A longitudinal study of fear of hypoglycaemia in adults with type 1 diabetes.

AIMS: To investigate fear of hypoglycaemia (FoH) longitudinally in a cross-sectional study of adult patients with type 1 diabetes. Specifically, we investigated two subgroups of patients who over 4 years either showed a substantial increase or decrease in level of FoH to identify factors associated with changes in FoH. METHODS: The Swedish version of the Hypoglycaemia Fear Survey (HFS) along with a questionnaire to assess hypoglycaemia history was sent by mail to 764 patients in 2010. The responders in 2010 (n = 469) received another set of the same two questionnaires in 2014. HbA1c, insulin regimen, weight and creatinine from 2010 and 2014 were obtained from medical records. Those with an absolute difference in HFS scores ≥ 75th percentile were included in the subgroup analyses. Statistical analyses included one-sample t tests, chi-square and McNemar's test. RESULTS: The absolute difference in the HFS total score (n = 347) between 2010 and 2014 was m = ±7.6, SD ± 6. In the increased FoH group, more patients reported a high level of moderate hypoglycaemic episodes as well as impaired awareness of hypoglycaemia in 2014 compared with the decreased FoH group. There were more subjects in the increased FoH group with insulin pumps in 2014 and in 2010. In the decreased FoH group, more patients had a high frequency of daily self-monitoring of blood glucose (SMBG) in 2010 and in 2014. CONCLUSIONS: Fear of hypoglycaemia is stable across time for most patients. Changes in fear level are associated with changes in hypoglycaemia frequency. Thus, asking patients about changes in hypoglycaemia experiences is of great importance.

Skin microvascular function in patients with type 1 diabetes: An observational study from the onset of diabetes.

BACKGROUND: The development of disturbances in skin microcirculation in type 1 diabetes is not well characterised. We assessed skin microcirculation longitudinally from the onset of diabetes up to 29 years of duration to investigate when such disturbances start. MATERIAL AND METHODS: Seventeen adult patients with type 1 diabetes participated. Skin microvascular function in digit IV of the left hand was investigated by laser Doppler fluxmetry (LDF, arbitrary units [AU]). LDF was carried out at rest and following one-min arterial occlusion. Time to peak LDF (s) and percentage increase of LDF (post-occlusive reactive hyperaemia, PRH%) were determined. Retinopathy was assessed from fundus photographs or ophthalmoscopic recordings. RESULTS: Skin microvascular function remained normal during the first five years. Compared with baseline and a non-diabetic reference group, time to peak LDF was prolonged after 7-9 years of diabetes ( p < 0.01). PRH% was lower than in the reference group after 7-9 years ( p < 0.01), and lower than baseline after 24-29 years of diabetes ( p < 0.05). All but one patient developed retinopathy and the first signs were found after 10 years of diabetes. CONCLUSIONS: Functional disturbances in total skin microcirculation were observed after seven years in patients with type 1 diabetes and preceded diabetic complications such as retinopathy.

Fibrin clot properties and haemostatic function in men and women with type 1 diabetes.

The increased risk of vascular complications in type 1 diabetes may in part be explained by changes in haemostatic function. In the present study, we investigated the fibrin clot properties in patients with type 1 diabetes in relation to sex and microvascular complications. The study included 236 patients (107 women) aged between 20-70 years and without any history of cardiovascular disease. Fibrin clot properties, assessed by determination of the permeability coefficient (Ks) and turbidimetric clotting and lysis assays, did not differ between men and women. Compared with men, women had worse glycaemic control as well as higher levels of prothrombin fragment 1+2 and peak thrombin generation in vitro, indicating increased thrombin generation both in vivo and in vitro. Subgroup analyses of patients younger than 30 years revealed less permeable fibrin clots and prolonged lysis time in females compared with age-matched men. Patients with microvascular complications had higher fibrinogen concentrations and denser and less permeable fibrin clots. Thus, we conclude that in vitro fibrin clot properties in patients with type 1 diabetes without cardiovascular disease are not different between the sexes, but associate with prevalence of microvascular complications. Tighter fibrin clot formation in younger women, as suggested by our results, may affect their future cardiovascular risk and should be investigated in a larger population.

