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Context The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known. Objective The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections. Materials and Methods Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later. Results In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since the last injection. Conclusions After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Context Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. Objective We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution–peripheral quantitative computed tomography (HR-pQCT). Methods Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect. Results Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P Conclusion In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

Summary Background Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. Methods T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50–74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8–11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. Findings Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was −0·95 mmol/L (SD 2·78) in the placebo group and −1·70 mmol/L (SD 2·47) in the testosterone group (mean difference −0·75 mmol/L, −1·10 to −0·40; p Interpretation Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. Funding Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

More than 10% of adults undergoing colonoscopy have type 2 diabetes (T2D) (1). The use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) has increased due to their glycemic control and benefits of lowering cardiovascular morbidity and mortality as well as reducing diabetic nephropathy (2,3). Diabetic ketoacidosis (DKA) is a rare complication associated with SGLT2i. Precipitating factors include fasting, dietary modifications, intercurrent illnesses, surgical stress, insulin insufficiency, and inappropriate management of SGLT2i in the periprocedural period. SGLT2i-induced ketoacidosis can present either with elevated blood glucose levels (BGL) or with near-normal BGL (

Background Perioperative diabetic ketoacidosis (DKA) with near-normal blood glucose concentrations, termed euglycaemic ketoacidosis (EDKA), is an adverse effect associated with sodium-glucose co-transporter-2 inhibitors (SGLT2i). Guidelines are still evolving concerning the perioperative management of patients on SGLT2i. We performed a systematic review of published reports of DKA from SGLT2i in the surgical setting to understand better the clinical presentation and characteristics of SGLT2i-associated DKA. Methods We searched PubMed, Embase, and ProQuest for reports of perioperative DKA involving SGLT2i up to January 2019. Results Forty-two reports of EDKA and five cases of hyperglycaemic diabetic ketoacidosis (HDKA) were identified from 33 publications. Canagliflozin was implicated in 26 cases. Presentation time varied from a few hours up to 6 weeks after operation. Precipitating factors may include diabetes medication changes, diet modifications, and intercurrent illnesses. There were 13 cases (12 EDKA and one HDKA) of bariatric surgery, 10 of them noted very-low-calorie diet regimes as a precipitating factor. No precise association between interruption of SGLT2i and the occurrence of DKA could be identified. Seven patients required mechanical ventilation, and acute kidney injury was noted in five. Five cases needed imaging to rule out anastomotic leak and pulmonary embolism, all of them revealed negative findings. Outcome data were available in 32 cases, all of them recovered completely. Conclusions EDKA is likely to be under-recognised because of its atypical presentation and may delay the diagnosis. Understanding this clinical entity, vigilance towards monitoring plasma/capillary ketones helps in early identification and assists in the management.

Background Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial. Methods An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50–74 years at high risk of developing diabetes. Study participation was promoted via mainstream media—television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff. Results Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941). Conclusion Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT. Trial registration ANZCTR, ID: ACTRN12612000287831. Registered on 12 March 2012. Electronic supplementary material The online version of this article (10.1186/s13063-019-3485-2) contains supplementary material, which is available to authorized users.

In men with obesity and IGT, serum testosterone (T) is inversely associated with incident T2D. Hypothesizing that T treatment prevents or reverses T2D beyond the effects of a lifestyle program alone, we conducted a multi-center, double-blinded placebo-controlled trial. Men (N=1007), aged 50-74 yrs., waist circumference (WC)>95cm, serum T≤14nmol/L (chemiluminescent assay), and IGT or newly diagnosed T2D, established by an OGTT, were randomized to receive, on a 1:1 basis, either IM T undecanoate (Reandron, Bayer) (1000mg/4ml) or vehicle (V) at baseline, 6 weeks and then 3-monthly for 2 yrs. All participants were enrolled in a lifestyle program (Weight Watchers® (WW)). Co-primary 2-yr outcomes: (1) OGTT 2-hr glucose ≥11 mmol/L: 55/443 (12.4%) in the T and 87/413 (21.1%) in V groups; RR (95% CI) 0.59 (0.43-0.80), P Disclosure G.A. Wittert: Research Support; Self; Bayer Inc., Lawley Pharmaceuticals, Lilly, Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins. K.P. Robledo: None. M. Grossmann: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Novartis Pharmaceuticals Canada Inc., Otsuka Pharmaceutical Co., Ltd., Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins Healthcare, Otsuka Pharmaceutical Co., Ltd. K. Bracken: None. B.B. Yeap: Advisory Panel; Self; Sanofi. Research Support; Self; Bayer AG, Lawley Pharmaceuticals. Speaker’s Bureau; Self; Besins, Sanofi. B.G.A. Stuckey: None. R.I. McLachlan: None. D.J. Handelsman: None. C. Allan: Advisory Panel; Self; Ferring Pharmaceuticals. Speaker’s Bureau; Self; Besins. W. Inder: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc. Speaker’s Bureau; Self; Amgen, Novo Nordisk Inc., Pfizer Inc. D. Jesudason: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. A.C. Keech: Advisory Panel; Self; Amgen, Kowa Research Institute, Inc. Consultant; Self; Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Amgen. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. M. Ng Tang Fui: None. M. Daniel: None. Funding National Health and Medical Council of Australia (1030123); Eli Lilly and Company; Bayer AG; Weight Watchers; University of Adelaide

