The Fusion Clinic: Integrating the care of people with severe mental illness and diabetes.

AIM: People with coexisting severe mental illness (SMI) and type 2 diabetes have a shorter life expectancy and poorer diabetes outcomes than those without SMI. This is partly explained by the separate treatment of diabetes and SMI, which occurs in parallel silos in many healthcare systems. The Steno Diabetes Center Sjaelland and Region Zealand established the Fusion Clinic to offer combined psychiatric and diabetes care delivered by both diabetes and mental healthcare professionals. This study describes how the clinic was established and the initial diabetes outcomes. METHODS: The Fusion Clinic was co-designed by people with diabetes and SMI and healthcare professionals to improve the care of adults with diabetes and SMI. The clinic approach utilised the F-ACT model. The 63 people referred to the Fusion Clinic between 01.02.2020 and 01.01.2022 who attended the clinic for more than 6 months were included in this study. Diabetes outcomes were recorded in the electronic medical records (Sundhedsplatformen EPIC). RESULTS: There was a high prevalence of diabetes complications at baseline. Furthermore, 70% had one or more additional concomitant diseases, as well as SMI and diabetes. Assessment of diabetes complications and measurements of HbA1c and lipid profile improved after referral to the clinic. HbA1c declined during the first 6 months of attendance at the clinic. CONCLUSIONS: This model of service delivery has the potential to improve the quality of care for people with SMI and type 2 diabetes.

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

AIM: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia. MATERIALS AND METHODS: The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia. RESULTS: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]). CONCLUSION: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

Comparison of treatment with insulin degludec and glargine U100 in patients with type 1 diabetes prone to nocturnal severe hypoglycaemia: The HypoDeg randomized, controlled, open-label, crossover trial.

AIM: To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). METHODS: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. RESULTS: Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100. CONCLUSIONS: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100.

Visit-to-visit variability of clinical risk markers in relation to long-term complications in type 1 diabetes.

BACKGROUND: Clinical characteristics such as HbA1c , systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. METHODS: This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA1c , SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR <15 ml/min/1.73 m2 , chronic dialysis or kidney transplantation; eGFR decline ≥30%; and mortality. Adjustment included age, sex, cholesterol, HbA1c , SBP, body mass index, smoking, albuminuria, eGFR, and mean, intercept, slope of respective exposure variables and regression models. RESULTS: SBP VV was significantly associated with CVE (adjusted hazard ratio per 50% increase, (CI 95%); p: 1.21 [1.05-1.39]; p = 0.008), ESKD (1.51 [1.16-1.96]; p = 0.002) and mortality (1.25 [1.09-1.44]; p = 0.002). HbA1c VV was significantly associated with mortality (1.51 [1.30-1.75]; p < 0.001); albuminuria VV with eGFR decline (1.14 [1.08-1.20]; p = 0.024) and ESKD (1.14 [1.02-1.27]; p < 0.001), but neither CVE nor mortality. Adjusted eGFR VV was not associated with endpoints. CONCLUSION: In type 1 diabetes, higher variability of basic clinical risk markers adds important risk stratification information for the development of micro- and macrovascular complications.

Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial.

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).

Effect of Metformin vs. Placebo in Combination with Insulin Analogues on Bone Markers P1NP and CTX in Patients with Type 2 Diabetes Mellitus.

