Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus.

AIM: The aim of the present study was to assess the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus. METHODS: A total of 188 patients were enrolled who had type 2 diabetes mellitus with poor glycemic profiles (hemoglobin A1c [HbA1c] ≥6.2%). Patients were assigned to one of three age groups (<65, 65-74 and ≥75 years) and received 50-100 mg of sitagliptin daily for 12 months. Changes in HbA1c classified by age and body mass index (BMI) were assessed in addition to physiological parameters. RESULTS: Mean HbA1c decreased significantly in all age groups (<65 years 8.01 ± 1.59% to 7.29 ± 1.23%; 65-74 years 7.61 ± 1.11% to 7.05 ± 0.99%; ≥75 years 7.21 ± 0.87% to 6.74 ± 0.96%). Reductions in HbA1c were not significantly different among age groups (P = 0.324). In older patients aged 65-74 years and ≥75 years, HbA1c decreased significantly in lean (BMI <25 kg/m2 ) patients (7.52 ± 1.10% to 6.99 ± 1.08%; P < 0.001) and in obese (BMI ≥25 kg/m2 ) patients (7.25% ± 0.90% to 6.86% ± 0.86%; P = 0.015); the changes in HbA1c were not significantly different between the lean and the obese groups (P = 0.943). Adverse events occurred in 12 patients (10.3%) aged ≥65 years, although there was no significant difference among the three age groups. CONCLUSIONS: Sitagliptin treatment offers elderly patients aged ≥65 years efficacious and safe reductions in HbA1c values regardless of BMI. Geriatr Gerontol Int 2018; 18: 631-639.

Effects of sitagliptin beyond glycemic control: focus on quality of life.

BACKGROUND: Recently, incretin hormones, including glucagon-like peptide-1 (GLP-1) analogue and dipeptidyl peptidase-4 (DPP-4) inhibitor, have been found to regulate glucose metabolism. The aim of this study was to elucidate the efficacy and safety of the clinical usage of DPP-4 inhibitors in Japan. METHODS: This study was designed as a prospective, open-label, multi-center trial. Patients with diabetes mellitus type 2 (T2DM) with poor glycemic profiles (HbA1c ≥ 6.2%) in spite of receiving a medical diet, therapeutic exercise, and/or medications were eligible for this study. The participants received 50 to 100 mg of the DPP-4 inhibitor sitagliptin once daily for 12 months. RESULTS: One hundred and eighty-eight subjects were enrolled. After 12 months of sitagliptin treatment, HbA1c levels decreased (7.65% ± 1.32% to 7.05% ± 1.10%, p < 0.001) as well as fasting plasma glucose (FPG) (145 ± 52 mg/dl to 129 ± 43 mg/dl, p = 0.005). The rate of glycemic control achieved (in accordance with the guidelines of the Japanese Diabetes Society) significantly increased. Blood pressure and serum levels of triglycerides and total cholesterol decreased significantly. Furthermore, the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Symptomatic Scores improved significantly. Adverse events such as hypoglycemia and loss of consciousness occurred in twenty three subjects (11%). CONCLUSIONS: These results suggest that the actions of DPP-4 inhibitors improve not only glycemic control, but also blood pressure, lipid profiles, and quality of life (QOL). Sitagliptin is a sound agent for use in the comprehensive treatment of patients with T2DM.

6-Deoxy-6-[131I]iodo-L-ascorbic acid for the in vivo study of ascorbate: autoradiography, biodistribution in normal and hypolipidemic rats, and in tumor-bearing nude mice.

