Fiona Mitchell

Bone: High body iron stores lead to bone loss

Even in healthy adults, elevated serum levels of the iron storage molecule ferritin are associated with an increased rate of bone loss. This finding is the result of a study conducted by a team of scientists in Seoul. Iron is a highly reactive metal and can act as a catalyst in the production of hydroxyl radicals. These molecules can cause tissue damage and a number of researchers have suggested that elevated iron stores can lead to a variety of adverse outcomes. Elevated serum ferritin levels have been associated with the development of type 2 diabetes mellitus in individuals without known risk factors for the disease. In addition, high serum levels of this molecule have been linked to hypertension, dyslipidaemia and the metabolic syndrome. Individuals with pathologic iron overload, such as those with haemochromatosis, have decreased BMD. Additionally, BMD and iron load are inversely correlated in men with haemochromatosis. “However, there was a possibility that the disease itself and not iron overload had an effect on bone metabolism,” explains Jung-Min Koh, who was involved in the current study. “Therefore, we compared changes in BMD annually in healthy men and women with their baseline serum ferritin levels.” This 3-year longitudinal study included 789 men and 940 women from a single BONE

Obesity: Glypican-4: role in insulin signalling

Glypican-4, a novel adipokine, interacts with the insulin receptor (IR) and influences insulin signalling. Investigators from Boston and Leipzig demonstrated that glypican-4 is secreted from white adipose tissue and enhances insulin sensitivity in mice. Glypican-4 is ordinarily a membranebound hormone, owing to a glycosylphosphatidylinositol (GPI) anchor. However, this anchor can be cleaved, allowing glypican-4 to be secreted. The researchers have previously shown that glypican-4 is differentially expressed in visceral and subcutaneous adipose tissue of mice and humans. In the new study they show that expression of this adipokine and its serum concentration in humans are dependent upon BMI and insulin sensitivity. The investigators found that cultured murine preadipocytes lacking glypican-4 failed to differentiate into adipocytes or to accumulate fat when stimulated to do so with a standard cocktail of drugs. Closer investigation revealed that induction of key adipogenic transcription factors such as PPAR-γ and C/EBPα was disrupted. However, when glypican-4 expression was restored, differentiation was rescued and expression of these key transcription factors was increased. This effect was independent of the integrity of the GPI anchor, indicating that glypican-4 can influence adipogenesis in both its membrane-bound and secreted forms. Glypican-4 appears to exert its effects by influencing insulin signalling. The research team found that glypican-4 associates with the IR and that insulin stimulation of IR phosphorylation was reduced by 33% in preadipocytes lacking glypican-4 in comparison with control cells. The team also found that low serum levels of glypican-4 were associated with insulin resistance in humans. Insulin resistance is characterized by a drop in circulating insulin levels. Cleavage of the GPI anchor might be regulated by insulin and so, during development of insulin resistance, insulin and glypican-4 levels would both fall. This compound effect might accelerate disease progression. Maintaining serum levels of glypican-4 in people with insulin resistance or diabetes mellitus could, therefore, reduce their need for insulin therapy.

Diabetes: PTEN mutations increase insulin sensitivity and obesity

Patients with Cowden syndrome, a monogenic cancer predisposition syndrome, are heterozygous for lossof-function mutations in the tumour suppressor PTEN. A new study shows that patients with the syndrome also have increased insulin sensitivity. PTEN antagonises the action of PI3K, a key kinase upstream of AKT in the insulin signalling cascade. “This study provides important evidence that signalling downstream of the growth factor receptor family is relevant to both diabetes mellitus and cancer in humans,” says Michael Pollak of McGill University, Montreal who was not involved in this study. “We wondered if the overlap between type 2 diabetes mellitus and cancer could be partly explained by defects in genes encoding proteins involved in regulating not only the cell cycle but also metabolic signalling,” explains senior author Anna Gloyn of the University of Oxford. “Cowden syndrome provided us with the opportunity to investigate such a gene, as PTEN had previously been implicated in both processes.” In the study, 15 patients with Cowden syndrome were matched to control individuals on the basis of age, sex and DIABETES

Screening: No need to fast before lipid level tests.

