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Objectives: To design an educational intervention on sexual dysfunction for patients suffering from schizophrenia and diabetes based on patients' and other relevant stakeholders' preferences, and to offer transparency into the basic decision-making process behind a final design. Methods: We conducted a three-part investigation to explore theory, preferences, and feasibility based on literature searches and interviews with patients, healthcare professionals, heads of Assertive Community Treatment Centres and experts. Based on a content analysis of this material, a draft of the intervention was developed. The draft was quality-checked by involvement of stakeholder representatives and refined to its final design. Results: The intervention evolved into having two components: One intervention for patients and one for healthcare professionals. In patient education, meeting peers and predictability were important factors. For healthcare professionals, daily clinical activities were prioritised. Conclusions: We present a framework for an educational intervention about sexual dysfunction, schizophrenia and diabetes targeting both patients and healthcare professionals. Innovation: The transparency of the design process underlying the interventions allows for reproduction and eases further refinement, extension, and adjustment if implemented in other contexts.

Abstract Aims In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short‐term treatment with the ketone body 3‐hydroxy butyrate (3‐OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3‐OHB predicted all‐cause mortality and sought to identify correlations between patient characteristics and circulating 3‐OHB levels. Methods and results We conducted a cohort study in 218 patients with HFrEF. Plasma 3‐OHB levels were measured using high‐performance liquid chromatography tandem mass spectrometry. Data on all‐cause mortality were obtained by reviewing the patients' medical records, which are linked to the national ‘Central Person Registry’ that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow‐up time was 7.3 (interquartile range 6.3–8.4) years. We observed large variations in 3‐OHB levels between patients (median 59 μM, range: 14–694 μM). Patients with 3‐OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3–3.5], P = 0.003}. In a multivariate analysis, 3‐OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001–1.007), P = 0.02] and with a similar statistical strength as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) [HR: 1.0005 (95% CI: 1.000–1.001), P = 0.02]. For every 100 μmol increase in plasma 3‐OHB, the hazard of death increased by 49%. The following factors significantly predicted 3‐OHB levels in the univariate analysis: free fatty acids (FFAs) [β: 238 (95% CI: 185–292), P 0.001]. Conclusions In patients with HFrEF, circulating 3‐OHB was a strong predictor of all‐cause mortality independently of NT‐proBNP. Circulating FFAs were the best predictor of 3‐OHB levels.

Abstract Background Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM). Methods The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed. Results After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI − 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference − 0.33 V (95% CI − 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA1c did not confound the associations. Conclusions Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA1c. Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H–D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Abstract Objective Gustatory sweating (GS) is characterized by profuse sweating during or immediately after ingestion of food and is known as a complication of diabetes mellitus (DM). This study aimed to determine the prevalence of GS and to characterize the sweating in a cohort of patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM) as compared with a control group. Methods In a cross‐sectional study, 665 outpatients with T1DM and 505 outpatients with T2DM filled in an 8‐point questionnaire about GS. Answers were paired with medical data from the electronic patient records to explore associations with DM complications. The control group consisted of 1158 persons without DM answering the same questionnaire in an online version. Results In people with T1DM and T2DM, the prevalence of GS was 10% (95% CI 7%–12%) and 13% (95% CI 10%–16%), respectively. In the control group, the prevalence of GS was 5% (95% CI 3%–6%). Most commonly, people sweat on the face and/or head and upper body with a duration of 10–30 min albeit in the control group 45.

