Comparison of calcaneal quantitative ultrasound and bone densitometry parameters as fracture risk predictors in type 2 diabetes mellitus.

AIM: To investigate the utility of calcaneal quantitative ultrasound compared with bone densitometry (DXA) in predicting incident low-trauma fracture in type 2 diabetes. METHODS: This retrospective cohort study included a subset of participants in the Dubbo Osteoporosis Epidemiology Study who had concurrent calcaneal quantitative ultrasound and DXA measurement, comprising 809 people without type 2 diabetes and 96 with type 2 diabetes. Fracture data had been collected prospectively. Cox proportional hazard models and receiver operating curves (ROC) were used to compare calcaneal quantitative ultrasound and DXA parameters as predictors for any low-trauma fracture. RESULTS: The median age of participants was 71 years (IQR 68-76, 50% men) for those without type 2 diabetes and 70 years (IQR 68-76, 55% men) for those with type 2 diabetes. There was no difference in low-trauma fracture incidence between groups when stratified by sex. In those without type 2 diabetes, the hazard ratio for fracture per 1 sd decrease in broadband ultrasound attenuation and femoral neck bone mineral density (BMD) was 1.47 [95% confidence interval (CI) 1.26-1.71] and 1.39 (95% CI 1.17-1.64), respectively. The corresponding figures in type 2 diabetes were 1.81 (95% CI 1.03-3.19) for broadband ultrasound attenuation and 2.55 (95% CI 1.28-5.08) for femoral neck BMD. CONCLUSION: Broadband ultrasound attenuation is comparable with femoral neck BMD as a predictor for low trauma incident fracture in type 2 diabetes. Calcaneal quantitative ultrasound offers several advantages over DXA and should be considered in further studies of bone health screening or in clinical practice where DXA is unavailable.

Interrogation of a longitudinal, national pharmacy claims dataset to explore factors that predict the need for add-on therapy in older and socioeconomically disadvantaged Australians with type 2 diabetes mellitus patients (T2DM).

PURPOSE: The management of type 2 diabetes mellitus (T2DM) is complex. The aim of this work is to explore factors that predict the need for add-on therapy in patients with T2DM in the community. METHODS: We accessed longitudinal, pharmacy payment claim records from the national Pharmaceutical Benefits Scheme (PBS) (Subsidises costs of medicines: government pays difference between patient co-payments, lower in concessional patients, and additional cost of drug.) for the period January 2006 to September 2014 (EREC/MI3127) from a 10% random sample of the Australian population validated to be representative of the population by the Australian Bureau of Statistics (ABS). Likely, T2DM patients were identified as those having been dispensed a single anti-hyperglycaemic drug (monotherapy). The time taken and possible factors that might lead to the addition of a second therapy were examined. An examination was made of trends in the co-prescription of either antihypertensive or anti-hyperlipidaemic agents in relation to the time (± 3 years) of initiating an anti-hyperglycaemic agent. RESULTS: Most (83%) presumed T2DM patients were initiated with metformin. The average time until the second agent was added was 4.8 years (95% CI 4.7-4.9). Satisfactory adherence, age, male gender, initiating therapy after 2012 and initiating with a sulphonylurea drug all were significant risks for add-on therapy. There was no overall trend in the initiation of antihypertensive and/or anti-hyperlipidaemic agents with respect to the time of anti-hyperglycaemic initiation. CONCLUSION: The usefulness of a longitudinal dataset of pharmacy-claim records is demonstrated. Over half of all older and socioeconmically disadvantaged T2DM patients captured in this longitudinal claims database will be prescribed a second anti-hyperglycaemic agent within 5 years of their first drug therapy. Several factors can predict the risk of prescription of add-on therapy, and these should be considered when prescribing medications to treat T2DM.

Trends in metformin utilisation and dose appropriateness in Australia.

PURPOSE: The study aimed to (1) determine the trends in the utilisation of metformin in Australia, (2) determine the appropriateness of metformin dosing in an Australian teaching hospital and (3) gather the opinions of prescribers on the relationship between metformin dose and renal function. METHODS: National prescription data between 1990 and 2012 were accessed. A retrospective audit (2008-2012) of metformin doses and patient renal function (20 % random sample of all in-patients prescribed metformin) was conducted at St Vincent's Hospital (SVH), Sydney. Prescribers of metformin were interviewed (semi-structured; consultants at SVH) or surveyed (Australian endocrinologists) to gather their understanding of metformin dosing in relation to renal function. RESULTS: Metformin utilisation increased fivefold nationally between 1995 and 2012. Metformin tended to be under-dosed in SVH patients with normal renal function (83.5 %) and over-dosed in patients with impaired renal function (estimated glomerular filtration rate (eGFR) <30 mL/min, 50 %). Consultants indicated that metformin doses needed to be reduced in renal impairment. Most endocrinologists (61 %) were comfortable prescribing metformin down to eGFRs around 30 mL/min. CONCLUSION: The use of metformin increased greatly over the period of the study. Metformin is prescribed frequently for patients with eGFR values below the minimal level approved in the product label (60 mL/min). While prescribers expressed their understanding of the need to reduce metformin doses in patients with renal impairment, we found that metformin doses were higher than appropriate in patients with impaired renal function. Metformin may be used safely when renal function is poor provided dosage is appropriately reduced.

