The combined diabetes and renal control trial (C-DIRECT) - a feasibility randomised controlled trial to evaluate outcomes in multi-morbid patients with diabetes and on dialysis using a mixed methods approach.

BACKGROUND: This cluster randomised controlled trial set out to investigate the feasibility and acceptability of the "Combined Diabetes and Renal Control Trial" (C-DIRECT) intervention, a nurse-led intervention based on motivational interviewing and self-management in patients with coexisting end stage renal diseases and diabetes mellitus (DM ESRD). Its efficacy to improve glycaemic control, as well as psychosocial and self-care outcomes were also evaluated as secondary outcomes. METHODS: An assessor-blinded, clustered randomised-controlled trial was conducted with 44 haemodialysis patients with DM ESRD and ≥ 8% glycated haemoglobin (HbA1c), in dialysis centres across Singapore. Patients were randomised according to dialysis shifts. 20 patients were assigned to intervention and 24 were in usual care. The C-DIRECT intervention consisted of three weekly chair-side sessions delivered by diabetes specialist nurses. Data on recruitment, randomisation, and retention, and secondary outcomes such as clinical endpoints, emotional distress, adherence, and self-management skills measures were obtained at baseline and at 12 weeks follow-up. A qualitative evaluation using interviews was conducted at the end of the trial. RESULTS: Of the 44 recruited at baseline, 42 patients were evaluated at follow-up. One patient died, and one discontinued the study due to deteriorating health. Recruitment, retention, and acceptability rates of C-DIRECT were generally satisfactory HbA1c levels decreased in both groups, but C-DIRECT had more participants with HbA1c < 8% at follow up compared to usual care. Significant improvements in role limitations due to physical health were noted for C-DIRECT whereas levels remained stable in usual care. No statistically significant differences between groups were observed for other clinical markers and other patient-reported outcomes. There were no adverse effects. CONCLUSIONS: The trial demonstrated satisfactory feasibility. A brief intervention delivered on bedside as part of routine dialysis care showed some benefits in glycaemic control and on QOL domain compared with usual care, although no effect was observed in other secondary outcomes. Further research is needed to design and assess interventions to promote diabetes self-management in socially vulnerable patients. TRIAL REGISTRATION NUMBER: Trial registered with the International Standard Randomised Controlled Trial (ISRCTN10546597). Registered 12 September 2016 (Retrospectively registered).

Smaller size of high metabolic rate organs explains lower resting energy expenditure in Asian-Indian Than Chinese men.

BACKGROUND: In Singapore, the obesity prevalence is disproportionately higher in the Asian-Indians and Malays than the Chinese. Lower resting energy expenditure (REE) may be a contributory factor. OBJECTIVE: We explored the association between ethnicity and REE in Chinese, Asian-Indian and Malay men living in Singapore and determined the influence of body composition, mass/volume of high metabolic rate organs, represented by brain volume and trunk fat-free mass (FFM), and physical activity on ethnic differences. DESIGN: Two hundred and forty-four men from Singapore (n=100 Chinese, 70 Asian-Indians and 74 Malays), aged 21-40 years and body mass index of 18.5-30.0 kg m(-2), were recruited in this cross-sectional study. REE was assessed by indirect calorimetry and body composition by dual-energy X-ray absorptiometry. Brain volume was measured by magnetic resonance imaging. Physical activity was assessed by the Singapore Prospective Study Program Physical Activity Questionnaire. RESULTS: REE was significantly lower in Asian-Indians compared with that in Chinese after adjusting for body weight. FFM (total, trunk and limb) and total fat mass were important predictors of REE across all ethnic groups. Brain volume was positively associated with REE only in Malays. Moderate and vigorous physical activity was positively associated with REE only in Asian-Indians and Malays. The difference in REE between Asian-Indians and Chinese was attenuated but remained statistically significant after adjustment for total FFM (59±20 kcal per day), fat mass (67±20 kcal per day) and brain volume (54±22 kcal per day). The association between REE and ethnicity was no longer statistically significant after total FFM was replaced by trunk FFM (which includes heart, liver, kidney and spleen) but not when it was replaced by limb FFM (skeletal muscle). CONCLUSIONS: We have demonstrated a lower REE in Asian-Indians compared with Chinese who may contribute to the higher rates of obesity in the former. This difference could be accounted for by differences in metabolically active organs.