BackgroundThere is a high prevalence of unexplained and unexplored obstructive sleep apnea (OSA) among patients with type 2 diabetes. The daytime symptoms of OSA include severe fatigue, cognitive problems, a decreased quality of life, and the reduced motivation to perform self-care. These symptoms impair the management of both diabetes and daily life. OSA may therefore have negative implications for diabetes self-management. Continuous positive airway pressure (CPAP) therapy is used to treat OSA. This treatment improves sleep quality, insulin resistance, and glycemic control. Although the benefits of using CPAP as a treatment for OSA are clear, the noncompliance rate is high, and the evidence for the perceived effect that CPAP treatment has on patients with type 2 diabetes and OSA is poor. ObjectiveThe purpose of this study was to analyze the impacts that comorbid diabetes and OSA have on the daily lives of older adults and to investigate the perceived effect that CPAP treatment for OSA has on patients’ diabetes self-management. MethodsA qualitative follow-up study that involved in-depth, semistructured dyad interviews with couples before and after CPAP treatment (N=22) was conducted. Patients were recruited from the Hilleroed Hospital in Denmark and were all diagnosed with type 2 diabetes, aged >18 years, and had an apnea-hypopnea index of ≥15. All interviews were coded and analyzed via thematic analysis. ResultsThe results showed that patients and their partners did not consider OSA to be a serious disorder, as they believed that OSA symptoms were similar to those of the process of aging. Patients experienced poor nocturnal sleep, took frequent daytime naps, exhibited reduced cognitive function, and had low levels of physical activity and a high-calorie diet. These factors negatively influenced their diabetes self-management. Despite the immediate benefit of CPAP treatment, most patients (11/12, 92%) faced technical challenges when using the CPAP device. Only the patients with severe OSA symptoms that affected their daily lives overcame the challenges of using the CPAP device and thereby improved their diabetes self-management. Patients with less severe symptoms rated CPAP-related challenges as more burdensome than their symptoms. ConclusionsIf used correctly, CPAP has the potential to significantly improve OSA, resulting in better sleep quality; improved physical activity; improved diet; and, in the end, better diabetes self-management. However, there are many barriers to undergoing CPAP treatment, and only few patients manage to overcome these barriers and comply with correct treatment.

Abstract Background Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial. Methods/design A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms. Discussion In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov: NCT02192450.

Abstract Aim Obstructive sleep apnoea (OSA) is frequent in type 2 diabetes (T2D). The aim was to investigate the effect of a 12‐week treatment with continuous positive airway pressure (CPAP) on glycaemic control assessed by continuous glucose monitoring (CGM), HbA1c and fasting blood glucose in patients with T2D and newly detected OSA. Methods In a randomized controlled multicentre study, 72 participants with T2D and moderate to severe OSA (78% male, age 62 ± 7, AHI 35 ± 15) were recruited from outpatient clinics in three Danish hospitals and were randomized to CPAP intervention or control. The main outcome was glycaemic control assessed by 6 days CGM at baseline and after 12‐week therapy, as well as by HbA1c and fasting blood glucose. Results No significant changes were found in average glucose levels, time in glucose range, time with hypoglycaemia, time with hyperglycaemia or coefficient of variability. HbA1c decreased 0.7 mmol/mol (0.07%; P = .8) in the CPAP group and increased 0.8 mmol/mol (0.08%; P = .6) in the control group (intergroup difference, P = .6). Fasting blood glucose increased by 0.2 mmol/L (P = .02) in the CPAP group and by 0.4 mmol/L (P = .01) in the control group (intergroup difference, P = .7). In a prespecified subgroup analysis comparing participants with high adherence (minimum usage of four hours/night for 70% of all nights) to CPAP to the control group, no significant changes were observed either, although these participants had a tendency towards better glycaemic indices. Conclusions CPAP treatment for 12 weeks does not significantly change glycaemic control in patients with type 2 diabetes and OSA.

Introduction A physically active lifestyle during pregnancy improves maternal and offspring health but can be difficult to follow. In Denmark, less than 40% of pregnant women meet physical activity (PA) recommendations. The FitMum study aims to explore strategies to increase PA during pregnancy among women with low PA and assess the health effects of PA. This paper presents the FitMum protocol, which evaluates the effects of structured supervised exercise training or motivational counselling supported by health technology during pregnancy on PA level and health of mother and offspring.Methods and analysis A single-site three-arm randomised controlled trial that aims to recruit 220 healthy, pregnant women with gestational age (GA) no later than week 15 and whose PA level does not exceed one hour/week. Participants are randomised to one of three groups: structured supervised exercise training consisting of three weekly exercise sessions, motivational counselling supported by health technology or a control group receiving standard care. The interventions take place from randomisation until delivery. The primary outcome is min/week of moderate-to-vigorous intensity PA (MVPA) as determined by a commercial activity tracker, collected from randomisation until GA of 28 weeks and 0-6 days, and the secondary outcome is gestational weight gain (GWG). Additional outcomes are complementary measures of PA; clinical and psychological health parameters in participant, partner and offspring; analyses of blood, placenta and breastmilk samples; process evaluation of interventions; and personal understandings of PA.Ethics and dissemination The study is approved by the Danish National Committee on Health Research Ethics (# H-18011067) and the Danish Data Protection Agency (# P-2019-512). Findings will be disseminated via peer-reviewed publications, at conferences, and to health professionals via science theatre performances.Trial registration number NCT03679130.Protocol version This paper was written per the study protocol version 8 dated 28 August 2019.

