Add-on treatment with intermediate-acting insulin versus sliding-scale insulin for patients with type 2 diabetes or insulin resistance during cyclic glucocorticoid-containing antineoplastic chemotherapy: a randomized crossover study.

The aim of this study was to compare the effectiveness and safety of intermediate-acting insulin (IMI) titrated on body weight and glucocorticoid dose with that of short-acting sliding-scale insulin (SSI) in patients on recurrent high-dose glucocorticoid-containing chemotherapy. We enrolled 26 patients with type 2 diabetes mellitus or random blood glucose level >12 mmol/l in a previous cycle of chemotherapy in a randomized crossover study. In two consecutive cycles of glucocorticoid-containing chemotherapy, participants were treated with either IMI or SSI, as add-on to routine diabetes medication. We compared time spent in target range (3.9-10 mmol/l), measured by continuous glucose monitoring (CGM), and the occurrence of hypoglycaemia. IMI resulted in a higher proportion of glucose values within target range than SSI (34.4 vs 20.9%; p < 0.001). There were no severe or symptomatic hypoglycaemic events. Two participants in each group had a subclinical hypoglycaemia detected only by CGM. Once-daily IMI resulted in better glycaemic control than SSI in patients with glucocorticoid-induced hyperglycaemia during chemotherapy. Safety was not compromised as the incidence of hypoglycaemia was low and not different between both regimens.

Frequency of cancer events with saxagliptin in the SAVOR-TIMI 53 trial.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized trial of 16,492 patients (placebo, n = 8212; saxagliptin, n = 8280) treated and followed for a median of 2.1 years afforded an opportunity to explore whether there was any association with cancer reported as a serious adverse event. At least one cancer event was reported by 688 patients (4.1%): 362 (4.3%) and 326 (3.8%) in the placebo and saxagliptin arms, respectively (p = 0.13). There were 59 (0.6%) deaths adjudicated as malignancy deaths with placebo and 53 (0.6%) with saxagliptin. Stratification by gender, age, race and ethnicity, diabetes duration, baseline glycated haemoglobin and pharmacotherapy did not show any clinically meaningful differences between the two study arms. The overall number of cancer events and malignancy-associated mortality rates were generally balanced between the placebo and saxagliptin groups, suggesting a null relationship with saxagliptin use over the median follow-up of 2.1 years. Multivariable modelling showed that male gender, dyslipidaemia and current smoking were independent predictors of cancer. These randomized data with adequate numbers of cancer cases are reassuring but limited, by the short follow-up in a trial not designed to test this hypothesis.

Physician's attitudes towards diagnosing and treating glucocorticoid induced hyperglycaemia: Sliding scale regimen is still widely used despite guidelines.

AIMS: Treatment with glucocorticoids for neoplasms and inflammatory disorders is frequently complicated by glucocorticoid induced hyperglycaemia (GCIH). GCIH is associated with adverse outcomes and its treatment has short term and long term benefits. Currently, treatment targets and modalities depend on local protocols and habits of individual clinicians. We explored current practice of screening and treatment of GCIH in patients receiving glucocorticoid pulse therapy. METHODS: A factorial survey with written case vignettes. All vignette patients received glucocorticoid pulse therapy. Other characteristics (e.g., indication for glucocorticoid therapy, pre-existent diabetes) varied. The survey was held between November 2013 and May 2014 on 2 nationwide conferences and in hospitals across The Netherlands. Pulmonologists and internists expressed their level of agreement with statements on ordering capillary glucose testing and treatment initiation. RESULTS: Respondents ordered screening for GCIH in 85% of vignette patients and initiated treatment in 56%. When initiating treatment, respondents opt for sliding scale insulin in 62% of patients. Sliding scale insulin was more frequently prescribed in patients with pre-existent insulin dependent diabetes (OR 2.4, CI 1.3-4.2) and by residents (vs. specialists, OR 2.1, CI 1.2-3.5). Sixty-nine percent of clinicians experienced a lack of guidelines for GCIH. CONCLUSIONS: Clinicians have a strong tendency to screen for GCIH but subsequent initiation of treatment was low. Sliding scale insulin is still widely used in episodic GCIH despite evidence against its effectiveness. This may be due to lacking evidence on feasible treatment options for GCIH.