Ethnic differences in insulin sensitivity and beta-cell function among Asian men.

BACKGROUND AND OBJECTIVES: Lean Asian Indians are less insulin sensitive compared with Chinese and Malays, but the pancreatic beta-cell function among these ethnic groups has yet to be studied in depth. We aimed to study beta-cell function in relation to insulin sensitivity among individuals of Chinese, Malay and Asian-Indian ethnicity living in Singapore. SUBJECTS AND METHODS: This is a sub-group analysis of 59 normoglycemic lean (body mass index (BMI) <23 kg m(-)(2)) adult males (14 Chinese, 21 Malays and 24 Asian Indians) from the Singapore Adults Metabolism Study. Insulin sensitivity was determined using fasting state indices (homeostatic model assessment-insulin resistance), the euglycemic-hyperinsulinemic clamp (ISI-clamp) and a liquid mixed-meal tolerance test (LMMTT) (Matsuda insulin sensitivity index (ISI-Mat)). Beta-cell function was assessed using fasting state indices (homeostatic model assessment-beta-cell function) and from the LMMTT (insulinogenic index and insulin secretion index). The oral disposition index (DI), a measure of beta-cell function relative to insulin sensitivity during the LMMTT, was calculated as a product of ISI-Mat and insulin secretion index. RESULTS: Asian Indians had higher waist circumference and percent body fat than Chinese and Malays despite similar BMI. Overall, Asian Indians were the least insulin sensitive whereas the Chinese were most insulin sensitive. Asian Indians had higher beta-cell function compared with Chinese or Malays but these were not statistically different. Malays had the highest incremental area under the curve for glucose during LMMTT compared with Asian Indians and Chinese. However, there were no significant ethnic differences in the incremental insulin area under the curve. The oral DI was the lowest in Malays, followed by Asian Indians and Chinese. CONCLUSION: Among lean Asians, Chinese are the most insulin sensitive whereas Asian Indians are the least insulin sensitive. However, Malays demonstrate higher postprandial glucose excursion with lower beta-cell response compare with Chinese or Asian Indians. The paths leading to type 2 diabetes mellitus might differ between these Asian ethnic groups.

Sensitivity of three widely used questionnaires for measuring psychological distress among patients with type 2 diabetes mellitus.

BACKGROUND: Although a range of generic and diabetes-specific instruments are available to assess emotional distress, no studies have evaluated sensitivity in relation to sample size requirement. The present study sets out to compare the sensitivity among the Diabetes Health Profile Psychological Distress scale (DHP-PD), Problem Areas in Diabetes (PAID) and Kessler-10 Psychological Distress scale (K10). We hypothesized that the diabetes-specific measures (DHP-PD and PAID) would require smaller sample sizes than the generic measure (K10), yet remain specific. RESEARCH DESIGN: A total of 208 patients with type 2 diabetes mellitus (mean age 45.2 (12.4) years; 63.1 % males, 45.8 % Chinese, 11.3 % Malay and 26.6 % Indian), recruited from a Singapore tertiary hospital diabetes clinic, completed the English DHP-PD, PAID and K10. Clinical information derived from medical records and HbA1c was recorded. Effect sizes (ES), ratio of ES and sample size requirement relative to the most sensitive questionnaire were computed. RESULTS: A comparison of patients with good versus poor glycaemic control (HbA1c ≥ 7.0) revealed that using K10 will require 4 times the sample size of a study using the PAID in order to detect the same level of psychological distress. The DHP-PD and PAID had similar sensitivity when comparing between patients with good versus poor glycaemic control. CONCLUSIONS: As hypothesized, sample size requirement is largest for K10 and remarkably similar for PAID and DHP-PD. This information is useful for designing clinical trials and studies.