Background: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC). Methods: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions. Results: The median age of YOCRC cases was 44 years (18–54) and of controls was 45 years (18–54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0–9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen. Conclusions: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients. Impact: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate. Refereed/Peer-reviewed

Background and objectiveTraditional masculinity is characterised by traits of independence, toughness, assertiveness, competitive-ness and physical competence. Multiple factors modulate the expression of masculinity, including age, social class, ethnicity and occupation. While there is a perception that physiological testosterone concen-tration impacts self-perceived masculinity in men, there are limited supporting data. This study aimed to examine the relationship between testosterone concentration and self-perceived masculinity as measured by the Masculinity in Chronic Disease Inventory (MCD-I), controlling for health-related and biopsycho-social factors in community-dwelling, middle-aged to elderly men.Materials and methodsParticipants were drawn from a longitudinally followed cohort (N=1195) of men participating in the Florey Adelaide Male Aging Study based in Adelaide, Australia. A final sample of 460 (mean age 65.15, stan-dard deviation 9.72) men consisted of those with serum testosterone concentrations measured at wave one (2002–2005) and wave two (2007–2010), and who, in 2017, completed the Masculinity in Chronic Disease Inventory questionnaire and provided information related to demographics, medical conditions, health and lifestyle behaviours.Adjusted multivariable regression analyses were undertaken to determine the relationship between serum testosterone concentration at wave 2 and MCD-1 total masculinity score and sub-scores. Given the temporal difference between the testosterone concentration assessment and MCD-1 completion, a further analysis was performed including participants with a stable serum testosterone concentration over a 5-year period.ResultsThere was no association between serum testosterone concentration and MCD-1 total masculinity score (p = 0.54) or sub-scores (p = 0.12–0.85). There was also no association between testosterone concentration and total masculinity score in men with stable serum testosterone over time (p = 0.35). Testosterone con-centration was associated with serum sex-hormone-binding globulin (SHBG) concentration (p < 0.001), age (p < 0.001), waist circumference (p < 0.001) and a history of diabetes (p = 0.021). Total masculinity score was lower in men without a partner (widowed p < 0.013, separated/divorced p < 0.019), a history of anxiety (p = 0.036) and moderate (p = 0.05) to severe erectile dysfunction (p < 0.001).ConclusionThis study provides evidence against the perception that physiological testosterone concentration impacts self-perceived masculinity. Rather, in middle-aged to older men, self-perceived masculinity is abrogated by psychosocial factors and chronic physical disorders.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been linked with diabetic ketoacidosis (DKA) (1–4). However, characteristics of “at-risk” patients are less well described. Clinical cases were collected from South Australia between December 2015 and March 2017. The audit was approved by the Royal Adelaide Hospital Human Research Ethics Committee (HREC reference no. HREC/17/RAH/185). The Therapeutic Goods Administration (TGA) of the Australian Government Department of Health was contacted, and a search of the Database of Adverse Event Notifications (medicines) for all reports of SGLT2 inhibitor–associated DKA was requested up until April 2017 using the search terms ketoacidosis, diabetic ketoacidosis, and generic and brand drug names. Full case line listings for each notification were provided by the TGA. Autoantibodies against glutamic acid decarboxylase (GAD) and insulinoma-associated antigen 2 (tyrosine phosphatase IA-2) were quantitated using commercial ELISA test kits (Euroimmun AG, Lubeck, Germany). These assays are calibrated in international units (IU) using the first World Health Organization reference reagent for islet cell antibodies (1999, reagent 97/550; National Institute for Biological Standards and Control, Hertfordshire, U.K.), which contains 100 IU of anti-GAD and 100 IU of anti–IA-2 per ampoule by definition. We identified thirteen cases of SGLT2 inhibitor–associated DKA occurring in South Australia between December 2015 and March 2017 (Table 1). Eight case subjects had type 2 diabetes (T2D) and five had …

