Endocrine Abstracts

A 71-year-old hypertensive and diabetic male patient was seen in the outpatient clinic for routine control. On laboratory examination his serum potassium level was 5.76 mmol/l and serum sodium level was 135 mmol/l. Control serum potassium level was 5.7 mmol/l. In past medical history he was prescribed telmisartan/hydrochlorothiazide combination (80 mg/12.5 mg) 1 month ago for treatment of hypertension. His other medications included nifedipine, fluvastatin sodium, aspirin, pio...

Objective: Diabetic ketoacidosis is one of the major complications in Diabetes. If not appropriately diagnosed and managed it could be life threatening. Our aim was to evaluate whether DKA was properly diagnosed, if prompt and appropriate treatment was initiated, to identify precipitants and to assess mortality.Method: We audited retrospectively patients admitted with DKA between August 2004 and August 2005. Management of DKA was audited against standard...

Introduction: We present a case of Dunnigan Kobberling type of lipodystrophy in a young female.Case report: A 25-year-old woman presented with hirsuitism, secondary amenorrhoea, increase in neck size and reduction in breast size. On examination she had moon like facies, broad neck, small breasts and well defined male pattern musculature. Testosterone and lutenising hormone were marginally raised, serum alanine transminase was raised. Overnight dexamethas...

We present the case of a Caucasian girl who in 1991 at the age of 4 started virilising and was diagnosed to have 21-hydroxylase deficiency. She started her periods at 10 and has been under regular follow up. In 2004 she underwent vaginoplasty and clitoral reduction and made good recovery. She has been stable on hydrocortisone 10 mg in the morning, 12.5 mg in the evening and fludrocortisone 50 mcg once daily (Testosterone<0.7 mmol/l (0.5–3.0), 17-hydroxy progesterone=1...

Previous published reports from Hong Kong have suggested iron markers may be increased in mothers with gestational diabetes. We examined this in our predominantly Caucasian population. Serum iron, ferritin and total iron saturation index (TSI)) where measured in sixty mothers with gestational diabetes compared to controls matched for age and parity. All participants were Caucasian. The study had LEC approval. Gestational diabetes was defined as glucose of 7.8 mmol/l or more in...

Background: Food intake and body weight are in a constant sense of balance, which is tightly regulated. The central control of appetite by the hypothalamus and areas in the brainstem has been established. The peripheral regulation of appetite via gut hormones has also been alluded to – previous studies have shown PYY and ghrelin hormones to be altered in obesity. Glucagon-like peptide-1 is a gut hormone released from L-cells in the distal ileum and colon. It has been impl...

A 19-year-old female presented with DKA. She had developed T1DM aged 5. She had an HbA1c of 12.9%, and numerous previous admissions with DKA. There was no other past medical history of note. She took 162 units of insulin/day, as a basal-bolus regime. She took no recreational drugs or other medications. She consumed up to 10 units of alcohol a week. On clinical assessment and investigation, there was no evidence of sepsis, and she was treated with intravenous insulin and fluids...

Objective: To test the hypothesis that poor adolescent diabetic control results in poor adult control.Methods: We conducted a retrospective case notes study involving 57 patients (M:F 30:27) in a teaching hospital. Patients who had diabetes atleast for a minimum period of 10 years were selected and their HbA1c when they were between 17 and 19 years of age were compared with the most recent HbA1c.The adolescent control was divided i...

Objectives: Patients with diabetes have longer and more complicated hospital stays than non-diabetic patients. The 2001 UK National Service Framework (NSF) recommends that the management of these patients should be supplemented by diabetes nurse specialists (DNS). This study aimed to audit the implementation of this recommendation, how it can be targeted and the impact it has on patient care.Study design and setting: One month long cross-sectional study ...

Background and aims: Subjects with primary (PAI) and secondary adrenal insufficiency (SAI)/hypopituitarism have an increased cardiovascular mortality for reasons that are unclear. Arterial stiffness is an independent risk factor for increased cardiovascular mortality. We sought to measure arterial stiffness in subjects with AI and aimed to identify which factors might account for any increase observed.Methods: Ethical approval was obtained for this study...

