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Background Diabetes is a major public health problem affecting about 1.4 million Australians, especially in South Western Sydney, a hotspot of diabetes with higher than average rates for hospitalisations. The current understanding of the international burden of diabetes and related complications is poor and data on hospital outcomes and/or what common factors influence mortality rate in people with and without diabetes in Australia using a representative sample is lacking. This study determined in-hospital mortality rate and the factors associated among people with and without diabetes. Methods Retrospective data for 554,421 adult inpatients was extracted from the population-based New South Wales (NSW) Admitted Patient Data over 3 financial years (from 1 July 2014–30 June 2015 to 1 July 2016–30 June 2017). The in-hospital mortality per 1000 admitted persons, standardised mortality ratios (SMR) were calculated. Binary logistic regression was performed, adjusting for potential covariates and co-morbidities for people with and without diabetes over three years. Results Over three years, 8.7% (48,038 people) of admissions involved people with diabetes. This increased from 8.4% in 2014–15 to 8.9% in 2016–17 (p = 0.007). Across all age groups, in-hospital mortality rate was significantly greater in people with diabetes (20.6, 95% Confidence intervals CI 19.3–21.9 per 1000 persons) than those without diabetes (11.8, 95%CI 11.5–12.1) and more in men than women (23.1, 95%CI 21.2–25.0 vs 17.9, 95%CI 16.2–19.8) with diabetes. The SMR for those with and without diabetes were 3.13 (95%CI 1.78–4.48) and 1.79 (95%CI 0.77–2.82), respectively. There were similarities in the factors associated with in hospital mortality in both groups including: older age (> 54 years), male sex, marital status (divorced/widowed), length of stay in hospital (staying longer than 4 days), receiving intensive care in admission and being admitted due to primary respiratory and cardiovascular diagnoses. The odds of death in admission was increased in polymorbid patients without diabetes (28.68, 95%CI 23.49–35.02) but not in those with diabetes. Conclusions In-patients with diabetes continue to have higher mortality rates than those without diabetes and the Australian population. Overall, similar factors influenced mortality rate in people with and without diabetes, but significantly more people with diabetes had two or more co-morbidities, suggesting that hospital mortality may be driven by those with pre-existing health/comorbidities. Urgent measures in primary care to prevent admissions among people with multiple co-morbidities are needed.

Background Obesity is a major risk factor for the development of type 2 diabetes (T2DM) and its complications. Significant weight loss has been shown to improve glycaemia in people with T2DM and obesity. National and international guidelines recommend considering bariatric surgery for body mass index (BMI) ≥ 35 kg/m2. We assessed the proportion of people with T2DM meeting criteria for surgery, how many had been offered a bariatric/obesity service referral, and compared the characteristics of people with BMI ≥ 35 kg/m2 and BMI 2. Methods Retrospective data were collected for all people with T2DM aged ≥18 years, attending a hospital specialist diabetes outpatient service over three calendar years, 2017–2019. Results Of 700 people seen in the service, 291 (42%) had BMI ≥ 35 kg/m2 (the “BMI ≥ 35 group”) and met criteria for bariatric surgery, but only 54 (19%) of them were offered referral to an obesity service. The BMI ≥ 35 group was younger than those with a BMI 2 (56.1 ± 14.8 vs 61.4 ± 14.6 years, p p = 0.078), and there was no significant difference in initial HbA1c (75 ± 27 vs 72 ± 26 mmol/mol, p = 0.118) (9.0 ± 2.5 vs 8.7 ± 2.4%) or proportion treated with insulin (62% vs 58%). There was more GLP1 agonist use in the BMI ≥ 35 group (13% vs 7%, p = 0.003) but similar rates of SGLT2 inhibitor use (25% vs 21%, p = 0.202). The BMI ≥ 35 group received more new medication and/or dose adjustments (74% vs 66%, p = 0.016). Only 29% in the BMI ≥ 35 kg group achieved HbA1c Conclusions In spite of frequently meeting the criteria for bariatric surgery and not achieving glycaemic targets, people with T2DM in this specialist clinic received limited medical or surgical management of their obesity. This study suggests opportunities for improvement in care of people with T2DM at several levels including increased referrals from T2DM services to weight management/bariatric services, as well as an increased use of GLP1 agonists and SGLT2 inhibitors where appropriate. Our data support the need to prioritise obesity management in the treatment of type 2 diabetes.

Background South Western Sydney (SWS) is a hotspot for diabetes in Australia. We compared intensive care unit (ICU) admission risk between people with and without diabetes admitted to public hospitals in this metropolitan health district. Methods Retrospective study of all admissions to ICU in the New South Wales Admitted Patient Data Collection (APDC) over three years. Data on demographic and health insurance status, primary admission diagnosis, comorbidities including death in admission for public hospital inpatients aged ≥18 years residing in South Western Sydney were analysed. The ICU length of stay was the main outcome variable classified into short stay (≤48hrs) and long stay (>48 hrs) were analysed. Potential predictors were analysed for possible association with long ICU stay among people with and without diabetes admitted to the hospital. Results Of the 187660 inpatients from SWS in the three years, 3.5% spent at least one hour in ICU [5.0% with diabetes versus 3.3% without diabetes, P

Background Although there is a strong association between obesity and obstructive sleep apnoea (OSA), the effects of OSA and CPAP therapy on weight loss are less well known. The aim of this study in adults with class 3 obesity attending a multidisciplinary weight management program was to assess the relationship between OSA and CPAP usage, and 12-month weight change. Methods A retrospective cohort study of all patients commencing an intensive multidisciplinary publicly funded weight management program in Sydney, Australia, between March 2018 and March 2019. OSA was diagnosed using laboratory overnight sleep studies. Demographic and clinical data, and use of CPAP therapy was collected at baseline and 12 months. CPAP use was confirmed if used ≥4 h on average per night on download. Results Of the 178 patients who joined the program, 111 (62.4 %) completed 12 months in the program. At baseline, 63.1 % (n=70) of patients had OSA, of whom 54.3 % (n=38) were using CPAP. The non-OSA group had more females compared to the OSA with CPAP group and OSA without CPAP group (90.2 % vs. 57.9 % and 62.5 %, respectively; p=0.003), but there were no significant baseline differences in BMI (50.4±9.3 vs. 52.1±8.7 and 50.3±9.5 kg/m2, respectively; p=0.636). There was significant weight loss across all three groups at 12 months. However, there were no statistically significant differences across groups in the percentage of body weight loss (OSA with CPAP: 6.3±5.6 %, OSA without CPAP: 6.8±6.9 %, non-OSA: 7.2±6.5 %; p=0.844), or the proportion of patients who achieved ≥5 % body weight loss (OSA with CPAP: 57.9 %, OSA without CPAP: 59.4 %, non-OSA: 65.9 %; p=0.743). In patients with T2DM, there was a significant reduction in HbA1c from baseline to 12 months (7.8±1.7 % to 7.3±1.4 %, p=0.03), with no difference between groups (p=0.997). Conclusions This multidisciplinary weight management program resulted in significant weight loss at 12 months, regardless of OSA diagnosis or CPAP use in adults with class 3 obesity. Larger studies are needed to further investigate the effects of severity of OSA status and CPAP use in weight management programs. Until completed, this study suggests that the focus should remain on implementing lifestyle changes and weight management regardless of OSA status.