Factors affecting school physical education provision in England: a cross-sectional analysis.

BACKGROUND: Attitudes towards physical activity are largely developed during childhood meaning that school physical education classes can have a strong influence. METHODS: National level data of school pupils (n = 21 515) in England were analysed to examine the association between school provision of physical education with sex, age, geographic and socioeconomic factors. RESULTS: Children attending independent schools had more scheduled physical education time (P < 0.001; 95% confidence interval (CI) 18 to 30 extra min per week). This association was true for males (P = 0.024); schools located in the South (P < 0.001; 95% CI 2 to 3) and rural areas (P < 0.001; 95% CI 3 to 5); or with a higher percentage of pupils eligible for free school meals (P < 0.001; 95% CI 3 to 4). Schools in more affluent areas (P < 0.001; 95% CI -1 to -2) and those with lower percentages of pupils from ethnic minorities (P < 0.001; 95% CI -1 to -2) also had higher minutes of physical education provision per week. Regarding age, 93% of schools met the guidelines in Years 1-9; only 45% did in Years 10-13. CONCLUSION: Differences in physical education were found in relation to school type, socioeconomic status and geographical factors. Age-related differences in compliance with guidelines are of concern; ways to increase provision for older children should be investigated.

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects.

AIMS/HYPOTHESIS: Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. METHODS: We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp. RESULTS: Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals. CONCLUSIONS/INTERPRETATION: These results highlight non-linearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely to be hyperactivated in response to hyperinsulinaemia. This facet of Akt signalling may contribute to multiple features of the metabolic syndrome.

Formoterol, a highly ß2-selective agonist, increases energy expenditure and fat utilisation in men.

BACKGROUND: The sympathetic nervous system regulates energy metabolism via ß-adrenoreceptors. Therapeutic exploitation of previous ß2-adrenegic agonists for metabolic benefits has been hindered by cross stimulation of cardiac ß1-adrenoceptor, causing tachycardia. Formoterol is a novel highly ß2-selective adrenergic agonist and holds promise as a ß2-agonist that could impart selective beneficial metabolic effects. OBJECTIVE: To investigate the metabolic effects of formoterol on energy and substrate metabolism. PARTICIPANTS: Healthy volunteers. DESIGN: (1) Dose-finding study, step-wise incremental design of weekly administration of 80, 160 and 320 µg daily of formoterol in four subjects and, (2) metabolic study, an open-label metabolic evaluation of 1-week treatment in eight men using a dose determined from (1). MAIN OUTCOME: Resting energy expenditure (EE), diet-induced thermogenesis (DIT) and fat oxidation (Fox) using indirect calorimetry, heart rate and plasma non-esterified fatty acid (NEFA) levels. RESULTS: In the dose-finding study, all three doses increased resting EE and Fox with the 320 µg dose significantly increasing heart rate. In the metabolic study, the selected 160 µg daily dose increased resting EE by 13 ± 2% (P<0.001) and Fox by 23 ± 4% (P<0.01), but not DIT. Plasma NEFA levels rose by 16 ± 2% (P<0.01). Heart rate did not change significantly. Out of the eight subjects, six reported tremor and palpitation, two lost appetite and one suffered from insomnia. CONCLUSIONS: At a dose of 160 µg per day, formoterol increases resting EE and fat utilization without inducing tachycardia. From this first metabolic evaluation in humans, we conclude that formoterol imparts beneficial metabolic changes that may be exploited for therapy of obesity.

Metformin therapy in patients with chronic kidney disease.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Recreational drug use in type 1 diabetes: an invisible accomplice to poor glycaemic control?

Recreational drug use during 'rave' parties is increasingly popular, but the impact of recreational drug use in type 1 diabetes (T1D) is not known. We determined the self-reported pattern and effects of recreational/illicit drug use in Australians with T1D people by inviting people with T1D to participate in an anonymous online/paper survey of drug use, through national radio broadcast and online/hospital advertising. Of the people with T1D who responded to our survey, more than three quarters reported having used recreational/illicit drug, but few people had informed health professionals about drug use. Drug use was associated with worse glycaemic control and higher risk of diabetic ketoacidosis. Medical awareness of common, currently underreported, drug use in young people with T1D is essential. It offers the possibility of helping such patients improve related suboptimal metabolic control.