Effects of sitagliptin on counter-regulatory and incretin hormones during acute hypoglycaemia in patients with type 1 diabetes: a randomized double-blind placebo-controlled crossover study.

AIMS: To assess whether the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin affects glucagon and other counter-regulatory hormone responses to hypoglycaemia in patients with type 1 diabetes. METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period crossover study. We studied 16 male patients with type 1 diabetes aged 18-52 years, with a diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 min after onset of the autonomic reaction. RESULTS: Sitagliptin treatment significantly increased active levels of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. No significant differences were observed for glucagon or adrenergic counter-regulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 min after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [median (IQR) 23 (0.2-211.0) mEq/l] compared with placebo [median (IQR) 90 (8.8-180) mEq/l; p = 0.008]. CONCLUSIONS: Sitagliptin does not affect glucagon or adrenergic counter-regulatory responses in patients with type 1 diabetes, but attenuates the growth hormone response during late hypoglycaemia.

Antibody response to a T-cell-independent antigen is preserved after splenic artery embolization for trauma.

Splenic artery embolization (SAE) is increasingly being used as a nonoperative management strategy for patients with blunt splenic injury following trauma. The aim of this study was to assess the splenic function of patients who were embolized. A clinical study was performed, with splenic function assessed by examining the antibody response to polysaccharide antigens (pneumococcal 23-valent polysaccharide vaccine), B-cell subsets, and the presence of Howell-Jolly bodies (HJB). The data were compared to those obtained from splenectomized patients and healthy controls (HC) who had been included in a previously conducted study. A total of 30 patients were studied: 5 who had proximal SAE, 7 who had distal SAE, 8 who had a splenectomy, and 10 HC. The median vaccine-specific antibody response of the SAE patients (fold increase, 3.97) did not differ significantly from that of the HC (5.29; P = 0.90); however, the median response of the splenectomized patients (2.30) did differ (P = 0.003). In 2 of the proximally embolized patients and none of the distally embolized patients, the ratio of the IgG antibody level postvaccination compared to that prevaccination was <2. There were no significant differences in the absolute numbers of lymphocytes or B-cell subsets between the SAE patients and the HC. HJB were not observed in the SAE patients. The splenic immune function of embolized patients was preserved, and therefore routine vaccination appears not to be indicated. Although the median antibody responses did not differ between the patients who underwent proximal SAE and those who underwent distal SAE, 2 of the 5 proximally embolized patients had insufficient responses to vaccination, whereas none of the distally embolized patients exhibited an insufficient response. Further research should be done to confirm this finding.

Ethnicity influences weight loss 1 year after bariatric surgery: a study in Turkish, Moroccan, South Asian, African and ethnic Dutch patients.

Several studies conducted in the USA have demonstrated that the effectiveness of bariatric surgery differs between patients from African and European origin. However, little is known on differences in outcomes after bariatric surgery between individuals from other ethnic backgrounds. In this retrospective study, we found that, in terms of weight loss, gastric bypass surgery is less effective in African, South Asian, Turkish and Moroccan patients than in their ethnic Dutch counterparts. Our results underscore that ethnic differences in the effectiveness of bariatric surgery are not limited to those between patients of African and European origin, but extend to other minority groups as well. Therefore, it is important that prospective studies both determine ethnic differences in weight loss-related improvement of co-morbidities and elucidate the exact reasons for these ethnic disparities.

What contributes to internists' willingness to disclose medical errors?