Background: This study measures the use of drugs within the therapeutic areas of antithrombotic agents (B01), the cardiovascular system (C), analgesics (N02), psycholeptics (N05), and psychoanaleptics (N06) among the general population (GP) in comparison to persons with diabetes in Denmark. The study focuses on drugs having pharmacogenomics (PGx) based dosing guidelines for CYP2D6, CYP2C19, and SLCO1B1 to explore the potential of applying PGx-based decision-making into clinical practice taking drug–drug interactions (DDI) and drug–gene interactions (DGI) into account. Methods: This study is cross-sectional, using The Danish Register of Medicinal Product Statistics as the source to retrieve drug consumption data. Results: The prevalence of use in particular for antithrombotic agents (B01) and cardiovascular drugs (C) increases significantly by 4 to 6 times for diabetic users compared to the GP, whereas the increase for analgesics (N02), psycoleptics, and psychoanaleptics (N06) was somewhat less (2–3 times). The five most used PGx drugs, both in the GP and among persons with diabetes, were pantoprazole, simvastatin, atorvastatin, metoprolol, and tramadol. The prevalence of use for persons with diabetes compared to the GP (prevalence ratio) increased by an average factor of 2.9 for all PGx drugs measured. In addition, the prevalence of use of combinations of PGx drugs was 4.6 times higher for persons with diabetes compared to GP. In conclusion, the findings of this study clearly show that a large fraction of persons with diabetes are exposed to drugs or drug combinations for which there exist PGx-based dosing guidelines related to CYP2D6, CYP2C19, and SLCO1B1. This further supports the notion of accessing and accounting for not only DDI but also DGI and phenoconversion in clinical decision-making, with a particular focus on persons with diabetes.

Abstract Background Diabetic foot ulcers are a common and severe complication of diabetes mellitus. Standard treatment includes debridement, offloading, management of infection and revascularisation where appropriate, although healing times may be long. The LeucoPatch® device is used to generate an autologous platelet-rich fibrin and leucocyte wound dressing produced from the patient’s own venous blood by centrifugation, but without the addition of any reagents. The final product comprises a thin, circular patch composed predominantly of fibrin together with living platelets and leucocytes. Promising results have been obtained in non-controlled studies this system, but this now needs to be tested in a randomised controlled trial (RCT). If confirmed, the LeucoPatch® may become an important new tool in the armamentarium in the management of diabetic foot ulcers which are hard-to-heal. Methods People with diabetes and hard-to-heal ulcers of the foot will receive either pre-specified good standard care or good standard care supplemented by the application of the LeucoPatch® device. The primary outcome will be the percentage of ulcers healed within 20 weeks. Healing will be defined as complete epithelialisation without discharge that is maintained for 4 weeks and is confirmed by an observer blind to randomisation group. Discussion Ulcers of the foot are a major source of morbidity to patients with diabetes and costs to health care economies. The study population is designed to be as inclusive as possible with the aim of maximising the external validity of any findings. The primary outcome measure is healing within 20 weeks of randomisation and the trial also includes a number of secondary outcome measures. Among these are rate of change in ulcer area as a predictor of the likelihood of eventual healing, minor and major amputation of the target limb, the incidence of infection and quality of life. Trial registration International Standard Randomised Controlled Trial, ISRCTN27665670 . Registered on 5 July 2013.

