2. afroz,afsana, alramadan,mohammed j., hossain,md nassif, et al. cost-of-illness of type 2 diabetes...

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1. Adeloye,Davies, Kit,Yee Chan, Thorley,Natasha, et al. Global and regional estimates of the morbidity due to type I diabetes among children aged 0-4 years: a systematic review and analysis. J GLOBAL HEALTH. 2018 8 2 1-12.Background: Epidemiology of type 1 diabetes mellitus (T1DM) among children aged 0-4 years globally is not well understood. We aim to assess the incidence of T1DM in low- and middle-income countries (LMIC) by conducting a systematic review of previous reports. We also aim to address possible contribution to child mortality and to identify any temporal trends.Methods: A systematic review was performed using a carefully designed search strategy to explore MEDLINE, EMBASE and Global Health databases. Data was extracted from all studies that satisfied the inclusion criteria -a total of 83 records extracted from 26 830 sources that were analysed. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process to assess quality of evidence and applied meta-analysis approaches to assess global and regional incidence and time trends.Results: The overall pooled incidence of T1DM in children aged 0-4 years globally is 11.2 (95% CI = 10.0-12.3) per 100 000 child years. The regional incidence were the highest for European Region A (EUR A) at 15.5 (95% CI = 13.5-17.5) per 100 000 child years. EUR C had the incidence of 10.0 (95% CI = 6.5-13.6) and EUR B 5.8 (95% CI = 4.7-7.0), Region of the Americas A (AMR A) 11.4 (95% CI = 7.8-14.9), AMR B of 2.5 (95% CI = 0.2-4.8), Eastern Mediterranean Region (EMR B) 7.1 (95% CI = 4.2-10.0) and Western Pacific Region (WPR A) 7.0 (95% CI = 2.9-11.0) per 100 000 child years, while other regions had very low rates or no data. When data points were categorised in the study periods and re-analysed, an increasing trend of the T1DM incidence was observed, with the incidence of 20.9 (95% CI = 7.8-34.1) per 100 000 child years in the years 2010-2015, preceded by 13.2 (95% CI = 11.0-15.5) in 2000-2009 study period, 10.0 (95% CI = 8.4-11.7) in 1990-1999 and 8.3 (95% CI = 5.1-11.6) in 1980-1989, respectively. Although the data are scarce, and variation and uncertainty are large, we estimated that the number of new cases of T1DM among children aged 0-4 years in the world each year is between 100 000 and 150 000.Conclusions: The identified large variation in incidence estimates for different parts of the world, along with scarcity of information and the identified strong temporal increase in T1DM incidence suggest a clear need for further research into this subject.

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2. Afroz,Afsana, Alramadan,Mohammed J., Hossain,Md Nassif, et al. Cost-of-illness of type 2 diabetes mellitus in low and lower-middle income countries: a systematic review. BMC Health Serv.Res. 2018 18 1 972-972.Background: Diabetes is one of the world's most prevalent and serious non-communicable diseases (NCDs). It is a leading cause of death, disability and financial loss; moreover, it is identified as a major threat to global development. The chronic nature of diabetes and its related complications make it a costly disease. Estimating the total cost of an illness is a useful aid to national and international health policy decision making. The aim of this systematic review is to summarise the impact of the cost-of-illness of type 2 diabetes mellitus in low and lower-middle income countries, and to identify methodological gaps in measuring the cost-of-illness of type 2 diabetes mellitus.; Methods: This systematic review considers studies that reported the cost-of-illness of type 2 diabetes in subjects aged 18 years and above in low and lower-middle income countries. The search engines MEDLINE, EMBASE, CINAHL, PSYCINFO and COCHRANE were used form date of their inception to September 2018. Two authors independently identified the eligible studies. Costs reported in the included studies were converted to US dollars in relation to the dates mentioned in the studies.; Results: The systematic search identified eight eligible studies conducted in low and lower-middle income countries. There was a considerable variation in the costs and method used in these studies. The annual average cost (both direct and indirect) per person for treating type 2 diabetes mellitus ranged from USD29.91 to USD237.38, direct costs ranged from USD106.53 to USD293.79, and indirect costs ranged from USD1.92 to USD73.4 per person per year. Hospitalization cost was the major contributor of direct costs followed by drug costs.; Conclusion: Type 2 diabetes mellitus imposes a considerable economic burden which most directly affects the patients in low and lower-middle income countries. There is enormous scope for adding research-based evidence that is methodologically sound to gain a more accurate estimation of cost and to facilitate comparison between studies.

3. Auzanneau,Marie, Lanzinger,Stefanie, Bohn,Barbara, et al. Area Deprivation and Regional Disparities in Treatment and Outcome Quality of 29,284 Pediatric Patients With Type 1 Diabetes in Germany: A Cross-sectional Multicenter DPV Analysis. Diabetes Care. 2018 41 12 2517-2525.Objective: This study analyzed whether area deprivation is associated with disparities in health care of pediatric type 1 diabetes in Germany.Research Design and Methods: We selected patients



significant.Conclusions: Area deprivation was associated not only with key outcomes in pediatric type 1 diabetes but also with treatment modalities. Our results show, in particular, that the access to CGMS and CSII could be improved in the most deprived regions in Germany. Order.

4. Barlovic,Drazenka Pongrac, Harjutsalo,Valma, Gordin,Daniel, et al. The Association of Severe Diabetic Retinopathy With Cardiovascular Outcomes in Long-standing Type 1 Diabetes: A Longitudinal Follow-up. Diabetes Care. 2018 41 12 2487-2494.Objective: It is well established that diabetic nephropathy increases the risk of cardiovascular disease (CVD), but how severe diabetic retinopathy (SDR) impacts this risk has yet to be determined.Research Design and Methods: The cumulative incidence of various CVD events, including coronary heart disease (CHD), peripheral artery disease (PAD), and stroke, retrieved from registries, was evaluated in 1,683 individuals with at least a 30-year duration of type 1 diabetes drawn from the Finnish Diabetic Nephropathy Study (FinnDiane). The individuals were divided into four groups according to the presence of diabetic kidney disease (DKD) and/or SDR (+DKD/+SDR, +DKD/-SDR, -DKD/+SDR, and -DKD/-SDR) at baseline visit. Furthermore, age-specific incidences were compared with 4,016 control subjects without diabetes. SDR was defined as laser photocoagulation and DKD as estimated glomerular filtration rate



anxiety, and sleep measures also improved significantly after intervention.Conclusions: CGM with remote monitoring was found to improve multiple measures of quality of life, reduce family stress, and improve parental sleep. Order.

6. Chow,Elaine, Iqbal,Ahmed, Walkinshaw,Emma, et al. Prolonged Prothrombotic Effects of Antecedent Hypoglycemia in Individuals With Type 2 Diabetes. Diabetes Care. 2018 41 12 2625-2633.Objective: Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes.Research Design and Methods: Twelve individuals with type 2 diabetes with no history of CV disease and 11 age- and BMI-matched volunteers without diabetes underwent paired hyperinsulinemic-euglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy.Results: Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased Δ 1.15 ± 0.28 fibers/μm2 at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only.Conclusions: Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short- and medium-term risk of CV mortality.