Associations between ethnicity, body composition, and bone mineral density in a Southeast Asian population.

CONTEXT AND OBJECTIVE: Chinese men in Singapore have a higher incidence of hip fractures than Malay and Indian men. We investigated whether there were corresponding ethnic differences in peak bone mineral density (BMD) in young men and whether differences in body composition influenced peak BMD. DESIGN AND SETTING: This was a cross-sectional study of healthy volunteers in a tertiary medical center. PARTICIPANTS: A total of 100 Chinese, 82 Malay, and 80 Indian men aged 21 to 40 years, with body mass index between 18 and 30 kg/m(2) underwent dual-energy x-ray absorptiometry to assess BMD, lean mass (LM) and fat mass (FM), and magnetic resonance imaging to quantify abdominal subcutaneous and visceral adipose tissue. Multiple linear regression models, with adjustment for age and height (as a proxy for skeletal size), were used. RESULTS: Malay and Indian men had significantly higher BMD than Chinese men at the lumbar spine (Malay: B, 0.06 ± 0.02, P = .001; Indian: B, 0.03 ± 0.02, P = .049), femoral neck (Malay: B 0.04 ± 0.02, P = .034; Indian: B, 0.04 ± 0.02, P = .041), hip (Malay: B, 0.05 ± 0.02, P = .016; Indian: B, 0.06 ± 0.02, P = .001), and ultradistal radius (Malay: B, 0.03 ± 0.01, P < .001; Indian: B, 0.02 ± 0.01, P = .029), and this difference was retained after adjustment for LM and FM, except in Malay men at the femoral neck and in Indian men at the ultradistal radius. LM was an important independent determinant of BMD at all sites, whereas FM, subcutaneous adipose tissue, and visceral adipose tissue were not significantly associated with BMD at any site. CONCLUSIONS: Lower peak BMD in Chinese men may partly explain the higher fracture incidence in this ethnic group. Further studies are needed to elucidate the reasons for these ethnic differences in bone accumulation.

Variability in fasting lipid and glycogen contents in hepatic and skeletal muscle tissue in subjects with and without type 2 diabetes: a 1H and 13C MRS study.

The measurement of tissue lipid and glycogen contents and the establishment of normal levels of variability are important when assessing changes caused by pathology or treatment. We measured hepatic and skeletal muscle lipid and glycogen levels using (1)H and (13)C MRS at 3 T in groups of subjects with and without type 2 diabetes. Within-visit reproducibility, due to repositioning and instrument errors was determined from repeat measurements made over 1 h. Natural variability was assessed from separate measurements made on three occasions over 1 month. Hepatic lipid content was greater in subjects with diabetes relative to healthy subjects (p = 0.03), whereas levels of hepatic and skeletal muscle glycogen, and of intra- and extra-myocellular lipid, were similar. The single-session reproducibility values (coefficient of variation, CV) for hepatic lipid content were 12% and 7% in groups of subjects with and without diabetes, respectively. The variability of hepatic lipid content over 1 month was greater than the reproducibility, with CV = 22% (p = 0.08) and CV = 44% (p = 0.004) in subjects with and without diabetes, respectively. Similarly, levels of variation in basal hepatic glycogen concentrations (subjects with diabetes, CV = 38%; healthy volunteers, CV = 35%) were significantly larger than single-session reproducibility values (CV = 17%, p = 0.02 and CV = 13%, p = 0.05, respectively), indicating substantial biological changes in basal concentrations over 1 month. There was a decreasing correlation in measurements of both hepatic lipid and glycogen content with increasing time between scans. Levels of variability in intra- and extra-myocellular lipid in the soleus muscle, and glycogen concentrations in the gastrocnemius muscle, tended to be larger than expected from single-session reproducibility, although these did not reach significance.