This study aimed to compare the prevalence of metabolic syndrome (MetS) and its components in different degrees of obesity. A total of 2309 adults (aged 25–75 years) who were referred to a large university general hospital, divided into four groups according to their body mass index (BMI); 1511 subjects were non-obese (BMI<30 kg/m2); 535 subjects were moderate (30≤BMI<35); 176 subjects were severe (35≤BMI<40) and 87 subjects were very se...

Introduction: The aetiology of obesity-related nephropathy (ORN) is uncertain but may involve hyperfiltration and systemic inflammation.Aims: To define ORN using novel urinary biomarkers that can identify damage to specific regions of the nephron.Methods: Clinical data, blood and urine samples were collected from a consecutive series of 22 patients attending a weight-management clinic (excluding those with diabetes), and from a con...

A 52 year old lady was admitted with collapse in May 2001 with h/o being nauseous, generally unwell, off her feet and food for several weeks. GP consultation five weeks before, for similar complaints, resulted in thyroid function tests confirming hypothyroidism. Thyroxine 25 mcg was commenced by the GP and uptitrated to 50 mcg. She however deteriorated despite this treatment becoming increasingly lethargic and sleepy. On admission she appeared tanned, BP was 93/50 she was dysa...

Introduction: The obesity epidemic is growing at an alarming rate. The body volume index (BVI) scanner is a novel machine that produces a true scale 3D body image of the whole body within 6 s and may have a role in the management of obesity.Method: In a pilot study, we set out to assess the impact of BVI scanning on weight loss during a standard weight loss programme in overweight subjects. Forty-three subjects were given standard dietary and lifestyle a...

Multiple aspects of physiology and pathophysiology, including endocrine function, are influenced by endogenous circadian timing mechanisms. In mammals, cell autonomous clocks are present in all major tissues throughout the body. These clocks are synchronised via complex signalling pathways and are believed to drive local aspects of physiology.Recently published data have revealed 24-h rhythms in up to 20% of the adipose transcriptome, suggesting profound...

Primary hyperaldosteronism is now recognised as the most frequent underlying cause of hypertension. We recruited 94 patients (age (mean±S.D.) 56±11 years) with hypertension from primary care in order to study the role of corticosteroid hormone action in this cohort. Random, blood pressure (BP), plasma renin activity (PRA) and aldosterone (Aldo) was measured both on and off antihypertensive medication. In addition, a 24 h ambulatory blood pressure (ABP)...

Objective: Insulin resistance (IR) has been reported in first-degree male relatives of patients with IC (FDMR). Retinol binding protein-4 (RBP4) has been shown to be increased in IR. We hypothesized that RBP4 would be: 1) increased in FDMR compared with controls and 2) correlated with features of IR.Methods: The study was approved by Leeds (West) Research Ethics Committee. We measured RBP4 in 162 healthy FDMR previously found to be more insulin resistant...

Background: The incidence of gestational diabetes appears to be rising, likely related to the increasing prevalence of overweight/obesity in the general population, and the trend of increasing maternal age. However, it must be remembered that some women newly diagnosed with diabetes in pregnancy have latent type 1 diabetes; GAD (glutamic acid decarboxylase) antibody measurement may be useful in cases with atypical features. We present two such cases.Case...

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) constitute the enteroinsular axis which promotes postprandial insulin secretion. The therapeutic potential of these hormones in diabetes is limited by their rapid inactivation by the enzyme dipeptidylpeptidase-IV (DPP-IV). Here we investigated the acute effects of metformin in the presence and absence of food on DPP-IV activity in type 2 diabetes....

The UKPDS study has shown that, intensive lowering of blood sugar and blood pressure decreases the risk of micro vascular complications in individuals with type 2 diabetes. The Steno-2 study has shown that target driven, long-term intensive treatment in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and micro vascular events by about 50%.We investigated the effect on the 10 years absolute CHD risk of our type 2 diab...

Objective: Aromatase deficiency in mice or men prevents conversion of androgens to oestrogens and results in central obesity and insulin resistance. In idiopathic obesity, higher aromatase mRNA levels in adipose tissue predict peripheral rather than central fat distribution, but any contribution of aromatase to metabolic complications is unknown. Here, we measured plasma steroids in a large cohort of men and post-menopausal women, in whom aromatase is the major source of oestr...