Fear of hypoglycemia: relationship to hypoglycemic risk and psychological factors.

OBJECTIVE: The major aims of this study were to examine (1) the association between fear of hypoglycemia (FOH) in adults with type 1 diabetes with demographic, psychological (anxiety and depression), and disease-specific clinical factors (hypoglycemia history and unawareness, A1c), including severe hypoglycemia (SH), and (2) differences in patient subgroups categorized by level of FOH and risk of SH. RESEARCH DESIGN AND METHODS: Questionnaires were mailed to 764 patients with type 1 diabetes including the Swedish translation of the Hypoglycemia Fear Survey (HFS) and other psychological measures including the Perceived Stress Scale, Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index, Social Phobia Scale, and Fear of Complications Scale. A questionnaire to assess hypoglycemia history was also included and A1c measures were obtained from medical records. Statistical analyses included univariate approaches, multiple stepwise linear regressions, Chi-square t tests, and ANOVAs. RESULTS: Regressions showed that several clinical factors (SH history, frequency of nocturnal hypoglycemia, self-monitoring) were significantly associated with FOH but R (2) increased from 16.25 to 39.2 % when anxiety measures were added to the model. When patients were categorized by level of FOH (low, high) and SH risk (low, high), subgroups showed significant differences in non-diabetes-related anxiety, hypoglycemia history, self-monitoring, and glycemic control. CONCLUSION: There is a strong link between FOH and non-diabetes-related anxiety, as well as hypoglycemia history. Comparison of patient subgroups categorized according to level of FOH and SH risk demonstrated the complexity of FOH and identified important differences in psychological and clinical variables, which have implications for clinical interventions.

Impaired endothelium-dependent skin microvascular function during high-dose atorvastatin treatment in patients with type 1 diabetes.

AIMS: The present study investigated the effects of lipid-lowering therapy with atorvastatin on skin microvascular function in patients with type 1 diabetes and dyslipidaemia. METHODS: Twenty patients received daily treatment with atorvastatin 80 mg or placebo during 2 months in a randomised, double-blind, cross-over study. Forearm skin microcirculation was investigated with laser Doppler perfusion imaging during iontophoresis of acetylcholine and sodium nitroprusside to assess endothelium-dependent and endothelium-independent microvascular reactivity, respectively. Various biochemical markers of endothelial function were also investigated. RESULTS: Endothelium-dependent microvascular reactivity decreased during atorvastatin (p < 0.001), showing a significant treatment effect compared with placebo (p = 0.04). Atorvastatin treatment was also associated with increased haemoglobin A1C levels from 7.45% to 7.77% (p = 0.008). CONCLUSIONS: The present study shows impaired endothelium-dependent skin microvascular function during high-dose atorvastatin treatment in patients with type 1 diabetes, thus implicating a risk for deterioration of microvascular function during such therapy in these patients.

Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial.

BACKGROUND: Diabetes mellitus (DM) is associated with hyperreactive platelets and increased platelet-leukocyte aggregation (PLA), but the impact of concomitant chronic kidney disease (CKD) has been much less studied. Lipid-lowering treatment (LLT) may have favorable effects on platelet activation and inflammation. The objective of this mechanistic study was to investigate the impact of CKD on platelet function and inflammatory parameters in patients with DM and the effects of LLT. METHODS: After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S + E) were compared in a randomized, double-blind, cross-over study on platelet reactivity, PLA formation and inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min × 1.73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were included. RESULTS: PLAs were elevated at baseline in DM-CKD compared with DM-only (P = 0.04). S + E reduced PLAs among total leukocytes and neutrophils in DM-CKD patients (P = 0.01 for both) but not in the DM-only group. Platelet reactivity did not differ between patient groups or with LLT. Plasma levels of sCD40L (P < 0.001), elastase (P < 0.01) and von Willebrand factor (VWF) (P < 0.001) were elevated in DM-CKD compared with DM-only. S + E reduced sCD40L in DM-CKD patients (P = 0.01), but LLT did not influence VWF or elastase. CONCLUSIONS: DM patients with CKD stages 3-4 had increased PLA and inflammatory activity compared with DM patients with normal GFR. Simvastatin + ezetimbe decreased PLAs and plasma sCD40L in DM patients with concomitant CKD. Clinical Trial registration http://www.clinicaltrials.gov. Identifier NCT01035320.

