Protein kinetics in human endotoxaemia and their temporal relation to metabolic, endocrine and proinflammatory cytokine responses.

BACKGROUND: Sepsis is associated with profound alterations in protein metabolism. The unpredictable time course of sepsis and the multiplicity of confounding factors prevent studies of temporal relations between the onset of endocrine and proinflammatory cytokine responses and the onset of protein catabolism. This study aimed to determine the time course of whole-body protein catabolism, and relate it to the endocrine, metabolic and cytokine responses in a human endotoxaemia model of early sepsis. METHODS: Six healthy male volunteers were studied twice in random order, before and for 600 min after administration of either an intravenous bolus of Escherichia coli lipopolysaccharide (LPS) or sterile saline. Whole-body protein synthesis, breakdown and net protein breakdown were measured by amino acid tracer infusion, and related to changes in plasma levels of growth hormone, glucagon, cortisol, insulin-like growth factor (IGF) 1, tumour necrosis factor (TNF) α and interleukin (IL) 6. RESULTS: Protein synthesis, breakdown and net protein breakdown increased and peaked 120 min after LPS administration (P < 0·001), the alterations persisting for up to 480 min. These peaks coincided with peaks in plasma growth hormone, TNF-α and IL-6 concentrations (P = 0·049, P < 0·001 and P < 0·001 for LPS versus saline), whereas plasma cortisol concentration peaked later. No alterations in plasma insulin or glucagon concentrations, or in the IGF axis were observed during the period of abnormalities of protein metabolism. CONCLUSION: LPS administration induced an early protein catabolic response in young men and this coincided with changes in plasma growth hormone, TNF-α and IL-6 concentrations, rather than changes in cortisol, glucagon, insulin or the IGF axis. Surgical relevance Sepsis in surgical patients is common and remains associated with substantial mortality. Although sepsis is a heterogeneous condition and its pathophysiology therefore difficult to study, a universal and profound clinical problem is protein catabolism not responsive to nutritional support. Human experimental endotoxaemia is a promising model of clinical sepsis that can be used to elucidate underlying pathophysiology and explore novel therapeutic approaches. This study demonstrates that human experimental endotoxaemia replicates the changes in whole-body protein turnover seen in clinical sepsis. Frequent measurements allowed identification of tumour necrosis factor (TNF) α, interleukin (IL) 6 and growth hormone as putative mediators. Human experimental endotoxaemia is a valid model for further study of mechanisms and putative therapies of catabolism associated with sepsis. In particular, effects of TNF-α and IL-6 blockade should be evaluated.

Continuous glucose monitoring in people with diabetes: the randomized controlled Glucose Level Awareness in Diabetes Study (GLADIS).

AIMS: To investigate the best glucose monitoring strategy for maintaining euglycaemia by comparing self-monitoring of blood glucose with continuous glucose monitoring, with or without an alarm function. METHODS: A 100-day, randomized controlled study was conducted at four European centres, enrolling 160 patients with Type 1 or Type 2 diabetes, on multiple daily insulin injections or continuous subcutaneous insulin infusion. Participants were randomized to continuous glucose monitoring without alarms (n = 48), continuous glucose monitoring with alarms (n = 49) or self-monitoring of blood glucose (n = 48). RESULTS: Time spent outside the glucose target during days 80-100 was 9.9 h/day for the continuous glucose monitoring without alarms group, 9.7 h/day for the continuous glucose monitoring with alarms group and 10.6 h/day for the self-monitoring of blood glucose group (P = 0.18 and 0.08 compared with continuous glucose monitoring without and with alarms, respectively).The continuous glucose monitoring with alarms group spent less time in hypoglycaemia compared with the self-monitoring of blood glucose group (1.0 h/day and 1.6 h/day, respectively; 95% CI -1.2 to -0.1; P = 0.030). Among those treated with continuous subcutaneous insulin infusion, time spent outside the glucose target was significantly different when comparing continuous glucose monitoring without alarms and self-monitoring of blood glucose (-1.9 h/day; 95% CI -3.8 to 0.0; P = 0.0461) and when comparing continuous glucose monitoring with alarms and self-monitoring of blood glucose (-2.4 h/day; 95% CI -4.1 to -0.5; P = 0.0134). There was no difference in HbA1c reduction from baseline in the three groups; however, the proportion of participants with a reduction of ≥ 6 mmol/mol (≥ 0.5%) was higher in the continuous glucose monitoring without alarms (27%) and continuous glucose monitoring with alarms groups (25%) than in the self-monitoring of blood glucose group (10.6%). CONCLUSIONS: This study shows that the use of continuous glucose monitoring reduces time spent outside glucose targets compared with self-monitoring of blood glucose, especially among users of insulin pumps.

