Insulin's Legacy: A Century of Breakthroughs and Innovation.

The clinical use of insulin to treat diabetes started just over 100 years ago. The past century has witnessed remarkable innovations in insulin therapy, evolving from animal organ extracts to bioengineered human insulins with ultra-rapid onset or prolonged action. Insulin delivery systems have also progressed to current automated insulin delivery systems. In this review, we discuss the history of insulin and the pharmacology and therapeutic indications for a variety of available insulins, especially newer analog insulins. We highlight recent advances in insulin pump therapy and review evidence on the therapeutic benefits of automated insulin delivery. As with any form of progress, there have been setbacks, and insulin has recently faced an affordability crisis. We address the challenges of insulin accessibility, along with recent progress to improve insulin affordability. Finally, we mention research on glucose-responsive insulins and hepato-preferential insulins that are likely to shape the future of insulin therapy.

Hypothalamic-pituitary dysfunction in Sturge-Weber syndrome: case report and review of the literature.

OBJECTIVES: Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder that is characterized by a segmental dermatomal facial port-wine stain birthmark and is frequently accompanied by ipsilateral brain and eye abnormalities. We present a case of a patient with SWS who exhibited hypogonadotropic hypogonadism, growth hormone (GH) deficiency, and central hypothyroidism at the age of 20 despite the absence of radiographic findings in the pituitary and hypothalamus. CASE PRESENTATION: A 20-year-old male with SWS with epilepsy and Klippel-Trenaunay syndrome presents with delayed pubertal development, short stature, and obesity. Upon further examination, he was found to have biochemical and clinical evidence of hypogonadism, hypothyroidism, and GH deficiency. A pituitary MRI displayed no abnormalities of the pituitary or hypothalamus. Treatment with testosterone cypionate and levothyroxine was initiated. Despite successful pubertal induction, IGF-1 levels have remained low and treatment with recombinant human growth hormone (rhGH) is now being considered for metabolic benefits. CONCLUSIONS: This case emphasizes the importance of endocrine evaluation and treatment of hormonal deficiencies in patients with SWS despite the absence of radiographic findings.

Multiple Deep Vein Thromboses After Curative Surgery for Cushing Disease: A Case Presentation and Review.

Background/Objective: Cushing syndrome (CS) is a prothrombotic state associated with an increased risk of postoperative venous thrombosis. We aim to present the case of a patient with Cushing disease who underwent pituitary surgery and subsequently developed acute lower extremity deep venous thromboses after anticoagulation was stopped. Case Report: We present the case of a 57-year-old woman who was admitted for intra-abdominal abscesses after a gastric bypass surgery and was found to have evidence of severe CS. Her 24-hour urinary free cortisol level was 898.6 µg/24 h. She was diagnosed with Cushing disease and underwent transsphenoidal resection of a pituitary adenoma, with an appropriate postoperative drop in the cortisol level. She received thromboprophylaxis during hospitalization; however, this was discontinued upon discharge, on postoperative day 9, because she was ambulating. Five days after hospital discharge and 14 days after her surgery, she developed left lower extremity edema and was found to have 4 deep venous thromboses. Discussion: As previously described, thrombotic risk can be elevated for at least 1 month after surgery for CS, and thromboprophylaxis can decrease this risk. Conclusion: This case highlights the need for clear recommendations for the duration of postoperative thromboprophylaxis in patients with CS. Clinicians should consider continuing thromboprophylaxis for at least 1 month after surgery for CS.

A "Grave" Case of Mitral Regurgitation: Cardio-Obstetric Approach to Severe Mitral Regurgitation With Cardiogenic Shock.

A 26-year-old woman presented at 26 weeks of pregnancy with severe mitral regurgitation (MR) and cardiogenic shock in the setting of profound hyperthyroidism. An intra-aortic balloon pump was placed, and surgical intervention was considered. However, with management of thyrotoxicosis and delivery, complete resolution of MR and cardiogenic shock was achieved. (Level of Difficulty: Intermediate.).

Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults.