High-dose aspirin is required to influence plasma fibrin network structure in patients with type 1 diabetes.

OBJECTIVE: Patients with type 1 diabetes form a less permeable fibrin network, which could contribute to their increased risk of cardiovascular disease (CVD). Low-dose aspirin treatment is the standard in the management of CVD; however, the effect seems reduced in patients with diabetes. We investigated the effects of low- and high-dose aspirin treatment on fibrin network formation in patients with type 1 diabetes (primary aim) and the possible interaction between the treatment effects of aspirin on fibrin network permeability and glycemic control in these patients (secondary aim). RESEARCH DESIGN AND METHODS: Forty-eight patients (24 subjects with good [HbA(1c) <7.4%] and 24 subjects with poor [HbA(1c) >8.4%] glycemic control) were randomly assigned to treatment with 75 or 320 mg/day aspirin during 4 weeks in a crossover fashion. A 4-week washout period separated the treatment periods. The plasma fibrin network was assessed by determination of the permeability coefficient (K(s)). RESULTS: Treatment with 75 mg aspirin did not influence fibrin network permeability (K(s)). However, K(s) increased significantly during treatment with 320 mg aspirin (P = 0.004), and a significant treatment effect was seen compared with treatment with 75 mg aspirin (P = 0.009). The increase in K(s) during high-dose aspirin treatment was significant in patients with poor glycemic control (P = 0.02), whereas K(s) only tended to increase in patients with good glycemic control (P = 0.06). CONCLUSIONS: A high dose of aspirin is required to influence fibrin network permeability in patients with type 1 diabetes. The observed lack of effect with low-dose aspirin may contribute to aspirin treatment failure in diabetes.

Basal insulin substitution with glargine or continuous subcutaneous insulin infusion in adult type 1 diabetes patients-a randomized controlled trial.

BACKGROUND: It is generally held that basal insulin substitution with continuous subcutaneous insulin infusion (CSII) provides less variable glucose levels than with long-acting insulin analogs, e.g., glargine, in patients with type 1 diabetes, although this has not been convincingly demonstrated by continuous glucose monitoring. METHODS: To compare glucose control assessed by a continuous glucose monitoring system (CGMS) during basal insulin substitution with glargine versus CSII, we conducted a non-blinded, randomized, crossover trial in 15 type 1 diabetes patients experienced with CSII. All subjects were randomly assigned to receive either a morning dose of insulin glargine, comprising their average 24-h basal insulin requirement, minus 2.4 U, which was delivered by the pump, or to continue as before for 4 weeks followed by a 1-week washout period and a crossover. All mealtime doses of insulin were given by the pump as before. CGMS data were blinded until the end of the study. RESULTS: The mean blood glucose was lower in the non-glargine arm according to self-monitoring of plasma glucose (9.2 vs. 10.6 mmol/L; P = 0.010) and CGMS (9.1 vs. 10.3 mmol/L; P = 0.002), and hemoglobin A1c was 6.5% without glargine versus 6.8% with (P = 0.018). There were no significant differences in glucose variability measured as SD of plasma glucose (SDPG) or mean amplitude of glycemic excursions (MAGE), although significantly longer periods of glucose values spent within the target of 4.5-10.0 mmol/L were demonstrated in the non-glargine arm using CGMS (P = 0.034). More episodes below 3.5 mmol/L were seen during the CSII period (P = 0.053). CONCLUSIONS: CSII provided improved glucose control compared to glargine with a lower mean plasma glucose and longer periods of glucose values within target on a somewhat lower insulin dose. There was a tendency with more episodes below 3.5 mmol/L during CSII. No difference with respect to glucose variability was found when calculated as SDPG or MAGE.

Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia.

INTRODUCTION: Diabetes is a prothrombotic state involving a more thrombogenic fibrin network. In the present study we investigated the effects of lipid-lowering therapy with atorvastatin on fibrin network structure and platelet-derived microparticles in patients with type 1 diabetes and dyslipidemia. MATERIALS AND METHODS: Twenty patients were treated with atorvastatin (80 mg daily) or placebo during 2 months in a randomized, double-blind, cross-over study. Fibrin network permeability, expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles, plasma endogenous thrombin potential, plasminogen activator inhibitor-1 and tissue plasminogen activator antigen levels were assessed. Additionally, levels of plasma fibrinogen, high-sensitivity C-reactive protein and glycated haemoglobin were measured. RESULTS: During treatment with atorvastatin, fibrin network permeability increased (p=0.01), while endogenous thrombin potential and expression of glycoprotein IIIa, P-selectin and tissue factor decreased (p<0.01). In vitro experiments indicated that platelet-derived microparticles influence the fibrin network formation as fibrin network permeability decreased significantly when platelet-derived microparticles were added to normal plasma. Baseline levels of plasminogen activator inhibitor-1 and tissue plasminogen activator antigen as well as plasma fibrinogen and high-sensitivity C-reactive protein were within reference values and not significantly changed during atorvastatin treatment, while glycated haemoglobin increased 0.3% (p<0.001). CONCLUSIONS: Novel treatment effects were found in patients with type 1 diabetes and dyslipidemia during atorvastatin therapy, i.e. a more porous fibrin network, to which reduced expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles may contribute. The observed impairment of glycemic control during long-term statin treatment deserves attention.

A cognitive behavior therapy-based intervention among poorly controlled adult type 1 diabetes patients--a randomized controlled trial.

OBJECTIVE: To examine the impact of a Cognitive Behavior Therapy (CBT)-based intervention on HbA(1c), self-care behaviors and psychosocial factors among poorly controlled adult type 1 diabetes patients. METHODS: Ninety-four type 1 diabetes patients were randomly assigned to either an intervention group or a control group. The intervention was based on CBT and was mainly delivered in group format, but individual sessions were also included. All subjects were provided with a continuous glucose monitoring system (CGMS) during two 3-day periods. HbA(1c), self-care behaviors and psychosocial factors were measured up to 48 weeks. RESULTS: Significant differences were observed with respect to HbA(1c) (P<0.05), well-being (P<0.05), diabetes-related distress (P<0.01), frequency of blood glucose testing (P<0.05), avoidance of hypoglycemia (P<0.01), perceived stress (P<0.05), anxiety (P<0.05) and depression (P<0.05), all of which showed greater improvement in the intervention group compared with the control group. A significant difference (P<0.05) was registered with respect to non-severe hypoglycemia, which yielded a higher score in the intervention group. CONCLUSION: This CBT-based intervention appears to be a promising approach to diabetes self-management. PRACTICE IMPLICATIONS: Diabetes care may benefit from applying tools commonly used in CBT. For further scientific evaluation in clinical practice, there is a need for specially educated diabetes care teams, trained in the current approach, as well as cooperation between diabetes care teams and psychologists trained in CBT.

Experience from a behavioural medicine intervention among poorly controlled adult type 1 diabetes patients.