Normal female rat distribution studies showed high and specific uptake of 6-deoxy-6-[(131)I]iodo-L-ascorbic acid (6-(131)IAsA) into the adrenal glands, known to highly express the ascorbate sodium-dependent vitamin C transporter-2 (SVCT-2), and the adrenal gland was clearly visualized by whole-body autoradiography. Preinjection of sulfinpyrazone, a known blocker of ascorbate transport, with 6-(131)IAsA resulted in decreased uptake of radioactivity in rat adrenal glands compared to the control group, seemingly illustrating the participation of the SVCT transporter (probably the SVCT-2 subtype) in the uptake process in vivo. 4-Aminopyrazolo[3,4-d]pyrimidine-induced hypolipidemic rats showed a 1.7-fold increase in adrenal uptake of radioactivity at 30 min postinjection of 6-(131)IAsA, compared to the control, with increased adrenal-to-liver and adrenal-to-kidney ratios. To further characterize 6-(131)IAsA for its tumor uptake properties, biodistribution studies were also performed using male nude mice implanted with either Y-1 adrenocortical tumor cells or adrenal medulla-derived PC12 cells. None of these tumors exhibited relevant uptake of 6-(131)IAsA while normal adrenal glands showed high uptake of radioactivity, suggesting that these tumors in this model have only a poor transport capacity for this agent. The present study demonstrates that the use of radioiodinated 6-IAsA may help to obtain information about functional alterations in diseased adrenal glands, but it does not exhibit desirable properties as a tumor-seeking agent for ascorbic acid bioactivity.

Adipose tissue-derived and bone marrow-derived mesenchymal cells develop into different lineage of steroidogenic cells by forced expression of steroidogenic factor 1.

Steroidogenic factor 1 (SF-1)/adrenal 4 binding protein is an essential nuclear receptor for steroidogenesis, as well as for adrenal and gonadal gland development. We have previously clarified that adenovirus-mediated forced expression of SF-1 can transform long-term cultured mouse bone marrow mesenchymal cells (BMCs) into ACTH-responsive steroidogenic cells. In the present study, we extended this work to adipose tissue-derived mesenchymal cells (AMCs) and compared its steroidogenic capacity with those of BMCs prepared from the identical mouse. Several cell surface markers, including potential mesenchymal cell markers, were identical in both cell types, and, as expected, forced expression of SF-1 caused AMCs to be transformed into ACTH-responsive steroidogenic cells. However, more elaborate studies revealed that the steroidogenic property of AMCs was rather different from that of BMCs, especially in steroidogenic lineage. In response to increased SF-1 expression and/or treatment with retinoic acid, AMCs were much more prone to produce adrenal steroid, corticosterone rather than gonadal steroid, testosterone, whereas the contrary was evident in BMCs. Such marked differences in steroidogenic profiles between AMCs and BMCs were also evident by the changes of steroidogenic enzymes. These novel results suggest a promising utility of AMCs for autologous cell regeneration therapy for patients with steroid insufficiency and also a necessity for appropriate tissue selection in preparing mesenchymal stem cells according to the aim. The different steroidogenic potency of AMCs or BMCs might provide a good model for the clarification of the mechanism of tissue- or cell-specific adrenal and gonadal steroidogenic cell differentiation.

Methylation of a conserved intronic CpG island of mouse SF-1 is associated with cell-specific expression of SF-1 in a culture system but not with tissue-specific expression.

The mechanism for the steroidogenic tissue or cell-specific expression of SF-1 has not been well clarified. We examined whether the methylation status of a large CpG island in the first intron of mouse SF-1 gene is associated with the expression level of SF-1 in cultured cells and in tissues. The island consists of three small islands (ICI-1, ICI-2, and ICI-3). In cultured adrenocortical Y-1 cells and in Leydig tumor cells, I-10, that both express high levels of SF-1, the upstream region of ICI-2, ICI-2-1, was clearly hypomethylated compared to cultured mouse bone marrow cells that do not express SF-1. However, this methylation status was not clearly associated with the tissue-specific expression of SF-1, in either adult or during development. These results suggest that methylation of ICI-2-1of SF-1 may partly determine the level of SF-1 expression at the cellular level, but may not be essential at the tissue level.

Steroidogenic factor 1/adrenal 4 binding protein transforms human bone marrow mesenchymal cells into steroidogenic cells.

Steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP) is an essential nuclear receptor for steroidogenesis as well as for adrenal and gonadal gland development. Mesenchymal bone marrow cells (BMCs) contain pluripotent progenitor cells, which differentiate into multiple lineages. In a previous study, we reported that adenovirus-mediated forced expression of SF-1 could transform mouse primary long-term cultured BMCs into steroidogenic cells. For future clinical application, trials using human BMCs would be indispensable. In this study, we examined whether SF-1 could transform human BMCs into steroidogenic cells and compared the steroid profile of these cells with that of mouse steroidogenic BMCs. Primary cultured human BMCs infected with adenovirus containing bovine SF-1 cDNA could produce progesterone, corticosterone, cortisol, dehydroepiandrosterone, testosterone, and estradiol. Such a mixed character of adrenal and gonadal steroid production in human BMCs was supported by the expressions of P450scc, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), P450c21, P450c11, P450c17, 17beta-HSD, and P450arom mRNAs. Unlike mouse steroidogenic BMCs, introduction of SF-1 into human BMCs caused dramatic inductions of both ACTH and LH receptors, thus leading to good responsiveness of the cells to ACTH and LH respectively. Importantly, among several factors that are known to be closely associated with adrenal and/or gonadal development, introduction of only SF-1 enabled the human BMCs to express P450scc and to produce cortisol and testosterone, suggesting that SF-1 is truly a master regulator for the production of steroidogenic cells from human BMCs.

Atrazine-induced aromatase expression is SF-1 dependent: implications for endocrine disruption in wildlife and reproductive cancers in humans.

BACKGROUND: Atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. The mechanism involves the inhibition of phosphodiesterase and subsequent elevation of cAMP. METHODS: We compared steroidogenic factor 1 (SF-1) expression in atrazine responsive and non-responsive cell lines and transfected SF-1 into nonresponsive cell lines to assess SF-1's role in atrazine-induced aromatase. We used a luciferase reporter driven by the SF-1-dependent aromatase promoter (ArPII) to examine activation of this promoter by atrazine and the related simazine. We mutated the SF-1 binding site to confirm the role of SF-1. We also examined effects of 55 other chemicals. Finally, we examined the ability of atrazine and simazine to bind to SF-1 and enhance SF-1 binding to ArPII. RESULTS: Atrazine-responsive adrenal carcinoma cells (H295R) expressed 54 times more SF-1 than nonresponsive ovarian granulosa KGN cells. Exogenous SF-1 conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells. Atrazine induced binding of SF-1 to chromatin and mutation of the SF-1 binding site in ArPII eliminated SF-1 binding and atrazine-responsiveness in H295R cells. Out of 55 chemicals examined, only atrazine, simazine, and benzopyrene induced luciferase via ArPII. Atrazine bound directly to SF-1, showing that atrazine is a ligand for this "orphan" receptor. CONCLUSION: The current findings are consistent with atrazine's endocrine-disrupting effects in fish, amphibians, and reptiles; the induction of mammary and prostate cancer in laboratory rodents; and correlations between atrazine and similar reproductive cancers in humans. This study highlights the importance of atrazine as a risk factor in endocrine disruption in wildlife and reproductive cancers in laboratory rodents and humans.

Herbicide atrazine activates SF-1 by direct affinity and concomitant co-activators recruitments to induce aromatase expression via promoter II.

The popular herbicide atrazine is an endocrine disruptor that demasculinizes and feminizes several species of animals, and co-relates with breast and reproductive disorders in mammalians. We recently reported that atrazine induces human aromatase gene expression via promoter II (ArPII) in a steroidogenic factor 1 (SF-1)-dependent manner. Here, we show that knockdown of SF-1 abolishes ArPII induction by atrazine in H295R cells, which harbor high SF-1 expression and are originally atrazine-responsive. Conversely, exogenous SF-1 enables atrazine to induce ArPII in the otherwise non-responsive KGN cells. Atrazine's effect is independent from protein kinase A and LRH-1, a close relative of SF-1. However, it binds directly to the SF-1, and concomitantly, enhances interactions of SF-1 with co-activator TIF2, and renders more SF-1 binding to ArPII chromatin. Intriguingly, LBD mutations do not alter SF-1's ability to mediate atrazine stimulation, suggesting that atrazine interacts with SF-1 via a region(s) other than the ligand binding pocket. These data suggest that atrazine binds to and activates SF-1 to induce ArPII.