Metabolic sequelae of ß-blocker therapy: weighing in on the obesity epidemic?

BACKGROUND: Sympathetic activation is an important metabolic adaptation limiting weight gain. Propensity of weight gain associated with ß-blocker therapy in the obese modern population is unknown. OBJECTIVE: To determine whether chronic ß-blocker therapy reduces energy expenditure (EE) and increases body weight. METHODS: We undertook (i) a mechanistic study comparing EE, diet-induced thermogenesis and habitual activity between healthy volunteers (n=11) with uncomplicated hypertension treated with a ß-blocker and anthropometrically matched controls (n=19) and (ii) three cross-sectional studies comparing body weight, body mass index (BMI) and waist circumference between ß-blocker treated and untreated patients from ambulatory patients attending (a) diabetes outpatient clinic (n=214), (b) hypertension outpatient (n=84) and (c) participants in a multi-centre type 2 diabetes trial (ADVANCE) (n=11140). RESULTS: Among weight-matched ß-blocker users, diet-induced thermogenesis, fat oxidation rate and weekly habitual activity were lower by 50% (P<0.01), 32% (P=0.04) and 30% (P<0.01), respectively, compared with controls. In ß-blocker treated patients, the adjusted mean body weight was 9.2 ± 1.2 kg (P=0.0002) higher among those attending the diabetes clinic, 17.2 ± 3.2 kg (P=0.004) higher among those attending the hypertension clinic and 5.2 ± 0.7 kg (P=0.0003) higher at baseline among participants in the ADVANCE trial compared with patients not treated with ß-blockers. BMI displayed a similar difference. CONCLUSIONS: EE is reduced and body weight increased in chronic ß-blocker users. We hypothesise that chronic ß-blockade causes obesity by blunting EE.

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

A family history of type 2 diabetes increases risk factors associated with overfeeding.

AIMS/HYPOTHESIS: The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. METHODS: We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp). RESULTS: Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ individuals having gained significantly more weight than FH- individuals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001). CONCLUSIONS: Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding. TRIAL REGISTRATION: ClinicalTrials.gov NCT00562393 FUNDING: The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).

Challenges in secondary stroke prevention: prevalence of multiple metabolic risk factors, including abnormal glycaemia, in ischaemic stroke and transient ischaemic attack.

BACKGROUND: Secondary prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA) mandates identification and treatment of multiple metabolic risk factors. The aim was to determine the prevalence of abnormal glycaemia, hypertension and dyslipidaemia in patients presenting to an Acute Stroke Unit of a tertiary referral teaching hospital with IS or TIA. METHODS: We reviewed the clinical characteristics of consecutive patients presenting with symptoms of acute stroke or TIA between 1 February 2006 and 30 June 2007 to determine the prevalence of diabetes, impaired fasting glucose (IFG), post-stroke dysglycaemia (PSD), hypertension and dyslipidaemia. RESULTS: Mean age +/- SD of the 224 patients (84 female) was 71 +/- 15 years. Seventy per cent (n= 157) of patients presented with IS and 30% (n= 67) with TIA. Of the cohort, 15% (n= 33) had previously diagnosed diabetes, 10% (n= 22) were diagnosed with diabetes during admission and 19% (n= 42) had IFG diagnosed during admission. A further 4% (n= 9) were classified as having PSD. Sixty-two per cent (n= 139) of patients had previously diagnosed hypertension; another 7% (n= 15) were diagnosed during admission. Eighty-eight per cent (n= 197) of patients had dyslipidaemia. Thirty per cent had all three risk factors concurrently. CONCLUSION: Abnormal glycaemia was present in almost half the patients presenting with IS/TIA, with the majority of cases undiagnosed. One-third of patients had abnormal glycaemia, hypertension and dyslipidaemia concurrently. Patients presenting with stroke should be routinely screened for abnormal glycaemia in concert with other vascular risk factors.

Managing young people with Type 1 diabetes in a 'rave' new world: metabolic complications of substance abuse in Type 1 diabetes.

The taxing transition from adolescence towards adulthood intensifies the impact of a chronic illness such as Type 1 diabetes. It is not uncommon for young people with Type 1 diabetes to use recreational drugs for emotional relief to escape the day-to-day burden of chronic disease. Despite increasing use, especially in the setting of 'rave' parties, there is professional lack of understanding of the impact of recreational drug use on glycaemia and metabolic complications. The current review describes the prevalence of substance abuse in Type 1 diabetes and the acute impact of designer drugs on its management. We propose a practical approach to improve care of young people with Type 1 diabetes using designer drugs.