Preclinical studies have shown a potential osteoanabolic effect of metformin but human studies of how metformin affects bone turnover are few. A post hoc sub-study analysis of an 18-month multicenter, placebo-controlled, double-blinded trial in type 2 diabetes mellitus (T2DM), randomizing participants to metformin versus placebo both in combination with different insulin analogue regimens (Metformin + Insulin vs. Placebo + Insulin). Patients were not treatment naive at baseline, 83% had received metformin, 69% had received insulin, 57.5% had received the combination of metformin and insulin before entering the study. Bone formation and resorption were assessed by measuring, N-terminal propeptide of type I procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX) at baseline and end of study. The influence of gender, age, smoking, body mass index (BMI), T2DM duration, glycosylated hemoglobin A1c (HbA1c), c-reactive protein (CRP) and insulin dosage was also included in the analyses. The levels of bone formation marker P1NP and bone resorption marker CTX increased significantly in both groups during the trial. P1NP increased less in the Metformin + Insulin compared to the placebo + insulin group (p = 0.001) (between group difference change), while the increases in CTX levels (p = 0.11) were not different. CRP was inversely associated (p = 0.012) and insulin dosage (p = 0.011) was positively related with change in P1NP levels. BMI (p = 0.002) and HbA1C (p = 0.037) were inversely associated with change in CTX levels. During 18 months of treatment with metformin or placebo, both in combination with insulin, bone turnover increased in both groups. But the pattern was different as the bone formation marker (P1NP) increased less during Metformin + Insulin treatment, while change in bone resorption (CTX) was not significantly different between the two groups.

Effect of 12 weeks continuous positive airway pressure on day and night arterial stiffness and blood pressure in patients with type 2 diabetes and obstructive sleep apnea: A randomized controlled trial.

The objective of this study was to evaluate the effect of continuous positive airway pressure treatment on pulse wave velocity and blood pressure in patients with type 2 diabetes and obstructive sleep apnea. A randomized controlled study was performed, including 72 patients with type 2 diabetes and newly diagnosed obstructive sleep apnea recruited from outpatient clinics at three Danish hospitals. The patients were randomized to continuous positive airway pressure for 12 weeks or no continuous positive airway pressure. Office measurements were performed at baseline, 4 weeks and 12 weeks. At baseline and 12 weeks, a 24-hr measurement of pulse wave velocity and blood pressure was performed. No significant change was observed in the primary outcome variable of carotid-femoral pulse wave velocity measured with SphygmoCor. With the Mobil-O-Graph, changes in office pulse wave velocity between the groups were significant: 0.3 m/s; 95% confidence interval, 0.1-0.6; p = .02. The group receiving continuous positive airway pressure had a larger decrease in pulse wave velocity than controls but none of the changes within the groups were significant. No significant change in ambulatory blood pressure was observed in any of the two groups after 12 weeks. In conclusion, continuous positive airway pressure treatment for 12 weeks does not significantly reduce pulse wave velocity or blood pressure in patients with type 2 diabetes and obstructive sleep apnea.

The impact of the glucagon-like peptide-1 receptor agonist liraglutide on natriuretic peptides in heart failure patients with reduced ejection fraction with and without type 2 diabetes.

AIM: To assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on urinary sodium excretion as well as on circulating adrenomedullin and copeptin levels in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In the LIVE study, patients (n = 241) with left ventricular ejection fraction ≤45% were randomized to liraglutide 1.8 mg daily or placebo for 24 weeks, and 30% had a concomitant diagnosis of T2D. Plasma levels of N-terminal brain-natriuretic-peptide (NT-proBNP) (a predefined secondary endpoint), midregional pro-atrial-natriuretic-peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM) and copeptin were measured at baseline and after 24 weeks in this substudy. The potential effect modification of T2D was assessed. RESULTS: In the eligible subgroup of 231 patients with available biomarkers (115 randomized to liraglutide and 116 to placebo), MR-proANP decreased by 12% (P = .002) and NT-proBNP by 9% (P = .009) during liraglutide treatment compared with placebo at week 24. Interaction with T2D for the treatment effect of change in MR-proANP and NT-proBNP levels was P = .003 and P = .03, respectively. Consequently, in patients with T2D, liraglutide decreased MR-proANP by 27% (P < .001) and NT-proBNP by 25% (P = .02) compared with placebo, whereas no change was observed in patients without T2D. There was no effect of liraglutide on MR-proADM (P = .10) or copeptin (P = .52). CONCLUSION: Liraglutide decreased the A- and B-type natriuretic peptides significantly in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant T2D, suggesting a beneficial mechanism of liraglutide in T2D patients with HFrEF.