Background Diabetes is a major public health problem affecting about 1.4 million Australians, especially in South Western Sydney, a hotspot of diabetes with higher than average rates for hospitalisations. The current understanding of the international burden of diabetes and related complications is poor and there is paucity of data on hospital outcomes and/or what common factors influence mortality rate in people with diabetes in Australia. This study determined in-hospital mortality rate and the factors associated among people with and without diabetes. Methods Retrospective data for 554,421 adult inpatients was extracted from the population-based New South Wales (NSW) Admitted Patient Data over 3 financial years (from 2014-15 to 2016-17). The in-hospital mortality per 1000 admitted persons, standardised mortality ratios (SMR) were calculated. Binary logistic regression was performed, adjusting for potential covariates and co-morbidities for people with and without diabetes over three years. Results Over three years 8.7% (48,038 people) of admissions involved those with diabetes. This increased from 8.4% in 2014-15 to 8.9% in 2016-17 (p = 0.007). Across all age groups, in-hospital mortality rate was significantly greater in people with diabetes (20.6, 95% Confidence intervals CI 19.3–21.9 per 1000 persons) than those without diabetes (11.8, 95%CI 11.5–12.1) and more in men than women (23.1, 95%CI 21.2–25.0 vs 17.9, 95%CI 16.2–19.8) with diabetes. The SMR for those with and without diabetes were 3.13 (95%CI 1.78–4.48) and 1.79 (95%CI 0.77–2.82), respectively. There were similarities in the factors associated with in hospital mortality in both groups including: aged > 54years, men, the widowed, those who stayed longer than 4 days or received intensive care in admission and had respiratory and cardiovascular comorbidities. Conclusions The study found that in-patients with diabetes continue to have higher mortality rates than those without diabetes and the Australian population. Overall, similar factors influenced mortality rate in people with and without diabetes in this region indicating that continued improved management of all inpatients is needed in order to minimise the persistent poor outcomes.

This study aimed to evaluate the risk of eating disorders, psychological distress, and health-related quality of life (HRQoL) in people with class 3 obesity (body mass index (BMI) ≥ 40 kg/m2), and the effect of multidisciplinary weight management over 12 months. This retrospective cohort study included all adults with class 3 obesity who enrolled in a weight management program from March 2018 to December 2019. Questionnaires included the Eating Disorder Examination Questionnaire Short (EDE-QS), Kessler Psychological Distress Scale (K10), and 36-Item Short Form Survey (SF-36) for HRQoL. Physical and Mental Component Summary scores (PCS and MCS) were derived from the SF-36. Of 169 participants who completed 12 months in the program, 65.7% (n = 111) completed questionnaires at baseline and 12 months, with 6.0 ± 6.8% weight loss over this period. Compared to baseline, there was significant improvement at 12 months in EDE-QS (15.7 ± 6.6 vs. 13.6 ± 6.2, p = 0.002), K10 (25.7 ± 9.7 vs. 21.2 ± 9.4, p &lt, 0.001), PCS (29.4 ± 10.1 vs. 36.1 ± 10.9, p &lt, 0.001), and MCS scores (40.2 ± 12.4 vs. 44.0 ± 13.4, p = 0.001). All, apart from EDE-QS scores, remained significant after adjusting for weight change. This study highlights the importance of multidisciplinary management in people with class 3 obesity to help reduce eating disorder risk and psychological distress, and improve HRQoL, in addition to weight loss.

AIMS To evaluate the effectiveness of a new locality-based integrated diabetes care service for people with Type 2 diabetes in an inner regional area. METHODS A quasi-experimental evaluation comparing baseline and follow up clinical data collected from general practices and specialist services participating in an integrated diabetes care programme in an inner-regional area. Patients had at least one specialist service consultation. The primary outcome was glycated haemoglobin (HbA1c). RESULTS Clinical data were collected for 178/239 patients (74.5% participation; aged 65± 11(SD) years, 46% female; median [interquartile range (IQR)] diabetes duration 19 (11.0-24.0) years from seven general practices over 33 months (median 18.5 months). There were reductions in HbA1c -0.7±1.6 % (8±18 mmol/mol) (p

Obesity is associated with significant comorbidities, including non-alcoholic fatty liver disease (NAFLD). Given its potential to progress to advanced liver disease, monitoring the extent and progress of liver fibrosis and assessing its fibrosis stage are essential. Although liver biopsy is considered to be the gold standard for liver fibrosis staging, it is an invasive procedure with risk of complications. Considering the rising prevalence of obesity and NAFLD globally, developing non-invasive diagnostic methods is a priority. Transient elastography (TE) is increasingly being used to assess the severity of liver disease. However, in the presence of severe obesity, the increased thickness of subcutaneous adipose tissue and changes in anatomy may affect its diagnostic accuracy. Two-dimensional shear wave elastography (2D-SWE) assesses the liver stiffness in real time along with simultaneous anatomic B-mode ultrasound imaging and allows selection of the region of interest. This would suggest that 2D-SWE has several advantages over TE in patients with severe obesity. The purpose of this review is to examine the current literature addressing the use of 2D-SWE in the assessment of liver fibrosis in patients with NAFLD. This review also examines the evidence on the use of 2D-SWE in patients with obesity and NAFLD and compares it to TE as a novel and non-invasive method of assessing liver fibrosis.

Introduction. Class 3 obesity (BMI≥40 kg/m2) is a growing health problem worldwide associated with considerable comorbidity including Type 2 diabetes mellitus (T2DM). The multidisciplinary medical management of obesity can be difficult in T2DM due to potential weight gain from medications including sulphonylureas and insulin. However, newer weight-neutral/losing diabetes medications can aid additional weight loss. The aim of this study was to compare weight loss outcomes of patients with and without T2DM, and in patients with T2DM, to compare diabetes outcomes and change in medications at 6 months.Methods. All patients entering a multidisciplinary weight management metabolic program in a publicly funded hospital clinic in Sydney between March 2018 and March 2019, withBMI≥40 kg/m2and aged ≥18 years were included. Data was collected from patient clinical and electronic notes at baseline and 6 months.Results. Of the 180 patients who entered the program, 53.3% had T2DM at baseline. There was no difference in percentage weight loss in those with or without T2DM (4.2±4.9%vs.3.6±4.7%,p=0.35). Additionally, T2DM patients benefited from a 0.47% reduction in HbA1c (p<0.01) and a reduction in the number of medications from baseline to 6 months (1.8±1.0/patient vs.1.0±1.2/patient,p<0.001). T2DM patients who started on weigh-neutral/losing medications in the program lost more weight than those started on weight-gaining medications (7.7±5.3%vs.2.4±3.8%,p=0.015).Conclusions. Patients with class 3 obesity had significant weight loss at 6 months in this program. Patients with T2DM at baseline had comparable weight loss at 6 months, a significant improvement in glycaemic control, and a reduction in diabetes medication load. Additionally, patients with T2DM who were started on weight-neutral/losing medications lost significantly more weight than those started on weight-gaining medications, and these medications should be preferentially used in class 3 obesity and comorbid T2DM.

Aims The Wollondilly Diabetes Program (WDP) is testing ways to improve uptake of diabetes prevention services. This project evaluated the reach of WDP in diabetes promotion while assessing diabetes knowledge and risk among residents. Methods A WDP member travelled in the DW weekly to community events including outreach programs between October 2016 and June 2019. Data from diabetes knowledge questionnaire (DKQ), the Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK), HbA1c and Random Blood Glucose (RBG) measurements obtained from participants who attended community events and road shows. Results Over the 32 months period, WDP attended 32 community events reaching 1415 people (∼3% of the Wollondilly adult population). DKQ was completed by 154 people (52.9% females, 78% Australian born, median age 69 years), 39% had diabetes and their mean score (25.0 ± 3.1, maximum possible score = 31) was similar to those without diabetes (24.0 ± 4.6, p = 0.093). AUSDRISK assessment was completed by 166 people with 85% at intermediate or high risk of diabetes. There were 65% results above range for RBG (≥5.5 mmol/l) and/or HbA1c (≥5.7%,39 mmol/mol). Conclusion A community outreach team set up in partnership with local stakeholders that offers opportunistic diabetes screening, is an effective way of engaging with the community to increase diabetes awareness and knowledge.