Severe insulin resistance due to anti-insulin antibodies: response to plasma exchange and immunosuppressive therapy.

Anti-insulin antibodies have been described in two contexts: in insulin-naive individuals (so-called 'insulin autoimmune syndrome') and in patients with insulin-treated diabetes, in whom antibodies are rarely of clinical significance. We report the case of an 68-year-old woman who exhibited a local allergic reaction to subcutaneous insulin followed by severe insulin resistance, evidenced by poor glycaemic control despite treatment with > 3.5 U/kg of insulin per day. She was found to have circulating polyclonal anti-insulin antibodies of the IgG subtype and responded clinically to a course of plasma exchange and immunosuppression with mycophenolate mofetil and, subsequently, intravenous immunoglobulin. Falling titres of antibodies on this regimen correlated with improved glycaemic control. This case suggests that clinicians should be alert to the possibility of insulin resistance due to anti-insulin antibodies and that immunosuppression in this situation may be a valuable therapeutic option.

Urinary steroid profiling in diagnostic evaluation of an unusual adrenal mass.

SUMMARY: Adrenal oncocytomas are rare tumours, with only approximately 160 cases reported in the literature. We report the use of urinary steroid profiling as part of their diagnostic evaluation and prognostication. A 45-year-old woman presented with clinical features of hyperandrogenism. Serum biochemistry confirmed androgen excess and computed tomography (CT) demonstrated a 3.2 cm adrenal tumour with density 39 HU pre-contrast. Urine steroid profiling showed elevated tetrahydro-11 deoxycortisol (THS), which is associated with adrenal malignancy. Laparoscopic adrenalectomy was performed, and histopathology diagnosed adrenal oncocytoma. Serum and urinary biochemistry resolved post-operatively and remained normal at 1-year follow-up. LEARNING POINTS: Differential diagnosis of adrenal masses is challenging. Current techniques for differentiating between tumour types lack sensitivity and specificity. 24-h urinary steroid profiling is a useful tool for reflecting steroid output from adrenal glands. Gas chromatography-mass spectrometry (GC-MS) of urinary steroid metabolites has sensitivity and specificity of 90% for diagnosing adrenocortical carcinoma. Adrenal oncocytoma are rare tumours. Differentiating between benign and malignant types is difficult. Data guiding prognostication and management are sparse.

Effect of weight-reducing agents on glycaemic parameters and progression to Type 2 diabetes: a review.

Weight loss is associated with improvements in glycaemic control and cardiovascular disease risk factors. However, in the diabetic population, weight management is more challenging, in part because of the weight-promoting effects of the majority of glucose-lowering therapies. This review summarizes evidence from 23 placebo-controlled randomized trials, of at least 1 year duration, on the effects of drugs promoting weight loss (orlistat, sibutramine and rimonabant) on glycaemic variables, diabetes incidence and diabetes control. Fifteen studies of non-diabetic subjects were found, eight of which included a longer treatment period. Eight studies in diabetic patients were reviewed. In non-diabetic subjects, weight loss agents led to a significant improvement in fasting glucose, fasting insulin and insulin resistance. In the diabetic population, glycated haemoglobin decreased by 0.28-1.1% with orlistat and 0.6% with sibutramine and rimonabant. Orlistat reduces progression to diabetes in patients with glucose intolerance treated for 4 years (risk reduction of 45%). In summary, despite leading to only modest weight loss after 12 months, agents promoting weight loss have beneficial effects on glycaemic parameters, glycaemic control and progression to diabetes. These additional benefits of weight loss agents need to be highlighted in order to increase their judicious use in clinical practice, although this may be limited by their well-known adverse side effects. The longer-term safety of these agents beyond a few years is yet to be established.

Complex interplay among adiposity, insulin resistance and bone health.

Obesity and osteoporosis are common public health problems. Paradoxically, while obesity is associated with higher bone density, type 2 diabetic obese individuals have an increased fracture risk. Although obesity and insulin resistance co-exist, some obese individuals remain insulin-sensitive. We suggest that the apparent paradox relating obesity, bone density and fracture risk in type 2 diabetes may be at least partly influenced by differences in bone strength and quality between insulin-resistant and insulin-sensitive obese individuals. In this review, we focus on the complex interplay between, adiposity, insulin resistance and osteoporotic fracture risk and suggest that this is an important area of study that has implications for individually tailored and targeted treatment to prevent osteoporotic fracture in obese type 2 diabetic individuals.