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.

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.