7. Dhalwani,N. N., Zaccardi,F., Davies,M. J. and Khunti,K. Body mass index and mortality in people with and without diabetes: A UK Biobank study. Nutr.Metab.Cardiovasc.Dis. 2018 28 12 1208-1216.Background and Aims: To investigate the association of body mass index with all-cause, cardiovascular and cancer mortality in individuals with and without diabetes.Methods and Results: We used data on 490,852 participants from the UK Biobank, with linkage to national mortality data between 2006 and 2016. Using Cox regression, we calculated hazard ratios (HRs) and 95% confidence intervals (95%CI) for all-cause, cardiovascular and cancer mortality within body mass index categories in people with and without diabetes adjusting for potential confounders. 24,789 (5.0%) participants reported having diabetes at baseline. Over a median follow-up of 6.9 years, 13,896 participants died, of which 1800 had diabetes. Compared with normal body mass index (18.5-24.9 kg/m2), mortality risk in the overweight group (25.0-29.9 kg/m2) was 33% lower in people with diabetes (HR 0.67, 95%CI 0.62-0.73) and 12% lower in participants without (HR 0.88, 95%CI 0.85-0.90). For class I obesity (30.0-34.9 kg/m2), mortality risk was 35% lower in participants with diabetes (HR 0.65, 95%CI 0.59-0.71) and 5% lower in participants without (HR 0.95, 95%CI 0.91-0.99). For class III obesity (≥40 kg/m2), there was a 10% non-significant lower mortality risk compared to normal body mass index in people with diabetes (HR 0.90, 95%CI 0.77-

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1.05); in contrast, the risk was 29% higher in people without diabetes (HR 1.29, 95%CI 1.13-1.45). Similar patterns were observed for cardiovascular mortality but not for cancer mortality.Conclusion: The impact of obesity on the risk of mortality was dependent on the presence of diabetes: for the same level of obesity, mortality risk was higher in people without diabetes compared to those with diabetes.

8. Ehrmann,Dominic, Kulzer,Bernhard, Schipfer,Melanie, Lippmann-Grob,Bernhard, Haak,Thomas and Hermanns,Norbert. Efficacy of an Education Program for People With Diabetes and Insulin Pump Treatment (INPUT): Results From a Randomized Controlled Trial. Diabetes Care. 2018 41 12 2453-2462.Objective: Continuous subcutaneous insulin infusion (CSII) is the most advanced form of insulin delivery, but it requires structured education to provide users with the necessary knowledge/skills and to support their motivation. Currently, no structured education program designed to provide this training has been evaluated. We developed a CSII-specific, structured education program (Insulin Pump Treatment INPUT]) and evaluated its impact on glycemic control, behavior, and psychosocial status.Research Design and Methods: This was a multicenter, randomized, parallel trial with a 6-month follow-up. Eligible participants (age 16-75 years) currently were treated with insulin pump therapy. Participants were randomly assigned (1:1) to the INPUT program or to usual care using a computer-generated algorithm, with study center as the stratification factor. The primary outcome was HbA1c change from baseline to 6 months. Secondary outcomes were incidence of severe hypoglycemia and changes in behavioral and psychosocial measures.Results: Between 1 April 2016 and 26 April 2016, 268 people with diabetes and a mean duration of CSII therapy of 9.5 years were randomly assigned to the INPUT group (n = 135) or control group (n = 133). At 6 months, HbA1c improved in the INPUT group (8.33 ± 0.8 vs. 8.04 ± 0.9; P < 0.0001) but not in the control group (8.33 ± 1.0 vs. 8.27 ± 1.0; P = 0.11). The between-group difference in HbA1c reduction was significant, favoring INPUT (-0.28% vs. -0.06%, Δ -0.22%, 95% CI -0.38 to -0.06; P = 0.0029). The incidence rate ratio of severe hypoglycemia was 3.55 times higher for participants in the control group than for those in the INPUT group (95% CI 1.50-8.43; P = 0.0041).Conclusions: The INPUT education program led to a significant improvement in glycemic control and incidence of severe hypoglycemia in insulin pump users. Order.

9. ELDerawi,Wafaa A., Naser,Ihab A., Taleb,Mahmmoud H. and Abutair,Ayman S. The Effects of Oral Magnesium Supplementation on Glycemic Response among Type 2 Diabetes Patients. Nutrients. 2018 11 1 Background: Magnesium (Mg) supplementation may help control glycemic response among type 2 diabetes (T2D) patients.; Objective: This study means to determine whether Mg supplementation improves glycemic control indicators in patients with T2D.; Methods: After one week of the dietary stabilization phase, 42 T2D patients were stratified according to sex, age, fasting blood sugar (FBS) and Mg levels and then randomly allocated into two groups. The intervention group was on 250 mg/day of elemental Mg for three months while the control group did not receive any type of supplements throughout the intervention period.; Results: The daily administration of 250 mg of elemental Mg indicated a significant improvement in HbA1C (8.32 to 7.96%, p < 0.001), insulin levels (IL) (15.56 to 12.18 μIU/mL, p < 0.001), C-peptide (2.28 to 1.90 ng/mL, p = 0.001), HOMA.IR (6.16 to 4.44, p < 0.001) and HOMA.β% (59.99 to 52.37, p = 0.036) of the intervention group when compared with the control group after three

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months of intervention.; Conclusion: The results of this study revealed that oral Mg supplementation reduces insulin resistance and improves the glycemic control indicators among T2D patients.; Trial Registration: current controlled trials PHRC/HC/32/15. Registered 5 October 2015.

10. Feig,Denice S., Corcoy,Rosa, Donovan,Lois E., et al. Pumps or Multiple Daily Injections in Pregnancy Involving Type 1 Diabetes: A Prespecified Analysis of the CONCEPTT Randomized Trial. Diabetes Care. 2018 41 12 2471-2479.Objective: To compare glycemic control, quality of life, and pregnancy outcomes of women using insulin pumps and multiple daily injection therapy (MDI) during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT).Research Design and Methods: This was a prespecified analysis of CONCEPTT involving 248 pregnant women from 31 centers. Randomization was stratified for pump versus MDI and HbA1c. The primary outcome was change in HbA1c from randomization to 34 weeks' gestation. Key secondary outcomes were continuous glucose monitoring (CGM) measures, maternal-infant health, and patient-reported outcomes.Results: At baseline, pump users were more often in stable relationships (P = 0.003), more likely to take preconception vitamins (P = 0.03), and less likely to smoke (P = 0.02). Pump and MDI users had comparable first-trimester glycemia: HbA1c 6.84 ± 0.71 vs. 6.95 ± 0.58% (51 ± 7.8 vs. 52 ± 6.3 mmol/mol) (P = 0.31) and CGM time in target (51 ± 14 vs. 50 ± 13%) (P = 0.40). At 34 weeks, MDI users had a greater decrease in HbA1c (-0.55 ± 0.59 vs. -0.32 ± 0.65%, P = 0.001). At 24 and 34 weeks, MDI users were more likely to achieve target HbA1c (P = 0.009 and P = 0.001, respectively). Pump users had more hypertensive disorders (P = 0.011), mainly driven by increased gestational hypertension (14.4 vs. 5.2%; P = 0.025), and more neonatal hypoglycemia (31.8 vs. 19.1%, P = 0.05) and neonatal intensive care unit (NICU) admissions >24 h (44.5 vs. 29.6%; P = 0.02). Pump users had a larger reduction in hypoglycemia-related anxiety (P = 0.05) but greater decline in health/well-being (P = 0.02).Conclusions: In CONCEPTT, MDI users were more likely to have better glycemic outcomes and less likely to have gestational hypertension, neonatal hypoglycemia, and NICU admissions than pump users. These data suggest that implementation of insulin pump therapy is potentially suboptimal during pregnancy.

