Animal models have been used extensively in diabetes research. Early studies used pancreatectomised dogs to confirm the central role of the pancreas in glucose homeostasis, culminating in the discovery and purification of insulin. Today, animal experimentation is contentious and subject to legal and ethical restrictions that vary throughout the world. Most experiments are carried out on rodents, although some studies are still performed on larger animals. Several toxins, including streptozotocin and alloxan, induce hyperglycaemia in rats and mice. Selective inbreeding has produced several strains of animal that are considered reasonable models of Type 1 diabetes, Type 2 diabetes and related phenotypes such as obesity and insulin resistance. Apart from their use in studying the pathogenesis of the disease and its complications, all new treatments for diabetes, including islet cell transplantation and preventative strategies, are initially investigated in animals. In recent years, molecular biological techniques have produced a large number of new animal models for the study of diabetes, including knock‐in, generalized knock‐out and tissue‐specific knockout mice.

Transsphenoidal surgery is a safe and effective treatment for Cushing's disease and our results compare favourably with those from published series, the majority of which comprise relatively small numbers. The presence of an intrasellar lesion and postoperative serum cortisol < 50 nmol/l are good predictors of remission in the long term but historically in our centre this can only be achieved in a significant number of patients at the expense of some degree of hypopituitarism. However, the surgical outcome for Cushing's disease, including a reduced frequency of hypopituitarism, can be improved if patients are operated on by a single pituitary surgeon, using selective adenomectomy as the preferred surgical approach wherever possible.

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess.METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis.RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients.CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism.FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.

Cortisol is a steroid hormone produced in response to stress. It is essential for maintaining health and wellbeing and leads to significant morbidity when deficient or present in excess. It is lipophilic and is transported bound to cortisol-binding globulin (CBG) and albumin; a small fraction (∼10%) of total serum cortisol is unbound and biologically active. Serum cortisol assays measure total cortisol and their results can be misleading in patients with altered serum protein concentrations. Automated immunoassays are used to measure cortisol but lack specificity and show significant inter-assay differences. Liquid chromatography - tandem mass spectrometry (LC-MS/MS) offers improved specificity and sensitivity; however, cortisol cut-offs used in the short Synacthen and Dexamethasone suppression tests are yet to be validated for these assays. Urine free cortisol is used to screen for Cushing's syndrome. Unbound cortisol is excreted unchanged in the urine and 24-h urine free cortisol correlates well with mean serum-free cortisol in conditions of cortisol excess. Urine free cortisol is measured predominantly by immunoassay or LC-MS/MS. Salivary cortisol also reflects changes in unbound serum cortisol and offers a reliable alternative to measuring free cortisol in serum. LC-MS/MS is the method of choice for measuring salivary cortisol; however, its use is limited by the lack of a single, validated reference range and poorly standardized assays. This review examines the methods available for measuring cortisol in serum, urine and saliva, explores cortisol in disease and considers the difficulties of measuring cortisol in acutely unwell patients and in neonates.

We retrospectively analyzed 90 patients who underwent transsphenoidal surgery (performed by three surgeons) in our center as initial therapy for acromegaly. We used a combination of modern, evidence-based remission criteria including mean day curve GH less than 2.5 micro g/liter (5 mU/liter), a nadir GH less than 1.0 micro g/liter (2 mU/liter) after an oral glucose tolerance test, and normal age-related IGF-I levels (where available). Fifty-seven of 90 (63%) patients remained in remission after surgery. Seventy-nine percent of patients with microadenomas but only 56% of patients with macroadenomas achieved remission (P < 0.001). Eighty-six percent of patients with preoperative GH levels below 10 micro g/liter (day profile or after oral glucose tolerance test) went into remission, compared with 51% of patients with GH levels above 25 micro g/liter at diagnosis (P < 0.002). The remission rate was also related to the period of surgery that was significantly higher in 1998-2001 (76%; P < 0.05) compared with 1990-1997 (54%) and 1980-1989 (63%). There were no recurrences or perioperative deaths. Meningitis occurred in 3% of patients, cerebrospinal fluid rhinorrhea in 7%, and permanent diabetes insipidus in 15%. The proportion of patients who developed new anterior pituitary hormone deficiencies and panhypopituitarism was significantly less in the period 1998-2001 (P < 0.001) when compared with the periods from 1990-1997 and 1980-1989. Transsphenoidal surgery is a safe and effective treatment for acromegaly, and our results compare favorably with those from published series. The presence of an intrasellar lesion and low preoperative GH levels is a good predictor of remission in the long term, but historically in our center this can only be achieved in a significant proportion of patients at the expense of some degree of hypopituitarism. However, surgical outcome in our center, including a reduced frequency of hypopituitarism, has improved significantly over time, coincident with the arrival of a dedicated pituitary neurosurgeon and the use of selective adenomectomy as the preferred surgical approach wherever possible.