AIM: To describe experience from a behavioural medicine intervention among poorly controlled adult type 1 diabetes patients, in terms of feasibility, predictors and associations of improved glycaemic control. METHODS: Data were collected on 94 poorly controlled adult type 1 diabetes patients who were randomised to a study evaluating the effects of a behavioural medicine intervention. Statistics covered descriptive and comparison analysis. Backward stepwise regression models were used for predictive and agreement analyses involving socio-demographic and medical factors, as well as measures of diabetes self-efficacy (DES), diabetes locus of control (DLOC), self-care activities (SDSCA), diabetes-related distress (Swe-PAID-20), fear of hypoglycaemia (HFS), well-being (WBQ), depression (HAD) and perceived stress (PSS). RESULTS: The participation rate in the study was 41% and attrition was 24%. Of those patients actually participating in the behavioural medicine intervention, 13% withdrew. From the regression models no predictors or associations of improvement in HbA(1c) were found. CONCLUSIONS: The programme proved to be feasible in terms of design and methods. However, no clear pattern was found regarding predictors or associations of improved metabolic control as the response to the intervention. Further research in this area is called for.

Psychometric evaluation of the Swedish version of the Hypoglycaemia Fear Survey.

OBJECTIVE: The objective of this study was to evaluate the psychometric properties of the Swedish version of the Hypoglycaemia Fear Survey (Swe-HFS) for use among Swedish-speaking patients with type 1 diabetes. METHODS: The HFS was translated using the forward-backward translation method and was thereafter answered by 325 type 1 patients. The psychometric properties were investigated using exploratory factor analysis, Cronbach's alpha, content and convergent validity. RESULTS: The factor analysis showed that a three-factor solution was reasonable with the subscales Behaviour/Avoidance (10 items), Worry (6 items) and Aloneness (4 items). Cronbach's alpha coefficient for the total score was 0.85. The result also supports the instrument's content validity and convergent validity. CONCLUSION: The Swedish version of the HFS appears to be a reliable and valid instrument for measuring fear of hypoglycaemia (FoH) in type 1 patients. PRACTICE IMPLICATIONS: The results from this study suggest that the Swe-HFS, an instrument that is brief and easy to administer, may be valuable in clinically assessing FoH among patients with type 1 diabetes.

The psychometric properties of the Swedish version of the Problem Areas in Diabetes Scale (Swe-PAID-20): scale development.

BACKGROUND: Considering the importance of psychological aspects in the management of diabetes, there is a need of validated measurements in this area. Such tools make it possible to screen patients for specific conditions as well as they serve as reliable measures when evaluating medical, psychological and educational interventions. OBJECTIVES: The current study was conducted to adapt the Problem Areas in Diabetes Scale for use among Swedish-speaking patients with type 1 diabetes and to evaluate the psychometric properties. DESIGN: Methodological research design was used in this study. SETTING AND PARTICIPANTS: A convenience sample of 325 type 1 diabetes patients was systematically selected from the local diabetes registry of a university hospital in Stockholm, Sweden. METHODS: Following the linguistic adaptation using the forward-backward translation method, the 20-item PAID was answered by the selected patients. Statistics covered exploratory factor analysis, Cronbach's alpha, convergent validity and content validity. RESULTS: In the factor analysis a three-factor solution was found to be reasonable with the sub-dimensions diabetes-related emotional problems (15 items), treatment-related problems (2 items) and support-related problems (3 items). Cronbach's alpha coefficient for the total score was 0.94 and varied between 0.61 and 0.94 in the three subscales. The findings also gave support for the convergent and content validity. CONCLUSIONS: The Swedish version of the Problem Areas in Diabetes Scale (Swe-PAID-20) seems to be a reliable and valid outcome for measuring diabetes-related emotional distress in type 1 diabetes patients.

Patient management of long-term continuous subcutaneous insulin infusion.