Altered adipokine levels may explain the link between obesity and insulin resistance. One potential candidate is retinol binding protein 4 (RBP4) which is elevated in type 2 diabetes and correlates with the magnitude of insulin resistance. Low adiponectin levels are also associated with insulin resistance. Adiponectin circulates in multimeric complexes and multimer distribution may also be important.We measured RBP4 and adiponectin multimers in 24 obese ...

Background and objectives: Obesity-associated inflammation is a key contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM). Murine studies have revealed potential links between obesity-induced activation of the innate immune response and endoplasmic reticular (ER) stress. Our aims were therefore to (1) examine whether human abdominal subcutaneous (AbSc) adipose tissue (AT) obtained from lean and obese patients, differs in the level of ER stress, through ass...

Introduction: It is not known if non-alcoholic fatty liver disease (NAFLD) predates type 2 diabetes. We will study the prevalence of NAFLD in women with previous gestational diabetes (GDM), a population at ≥60% risk for the development of type 2 diabetes, while glucose tolerance is non-diabetic. It is not known if hepatic fat accumulation in NAFLD is disproportionate to fat accumulation in other tissues. We aim to study the association between fat in the liver and in tis...

Background: Size at birth has been shown to have important consequences on later health, including the development of the metabolic syndrome. Tissue sensitivity to cortisol is regulated, in part, by the GCR and alterations in GCR expression have been observed in obesity and type 2 diabetes.Objectives: To examine whether birth weight influences the expression of GCR mRNA in skeletal muscle (SM) at days 7 and 14 of postnatal life.Met...

We investigated effects of ethanolic Persea americana Mill. (‘Avocado’) leaf extracts (PAE) on blood glucose and kidney function in rats. Extracts of the plant have been employed to treat hypertension and diabetes mellitus. Oral glucose tolerance tests (OGTT) were conducted in fasted non-diabetic and STZ-diabetic rats following a glucose load (0.86 g/kg, p.o.), followed by various PAE doses (60, 120 and 240 mg/kg). Rats treated with deionised water or standard...

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), regenerates active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone) and has been implicated in the pathogenesis of the metabolic syndrome. 11β-HSD1 expression is increased in adipose tissue and decreased in liver in human and rodent obesity. Paradoxically, in chronically high fat-fed mice 11β-HSD1 is down-regulated in adipose tissue. Transcri...

Aim: We propose that the circulating immune system and adipocyte size plays a role in the development of obesity related co-morbidities independent of body mass index (BMI).Methods: Clinical data and blood samples were collected from patients with severe obesity attending a hospital weight-management clinic and lean healthy controls. Patients were classified into metabolically ‘healthy obese’ or ‘unhealthy obese’ groups, based upon st...

Maternal nutrient restriction predisposes the adult offspring to metabolic syndrome. We investigated the effect of energy restriction during early or late gestation on glucose-insulin dynamics during a GTT (0.5 g/kg i.v. glucose) and/or an ITT (0.75 IU/kg) prior to and after significant gain in adipose tissue. 20 sheep were either fed to maintenance (1 M; CE, n=6) or to 0.65 M during early (0–65 days, term=147days, LEE, n=7) or late (65–125 days, LEL; <...

Systemically administered glucocorticoids are known to cause hyperglycaemia, however there is a paucity of literature on the true prevalence, predictors or clinical impact of glucocorticoid-induced hyperglycaemia in hospital in-patients.This study examined glucocorticoid-induced hyperglycaemia in patients receiving >25 mg prednisolone; or >8 mg dexamethasone; or equivalent, for any indication over a 3 month period.64 consec...

Thyrotropin receptor (TSHR, signals via CREB) expression increases during adipogenesis, a process occurring in Graves’ orbits. CREB activation has been reported ‘necessary and sufficient’ to induce adipogenesis. However, we previously demonstrated that expression of constitutively active TSHR in orbital preadipocytes stimulated early but inhibited later differentiation stages, even when PPARγ agonist induced. Overproduction of proteoglycans is also a featur...

