Cary N Mariash

Indiana University School of Medicine | IUSOM · Department of Medicine

Background Congenital Adrenal Hyperplasia (CAH) is classically attributed to defective 21-hydroxylase, caused by mutations in CYP21A2, impairing the production of mineralocorticoids and glucocorticoids and subsequently shifting steroidogenesis towards androgen production. This produces a classic constellation of neonatal symptoms, including genital...

Background/Objective Nonclassic Congenital Adrenal Hyperplasia (NCCAH) may be overlooked or mistaken for polycystic ovarian syndrome (PCOS). Unlike Congenital Adrenal Hyperplasia (CAH), the enzymatic activities of 21-hydroxylase or 11-β-hydroxylase in NCCAH are not completely lost. In this case, NCCAH presented in a patient with CYP21A2 and CYP11B1...

OBJECTIVE Differences in type 2 diabetes phenotype by age are described, but it is not known whether these differences are seen in a more uniformly defined adult population at a common early stage of care. We sought to characterize age-related clinical and metabolic characteristics of adults with type 2 diabetes on metformin monotherapy, prior to t...

[This corrects the article DOI: 10.3389/fendo.2021.662865.].

COVID-19, a multi-system disease, could potentially play a role in thyroid dysfunction. New reports show a prevalence of COVID-related thyroiditis. Recent studies suggest that there may be a higher risk of thyroiditis in the setting of SARS-CoV-2, and several cases of Graves' disease have been reported in individuals with SARS-CoV-2, although the i...

Introduction/purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, ht...

Introduction: Aromatase excess syndrome is a rare disorder with gynecomastia being the main symptoms. Its prevalence is unknown with approximately twenty cases reported. We describe an unusual case of Aromatase excess syndrome. It was diagnosed incidentally at a much older age than expected while evaluating for hypersomnia. Case presentation: A 28...

Background: Humoral hypercalcemia of malignancy is classically associated with increased tumor production of parathyroid hormone-related peptide (PTHrP). While 1,25 dihydroxy vitamin D (1,25D) mediated hypercalcemia has been demonstrated with a range of granulomatous disorders and lymphomas, there have only been 11 cases reported in ovarian dysgerm...

Introduction: Despite widespread use of insulin in diabetes, reports of intentional overdose are rare. Insulin kinetics are different in acute poisoning from that in therapeutic doses in part due to delayed absorption from the injection site and reduced clearance. We present a case of insulin glargine overdose where the peak serum insulin levels we...

This chapter investigates the role of thyroid hormones (TH) in late brain development. A lack of TH during late brain development results in permanent deficits in brain function, including intellectual development and behavior. The effects of TH on cellular development and brain gene transcription and the molecular basis of TH are also investigated...

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Objective: To describe the temporal distribution of hypoglycemia and its rate of recurrence during hospitalization to aid in the development of strategies to prevent hypoglycemia in hospitalized patients. Methods: Retrospective review of hypoglycemia (blood glucose <50 mg/dL) audit data in adult hospitalized patients at 2 academic hospitals. Dem...

Myxedema coma, a rare entity, with a reported 25%-65% mortality had no objective criteria for making the diagnosis when we began our study. We developed an objective screening tool for myxedema coma to more easily identify patients and examine the best treatment method in future prospective studies to reduce the mortality of this entity. We conduct...

The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary...

Objective: To provide a comprehensive review of the discovery and development of selective thyroid hormone receptor agonists and provide a discussion of their use in hyperlipidemia, obesity, and type 2 diabetes mellitus. Methods: Preclinical and clinical English language literature from 1930 to present was reviewed and thematically summarized....

Vitamin D has in vitro and in vivo effects on β cells and insulin sensitivity. Vitamin D deficiency (VDD) has been associated with the onset and progression of type 2 diabetes mellitus (DM-2). However, studies involving supplementation of vitamin D in subjects with previously established diabetes have demonstrated inconsistent effects on insulin se...

The Spot 14 (S14; Thrsp) gene has been implicated in supporting regulated lipogenesis in mammals. S14 gene expression in liver is controlled by a wide variety of hormones and dietary factors in parallel with the major lipogenic enzyme genes. In addition, mice deleted for the S14 gene display reduced de novo lipogenesis in the lactating mammary glan...