Administration of metformin increases healthspan and lifespan in model systems, and evidence from clinical trials and observational studies suggests that metformin delays a variety of age-related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~70-year-old participants (n = 14) in a randomized, double-blind, placebo-controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Following each treatment period, skeletal muscle and subcutaneous adipose tissue biopsies were obtained, and a mixed-meal challenge test was performed. As expected, metformin therapy lowered 2-hour glucose, insulin AUC, and insulin secretion compared to placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and nonmetabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR and SREBP signaling, mitochondrial fatty acid oxidation, and collagen trimerization in adipose. While each tissue had a signature reflecting its own function, we identified a cascade of predictive upstream transcriptional regulators, including mTORC1, MYC, TNF, TGFß1, and miRNA-29b that may explain tissue-specific transcriptomic changes in response to metformin treatment. This study provides the first evidence that, in older adults, metformin has metabolic and nonmetabolic effects linked to aging. These data can inform the development of biomarkers for the effects of metformin, and potentially other drugs, on key aging pathways.

An Unusual Case of Metastatic Functional Thyroid Carcinoma With a Remarkable Treatment Response to Radioactive Iodine.

Functional thyroid carcinoma is an unusual cause of thyrotoxicosis. We describe the clinical presentation and treatment of a patient with thyrotoxicosis due to functional thyroid carcinoma and Graves disease, and discuss potential mechanisms causing the thyrotoxicosis. A 79-year-old woman with a remote history of hemithyroidectomy and current hyperthyroidism came to the hospital with upper and lower extremity weakness. Hospital evaluation revealed a suppressed thyroid-stimulating hormone (TSH) level, positive test for thyroid-stimulating immunoglobulins, as well as a thyroid nodule, lung masses, and a 4.4-cm gluteal mass. Fine-needle aspiration of the gluteal mass revealed metastatic differentiated thyroid carcinoma. Even after completion thyroidectomy and excision of her gluteal mass, her hyperthyroid status continued when she was not receiving levothyroxine. A radioactive iodine uptake and scan revealed unusually high lung uptake of 40%, and she was successfully treated with radioactive iodine (RAI) despite complete TSH suppression. The patient developed hypothyroidism 2 months after RAI administration; 6 months after RAI administration, her thyroglobulin (Tg) levels had fallen from a peak of 1976 ng/mL to 1.4 ng/mL. She had no anti-Tg antibodies. Repeated positron emission tomography-computed tomography nearly 1 year after RAI treatment shows substantial regression in the lung nodules, and Tg measured by mass spectroscopy is undetectable. This case demonstrates that thyrotoxicosis in the setting of metastatic thyroid carcinoma may be the result of functional thyroid carcinoma and may be successfully treated with selective surgery and RAI administration.

Longitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study.

INTRODUCTION: Natriuretic peptides have a well-recognized role in cardiovascular homeostasis. Recently, higher levels of B-type natriuretic peptide (BNP) have also been associated with decreased risk of diabetes in middle-aged adults. Whether this association persists into older age, where the pathophysiology of diabetes changes, has not been established, nor has its intermediate pathways. METHODS: We investigated the relationship between N-terminal (NT)-proBNP and incident diabetes in 2359 older adults free of cardiovascular disease or chronic kidney disease in the Cardiovascular Health Study. RESULTS: We documented 348 incident cases of diabetes over 12.6years of median follow-up. After adjusting for age, sex, race, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL, each doubling of NT-proBNP was associated with a 9% lower risk of incident diabetes (HR=0.91 [95% CI: 0.84-0.99]). Additional adjustment for waist circumference, physical activity, estimated glomerular filtration rate or C-reactive protein did not influence the association. Among putative mediators, HDL and triglycerides, adiponectin, and especially homeostasis model assessment of insulin resistance, all appeared to account for a portion of the lower risk associated with NT-proBNP. CONCLUSION: In older adults without prevalent cardiovascular or kidney disease, higher NT-proBNP is associated with decreased risk of incident diabetes even after adjustment for traditional risk factors. These findings suggest that the metabolic effects of natriuretic peptides persist late in life and offer a potential therapeutic target for prevention of diabetes in older people.

Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.

BACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse. METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic. RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models. CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.

Medullary thyroid cancer with undetectable serum calcitonin.