Heart rate increases in liraglutide treated chronic heart failure patients: association with clinical parameters and adverse events.

Background. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. Methods. This was a sub-study of the LIVE study. CHF patients (N = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms (N = 117) and readouts from cardiac implanted electronic devices (N = 20) were analysed for HR and arrhythmias. Results. In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all p<.005). Increases in HR correlated with liraglutide dose (p=.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes. Conclusions. During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.

Progression in risk factors during 36 years of follow-up and prediction of carotid intima-media thickness in a large cohort of adults with and without diabetes.

Carotid intima-media thickness (IMT) can assess the cumulative effect of atherosclerotic risk factors and provides an independent predictor of future cardiovascular (CV) risk. The aim of this study was to investigate the progression of conventional risk factors in 933 long-term survivors from a Danish cohort with and without diabetes mellitus (DM) as predictors for attained carotid IMT during 35.6 (0.7) years of follow-up. Persons who participated in the first, the last and one of the intermediate rounds of the Copenhagen City Heart Study, and who had had an ultrasound-derived measure of the carotid IMT performed at the last examination were included in the analyses. The risk factors varied between persons with and without DM during the 36 years, but the difference in blood pressure disappeared in the fifth examination, where, in addition, total cholesterol was found to be lower in persons with DM. In this cohort there were no difference in attained carotid IMT between persons with and without DM at the last examination. The following risk factors were found to best predict carotid IMT: age, maximum systolic BP, average systolic BP, average BMI, minimum BMI, sex and years of smoking. The prediction of carotid IMT was clinically poor with a root mean-squared error of prediction (RMSEP) of 0.134 mm and a 95% prediction error probability interval of (-0.22; 0.30). Furthermore, the distribution of prediction errors was skewed to the right indicating that the prediction errors were larger among persons with high carotid IMT.

Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study.

BACKGROUND: The glucagon-like peptide-1 analog liraglutide increases heart rate and may be associated with more cardiac events in chronic heart failure (CHF) patients. We studied whether this could be ascribed to effects on myocardial glucose uptake (MGU), myocardial blood flow (MBF) and MBF reserve (MFR). METHODS AND RESULTS: CHF patients with left ventricular ejection fraction ≤45% and without type 2 diabetes were randomized to liraglutide (N = 18) 1.8 mg once daily or placebo (N = 18) for 24 weeks in a double-blinded design. Changes in MGU during an oral glucose tolerance test (OGTT) and changes in MBF and MFR from baseline to follow-up were measured quantitatively by 18F-FDG and 15O-H2O positron emission tomography. Compared with placebo, liraglutide reduced weight (P = 0.03), HbA1c (P = 0.03) and the 2-hour glucose value during the OGTT (P = 0.004). Despite this, changes in MGU (P = 0.98), MBF (P = 0.76) and MFR (P = 0.89) from baseline to follow-up did not differ between groups. Furthermore, there was no association between the level of insulin resistance at baseline and changes in MGU in patients treated with liraglutide. CONCLUSION: Liraglutide did not affect MGU, MBF, or MFR in non-diabetic CHF patients. Any potential increase in cardiac events in these patients seems not to involve changes in MGU, MBF, or MFR. TRIAL REGISTRATION: Trial registry: http://www.ClinicalTrials.org . Identifier: NCT01472640. Url: https://clinicaltrials.gov/ct2/show/NCT01472640?term=NCT01472640&rank=1.

The effect of insulin degludec on risk of symptomatic nocturnal hypoglycaemia in adults with type 1 diabetes and high risk of nocturnal severe hypoglycaemia (the HypoDeg trial): study rationale and design.

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.

Intermittent vacuum treatment with VacuMed does not improve peripheral artery disease or walking capacity in patients with intermittent claudication.