11. Fortin,A., Rabasa-Lhoret,R., Lemieux,S., Labonté,M. -E and Gingras,V. Comparison of a Mediterranean to a low-fat diet intervention in adults with type 1 diabetes and metabolic syndrome: A 6-month randomized trial. Nutr.Metab.Cardiovasc.Dis. 2018 28 12 1275-1284.Background and Aims: The metabolic syndrome (MS) is an emerging complication in patients with type 1 diabetes (T1D), with no preventive or therapeutic treatment reported yet. We wanted to compare the impact of two 6-month nutritional interventions, based on a Mediterranean (MED) or a low-fat diet, on waist circumference, anthropometric and metabolic outcomes in patients with both T1D and the MS.Methods and Results: Participants were randomized into 2 intervention groups: 1) MED-diet or 2) low-fat diet. The 6-month study included 9 teaching sessions with a registered dietitian. Anthropometric (primary outcome: waist circumference), metabolic and nutritional assessments were performed at inclusion, 3 and 6-month. We used mixed effects models to assess the effects of both interventions. 28 participants were included (50.9 ± 10.3 years old) with a mean BMI of 30.7 ± 3.3 kg/m2 and a waist circumference of 105.5 ± 8.9 cm at inclusion. A trend towards a greater reduction of

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dietary fat intakes in the low-fat diet group was observed (P-interaction = 0.09). Waist circumference was reduced at 6-month in both groups (-3.5 cm low-fat; -1.5 cm MED-diet) with no significant difference between groups (P-interaction = 0.43). Body mass index also significantly decreased in both groups (-0.7 kg/m2 low-fat; -1.1 kg/m2 MED-diet; P-interaction = 0.56). No significant differences between groups were observed for other metabolic parameters.Conclusions: This study suggests that a 6-month non-restrictive dietary intervention in patients with T1D and MS could contribute to weight management, without significant differences between interventions for anthropometric and metabolic parameters. Further studies should investigate the long-term benefits of these diets.

12. Fullerton,Birgit, Siebenhofer,Andrea, Jeitler,Klaus, et al. Short-acting insulin analogues versus regular human insulin for adult, non-pregnant persons with type 2 diabetes mellitus. Cochrane Database Syst.Rev. 2018 12 CD013228.Background: The use of short-acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine) for adult, non-pregnant people with type 2 diabetes is still controversial, as reflected in many scientific debates.; Objectives: To assess the effects of short-acting insulin analogues compared to regular human insulin in adult, non-pregnant people with type 2 diabetes mellitus.; Search Methods: For this update we searched CENTRAL, MEDLINE, Embase, the WHO ICTRP Search Portal, and ClinicalTrials.gov to 31 October 2018. We placed no restrictions on the language of publication.; Selection Criteria: We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues to regular human insulin in the treatment of people with type 2 diabetes, who were not pregnant.; Data Collection and Analysis: Two review authors independently extracted data and assessed the risk of bias. We assessed dichotomous outcomes by risk ratios (RR), and Peto odds ratios (POR), with 95% confidence intervals (CI). We assessed continuous outcomes by mean differences (MD) with 95% CI. We assessed trials for certainty of the evidence using the GRADE approach.; Main Results: We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results.None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence).The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the

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overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence).No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects.; Authors' Conclusions: Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.

13. Giani,Elisa, Macedoni,Maddalena, Barilli,Anna, et al. Performance of the Flash Glucose Monitoring System during exercise in youth with Type 1 diabetes. Diabetes Res.Clin.Pract. 2018 146 321-329.Aim: Metabolic changes during exercise may affect the accuracy of glucose sensors impacting on Type 1 diabetes (T1D) management. The present study aimed at assessing the performance of the Flash Glucose Monitoring system (isCGM) during exercise and in free-living condition in youth with T1D.Methods: Seventeen youth (53% male), aged 13.7 ± 3.8 years, with T1D for 5.4 ± 3.8 years, HbA1c 7.4 ± 1.0% (57 ± 11 mmol/mol), were enrolled. Paired isCGM, plasma (PG) and capillary (CG) glucose values (total of 136) were collected during an interval exercise (45 min at 55% VO2max load with 20 s sprints at 80% VO2max every 10 min). Paired isCGM and CG (total of 832) were collected during free-living condition.Results: During exercise, isCGM absolute relative difference (ARDs) means/medians were 12.5/9.4% versus PG and 15.4/10.8% versus CG. During rest, ARDs means/medians were 16.6/12.0%. The Consensus Error Grid analysis showed 98.4% of readings during exercise and 97.24% during rest in zones A + B. Percentage of readings meeting the ISO criteria for CG levels



dental clinical field trials identified, 10 were systematically reviewed. High rates of undiagnosed dysglycaemia were detected among dental patients by biological screening in all trials. Notably, substantive differences in study design and population characteristics were identified, precluding meta-analysis.Conclusion: Screening for dysglycaemia in dental offices effectively identified high-risk patients requiring triage for glycaemic management. Considerations for future clinical trial design were advanced to establish an evidence base amenable to meta-analysis of the relative translational value of glycaemic screening in dental settings.

15. Gourgari,Evgenia, Playford,Martin P., Campia,Umberto, et al. Low cholesterol efflux capacity and abnormal lipoprotein particles in youth with type 1 diabetes: a case control study. Cardiovasc Diabetol. 2018 17 1 158-158.Background: Patients with type 1 diabetes (T1DM) have increased mortality from cardiovascular disease (CVD). Risk factors for CVD include an elevation of LDL (LDLp) and small HDL (sHDLp) particles, and a decrease in reverse cholesterol transport i.e. HDL-cholesterol efflux capacity (CEC). Our objective was to compare lipoprotein particles and CEC between T1DM and healthy controls (HC) and to explore the associations between NMR lipid particles and cholesterol efflux.; Methods: 78 patients with T1DM and 59 HC underwent fasting lipoprotein profile testing by NMR and measurements of CEC by cell-based method. The associations between NMR lipid particles with CEC were analyzed using multivariable linear regression models.; Results: Youth with T1DM had higher total LDLp 724 (563-985) vs 622 (476-794) nmol/L (P = 0.011)] (Maahs et al. in Circulation 130(17):1532-58, 2014; Shah et al. in Pediatr Diabetes 16(5):367-74, 2015), sHDLp 11.20 (5.7-15.3) vs 7.0 (3.2-13.1) μmol/L (P = 0.021)], and lower medium HDLp 11.20 (8.5-14.5) vs 12.3 (9-19.4), (P = 0.049)] and lower CEC (0.98 ± 0.11% vs 1.05 ± 0.15%, P = 0.003) compared to HC. Moreover, CEC correlated with sHDLp (β = - 0.28, P = 0.045) and large HDLp (β = 0.46, P



and white matter connectivity (effect size: 0.55, p = 0.054) were also reduced in patients with versus without cognitive impairment, albeit not statistically significant. White matter hyperintensity volumes and occurrence of other vascular lesions did not differ between the two patient groups.Conclusion: In patients with T2DM, grey matter atrophy rather than vascular brain injury appears to be the primary imaging correlate of MCI and early dementia.

17. Gujral,Unjali P., Mohan,Viswanathan, Pradeepa,Rajendra, Deepa,Mohan, Anjana,Ranjit Mohan and Narayan,K. M. Ethnic differences in the prevalence of diabetes in underweight and normal weight individuals: The CARRS and NHANES studies. Diabetes Res.Clin.Pract. 2018 146 34-40.Aims: Type 2 diabetes in lean individuals has recently come to attention. We assessed type 2 diabetes prevalence and the associated risk factors in underweight and normal weight individuals in two ethnic populations.Methods: We conducted cross-sectional analyses, using representative samples of 4930 Asian Indians from the CARRS-Chennai Study and 2868 Whites from the NHANES Survey. Diabetes was defined as use of glucose lowering medication, fasting glucose ≥126 mg/dl, or 2 h glucose ≥200 mg/dl. Body mass index (BMI) was classified using WHO standard criteria.Results: Prevalence of type 2 diabetes by BMI varied by ethnicity and sex. In men, type 2 diabetes prevalence was 5.4% and 23.5% in underweight and normal weight Asian Indians and 0.0% and 6.1% in underweight and normal weight Whites. In women, the prevalence was 5.6% and 13.6% in underweight and normal weight Asian Indians and 2.3% and 2.8% in underweight and normal weight Whites. Adjustment for waist circumference, insulin resistance, and insulin secretion did not explain the increased prevalence in Asian Indians.Conclusions: These findings suggest significant ethnic differences in type 2 diabetes prevalence without overweight or obesity. Future studies should examine the pathophysiology of type 2 diabetes development in lean individuals.

