Irish Endocrine Society 41st Annual Meeting

rish Endocrine Society 41st Annual Meeting, 13-14 October 2017, Grand Hotel, Malahide, Dublin

Vitamin D deficiency common in nursing home patients

Vitamin D insufficiency and deficiency is more common in patients in nursing homes than in patients in a community hospital setting, according to a new study presented at the 2017 Irish Endocrine Society Annual Meeting.

The aim of this study was to compare the prevalence of vitamin D deficiency, insufficiency and sufficiency in samples collected from adult patients in the community, hospital and nursing homes in the West of Ireland.

A cross-sectional study was designed and laboratory data system was interrogated to identify all requests for 25-hydroxyvitamin D (25(OH)D) analysis carried out in Galway University Hospitals between April 2011 and December 2015.

In total 34,063 samples from adult (≥18 years) patients were identified. Only the first sample from individual patients was included.

Baseline demographics, location (community, hospital or nursing home), and date and time of sample collection were recorded.

Vitamin D deficiency, insufficiency and sufficiency were classified according to the following 25(OH)D cut-offs: <25nmol/L, 25-50nmol/L and >50nmol/L respectively.

A total of 24,302 patient samples were eligible for inclusion: Community (15,319), hospital (8,710), and nursing home residents (273).

More females than males were 25(OH)D sufficient (50 per cent versus 42 per cent).

There was a significant difference observed in vitamin D status between patients sampled in the community (deficiency: 13 per cent; insufficiency: 36 per cent; sufficiency: 51 per cent), in hospital (deficiency: 23 per cent; insufficiency: 34 per cent; sufficiency: 43 per cent) and in nursing homes (deficiency: 42 per cent; insufficiency: 25 per cent; sufficiency: 33 per cent).

“In a hospital setting, vitamin D insufficiency/deficiency is more common in inpatients than outpatients,” according to Dr Thomas Griffin, who presented the findings of the study, which was conducted jointly by Galway University Hospitals and the National University of Ireland Galway.

“Vitamin D deficiency is more common in winter/spring than summer/autumn. More males than females have vitamin D insufficiency/deficiency. Severe deficiency increases with age and is most prevalent in those over 80.”

Potential biomarker identified for treatment of diabetic cardiac angiogenesis

KBPL may be a key early regulator of cardiac angiogenesis in diabetes, and therefore could hold novel biomarker and therapeutic potential, according to new research presented at the 2017 Irish Endocrine Society Annual Meeting.

FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis.

A first-in-class clinical FKBPL peptide mimetic, ALM201,is currently in phase 1/2 clinical trials for treatment of solid tumours.

More recently, in FKBPL knockdown (FKBPL+/-) mice, a pro-angiogenic phenotype was observed, accompanied by vascular dysfunction and a propensity to become overweight and glucose intolerant when fed a high-fat diet.

A new Irish/US study investigated a specific role for FKBPL in myocardial angiogenesis associated with diabetes.

In streptozotocin (STZ) mice, cardiac FKBPL mRNA levels were significantly downregulated at 12 weeks post STZ injection versus vehicle controls (p<0.05, n=5), in association with diastolic dysfunction (eg, mitral valve E/A ratio).

This was in concert with a reduction of FKBPL protein in hearts from STZ-induced vs control diabetic rats (p<0.01, n=3), also at 12 weeks.

Complementary in vitro studies in cultured endothelial cells (HUVEC) demonstrated two-fold reduction in FKBPL protein levels following exposure to hypoxia (1 per cent) for 24 hours (p<0.01, n=6), indicating that reduced FKBPL levels observed in vivo may be, at least in part, driven by impaired oxygenation.

Indeed, in an experimental mouse model of myocardial infarction (MI), associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were down regulated versus sham controls (n≥3).

The study was conducted by the Centre for Experimental Medicine, Queen’s University Belfast, in association with the University of South Carolina, Charleston, US, and the Irish Centre for Vascular Biology, Molecular and Cellular Therapeutics, RCSI.

‘Irish’ gene for gigantism identified

The area around Lough Neagh in Northern Ireland is associated with a rare genetic mutation, which leads to gigantism, the recent 2017 Annual Meeting of the Irish Endocrine Society heard.

Delivering the Hadden Lecture at the meeting, Professor of Endocrinology and Deputy Director of the William Harvey Institute of the Barts and the London Medical School, Prof Marta Korbonits said the gene AIP, which can cause excess growth hormone production in the pituitary grand, is common in Irish cases of gigantism.

The AIP mutation was identified to be the cause of gigantism in Mr Charles Byrne, who was born in 1761 near Cookstown, and after reaching the height of 7ft 6in was known as the ‘Irish giant’.

Prof Korbonits, whose talk was entitled ‘Truth in the Folktale’, speculated the gene could be responsible for mythological tales of Irish giants, such as Fionn mac Cumhaill.

