Summary Background We assessed whether overnight home use of automated closed loop insulin delivery (artificial pancreas) improves glucose control. Methods We studied 24 adults with type 1 diabetes in a multicentre crossover study design comparing four weeks of overnight closed loop using a model predictive control algorithm to direct insulin delivery, with four weeks of insulin pump therapy in which participants used real-time display of continuous glucose monitoring independent of their pumps as control. Primary outcome was time when glucose was in the target range of 3·9 and 8·0mmol/l between midnight to 07:00. Analyses were by intention to treat. Trial registration ClinicalTrials.gov NCT01440140. Findings Closed loop was utilised over median 8·3 (interquartile range 6·0, 9·6)hours on 555nights (86%). Proportion of time when overnight glucose was in target range was significantly higher during closed loop compared to control by 13·5% (95% CI, 7·3–19·7; p<0·001). Mean overnight glucose (8·2±0·9 vs. 9·0±1·3mmol/l; p=0·005) and time spent above target (44·3%±11·9 vs. 57·1%±15·6; p=0·001) were significantly lower during closed loop. Time spent below target was low and comparable [1·8%(0·6, 3·6) vs. 2·1%(0·7, 3·9); p=0·28]. Lower mean overnight glucose was brought about by increased overnight insulin delivery [6·4 (4·5, 8·1) vs. 4·9 (3·7, 6·3)units; p<0·001) without changing the total daily insulin amount [34·5 (29·3, 48·4) vs. 35·4 (29·7, 45·2)units; p=0·32]. No severe hypoglycaemia episodes occurred during control period and two during closed loop not related to algorithm instructions. Interpretation Unsupervised overnight closed loop at home is feasible and may improve glucose control in adults with type 1 diabetes.

This study in healthy, glucose-tolerant humans shows for the first time different ABS rates during OGTT in women and men and a negative relationship between body height and gut glucose half-life. Prolonged ABS in females might therefore contribute to higher plasma glucose concentrations at the end of OGTT.

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Background Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026). Conclusions GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.

Aims/hypothesis The first-degree offspring of patients with type 2 diabetes are prone to develop type 2 diabetes, and have both insulin resistance and beta cell impairment. However, it is still unclear whether both pathophysiological features are inseparably combined and which is the outstanding determinant in the offspring. Methods Glucose metabolism, insulin sensitivity (calculated as M value divided by insulin [M/I]) and beta cell function were studied in the offspring of individuals with type 2 diabetes (n=187; 57% females; age 43.8±8.1 years; BMI 26.8±4.5 kg/m 2 ) and in individuals without a family history of type 2 diabetes (controls, n=519, 55% females; age 43.4± 8.2 years; BMI 26.4± 3.7 kg/m 2 , no significant differences between the groups for any characteristic) by performance of 75 g OGTT and 2 h hyperinsulinaemic (40 mU min −1 m −2 )-isoglycaemic clamp tests. Beta cell function was evaluated by calculating insulinogenic index (IGI) from C-peptide AUC:glucose AUC ratios from the first hour of OGTT (IGI[60 min]) and from the total OGTT (IGI[120 min]). Results During the OGTT, the offspring of individuals with type 2 diabetes showed 4-14% higher plasma glucose from 30 to 120 min (p<0.05) and 20-29% higher serum insulin from 90 to 120 min, but decreased IGI(60 min) and IGI (120 min) (p<0.05). M/I was 11% lower in the offspring of affected individuals than in controls (p<0.01). To study the offspring of patients with type 2 diabetes with insulin sensitivity similar to that of the control group, the offspring of affected patients were divided into M/I quartiles. Those in the third M/I quartile showed M/I values and major anthropometric characteristics similar to those of the controls, but insulin AUC and C-peptide AUC values were lower in the first hour and the total OGTT (p<0.05). The third M/I quartile had lower IGI values at 60 min and 120 min: 11% and 14% lower, respectively (p<0.02). Conclusions/interpretation The first-degree offspring of type 2 diabetic patients show insulin resistance and beta cell dysfunction in response to oral glucose challenge. Beta cell impairment exists in insulin-sensitive offspring of patients with type 2 diabetes, suggesting beta cell dysfunction to be a major defect determining diabetes development in diabetic offspring.