Objective Obstructive sleep apnea (OSA) is generally considered to lower serum testosterone concentration in men, although data supporting this as a direct effect are limited. The aim of this study was to determine the relationship between the presence and severity of OSA and testosterone in a community-based cohort of men aged over 40 years. Design and methods Anthropometry, polysomnography and biomedical information were collected from enrolled, consenting men from the prospective, longitudinal MAILES study cohort. Fasting morning blood samples (n = 1869) were drawn between 2010 and 2012 for measurement of testosterone using liquid chromatography mass spectrometry. Home polysomnography was completed in 861 men between 2010 and 2012. The final analysis sample consisted of 623 men aged 41–86 years. The effect of OSA on testosterone were analyzed using linear regression models controlling for potential confounders (age, BMI and sex hormone binding globulin (SHBG)). Results The mean (s.d.) cohort characteristics were: age 59.0 (10.2) years, testosterone 16.8 (5.3) nmol/L, SHBG 32.9 (13.1) nmol/L, BMI 28.6 (4.2) kg/m2 and apnoea hypopnoea index (AHI) 14.9 (13.7). OSA was present in 51.5%. There was an inverse relationship between AHI and testosterone (P = 0.01), which was lost after covariate adjustment. Conclusions These data suggest that obesity, rather than OSA per se, determine testosterone concentration. This accords with the graded effect of weight loss, but limited effect of continuous positive airway pressure to increase testosterone, and highlights the importance of managing obesity in men with low testosterone concentration, particularly in the context of OSA.

Psychologists are subject to multiple competing emotional demands that increase the risk of burnout. Research has demonstrated that burnout arises from both organizational and personal factors, including psychologists' personal beliefs and coping. Preliminary research indicates that Early Maladaptive Schemas (EMS) are associated with high burnout, yet, to date, the role of EMS and associated coping responses (Maladaptive Coping Modes [MCM]) in predicting high burnout among psychologists has not been investigated. Four hundred and forty‐three psychologists completed a self‐report online questionnaire comprising the Maslach Burnout Inventory—Emotional Exhaustion Scale (EE), Young Schema Questionnaire (YSQ), and Schema Mode Inventory (SMI). The two most common EMS amongst psychologists were Unrelenting Standards and Self Sacrifice. There was substantial indication of burnout, with 18.3% in the high range and 29.6% in the moderate range of EE. The most common MCM were Detached Protector and Detached Self‐Soother. Controlling for demographics and job demands, EMS accounted for an additional 18% variance in EE. MCM accounted for an additional 6% beyond the variance explained by demographics, job demands and EMS. Practical recommendations are suggested to reduce psychologist burnout. Refereed/Peer-reviewed

We have shown that the capacity of 25 g whey preloads to slow gastric emptying and reduce post prandial glycaemia persists after 4 weeks regular exposure in patients with diet controlled type 2 diabetes. This dietary strategy therefore appears feasible for larger clinical trials to evaluate beneficial effects on long-term glycaemic control. Registered with the Australian New Zealand Clinical Trials Registry:ACTRN12614000831684. Refereed/Peer-reviewed