AIM: This paper reports a study of patients' current practice with continuous subcutaneous insulin infusions, particularly with respect to the management of the pump. BACKGROUND: Successful implementation of continuous subcutaneous insulin infusion requires a motivated patient with a range of technical skills and self-management capabilities. The therapy should be prescribed, implemented and monitored by a skilled professional team familiar with it and capable of supporting the patient. METHODS: A questionnaire was mailed to 102 continuous subcutaneous insulin infusion treated patients at a Swedish university hospital with experience of pump treatment for at least 6 months. RESULTS: The questionnaire was answered by 88% of the patients, 53 women and 37 men, aged 22-71 years with a duration of continuous subcutaneous insulin infusion use of between 7 months and 19 years. The changing interval for soft infusion set ranged from 2.0 to 10.0 days (mean 4.8) and for metal needles from 1.5 to 7.5 days (mean 3.8), P = 0.001. Catheter occlusions were significantly more often reported in patients with presence of bleeding at the infusion site (P = 0.011) and among those using insulin lispro (P = 0.032). CONCLUSIONS: Patients having long-term continuous subcutaneous insulin infusion should be carefully audited with respect to the management of the insulin pump and its accessories. In patients who frequently experience problems, shorter intervals between changes of infusion sets are strongly advocated and type of insulin preparation may be of importance in some cases.

[Episodes of severe hypoglycemia--increasing problem in type 1 diabetes]. / Tillbud av allvarlig hypoglykemi--ökande problem vid diabetes typ 1.

A cross-sectional survey of severe hypoglycaemia was performed in type 1 diabetes mellitus patients in 1984 and repeated in 1998 at the diabetes out-patient clinic of a Swedish university hospital. The study revealed that the prevalence of severe hypoglycaemia had increased by more than 50 per cent over 14 years, in spite of more frequent use of multiple insulin injection therapy and daily self monitoring of blood glucose. A multiple logistic regression analysis of risk factors for severe hypoglycaemia explained less than 10% of the variance, implicating only unawareness of hypoglycaemia and HbA1c. It is concluded that long duration type 1 diabetes mellitus patients are increasingly vulnerable with respect to severe hypoglycaemia and that this should be taken into account when individual treatment goals are being proposed to patients. Novel short-acting and long-acting analogs of insulin as well as insulin pumps may prove useful to minimize the risk of severe hypoglycaemic episodes. It is argued that the ability of currently marketed glucose monitoring systems to sensitively and specifically detect hypoglycaemia is limited.

Alteration of the counterregulatory responses to insulin-induced hypoglycemia and of cognitive function after massive weight reduction in severely obese subjects.

The autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are reported as activated in excess in the morbidly obese state and, therefore, changes after weight loss can be anticipated. The aim of this study was to investigate the impact of a massive (approximately 30%) weight reduction on the activation of the HPA axis and the ANS following bariatric surgery. Eight (7 women, 1 man) severely obese (125+/-12 kg; body mass index [BMI], 45+/-4 kg/m2) nondiabetic subjects, underwent a 3-hour hyperinsulinemic (1,034 pmol/kg/h) glucose clamp study at hypoglycemia of arterial B-glucose concentration of 3.4 mmol/L. Cognitive function was evaluated by a visuospatial computerized problem-solving test, the Perceptual Maze Test (PMT). The mean weight loss was 40+/-9 kg approximately 12 months postsurgery when their weight was stabilized (85+/-6 kg; BMI, 31+/-3 kg/m2), and insulin sensitivity improved to an average increase of 376%+/-250% (P<.01) of initial value. Before weight reduction, all patients demonstrated brisk peak responses in glucagon, epinephrine, pancreatic polypeptide (PP), norepinephrine, and cortisol, indicative of preserved or exaggerated activation of ANS and HPA axis. In the reduced-obese state, all these responses were attenuated and most markedly so for glucagon, which was totally abolished. In contrast, the growth hormone (GH) response was increased after weight reduction. The cognitive function was clearly modified by weight reduction both during normoglycemia and hypoglycemia and was changed preferentially to a speed-preferring strategy in the reduced-obese state compared with a more accuracy preferred problem-solving process of PMT test presurgery. These results demonstrate a reduction of the glucose counterregulatory hormonal responses, increased insulin sensitivity, and perturbed cognitive function after massive weight reduction. It may be speculated on if the increased insulin sensitivity and reduced counterregulation to hypoglycemia could predispose to low plasma glucose concentrations.