OBJECTIVE To develop and pilot a novel intervention addressing motivational and cognitive barriers to avoiding hypoglycemia in people with type 1 diabetes and persistent impaired awareness of hypoglycemia (IAH) despite training in flexible insulin therapy. RESEARCH DESIGN AND METHODS A 6-week intervention using motivational interviewing and cognitive behavioral techniques was designed. Diabetes educators were trained and supported in its delivery to 23 people with IAH (Gold score ‡4). RESULTS Twelve months postcourse, hypoglycemia awareness had improved (P < 0.001). Median (range) rates of severe hypoglycemia (SH) fell from 3 (0-104) to 0 (0-3) per person per year (P < 0.0001) and moderate from 14 (0-100) to 0 (0-18) per person per 6 weeks (P < 0.001). Worry and behavior around hyperglycemia improved. HbA 1c was unchanged. CONCLUSIONS A pilot intervention targeting motivation and cognitions around hypoglycemia engaged patients with resistant IAH and recurrent SH and was associated with significant improvement, supporting the hypothesis that these factors underpin problematic hypoglycemia. Hypoglycemia and fear of hypoglycemia remain major barriers to achieving optimal glucose control and quality of life for people with type 1 diabetes. Structured education in flexible insulin therapy (e.g., the U.K.'s Dose Adjustment for Normal Eating [DAFNE]) and/or use of insulin pump therapy reduces severe hypoglycemia (SH) (1), but some continue to experience impaired awareness of hypoglycemia (IAH) with high rates of SH, their problematic hypoglycemia resistant to intervention. We hypothesized that many such people have motivational and cognitive barriers to hypoglycemia avoidance and resolution of IAH. We designed and piloted an intervention using motivational interviewing and cognitive behavioral theory targeting these barriers.

AimsThe relevance of lipoprotein(a) [Lp(a)] concentrations and low-molecular-weight (LMW) apo(a) phenotypes in peripheral arterial disease (PAD) has only been investigated by few studies. Therefore, we analysed this association in three independent cohorts and performed a Mendelian Randomization approach using instrumental variable regression.Methods and resultsLp(a) concentrations, apo(a) phenotypes, and one SNP in the LPA gene (rs10455872) were measured in the CAVASIC study, including 241 male patients with intermittent claudication and 246 age- and diabetes-matched controls as well as in the two population-based studies KORA F3 (n = 3184) and KORA F4 (n = 3080). In KORA F3/F4, 109/80 persons suffered from intermittent claudication, 200/144 from PAD, and 128/103 showed an ankle–brachial index (ABI) <0.9. In CAVASIC, adjusted logistic regression analyses revealed significant associations between an increase of log-Lp(a) per one standard deviation (SD) (OR = 1.28, P = 0.02) as well as LMW apo(a) phenotypes and symptomatic PAD (OR = 1.65, P = 0.03). Linear regression models with continuous ABI showed a significant association in the combined analyses of KORA F3/F4: an increase in log-Lp(a) per one SD (β = −0.006, P = 0.005) and the presence of LMW apo(a) phenotypes (β = −0.011, P = 0.02) or the minor allele of rs10455872 (ß = −0.016, P = 0.03) were associated with a decrease in ABI in the fully adjusted linear and instrumental variable regression models.ConclusionAnalyses in three independent populations showed significant associations of Lp(a) concentrations, LMW apo(a) phenotypes, and rs10455872 with PAD. This points to a causal relationship between Lp(a) and PAD since the genetically determined apo(a) phenotypes and SNP alleles are indeed associated with PAD.

Statement of all funding sources: BMBF Kompetenznetz Diabetes mellitus (FKZ 01GI1106); DZD; EFSD, BMBF Kompetenznetz Adipositas (FKZ01GI1130)Conflicts of interest The authors have no conflict of interest to declare.Key words: double diabetes, T1DM, diabetes mellitus type 1, insulin resistance, diabetic nephropathy, macroangiopathy, microangiopathy, coronary heart disease, LADA Novelty statement: The outlined paper analyzes 392 diabetes centers with 31119 patients with autoimmune diabetes for the prevalence and comorbidities of double diabetes. We could show for the first time that insulin requirement or insulin resistance is an independent risk factor for patients with type 1 diabetes and that even in well controlled diabetes an additional metabolic syndrome is a major risk factor for developing macrovascular as well as microvascular complications. Aim of this cross sectional study is to better estimate the prevalence of MS in T1DM, and to assess its association with comorbidities. AbbreviationsMethods: Data of 31119 persons with autoimmune diabetes mellitus were analyzed for signs of MS and presence of late complications. Double diabetes was defined as T1DM coexisting with MS (obesity, hypertension, dyslipidemia). Multiple linear or logistic regression analyses were performed to identify associations between double diabetes and late complications.Results: 25.5% (n=7926) of persons with T1DM presented additionally the MS. Persons with double diabetes showed significantly more macrovascular comorbidities (coronary heart disease 8.0 versus 3.0% w/o MS, stroke 3.6 versus 1.6%, diabetic foot syndrome 5.5% versus 2.1%).Also microvascular diseases were increased in people with double diabetes (retinopathy 32.4% versus 21.7%, nephropathy 28.3% versus 17.8%). Both macrovascular and microvascular comorbidities were increased independent of glucose control, even if patients with good metabolic control (HbA1c <7.0%, 53mmol/mol) showed significantly less macrovascular (coronary heart disease 2.3% versus 1.8%, p<0.0001) and microvascular problems (retinopathy 8.7% versus 6.6%, p<0.0001).Conclusions: Double diabetes seems to be an independent and important risk factor for persons with T1DM in developing macrovascular and microvascular comorbidities. Therefore, patients should be identified and development of MS should be avoided. Longtermstudies are needed to observe the effect of insulin resistance on patients with autoimmune diabetes.