BACKGROUND: The release of the report 'To err is human' put medical safety and the disclosure of errors to the forefront of the health care agenda. Disclosure of medical errors by physicians is vital in this process. We studied the role of background and social psychological factors in internists' willingness to report medical errors. METHODS: Survey among a random sample of internists from five teaching hospitals in the Netherlands, all internists and internists in training at the Departments of Internal Medicine of the participating hospitals. RESULTS: Questionnaires were received from 115 participants (response 51%). The willingness to disclose was related to the severity of the error, with the majority of near misses not reported to the head of department or the hospital error committees. Errors were more often reported to colleagues. Positive factors in favour of disclosing were reported more often than negative ones prohibiting disclosure. Motivation, behavioural control and social barriers were related to the disclosure of errors. CONCLUSION: Personal and social issues contributing to the will and addressed properly to stimulate disclosure. The creation of an atmosphere where disclosing errors is routine seems vital. In addition, it is essential to create a departmental culture where medical errors are discussed in a non-judgmental, safe environment. In order to improve reporting of medical errors, more emphasis should be placed on the individual barriers that preclude adequate reporting.

The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus.

Obesity and type 2 diabetes mellitus (T2DM) are attributed to a combination of genetic susceptibility and lifestyle factors. Their increasing prevalence necessitates further studies on modifiable causative factors and novel treatment options. The gut microbiota has emerged as an important contributor to the obesity--and T2DM--epidemic proposed to act by increasing energy harvest from the diet. Although obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota, the pathophysiological processes remain only partly understood. In this review we will describe the development of the adult human microbiome and discuss how the composition of the gut microbiota changes in response to modulating factors. The influence of short-chain fatty acids, bile acids, prebiotics, probiotics, antibiotics and microbial transplantation is discussed from studies using animal and human models. Ultimately, we aim to translate these findings into therapeutic pathways for obesity and T2DM in humans.

The association of physical inactivity with Type 2 diabetes among different ethnic groups.

AIMS: To study differences in the association between physical inactivity and Type 2 diabetes among subjects from different ethnic groups. METHODS: We analysed data on 508 Caucasian, 596 African-Surinamese and 339 Hindustani-Surinamese participants, aged 35-60 years, in the population-based, cross-sectional Surinamese in the Netherlands Study on Health and Ethnicity (SUNSET) study. Physical inactivity was defined as the lowest quartile of reported activity, measured with the validated Short Questionnaire to Assess Health-Enhancing Physical Activity. Type 2 diabetes was defined as fasting plasma glucose levels ≥7.0 mmol/l or self-reported diagnosis. RESULTS: Physical inactivity was associated with Type 2 diabetes (OR 1.63, 95% CI 1.12-2.38) in the total group after adjustment for sex, age, BMI, ethnicity, resting heart rate, hypertension, smoking, history of cardiovascular disease, having a first-degree relative with Type 2 diabetes and educational level. However, this association was only significant in Caucasians (OR 3.17, 95% CI 1.37-7.30). Moreover, it appeared stronger in Caucasians than in Hindustani-Surinamese (OR 1.43, 95% CI 0.78-2.63) and African-Surinamese (OR 1.13, 95% CI 0.58-2.19), although the P-value for interaction was not significant. CONCLUSIONS: Physical inactivity was associated with Type 2 diabetes in the total group after adjustment for multiple risk factors, but this association was only significant in Caucasians. Also, it appeared stronger in Caucasians than in Hindustani and African-Surinamese, but formal testing for interaction provided no further evidence. These findings confirm the importance of exercise, but suggest that potential health gain may differ between ethnic groups. However, it should be noted that, in general, promotion of physical activity in populations with an increased a priori risk of Type 2 diabetes, remains of the utmost importance.

Hip surgery sequentially induces stress hyperglycaemia and activates coagulation.