Metabolic outcomes 2 years following gastric bypass surgery in people with type 2 diabetes: an observational cohort study.

BACKGROUND: Gastric bypass surgery induces early remission or significant improvement in type 2 diabetes (T2D). AIM: To assess effectiveness of stopping glucose-lowering treatment at the time of surgery. DESIGN: Observational cohort analysis. METHODS: We identified 101 patients (62 women) with T2D who had undergone gastric bypass surgery at a mean (SD, standard deviation) age of 51.4 (9.0) years. We recorded weight, body mass index (BMI), glycosylated haemoglobin (HbA1c), blood pressure (BP), total and high-density lipoprotein (HDL) cholesterol preoperatively and at a median 4, 12 and 24 months postoperatively, and changes to glucose-lowering therapy. RESULTS: Mean (SD) baseline BMI was 50.3 (6.3) kg/m(2), HbA1c 65.3 (18.5) mmol/mol, systolic BP 146.0 (18.0) mmHg, diastolic BP 87.0 (10.8) mmHg and total cholesterol-to-HDL cholesterol ratio 4.0 (1.2). Mean (95% confidence interval) reduction in BMI was 16.4 (14.1-18.7) kg/m(2), HbA1c 23.6 (17.6-29.6) mmol/mol, systolic BP 12.9 (5.9-19.8) mmHg, diastolic BP 6.1 (1.8-10.5) mmHg and total cholesterol-to-HDL cholesterol ratio 1.1 (0.6-1.5) at 24 months (P < 0.001 for all measures). Although 91% of patients were receiving glucose-lowering therapies preoperatively, complete (HbA1c < 42 mmol/mol) and partial (HbA1c 42-48 mmol/mol) remissions of T2D were seen in 62.1% and 5.2% at 2 years postoperatively. CONCLUSIONS: Cessation of glucose-lowering therapies in people with T2D at the time of gastric bypass surgery was clinically effective. The majority of patients remained in complete or partial remission of diabetes up to 2 years postoperatively.

Five-year outcome of bariatric surgery in a patient with melanocortin-4 receptor mutation.

Monogenic obesity is characterized by mutations in genes involved in the central regulation of food intake. Melanocortin-4 receptor (MC4R) mutations are the most frequent monogenic cause of severe early onset human obesity. Although bariatric surgery is the most effective therapy for idiopathic morbid obesity in adults, little is known about its effectiveness in patients with monogenic obesity syndromes. We report 5-year outcome of gastric bypass surgery in a young man with severe super-obesity associated with MC4R mutation. A 22-year-old man with a weight of 221.6 kg and body mass index of 76.7 kg m(-2) associated with a heterozygous MC4R mutation was referred to our centre for bariatric surgery. He underwent Roux-en-Y gastric bypass (RYGB) surgery and achieved weight loss of 76% of excess weight over a follow-up period of 58 months. Heterozygous MC4R mutations have been associated with dominantly inherited obesity in various ethnic groups, and non-surgical interventions are rarely effective in the long term. One previous report of bariatric surgery in a patient with complete MC4R deficiency reported poor weight loss after gastric banding. We speculate that patients with MC4R mutations achieve superior weight loss outcomes from procedures such as RYGB that produce neurohormonal changes rather than gastric restriction alone due to beneficial effects on appetite and satiety regulation.

Bariatric surgery in women of childbearing age.