Aims: Diabetes management in hospital often focuses on tight glycemic control. Insulin use is, therefore, more common in the hospital inpatient setting. We sought to determine the prevalence and patterns of insulin use and hypoglycemia among inpatients with diabetes on medical wards in a tertiary Sydney hospital. Methods: A daily census was conducted on three medical wards (79 beds) over 44 weeks from June 2017. Inpatients with diabetes were audited using a questionnaire based on the UK National Diabetes Inpatient Audit. Those admitted for >7 days were audited for the last 7 days of admission. Results: Among 822 patients with diabetes, 96% had T2DM, mean age (SD) was 69.1(12.3) years, 54.8% male. Overall, 29.6% were on insulin on admission but 44.7% were prescribed insulin during their hospital stay. Hypoglycemia ( Conclusions: Hypoglycemia and severe hypoglycemia were common among hospital inpatients, and insulin use in this group was high. Insulin use was a major risk factor for hypoglycemia, particularly with new insulin initiation and after hours. These data highlight the need to weigh the risk of hypoglycemia against the benefit of tight glycemic control when considering insulin initiation in hospital. Extra vigilance is also needed after hours when there is a higher risk of hypos with fewer staff. Disclosure M.K. Piya: None. T. Fletcher: None. K. Myint: None. R. Zarora: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic. Funding South Western Sydney Local Health District

Impaired physical capacity is common in people with severe levels of obesity. We aimed to investigate changes in physical capacity outcomes in patients with severe obesity following 12 months of physician-led multidisciplinary care from a "real world" Australian public hospital setting using a case series study design. We extracted data from medical records for all of the eligible patients referred to our clinical obesity service from 2010 to 2015 (69 of 239). We found significant (P < .05) pre-test/post-test (mean ± SD) improvements in the 6-minute walk test (6MWT) (339 ± 120 to 417 ± 112 m); 30-second sit-to-stand test (11 ± 4 to 15 ± 6 counts) and sit-and-reach test (-12 ± 13 to -8 ± 15 cm). Using linear mixed-effects models adjusting for repeated measurements over time (baseline vs 12 months) and testing for potential predictors, we found: mean 6MWT was associated with 12-month time period (56 m), body mass index (BMI, -3 m), no walking aid over 12 months (106 m) and no opioid analgesics (75 m); mean sit-to-stand was associated with 12-month time period (3 counts), age at referral (-0.2 counts), BMI (-0.2 counts), and diabetes (3 counts); and mean sit-and-reach was associated with 12-month time period (5 cm), female gender (5 cm) and total medications (-0.9 cm). Using causal mediation analysis, our results show that total exercise classes partially mediates change in walking capacity among those with cardiovascular disease. Our study shows that significant and clinically important improvements in physical capacity outcomes in patients with severe obesity can be achieved following 12 months of intensive specialist obesity services, such as ours.

BACKGROUND Obstructive sleep apnea (OSA) is associated with increased nitrosative stress, endothelial dysfunction, and peripheral neuropathy in patients with type 2 diabetes. We hypothesized that OSA is associated with Poly ADP ribose polymerase (PARP) activation, lower intra-epidermal nerve fiber density (IENFD), and diabetic foot ulceration (DFU). METHODS A cross-sectional study of adults with type 2 diabetes recruited from a secondary care hospital in the UK. OSA was assessed by multi-channel home-based cardio-respiratory device (Alice PDX, Philips Respironics). DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). IENFD and % PAR stained nuclei were assessed using immunohistochemistry staining on skin biopsies. DFU was assessed based on MNSI. RESULTS Skin biopsies and DFU data were available from 52 and 234 patients respectively. OSA was associated with lower IENFD (12.75±1.93 vs. 10.55±1.62 vs. 9.42±1.16 fibers/mm of epidermis for no OSA, mild OSA and moderate to severe OSA respectively, p

Rates of eating disorders (EDs) are increasing in Australia, as are rates of bariatric and cosmetic surgery including weight-related procedures. It is known that binge eating disorder (BED) is common in bariatric surgery candidates and that people with EDs are likely to undergo weight-related cosmetic procedures, however, most of the literature is based on clinic samples and focuses on young women and BED. Aims of this study were to determine the prevalence of (1) actual or intended bariatric surgery and (2) actual or intended cosmetic surgery including weight-related procedures in people with a current ED and a lifetime history of BED or bulimia nervosa (BN), and the associations with actual or intended bariatric or cosmetic surgery and demographic features. Using a general population survey, 2977 individuals were interviewed regarding sociodemographic status, ED symptoms, mental health-related quality of life (MHRQoL) and actual or intended use of bariatric and cosmetic surgery, prevalence estimates of which were 2.0% and 1.1%, respectively. People who had planned or received either type of surgery were more likely to be (1) women and (2) have a higher BMI, (3) poorer MHRQoL and (4) a current ED, lifetime BN or BED or features of EDs (all p &lt, 0.05). Age and household income were not significantly associated with increased use of either type of surgery. Given the potential for an ED to affect outcomes of surgery, screening and treatment for EDs should be considered in such surgical candidates.

Background Type 2 diabetes (T2DM) is increasing in prevalence worldwide, and is closely linked to obesity. Binge Eating Disorder (BED) and Night Eating Syndrome (NES) are eating disorders that are common in obesity, and may affect the management as well as long term outcomes of T2DM. Therefore, the aim of this review was to assess the prevalence and associations of BED or NES in adults with T2DM. Methods We conducted a systematic review. The databases MEDLINE, CINAHL and AMED were searched for articles which met the inclusion criteria; including patients > 18 years old, with T2DM, and BED and/or NES. The reference lists of included studies were also searched. Meta-analysis was not attempted due to the limited number of studies that measured the outcomes of interest. Results A total of 10 studies (2 included NES) were included in this systematic review. The number screened for BED and NES were 6527 and 1039 participants, respectively. Point prevalence was 1.2–8.0% for BED and 3.8–8.4% for NES. Patients with T2DM and BED had higher BMI than patients with T2DM without BED in the two studies that reported BMI. There was no statistically significant difference in HbA1c between patients with and without BED in the two studies that measured HbA1c. Conclusions BED and NES are common in adults with T2DM, and BED is associated with higher BMI in patients with T2DM. However, only two studies reported important outcomes measures such as BMI and HbA1c in patients with T2DM. Hence, further well-designed studies are needed to assess the impact of BED and NES in patients with T2DM. Health Care Professionals should consider the diagnosis of BED and NES in patients with T2DM.

Background: Vitamin D deficiency is associated with obesity and type 2 diabetes mellitus (T2DM), although the use of circulating Vitamin D levels as a predictor of weight loss induced T2DM remission is unclear. Therefore, the aim of this study was to analyze whether pre-bariatric surgery vitamin D levels may predict T2DM outcomes 12 months post-SG. Method: A cohort of 220 obese participants (74.5% female) with T2DM (Age: 50±9.5yr, BMI: 51.4±7Kg/m2; n=103) and without T2DM (Age: 46±9yr, BMI: 53.5±6.5Kg/m2; n=117) undergoing SG participated in an ethics approved study in a single bariatric centre in the UK. Patient anthropometric and biochemical data including vitamin D were collected at baseline and 12 months post-SG; no vitamin D supplementation at baseline was given. Results: Baseline vitamin D levels inversely correlated with baseline BMI (P Conclusion: Baseline Vitamin D levels appear to be an independent indicator for successful T2DM remission and weight loss, 12 months following SG. The use of baseline Vitamin D levels may help us predict those more likely to do well and prioritize post-surgery support to achieve success for all participant groups. Disclosure A. Aladel: None. M.K. Piya: None. S. Azharian: None. M. Christian: None. V. Menon: None. P.G. McTernan: None.