“This AIP mutation around Lough Neagh could explain the long history of Irish giants,” Prof Korbonits told the Medical Independent (MI).

She said identifying the genetic cause for gigantism is very important to screen family members for the condition.

“It is very important for the family members of a giant because if they have a mutation then their family members also have a mutation and they would have a chance of developing the disease,” according to Prof Korbonits.

“If you diagnose the disease at a later stage it is more difficult to treat and they might already gain the height that would give them a lot of problems. If you can diagnose the patient early and screen them and catch the patient before they grow to be a giant, or grow to have a tumour, which is huge, then you have enormous benefit for the family members.  For the patients themselves it might help you decide what sort of treatment you will give. But I think the main benefit is actually for the family members and especially the children in the family.”

She added that treatments for gigantism are improving, but again stressed these are more beneficial when administered at an early stage.

“If you can identify the disease at a young age then the treatment options are very good. If you identify the disease at a later stage, we can still treat, but they may need lifelong treatment,” Prof Korbonits stated.

“They may need radiotherapy, which could have long-term side effects. They may need injection treatment for the rest of their life. They may need hormone replacement of all the other pituitary hormones for the rest of their life. So we can do a lot, we are in a much better position than in the old days, but you could avoid the majority of these problems if you pick up the cases early.”

Unclear how Brexit will impact on European Society of Endocrinology

The European Society of Endocrinology (ESE) is examining the possibility of relocation from the UK as a result of Brexit.

ESE President Prof A J van der Lely stated the impact of Brexit on the long-term future of the Society, which is a charity based on British law and is located in Bristol, is unclear at present.

“At least we are contemplating having an office somewhere in continental Europe as well, to be prepared,” Prof van der Lely told the 2017 Irish Endocrine Society Annual Meeting in Dublin.

He stressed, however, that the ESE was a European, not an EU, body.

He also explained how the Society, which has approximately 4,000 members from a number of different countries, recently rebranded its identity in order to become a stronger voice for endocrinology.

“We went from a small society without any personnel … to a more business-driven society. We now have our own CEO and marketing manager. We have tried to make it more professional,” he stated.

Future plans for the Society include the launch of a new website and pan-European certification for the specialty of endocrinology.

Prof van der Lely, who wants to encourage more Irish endocrinologists to join the ESE, said it was also important for the Society to promote the range of sub-specialties that define the area.

“To the outside, including industry, we did not tell properly what we in fact do,” he stated.

“By chopping it up into what we are – ‘focus-networks’, we are much more visible in what we are doing and addressing. I think that will help the Society a lot in becoming more clear and bringing in more members and also corporate members.”

Prof van der Lely added that scientific research is facing a number of challenges at present.

“Things are happening in almost all of the [EU] member states, in all directions,” he said.

“We should be very careful not to lose science. At least in my country, and I think in other countries, science is a bit under fire. Governments want to cut budgets, want to have science on demand, want to know what science is doing and is just asking science to address certain issues. And this doesn’t let science do what it is good at, and that is having new results and new data by serendipity and I think that is essential.”

TRAIL found to be good biomarker to detect heart disease in diabetes patients

erum tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) may be a useful biomarker of underlying cardiovascular disease (CVD) in patients with type 2 diabetes, according to a presentation made at the recent 2017 Irish Endocrine Society Annual Meeting.

CVD is the leading cause of mortality in type 2 diabetes.

According to Ms Hannah Forde, who made the presentation, identification of serum biomarkers for early detection of so-called ‘silent’ CVD may allow timely cardiovascular intervention.

Epidemiological studies have demonstrated that low serum levels of TRAIL are associated with increased risk of death in patients with known CVD.

The new study, which was a collaboration between the Department of Endocrinology, RCSI; Beaumont Hospital, Dublin; and the School of Biotechnology, and the School of Health and Human performance, Dublin City University; aimed to examine the utility of serum TRAIL as a marker of cardiovascular risk in patients with type 2 diabetes.

Serum TRAIL levels were measured in 133 adults by ELISA (Enzyme-Linked Immunosorbent Assay).

The cohort was divided into three groups: Non-diabetic controls; newly diagnosed type 2 diabetes patients; and patients with type 2 diabetes and a documented history of a CV event.

Clinical information, demographics, anthropometric measurements and other laboratory parameters were recorded.

In a multivariable regression analysis adjusted for potential confounders, including HbA1c (glycated haemoglobin), CRP (C reactive protein), cholesterol levels and medications, serum TRAIL was inversely associated with the presence of CVD in patients with type 2 diabetes.

A serum TRAIL cut-off of 178pg/ml predicts the presence of CVD in a patient with type 2 diabetes with a sensitivity of 86 per cent and specificity of 70 per cent.