To assess distal blood pressures (BPs) in ankle and toe, walking capacity, intermittent claudication symptoms, physical activity and self-rated health after intermittent vacuum treatment (IVT) for peripheral artery disease (PAD). Forty-eight patients with PAD were randomised to either a control (C)-group with lifestyle changes or lifestyle changes in combination with VacuMed® treatment thrice weekly for 6 weeks. Ankle and toe BPs were measured before, after 6 weeks of intervention and after 6 weeks follow-up. Walking capacity, intermittent claudication symptoms, physical activity and self-rated health (Likert scale) were also assessed. The ankle to brachial index (ABI) and BPs in the ankle and toe decreased after 6 and 12 weeks in both groups with no difference between the groups. In the legs with the lowest ABI at baseline in each patient, there were no differences regarding ABI, BPs and toe-systolic BP index between the groups after either the intervention or the follow-up period. The BPs decreased in both groups. The walking distance and the time to pain were unchanged in the IVT-group and increased in the C-group after the follow-up period, but without any significant differences between the groups. The level of objectively tested physical activity and self-rated health remained unchanged throughout the study in both the IVT- and the C-group. There were no differences between the changes of the self-rated health data during the study period between the IVT- and the C-group. VacuMed® had no effect per se on distal blood pressures, walking capacity, intermittent claudication symptoms, physical activity and self-rated health.

Carotid intima media thickness and ankle brachial index are inversely associated in subjects with and without diabetes.

Carotid intima-media thickness (IMT) and ankle brachial index (ABI) are non-invasive indicators of generalised atherosclerosis. The aim was to determine the association between carotid IMT and ABI in subjects with and without diabetes mellitus (DM), and to analyse specific age change-points. We included 2744 subjects from the Copenhagen City Heart Study (mean age (SD) 56.6 (17.2) years, 56.8% women and body mass index (BMI) 25.4 (4.1) kg/m2). Carotid IMT and ABI measurements were performed during the fifth examination. Of the 2744 subjects, 125 subjects (4.6%) had DM. Average carotid IMT was 0.667 (0.145) mm and ABI was 1.06 (0.14). Subjects with DM were older, had higher BMI and systolic blood pressure (SBP) (all p < .001). Carotid IMT was higher in subjects with DM (0.754 (0.150) mm) compared to subjects without DM (0.662 (0.144) mm) (p < .001), whereas there was no difference in ABI between the two groups. ABI was inversely associated with carotid IMT (slope = -0.17 [-0.207; -0.137] (p < .001). The association remained significant after adjustment for risk factors both in subjects with DM (slope = -0.168 [-0.328; -0.007], p = .040), and in subjects without DM (slope = -0.100 [-0.148; -0.052], p < .001), with a stronger effect of carotid IMT on ABI among subjects with DM. Carotid IMT and ABI were inversely associated in subjects with DM and without DM, but with a stronger effect in subjects with DM. Age and ABI revealed a change-point with a stronger inverse association among subjects aged >60 years.

Plasma high-sensitivity troponin T predicts end-stage renal disease and cardiovascular and all-cause mortality in patients with type 1 diabetes and diabetic nephropathy.

