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Hyperglycemia is the consequence of blood glucose dysregulation and a driving force of diabetic complications including retinopathy, nephropathy and cardiovascular diseases. The serum and glucocorticoid inducible kinase-1 (SGK1) has been suggested in the modulation of various pathophysiological activities. However, the role of SGK1 in blood glucose homeostasis remains less appreciated. In this review, we intend to summarize the function of SGK1 in glucose level regulation and to examine the evidence supporting the therapeutic potential of SGK1 inhibitors in hyperglycemia. Ample evidence points to the controversial roles of SGK1 in pancreatic insulin secretion and peripheral insulin sensitivity, which reflects the complex interplay between SGK1 activation and blood glucose fluctuation. Furthermore, SGK1 is engaged in glucose absorption and excretion in intestine and kidney and participates in the progression of hyperglycemia-induced secondary organ damage. As a net effect, blockage of SGK1 activation via either pharmacological inhibition or genetic manipulation seems to be helpful in glucose control at varying diabetic stages.

In the context of reproduction, glucocorticoids (GCs) are generally considered to have negative effects. However, in well-studied model species, GCs fluctuate predictability across the estrous cycles, and short-term increases promote healthy ovarian function. Reproductive challenges have plagued captive elephant populations, which are not currently self-sustaining. Efforts to understand reproductive dysfunction in elephants have focused on the suppressive effects of cortisol, but the potential permissive or stimulatory effects of cortisol are unknown. In this study, we provide a detailed examination of cortisol patterns across the estrous cycle in Asian elephants (Elephas maximus). Time series analysis was used to analyze cortisol and progesterone data for a total of 73 cycles from eight females. We also compared cortisol profiles between females that successfully conceived and females that failed to conceive despite repeated mating attempts. Our results revealed that cortisol fluctuates predictably across the estrous cycle, with a peak during the second half of the follicular phase followed by low levels throughout the luteal phase. Furthermore, this pattern was significantly altered in nulliparous females; cortisol concentrations did not decline during the luteal phase to the same extent as in parous females. This study highlights the complexity of cortisol signaling and suggests future directions for understanding the role of cortisol in reproductive dysfunction.

The distinction between pseudo-Cushing’s states (PCS) and Cushing’s syndrome (CS) poses a significant clinical challenge even for expert endocrinologists. A patient’s clinical history can sometimes help to distinguish between them (as in the case of alcoholic individuals), but the overlap in clinical and laboratory findings makes it difficult to arrive at a definitive diagnosis. We aim to describe the most common situations that can give rise to a condition resembling overt endogenous hypercortisolism and try to answer questions that physicians often face in clinical practice. It is important to know the relative prevalence of these different situations, bearing in mind that most of the conditions generating PCS are relatively common (such as metabolic syndrome and polycystic ovary syndrome), while CS is rare in the general population. Physicians should consider CS in the presence of additional features. Appropriate treatment of underlying conditions is essential as it can reverse the hormonal abnormalities associated with PCS. Close surveillance and a thorough assessment of a patient’s hormone status will ultimately orient the diagnosis and treatment options over time.

Steroid hormones play clinically important and specific regulatory roles in the development, growth, metabolism, reproduction and brain function in human. The type 1 and 2 11-beta hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 2) have key roles in the pre-receptor modification of glucocorticoids allowing aldosterone regulation of blood pressure, control of systemic fluid and electrolyte homeostasis and modulation of integrated metabolism and brain function. Although the activity and function of 11β-HSDs is thought to be understood, there exists an open reading frame for a distinct 11βHSD-like gene; HSD11B1L, which is present in human, non-human primate, sheep, pig and many other higher organisms, whereas an orthologue is absent in the genomes of mouse, rat and rabbit. We have now characterised this novel HSD11B1L gene as encoded by 9 exons and analysis of EST library transcripts indicated the use of two alternate ATG start sites in exons 2 and 3, and alternate splicing in exon 9. Relatively strong HSD11B1L gene expression was detected in human, non-human primate and sheep tissue samples from the brain, ovary and testis. Analysis in non-human primates and sheep by immunohistochemistry localised HSD11B1L protein to the cytoplasm of ovarian granulosa cells, testis Leydig cells, and gonadatroph cells in the anterior pituitary. Intracellular localisation analysis in transfected human HEK293 cells showed HSD1L protein within the endoplasmic reticulum and sequence analysis suggests that similar to 11βHSD1 it is membrane bound. The endogenous substrate of this third HSD enzyme remains elusive with localisation and expression data suggesting a reproductive hormone as a likely substrate.

Glucocorticoids (GC) are used for the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited, amongst others, by adverse effects on bone. The Wnt and bone formation inhibitor sclerostin was recently implicated in the pathogenesis of GC-induced osteoporosis. However, data are ambiguous. The aim of this study was to assess the regulation of sclerostin by GC using several mouse models with high GC levels and two independent cohorts of patients treated with GC. Male 24-week-old C57BL/6 and 18-week-old DBA/1 mice exposed to GC and 12-week-old mice with endogenous hypercortisolism displayed reduced bone formation as indicated by reduced levels of P1NP and increased serum sclerostin levels. The expression of sclerostin in femoral bone tissue and GC-treated bone marrow stromal cells, however, was not consistently altered. In contrast, GC dose- and time-dependently suppressed sclerostin at mRNA and protein levels in human mesenchymal stromal cells, and this effect was GC receptor dependent. In line with the human cell culture data, patients with rheumatoid arthritis (RA, n = 101) and polymyalgia rheumatica (PMR, n = 21) who were exposed to GC had lower serum levels of sclerostin than healthy age- and sex-matched controls (−40%, P < 0.01 and −26.5%, P < 0.001, respectively). In summary, sclerostin appears to be differentially regulated by GC in mice and humans as it is suppressed by GCs in humans but is not consistently altered in mice. Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.

Pancreatic islets from pregnant rats develop a transitory increase in the pancreatic β-cell proliferation rate and mass. Increased apoptosis during early lactation contributes to the rapid reversal of those morphological changes. Exposure to synthetic glucocorticoids during pregnancy has been previously reported to impair insulin secretion, but its impacts on pancreatic islet morphological changes during pregnancy and lactation have not been described. To address this issue, we assessed the morphological and molecular characteristics of pancreatic islets from rats that underwent undisturbed pregnancy (CTL) or were treated with dexamethasone between the 14th and 19th days of pregnancy (DEX). Pancreatic islets were analyzed on the 20th day of pregnancy (P20) and on the 3rd, 8th, 14th and 21st days of lactation (L3, L8, L14 and L21, respectively). Pancreatic islets from CTL rats exhibited transitory increases in cellular proliferation and pancreatic β-cell mass at P20, which were reversed at L3, when a transitory increase in apoptosis was observed. This was followed by the appearance of morphological features of pancreatic islet neogenesis at L8. Islets from DEX rats did not demonstrate an increase in apoptosis at L3, which coincided with an increase in the expression of M2 macrophage markers relative to M1 macrophage and T lymphocyte markers. Islets from DEX rats also did not exhibit the morphological characteristics of pancreatic islet neogenesis at L8. Our data demonstrate that maternal pancreatic islets undergo a renewal process during lactation that is impaired by exposure to DEX during pregnancy.