Systematic review and meta-analysis of psychological interventions in people with diabetes and elevated diabetes-distress.

AIMS: The clinical relevance of diabetes-distress is increasingly recognized, but little is known about the efficacy of interventions specifically targeted to treat elevated diabetes-distress. Therefore, this systematic review sought to determine the efficacy of psychological interventions aimed at treating elevated diabetes-distress in people with Type 1 or Type 2 diabetes. METHODS: We systematically searched literature from five databases. Randomized controlled trials (RCTs) with an English abstract, describing the results of a psychological intervention in adults with diabetes were included. Articles were eligible for inclusion if the primary outcome was diabetes-distress measured by the Problem Areas in Diabetes Scale (PAID-5/PAID-20) or the Diabetes Distress Scale (DDS-17). Only mean group diabetes-distress values above cut-off at baseline or the results of a subgroup above cut-off (PAID-5 ≥ 8, PAID-20 ≥ 40 or DDS-17 ≥ 3) were included. RESULTS: The search yielded 8907 articles. After removing 2800 duplicates, 6107 articles remained. Titles and abstracts were screened, leaving 394 potential articles of interest, nine of which were RCTs. In a random-effects meta-analysis, the pooled effect size for diabetes-distress was 0.48 (Cohen's d), Z = 3.91, P < 0.0001. Statistical heterogeneity was I² = 46.67% (confidence intervals 45.06% to 48.28%). Diabetes-tailored psychological interventions reduced HbA1c (Cohen's d = 0.57), whereas mindfulness-based interventions did not (Cohen's d = 0.11). CONCLUSIONS: This systematic review shows that specifically diabetes-tailored psychological interventions are effective in reducing elevated diabetes-distress and HbA1c . More rigorous studies are warranted to establish the full potential of these interventions. PROSPERO database registration ID: CRD42017075290.

Continuous glucose monitoring during diabetic pregnancy (GlucoMOMS): A multicentre randomized controlled trial.

AIM: Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self-measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies. MATERIAL AND METHODS: We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5-7 days every 6 weeks in the CGM group, while self-monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications. RESULTS: Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83-1.37). HbA1c levels were similar between treatment groups. CONCLUSIONS: In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome.

Cinacalcet for secondary hyperparathyroidism: from improved mineral levels to improved mortality?

Secondary hyperparathyroidism is an almost inevitable complication of advanced kidney failure. The introduction of the calcimimetic cinacalcet for the treatment of secondary hyperparathyroidism in patients on dialysis was based on its ability to reduce elevated levels of parathyroid hormone (PTH). Subsequent clinical studies confirmed the beneficial effects of cinacalcet on biochemical parameters reflecting mineral disturbances and bone disease. In this review we summarise the impact of cinacalcet on biochemical, intermediate and clinical outcomes. We also present previously unpublished mineral metabolism data from 144 Dutch dialysis patients treated with cinacalcet who participated in the pan-European ECHO observational study. Although secondary hyperparathyroidism tended to be more severe in our Dutch cohort, compared with the entire ECHO cohort, cinacalcet was nevertheless effective in reducing PTH in these patients. Two recent clinical studies evaluated, respectively, the efficacy of cinacalcet in improving the intermediate endpoint of cardiovascular calcifications (ADVANCE trial), and its impact on clinical outcomes, including all-cause mortality and cardiovascular events (EVOLVE trial). The ADVANCE trial provided evidence that cinacalcet may indeed improve calcification in both large arteries and cardiac valves. The EVOLVE trial, however, did not meet its clinical primary endpoint (time to all-cause mortality, myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event), although secondary and sensitivity analysis suggested a beneficial effect. The clinical implications of these important studies are also addressed in this review.

Familial LCAT deficiency: from renal replacement to enzyme replacement.

Familial LCAT deficiency (FLD) is a recessive lipid disorder ultimately leading to end-stage renal disease (ESRD). We present two brothers with considerable variation in the age at which they developed ESRD. Kidney biopsies revealed both tubular and glomerular pathology. To date, no causal therapy is available, yet enzyme replacement therapy is in development.

Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study.

OBJECTIVES: To evaluate neuromuscular signs and symptoms in patients with newly diagnosed hypothyroidism and hyperthyroidism. METHODS: A prospective cohort study was performed in adult patients with newly diagnosed thyroid dysfunction. Patients were evaluated clinically with hand held dynamometry and with electrodiagnosis. The clinical features of weakness and sensory signs and the biochemical data were evaluated during treatment. RESULTS: In hypothyroid patients 79% had neuromuscular complaints, 38% had clinical weakness (manual muscle strength testing) in one or more muscle groups, 42% had signs of sensorimotor axonal neuropathy, and 29% had carpal tunnel syndrome. Serum creatine kinase did not correlate with weakness. After 1 year of treatment 13% of the patients still had weakness. In hyperthyroid patients 67% had neuromuscular symptoms, 62% had clinical weakness in at least one muscle group that correlated with FT4 concentrations, but not with serum CK. Nineteen per cent of the patients had sensory-motor axonal neuropathy and 0% had carpal tunnel syndrome. The neuromuscular signs developed rapidly, early in the course of the disorder and were severe, but resolved rapidly and completely during treatment (average time 3.6 months). CONCLUSIONS: Neuromuscular symptoms and signs were present in most patients. About 40% of the hypothyroid patients and 20% of the hyperthyroid patients had predominantly sensory signs of a sensorimotor axonal neuropathy early in the course of thyroid disease. Weakness in hyperthyroidism evolved rapidly at an early stage of the disorder and resolved completely during treatment, suggesting a functional muscle disorder. Hand held dynamometry is sensitive for the detection of weakness and for the clinical evaluation of treatment effects. Weakness in hypothyroidism is more difficult to treat, suggesting myopathy.

D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study.

A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.

Acute cardiorespiratory failure as presenting symptom of chronic lymphocytic leukemia.

A patient with acute cardiorespiratory failure caused by hyperleukocytosis due to chronic lymphocytic leukaemia (CLL) is described. Although acute pulmonary failure due to leukostasis is a known and often postmortem finding in patients with acute myelocytic leukaemia (AML) or chronic myelocytic leukaemia (CML) in blastic crises, it is rare in CLL.

Technetium-99m-sestamibi/thallium-201 mismatch of thyroid and parathyroid adenoma in chronic renal failure.

We report on a patient who had chronic renal failure and relapse of secondary hyperparathyroidism after earlier extirpation of three glands. Whereas 201Tl-chloride uptake was absent in the thyroid and an ectopic parathyroid adenoma during routine subtraction 201Tl-99mTc scintigraphy, both glands could be visualized with 99mTc-sestamibi and [123I]sodium.

Insulin-induced decline of plasma amino acid concentrations in obese subjects with and without non-insulin-dependent diabetes.

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood fibrinolysis and the response to desmopressin in glomerulonephritis.

Fibrinolytic parameters and von Willebrand factor (VWF) antigen were measured in 22 patients with glomerulonephritis (GN) who underwent renal biopsy after desmopressin (DDAVP) infusion. Blood was collected immediately before and after DDAVP infusion, after one week, and 3-6 months later. The main abnormalities on admission were the following: the mean baseline levels of t-PA antigen and VWF were significantly higher in GN patients than in 22 healthy controls; the median t-PA activity and the mean scu-PA level were significantly lower than normal. The t-PA response to DDAVP was impaired in 7 patients (32%), the response of VWF in 9 patients (41%), and the u-PA:Ag response in 11 patients (50%). When the patients were stratified according to creatinine clearance rate, significant differences between the subgroups with severely and moderately impaired renal function were noted: the baseline levels of PAI activity and VWF were higher in patients with severe renal failure and the VWF response to DDAVP was significantly lower. The response of u-PA (not of t-PA or VWF) to DDAVP appeared to correlate with urine flow during the first 24 h, suggesting the dependence of u-PA release on intact nephrons. A series of 18 patients with adult-type polycystic kidney disease (APKD) with creatinine clearance rates in the same abnormal range as the GN patients, had lower mean PAI and a significantly higher mean scu-PA level.(ABSTRACT TRUNCATED AT 250 WORDS)

The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance.