High-sensitivity troponin T (hsTnT) is a marker of cardiovascular disease (CVD) and in type 2 diabetes also a marker of renal events, but has not been evaluated in type 1 diabetics. We therefore reviewed a type 1 diabetes cohort of 442 without and 458 with diabetic nephropathy. Baseline samples were analyzed for hsTnT levels. Cox regression analyses assessed predictive value in relation to the development of end-stage renal disease (ESRD) in 99 patients, all-cause mortality in 178, and CVD events in 134 after up to 12 years of follow-up. To assess if hsTnT improved risk prediction beyond traditional clinical risk markers, we calculated c statistics and relative integrated discrimination improvement. HsTnT was significantly higher in patients with diabetic nephropathy compared to normoalbuminuria (median 8.9 vs 3.1 ng/L). For a doubling in hsTnT levels, and after adjustment for well-known risk factors, including NT-proBNP and hsCRP, the hazard ratio for ESRD at 1.26 was not significant in the diabetic nephropathy group, but there was a significant association with GFR decline after adjustment during follow-up (2.9 ml/min/1.73 m2 annual decline per doubling in hsTnT). The unadjusted and adjusted hazard ratios for mortality (1.64 and 1.32, respectively) were significant in patients with, but not for patients without, nephropathy. Adjusted hazard ratios for fatal and non-fatal CVD events were significant for the whole cohort (1.13), and those with nephropathy (1.14), but not significant for normoalbuminuria (1.06). Addition of hsTNT to traditional risk factors significantly increased the area under the curve by 0.01 in a receiver-operating characteristic curve for mortality. The relative integrated discrimination improvement was increased 15.7% for mortality, 6.3% for CVD, and 1.9% for ESRD (all significant). Thus, higher hsTnT is an independent predictor of renal decline and cardiovascular events in patients with type 1 diabetes and diabetic nephropathy.

Circulating matrix metalloproteinases are associated with arterial stiffness in patients with type 1 diabetes: pooled analysis of three cohort studies.

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 [ß 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 [ß 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.

Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes.

We investigated the short-term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m2 ) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24-week double-blinded, placebo-controlled trial. At baseline and after 24 weeks of treatment, 24-hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima-media thickness were evaluated. Compared with placebo, liraglutide increased 24-hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night-time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long-standing type 1 diabetes, liraglutide as add-on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.

Infrared thermographic assessment of changes in skin temperature during hypoglycaemia in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Hypoglycaemia is associated with reduced skin temperature (Ts). We studied whether infrared thermography can detect Ts changes during hypoglycaemia in patients with type 1 diabetes and how the Ts response differs between patients with normal hypoglycaemia awareness and hypoglycaemia unawareness. METHODS: Twenty-four patients with type 1 diabetes (ten aware, 14 unaware) were studied during normoglycaemia (5.0-6.0 mmol/l), hypoglycaemia (2.0-2.5 mmol/l) and during recovery from hypoglycaemia (5.0-6.0 mmol/l) using hyperinsulinaemic glucose clamping. During each 1 h phase, Ts was measured twice by infrared thermography imaging in pre-defined areas (nose, glabella and the five left fingertips), symptoms of hypoglycaemia were scored and blood was sampled. RESULTS: Ts decreased during hypoglycaemia on the nose and glabella. The highest decrements were recorded on the nose (aware: -2.6 °C, unaware: -1.1 °C). In aware patients, the differences in temperature were statistically significant on both nose and glabella, whereas there was only a trend in the unaware group. There was a significant difference in hypoglycaemia-induced temperature changes between the groups. Patients in the aware group had higher hypoglycaemia symptom scores and higher adrenaline (epinephrine) levels during hypoglycaemia. CONCLUSIONS/INTERPRETATION: The hypoglycaemia-associated decrement in Ts can be assessed by infrared thermography and is larger in patients with normal hypoglycaemia awareness compared with unaware patients.

SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes.

AIMS/HYPOTHESIS: The genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy. METHODS: We performed a genome-wide association study using 1000 Genomes-based imputation to compare type 1 diabetic nephropathy cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease. RESULTS: None of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p < 10(-5)) were then sought for first-stage analysis in the Genetics of Kidneys in Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were consistently and significantly (p < 10(-4)) associated with diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95% CI 0.60, 0.82). However, this association was not observed in a second stage with two additional diabetic nephropathy cohorts, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK and Republic of Ireland (UK-ROI; p = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; p = 0.44) studies, totalling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analysed rs1326934-C allele OR for diabetic nephropathy was 0.83 (95% CI 0.72, 0.96; p = 0.009). CONCLUSIONS/INTERPRETATION: These data suggest that SORBS1 might be a gene involved in diabetic nephropathy.

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes.

AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.