyolipoma (PEComa) in a Patient with Tuberous Sclerosis Complex: Report of a Case and Review of the Literature.

Epithelioid angiomyolipomas (EAMLs) are mesenchymal tumors that are part of the family of the perivascular epithelioid cell neoplasms (PEComas). These tumors portray a potential aggressive behavior with metastatic lesions found in around 30% of reported cases. EAMLs might present sporadically or in association with the tuberous sclerosis complex (TSC). They typically involve the kidneys, liver, and lungs. It is extremely rare for these tumors to arise from other organs. The present report describes an unusual case of an adult patient with a history of TSC who developed EAML of the adrenal gland. Moreover, he presented with metastatic disease to the liver, a feature rarely described. The diagnosis of EAMLs can be challenging as they are hard to distinguish from other adrenal or renal tumors without a thorough histopathologic and immunohistochemical evaluation. Due to the potential aggressive behavior of these malignancies, timely diagnosis is extremely important and has significant therapeutic and prognostic implications.

Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives.

Over the past three decades, the incidence and prevalence of neuroendocrine tumors have gradually increased. Due to the slow-growing nature of these tumors, most cases are diagnosed at advanced stages. Prognosis and survival are associated with location of primary lesion, biochemical functional status, differentiation, initial staging, and response to therapy. Octreotide, the first synthetic somatostatin analog, was initially used for the management of gastrointestinal symptoms associated with functional carcinoid tumors. Its commercial development over time led to long-acting repeatable octreotide acetate, a long-acting version that provided greater administration convenience. Recent research demonstrates that octreotide's efficacy has evolved beyond symptomatic management to targeted therapy with antitumoral effects. This review examines the history and development of octreotide, provides a synopsis on the classification, grading, and staging of neuroendocrine tumors, and reviews the evidence of long-acting repeatable octreotide acetate as monotherapy and in combination with other treatment modalities in the management of non-pituitary neuroendocrine tumors with special attention to recent high-quality Phase III trials.

Metformin: An Old Drug for the Treatment of Diabetes but a New Drug for the Protection of the Endothelium.

The anti-diabetic and oral hypoglycaemic agent metformin, first used clinically in 1958, is today the first choice or 'gold standard' drug for the treatment of type 2 diabetes and polycystic ovary disease. Of particular importance for the treatment of diabetes, metformin affords protection against diabetes-induced vascular disease. In addition, retrospective analyses suggest that treatment with metformin provides therapeutic benefits to patients with several forms of cancer. Despite almost 60 years of clinical use, the precise cellular mode(s) of action of metformin remains controversial. A direct or indirect role of adenosine monophosphate (AMP)-activated protein kinase (AMPK), the fuel gauge of the cell, has been inferred in many studies, with evidence that activation of AMPK may result from a mild inhibitory effect of metformin on mitochondrial complex 1, which in turn would raise AMP and activate AMPK. Discrepancies, however, between the concentrations of metformin used in in vitro studies versus therapeutic levels suggest that caution should be applied before extending inferences derived from cell-based studies to therapeutic benefits seen in patients. Conceivably, the effects, or some of them, may be at least partially independent of AMPK and/or mitochondrial respiration and reflect a direct effect of either metformin or a minor and, as yet, unidentified putative metabolite of metformin on a target protein(s)/signalling cascade. In this review, we critically evaluate the data from studies that have investigated the pharmacokinetic properties and the cellular and clinical basis for the oral hypoglycaemic, insulin-sensitising and vascular protective effects of metformin.