We created a Thrsp (Spot 14 or S14) null mouse (Thrsp(tm1cnm)) to study the role of Thrsp in de novo lipid synthesis. The Thrsp null mouse exhibits marked deficiencies in de novo lipogenesis in the lactating mammary gland. We now report the Thrsp gene deletion affects body weight and glucose tolerance associated with increased insulin sensitivity....

To demonstrate the direct stimulation of thyroid tissue in the absence of thyroid-stimulating immunoglobulin after exposure to epoprostenol. Seronegative thyrotoxicosis, diffuse goiter, and homogeneous uptake on thyroid scintigraphy were noted in a patient with pulmonary arterial hypertension (PAH) being treated with intravenously administered epop...

To determine whether a difference exists in the free thyroxine level required to achieve a normal thyrotropin (thyroid-stimulating hormone or TSH) level between patients with primary hypothyroidism and euthyroid control subjects and compare the free thyroxine levels in patients with primary and secondary hypothyroidism receiving thyroid hormone rep...

The Spot 14 (S14) gene is rapidly up-regulated by signals that induce lipogenesis such as enhanced glucose metabolism and thyroid hormone administration. Previous studies in S14 null mice show that S14 is required for normal lipogenesis in the lactating mammary gland, but not the liver. We speculated that the lack of a hepatic phenotype was due to...

Edema fluid resorption is critical for gas exchange and requires active epithelial ion transport by Na, K-ATPase and other ion transport proteins. In this study, we sought to determine if alveolar fluid clearance (AFC) is stimulated by 3,3',5 triiodo-L-thyronine (T(3)). AFC was measured in in situ ventilated lungs and ex vivo isolated lungs by inst...

Thyroid hormone (T3) increases Na-K-ATPase activity in rat adult alveolar type II cells via a PI3K-dependent pathway. In these cells, dopamine and beta-adrenergic agonists can stimulate Na-K-ATPase activity through either PI3K or MAPK pathways. We assessed the role of the MAPK pathway in the stimulation of Na-K-ATPase by T3. In the adult rat alveol...

Nongenomic actions of 3,3',5-triiodo-L-thyronine (T3) occur quite rapidly usually via activation of signaling cascades. In this review, we focus on recent advances made in the understanding of activation of the phosphatidylinositol 3-kinase pathway by T3 in alveolar epithelial cells, resulting in upregulation of Na,K-ATPase hydrolytic activity and...

Late in gestation, the developing air space epithelium switches from chloride and fluid secretion to sodium and fluid absorption. Absorption requires Na-K-ATPase acting in combination with apical sodium entry mechanisms. Hypothyroidism inhibits perinatal fluid resorption, and thyroid hormone [triiodothyronine (T3)] stimulates adult alveolar epithel...

Spot 14 (S14) is a protein whose mRNA is rapidly up-regulated by lipogenic stimuli including thyroid hormone and a high-carbohydrate diet. Previous investigation into the role of S14 suggested that it is involved in de novo lipogenesis. Knockout of the gene in mice has given further support to this hypothesis. The lack of S14 in different tissues r...

Spot 14 (S14) is a protein whose mRNA is rapidly up-regulated by lipogenic stimuli including thyroid hormone and a high-carbohydrate diet. Previous investigation into the role of S14 suggested that it is involved in de novo lipogenesis. Knockout of the gene in mice has given further support to this hypothesis. The lack of S14 in different tissues r...

Spot 14 (S14) is a 17 kD protein located in tissues that synthesize fatty acids. In the lactating mammary glands of S14 null mice there is significantly reduced triglyceride content due to a 70% reduction in lipogenesis with a 90% reduction in medium-chain fatty acids. However, the site and role of the S14 protein in the regulation of lipid synthes...

Anti-Gal is a natural antibody specific for the alpha-galactosyl epitope. Previous studies suggested that Graves' disease (GD) patients had elevated anti-Gal titers compared to normal controls, but titers returned to normal after treatment. We developed an anti-Gal enzyme-linked immunosorbent assay (ELISA) using the property of anti-Gal to bind tig...

We generated a Spot 14 null mouse to assess the role of Spot 14 in de novo lipid synthesis and report the Spot 14 null mouse exhibits a phenotype in the lactating mammary gland. Spot 14 null pups nursed by Spot 14 null dams gain significantly less weight than wild-type pups nursed by wild-type dams. In contrast, Spot 14 null pups nursed by heterozy...