Introduction: With the onset of puberty blood pressure increases more in men than in women while boys and girls do not show any gender differences in blood pressure. Androgens are known to play an important role in renal tubular epithelial cell growth, hypertrophy and erythropoetin production and may be important determinants of sex-specific differences in blood pressure. However the exact mechanisms are not clear yet.Methods: Male Wistar rats aged 8&#15...

Women with Turner’s syndrome (TS) have been reported to have 11.5% relative risk of type 1 diabetes mellitus (DM) and 4.3% relative risk of type 2 DM. However, it is now evident that the traditional categorisation of DM may not be appropriate in this condition as the defect of glucose homeostasis often presents in young non-obese women. In fact, the pattern of insulin secretion in TS seems more likely to be due to beta cells dysfunction or insufficiency, which is reminisc...

Background: Mutations in the UMOD gene, which encodes the Tamm-Horsfall Glycoprotein (THP), cause FJHN, an autosomal dominant disorder characterised by gout and renal failure. THP is a 640 amino acid glycosylphosphatidylinositol-anchored protein, containing three Epidermal Growth Factor (EGF)-like domains, a cysteine-rich region and a Zona Pelllucida (ZP) domain. THP is translated into the Endoplasmic Reticulum (ER) lumen, glycosylated in the Golgi apparatus, trafficked...

Background: CB1 antagonism has potential benefits in the metabolic syndrome, with effects mediated through central orexigenic mechanisms and peripheral action on adipose tissue. We have previously demonstrated the inhibitory effects of CB1 inactivation on preadipocyte proliferation and now extend these studies to in vitro adipogenesis.Aims: To compare the effects of CB1 agonism and antagonism on differentiation in both preadipocyte cell lines and ...

Introduction: Microvascular systems alteration is responsible for the most devastating complications of diabetic patients. Similar to the microvascular systems of retina and kidney the choroid plexus can be a vulnerable target organ for hyperglycemia. Hyperglycemia alters the electrolyte composition of CSF which probably reflects the microvascular alteration of choroids plexus. In the present study we examined the effects of maternal hyperglycemia on the vascular structure of ...

TSH receptor (TSHR) expression increases >100-fold during adipogenesis and signals via CREB. Since CREB activation has been reported to be ‘necessary and sufficient to induce adipogenesis’, we investigated whether TSHR activation, a feature of most thyroid dysfunction, has a role in adipocyte biology and evaluated the contribution of Gsα and Gβγ signalling.Retroviral vectors for WT or constitutively active mutant TSHR* or ...

Endothelial dysfunction is a key step in the initiation of atherosclerosis, resulting from a decrease in bioavailability of nitric oxide (NO). IGF-1 may play a part in regulation of NO production via the PI3-kinase/Akt/eNOS pathway. We have investigated whether disturbances of this pathway occur in dietary-induced obesity.Obesity was induced in mice fed a high fat diet for 20 weeks (n=12), compared to chow fed controls, with an age-related increas...

Hexose-6-phosphate dehydrogenase (H6PD) is a sarcoplasmic reticulum (SR) resident enzyme that metabolizes glucose-6-phosphate and generates NADPH that drives the activation of glucocorticoids by 11β-hydroxysteorid dehydrogenase type 1. H6PD KO mice exhibit improved skeletal muscle insulin sensitivity increased glucose uptake and glycogen storage. However, H6PD KO mice also develop a myopathy with switching from Type II to Type I fibers. Affected muscles have apparently no...

The epidemic of obesity, insulin resistance and type 2 diabetes has heightened the need to understand the mechanisms that contribute to their pathogenesis. Endogenous glucocorticoid (GC) production and metabolism have been implicated based upon parallels with Cushing’s syndrome. The interaction between GC metabolism and insulin sensitivity in the context of significant weight loss has not been explored. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that gen...

Peroxisome proliferator activated receptor gamma (PPARγ), a ligand-inducible transcription factor, is essential for adipocyte differentiation and lipogenesis. We previously described a kindred in which some individuals were heterozygous for a frameshift/premature stop mutation, (A553ΔAAAiT)fs.185(stop186) in PPARγ, with the truncated protein being non-functional and lacking dominant negative activity1. PPARγ null heterozygotes had norm...