Background: Diabetes is a common co-morbidity among hospital inpatients, particularly in medical wards. Diabetes is linked to increased length of stay and mortality in hospital inpatients, and hypoglycemia (hypo) is considered a contributory factor. We sought to determine the prevalence of diabetes in medical wards and the prevalence and patterns of hypo during their hospital stay. Methods: A daily census on three medical wards (79 beds) was conducted over a 4 month period from June 2017 in a 3bed tertiary Sydney hospital. Charts and medications for inpatients with diabetes were audited each Friday using a questionnaire based on the UK National Diabetes Inpatient Audit. Patients admitted under the care of the diabetes team were excluded. Readmissions were counted as separate episodes. Results: The mean prevalence of diabetes was 27%, of which 2.4% had T1DM, with 212 patient episodes audited in 196 patients (16 readmissions). Mean age (SD) was 71 years (11.2), 54% male. Only 5.6% had a diabetes related admission. Insulin use was 34% on admission but 52% during hospital stay. There were 74 events of hypo ( Conclusion: Hypoglycemia is a major burden in patients with diabetes in hospital, particularly in the first week of admission, even when patients are not admitted due to diabetes related problems. Insulin use was the major risk factor and many patients had multiple hypo events. We recommend early involvement of the diabetes inpatient team as well as centralized point of care testing of glucose to allow early identification of patients at risk. Disclosure M.K. Piya: None. R. Zarora: None. T. Fletcher: None. D. Simmons: Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions, AstraZeneca, Novo Nordisk Inc., Medtronic.

Background: Fibroblast growth factor 19 (FGF-19) and FGF-21 regulate glucose tolerance and insulin sensitivity, which in type 2 diabetes mellitus (T2DM) conditions becomes dysregulated. Whilst weight loss can restore this functionality, bariatric surgery can have a specific impact due to mechanical changes on gut/liver physiology. We aimed to analyse the effects of different bariatric surgeries: sleeve gastrectomy (SG), laparoscopic adjusted gastric banding (LAGB) and biliopancreatic diversion (BPD) on changes in FGF-19 and FGF-21 levels. Methods: Obese and T2DM women (n=41 BMI>35 Kg/m2) undergoing SG (n=14), LABG (n=13), and BPD (n=14) participated in an ethics approved study. Anthropometry, biochemical data, and adipose tissue (AT) biopsies were collected before and 6 months after surgery. FGF-19, FGF-21 levels and AT inflammation (TLR2, MYD88, TRAF6, IKK and NFkb) was assessed. Results: Post surgery SG led to 63% reduction in FGF-21 whilst LABG and BPD led to 41% and 4% decrease respectively. There was a significant differences in FGF-21 levels between SG and BPD (p=0.021). Moreover, FGF-21 change in SG positivly correlated with changes in glucose (p=0.019), insulin (p=0.047), HOMA-IR (p=0.022) and triglyceride (p=0.027); absent in BPD and LABG. FGF-21 levels in SG appeared as a significant predictor of HOMA-IR change post surgery (p Inflamatory markers post surgery were significantly reduced in all surgeries (TLR2: p Conclusion: SG appears to have a beneficial influence on FGF-21 and FGF-19 levels irrespective of reduced AT inflammation. Our FGF findings therfore suggests that SG provides better glucose homeostatis outcomes than LAGB and BPD. Disclosure S. Azharian: None. A. Murphy: None. P.G. McTernan: None. M.K. Piya: None. G. Tripathi: None.

Background Irisin, a novel myokine, has been shown to increase following vigorous exercise, with studies suggesting that it mediates some of the beneficial effects of exercise. Irisin might play a role in ‘browning’ of white adipocytes, thus increasing energy expenditure. The role of irisin in exercise and energy expenditure in subjects with diabetes mellitus type 2 (DMT2) remains largely unknown. We aimed to investigate the association between circulating irisin and habitual physical activity in subjects with and without DMT2. Material and methods In this cross-sectional study, 164 Saudi adults: 81 non-DMT2 controls [age: (mean ± SD) 51·6 ± 10·9; BMI: 29·6 ± 4·3 kg/m2] and 83 DMT2 subjects [age: 54·3 ± 10·3 year; BMI: 29·4 ± 4·7 kg/m2] were studied. Anthropometric and fasting serum biochemical data were collected. Circulating irisin was measured using an enzyme-linked immunosorbent assay (ELISA). Frequency intensity time (FIT) index was used to assess the level of habitual physical activity. Results We observed significantly higher levels of irisin in DMT2 subjects than in controls (P < 0·001). FIT index was positively associated (r = 0·20, P = 0·03) with circulating irisin in controls only. Additionally, irisin levels were significantly higher in tertile 3 (0·75 ± 0·07 μg/mL) than tertile 1 (0·49 ± 0·06 μg/mL) of the FIT index in healthy controls, whilst no such relation with physical activity was observed in DMT2 subjects. Conclusion This cross-sectional study has shown a weak association of irisin with physical activity levels in healthy controls but not in DMT2 subjects, suggesting the possibility of discordant regulation in the condition of DMT2.

Objective Meal duration may influence cardiometabolic health. The aim of this study was to explore postprandial effects of meal duration on human metabolism and appetite. Design Postprandial comparisons following a standard meal eaten slowly over 40 min (‘D40’) and the same meal eaten quickly over 10 min (‘D10’) on a different day. Each participant therefore acted as their own control, thereby limiting confounding factors. Patients Obese premenopausal Caucasian women (n = 10) with confirmed normoglycaemia were recruited from an obesity clinic at UHCW, Coventry UK. Subjects underwent whole-body calorimetry (8-h) on two separate days. Measurements Following standard lunch (D40 vs D10), 4-h postprandial analysis included thermic effect of food (TEF) and bloods taken at predefined times (including baseline fasting). Analytes included lipid profile, adiponectin, insulin, glucose, ghrelin, leptin, endotoxin, gut and pancreatic hormones. Appetite was measured using visual-analogue scales and ad libitum food intake at subsequent meal. Paired sample t-tests [including area under the curve (AUC)] were used to compare D40 and D10 trials. Results Postprandial TEF (over 240-min) was significantly greater for D40 than D10 [mean (SEM): 80·9 kcal (3·8) vs 29·9 kcal (3·4); 10·6% vs 3·9%, respectively, P = 0·006; AUC 71·7 kcal.h vs 22·4 kcal.h, respectively, P = 0·02]. Postprandial plasma NEFA was significantly lower, and adiponectin levels were significantly higher for D40 than D10 [AUC (SEM): NEFA 627 μmol.h/l (56) vs 769 μmol.h/l (60), respectively, P = 0·02; adiponectin 33·4 μg.h/ml (3·9) vs 27·3 μg.h/ml (3·8), respectively, P = 0·04]. Other postprandial analytes and appetite measures were equivalent. Conclusions In obese women, eating slowly associates with enhanced TEF, elevated serum adiponectin and suppressed NEFA.