We previously reported that thyroid hormone, 3,3′,5-triiodo-L- thyronine (T3), increased Na,K-ATPase activity of adult rat alveolar epithelial cells in a transcription-independent manner via increased cell surface expression of the α1 and β1 subunits of Na,K-ATPase. Now we sought to identify signaling molecules necessary for T3 stimulation of Na,K-...

Thyroid hormone (TH) is necessary for normal axonal myelination. Myelin basic protein (MBP) is a structural protein essential for myelin function. In this study, we demonstrate that perinatal hypothyroidism regulates MBP mRNA levels via indirect mechanisms. We observed decreased MBP mRNA accumulation in the hypothyroid rat brain at postnatal (PN) d...

Spot 14 is a 17-kDa protein expressed in lipogenic tissues and is postulated to play a role in thyroid hormone stimulation of lipogenesis. To further our understanding of Spot 14 regulation in humans, our laboratory recently cloned the human Spot 14 gene. The gene is highly homologous to the rat Spot 14 ortholog and located on a chromosomal region...

Na-K-ATPase protein is critical for maintaining cellular ion gradients and volume and for transepithelial ion transport in kidney and lung. Thyroid hormone, 3,3',5-triiodo-l-thyronine (T3), given for 2 days to adult rats, increases alveolar fluid resorption by 65%, but the mechanism is undefined. We tested the hypothesis that T3 stimulates Na-K-ATP...

Both in vivo and in primary rat hepatocyte culture, carbohydrate and triiodothyronine (T(3)) rapidly induce transcription of the rat S14 gene. To determine if regulation of this gene by T(3) is similar in human liver cells, we transfected the S14 upstream region into HepG2 cells. We chose this cell line because many others have used this cell line...

Thyroid hormone plays an important role in oligodendrocyte development. The studies presented here suggest that thyroid hormone is required for oligodendrocyte survival during development. Oligodendrocyte precursor cells, astrocytes and microglia were cultured in a defined media. Oligodendrocyte precursor cell differentiation was induced by growth...

This chapter discusses the molecular aspects of thyroid hormone (TH)-regulated behavior. TH has an important role during late brain development. A lack of TH during this time results in permanent deficits in brain function, including intellectual development and behavioral changes. TH also appears to exert effects on adult-brain function. Function...

Previous studies have investigated the relationship between the Spot 14 gene and hepatic lipogenesis. Those studies found that the Spot 14 protein was induced when lipogenesis was induced and suggested that induction of the Spot 14 protein was required for induction of hepatic lipogenesis by thyroid hormone and dietary carbohydrate. Analysis of tho...

Previous studies have shown that, in patients with primary alterations in thyroid hormone secretion, the level of the natural logarithm of serum TSH (lnTSH) is negatively related to the level of free T4. Because such patients can generally be assumed to exhibit normal tissue responsivity to thyroid hormone, we were interested in determining whether...

Thyroid hormone (T3) nuclear receptors (TR) are ligand-dependent transcription factors which regulate growth, differentiation, and development. One emerging hypothesis suggests that TR mediate these diverse effects via a large network of coregulators. Recently, we found that TR-mediated transcriptional responses varied in six cell lines derived fro...

Carbohydrate feeding increases the transcriptional activity of the hepatic S14 gene. The region of the S14 promoter between -1384/-1275 contributes to the transcriptional regulation by carbohydrate. A previously identified element (-1303/-1289) within this region is required but is not sufficient for the carbohydrate effect. Therefore, we ligated -...

In rat hepatocyte culture, the S14 gene is necessary for induction of lipogenesis by carbohydrate metabolism and thyroid hormone. To determine if this gene plays a role in regulation of lipid storage in humans we compared the response to fasting of the human S14 gene between obese and nonobese subjects. We measured the relative content of human S14...

The cerebellar Purkinje cell-specific PCP-2 gene is transcriptionally activated by thyroid hormone during the 2nd and 3rd weeks of postnatal life in the rat. In contrast, thyroid hormone has no detectable effects on PCP-2 expression in the fetal rat. We now present data that suggest that the orphan nuclear receptor chicken ovalbumin upstream promot...