Abstract Background Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. Methods Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. Results After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [β per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [β per 1 SD higher lnMMP-1 and lnMMP-2 = − 0.83 mmHg (95% CI − 1.50; − 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. Conclusions MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets.

The role of the autonomic nervous system in the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 1 diabetes is unknown. We assessed the association between autonomic function and weight loss induced by the GLP-1 RA liraglutide.Methods: Lira-1 was a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of 1.8 mg liraglutide once-daily for 24 weeks in overweight patients with type 1 diabetes. Autonomic function was assessed by heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio), to the Valsalva maneuver and resting heart rate variability (HRV) indices. Associations between baseline the cardiovascular autonomic neuropathy (CAN) diagnosis (> 1 pathological non-resting test) and levels of test outcomes on liraglutide-induced weight loss was assessed by linear regression models.Results: Ninety-nine patients with mean age 48 (SD 12) years, HbA1c 70 (IQR 66;75) mmol/mol and BMI of 30 (SD 3) kg/m2 were assigned to liraglutide (N = 50) or placebo (N = 49). The CAN diagnosis was not associated with weight loss. A 50% higher baseline level of the 30/15 ratio was associated with a larger weight reduction by liraglutide of −2.65 kg during the trial (95% CI: −4.60; −0.69; P = 0.009). Similar significant associations were found for several HRV indices.Conclusions: The overall CAN diagnosis was not associated with liraglutide-induced weight loss in overweight patients with type 1 diabetes. Assessed separately, better outcomes for several CAN measures were associated with higher weight loss, indicating that autonomic involvement in liraglutide-induced weight loss may exist.

Background: Clopidogrel and proton pump inhibitors (PPIs) are among the most used drugs in Denmark for which there exists pharmacogenomics (PGx)-based dosing guidelines and FDA annotations. In this study, we further scrutinized the use of clopidogrel and PPIs when prescriptions were redeemed from Danish Pharmacies alone or in combination in the Danish population and among persons with diabetes in Denmark. The focus deals with the potential of applying PGx-guided antiplatelet therapy taking both drug–drug interactions (DDI) and drug–gene interactions (DGI) into account. Methods: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption data. Results: The consumption of PPIs and clopidogrel in terms of prevalence (users/1000 inhabitants) increased over a five-year period by 6.3% to 103.1 (PPIs) and by 41.7% to 22.1 (clopidogrel), respectively. The prevalence of the use of clopidogrel and PPIs in persons with diabetes are 3.8 and 2.1–2.8 times higher compared to the general population. When redeemed in combination, the prevalence increased to 4.7. The most used combination was clopidogrel and pantoprazole. Conclusions: The use of clopidogrel and PPIs either alone or in combination is quite widespread, in particular among the elderly and persons with diabetes. This further supports the emerging need of accessing and accounting for not only DDI but also for applying PGx-guided drug therapy in clinical decision making for antiplatelet therapy with clopidogrel having a particular focus on persons with diabetes and the elderly.

Introduction: Obstructive sleep apnea (OSA) is associated with increased cardiovascular (CV) risk. OSA is highly prevalent among patients with type-2 diabetes (T2D). Patients with T2D have increased risk of cardiovascular events, and have an increased aortic stiffness. Continuous Positive Airway Pressure (CPAP) treatment reduces severity of OSA, but whether it reduces CV risk remains unclear. One randomized trial with CPAP intervention and pulse wave velocity (PWV) as endpoint has shown a significant reduction in PWV after four months, in non-diabetic patients. The effect on patients with diabetes remains unknown. Aim: Investigate the effects of CPAP treatment on PWV in patients with T2D and newly diagnosed OSA. Furthermore, investigate the relationship between PWV and severity of OSA. Method: A randomized, controlled, multicenter study. 70 patients with T2D and newly diagnosed OSA randomized to: CPAP treatment or a control group. Data will be collected at baseline, 4 and 12 weeks. PWV was measured using SphygmoCor (AtCor Medical, Sydney, Australia) and AHI measured using ApneaLink (ResMed, Poway, CA, USA). Relationship between PWV and AHI was evaluated at baseline. Results: Baseline data from the first 21 patients showed mean age 63 years (±8.1), mean systolic blood pressure (BP) was 134 (±12.5) mmHg, mean AHI was 30.2 (±12.4) and mean PWV was 11.6 (±1.9) m/s. AHI was associated with PWV in multivariate analysis with adjustment for age and systolic BP, beta-coefficient 0.08, p = 0.029. Conclusion: At baseline PWV and AHI were correlated. Progression of the study will reveal if CPAP treatment can lower PWV in this cohort.