Objectives.To compare the prevalence of diabetic peripheral neuropathy (DPN) and that of cardiac autonomic neuropathy (CAN) between South Asians and White Caucasians with type 2 diabetes and to explore reasons for observed differences.Methods.A cross-sectional study of casually selected South Asian and White Caucasian adults attending a hospital-based diabetes clinic in the UK. DPN and CAN were assessed using the Michigan Neuropathy Screening Instrument (MNSI) and heart rate variability testing, respectively.Results.Patients (n=266) were recruited (47.4% South Asians). DPN was more common in White Caucasians compared to South Asians (54.3% versus 38.1%,p=0.008). Foot insensitivity as assessed by 10 g monofilament perception was more common in White Caucasians (43.9% versus 23.8%,p=0.001). After adjustment for confounders, White Caucasians remained twice as likely to have DPN as South Asians, but the impact of ethnicity became nonsignificant after adjusting for adiposity measures or height. No difference in prevalence of standardized CAN test abnormalities was detected between ethnicities. Skin microvascular assessment demonstrated that South Asians had reduced heating flux but preserved acetylcholine response.Conclusions.South Asians with type 2 diabetes have fewer clinical signs of DPN compared to White Caucasians. Differences in adiposity (and its distribution) and height appear to explain these differences.

A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (iAUC) = 22.9 +/- 6.8 pg/mL x 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 +/- 0.5 mmol/L X 6 h vs. 6.0 +/- 0.5 mmol/L X 6 h; P=0.015) but not in the normal-weight group (4.3 +/- 0.5 mmol/L X 6 h vs. 4.8 +/- 0.5 mmol/L x 6 h; P=0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068.

The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR > 3.4 mg/mmol) or an estimated (eGFR)

Peripheral action of irisin improves glucose homeostasis and increases energy expenditure, with no data on a central role of irisin in metabolism. These studies sought to examine 1) presence of irisin in human cerebrospinal fluid (CSF) and banked human hypothalamic tissue, 2) serum irisin in maternal subjects across varying adiposities with or without gestational diabetes (GDM), and 3) their respective neonate offspring. CSF, serum, and neonatal cord serum were collected from 91 pregnant women with and without GDM attending for an elective cesarean section [body mass index (BMI): 37.7 ± 7.6 kg/m2; age: 32 ± 8.3 yr]. Irisin was assessed by ELISA and correlated with biochemical and anthropometric data. Irisin expression was examined in human hypothalamus by immunohistochemical staining. Serum irisin in pregnant women was significantly lower in nonobese compared with obese and GDM subjects, after adjusting for BMI, lipids, and glucose. Irisin was present in neonatal cord serum (237 ± 8 ng/ml) and maternal CSF (32 ± 1.5 ng/ml). CSF irisin correlated positively with serum irisin levels from nonobese and obese pregnant women ( P < 0.01), with CSF irisin significantly raised in GDM subjects ( P < 0.05). Irisin was present in human hypothalamic sections in the paraventricular neurons, colocalized with neuropeptide Y. Irisin was detectable in CSF and in paraventricular neurons. Maternal serum irisin was lower in nonobese pregnant women after adjusting for BMI and a number of metabolic parameters. These studies indicate that irisin may have a central role in metabolism in addition to the known peripheral role. Further studies investigating the central action of irisin in human metabolic disease are required.

Obesity is a rapidly increasing problem that has wide implications for the National Health Service. At present, obesity is not being addressed in a joined-up and standardised manner. This has downstream effects for the health service, the economy and society as a whole. As highlighted by a recent RCP report, there is a need for a new class of dedicated specialists who can evaluate individuals with health problems that are related to obesity, direct their care in a coordinated fashion, act as an advocate for their needs and be able to liaise with multiple different services to improve the provision of patient care. In this article, we discuss the role of this specialist - the bariatric physician.

There is uncertainty regarding preoperative predictors of a successful outcome for bariatric surgery (BarSurg), on which to determine appropriateness for such a procedure. Our aims were to identify preoperative clinical and psychosocial predictors of success following BarSurg and to explore the influence of body mass index (BMI) on these parameters.Preoperative data, including Impact of Weight on Quality of Life-Lite (IWQOL-Lite) scores transformed to Health-Related Quality of Life (HRQOL) scores, were accrued from 76 morbidly obese adults awaiting BarSurg. Pre- and postoperative data were also accrued for 26 patients who had completed 1-year follow-up post-bariatric surgery (laparoscopic adjustable gastric banding-LAGB). Statistical analysis was performed to assess the relationships between preoperative HRQOL scores, preoperative BMI and excess weight loss 1 year following BarSurg (EWL-1 year).Preoperative BMI showed a significant independent, negative linear correlation with the public distress domain of preoperative quality of life (QOL) (r = -0.368, p = 0.001; β = -0.245, p = 0.009). Preoperative BMI had a significant, positive and independent association with EWL-1 year (r = 0.499, p = 0.009; β = 0.679, p = 0.015). Preoperative QOL scores had no association with EWL-1 year.Preoperative BMI appears to predict EWL-1 year following restrictive bariatric surgery (LAGB). Preoperatively, patients with higher BMI appear to manifest greater public distress. Preoperative QOL scores, however, do not appear to have any predictive value for EWL-1 year post-LAGB. Preoperative BMI should therefore be employed as a predictor of EWL-1 year post-LAGB. Other measures of successful outcomes of bariatric surgeries (such as effects on QOL scores at 1 year) should be explored in future, larger and longer term studies.

OBJECTIVE Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN. RESEARCH DESIGN AND METHODS This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) RESULTS A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA−) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13–6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA− patients (median −6.8% [interquartile range −16.1 to 2.2] vs. −1.6% [−7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = −3.8, P = 0.044) and AHI (B = −4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = −0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment. CONCLUSIONS OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed.

To assess and compare obstructive sleep apnea (OSA) prevalence in South Asians and White Europeans with type 2 diabetes mellitus (T2DM). Secondary aims included exploring possible causes for observed ethnic differences.A cross-sectional study of patients with T2DM recruited from secondary care diabetes clinics. OSA was defined as an apnea-hypopnea index (AHI) ≥ 5 events/h using home-based, multi-channel respiratory monitoring.Two hundred thirty-four patients (105 South Asian and 129 White Europeans) were studied. The prevalence of mild, moderate, and severe OSA in South Asians was 36.2% (n = 38/105), 9.5% (n = 10/105), and 5.7% (n = 6/105) respectively. After adjustment, OSA was associated with a higher body mass index in South Asians. OSA was significantly less common in South Asians compared to White Europeans (51.4% [54/105] versus 75.2% [97/129],South Asians with T2DM are at considerable risk of OSA. OSA in South Asians was associated with obesity. However, OSA prevalence was lower in South Asians than in White Europeans. Obesity measures accounted for the observed ethnic differences. Examining factors contributing to ethnic differences will be important to inform screening and treatment strategies.