e15005 Background: Colorectal cancer (CRC) is rising in incidence in young adults. Because they are not included in population screening, and are more likely to present at an advanced stage, there is a need to identify young adults at increased risk for CRC. An association has been reported between type 2 diabetes (T2D) and CRC in the general population. Though lifestyle risk factors may be involved, the early occurrence of CRC in young adults suggests that there may also be a role for inherited predispositions. We therefore investigated whether having a personal and/or first-degree family history of T2D was a potential risk marker for early onset CRC. Methods: The South Australian Young Onset (SAYO) CRC study is an unselected series of young adults with CRC up to age 55. Fifty unrelated young adults (31/50 or 62% female) diagnosed with CRC were recruited to the study. Personal history of T2D was confirmed. Detailed family history of T2D was recorded. 253 patients with clear colonoscopies and no known CRC predisposition served as controls for personal history studies of T2D. Diabetes status was recorded on admission for colonoscopy controls. Associations were explored using a chi-squared statistic. Results: CRC patients ranged in age from 23-54 years (median age 42) and controls from 18-54 (median age 45). Six patients (12%) met the WHO clinical criteria for serrated polyposis, and two (4%) carried a Lynch syndrome mutation. CRC was present in the distal colon in 15/19 males (79%) and 17/31 females (55%) (p = 0.12). A personal history of T2D was confirmed in 12/50 (24%) CRC patients compared with clear colonoscopy controls under 55 years (13/258 or 5% P < 0.001; OR = 5.9; 95%CI 2.5-13.8). T2D was seen in 7/31 or 23% females and 5/19 or 26% males. Young adults with CRC frequently reported at least one first-degree relative with T2D (24/47 or 51%). All patients with personal history of T2D also had first-degree relatives with T2D. A first-degree family history of T2D was observed in 12/27 (44%) CRC patients aged under 45 yrs and 12/20 (60%) of CRC patients aged between 45 and 54 yrs having this characteristic (p = 0.29), and was present in both males and females (10/17 or 58% and 13/30 or 43% respectively; p = 0.37). Conclusions: Though the mechanism remains unclear, given the prevalence of T2D in those aged < 55yrs is 5% in Australia, our observations suggest that there is a striking enrichment for personal and first-degree family history of T2D in young adults with CRC. These features could potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.

As the incidence of obesity and the metabolic syndrome has increased, research has focused on the importance of the endocannabinoid system in the brain and peripheral tissues. Rimonabant, an inverse agonist of the CB1 receptor is being used therapeutically. This review presents recent advances in endocannabinoid physiology.The endocannabinoid system interacts with other anorexigenic and orexigenic pathways to regulate food intake in the hypothalamus, and the hedonistic value of food in the mesolimbic system. Endocannabinoid system overactivity contributes to hepatic steatosis, increased adipose tissue inflammation, dysregulated insulin signalling in the pancreas and disturbed oxidative pathways in skeletal muscle. The breakdown pathways for anandamide and 2-arachidonoylglycerol, the endocannabinoid receptor ligands, are reviewed, and the recent discoveries of endocannabinoid receptor polymorphisms and their relationship to obesity and metabolic disease noted. The favourable effect of rimonabant on fat mass glycaemic control, lipid metabolism and overall cardiovascular risk must be tempered by adverse effects on mood.The ubiquitous role of the endocannabinoid system in food intake and energy metabolism is now established. Drugs that manipulate different aspects of this system may benefit subjects with the metabolic and cachectic syndromes.

Refereed/Peer-reviewed

OBJECTIVE—The use of fasting plasma glucose (FPG) level ≥7.0 mmol/l leads to underdiagnosis of type 2 diabetes compared with the oral glucose tolerance test (OGTT). The OGTT is of limited use for population screening. Most of the increase in cardiovascular risk in relation to increasing blood glucose occurs before the threshold at which the diagnosis of type 2 diabetes is made. The aim of this study was to evaluate the use of HbA1c and FPG as predictors of type 2 diabetes and cardiovascular risk and, accordingly, to develop a rational approach to screening for abnormalities of glucose tolerance. RESEARCH DESIGN AND METHODS—OGTT and measurement of HbA1c and FPG levels were performed in 505 subjects screened for type 2 diabetes. Anthropomorphic measurements were obtained. A cardiovascular risk factor questionnaire was completed. RESULTS—The subjects were aged 19–88 years (mean 53.8). The incidence of type 2 diabetes was 10.4% based on the OGTT and 4% based on an FPG level ≥7.0 mmol/l. Using high-performance liquid chromatography (HPLC), HbA1c of CONCLUSIONS—Measurement of FPG and HbA1c levels will diagnose or exclude type 2 diabetes with certainty in a minority (15%) of people. There is a continuous relationship between FPG and HbA1c and cardiovascular risk. Accordingly, we propose that there is a rational basis for using either FPG and HbA1c for purposes of screening and assigning risk. Individuals with an HbA1c level of 5.6–6.1% and an FPG level of 5.6–6.3 mmol/l are at greatest risk for cardiovascular disease and should be targeted for further evaluation. An algorithm outlining a cost-effective approach is presented.