18. Hadi,Amir, Mohammadi,Hamed, Pourmasoumi,Makan, Miraghajani,Maryam and Symonds,Michael. The effects of silymarin supplementation on metabolic status and oxidative stress in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of clinical trials. Complement.Ther.Med. 2018 41 311-319.Objective: The effect of silymarin supplementation on metabolic status and oxidative stress of subjects with type 2 diabetes mellitus (T2DM) has not been conclusively studied. Therefore, the efficacy of silymarin supplementation in these patients was assessed through a meta-analysis.Methods: The following databases were searched up to May 15, 2018: PubMed, Scopus, Ovid (Cochrane library), Google scholar and ISI web of science. All randomized clinical trials using silymarin supplements to improve T2DM included in this meta-analysis. Mean Difference (MD) was pooled using a random-effects model.Results: Eight eligible publications from seven trials were identified for the present meta-analysis. Our results revealed that supplementation with silymarin can decrease fasting blood sugar, hemoglobin A1C, insulin, low-density lipoprotein cholesterol and malondialdehyde and increase high-density lipoprotein cholesterol levels. However, silymarin did not have any significant effects on total cholesterol or triglyceride concentrations.Conclusion: Our data suggest that silymarin supplements have beneficial effects on metabolic status and oxidative stress among patients with T2DM. However, there is currently insufficient evidence to make firm conclusions about the full efficacy of supplementation.

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19. Huhtala,Mikael S., Tertti,Kristiina, Pellonperä,Outi and Rönnemaa,Tapani. Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin. Diabetes Res.Clin.Pract. 2018 146 8-17.Aims: We compared the effects of metformin and insulin treatments of gestational diabetes mellitus (GDM) on amino acid metabolism.Methods: 217 pregnant women diagnosed with GDM were randomized to receive either metformin or insulin. 1H nuclear magnetic spectroscopy was used to determine serum concentrations of alanine, glutamine, glycine, isoleucine, leucine, valine, histidine, phenylalanine, tyrosine, glucose and lactate at the time of diagnosis and at 36 gestational weeks (gw).Results: Majority of the amino acid concentrations increased from 30 to 36 gw. The rise in alanine (16% vs. 8%, p



disease although it is started by presumed non-genetic events operating in children. It also states that genetic analyses of autoimmune diseases suggest that only a small number of pathways contribute to risks for diseases.

22. Lotta,Luca A., Wittemans,Laura B. L., Zuber,Verena, et al. Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors. JAMA. 2018 320 24 2553-2563.Importance: Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown.Objective: To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their association with cardiometabolic risk.Design, Setting, and Participants: Genome-wide association studies (GWAS) for WHR combined data from the UK Biobank cohort and summary statistics from previous GWAS (data collection: 2006-2018). Specific polygenic scores for higher WHR via lower gluteofemoral or via higher abdominal fat distribution were derived using WHR-associated genetic variants showing specific association with hip or waist circumference. Associations of polygenic scores with outcomes were estimated in 3 population-based cohorts, a case-cohort study, and summary statistics from 6 GWAS (data collection: 1991-2018).Exposures: More than 2.4 million common genetic variants (GWAS); polygenic scores for higher WHR (follow-up analyses).Main Outcomes and Measures: BMI-adjusted WHR and unadjusted WHR (GWAS); compartmental fat mass measured by dual-energy x-ray absorptiometry, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting glucose, fasting insulin, type 2 diabetes, and coronary disease risk (follow-up analyses).Results: Among 452 302 UK Biobank participants of European ancestry, the mean (SD) age was 57 (8) years and the mean (SD) WHR was 0.87 (0.09). In genome-wide analyses, 202 independent genetic variants were associated with higher BMI-adjusted WHR (n = 660 648) and unadjusted WHR (n = 663 598). In dual-energy x-ray absorptiometry analyses (n = 18 330), the hip- and waist-specific polygenic scores for higher WHR were specifically associated with lower gluteofemoral and higher abdominal fat, respectively. In follow-up analyses (n = 636 607), both polygenic scores were associated with higher blood pressure and triglyceride levels and higher risk of diabetes (waist-specific score: odds ratio OR], 1.57 95% CI, 1.34-1.83], absolute risk increase per 1000 participant-years ARI], 4.4 95% CI, 2.7-6.5], P



measures the average gene expression levels for a population of cells and cannot capture the inter-cell heterogeneity. The single-cell RNA-sequencing technology can provide additional information about the molecular mechanisms of T2D at single-cell level.; Results: In this work, we analyze three datasets of single-cell transcriptomes to reveal β-cell dysfunction and deficit mechanisms in T2D. Focused on the expression levels of key genes, we conduct discrimination of healthy and T2D β-cells using five machine learning classifiers, and extracted major influential factors by calculating correlation coefficients and mutual information. Our analysis shows that T2D β-cells are normal in insulin gene expression in the scenario of low cellular stress (especially oxidative stress), but appear dysfunctional under the circumstances of high cellular stress. Remarkably, oxidative stress plays an important role in affecting the expression of insulin gene. In addition, by analyzing the genes related to apoptosis, we found that the TNFR1-, BAX-, CAPN1- and CAPN2-dependent pathways may be crucial for β-cell apoptosis in T2D. Finally, personalized analysis indicates cell heterogeneity and individual-specific insulin gene expression.; Conclusions: Oxidative stress is an important influential factor on insulin gene expression in T2D. Based on the uncovered mechanism of β-cell dysfunction and deficit, targeting key genes in the apoptosis pathway along with alleviating oxidative stress could be a potential treatment strategy for T2D.

24. Marušić,Srećko, Meliš,Petra, Lucijanić,Marko, et al. Impact of pharmacotherapeutic education on medication adherence and adverse outcomes in patients with type 2 diabetes mellitus: a prospective, randomized study. Croat.Med.J. 2018 59 6 290-297.Aim: To evaluate the impact of pharmacotherapeutic education on 30-day post-discharge medication adherence and adverse outcomes in patients with type 2 diabetes mellitus (T2DM).; Methods: The prospective, randomized, single-center study was conducted at the Medical Department of University Hospital Dubrava, Zagreb, between April and June 2018. One hundred and thirty adult patients with T2DM who were discharged to the community were randomly assigned to either the intervention or the control group. Both groups during the hospital stay received the usual diabetes education. The intervention group received additional individual pre-discharge pharmacotherapeutic education about the discharge prescriptions. Medication adherence and occurrence of adverse outcomes (adverse drug reactions, readmission, emergency department visits, and death) were assessed at the follow-up visit, 30 days after discharge.; Results: The number of adherent patients was significantly higher in the intervention group (57/64 89.9%] vs 41/61 67.2%]; χ2 test, P=0.003]. There was no significant difference between the groups in the number of patients who experienced adverse outcomes (31/64 48.4%] vs 36/61 59.0%]; χ2 test, P=0.236). However, higher frequencies of all adverse outcomes were consistently observed in the control group.; Conclusion: Pharmacotherapeutic education of patients with T2DM can significantly improve 30-day post-discharge medication adherence, without a significant reduction in adverse clinical outcomes. ClinicalTrial.gov identification number:

25. Metcalfe,Richard S., Fitzpatrick,Ben, Fitzpatrick,Sinead, et al. Extremely short duration interval exercise improves 24-h glycaemia in men with type 2 diabetes. Eur.J.Appl.Physiol. 2018 118 12 2551-2562.Purpose: Reduced-exertion high-intensity interval training (REHIT) is a genuinely time-efficient exercise intervention that improves aerobic capacity and blood pressure in men with type 2 diabetes. However, the acute effects of REHIT on 24-h glycaemia have not been

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examined.Methods: 11 men with type 2 diabetes (mean ± SD: age, 52 ± 6 years; BMI, 29.7 ± 3.1 kg/m2; HbA1c, 7.0 ± 0.8%) participated in a randomised, four-trial crossover study, with continual interstitial glucose measurements captured during a 24-h dietary-standardised period following either (1) no exercise (CON); (2) 30 min of continuous exercise (MICT); (3) 10 × 1 min at ~ 90 HRmax (HIIT; time commitment, ~ 25 min); and (4) 2 × 20 s 'all-out' sprints (REHIT; time commitment, 10 min).Results: Compared to CON, mean 24-h glucose was lower following REHIT (mean ± 95%CI: - 0.58 ± 0.41 mmol/L, p = 0.008, d = 0.55) and tended to be lower with MICT (- 0.37 ± 0.41 mmol/L, p = 0.08, d = 0.35), but was not significantly altered following HIIT (- 0.37 ± 0.59 mmol/L, p = 0.31, d = 0.35). This seemed to be largely driven by a lower glycaemic response (area under the curve) to dinner following both REHIT and MICT (- 11%, p 0.9 for both) but not HIIT (- 4%, p = 0.22, d = 0.38). Time in hyperglycaemia appeared to be reduced with all three exercise conditions compared with CON (REHIT: - 112 ± 63 min, p = 0.002, d = 0.50; MICT: -115 ± 127 min, p = 0.08, d = 0.50; HIIT - 125 ± 122 min, p = 0.04, d = 0.54), whilst indices of glycaemic variability were not significantly altered.Conclusion: REHIT may offer a genuinely time-efficient exercise option for improving 24-h glycaemia in men with type 2 diabetes and warrants further study.

26. Mirmiran,P., Carlström,M., Bahadoran,Z. and Azizi,F. Long-term effects of coffee and caffeine intake on the risk of pre-diabetes and type 2 diabetes: Findings from a population with low coffee consumption. Nutr.Metab.Cardiovasc.Dis. 2018 28 12 1261-1266.Background and Aim: Here, we examined the potential effect of coffee consumption and total caffeine intake on the occurrence of pre-diabetes and T2D, in a population with low coffee consumption.Methods and Results: Adults men and women, aged 20-70 years, were followed for a median of 5.8 y. Dietary intakes of coffee and caffeine were estimated using a 168-food items validate semi-quantitative food frequency questionnaire, at baseline. Cox proportional hazards regression models, adjusted for potential cofounders, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between coffee and caffeine intakes and incidence of pre-diabetes and T2D. The total population was 1878 adults (844 men, 1034 women) and 2139 adults (971 men, 1168 women) for analysis of pre-diabetes and T2D, respectively. During the follow-up period the incidence of pre-diabetes and T2D was 30.8% and 6.6%, respectively. Forty-three percent of our subjects were no coffee drinker whereas 51.4% consumed 1 cup of coffee/week and 6.0% consumed more than 1 cup of coffee/week. A lower risk of pre-diabetes (HR = 0.73, 95% CI = 0.62-0.86) and T2D (HR = 0.66, 95% CI = 0.44-1.00) was observed in coffee drinkers compared to non-drinkers, in the fully adjusted models. Higher dietary intake of caffeine (≥152 vs.



tear and a minimum of 1-year follow-up. Clinical outcome measures included range of motion (ROM) and the Japanese Orthopaedic Association (JOA) and University of California, Los Angeles (UCLA) scores preoperatively and at final follow-up. Rotator cuff retear was evaluated with magnetic resonance imaging at 3 months post-surgery and final follow-up. Diabetic patients with poor control were pre-operatively hospitalized for intensive diabetic control.Results: Our inclusion criteria were met by 30 diabetic patients and 126 non-diabetic patients. Demographic data were not significantly different between the groups, except body mass index (p = 0.021). Preoperative JOA and UCLA scores of the diabetic patients were significantly lower than those of the non-diabetic patients (p



trials compared AGI with placebo (N = 4) or no intervention (N = 4).Acarbose reduced the incidence of T2DM compared to placebo: 670 out of 4014 people (16.7%) in the acarbose groups developed T2DM, compared to 812 out of 3994 people (20.3%) in the placebo groups (RR 0.82, 95% CI 0.75 to 0.89; P < 0.0001; 3 trials; 8008 participants; moderate-certainty evidence). One trial including participants with coronary heart disease and IGT contributed 64% of cases for this outcome. Acarbose reduced the risk of T2DM compared to no intervention: 7 out 75 people (9.3%) in the acarbose groups developed T2DM, compared to 18 out of 65 people (27.7%) in the no-intervention groups (RR 0.31, 95% CI 0.14 to 0.69; P = 0.004; 2 trials; 140 participants; very low-certainty evidence).Acarbose compared to placebo did not reduce or increase the risk of all-cause mortality (RR 0.98, 95% CI 0.82 to 1.18; P = 0.86; 3 trials; 8069 participants; very low-certainty evidence), cardiovascular mortality (RR 0.88; 95% CI 0.71 to 1.10; P = 0.26; 3 trials; 8069 participants; very low-certainty evidence), serious adverse events (RR 1.12, 95% CI 0.97 to 1.29; P = 0.13; 2 trials; 6625 participants; low-certainty evidence), non-fatal stroke (RR 0.50, 95% CI 0.09 to 2.74; P = 0.43; 1 trial; 1368 participants; very low-certainty evidence) or congestive heart failure (RR of 0.87; 95% CI 0.63 to 1.12; P = 0.40; 2 trials; 7890 participants; low-certainty evidence). Acarbose compared to placebo reduced non-fatal myocardial infarction: one out of 742 participants (0.1%) in the acarbose groups had a non-fatal myocardial infarction compared to 15 out of 744 participants (2%) in the placebo groups (RR 0.10, 95% CI 0.02 to 0.53; P = 0.007; 2 trials; 1486 participants; very low-certainty evidence). Acarbose treatment showed an increased risk of non-serious adverse events (mainly gastro-intestinal events), compared to placebo: 751 of 775 people (96.9%) in the acarbose groups experienced an event, compared to 723 of 775 people (93.3%) in the placebo groups (RR 1.04; 95% CI 1.01 to 1.06; P = 0.0008; 2 trials; 1550 participants). Acarbose compared to no intervention showed no advantage or disadvantage for any of these outcome measures (very low-certainty evidence).One trial each compared voglibose with placebo (1780 participants) or diet and exercise (870 participants). Voglibose compared to placebo reduced the incidence of T2DM: 50 out of 897 participants (5.6%) developed T2DM, compared to 106 out of 881 participants (12%) in the placebo group (RR 0.46, 95% CI 0.34 to 0.64; P < 0.0001; 1 trial; 1778 participants; low-certainty evidence). For all other reported outcome measures there were no clear differences between voglibose and comparator groups. One trial with 90 participants compared acarbose with diet and exercise and another trial with 98 participants reported data on acarbose versus metformin. There were no clear differences for any outcome measure between these two acarbose interventions and the associated comparator groups.None of the trials reported amputation of lower extremity, blindness or severe vision loss, end-stage renal disease, health-related quality of life, time to progression to T2DM, or socioeconomic effects.; Authors' Conclusions: AGI may prevent or delay the development of T2DM in people with IGT. There is no firm evidence that AGI have a beneficial effect on cardiovascular mortality or cardiovascular events.