The cardiovascular risk factor plasminogen activator inhibitor type 1 (PAI-1) has been associated with abdominal obesity, hypertension, hypertriglyceridemia, hyperinsulinemia, glucose intolerance, and type II diabetes, conditions known to be linked with insulin resistance. To determine whether PAI-1 is related to insulin resistance, we studied nine obese nondiabetics and 10 obese type II diabetics by means of a sequential hyperinsulinemic euglycemic clamp study. Plasma PAI-1 antigen (Ag) correlated significantly with peripheral insulin resistance, represented by the insulin level at which peripheral glucose uptake (PGU) is half-maximal ([ED50PGU] r = .87, P < .001). Multiple regression analysis including indices of hepatic and peripheral insulin action, fasting plasma insulin levels, triglyceride levels, blood pressure (BP), waist to hip ratio (WHR), and body mass index (BMI) disclosed ED50PGU to account for 76% of the variance of PAI-1 Ag. We suggest that PAI-1 contributes to the increased cardiovascular risk encountered with insulin resistance.

Long term use of captopril or nifedipine in normotensive microalbuminuric patients with insulin-dependent diabetes mellitus.

Several studies have suggested that ACE-inhibition may be effective in postponing the onset of nephropathy in insulin-dependent diabetic subjects. In contrast, other drugs might have opposing effects. To study the long term effects of either captopril or nifedipine in normotensive, microalbuminuric patients with insulin-dependent diabetes mellitus, eighteen subjects received either placebo (n = 5, P), 20 mg nifedipine daily (n = 7, N) or 50 mg captopril daily (n = 6, C) for one year. Baseline clinical and laboratory variables were comparable in the three groups. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and blood pressure did not differ between groups before and after one years medication. UAER did not change in the captopril and the placebo group (C: -12.6% (-58.1 to 51.8%)' P: -17.3 (-55.9 to 99.3%), medians and ranges. In contrast, in the patients that received nifedipine, UAER rose by 43.1% (-8.5 to 261.8%), (p < 0.05 Baseline vs one year, and one year nifedipine vs captopril and placebo). We therefore conclude, that long-term use of nifedipine increases UAER in normotensive microalbuminuric insulin-dependent subjects, in contrast to captopril or placebo. Whether this enhancement of microalbuminuria exerts an adverse effect on renal function in the long-term is yet unknown, but caution seems warranted.

Fluoxetine increases insulin action in obese type II (non-insulin dependent) diabetic patients.

Insulin resistance contributes to the metabolic defects in non-insulin dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. In a double-blind placebo-controlled cross-over study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinaemic-euglycaemic clamp technique with infusion of 3-[3H]-glucose in eight obese NIDDM patients and in eight obese non-diabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu: 180.5 +/- 25.8 vs. 225.3 +/- 39.9 mU/l, P < 0.05), but not in non-diabetics (140 +/- 15.3 vs. 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and non-diabetics. When non-diabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P < 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production (HGP) is completely suppressed (HGP0) (P < 0.01). In conclusion, fluoxetine improves peripheral and hepatic insulin action in obese insulin-resistant subjects irrespective of its weight lowering effect.

Fibrinolytic system during long-distance running in IDDM patients and in healthy subjects.