It is known that nursing-home patients with vitamin D insufficiency have elevated serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase (ALP). Although it is well known that vitamin D insufficiency and secondary hyperparathyroidism are common among the elderly in western countries, there is continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D] necessary for bone health. We approached this issue by examining the relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the urinary bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr, respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who were referred to our osteoporosis and menopause clinics for investigation. When the patients were divided into two groups with 25(OH)D above and below 20 nmol/L, 30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant differences between the two groups thus derived was found at a serum 25(OH)D level of 60 nmol/L (P < 0.001 for all markers). The most significant difference between groups for serum PTH was found when the patients were divided at a serum 25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a trend for ionized calcium to be positively related to 25(OH)D, but this did not reach statistical significance. We conclude that rises in three bone resorption markers and ALP can be detected in postmenopausal women when the serum 25(OH)D level falls below 60 nmol/L. Levels above this may be required for optimal bone health.

Many studies have confirmed Daniell’s observation in 1976 that postmenopausal women who smoke have more fractures and less bone than postmenopausal women who do not smoke. Comparison of the bone density of smokers with that of their nonsmoking twins perhaps makes the point most strongly. There are many potential causes of these differences, including less calcium and vitamin D intake and less physical activity in smokers compared with nonsmokers. There is also evidence for direct toxic effects of smoking on bone cells. Decreased new bone formation in smokers has been suggested by decreased biochemical bone marker levels in several studies. Impaired osteoblastic proliferation, differentiation, and function in vitro have also been described. A few studies found an increase in bone resorption but most did not. Several authors have reported decreased intestinal calcium absorption efficiency in smokers. This is most likely caused by low levels of serum calcitriol (1,25-dihydroxyvitamin D), the hormone that controls calcium absorption. Although many smokers also have low levels of the storage form of vitamin D, 25-hydroxyvitamin D [25(OH)D], this does not appear to be the cause of their low serum calcitriol. Most studies, but not all, indicate that serum parathyroid hormone (PTH) is suppressed in smokers, and this is most likely the cause of both the low serum calcitriol and decreased calcium absorption. Why PTH is decreased is not clear. It could be because of increased degradation or decreased production of PTH. Two studies report normal serum ionized calcium levels in smokers, but one suggests ionized calcium levels are increased, which might cause a secondary decrease in serum PTH. Management of the increased bone loss found in smokers will remain empirical until its causes are better understood.

Background: It has been hypothesized that hip-fracture rates are higher in developed than developing countries because high-protein (HP) Western diets induce metabolic acidosis and hypercalciuria. Confounders include interactions between dietary protein and calcium, sodium, and potassium. Objective: We determined whether an HP or high-normal–protein (HNP) weight-loss diet caused greater loss in bone mineral density (BMD) over 24 mo. Design: The Weight Loss, Protein and Bone Density Study was conducted from 2008 to 2011 in 323 overweight [body mass index (BMI; (in kg/m 2 ) .27] postmenopausal women, with a total hip BMD t score less than 22.0. Subjects were randomly assigned to receive an isocaloric calcium-replete HP ($ 90 gp rotein/d) or HNP (, 80 gp rotein/d) weight-loss diet, with the aim of a difference of 20 g protein/d. A total of 186 subjects (90 subjects in the HP group, 96 subjects in the HNP group) completed 12 mo, and 137 subjects (69 subjects in the HP group, 68 subjects in the HNP group) completed 24 mo. Results: Biomarkers confirmed a difference in protein intake of 16 and 13.1 g at 12 and 24 mo, respectively. Mean (6SE) weight loss was equal; HP subjects lost 7.9 6 0.9 kg and HNP subjects lost 8.96 0.9 kg at 24 mo. Subjects lost 1–2% BMD annually at lumbar spine vertebrae 2–4, the forearm, the femoral neck, and hip. ANCOVA showed no effect of the HP or HNP diet (P . 0.05 for diet and diet-time interactions). A diet-by-time analysis showed that the HNP diet increased C-terminal telopeptide and osteocalcin (P # 0.001 for each) despite hypercalciuria (P = 0.029). Conclusion: High dietary protein intake during weight loss has no clinically significant effect on bone density but slows bone turnover. This trial was registered at the Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au) as ACTRN12608000229370. Am J Clin Nutr doi: 10.3945/ajcn.113.058586.