29. Nataraj,Nisha, Ivy,Julie Simmons, Payton,Fay Cobb and Norman,Joseph. Diabetes and the hospitalized patient : A cluster analytic framework for characterizing the role of sex, race and comorbidity from 2006 to 2011. HEALTH CARE MANAGE SCI. 2018 21 4 534-553.In the US, one in four adults has two or more chronic conditions; this population accounts for two thirds of healthcare spending. Comorbidity, the presence of multiple simultaneous health conditions in an

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individual, is increasing in prevalence and has been shown to impact patient outcomes negatively. Comorbidities associated with diabetes are correlated with increased incidence of preventable hospitalizations, longer lengths of stay (LOS), and higher costs. This study focuses on sex and race disparities in outcomes for hospitalized adult patients with and without diabetes. The objective is to characterize the impact of comorbidity burden, measured as the Charlson Weighted Index of Comorbidities (WIC), on outcomes including LOS, total charges, and disposition (specifically, probability of routine discharge home). Data from the National Inpatient Sample (2006-2011) were used to build a cluster-analytic framework which integrates cluster analysis with multivariate and logistic regression methods, for several goals: (i) to evaluate impact of these covariates on outcomes; (ii) to identify the most important comorbidities in the hospitalized population; and (iii) to create a simplified WIC score. Results showed that, although hospitalized women had better outcomes than men, the impact of diabetes was worse for women. Also, non-White patients had longer lengths of stay and higher total charges. Furthermore, the simplified WIC performed equivalently in the generalized linear models predicting standardized total charges and LOS, suggesting that this new score can sufficiently capture the important variability in the data. Our findings underscore the need to evaluate the differential impact of diabetes on physiology and treatment in women and in minorities.

30. Nguyen,Elaine, Coleman,Craig I., Kohn,Christine G. and Weeda,Erin R. Ranolazine in patients with type 2 diabetes and chronic angina: A cost-effectiveness analysis and assessment of health-related quality-of-life. Int.J.Cardiol. 2018 273 34-38.Background: Type 2 diabetes (T2D) is associated with a high burden of angina. Ranolazine has been shown to reduce angina frequency versus placebo in patients with T2D and stable angina. We sought to estimate the cost-effectiveness of ranolazine when added to standard-of-care (SoC) versus SoC alone in patients with T2D and stable, but symptomatic coronary disease despite treatment with 1-2 antianginals.; Methods: A Markov model was developed and evaluated using cohort simulation. The model utilized a US societal perspective, 1-month cycle length and 1-year time horizon and was developed to estimate the cost-effectiveness of ranolazine versus SoC. Patients entered the model in 1 of 4 angina frequency health states based on baseline Seattle Angina Questionnaire Angina Frequency scores (100 = no; 61-99 = monthly; 31-60 = weekly; 0-30 = daily) and could transition between health states (first cycle only) or to death (any cycle) based on probabilities derived from the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina trial.; Results: Our model estimated patients treated with ranolazine lived a mean of 0.728 quality adjusted life years (QALYs) at a cost of $16,654. Those not receiving ranolazine lived a mean of 0.702 QALYs and incurred costs of $15,476. The incremental cost-effectiveness ratio for the addition of ranolazine to SoC was $45,308/QALY. Short Form-36 data suggest improvements in patients' bodily pain drove the gain in QALYs associated with ranolazine (2.73 versus 3.96, p = 0.01).; Conclusion: Our model suggests the addition of ranolazine to SoC is likely cost-effective from a US societal perspective for the treatment of patients with T2D and stable, symptomatic coronary disease despite treatment with 1-2 antianginals.

31. Paing,Aye C., Kirk,Alison F., Collier,Andrew, Kubiak,Thomas and Chastin,Sebastien F. M. Are glucose profiles well-controlled within the targets recommended by the International diabetes Federation in type 2 diabetes? A meta-

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analysis of results from continuous glucose monitoring based studies.

32. Papp,Zoltán, Radovits,Tamás, Paulus,Walter J., Hamdani,Nazha and Seferović,Petar M.

Diabetes Res.Clin.Pract. 2018 146 289-299.Aims: To assess continuous glucose monitoring (CGM) derived intra-day glucose profiles using global guideline for type 2 diabetes recommended by the International Diabetes Federation (IDF).Methods: The Cochrane Library, MEDLINE, PubMed, CINAHL and Science Direct were searched to identify observational studies reporting intra-day glucose profiles using CGM in people with type 2 diabetes on any anti-diabetes agents. Overall and subgroup analyses were conducted to summarise mean differences between reported glucose profiles (fasting glucose, pre-meal glucose, postprandial glucose and post-meal glucose spike/excursion) and the IDF targets.Results: Twelve observational studies totalling 731 people were included. Pooled fasting glucose (0.81 mmol/L, 95% CI, 0.53-1.09 mmol/L), postprandial glucose after breakfast (1.63 mmol/L, 95% CI, 0.79-2.48 mmol/L) and post-breakfast glucose spike (1.05 mmol/L, 95% CI, 0.13-1.96 mmol/L) were significantly higher than the IDF targets. Pre-lunch glucose, pre-dinner glucose and postprandial glucose after lunch and dinner were above the IDF targets but not significantly. Subgroup analysis showed significantly higher fasting glucose and postprandial glucose after breakfast in all groups: HbA1c



fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity discovered outside of pregnancy influence GDM risk. Order.

34. Rak,Karolina and Bronkowska,Monika. Immunomodulatory Effect of Vitamin D and Its Potential Role in the Prevention and Treatment of Type 1 Diabetes Mellitus-A Narrative Review. Molecules. 2018 24 1 Type 1 diabetes mellitus is a chronic autoimmune disease associated with degeneration of pancreatic β-cells that results in an inability to produce insulin and the need for exogenous insulin administration. It is a significant global health problem as the incidence of this disorder is increasing worldwide. The causes are still poorly understood, although it certainly has genetic and environmental origins. Vitamin D formed profusely in the skin upon exposure to sunlight, as well as from dietary sources, exhibits an immunomodulatory effect based on gene transcription control. Indeed, vitamin D can downregulate mechanisms connected with adaptive immunity, induce immunological tolerance and decrease auto-aggression-related inflammation. These properties provide the basis for a preventive and therapeutic role of vitamin D. As many studies have demonstrated, appropriate supplementation with vitamin D reduces the risk of autoimmune diseases, including type 1 diabetes mellitus, and alleviates disease symptoms in patients. The aim of this narrative review is to present the molecular mechanisms for the vitamin D immunomodulatory effect as well as review human clinical studies on the use of vitamin D as adjuvant therapy in type 1 diabetes mellitus.

35. Rosenstock,Julio, Marquard,Jan, Laffel,Lori M., et al. Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials. Diabetes Care. 2018 41 12 2560-2569.Objective: To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D).Research Design and Methods: The EASE (Empagliflozin as Adjunctive to inSulin thErapy) program (N = 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (n = 243), 25 mg (n = 244), and placebo (n = 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (n = 241), 10 mg (n = 248), 25 mg (n = 245), and placebo (n = 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia.Results: The observed largest mean placebo-subtracted glycated hemoglobin reductions were -0.28% (95% CI -0.42, -0.15) for 2.5 mg, -0.54% (-0.65, -0.42) for 10 mg, and -0.53% (-0.65, -0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by -1.8/-3.0/-3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by -6.4/-13.3/-12.7% (all P < 0.0001); and decreased systolic blood pressure by -2.1/-3.9/-3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo.Conclusions: Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with

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10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk. Order.