BACKGROUND: Although bariatric surgery in women of childbearing age reduces the risks of pregnancy complications associated with maternal obesity, little is known of the effect of gestation on weight loss outcomes. AIM: To study weight loss and pregnancy outcomes after bariatric surgery in women of childbearing age. DESIGN AND METHODS: We performed a retrospective, observational cohort analysis of women aged 18-45 years in a university teaching hospital. The results shown represent mean ± standard deviation where appropriate. RESULTS: A total of 232 women aged 34.0 ± 5.9 years with pre-operative weight 137.7 ± 21.3 kg and body mass index (BMI) 50.6 ± 7.2 kg/m(2) underwent bariatric surgery that included 197 (84.9%) gastric bypass, 19 (8.2%) gastric banding, 8 (3.4%) sleeve gastrectomy and 8 other procedures. Twenty-one women had 28 pregnancies following bariatric surgery, of which 24 (85.7%) resulted in live births, 3 (10.7%) terminations of pregnancy and 1 (3.6%) spontaneous miscarriage. The pregnancy group was younger compared with the non-pregnancy group (28.0 ± 5.4 vs. 34.6 ± 5.6 years; P < 0.001) but well matched for pre-operative weight (136.5 ± 18.5 vs. 137.8 ± 21.6 kg), BMI (49.2 ± 7.4 vs. 50.7 ± 7.2 kg/m(2)) and bariatric procedure. The interval between bariatric surgery and first pregnancy was a median 11 months. The pregnancy group lost 70.4% of excess weight compared with 70.0% in the non-pregnancy group at median 30 months of follow-up. CONCLUSION: Pregnancy after bariatric surgery is safe and does not adversely affect weight loss outcomes.

The high prevalence of unrecognized anaemia in patients with diabetes and chronic kidney disease: a population-based study.

BACKGROUND: Anaemia occurs early in the course of diabetes-related chronic kidney disease (CKD). There is little evidence about the prevalence of anaemia in people with diabetes. The aim of this study was to assess the prevalence of anaemia, by stage of CKD, in the general diabetic population. METHODS: Haemoglobin (Hb) was measured on all glycated haemoglobin (HbA1c) samples and the most recent (< 4 months) estimated glomerular filtration rate (eGFR) was obtained. Anaemia (at treatment level) was defined as Hb < 110 g/l or the use of erythropoetic stimulating agents (ESA). RESULTS: Twelve per cent (10-14%) of people had Hb < 110 g/l. The prevalence of anaemia increased progressively with worsening CKD. People with CKD stage 3 accounted for the largest number of people with anaemia; 18% (95% CI 13-24%) had Hb < 110 g/l. Those with eGFR < 60 ml/min/1.73 m2 and not on ESA or dialysis were four (2-7) times more likely than patients with better renal function to have Hb < 110 g/l. The relation between Hb and eGFR became approximately linear below an eGFR of 83 ml/min/1.73 m2, where, for every 1 ml/min/1.73 m2 fall in eGFR, there was a 0.4 (0.3-0.5) g/l fall in haemoglobin. CONCLUSIONS: This study demonstrates that anaemia, at levels where treatment is indicated, occurs commonly in people with diabetes and CKD stage 3 or worse. The screening for anaemia in current diabetes management should be extended.

Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared with those without diabetes in general practice.

AIMS: To compare rates of chronic kidney disease (CKD) in patients with diabetes and management of risk factors compared with people without diabetes using general practice computer records, and to assess the utility of serum creatinine and albuminuria as markers of impaired renal function. METHODS: The simplified Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (eGFR) and stage of CKD. Further data were extracted to assess how effectively impaired renal function was being identified and how well potentially modifiable risk factors were being managed. The setting was 17 practices in Surrey, Kent and Greater Manchester (2003-2004). Participants were all patients with serum creatinine (SCr) recorded. RESULTS: Of the total population of 162 113, 5072 were recorded as having a diagnosis of diabetes, giving a prevalence of 3.1%. Of patients with diabetes, 31% had clinically significant CKD (defined as eGFR < 60 ml/min per 1.73 m(2); CKD stages 3-5) compared with 6.9% of those without diabetes. Only 33% of patients with diabetes at CKD stage 3 had serum creatinine > 120 micromol/l. Of patients with diabetes with eGFR < 60 ml/min per 1.73 m(2), 63% had normoalbuminuria. Considering those with eGFR 30-60 ml/min per 1.73 m(2), 42% of people with diabetes were on an ACE inhibitor compared with 25% of those without diabetes; 32% of patients with diabetes who had any record of micro- or macroalbuminuria at CKD stage 3 were taking an ACE inhibitor. Of people with diabetes and hypertension (BP > 140/80 mmHg), 26% were not prescribed any hypertensive medication, regardless of level of CKD. CONCLUSIONS: CKD is common in people with diabetes living in the community in the UK. The study found a similar rate of stage 3-5 CKD to that found previously in the USA. Currently used measures of renal function fail to identify CKD as effectively as eGFR. Risk factors for CKD and its progression are suboptimally managed.