In rat pups, thyroid hormone dependent brain development coincides with the appearance of the thyroid hormone receptor (TR)beta1 isoform. This finding led to the suggestion that TRbeta1 plays an essential role in brain development. The recent availability of a mouse TRbeta knockout strain allowed us to test this possibility by determining whether T...

Previous studies in our laboratory show that triiodothyronine upregulates expression of the cerebellar Purkinje cell-specific gene Pcp-2 during the first 2 weeks of rat neonatal life. A specific thyroid hormone response element, the A1 TRE, mediates this regulation. The finding that the contiguous 68 bases (-267/ -199) of the Pcp-2 promoter 3' to t...

The rat S14 gene has been a useful model to study carbohydrate and triiodothyronine (T3) regulation of hepatic gene expression. To gain insight into the regulation and function of the S14 gene, we isolated the human S14 gene and studied its sequence, tissue specific expression, and transcriptional regulation by glucose and T3. The deduced amino aci...

S14 is a nuclear protein that is rapidly and synergistically induced by glucose and thyroid hormone, and the level of it's messenger RNA correlates with hepatocyte and adipocyte lipogenesis. We previously reported that the calcium ionophore A23187 markedly inhibits the carbohydrate response of the S14 gene without inhibiting glucose metabolism. Bec...

Graves' disease has a multitude of presentations, and certain symptoms can mimic sports-related concerns such as overtraining. A review of three cases of Graves' disease in young athletes illustrates the spectrum of symptoms and the pathophysiology. Diagnosis involves a detailed patient history, physical exam, and appropriate lab studies, including...

Graves' disease has a multitude of presentations, and certain symptoms can mimic sports-related concerns such as overtraining. A review of three cases of Graves' disease in young athletes illustrates the spectrum of symptoms and the pathophysiology. Diagnosis involves a detailed patient history, physical exam, and appropriate lab studies, including...

To characterize the mechanism by which carbohydrate feeding regulates S14 gene transcription, we created mutations within footprinted sequences of the carbohydrate response region of the S14 gene and either transiently transfected these mutations into rat primary hepatocytes or end-labeled them for gel mobility shift assays. The wild type DNA gave...

S14 is a nuclear protein that is rapidly and synergistically induced by glucose and thyroid hormone, and the level of it's messenger RNA correlates with hepatocyte and adipocyte lipogenesis. We previously reported that the calcium ionophore A23187 markedly inhibits the carbohydrate response of the S14 gene without inhibiting glucose metabolism. Bec...

Feeding a lipogenic diet increases transcription and enhances processing of the rat hepatic messenger RNA (mRNA)-S14 gene. To determine the separate roles of insulin and increased glucose in these processes, we used the streptozotocin-induced diabetic rat model. Diabetes caused a reduction in mature mRNA-S14 in chow- and lipogenic diet-fed animals...

“Spot 14” is a nuclear protein that is rapidly induced by thyroid hormone (T3) and dietary carbohydrate in liver. We used an antisense oligonucleotide to inhibit induction of spot 14 protein by T3 and glucose in primary cultures of rat hepatocytes to test the hypothesis that the protein could function in the regulation of lipid synthesis. Spot 14 p...

Transcription of the rat S14 gene is induced in response to increased carbohydrate metabolism in the liver. Because carbohydrate-induced changes in lipogenesis are mediated in part by changes in phosphorylation of multiple proteins, we investigated the role of protein phosphorylation on transcriptional regulation of the two carbohydrate response el...

We found in preliminary experiments that multiple daily injections of triiodothyronine (T3) resulted in an apparent prolongation in the half time (t1/2) of mRNA-S14 decay. To appropriately interpret these observations, we developed a mathematical model of the fluctuations of mRNA-S14 and its nuclear precursor after a single injection or multiple da...

The rat S14 gene provides an excellent model to examine the DNA sequences associated with carbohydrate regulation of hepatic gene transcription. We constructed internal deletions within 5 kilobases of the 5'-up-stream region and ligated these to a luciferase reporter gene. The constructs were transfected into primary hepatocytes and pancreatic HIT...

The rat S14 gene provides an excellent model to examine the DNA sequences associated with carbohydrate regulation of hepatic gene transcription. We constructed internal deletions within 5 kilobases of the 5'-up-stream region and ligated these to a luciferase reporter gene. The constructs were transfected into primary hepatocytes and pancreatic HIT...