OBJECTIVE: Endurance exercise has been advocated in diabetes mellitus to improve both metabolic control and prevent atherosclerotic complications. The response of the fibrinolytic system during prolonged exercise has not been studied in diabetes. RESEARCH DESIGN AND METHODS: In seven male marathon runners with IDDM and eight healthy nondiabetic male control subjects, matched for age and degree of training, we studied fibrinolytic and coagulation parameters during a 3-h 32-km outdoor running session. Measurements included t-PA, u-PA, PAI-1, PAP (as a measure of in vivo activation of fibrinolysis), FbDPs, FGN, vWF, and VIII:C. RESULTS: In both IDDM and control subjects, levels of t-PA, u-PA, PAP, vWF, and VIII:C continued to rise throughout the exercise, whereas PAI-1 showed a similar decline in both groups. FbDP rose slightly in both groups, and FGN remained unchanged. t-PA levels during exercise correlated closely with exercise intensity. These findings indicate that continued stimulation by exercise does not deplete endothelial PA stores. Differences between IDDM and control subjects were seen only for t-PA, vWF, and u-PA. The AUC during exercise (AUC0.5-3.0) of t-PA in IDDM was insignificantly lower than in control subjects (53 +/- 19 vs. 67 +/- 31 ng.ml-1.h), but the ratio of t-PA to exercise intensity was lower in IDDM (0.24 +/- 0.11 vs. 0.31 +/- 0.13, P less than 0.05). The AUC0.5-3.0 of vWF was lower in IDDM than in control subjects (569 +/- 268 vs. 880 +/- 265%.h, P less than 0.05). The AUC0.5-3.0 of u-PA was higher in IDDM than in control subjects (15.1 +/- 3.5 vs. 11.2 +/- 1.8 ng.ml-1.h, P less than 0.05). CONCLUSIONS: Despite a defect in the exercise-induced endothelial release of vWF and t-PA, the overall potential to activate fibrinolysis is intact in IDDM, possibly by enhancement of u-PA after exercise. Our data suggest that in IDDM, as in nondiabetic subjects, long-distance running may slow the progression of atherosclerosis by stimulating fibrinolysis.

Fluoxetine increases insulin action in obese nondiabetic and in obese non-insulin-dependent diabetic individuals.

Insulin resistance contributes to the metabolic defects in non-insulin-dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. The serotonin-reuptake inhibiting agent fluoxetine has recently been recognized as an anorectic agent. The effect of fluoxetine on insulin action has not yet been determined. In a double blind placebo controlled crossover study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinemic euglycemic clamp technique with infusion of 3-3H-glucose in eight obese NIDDM and in eight obese nondiabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu 180.5 +/- 25.8 vs 225.3 +/- 39.9 mU/l, P less than 0.05), but not in nondiabetics (140 +/- 15.3 vs 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Basal hepatic glucose production (HGP) was reduced after fluoxetine in both NIDDM (9.45 vs 10.37 mumol/kg/min) and in nondiabetics (8.57 vs 9.16 mumol/kg/min), although the difference was only significant in nondiabetics (P less than 0.05). Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and nondiabetics. When nondiabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P less than 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production is completely suppressed (HGP0) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The amount of plasminogen, tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in human thrombi and the relation to ex-vivo lysibility.

Thrombolytic therapy successfully reopens obstructed blood vessels in the majority of cases. However, it is not known why a substantial amount of thrombi are resistant to lysis by a fibrinolytic agent. In vitro studies have demonstrated that tissue-type plasminogen activator (t-PA) and plasminogen incorporated in the clot (during formation) increase lysibility. To test whether lysibility of in vivo formed human thrombi is related to their composition, we studied 25 venous thrombi obtained at autopsy and 21 arterial thrombi obtained during embolectomy. Plasminogen activator inhibitor-1 (PAI-1) antigen was measured in a phosphate-buffered saline (PBS) extract of each thrombus; t-PA antigen and plasminogen antigen were determined in a 6 M urea extract of the thrombus, representing bound proteins. Lysibility was measured as weight reduction during 8 h of incubation in PBS containing streptokinase (SK) 100 U/ml, corrected for spontaneous lysis, reflected by weight loss in PBS without SK. In addition, lysibility in SK was compared with lysibility in urokinase (UK) 100 U/ml and in t-PA 200 U/ml. Spontaneous lysis amounted to 29 +/- 5% (mean +/- SEM) and 33 +/- 5% in venous and arterial thrombi, respectively, and inversely correlated with the PAI-1 content of thrombi (r = -0.43, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)