Comparison of processes and intermediate outcomes between South Asian and European patients with diabetes in Blackburn, north-west England.

BACKGROUND: Diabetes and its complications are more prevalent among South Asians than people of European origin and there is some evidence that patients of South Asian origin with diabetes receive poorer quality care. METHODS: Longitudinal study of patients with diabetes in Blackburn, UK. Processes of care indicators [measurement of blood pressure (BP), cholesterol and glycosolated haemoglobin (HbA1c)] and values of these intermediate outcomes were extracted for all patients registered on a diabetes information system for the period 1995-2001. Differences in processes of care indicators and intermediate outcomes between ethnic groups were estimated after adjusting for the potential confounding factors of sex, age and socioeconomic status (SES). Generalized estimating equations were used to model trends and to test for differences in trends over time. RESULTS: Process of care was similar in South Asian and European patients. Mean BP and cholesterol concentration fell during the study period. South Asians had a higher level of HbA1c throughout the study period. South Asians had lower levels of BP and cholesterol in 1995 but the differences diminished or were abolished over time. SES did not explain differences between ethnic groups. Analyses stratified by baseline levels of intermediate outcomes (above or within target) demonstrated improvements among above target patients were greater among European patients. CONCLUSIONS: Processes of care indicators are similar in diabetic patients of South Asian and European origin, irrespective of SES. However, there are worrying differences in improvements over time in the intermediate outcomes, and glycaemic control remained poorer among patients of South Asian origin patients throughout.

Evaluation of a bedside blood ketone sensor: the effects of acidosis, hyperglycaemia and acetoacetate on sensor performance.

AIMS: To assess the performance of a handheld bedside ketone sensor in the face of likely metabolic disturbances in diabetic ketoacidosis, namely: pH, glucose and acetoacetate. METHODS: The effects of pH (7.44-6.83), glucose (5-50 mmol/l) and acetoacetate (0-5 mmol/l) were examined in venous blood to investigate the accuracy of betahydroxybutyrate measurement (0-5 mmol/l) by a handheld ketone sensor. Sensor results were compared with a reference method. Linear regression models were fitted to the difference between the methods with the concentration of metabolite as the explanatory factor. RESULTS: Decreasing pH and increasing glucose had no effect on the accuracy of the handheld ketone sensor; the gradients of the fitted lines were -0.14 and -0.003, respectively. The 95% confidence intervals were -0.7-0.4 and -0.01-0.004, respectively (P = 0.59 and 0.4, respectively). In the acetoacetate study, a positive relationship between the sensor and reference method results was found, the gradient was 0.09. The 95% confidence interval was 0.05-0.14 (P < or = 0.001), indicating that high concentrations of acetoacetate interfere with the sensor performance. CONCLUSIONS: Acidosis and hyperglycaemia have minimal effects on the sensor performance. However, high concentrations of acetoacetate result in some overestimation of betahydroxybutyrate. This bedside ketone sensor provides useful data over a broad range of conditions likely to be encountered during moderate to severe diabetic ketoacidosis.

Educational outreach in diabetes to encourage practice nurses to use primary care hypertension and hyperlipidaemia guidelines (EDEN): a randomized controlled trial.