Elevation of alanine transaminase and markers of liver fibrosis after a mixed meal challenge in individuals with type 2 diabetes.

BACKGROUND: Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes. AIM: We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM). METHODS: Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m(2); and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m(2)) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by (1)H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial). RESULTS: Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p < 0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001). CONCLUSIONS: In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state.

Ethnicity modifies the relation between fasting plasma glucose and HbA1c in Indians, Malays and Chinese.

AIMS: To study whether HbA(1c) , and its relationship with fasting plasma glucose, was significantly different among Chinese, Malays and Indians in Singapore. METHODS: A sample of 3895 individuals without known diabetes underwent detailed interview and health examination, including anthropometric and biochemical evaluation, between 2004 and 2007. Pearson's correlation, analysis of variance and multiple linear regression analyses were used to examine the influence of ethnicity on HbA(1c) . RESULTS: As fasting plasma glucose increased, HbA(1c) increased more in Malays and Indians compared with Chinese after adjustment for age, gender, waist circumference, serum cholesterol, serum triglyceride and homeostasis model assessment of insulin resistance (P-interaction < 0.001). This translates to an HbA(1c) difference of 1.1 mmol/mol (0.1%, Indians vs. Chinese), and 0.9 mmol/mol (0.08%, Malays vs. Chinese) at fasting plasma glucose 5.6 mmol/l (the American Diabetes Association criterion for impaired fasting glycaemia); and 2.1 mmol/mol (0.19%, Indians vs. Chinese) and 2.6 mmol/mol (0.24%, Malays vs. Chinese) at fasting plasma glucose 7.0 mmol/l, the diagnostic criterion for diabetes mellitus. CONCLUSIONS: Using HbA(1c) in place of fasting plasma glucose will reclassify different proportions of the population in different ethnic groups. This may have implications in interpretation of HbA(1c) results across ethnic groups and the use of HbA(1c) for diagnosing diabetes mellitus.

Effects of exenatide on circulating glucose, insulin, glucagon, cortisol and catecholamines in healthy volunteers during exercise.

AIMS/HYPOTHESIS: Exenatide, a glucagon like peptide-1 agonist, is a treatment for type 2 diabetes mellitus that stimulates insulin and suppresses glucagon secretion in a glucose-dependent manner. By contrast, during aerobic exercise, the serum insulin concentration normally falls, with a rise in plasma glucagon. We therefore assessed whether exenatide might predispose to hypoglycaemia during exercise. METHODS: We studied eight non-diabetic men, who were 35.3 +/- 6.3 years of age with BMI of 24.7 +/- 1.7 kg/m(2) (mean +/- SD), using a randomised, crossover, double-blind design investigation. After an overnight fast, participants received 5 microg of subcutaneous exenatide or placebo and rested for 105 min before cycling at 60% of their maximal oxygen uptake (VO(2max)) for 75 min and then recovering for a further 60 min. RESULTS: The insulin/glucagon molar ratio rose with exenatide at rest (p < 0.01), then fell during exercise with placebo and with exenatide. At rest, fasting blood glucose fell by approximately 1 mmol/l with exenatide to a nadir of 3.4 +/- 0.1 mmol/l (p < 0.01). During exercise, blood glucose fell with placebo but, unexpectedly, rose with exenatide. Plasma adrenaline (epinephrine) and noradrenaline (norepinephrine), but not cortisol concentrations increased to a greater extent during exercise after exenatide. No participant developed symptomatic hypoglycaemia and the lowest individual blood glucose recorded was 2.8 mmol/l with exenatide at 50 min in the pre-exercise period. CONCLUSIONS/INTERPRETATION: In non-diabetic participants given exenatide, blood glucose concentrations rise rather than fall during aerobic exercise with an associated greater catecholamine response.