36. Samkani,Amirsalar, Skytte,Mads J., Anholm,Christian, et al. The acute effects of dietary carbohydrate reduction on postprandial responses of non-esterified fatty acids and triglycerides: a randomized trial. Lipids Health Dis. 2018 17 1 295-295.Background: Postprandial non-esterified fatty acid (NEFA) and triglyceride (TG) responses are increased in subjects with type 2 diabetes mellitus (T2DM) and may impair insulin action and increase risk of cardiovascular disease and death. Dietary carbohydrate reduction has been suggested as non-pharmacological therapy for T2DM, but the acute effects on NEFA and TG during subsequent meals remain to be investigated.; Methods: Postprandial NEFA and TG responses were assessed in subjects with T2DM by comparing a carbohydrate-reduced high-protein (CRHP) diet with a conventional diabetes (CD) diet in an open-label, randomized, cross-over study. Each diet was consumed on two consecutive days, separated by a wash-out period. The iso-caloric CRHP/CD diets contained 31/54 E% from carbohydrate, 29/16 E% energy from protein and 40/30 E% from fat, respectively. Sixteen subjects with well-controlled T2DM (median HbA1c 47 mmol/mol, (37-67 mmol/mol) and BMI 30 ± 4.4 kg/m2) participated in the study. NEFA and TG were evaluated following breakfast and lunch.; Results: NEFA net area under curve (AUC) was increased by 97 ± 38 μmol/Lx270 min (p = 0.024) after breakfast but reduced by 141 ± 33 μmol/Lx180 min (p



risk of GDM in a future first pregnancy can be accurately identified based on preconception lifestyle and health-related characteristics. Further studies are needed to test our model in other populations.

38. Sharif,S., Bots,M. L., Schalkwijk,C., Stehouwer,C. D. A., Visseren,F. L. J. and Westerink,J. Association between bone metabolism regulators and arterial stiffness in type 2 diabetes patients. Nutr.Metab.Cardiovasc.Dis. 2018 28 12 1245-1252.Background and Aim: Osteopontin (OPN), osteonectin (ON) and osteocalcin (OC) play an important role in the development of vascular calcifications, but it is unclear whether these bone metabolism regulators contribute to the development of arterial stiffness in type 2 diabetes patients. We therefore aim to determine the relationship between plasma concentrations of OPN, ON, OC and arterial stiffness in type 2 diabetes patients.Methods: Cross-sectional study of 1003 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART)-cohort. Generalized linear models were used to evaluate the relation between plasma levels of OPN, ON and OC and arterial stiffness as measured by pulse pressure (PP), ankle-brachial index (ABI) (≥0.9), carotid artery distension and an arterial stiffness summary score. Analyses were adjusted for age, sex, kidney function, diabetes duration and diastolic blood pressure. Higher OPN plasma levels were significantly related to a lower ABI (β-0.013; 95%CI -0.024 to -0.002) and a higher arterial stiffness summary score (OR1.24; 95%CI 1.03-1.49). OPN levels were not related to PP (β 0.59; 95%CI -0.63-1.81) or absolute carotid artery distention (β -7.03; 95%CI -20.00-5.93). ON and OC plasma levels were not related to any of the arterial stiffness measures.Conclusion: Only elevated plasma levels of OPN are associated with increased arterial stiffness in patients with type 2 diabetes as measured by the ankle-brachial index and arterial stiffness summary score. These findings indicate that OPN may be involved in the pathophysiology of arterial stiffness and call for further clinical investigation.

39. Skelin,Marko, Javor,Eugen, Lucijanić,Marko, Lucijanić,Tomo, Jakupović,Lejsa and Rahelić,Dario. The role of glucagon in the possible mechanism of cardiovascular mortality reduction in type 2 diabetes patients. Int.J.Clin.Pract. 2018 72 12 N.PAG-N.PAG.Aim: Type 2 diabetes (T2D) is one of the major public health issues worldwide. The main cause of mortality and morbidity among T2D patients are cardiovascular (CV) causes. Various antidiabetics are used in T2D treatment, but until recently they lacked clear evidence of the reduction in CV mortality and all-cause mortality as independent study end-points. The aim of this article was to present and critically evaluate potential mechanisms behind the remarkable results documented in trials with new antidiabetics for the treatment of T2D.Methods: Relevant data were collected using the MEDLINE, PubMed, EMBASE, Web of Science, Science Direct, and Scopus databases with the key words: "type 2 diabetes," "mortality," "glucagon," "empagliflozin," "liraglutide," "insulin" and "QTc." Searches were not limited to specific publication types or study designs.Results: The EMPA-REG OUTCOME trial with empagliflozin and LEADER trial with liraglutide presented remarkable results regarding the reduction in mortality in T2D treatment. However, the potential mechanism for those beneficial effects is difficult to determine. It is not likely that improvements in classic CV risk factors are responsible for the observed effect. A potential mechanism may be caused by the elevation of postprandial (PP) glucagon concentrations that can be seen with an empagliflozin and liraglutide therapy, which could have beneficial effects considering the

mailto:[email protected]�http://dx.doi.org/10.1016/j.numecd.2018.06.004�http://dx.doi.org/10.1016/j.numecd.2018.06.004�http://dx.doi.org/10.1111/ijcp.13274�http://dx.doi.org/10.1111/ijcp.13274�



myocardial electrical stability in T2D patients.Conclusion: This hypothesis throws new light upon possible mechanisms of reduction in mortality in T2D patients.

40. Skinner,Sarah C., Diaw,Mor, Pialoux,Vincent, et al. Increased Prevalence of Type 2 Diabetes-Related Complications in Combined Type 2 Diabetes and Sickle Cell Trait. Diabetes Care. 2018 41 12 2595-2602.Objective: The prevalence of type 2 diabetes (T2D) is rapidly increasing in sub-Saharan Africa, where sickle cell trait (SCT) is also frequent. Although SCT is generally considered a benign condition, evidence suggests that SCT could exaggerate vascular dysfunction in T2D. However, it remains unclear whether SCT could increase the risk of the development of T2D complications. Therefore, this study was conducted to determine whether T2D complications were more prevalent among Senegalese individuals with SCT and T2D than among those with T2D only.Research Design and Methods: Rates of hypertension, retinopathy, peripheral neuropathy, peripheral artery disease, and impaired renal function as well as arterial stiffness, blood rheology, and concentrations of plasma advanced glycation end products (AGEs) and cytokines were compared between groups of Senegalese individuals with combined SCT and T2D (T2D-SCT) (n = 60), T2D (n = 52), SCT (n = 53), and neither T2D nor SCT (control) (n = 56). Human aortic endothelial cell (HAEC) expression of inflammatory and adhesion factors was measured after treatment with tumor necrosis factor-α and subjects' plasma. Effects of AGE inhibition or tiron on HAEC expression of E-selectin were measured.Results: Retinopathy, hypertension, and reduced renal function were more prevalent, and arterial stiffness, blood viscosity at high shear rates, and thixotropic index were higher, in the SCT group compared with the other groups. Multivariable analysis showed that plasma AGE concentration was significantly associated with arterial stiffness. E-selectin expression was elevated in HAECs treated with T2D-SCT plasma compared with the other groups, but AGE inhibition reversed this.Conclusions: SCT could potentially augment the risk of the development of T2D-related complications, including retinopathy, nephropathy, and hypertension. Order.