OBJECTIVE: To determine the effectiveness of specialist nurse delivered education in primary care to improve control of hypertension and hyperlipidaemia in patients with diabetes. DESIGN AND SETTING: Practice-level randomized controlled trial, Salford, England. SUBJECTS: From 44 practices, 10 303 subjects presenting in general practice with raised blood pressure (= 140/80 mmHg), raised total cholesterol (= 5.0 mmol/l) or both. INTERVENTIONS: Practices were randomized to receive either the intervention for hyperlipidaemia or for hypertension; practices acted as control for the intervention not received. Specialist nurses arranged a schedule of visits with general practitioners and general practice nurses, reminding them of diabetes protocols and clinical targets. They provided educational materials and protocols used in secondary care for nurse and doctor interventions including stepping up pharmacotherapy when necessary. Practices received a list of patients in their practice who were poorly controlled at their last annual review; new and recalled patients were targeted. OUTCOME MEASURES: At subsequent annual review, blood pressure and total cholesterol values were obtained from the Salford electronic diabetes register for patients from participating practices. RESULTS: Overall, specialist nurse-led educational outreach to primary care was associated with no improvement in patients achieving target after 1 year-odds ratio (OR): 1.03 (95% CI 0.95-1.11; P = 0.52). Similar results were achieved with hyperlipidaemia OR: 1.04 (95% CI 0.88-1.23; P = 0.62) and hypertension OR: 1.01 (95% CI 0.80-1.27; P = 0.93). CONCLUSION: This study provides evidence that the use of specialist nurses to perform educational outreach to improve target adherence to patients with diabetes in primary care is not effective.

Variations in process and outcomes of diabetes care by socio-economic status in Salford, UK.

AIMS/HYPOTHESIS: Our aim was to investigate trends in provision and outcomes of care by socio-economic status among patients with diabetes in Salford, United Kingdom. METHODS: Salford is a deprived urban area in North West England. Data for people with diabetes who were younger than 20 years of age (4034 patients in the year 1993 and 5671 by the year 2000) were extracted from the Diabetes Information System. Age-standardised means, proportions and attainment of targets were calculated for: processes of care indicators, intermediate outcomes and prescribing of preventive drug treatments in 1993 to 1994 and in 2000 to 2001 by quintiles of Townsend deprivation score. We did comparisons of means and proportions using age-adjusted linear regression and of trends using generalised estimating equations. Rate ratios for first microvascular and first macrovascular complication were estimated from proportional hazards models. RESULTS: Marked improvements occurred in all indicators. For patients managed in primary care, blood pressure and cholesterol measurement increased from 53% to 64% (p<0.001) and 27% to 61% (p<0.001) respectively; whilst mean systolic blood pressure decreased from 147 to 140 mmHg (p<0.001) and cholesterol concentrations from 6.0 to 5.1 mmol/l (p<0.001). Mean HbA(1c) increased from 7.8 to 8.1% (p<0.001). Prescribing of aspirin, anti-hypertensive and lipid-lowering drugs increased greatly. Trends varied little by socio-economic status. Patients from more affluent areas generally received more frequent clinical monitoring and preventive treatments, and had a lower BMI (29.5 vs 30.2 kg/m(2); p=0.009) and HbA(1c) (7.8 vs 8.2% p=0.006), though risks of first microvascular or macrovascular complications were similar. CONCLUSION/INTERPRETATION: Improvements in process and outcomes of care are possible for patients from all socio-economic groups. Socio-economic deprivation does not preclude high quality diabetes care.

Alternate site blood glucose testing: do patients prefer it?

AIMS: To examine patients' perspectives on ease of use and pain with the MediSense alternate site blood glucose testing device (Soft-Sense) compared with their current glucose testing method, and to evaluate the analytical performance of the MediSense device with the laboratory reference method. METHODS: Study participants were shown how to use the Soft-Sense glucose device and asked to perform two tests on their forearm. A capillary sample was collected from their finger and tested on the external port of the Soft-Sense meter and a laboratory method (YSI Glucose Analyser). Finally, one drop of blood was also directly tested from the finger onto the external port. Patients completed a questionnaire comparing ease of use and associated pain of their current testing method with the Soft-Sense meter. RESULTS: Patients preferred the Soft-Sense device to their own for ease of use and for less pain (93% found it easier to use and 96% less painful; P < 0.001). Glucose results correlated closely with the laboratory method (mean absolute percentage bias for the forearm 11.0%, finger 6.0%, and collected capillary sample 5.7%). Error grid analysis showed that all Soft-Sense results were clinically acceptable. CONCLUSIONS: Patients prefer the Soft-Sense alternate site testing device to their existing measuring method. The device accurately measures whole blood glucose.