Intra-abdominal adiposity is associated with insulin resistance and increased cardiovascular morbidity and mortality. Obesity occurs as a consequence of increased adipocyte size (hypertrophy) and number (differentiation or hyperplasia). Whilst differences in gene expression between omental (om) and subcutaneous (sc) adipose tissue have been described, the molecular mechanisms that underpin the differences in adipose tissue biology and the depot specific metabolic risks that th...

The adrenal steroid dehydroepiandrosterone (DHEA) and its sulphate ester, DHEAS have been shown to oppose the effects of glucocorticoids, thereby producing beneficial effects on insulin sensitivity in rodent models of diabetes and obesity and in hypoadrenal patients. Glucocorticoids, key regulators of adipose differentiation and insulin sensitivity, are reactivated locally by 11β-hydroxysteroid dehydrogenase type (11β-HSD1) oxoreductase activity, which increases with...

Fat-derived adipokine genes that modulate metabolic and inflammatory responses, such as resistin (rstn) and fasting-induced adipose factor (fiaf), are also expressed in mouse brain and pituitary gland. We, and others, reported that central fiaf and rstn mRNA levels were increased following a brain injury-induced inflammatory response, and central injection of resistin reduced food intake and increased hepatic glucose production. Since LPS-induced en...

Familial Juvenile Hyperuricaemic Nephropathy (FJHN) is an autosomal dominant disorder that is associated with gout and progressive renal failure. FJHN in 43 families has been reported to be caused by mutations in the UMOD gene, which encodes Uromodulin, also known as the Tamm-Horsfall Glycoprotein, and two families have been reported to have mutations in the transcription factor Hepatocyte Nuclear Factor 1β (HNF-1β), mutations of which usually cause maturity-o...

We have recently demonstrated expression of a functional calcium sensing receptor (CaSR) in human aortic smooth muscle cells (HAoSMC) and human arteries and demonstrated a correlation between CaSR expression and medial calcification (a major cause of cardiovascular mortality in chronic kidney disease). Apoptosis of vascular SMC occurs early in the development of calcification and apoptotic bodies accumulate calcium. Here, we have examined CaSR-mediated signalling pathways in H...

The role of endogenous glucocorticoid (GC) production and metabolism in the pathogenesis of obesity, insulin resistance and type 2 diabetes remains unclear. Patients with Cushing’s syndrome develop central obesity, insulin resistance and in some cases type 2 diabetes (T2DM), yet circulating cortisol levels are not elevated in simple obesity. Alterations in GC metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that generates active cortisol ...

Synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligands are used clinically to improve insulin sensitivity. Although designed as specific ligands for PPARγ, there is evidence for some ‘off target’ effects being mediated by a non-classical, non-PPARγ mechanism. Recent evidence further suggests that some of these effects may be glucocorticoid receptor (GR)-dependent.To analyse activation of GR following exposure ...

There is an increase in cardiovascular risk factors in polycystic ovarian syndrome (PCOS) compared with BMI matched controls. Almost all women with PCOS are insulin resistant and increased cardiovascular risk is commonly attributed to insulin resistance (IR). However, it is unclear if cardiovascular risk differs in women with PCOS compared to equally insulin resistant women. We performed a case–control study (n=56 pairs) of women with PCOS (NIH criteria) compared t...

Aims/hypothesis: Resistin could be implicated in the mechanism of insulin resistance and recent evidence suggests this occurs, in part, via a brain-dependent pathway. Given the emerging role of hypothalamic AMP-activated protein kinase (AMPK) in the modulation of appetite and glucose levels, we hypothesized that its activity would be modulated by resistin. To verify such a pathway, we employed the N-1 hypothalamic neuronal cell line, which expresses a variety of neuropeptides ...

In adipose tissue, glucocorticoids (GC) are known to regulate lipogenesis and lipolysis. Hexose-6-phosphate dehydrogenase (H6PDH), a protein located in the endoplasmic reticulum (ER) provides co-factor for the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), thus regulating the set point of its activity and allowing for tissue specific activation of GCs. The aim of this study was to examine the effect of lack of H6PDH on adipose tissue biology using the H6P...