41. Varpuluoma,Outi, Försti,Anna-Kaisa, Jokelainen,Jari, et al. Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study. J.Am.Acad.Dermatol. 2018 79 6 1034-1034.Background: Dipeptidyl peptidase 4 inhibitors (DPP4is) used to treat diabetes have been reported to be associated with an increased risk of bullous pemphigoid (BP). There are no previous reports analyzing the risk of BP in patients who are using other diabetes medications.Objective: To evaluate the association between diabetes medications other than DPP4i and development of BP.Methods: We investigated the prevalence of diabetes among patients with BP and the association between the use of diabetes drugs (excluding DPP4i, metformin, and insulin) and BP by analyzing national Finnish registry data for 3397 patients with BP and 12,941 patients with basal cell carcinoma as controls.Results: Our results show that 19.6% of patients with BP have type 2 diabetes. Use of none of the investigated medications was associated with an increased risk of BP.Limitations: Because this was a registry-based study, it was not possible to verify the accuracy of the diagnoses. The risk of BP in users of glucagon-like peptide 1 receptor agonists could not be analyzed.Conclusion: Our study shows that the investigated diabetes drugs are not associated with an increased risk of BP in a Finnish patient database,

mailto:[email protected]�mailto:[email protected]�http://dx.doi.org/10.1016/j.jaad.2018.05.030�http://dx.doi.org/10.1016/j.jaad.2018.05.030�http://dx.doi.org/10.1016/j.jaad.2018.05.030�



indicating they can be safely used in this population. Generalization of these results to other populations will require further study.

42. Wang,S. K., Green,Linden A., Gutwein,Ashley R., et al. Metformin does not reduce inflammation in diabetics with abdominal aortic aneurysm or at high risk of abdominal aortic aneurysm formation. VASCULAR. 2018 26 6 608-614.Introduction: The protective effect of diabetes mellitus on abdominal aortic aneurysm formation and growth has been repeatedly observed in population studies but continues to be poorly understood. However, recent investigations have suggested that metformin, a staple antihyperglycemic medication, may be independently protective against abdominal aortic aneurysm formation and growth. Therefore, we describe the effect of metformin in abdominal aortic aneurysm and at-risk patients on markers of inflammation, the driver of early abdominal aortic aneurysm formation and growth.Methods: Peripheral blood was collected from patients previously diagnosed with abdominal aortic aneurysm or presenting for their U.S. Preventive Task Force-recommended abdominal aortic aneurysm screening. Plasma and circulating peripheral blood mononuclear cells were isolated using Ficoll density centrifugation. Circulating plasma inflammatory and regulatory cytokines were assessed with enzyme-linked immunosorbent assays. CD4+ cell phenotyping was performed using flow cytometric analysis and expressed as a proportion of total CD4+ cells. To determine the circulating antibody to self-antigen response, a modified enzyme-linked immunosorbent assay was performed against antibodies to collagen type V and elastin fragments.Results: Peripheral blood was isolated from 266 patients without diabetes mellitus ( n=182), with diabetes mellitus not treated with metformin ( n=34), and with diabetes mellitus actively taking metformin ( n=50) from 2015 to 2017. We found no differences in the expression of Tr1, Th17, and Treg CD4+ fractions within diabetics ± metformin. When comparing inflammatory cytokines, we detected no differences in IL-1β, IL-6, IL-17, IL-23, IFN-γ, and TNF-α. Conversely, no differences were observed pertaining to the expression to regulatory cytokines IL-4, IL-10, IL-13, TSG-6, or TGF-β. Lastly, no differences in expression of collagen type V and elastin fragment antigen and/or antibodies were detected with metformin use in diabetics.Conclusion: Metformin in diabetics at-risk for abdominal aortic aneurysm or diagnosed with abdominal aortic aneurysm does not seem to alter the peripheral inflammatory environment. Order.

43. Xiang,Anny H., Trigo,Enrique, Martinez,Mayra, et al. Impact of Gastric Banding Versus Metformin on β-Cell Function in Adults With Impaired Glucose Tolerance or Mild Type 2 Diabetes. Diabetes Care. 2018 41 12 2544-2551.Objective: Type 2 diabetes (T2D) results from progressive loss of β-cell function. The BetaFat study compared gastric banding and metformin for their impact on β-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D.Research Design and Methods: Eighty-eight people aged 21-65 years, BMI 30-40 kg/m2, with IGT or diabetes known for 25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I).Results: At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P 25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I).Results: At 24 months, the band

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group lost 10.7 kg; the metformin group lost 1.7 kg (P 25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I).Results: At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg (P 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months (P = 0.66 between groups).Conclusions: Gastric banding and metformin had similar effects to preserve β-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D. Order.

44. Xiang,Anny H., Wang,Xinhui, Martinez,Mayra P., et al. Maternal Gestational Diabetes Mellitus, Type 1 Diabetes, and Type 2 Diabetes During Pregnancy and Risk of ADHD in Offspring. Diabetes Care. 2018 41 12 2502-2508.Objective: To examine the relative importance of maternal preexisting type 1 diabetes (T1D), preexisting type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) on risk of attention deficit/hyperactivity disorder (ADHD) in offspring.Research Design and Methods: This retrospective birth cohort study included 333,182 singletons born in 1995-2012 within Kaiser Permanente Southern California hospitals. Children were prospectively followed through electronic medical records from age 4 years. Relative risks of ADHD associated with diabetes exposures in utero were estimated by hazard ratios (HRs) using Cox regression with adjustment for potential confounders. For GDM, timing of exposure was evaluated by gestational age at diagnosis and severity was assessed by the need for antidiabetes medication treatment during pregnancy.Results: A total of 37,878 (11.4%) children were exposed to diabetes (522 exposed to T1D, 7,822 T2D, and 29,534 GDM). During a median of 4.9 years (interquartile range 2.2, 9.6) of follow-up after age 4 years, 17,415 (5.2%) children were diagnosed with ADHD. ADHD risk was not associated with GDM taken as a whole (P = 0.50) or with gestational age at GDM diagnosis (P = 0.16). However, the risk was significantly greater for the GDM requiring versus not requiring antidiabetes medications (P < 0.001). Compared with children unexposed to diabetes, the adjusted HRs for ADHD in children were 1.57 (95% CI 1.09-2.25) for exposure to T1D, 1.43 (1.29-1.60) for T2D, 1.26 (1.14-1.41) for GDM requiring antidiabetes medications, and 0.93 (0.86-1.01) for GDM not requiring medications.Conclusions: The hierarchy of risks suggests that severity of maternal diabetes (T1D vs. T2D vs. GDM requiring antidiabetes medications) influences the risk of ADHD in offspring of mothers with diabetes. Ordered.

45. Zhang,Qi, Ji,Lijin, Zheng,Hangping, et al. Low serum phosphate and magnesium levels are associated with peripheral neuropathy in patients with type 2 diabetes mellitus. Diabetes Res.Clin.Pract. 2018 146 1-7.Aims: To determine the relationship of serum phosphate, serum magnesium and peripheral nerve function in patients with type 2 diabetes mellitus (T2DM).Methods: A total of 254 patients diagnosed with T2DM were included. Peripheral nerve function was evaluated by nerve conduction study with the use of electromyography. Composite z scores of conduction velocity, latency, and amplitude were constructed, respectively. Demographic, medical and laboratory data including serum phosphate and magnesium were collected.Results: Serum phosphate and serum magnesium levels were significantly lower in patients with diabetic peripheral neuropathy (DPN) (P



were positively associated with serum phosphate levels and the composite z score of amplitude (P

2. afroz,afsana, alramadan,mohammed j., hossain,md nassif, et al. cost-of-illness of type 2 diabetes...

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