A protocol for improved glycaemic control following corticosteroid therapy in diabetic pregnancies.

AIMS: Diabetic pregnancies have an increased risk of respiratory distress syndrome (RDS) and preterm delivery. Antenatal corticosteroids can prevent RDS but induce acute severe hyperglycaemia. We have developed a protocol which prevents hyperglycaemia and can be used easily by ward staff. METHODS: Intramuscular dexamethasone is given in two doses 12 h apart. Subcutaneous insulin and diet are continued but from the first dexamethasone dose until 12 h after the second, supplementary intravenous insulin is infused according to hourly blood glucose measurements. The protocol incorporates four graded sliding scales. The initial scale is selected according to the patient's current subcutaneous insulin dose and advanced if the blood glucose is > or = 10.1 mmol/l for 2 consecutive hours. RESULTS: In a 10-month period eight (three gestational, five pre-gestational) women received antenatal corticosteroids from a total of 37 diabetic pregnancies. The median amount of supplementary intravenous insulin required was 74 U (range 32-88 U); the median glucose values achieved were 5.8-8.9 mmol/l. Seventy-five percent of glucose measurements were within an acceptable range of 4-10 mmol/l. Only one baby developed RDS. DISCUSSION: Large amounts of supplementary intravenous insulin are needed to achieve even moderate glycaemic control. This protocol enables routine ward staff to manage this successfully.

In-patient management of diabetes mellitus and patient satisfaction.

AIMS: To devise a system for assessing in-patient glycaemic control and care satisfaction in diabetic patients admitted to hospital for reasons other than their diabetes. METHODS: Consecutive January to March 2001 case-notes were reviewed. Admissions with acute metabolic complications, acute myocardial infarction and pregestational or gestational diabetes were excluded. Glycaemic control, frequency of blood monitoring and management of hyperglycaemia were recorded. The diabetes treatment satisfaction questionnaire was used to assess preadmission satisfaction with care. Post-admission a 12-stem questionnaire was used to assess satisfaction with in-patient diabetes management. RESULTS: Hypoglycaemia was common. Although none developed a hyperglycaemic emergency, high blood glucose was prevalent and, frequently, persistent hyperglycaemia or recurrent hypoglycaemia was not acted on appropriately. The overall score for in-patient satisfaction with treatment was fair (4.1 +/- 1.8 on a six-point scale; 6 = very satisfied and 1 = very dissatisfied). Scores were higher among patients on surgical wards than on medical wards (P = 0.008), but satisfaction did not vary when patients were stratified according to sex, age and mode of treatment. CONCLUSION: Current systems are not achieving satisfactory in-patient glycaemic control and there is poor satisfaction with medical in-patient diabetes care. Following changes intended to produce improvements, this assessment system can be used recurrently to monitor in-patient care and satisfaction.

Measuring clinical performance and outcomes from diabetes information systems: an observational study.

AIMS/HYPOTHESIS: To examine changes in diabetes care provision after the introduction of a district diabetes information system. METHODS: All patients with diabetes registered on the system between 1993 and 1998 (n = 6544) were included in the analysis. Drop-out cohort analysis was used to handle population changes, logistic regression models with general estimating equations were used to examine changes in clinical performance over time. RESULTS: After the introduction of the system, care processes improved appreciably, in both primary and secondary care. The proportion of patients receiving a preventative care review within the calendar year rose from 56% in 1993 to 67% in 1998. The proportion of these in whom each process was completed improved in all categories from 1993 to 1998: blood pressure 96% to 98%; glycaemic check 67% to 93%; lipid check 31% to 68%; renal check 46% to 87%; fundoscopy 79% to 92%; foot screen 87% to 87%. Similarly there was an increase in the proportion of patients achieving intermediate outcome treatment targets (HbA1c < or = 9.0% from 29% to 43%; cholesterol < or = 5.5 mmol/1 5% to 19%; blood pressure < or = 160/90 37% to 46%). CONCLUSION/INTERPRETATION: Our results suggest appreciable improvements in diabetes care between 1993 and 1998. These changes apply to an entire population of patients across primary and shared care. We believe that these improvements could, in part, be attributable to the way in which the district diabetes information system has facilitated the structured cascade of diabetes care.