Modification of glucocorticoid sensitivity by MAP kinase signaling pathways in glucocorticoid-induced T-cell apoptosis.

OBJECTIVE: Glucocorticoid is widely used for the treatment of diseases such as hematological malignancies. Glucocorticoid sensitivity is different from person to person and the mechanism of the regulation of glucocorticoid sensitivity is not well known. Glucocorticoid resistance is a major clinical problem. METHODS AND RESULTS: Here, using glucocorticoid-induced T-cell apoptosis, a model system for the analysis of the mechanism of glucocorticoid action, we clarified that mitogen-activated protein kinases (MAPKs) modify glucocorticoid sensitivity, namely that the activation of extracellular signal-regulated protein kinase (ERK) and p38 MAP kinase reduce and enhance glucocorticoid sensitivity, respectively. CONCLUSION: These findings might provide new tools for overcoming glucocorticoid-resistance.

Differentiation and regeneration of adrenal tissues: An initial step toward regeneration therapy for steroid insufficiency.

In animal experiments, adrenal cortical tissue has been successfully regenerated through xenotransplantation of cloned adrenocortical cells, suggesting that the intraadrenal stem cells required for such tissue formation may be present in the adrenal cortex. Stable expression of Ad4BP/SF-1, a key factor for adrenal and gonadal development and steroidogenesis, has been shown to direct embryonic stem cells toward the steroidogenic lineage. However, this steroidogenic capacity was very limited since progesterone was only produced in the presence of an exogenous substrate. Bone marrow mesenchymal cells are thought to contain pluripotent progenitor cells, which differentiate into multiple lineages. We have demonstrated that adenovirus-mediated forced expression of SF-1 in long-term cultured bone marrow cells can produce steroidogenic cells with the capacity for de novo synthesis of various steroid hormones in response to ACTH. This discovery may represent the first step in autologous cell transplantation therapy for patients with steroid hormone deficiency.

SF-1/Ad4BP transforms primary long-term cultured bone marrow cells into ACTH-responsive steroidogenic cells.

Bone marrow stem cells develop into haematopoietic and mesenchymal lineages, but have not been known to participate in steroidogenic cell production. Steroidogenic factor 1 (SF-1), also designated adrenal 4 binding protein (Ad4BP), is an essential orphan nuclear receptor for steroidogenesis as well as for adrenal and gonadal gland development. In the present study, we revealed that the adenovirus-mediated forced expression of SF-1 can transform cultured primary long-term cultured bone marrow cells into steroidogenic cells, showing the de novo synthesis of multiple steroid hormones in response to adrenocorticotropic hormone (ACTH). This finding may provide an initial step in innovative autograft cell transfer therapy for steroid hormone deficiencies.

[Trials of regeneration and gene therapies in endocrine organs, especially in adrenal glands].

Recent progress in trials of regeneration and gene therapy in endocrine organs, especially in adrenal glands has been reviewed. Gene therapies using adenovirus have been most frequently tested in vivo and in vitro, aiming at improvement of steroidogenesis and suppression of adrenal tumor growth. Although the effects were temporal, promising results have been obtained. Interestingly, adrenocortical tissue was shown to be formed by transplantation of adrenocortical cells and to replace the adrenal functions of adrenalectomized animals. Engineered ES cells stably expressing Ad4BP/SF-1 were shown to be directed toward steroidogenic lineage, suggesting a future possibility of regeneration of adrenal cells.