Background. Obstructive sleep apnoea (OSA) is related to type 2 diabetes (T2DM), and it may be associated with reduced inspiratory muscle strength (IMS). The aim of this study was to investigate the IMS in patients with T2DM, with or without OSA. Methods. Patients with T2DM with OSA (n=33) and without OSA (n=28) were included. The maximum IMS was tested using the POWERbreathe KH2 device. Reference IMS values were data calculated using an algorithm based on general populations and adjusted for age and gender. Results. There was no difference in IMS between the OSA group (median (range) 77 (35–124) cmH2O) and the non-OSA group (84 (33–122) cmH2O) (p=0.97). The IMS values were reduced in the OSA group compared with the reference values (92.9 (62.3–100.0) cmH2O) (p=0.030), whereas the non-OSA group did not have reduced IMS. When the IMS values of all T2DM patients were compared with reference values, the IMS values were 79 (33–124) cmH2O and 93.8 (62.3–102.4) cmH2O, respectively (p=0.017). Conclusion. No difference in IMS between patients with T2DM with or without OSA was found. However, patients with T2DM and OSA had reduced IMS compared with age- and gender-matched references whereas the non-OSA group did not have reduced IMS.

Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice. In addition, uCTGF was measured in type 1 DN patients and compared with glomerular and tubular dysfunction and damage markers. In diabetic mice, uCTGF was increased and fractional excretion (FE) of recombinant CTGF was substantially elevated indicating reduced tubular reabsorption. FE of recombinant CTGF correlated with excretion of endogenous CTGF. CTGF mRNA was mainly localized in glomeruli and medullary tubules. Comparison of FE of endogenous and recombinant CTGF indicated that 60% of uCTGF had a direct renal source, while 40% originated from plasma CTGF. In DN patients, uCTGF was independently associated with markers of proximal and distal tubular dysfunction and damage. In conclusion, uCTGF in DN is elevated as a result of both increased local production and reduced reabsorption due to tubular dysfunction. We submit that uCTGF is a biomarker reflecting both glomerular and tubulointerstitial hallmarks of diabetic kidney disease.

In this study we estimate the subcutaneous tissue counter pressure during drug infusion from a series of injections of insulin in type 2 diabetic patients using a non-invasive method. We construct a model for the pressure evolution in subcutaneous tissue based on mass continuity and the flow laws of a porous medium. For equivalent injection forces we measure the change in the infusion rate between injections in air at atmospheric pressure and in tissue. From a best fit with our model, we then determine the flow permeability as well as the bulk modulus of the tissue, estimated to be of the order 10-11-10-10 m2 and 105 Pa, respectively. The permeability is in good agreement with reported values for adipose porcine tissue. We suggest our model as a general way to estimate the pressure build-up in tissue during subcutaneous injection.

The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO) enhances cognitive function during hypoglycemia.Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint), hypoglycemic symptoms, and counter-regulatory hormonal response were recorded.Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (-4.7 (-8.1 to -1.3), p = 0.01) and a less reaction time prolongation (-66 (-117 to -16) msec, p = 0.02). EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment.In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment.ClinicalTrials.gov NCT00615368.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

BackgroundDiabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.Methods and resultsWe performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPL(pairs) LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets.ConclusionsThis study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21-q25 and 19q13.

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.

Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control.One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA(1c) (HbA(1c)) > or = 8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA(1c) after one year of treatment. At enrolment, mean (standard deviation) HbA(1c) was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA(1c), 0.13% (-0.19; 0.44), p = 0.422; Total daily insulin dose, -5.7 U/day (-8.6; -2.9), p

Background. Intervention studies in microalbuminuric type 2 diabetic patients have demonstrated that it is possible to avoid progression to overt diabetic nephropathy and even to achieve regression to normoalbuminuria. However, the long-term impact of stabilization/regression in albuminuria on decline in glomerular filtration rate (GFR) has not been established.Methods. 151 patients with type 2 diabetes and microalbuminuria at baseline in whom GFR was measured at least three times during 7.8 years of follow-up were divided into three groups according to the level of albuminuria during follow-up. Overt nephropathy was diagnosed as a urinary albumin excretion rate (AER) >300?mg/24?h and remission to normoalbuminuria was defined as an AER <30?mg/24?h at the last examination.Results. During follow-up, 46 patients achieved remission to normoalbuminuria, 58 remained microalbuminuric and 47 patients progressed to overt nephropathy. The mean (?SE) yearly decline in GFR was lowest (2.30.4?ml/min/year) in patients who obtained remission, in comparison with patients remaining microalbuminuric, in whom the decline was 3.70.4?ml/min/year, and patients progressing to overt nephropathy, who had a decline in GFR of 5.40.5 ml/min/year (ANOVA, P<0.001). Start of antihypertensive treatment during follow-up was strongly associated with remission to normoalbuminuria [odds ratio: 2.32; 95% confidence interval (CI): 1.094.93] whereas a decrease in HbA1c by 1% increased the probability for remission (odds ratio: 1.48; 95% CI: 1.111.97).Conclusions. Remission to normoalbuminuria was associated with a decreased GFR decline during 7.8 years of follow-up in type 2 diabetic patients with microalbuminuria. Antihypertensive therapy and improved glycaemic control were independent predictors for remission. [ABSTRACT FROM AUTHOR]

Background. Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems. Methods. Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n = 2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent–offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing. Results. In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA1c, blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA1c and smoking as well as pair-wise interactions. Conclusions. The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

Background. Circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are elevated in patients with diabetic nephropathy and independently predict excess cardiovascular morbidity and mortality. Therefore, we investigated the association between two polymorphisms –381T/C and 1551G/A of the BNP gene, plasma NT-proBNP levels and mortality prognosis in 380 type 1 diabetic patients with and without diabetic nephropathy. Methods. In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy {121 men, age [mean (SD)] 41 ± 9.5 years, duration of diabetes 28 ± 8.0 years, glomerular filtration rate 67 ± 28 ml/min/1.73 m2}, and a matched control group of 183 patients with longstanding type 1 diabetes and persistent normoalbuminuria (111 men, age 43 ± 10.0 years, duration of diabetes 27 ± 8.3 years) were followed for 12.6 (0.0–12.9) years. Plasma NT-proBNP concentration was determined by immunoassay at baseline. The BNP genotypes were determined by TaqMan chemistry based assays. Results. The two polymorphisms were in almost complete linkage disequilibrium (r2 = 0.883) and thus only the results of the –381T/C promoter polymorphism are shown. There was no significant difference between cases and controls in either genotype distributions (cases TT 32%, TC 53%, CC 15%; controls TT 28%, TC 52%, CC 20%) or allele frequencies (cases T/C 0.58/0.42; controls T/C 0.54/0.46) for the –381T/C polymorphism. Among the 164 normoalbuminuric patients without antihypertensive treatment and previous major cardiovascular disease (CVD), the –381T/C polymorphism was associated with circulating levels of NT-proBNP [median (interquartile range) 21 (5–32), 34 (12–67) and 32 (12–58) ng/l for TT, TC and CC, respectively (P = 0.041)] persisting after adjustment for covariates (P = 0.018). During follow-up, the –381T/C polymorphism did not predict all-cause or cardiovascular mortality among type 1 diabetic patients with or without diabetic nephropathy. Conclusions. The BNP –381T/C and 1551G/A polymorphisms are associated with circulating levels of NT-proBNP but not with prevalent overt diabetic nephropathy. These polymorphisms do not predict all-cause or cardiovascular mortality in Caucasian type 1 diabetic patients with or without diabetic nephropathy. [ABSTRACT FROM AUTHOR]