“We propose that TRAIL may be a suitable biomarker to diagnose clinically relevant CVD in patients with type 2 diabetes,” according to Ms Forde.

“Larger studies are required to determine if the addition of serum TRAIL measurements to traditional risk factors improves risk stratification for CVD in patients with type 2 diabetes.”

In another study of TRAIL by the School of Biotechnology, Dublin City University and the Department of Endocrinology, Beaumont Hospital, Dublin, it was found the protein has the ability to block the pro-calcifying actions of RANKL (receptor-activator of nuclear factor kappa-beta ligand) in the vasculature, in part via attenuation of NF-κB-dependent pro-calcific signalling, yielding valuable mechanistic information on vascular calcification (VC) pathogenesis and on the potential therapeutic value of TRAIL in this context.

VC, an arterial hardening process prevalent in type 2 diabetics, is a leading risk factor for cardiovascular morbidity/mortality.

No evidence found to link hyperandrogenism or PCOS with cardiovascular risk

A  new Irish and UK study has found a lack of evidence that clinical features of hyperandrogenism or polycystic ovary syndrome (PCOS) were associated with lipoprotein disturbance, systemic inflammation or early atherosclerosis in type 1 diabetes.

Hyperandrogenaemia and PCOS are common in women with type 1 diabetes, but it is not known if they contribute to increased cardiovascular risk.

The study, presented at the 2017 Irish Endocrine Society Annual Meeting, aimed to compare associations between androgen levels, lipid variables and early atherosclerosis in reproductive-age women with and without type 1 diabetes.

A total of 87 women (16 with PCOS) with type 1 diabetes, and 87 (16 PCOS) non-diabetic women were studied.

Androgens (LCMS), plasma lipids and lipoprotein subclasses (polyacrylamide-gel-tube-electrophoresis) and carotid-intima-media-thickness (CIMT), a validated marker of atherosclerosis were measured.

In non-diabetic women, sex hormone-binding globulin (SHBG) correlated negatively and free testosterone positively with very low-density lipoprotein (VLDL), triglyceride (TG) while dehydroepiandrosterone (DHEAS) correlated negatively with LDL-C.

In type 1 diabetes, SHBG correlated negatively and free testosterone positively with TG and TG/HDL-C while androstenedione correlated positively with TC, VLDL and LDL-C.

TC, LDL-C and TG were not associated with CIMT in either group, but VLDL and the proportion of atherogenic small-dense LDL  (sdLdL) correlated with CIMT only in women with type 1 diabetes.

Androgens did not correlate with CIMT in either group.

In summary, in type 1 diabetes and non-diabetic women, SHBG and free testosterone correlated with lipid and inflammatory markers characteristic of insulin resistance, but did not correlate with CIMT.

VLDL and sdLDL were associated with CIMT in type 1 diabetes only.

“The model of type 1 diabetes in which systemic insulin levels are normal or elevated and portal insulin levels are low, provides insights into associations with androgens and metabolism and inflammation in reproduction-age women,” according to the authors.

These results do not support a role of hyperandrogenaemia in atherogenesis in type 1 diabetes.

The role of VLDL and sdLDL in early atherogenesis in type 1 diabetes requires further exploration, the study, which was a collaboration between Tallaght Hospital, Dublin, and the University of Birmingham, concluded.

GPCRs offer great potential as target for diabetic treatment

G-protein coupled receptors (GPCRs) in the islets represents an “untapped opportunity” for novel diabetic therapies, according to a leading Irish researcher.

Islet dysfunction is characterised by defective insulin, high glucose secretion and reduced beta cell mass.

GPCRs play a pivotal role in cell signalling and control many processes including: Immunity; growth; cellular differentiation; neurological pathways; and hormone secretions.

Prof Aine McKillop, Professor of Biomedical Sciences at Ulster University, who delivered this year’s IES McKenna Lecture at the 2017 Irish Endocrine Society Annual Meeting, stated GPCRs account for 50/60 per cent of drugs in development and 30 per cent of clinically used medications.

“The discovery of new GPCR drugs offers therapeutic promise for diabetes, particularly if combined with DPP-4 inhibition,” according to Prof McKillop.

In her talk, Prof McKillop focused particularly on GPCR55, which is highly expressed in the endocrine pancreas and intestine, and GPCR199.

“GPCRs have a key role and are certainly of interest to pharma in terms of a new pipeline for new therapeutic treatments,” she stated.

“We know that these receptors are widely expressed in the pancreas and also in the intestine in terms of the K and L cells … in terms of insulin secretion, we know they are potent insulin secretors. And we also know they activate a number of downstream signalling events, which will potentiate insulin secretion with impaired glucose tolerance. So we have glucose lowering and an insulin tropic activity in vivo, but positive changes in terms of appetite and in terms of lipid profile and no adverse effects in terms of liver toxicity currently.”