BACKGROUND: A frequent complication of orthopaedic procedures is venous thromboembolism (VTE ). Hyperglycaemia has been shown to activate the coagulation system and is associated with postoperative morbidity and mortality. Therefore, we hypothesised that glucose levels increase during orthopaedic surgery and are associated with an activation of the coagulation system. METHODS: Nine adult patients undergoing elective hip replacement were included. Venous blood samples were taken before, during and after surgery. Plasma glucose levels, factor VIII clotting activity (fVIII:c), von Willebrand ristocetin cofactor activity, von Willebrand factor antigen and prothrombin fragment 1+2 were measured. RESULTS: Immediately after induction of anaesthesia, plasma glucose levels started to increase until the second day postoperatively (peak 8.0 mmol/l). After seven weeks glucose values had returned to baseline (6.1 mmol/l), p<0.001 with ANOVA. All coagulation parameters increased during surgery, subsequent to the rise in glucose. The change in mean FVIII:c and von Willebrand ristocetin cofactor activity was significantly correlated with mean glucose values. CONCLUSIONS: These observations indicate that total hip replacement surgery causes an increase in glucose levels that precedes the proportional rise of the measured coagulation parameters. This suggests a possible role of glucose in the activation of the coagulation system during hip surgery.

[Intensive blood glucose-lowering therapy: to which extent?]. / Intensieve verlaging van de bloedglucosewaarde: waar ligt de grens?

The excess mortality in the group of intensively treated patients in the 'Action to control cardiovascular risk in diabetes' (ACCORD) study casts doubts on the safety ofglycated haemoglobin (HbA(1C)) levels below 7%. However, comparison of the ACCORD study with the 'Action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation' (ADVANCE) trial, which showed no excess mortality, indicates that not a low HbA(1C) level per se, but the method by which it was achieved, was responsible for the adverse outcome. Although no specific cause was identified, the excessive use of rosiglitazone, and the combination of up to 5 glucose-lowering drugs, most strikingly distinguishes the ACCORD study from other studies. Thus, the data from ACCORD added to previously voiced concerns about the safety of rosiglitazone and polypharmacy. Several large studies have failed to prove that improved glycaemic control reduces macrovascular events. However, the beneficial effects on microvascular events are undisputed. Thus, the benefits of HbA(1C) levels below 7% should be weighed against the risks of 'modern' polypharmacy.

[Lower incidence of type 2 diabetes mellitus with changes in lifestyle: clues from World War II]. / Lagere incidentie van diabetes mellitus type 2 bij verandering van leefstijl: aanwijzingen uit de Tweede Wereldoorlog.

OBJECTIVE: To investigate the relation between diabetes and food consumption on a population level. DESIGN: Retrospective, descriptive. METHOD: Data were collected from the archives of the Public Health Service of Amsterdam and the diabetes aftercare outpatient clinic ('Diabetes Nazorg') in Utrecht, the Netherlands, to determine the incidence of diabetes between 1940 and 1950. The number of outpatient visits for newly-diagnosed diabetes in Amsterdam and Utrecht were used to investigate whether the incidence of diabetes decreased during World War II, when food was scarce. RESULTS: Between 1940 and 1945 there was a considerable decrease in the incidence of diabetes in the Netherlands. The number of outpatient consultations at the Public Health Service of Amsterdam for newly-diagnosed diabetes declined from 140 in 1940 (18% of the total number of consultations) to only 3 in 1940 (2%). This figure rose to 112 (21%) in 1949. CONCLUSION: The marked decrease in the number of new cases of diabetes during the last years ofWorld War II supports the hypothesis that shortage of food induced a decrease in the incidence of type 2 diabetes in The Netherlands.