Background: Higher-protein weight-loss diets (defined as .25% of energy as protein) are not recommended for individuals with type 2 diabetes because of their potential adverse effect on renal function. Objective: We aimed to examine the effect of such diets on renal function over 12 mo in people with type 2 diabetes and early renal disease. Design: Overweight and obese people with type 2 diabetes were screened to identify those with an albumin:creatinine ratio from 3 to 30 mg/mmol. Seventy-six subjects were randomly assigned to either a moderate-protein weight-loss diet or a standard-protein weightloss diet for 12 mo. The primary endpoint was the change in renal function as assessed by the isotope glomerular filtration rate (GFR), estimated GFR, and cystatin C. Forty-five subjects (moderate protein: n = 21; standard protein: n = 24) completed the study. Results: The mean (6SE) weight loss was not different between diets at 9.7 6 13.4 kg for the moderate-protein diet and 6.6 6 7.1 kg for the standard-protein diet. There were no changes in renal function or albuminuria or blood pressure, although glycated hemoglobin was lowered with both diets. Changes in renal function were related to the baseline estimated GFR. Patients with stage 1‐3 renal disease (,120 mL $ min 21 $ 1.73 m 22 ; n = 33) had an improvement in renal function, whereas patients with hyperfiltration (.120 mL $ min 21 $ 1.73 m 22 ; n = 12) had a decrease in the GFR. After adjustment for weight loss, the baseline GFR remained a significant predictor of outcomes with no effect of dietary treatment. An average difference in protein intake between diets of 19 6 6 g/d was achieved. Conclusion: Weight loss improved renal function, but differences in dietary protein had no effect. This trial was registered at the Australian and New Zealand Clinical Trial Register as ACTRN12608000045314. Am J Clin Nutr 2013;98:494‐501.

Background and aim: Diets where carbohydrate has been partially exchanged for protein have shown beneficial changes in persons with type 2 diabetes but no studies have enrolled people with albuminuria. We aim to determine if a high protein to carbohydrate ratio (HPD) in an energy reduced diet has a beneficial effect on metabolic control and cardiovascular risk factors without negatively affecting renal function. Method and results: Adult, overweight participants with type 2 diabetes, with albuminuria (30–600 mg/24 h or an albumin-to-creatinine ratio of 3.0–60 mg/mmol), and estimated GFR of >40 ml/min/1.73 m2 were enrolled. Participants were randomized to an HPD or an SPD. Protein:fat:carbohydrate ratio was 30:30:40% of energy for the HPD and 20:30:50% for the SPD. Main outcomes were renal function, weight loss, blood pressure, serum lipids and glycaemic control. We recruited 76 volunteers and 45 (35 men and 10 women) finished. There were no overall changes in renal function at 12 months and no significant differences in weight loss between groups (9.7 ± 2.9 kg and 6.6 ± 1.4 kg HPD and SPD group respectively; p = 0.32). Fasting blood glucose decreased significantly with no treatment effect. The decrease in HbA1c differed between treatments at 6 months (HPD −0.9 vs. SPD −0.3%; p = 0.039) but not at 12 months. HDL increased significantly with no treatment effects. There were no changes in LDL or blood pressure overall but DBP was lower in the HPD group (p = 0.024) at 12 months. Conclusion: Weight loss improved overall metabolic control in this group of well controlled participants with type 2 diabetes regardless of diet composition. Refereed/Peer-reviewed

The role of dietary protein in bone health has been controversial. On the one hand, a plentiful supply of dietary amino acids has been considered important to support bone remodeling while on the other hand there have been concerns that the dietary acid load associated with protein consumption promotes hypercalciuria and loss of bone calcium stores. This article reviews the effect of dietary protein on bone mass and bone density, and the effect on markers of bone resorption and formation and also on fracture risk,looking at both cross-sectional and longitudinal studies and examining both meat and vegetable protein including soy and milk basic protein. The results are not entirely consistent and suggest that the interaction between dietary protein and other components in a mixed diet, such as calcium intake and vegetables and fruit to neutralize acid, are important and may determine whether high-protein diets are beneficial to bone health. Overall the results suggest that dietary protein has a modest beneficial effect on bone markers and bone density.This effect has yet to be consistently linked to reduced fracture risk, probably because of the role of other etiological factors such as the risk of falls. There is not enough evidence currently to suggest that animal protein is superior or inferiorto vegetable protein, or that milk or soy protein, respectively,is more favorable than other protein sources. Refereed/Peer-reviewed