Prof McKillop said they are also interesting in terms of the proliferation of B cells and the expansion of B cell mass.

“That is really interesting and something we are going to look at further,” she concluded.

Metformin recommended for gestational diabetes

Metformin should be used as a standard treatment for gestational diabetes (GDM) in pregnant women, a new study presented at the 2017 Irish Endocrine Society Annual Meeting recommended.

Treatment options for GDM include lifestyle modifications, insulin or metformin.

For the study, a retrospective study in patients with GDM attending the National Maternity Hospital, Holles Street, in 2015 and 2016 took place.

The aim of the study was to review the treatment of patients with GDM; to review the birth outcome on treatment; and to compare the difference in pre-treatment parameters.

The majority of patients were overweight (30 per cent); obese (35  per cent) and European (75.9  per cent).

While 423 (61.9 per cent) of the GDM patients continued on lifestyle modification, 116 (17 per cent); 111 (16.3 per cent) and 19 (2.8 per cent) required metformin, insulin or both treatments respectively.

Spontaneous vaginal delivery, Caesarean section and assisted delivery accounted for 346 (50.7 per cent), 213 (31.2 per cent) and 71 (10.4 per cent) deliveries, while 25 (3.7 per cent) patients had miscarriages.

Macrosomia (>4kg) accounted for 116 babies (17 per cent), with no differences in macrosomia and delivery methods between treatments.

The study found that Asian (28.1 per cent) and African (26.1 per cent) women required more insulin compared to Europeans (14.2 per cent, p=0.006).

Women treated with insulin had higher 50g-glucose challenge (GCT) values (11.24 ± 2.33mmol/L) compared to metformin-treated (9.35 ± 1.64mmol/L) and lifestyle modification-treated (9.41 ± 1.9mmol/L, p <0.005) patients. Plasma glucose at OGTT  (fasting, one hour post OGTT) were also higher in insulin-treated (5.8 ± 0.9, 12.41 ± 1.72mmol/L) compared to metformin-treated (5.19 ± 0.53, 11.18 ± 1.21mmol/L) and lifestyle modification-treated (4.7 ± 0.55, 10.7 ± 1.38mmol/L, p <0.005) patients respectively.

Equal numbers of patients were treated with metformin and insulin without differences in the outcome for mothers and babies.

“We found in our study that obesity at booking is associated with hyperglycaemia, macrosomia and the need for pharmacological treatment,” according to Dr WA Mahmood Wan, who presented the findings.

“In our study, metformin is as safe as insulin in the treatment of GDM and we would suggest it to be a standard line of management for GDM.

Potential for boarfish as diabetes treatment, finds new Irish research

Boarfish could be useful in the treatment of diabetes, according to a new study presented at the 2017 Irish Endocrine Society Annual Meeting in Dublin.

The study, which was conducted by the School of Biomedical Sciences, Ulster University, Coleraine, and the Department of Life Sciences, University of Limerick, sought to examine the anti-diabetic actions of orally administered boarfish protein hydrolysates in leptin-deficient obese diabetic (ob/ob) mice.

Protein hydrolysates were generated from boarfish (Capros aper) using combined food-grade alcalase 2.4L/flavourzyme 500L digestion.

Treatment groups consisted of boarfish (50 mg/kg/bw), metformin (200 mg/kg/bw) and saline controls. Treatments were administered by oral gavage twice daily for 30 days to male obese diabetic ob/ob mice (aged eight to 12 weeks).  Diabetic status was monitored every three days, including non-fasting blood glucose, plasma insulin and bodyweight during the study, with terminal analysis of HbA1c, LDL, HDL, total cholesterol and triglyceride concentrations. Diabetic mice exposed to chronic oral treatment with boarfish protein hydrolysate for 30 days displayed significantly lower circulating non-fasting blood glucose concentrations from day 18 to 27 (p<0.01 to p<0.001) versus the saline-treated control group.

Circulating blood glucose concentrations were lowered on average by 48 per cent (p<0.01) within the boarfish treatment group compared to saline controls.

According to the authors, terminal analysis of HbA1c displayed a 27 per cent reduction (p<0.01) within the boarfish group versus saline-treated controls.

Also, terminal plasma lipid analysis displayed a 20 per cent reduction in total cholesterol, 28 per cent reduction in triglycerides and 40 per cent reduction in low-density lipoprotein (LDL), compared to saline-treated controls.

“Boarfish hydrolysate actions matched or exceeded the antidiabetic efficacy of the metformin group,” according to the study.

“This intervention with boarfish protein hydrolysate had potent antidiabetic actions, improving glycaemic control and plasma lipid profiles in diabetic ob/ob mice. In conclusion, protein hydrolysates could provide a novel dietary approach in the management of dyslipidaemia and hyperglycaemia found in type 2 diabetes.”