Glucose fluctuations and activation of oxidative stress in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Glucose fluctuations may help predict diabetic complications. We evaluated the relation between glucose variability and oxidative stress in patients with type 1 diabetes. METHODS: Continuous glucose monitors were inserted subcutaneously in 25 patients. During the measurement, patients collected two 24 h urine samples, while 24 healthy controls collected one 24 h urine sample for determination of 15(S)-8-iso-prostaglandin F2alpha(PGF2alpha) using HPLC tandem mass spectrometry. Mean of the daily differences (MODD), mean amplitude of glycaemic excursions (MAGE) and continuous overlapping net glycaemic action calculated with n hour time-intervals (CONGA-n) were calculated as markers for glucose variability and correlation with 15(S)-8-iso-PGF2alpha excretion was calculated. RESULTS: Median [interquartile range (IQR)] urinary 15(S)-8-iso-PGF2alpha was higher in patients than healthy controls: 161 (140-217) pg/mg creatinine vs 118 (101-146) pg/mg creatinine (p = 0.001). Median (IQR) MODD was 3.7 (3.2-5.0) mmol/l, MAGE 7.6 (6.4-9.0) mmol/l and CONGA-1 2.3 (2.1-2.8) mmol/l. Univariate regression did not reveal an association for MODD (r2 = 0.01), MAGE (0.08) or CONGA-1 (0.07) with 15(S)-8-iso-PGF2alpha excretion, nor was an association revealed when corrected for HbA1c, age, sex and smoking. Spearman correlation coefficients (r) between 15(S)-8-iso-PGF2alpha excretion and MODD, MAGE and CONGA-1 were non-significant: -0.112, -0.381 and -0.177. CONCLUSIONS/INTERPRETATION: We report that there is no relationship between glucose variability and urinary 15(S)-8-iso-PGF2alpha. We also confirm that patients with type 1 diabetes have higher levels of urinary 15(S)-8-iso-PGF2alpha than healthy controls, suggesting that in addition to glucose variability, other factors favouring oxidative stress may exist. We did not see a relation between high glucose variability and elevated levels of oxidative stress in patients with type 1 diabetes.

A new tool, a better tool? Prevalence and performance of the International Diabetes Federation and the National Cholesterol Education Program criteria for metabolic syndrome in different ethnic groups.

We used a population based study in the Netherlands of 330 Hindustani Surinamese, 586 African Surinamese, and 486 ethnic Dutch (Dutch) to describe the prevalence of the metabolic syndrome (MS) and the association with differences in cardiovascular disease in and between ethnic groups. Fasting blood samples, blood pressure, and anthropometric measurements were obtained. MS was defined according to the criteria of the International Diabetes Federation (IDF) and the criteria of the National Cholesterol Education Program (NCEP). Cardiovascular disease was assessed by the Rose questionnaire and included questions on previous diagnoses of angina pectoris/myocardial infarction, cerebrovascular accident, intermittent claudication. The prevalence of MS (IDF and NCEP) was highest in Hindustani Surinamese men, followed by Dutch and African Surinamese men: 51.0%, 19.4%, and 31.2% (IDF), respectively. Among women, both the Hindustani and African Surinamese participants had a higher prevalence of MS (IDF and NCEP) than the Dutch. The association between the components, MS and cardiovascular disease differed between ethnic groups, in particular among men; OR for MS (NCEP) = 1.0 (0.4-2.7) among Hindustani Surinamese, OR = 4.9 (1.3-18.3) among African Surinamese, and OR = 2.8 (1.1-7.1) among Dutch. However, the differences in MS could not account for the ethnic differences in cardiovascular disease, regardless of the criteria used. The results suggest that, before the criteria can be used to guide practice, they may need to be changed and refined to take into account the differences between ethnic groups as well as the variations by gender.

[Hyperglycaemia during hospitalisation]. / Hyperglykemie tijdens ziekenhuisopname.

Patients who are admitted to an intensive care unit for 3 days or longer have an increased survival rate if their blood-glucose levels are strictly controlled by means of intensive insulin therapy. This is true of patients admitted for either surgical or non-surgical indications. For patients undergoing cardiac surgery, strict peri- and postoperative glycaemic control lowers the postoperative complication rate and possibly also mortality. Patients suffering from an acute myocardial infarction, and possibly also patients with acute ischaemic stroke, are likely to benefit from strict glycaemic control. The value of treating hyperglycaemia in other patient groups has not been established. The workload on the nursing staff and the risk of prolonged and serious hypoglycaemia are the most important disadvantages of strict glycaemic control. The optimal duration of strict glycaemic control and the precise target range are not well defined and may well differ per patient group.

Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis.

AIMS/HYPOTHESIS: Cardiovascular disease contributes to mortality in type 1 diabetes mellitus, but the specific pathophysiological mechanisms remain to be established. We recently showed that the endothelial glycocalyx, a protective layer of proteoglycans covering the endothelium, is severely perturbed in type 1 diabetes, with concomitantly increased plasma levels of hyaluronan and hyaluronidase. In the present study, we evaluated the relationship between hyaluronan and hyaluronidase with carotid intima-media thickness (cIMT), an established surrogate marker for cardiovascular disease. SUBJECTS AND METHODS: Non-smoking type 1 diabetes patients without micro- or macrovascular complications and matched controls were recruited and cIMT of both carotid arteries was measured. To evaluate the relationship between cIMT and hyaluronan and hyaluronidase as well as other parameters, uni- or multivariate regression analyses were performed. RESULTS: We included 99 type 1 diabetes patients (age 10-72 years) and 99 age- and sex-matched controls. Mean cIMT, HbA(1c), high sensitivity C-reactive protein, hyaluronan and hyaluronidase were significantly increased in type 1 diabetes vs controls. Plasma hyaluronan and hyaluronidase were correlated in type 1 diabetes. In univariate regression analyses, mean IMT was associated with plasma hyaluronan, age and male sex, whereas after multivariate analysis only age and sex remained statistically significant. CONCLUSIONS/INTERPRETATION: We conclude that type 1 diabetes patients show structural changes of the arterial wall associated with increased hyaluronan metabolism. These data may lend further support to altered glycosaminoglycan metabolism in type 1 diabetes as a potential mechanism involved in accelerated atherogenesis.

[Iron-deficiency anaemia: a sign that requires an adequate explanation]. / IJzergebreksanemie: zoeken naar een overtuigende verklaring.

In three patients, aged 79, 58 and 59 years, respectively, iron-deficiency anaemia (IDA) was diagnosed. All three had a right-sided colonic adenocarcinoma. In the first patient, a cardiologic cause was looked for instead of a simple laboratory investigation of the anaemia. The second patient received iron supplementation without sufficient diagnostic evaluation, and in the third patient the abdominal X-ray was inadequate for evaluation of the ascending colon; moreover, she responded well to iron supplementation therapy. IDA is a common problem in clinical practice that may have various causes. In the Netherlands, gastrointestinal bleeding is the major cause of IDA in men and women over 50 years of age. The three patients described illustrate that IDA should be considered a clinical sign. An accurate evaluation of the IDA to detect a convincing explanation is therefore necessary. Various causes can be found on duodenoscopy and colonoscopy, e.g. neoplasms, ulcers, angiodysplasia or polyps. Carcinoma of the ascending colon is a frequent cause of IDA, especially in those over 50 years of age and without upper gastrointestinal symptoms. Evaluation to exclude a right-sided carcinoma of the colon has a high priority in these cases.

[Screening for diabetic retinopathy]. / Screening op diabetische retinopathie.

Concurrent with the increasing incidence of diabetes mellitus, the incidence of diabetic retinopathy is also rising. Timely recognition with the aid of screening, followed by laser therapy, can prevent the greater part of the resulting visual impairment and blindness. However, many patients with diabetes are not screened or not screened adequately. The necessary screening frequency is annually or biannually, depending on the degree of retinopathy and the presence of risk factors, of which glycaemic control, duration of diabetes, blood pressure, lipid profile, and race are the most important. Digital 2-field fundus photography, preferably in mydriasis, is of sufficient quality for routine screening. The impact of screening programmes can be further improved by applying the optimal method and by initiating an active implementation strategy.