Background: Human obesity can significantly contribute to hypertension risk, often referred to as the ‘silent killer’, although targeting whom with weight gain becomes clinically hypertensive is unclear. Whilst therapeutic intervention such as bariatric surgery can mitigate both obesity and hypertension, it is not the most suitable solution for all patients. Therefore an early biomarker detection system to assess hypertension in subjects with weight gain could reduce mortality risk. Such a platform could be developed through a urine centred biomarker system identifying disease related signatures based upon volatile organic compounds (VOCs). The focus of this study was to determine whether urinary VOCs could be used as a potential monitoring tool for detection of blood pressure change in obese- hypertensive bariatric patients. Methodology: Pre-surgery urine of 23 obese female patients undergoing bariatric surgery was analysed by Field-Asymmetric Ion Mobility Spectrometer (FAIMS). The data was processed by dividing the cohort into two classifications (high and low) based on individual median values: systolic and diastolic blood pressure, mean arterial pressure (MAP), C-reactive protein (CRP) and heart rate. Support Vector Machine (SVM) classifiers were trained with features selected using the Wilcoxon rank sum test. Performance was assessed using 10-fold cross-validation and the area under the ROC curve (AUC). Results: FAIMS urinary VOC analysis highlighted a significant association with blood pressure markers as determined by systolic (ROC curve AUC: 0.918, P

Background Identifying patients with diabetes at increased risk of chronic kidney disease (CKD) is essential to prevent/slow the progression to end-stage renal disease (ESRD). CKD and diabetic peripheral neuropathy (DPN) share common mechanisms. Hence, we aimed to examine the relationship between foot insensitivity and CKD in patients with Type 2 diabetes. Methods A prospective observational cohort study in adults with Type 2 diabetes. Patients with ESRD were excluded. Foot insensitivity was assessed using the 10-g monofilament test. Renal function was assessed using estimated glomerular filtration rate (eGFR) based on the MDRD equation. Albuminuria was defined as the presence of urinary albumin/creatinine ratio (ACR) >3.4 mg/mmol. Results Two hundred and twenty eight patients were recruited and followed-up for 2.5 years. One hundred and ninety patients (83.4%) had eGFR ≥ 60 ml/min/1.73 m2. Seventy six (33.3%) patients had foot insensitivity (i.e. abnormal monofilament test). Patients with foot insensitivity had lower eGFR and higher prevalence of albuminuria compared to patients with normal monofilament test. After adjustment for age, gender, ethnicity, diabetes duration, HbA1c, body mass index, insulin treatment, number of anti-hypertensives, history of peripheral vascular disease, and baseline eGFR (R2 0.87), baseline foot insensitivity was associated with study-end eGFR (B = −3.551, p = 0.036). Conclusions Patients with Type 2 diabetes and foot insensitivity are at increased risk of eGFR decline. Identifying these patients offers an opportunity to intensify metabolic and blood pressure control to prevent/retard the development of CKD. Future studies of larger sample size and longer follow up from multiple centres are needed to assess the diagnostic performance of our findings in predicting CKD development, and to compare the performance of the monofilament test with albuminuria.

Rationale: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. Objectives: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. Methods: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. Measurements and Main Results: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0–93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44–5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. Conclusions: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.

Left ventricular torsion is increased and cardiac energetics are reduced in uncomplicated type 1 diabetes mellitus (T1DM). Our aim was to determine the relationships of these abnormalities to cardiovascular autonomic neuropathy (CAN) in subjects with T1DM. A cross-sectional study was conducted in 20 subjects with T1DM free of known coronary heart disease attending an outpatient clinic. Cardiovascular autonomic neuropathy was assessed using heart rate variability studies and the continuous wavelet transform method. Left ventricular function was determined by speckle tracking echocardiography. Magnetic resonance spectroscopy and stress magnetic resonance imaging were used to measure cardiac energetics and myocardial perfusion reserve index, respectively. Twenty subjects (age, 35 ± 8 years; diabetes duration, 16 ± 9 years; hemoglobin A(1c), 8.0% ± 1.1%) were recruited. Forty percent of the subjects exhibited definite or borderline CAN. Log peak radial strain was significantly increased in subjects with CAN compared with those without (1.56 ± 0.06 vs 1.43 ± 0.14, respectively; P = .011). Data were adjusted for log duration of diabetes, and log left ventricular torsion correlated (r = 0.593, P = .01) with log low-frequency to high-frequency ratio during the Valsalva maneuver. Log isovolumic relaxation time correlated significantly with log Valsalva ratio and log proportion of differences in consecutive RR intervals of normal beats greater than 50 milliseconds during deep breathing. However, CAN did not correlate with cardiac energetics or myocardial perfusion reserve index. Spectral analysis of low-frequency to high-frequency ratio power during the Valsalva maneuver is associated with altered left ventricular torsion in subjects with T1DM. Parasympathetic dysfunction is closely associated with diastolic deficits. Cardiovascular autonomic neuropathy is not however the principal cause of impaired cardiac energetics. The role of CAN in the development of cardiomyopathy warrants further evaluation.

Biju Jose1, Abd A Tahrani1,2, Milan K Piya1,2, Anthony H Barnett1,21Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK; 2School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UKBackground: Type 2 diabetes mellitus (T2DM) is a complex disorder in which interactions between environmental and genetic factors result in the development of insulin resistance (in most cases) and progressive pancreatic β-cell failure. The currently available oral anti-diabetes treatments are effective as monotherapy; however, due to the progressive decline in β-cell function, most patients will require the use of combination therapy and eventually insulin to reach glycemic targets. These therapeutic options are not without undesirable side effects such as weight gain and hypoglycemia. Furthermore, T2DM is associated with impaired quality of life (QOL) and poor compliance with treatment. Hence, there is a need for anti-diabetes agents that result in sustained improvements in glycemic control without hypoglycemia or weight gain and have a positive impact on patients QOL and thereby hopefully improve compliance. Incretin-based therapy is the latest addition to anti-diabetes treatments which addresses some of the shortcomings of older treatments.Aims: To review the evidence for the use of exenatide once-weekly.Methods: We have searched Medline using the terms “exenatide”, “exenatide once-weekly”, and “exenatide LA”.Results: Exenatide once-weekly is an incretin mimetic that is currently undergoing phase 3 clinical trials, and has been shown to improve glycemic parameters (HbA1c and fasting and postprandial glucose levels), with low risk of hypoglycemia, causes weight loss, and use was associated with improvements in patient satisfaction which might have a positive impact on treatment compliance.Conclusions: Exenatide once-weekly is effective, well tolerated in patients with T2DM and should be a useful addition to the available range of anti-diabetes treatments.Keywords: diabetes mellitus, incretins, exenatide once-weekly, quality of life, treatment satisfaction

Type 2 diabetes mellitus (T2DM) is rapidly increasing in prevalence and is a major public health problem. It is a progressive disease which commonly requires multiple pharmacotherapy. Current options for treatment may have undesirable side effects (particularly weight gain and hypoglycaemia) and contraindications, and little effect on disease progression. Incretin based therapy is one of several newer therapies to improve glycaemia and is available in two different forms, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Use of these agents results in a ‘glucose-dependant’ increase in insulin secretion and glucagon suppression resulting in improved glycaemia with low incidence of hypoglycaemia. DPP-4 inhibitors are oral drugs which are weight neutral, while GLP-1 agonists are injected subcutaneously and help promote weight loss while improving glycaemia. GLP-1 agonists have also been shown to increase beta cell mass in rat models. Bariatric surgery is another option for the obese patient with T2DM, with blood glucose normalizing in over half of the patients following surgery. Other therapies in development for the treatment of T2DM include sodium-glucose transporter 2 (SGLT-2) inhibitors, glucagon receptor antagonists, glucokinase activators and sirtuins. In this article, we will review the various existing and emerging treatment options for T2DM.