The rat S14 gene is synergistically regulated by thyroid hormone and carbohydrates. The 5'-flanking region of this gene contains both carbohydrate and thyroid hormone response elements (TREs). We recently located the carbohydrate response element (CHORE) between -1583 and -1069 bases from the start site of transcription that is required for glucose...

We have compared the dose of levothyroxine (L-T4) required to suppress serum TSH to given levels in two clinical groups: 1) 44 patients with thyroid cancer whose thyroid glands had been ablated by surgical thyroidectomy and 131I treatment, and 2) 113 patients with thyroidal failure due either to spontaneous primary hypothyroidism (31 patients) or a...

Carbohydrate administration rapidly regulates hepatic mRNA-S14 content. Both sucrose and fructose but not glucose increase the transcription of hepatic mRNA-S14 in vivo. In primary hepatocyte cultures, mRNA-S14 transcription responds to either fructose or glucose. To test the hypothesis that the difference in hexose response is due to differences i...

We report a simple and inexpensive method to quantitate loading and transfer of RNA and to examine RNA integrity for use with Northern hybridization. This technique involves quantitation by computer-assisted video densitometry of a negative photograph of 28S and 18S rRNA from ethidium bromide-stained RNA fixed to nylon membranes. This method elimin...

The rapid response of rat hepatic mRNA-S14 to hormonal or dietary manipulation makes it an excellent model to study the control of lipogenic enzyme mRNA. The mechanism of regulation of this mRNA by triiodothyronine (T3) or sucrose remains controversial. Although initial studies suggested that T3 stabilized the nuclear precursor, subsequent studies...

To compare the rate of local complications resulting from radioiodine ablation of thyroid cancer in patients with a residual intact thyroid lobe to that in patients who had more extensive surgical treatment prior to radioiodine administration. We retrospectively studied 59 patients who had received 131I between 1979 and 1989. The patients were divi...

We describe a technique for quantitation of viral DNA in blood leukocytes during viremic infection with human cytomegalovirus (CMV). Using a cloned subgenomic DNA probe and a blot hybridization assay, small amounts of viral DNA within samples of leukocyte DNA could be quantitated reproducibly using a videodensitometer. Critical components of the as...

Selection of appropriate laboratory determinations will enable the clinician to diagnose thyroid dysfunction readily in the majority of patients. At the present time, estimation of free thyroxine and a "sensitive" thyrotropin assay are recommended as the principal laboratory tests for thyroid disease. A decrease in serum free thyroxine estimate and...

We have compared the affinities for T3 and the T3 analog binding characteristics of the in vitro translational products of seven c-erbA cDNAs (chicken c-erbA alpha; human placental c-erbA beta; rat c-erbA beta-1; rat c-erbA alpha-1; rat c-erbA alpha-2; human testis c-erbA alpha-2; and human kidney c-erbA alpha-2). Four of these (chicken c-erbA alph...

We have examined the mechanism of the carbohydrate induction of rat hepatic mRNA-S14 to the intragastric administration of sucrose and its constituent hexoses, fructose and glucose. A maximal sucrose response (26-fold) was obtained with 2 ml of 60% sucrose/100 g of body weight, yet equimolar concentrations of fructose and glucose were not able to r...

In rat liver, triiodothyronine (T3) and dietary carbohydrate induce the expression of the genes coding for malic enzyme (ME) (EC 1.1.1.40) and S14 protein. The mRNAs for both ME and S14 are elevated under circumstances associated with augmented lipogenesis. Since the lag time in the induction of mRNA coding for S14 is short (20 min) and the lag tim...

In rat liver, triiodothyronine (T3) and dietary carbohydrate induce the expression of the genes coding for malic enzyme (ME) (EC 1.1.1.40) and S14 protein. The mRNAs for both ME and S14 are elevated under circumstances associated with augmented lipogenesis. Since the lag time in the induction of mRNA coding for S14 is short (20 min) and the lag tim...

To determine whether the rapid response of hepatic mRNA-S14 to carbohydrate feeding was associated with an alteration in a specific hepatic nucleotide, acid extracts of liver tissue were analyzed by ion-paired reverse phase HPLC. A nucleotide present in nanomoles per g quantity correlated with the induction of this mRNA by sucrose. Four hours after...