Measuring serum lipid levels in the nonfasted state is as good, if not better, than obtaining measurements in the fasted state, according to findings of a new study. Currently measurement of blood lipid levels is recommended only after a >8 h fast. However, this requirement is inconvenient for patients and could lead to reduced adherence to testing schedules. Several studies have suggested that fasting and nonfasting lipid levels are equally indicative of coronary-heart-disease and stroke risks, and that nonfasting lipid levels can be even better predictors of cardiac events than fasting lipid levels. The researchers examined test results from 209,180 individuals who presented at the clinic over a 6-month period for blood lipid level testing. “I was getting numerous patient complaints about patients showing up in the clinic and being turned away because they were not fasting,” says senior investigator Christopher Naugler, Chemistry Department Head of Calgary Laboratory Services in Alberta, Canada. “We do ~36,000 cholesterol tests a month and are the only lab to do such tests for a SCREENING

Diabetes: Extended genetic testing improves MODY diagnosis.

Twice as many patients with maturityonset diabetes of the young (MODY) would receive a correct diagnosis if the criteria for genetic screening were expanded, suggest the results of a new study published in Diabetes Care. An estimated 80% of patients with MODY are incorrectly diagnosed as having type 1 or type 2 diabetes mellitus (T1DM or T2DM, respectively). Typically, patients are only referred for screening if they are aged <25 years at diagnosis, have a parental history of diabetes mellitus and are noninsulin dependent. In a group of 247 patients diagnosed as having T1DM, residual β-cell function was found in 20 patients. Among 322 patients diagnosed as having T2DM, 80 were not insulin resistant or had an age of disease onset <30 years. Patients with these features atypical of T1DM and T2DM were tested for mutations in the HNF1 homeobox A and hepatocyte nuclear factor 4α genes. Mutations confirming MODY were found DIABETES

Obesity: bariatric surgery in youth.

Laparoscopic sleeve gastrectomy is an effective and safe procedure for use in young patients, according to a group of researchers from Saudi Arabia. Results of their retrospective study show that, in 108 patients aged 5–21 years, this surgery led to substantial excess weight loss in more than 90% of patients and most patients experienced a reduction in the prevalence of obesity comorbidities. “I don’t think it is ethical to deny obesity treatment to those who need it just because they are children,” says lead researcher Aayed Alqahtani of King Saud University, Riyadh. “When I see the positive changes in their lives following surgery, I recognize the benefit of such an approach,” he adds. While previous studies have demonstrated the benefits of bariatric surgery in adults, the suitability of this approach for children has been a subject of debate, and surgery is often rejected in favour of dietary and behavioural interventions. However, while these lifestyle changes can have substantial success in treating children with mild to moderate obesity, they are less successful when applied to children with severe obesity. Therefore, several studies have been undertaken in the past decade to examine the effectiveness and safety of surgery to treat young people with obesity. “This report details surgery outcomes of a sizeable number of the youngest paediatric patients ever reported in the bariatric surgery literature,” comments Thomas Inge of Cincinnati Children’s Hospital Medical Center, Ohio, USA, who was not involved in the study. “The comorbidity change information that the researchers report is critically needed,” he adds, “as the adverse health effects of obesity are what should drive such intensive therapy.” The investigators found that most of their patients had measurable improvements in known obesity comorbidities, such as dyslipidaemia, hypertension, prehypertension, obstructive sleep apnea, diabetes mellitus and prediabetes mellitus (rates of resolution 70%, 75%, 83%, 91%, 94% and 100%, respectively). None of the patients experienced serious complications and no deaths resulted from surgery.

Diabetes: Drink coffee or tea to reduce risk of type 2 diabetes mellitus?