Type 2 diabetes mellitus (T2DM) is a worldwide public health challenge. Despite the availability of many antidiabetes agents and pharmacotherapies targeting cardiovascular risk factors, the morbidity, mortality and economic consequences of T2DM are still a great burden to patients, society, health care systems and the economy. The need for new therapies for glycaemic control is compounded by the fact that existing treatments have limitations either because of their side effects (particularly weight gain and hypoglycaemia) or contraindications that limit their use. Furthermore, none of the current therapies have a significant impact on disease progression. Incretin-based therapies offer a new therapeutic approach to the management of T2DM, and there are also several even newer therapies in development. There are two groups of incretin-based therapies currently available; dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 analogues/mimetics. The former are given orally while the latter subcutaneously. These drugs result in glucose-dependent insulin secretion and glucose-dependent glucagon suppression, with consequent low risk of hypoglycaemia when used as mono- or combination therapy (except when used with sulphonylureas). In addition, they are either weight neutral in the case of DPP-4 inhibitors or cause weight loss in the case of incretin mimetics/analogues. Furthermore, animal studies have shown that these agents prolong beta cell survival which offers the theoretical possibility of slowing the progression to T2DM. In this article we will review the currently available antidiabetes agents with particular emphasis on incretin-based and future therapies. In addition, we will review and discuss the evidence relating to glycaemic control and cardiovascular disease.

Type 2 diabetes is a very common worldwide disorder, with major consequences for patients, society, and health care services. Good glycemic control is an important aspect of diabetes management because it has a significant impact on diabetes-related microvascular and possibly macrovascular complications. Based on our understanding of the pathogenesis of diabetes, multiple pharmacological interventions have been developed in the past 60 years. Although effective, none have had a lasting effect on glycemic control because of the progressive nature of type 2 diabetes requiring combination therapies and insulin treatment. In addition, several pharmacologic interventions have undesirable side effects, including hypoglycemia and weight gain. Drugs targeting the incretin pathway are the latest addition to the available antidiabetes agents. Incretin-based therapy is either delivered orally (dipeptidyl peptidase-4 [DPP-4]) inhibitors or injected subcutaneously (glucagon-like peptide-1 [GLP-1] mimetics and analogues). Dipeptidyl peptidase-4 inhibitors are effective either as a single or combination therapy in lowering glycated hemoglobin, fasting and postprandial glucose levels, with a low incidence of hypoglycemia and no weight gain. There are 3 DPP-4 inhibitors currently available (sitagliptin, saxagliptin, and vildagliptin), with more expected to be available in the future. In this article, we review the scientific background for incretin-based therapy and the available evidence regarding the role and efficacy of DPP-4 inhibitors in the treatment of patients with type 2 diabetes.

Exenatide is the first in a novel class of drugs that mimics naturally occurring glucagon-like peptide 1. In patients with Type 2 diabetes mellitus (T2DM), control of both glycemia and bodyweight are important to minimize the risk of diabetes complications. Exenatide improves glycemic control through glucose-dependent insulin secretion, suppression of glucagon secretion, delaying gastric emptying and suppressing appetite. Exenatide therapy significantly reduced glycated hemoglobin (HbA1c) and fasting and postprandial plasma glucose when added to metformin and/or sulfonylureas, with an average weight loss of 2 kg. Furthermore, exenatide-treated patients sustained the reductions achieved in HbA1c at 12 weeks with a progressive reduction in bodyweight during 3-year follow-up. Exenatide is generally well tolerated; nausea is the most common side effect but significantly reduces over time and with gradual dose titration. Hypoglycemia at a rate greater than placebo only occurred in combination with sulfonylurea...

They work by eitherimproving insulin sensitivity or bytemporarily improving beta cellfunction. The currently availableOADs do not address the underly-ing pathophysiological mechanismof type 2 diabetes, and their side-effects (which include hypogly-caemia, weight gain and gastroin-testinal disturbances) limit theireffectiveness.Insulin treatment is effective,but it causes weight gain and hypo-glycaemia. Hyperinsulinaemia hasalso been implicated in the develop-ment of cardiovascular disease andhypertension. Hence, there is aneed for new classes of drugs thataddress the underlying pathologicaldisturbances in type 2 diabetes,reduce insulin resistance, improvebeta-cell survival and cause weightloss without hypoglycaemia and/orgastrointestinal side effects.Incretin mimetics and dipep-tidyl peptidase-4 (DPP-4) inhibitorsare recent additions to diabetestreatment. DPP-4 inhibitors are oralagents that block the enzyme thatdegrades glucagon-like peptide-1(GLP-1), and are well tolerated andweight neutral. GLP-1 receptor ago-nists (incretin mimetics) areinjectable and can result in signifi-cant weight loss. Exenatide is thefirst of the GLP-1 receptor agonistsand is administered twice daily.Liraglutide is a GLP-1 analogue thatis administered once daily.In this article we review theproperties of liraglutide and theevidence for its use in patients withtype 2 diabetes.I

Type 2 diabetes mellitus (T2DM) is a major challenge to healthcare systems around the world, with an estimated prevalence of 6% (246 million) in 2007 rising to 7.3% (380 million) in 2025 worldwide.1–5 In this article, the authors consider the significance of the GLP-1 path-way in the management of T2DM, and some of the advantages of incretin-based therapy. Copyright © 2008 John Wiley & Sons, Ltd.

Diabetic neuropathy (DN), an important microvascular complication of diabetes, is one of the major causes of morbidity in patients with diabetes. Studies have confirmed that glycaemic control and duration of diabetes are important factors for the development of DN. However, the exact mechanism of damage to peripheral nerves due to prolonged hyperglycaemic exposure is still not clear. Recent epidemiological studies have highlighted the importance of cardiovascular risk factors such as hypertension, smoking, raised serum cholesterol, triglycerides and lipoprotein a to the development of DN. Various mechanisms of microvascular and haemodynamic dysfunction of capillaries of nerve fibres have been postulated in the development of DN. Similarly endothelial dysfunction due to activation of protein kinase C, oxidative stress, advanced glycation end products and polyol pathway activation has been shown to be related to DN in human and experimental DN. Other possible mechanisms such as plate let dysfunction, essential fatty acid deficiency, immunological mechanisms, nerve growth factor deficiency and presence of adhesion molecules have been described in relation to DN. However, no single theory can explain the exact pathogenic mechanism of the development of DN. This review looks into different theories that have been proposed and describes the inter-relationship of various factors that can lead to the development of DN. (Int J Diabetes Metab 13:135-140, 2005)

The recently discovered myokine irisin has been implicated in several observational studies as a potential therapeutic target for obesity-related diseases. However, no information is available as to the heritability of this hormone. The present study aims to fill this gap. A total of 120 families (n=254; 121 adults and 133 children) were included in the study taken from the Riyadh Biomarkers Research Program cohort. Information gathered include anthropometrics, and glycaemic, lipid and adipocytokine profiles. Irisin was measured using ELISA. Examining heritability between mother and offspring, the most significant heritable traits in sons included irisin (P=1.6×10−5), systolic blood pressure (P=3.6×10−4), total cholesterol (P=3.5×10−7) and LDL (low-density lipoprotein)-cholesterol (P=1.2×10−6). Heritable traits between mother and daughter again included irisin (P

Background Irisin, a novel myokine, increases energy expenditure and glucose tolerance and, thus, improves carbohydrate homeostasis in humans. This hormone has potential therapeutic applications for weight loss and improvement in insulin resistance in subjects with obesity and diabetes mellitus type 2 (T2DM). In this cross-sectional study, we aimed to associate circulating levels of irisin and several anthropometric and metabolic parameters among Arab children. Methods A cohort of 153 Saudi children, 81 boys [age: 12·4 ± 3·2 years; BMI: 19·5 ± 5·9 kg/m2] and 72 girls: [age: 12·9 ± 3·2 years; BMI: 20·6 ± 5·2], were examined. Anthropometry was obtained, and fasted bloods were collected for biochemical analyses. Irisin was assessed by a specific enzyme-linked immunosorbent assay (ELISA). Results Girls had higher circulating irisin levels than boys (P = 0·04). There were several significant correlations between circulating irisin and fasting blood glucose (FBG) (r = −0·35, P < 0·001), sagittal abdominal diameter (SAD) (r = −0·34, P < 0·001) and HDL cholesterol (r = 0·17, P = 0·04) across the entire cohort studied. Notably in girls, but not in boys, HOMA-IR correlated negatively with irisin levels (r = −0·32, P = 0·02), as previously noted in adults. FBG was a significant predictor of circulating irisin (R2 = 0·16) followed by SAD. In multivariate linear regression analysis, after controlling for potential confounders such as gender, age and BMI, irisin levels were independently associated with FBG (β = −0·34, P = 0·01), particularly in girls. Conclusion Serum irisin levels were higher in girls than in boys and correlated negatively with HOMA-IR. They were also independently associated with FBG predominantly in girls, suggesting that this hormone may play a crucial role in glucose metabolism from an early age.