CONTEXT: Calcitonin is a sensitive biomarker that is used for diagnosis and follow-up in medullary thyroid cancer (MTC). In patients with tumors > 1 cm, it is uncommon for preoperative serum calcitonin to be in the normal laboratory reference range in patients with MTC, and even more unusual for serum calcitonin to be undetectable. THE CASE: A 39-year-old woman was found to have a left thyroid nodule on magnetic resonance imaging done for neck pain. Ultrasound and fine-needle aspiration biopsy were performed, and cytopathology was positive for malignant cells. The cells also had features suggestive of a neuroendocrine tumor, and the specimen was immune-stained with calcitonin. There was positive immunoreactivity for calcitonin in isolated cells of the cytospin, highly favoring a diagnosis of MTC. Serum calcitonin was < 2 pg/mL (<6 pg/mL), and serum carcinoembryonic antigen was 3.1 ng/mL (<5.2 ng/mL). Given the low calcitonin levels, procalcitonin was also tested and was elevated at 0.21 ng/mL (< 0.1 ng/mL). The patient subsequently underwent a total thyroidectomy and central and ipsilateral lateral lymph node dissection. Histopathology confirmed a 2.6 × 2.0 × 1.2-cm MTC, with strong, diffuse immunostaining for calcitonin. Postoperatively, serum calcitonin has remained undetectable, carcinoembryonic antigen has remained within the reference range, and procalcitonin has become undetectable. CONCLUSIONS: We present a rare case of a patient with MTC with undetectable preoperative serum calcitonin, whose tumor demonstrated strong, diffuse immunohistochemical staining for calcitonin. We discuss the possible pathogenesis of calcitonin-negative MTC and the challenges in following patients with this condition.

The clinical impact of inpatient hypoglycemia.

Hypoglycemia is common in hospitalized patients and is associated with poor outcomes, including increased mortality. Older individuals and those with comorbidities are more likely to suffer the adverse consequences of inpatient hypoglycemia. Observational studies have shown that spontaneous inpatient hypoglycemia is a greater risk factor for death than iatrogenic hypoglycemia, suggesting that hypoglycemia acts as a marker for more severe illness, and may not directly cause death. Initial randomized controlled trials of intensive insulin therapy in intensive care units demonstrated improvements in mortality with tight glycemic control, despite high rates of hypoglycemia. However, follow-up studies have not confirmed these initial findings, and the largest NICE-SUGAR study showed an increase in mortality in the tight control group. Despite these recent findings, a causal link between hypoglycemia and mortality has not been clearly established. Nonetheless, there is potential for harm from inpatient hypoglycemia, so evidence-based strategies to treat hyperglycemia, while preventing hypoglycemia should be instituted, in accordance with current practice guidelines.

Adrenal cortical carcinoma with late pulmonary metastases causing clinicical Cushing's syndrome: case report with immunohistochemical analysis of steriodogenic enzyme production.

OBJECTIVE: To present a case of pulmonary metastases from adrenocortical carcinomas (ACC) that were secreting fully-functional cortisol resulting in clinical Cushing's syndrome and to compare the steroidogenic enzyme expression in the primary tumor and lung. METHODS: We analyzed and summarized the patient's medical history, physical examination results, laboratory data, imaging studies, and histopathologic results. The original tumor and the pulmonary metastases were then immunohistochemically evaluated for steroidogenic enzymes. RESULTS: Initial endocrinological workup revealed hyperandrogenism and adrenocorticotropic hormone (ACTH) independent Cushing's due to a 4 cm left adrenal mass. The patient was initially diagnosed with an adrenal adenoma. Four years later, the patient developed recurrent Cushing's syndrome. Repeat magnetic resonance imaging (MRI) showed no adrenal masses; however, chest computed tomography (CT) showed multiple bilateral lung nodules and biopsy revealed metastases of adrenal origin. Upon immunohistochemical analysis, side chain cleavage, 17α hydroxylase, 3ß hydroxysteroid dehydrogenase, and 21 hydroxylase immunoreactivity were detected in both the original and pulmonary metastatic lesions with patterns of disorganized steroidogenesis. Dehydroepiandrosterone-sulfotransferase (DHEA-ST) immunoreactivity was detected in the original tumor but not in the lung metastases. CONCLUSION: This case demonstrates some interesting features of ACC that pose challenges to its management, including the difficulties in establishing the pathologic diagnosis, the potential for fully functional steroidogenesis even in late metastases, and the plasticity of steroidogenic potential in tumor cells.