Drinking coffee or tea could reduce a person’s risk of developing type 2 diabetes mellitus (T2DM). A research group from Boston used data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) to investigate the relationship between beverage intake and T2DM risk. The NHS took place between 1984 and 2008, and was a cohort study involving 121,701 US women who were aged 30–55 years at the time of enrollment. The HPFS, which took place between 1986 and 2008 in the USA, was a prospective study involving 51,529 men who were enrolled aged 40–75 years. In both studies, food and beverage intake were ascertained using food-frequency questionnaires that were sent out every 4 years. The investigators in the current study used data from both the NHS and the HPFS to calculate patient-years from receipt of a baseline questionnaire to self-reported T2DM diagnosis, death or end of follow-up. DIABETES

Diabetes: Add-on aliskiren has limited benefit.

A trial of the renin inhibitor aliskiren to treat cardiovascular and renal complications in patients with type 2 diabetes mellitus (T2DM) has been ended prematurely after the second interim efficacy analysis showed that use of aliskiren as an addon to first-line interventions resulted in a higher frequency of adverse events than use of a placebo. Inhibitors of the renin–angiotensin– aldosterone system are routinely prescribed to reduce blood pressure. Dual targeting of this system has been investigated in a number of studies, but treatment with an angiotensinconverting-enzyme (ACE) inhibitor and an angiotensin-receptor blocker has been shown to increase the risks of experiencing hyperkalaemia or hypotension. Aliskiren is effective alone as an antihypertensive drug and previous studies have shown that aliskiren used as an add-on to an angiotensin-receptor blocker reduces albuminuria to a greater extent than does treatment with an angiotensin-receptor blocker alone. As an add-on to an ACE inhibitor or an angiotensin-receptor blocker, aliskiren has been shown to improve surrogate markers of adverse cardiovascular and renal outcomes. In this double-blind, multicentre study, 8,561 patients who were already being treated with an ACE inhibitor or an angiotensin-receptor blocker were randomized to receive either the renininhibitor aliskiren or a placebo as add-on therapies. Patients were aged ≥35 years, and had T2DM as well as albuminuria or cardiovascular disease. The primary end point was a composite of fatal and nonfatal renal and cardiovascular events. Blood pressure increased in both groups, but the increase was smaller in the group receiving aliskiren than in the group receiving a placebo. However, the primary endpoint occurred more frequently in the group receiving aliskiren than in the group receiving placebo (18.3% versus 17.1%, respectively). Additionally, death from cardiovascular causes, cardiac arrest requiring resuscitation, myocardial infarction and stroke all occurred more frequently in the aliskiren group. The benefits of using aliskiren as an add-on therapy to an ACE inhibitor or an angiotensin-receptor blocker do not seem to outweigh the adverse effects of the drug.

Diabetes: Basal insulin and n-3 fatty acids—no effect on cardiovascular outcomes

Neither provision of basal insulin nor of n-3 fatty acids to patients with poor glycaemic control who are at a high risk of adverse cardiovascular events confers significant cardiovascular protection. These findings of a two-by-two factorial study conducted by the ORIGIN trial investigators have been published in The New England Journal of Medicine. The presence of elevated fasting glucose levels is a known cardiovascular risk factor and the researchers hypothesized that provision of basal insulin (insulin glargine) to at-risk patients to normalize fasting glucose levels could reduce the incidence of cardiovascular events. Results of previous studies have been conflicting, with some reports showing an association between insulin treatment and increased mortality, DIABETES

Thyroid function: Low T4 levels a risk factor for fatty liver?

Investigators in Germany have found an inverse correlation between serum free T4 levels and fatty liver in a population of individuals without known thyroid or liver disease living in West Pomerania. However, the presence of fatty liver did not correlate with levels of TSH or free T3. The liver metabolizes thyroid hormones and so its function influences the levels of these hormones. Also, the liver is a thyroid hormone target tissue, so changes in thyroid hormone levels are likely to alter the regulation of liver metabolic processes. Findings from a number of studies have suggested links between levels of thyroid hormones and fatty liver. The new study was larger than prior studies and the data were adjusted for participant sex, age, physical activity, alcohol consumption, waist circumference and food intake. The analysis involved participants of the Study of Health in Germany. Individuals with self-reported thyroid disease or liver cirrhosis, those receiving thyroid-related medication or those who tested positive for hepatitis antibodies were excluded from the THYROID FUNCTION