Purpose of review This article reviews the evidence linking gut bacteria, endotoxin, and its circulating levels with inflammatory induced obesity and metabolic disease (metabolic endotoxaemia). Recent findings Gut flora analyses have allowed gut microbiota signatures (GMS) to be observed in animal studies of obesity/metabolic disease. In these studies, specific GMS result in a change in obesity and metabolic disease state whereas in humans, analysis remains unclear. Serum studies, examining metabolic endotoxaemia as a biomarker, appear to link long-term cardiovascular disease and type 2 diabetes mellitus (T2DM) through activation of inflammatory pathways. More recent studies note the importance of diet, which shows the dramatic rise in endotoxin following acute or long-term high-fat diet, with the effects exacerbated in T2DM. Summary Gut flora appears to act as an important determinant in the pathogenesis of inflammatory induced obesity/T2DM. Endotoxin may act as the systemic insult, impacted by a high-fat diet, which may regulate this effect, combined with an altered GMS. As such, clinical and dietary intervention to affect this process - on the gut flora, the 'leaky' mucosal membrane and endotoxin coupled lipid absorption or removal of circulating endotoxin - could reduce the progression of inflammatory induced metabolic disease.

OBJECTIVE Impairment of skin quality may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether high-risk patients exhibited specific skin structural and metabolic deficits that could predispose to foot complications. RESEARCH DESIGN AND METHODS A total of 46 patients comprising 9 diabetic control subjects, 16 with diabetic peripheral neuropathy (DPN) alone, and 21 with recurrent DFUs (including 9 with Charcot neuroarthropathy [CNA]) were recruited and compared with 14 nondiabetic control (NDC) subjects. DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Skin punch biopsies (3 mm) were performed on upper and lower leg skin for measurements of intraepidermal nerve fiber density (IENFD), structural analysis, type 1 procollagen abundance, tissue degrading matrix metalloproteinases (MMPs), and poly(ADP-ribose) (PAR) immunoreactivity. RESULTS MNSI scores were comparable across DPN groups. IENFD was decreased by diabetes and DPN but did not differ between neuropathic groups. Skin structural deficit scores were elevated in all neuropathic subjects, particularly in the DFU group. Type 1 procollagen abundance was reduced in DFU subjects 387 ± 256 units (mean ± 1 SD) compared with NDC subjects (715 ± 100, P < 0.001). MMP-1 and MMP-2 were activated by diabetes. PAR immunoreactivity was increased in DFU (particularly in the CNA group; P < 0.01) compared with other DPN subjects. CONCLUSIONS Increased PAR, reduced type 1 procollagen abundance, and impaired skin structure are associated with foot complications in diabetes. The potential of therapies that improve skin quality to reduce DFU needs to be investigated.

Reports have highlighted a shortage of con- sultant diabetologist posts in the UK. The number of doctors completing specialist training in diabetes has increased in recent years, but little is known about their employment after they receive their certificate of completion of training. An online survey was sent to all doctors who completed specialist diabetes training from January 2008 to September 2010. Of the 95 eligible respondents, 69 (73%) completed the survey (61% men; median age 36 years). Forty-three (62%) respond- ents secured substantive NHS consultant posts, and of those who gave their job breakdown, 48/51 (94%) were contributing to specialist diabetes care. Five (7%) respondents held substan- tive academic positions, while 11 (16%) were locum consult- ants. Seven (9%) respondents worked abroad, with half of these attributing their emigration to lack of opportunities in the UK. When asked about alternative choices, 39% of respond- ents were likely to seek 'general physician' roles, which equalled the number who would consider emigrating. Overall, only two-thirds of doctors who complete specialist training in diabetes secure substantive NHS consultant positions, which suggests a failure in workforce planning and a lack of expan- sion of the number of consultant posts despite progression of the diabetes epidemic.

Type 2 diabetes mellitus (T2DM) is a major public health problem that affects an increasingly larger number of individuals worldwide. Metformin, unless contraindicated, is the recommended first line pharmacological treatment as it can achieve good glycemic control without weight gain or hypoglycemia and with evidence for cardioprotection. T2DM is a progressive disease, and consequently further therapeutic agents are needed in order to maintain good glycemic control and prevent long-term complications. These drugs are commonly associated with undesirable side effects such as weight gain and hypoglycaemia. Moreover, none have been proven to slow or prevent the progression of T2DM (which is mainly due to progressive β-cell failure). As a result, new agents based on newer therapeutic targets are needed. Incretin based therapy is the latest addition to the currently available anti diabetes treatment and includes two groups of agents: glucagon-like peptide-1 (GLP-1) analogues/mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors. These agents act either by supplying exogenous GLP-1 (GLP-1 analogues/mimetics) or by preventing the degradation of endogenous GLP-1 (DPP-4 inhibitors). GLP-1 is a gut hormone that is mainly secreted secondary to oral glucose ingestion and results in glucose-dependent insulin secretion and glucose-dependant glucagon suppression which in turn improve fasting and post-prandial glucose levels. GLP-1 is rapidly inactivated by the DPP-4 enzyme. There are several DPP-4 inhibitors currently available, including sitagliptin, vildagliptin and saxagliptin while others are in development. Due to their mechanism of action, DPP-4 inhibitors are associated with low risk of hypo - glycemia and are weight neutral. As a result, they are attractive agents particularly in combination with metformin therapy. In this article we will examine the potential use of saxagliptin as an add-on therapy to metformin in patients with T2DM.

Type 2 diabetes mellitus (T2DM) is a global epidemic with increasing impact on individuals and healthcare providers. Available treatments (such as metformin, sulfonylureas, glitazones, and insulin) have proven unsatisfactory in producing a long-lasting impact on glycemic control. In addition, most of these treatments have undesirable side effects such as weight gain and hypoglycemia. As a result, exploring new treatment targets and new therapies is mandatory in order to treat this condition. The incretin pathway, in particular glucagon-like peptide (GLP-1), plays an important pathological role in the development of T2DM, and treatments targeting the incretin system have recently become available. These can mainly be divided into two broad categories; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase-4 (DPP-4; the enzyme responsible for rapid inactivation of incretins) inhibitors (sitagliptin, vildagliptin). Saxagliptin is a novel DPP-4 inhibitor that has recently completed phase 3 studies. Saxagliptin is a potent and specific inhibitor of DPP-4 (in comparison with other dipeptidyl peptidase enzymes) that is given once daily. Current data suggest that saxagliptin as monotherapy or in combination with metformin, glyburide, or a glitazone results in significant reductions in fasting and postprandial plasma glucose and hemoglobin A(1c) (HbA(1c)). Saxagliptin is well tolerated and does not increase hypoglycemia compared with the placebo, and is probably weight neutral. Saxagliptin will be a new effective drug in the currently available variety of antidiabetic medications for patients with T2DM.