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The objective of this study was to examine measures of insulin resistance and beta cell function in relation to ethnicity and the development of diabetes after gestational diabetes mellitus (GDM). Glucose homeostasis was assessed during a 75 g oral glucose tolerance test 1–2 years after delivery in 456 women with previous GDM (362 European, 94 non-European; including 41 Arab and 43 Asian women) and 133 control women. Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). The insulinogenic index (I/G30) and the disposition index [(I/G30)/HOMA-IR] were used to quantify insulin secretion. Women developing diabetes after GDM were characterized by increased HOMA-IR [ p  = 0.010, adjusted for body mass index (BMI)], whereas the disposition index was decreased in all women with previous GDM irrespective of glucose tolerance, most pronounced in the presence of diabetes (BMI-adjusted p  = 1 × 10 −5 ). Non-European origin was associated with increased HOMA-IR ( p  = 0.001 vs. European), strengthened by adjustment for BMI in Asian women ( p  = 0.046 vs. p  = 0.016), but eradicated among Arab women ( p  = 0.004 vs. p  = 0.65). Non-European women exhibited an increased frequency of diabetes after GDM (17 % vs. European 4 %, p  = 2 × 10 −5 ). In addition to BMI, non-European and Asian origin was associated with the development of diabetes after GDM in a multivariate logistic regression analysis, whereas Arab origin was not. Our results highlight the importance of preventive measures to ensure a healthy lifestyle in women with GDM, particularly in high-risk ethnic groups.

Molecular biomarkers, like gene transcripts or enzyme activities, are potentially powerful tools for early warning assessment of pollution. However, a thorough understanding of response and baseline variation is required to distinguish actual effects from pollution. Here, we assess the freshwater mussel Anodonta anatina as a biomarker model species for freshwater ecosystems, by testing responses of six transcriptional ( cat , gst , hsp70 , hsp90 , mt , and sod ) and two biochemical (AChE and GST) biomarkers to environmentally relevant Cu water concentrations. Mussels ( n =  20), collected from a stream free from point source pollution, were exposed in the laboratory, for 96 h, to Cu treatments (< 0.2 μg/L, 0.77 ± 0.87 μg/L, and 6.3 ± 5.4 μg/L). Gills and digestive glands were extracted and analyzed for transcriptional and biochemical responses. Biological and statistical effect sizes from Cu treatments were in general small (mean log 2 fold-change ≤ 0.80 and Cohen’s f  ≤ 0.69, respectively), and no significant treatment effects were observed. In contrast, four out of eight biomarkers ( cat , gst , hsp70 , and GST) showed a significant sex:tissue interaction, and additionally one ( sod ) showed significant overall effects from sex. Specifically, three markers in gills ( cat , mt , GST) and one in digestive gland (AChE) displayed significant sex differences, independent of treatment. Results suggest that sex or tissue effects might obscure low-magnitude biomarker responses and potential early warnings. Thus, variation in biomarker baselines and response patterns needs to be further addressed for the future use of A. anatina as a biomarker model species.

Study question What are the effects of liraglutide, an incretin based treatment, on glycaemic control in people with type 2 diabetes treated with multiple daily insulin injections?Methods The study was a randomised, double blind, placebo controlled trial with a parallel group design carried out at 13 hospital based outpatient clinics and one primary care unit in Sweden. Patients were considered eligible for inclusion if they had type 2 diabetes and inadequate glycaemic control (HbA1c concentrations ≥58 mmol/mol (7.5%) and ≤102 mmol/mol (11.5%)), a body mass index of 27.5-45 kg/m2, and required multiple daily insulin injections. Overall, 124 participants were randomised 1:1 to subcutaneous liraglutide or placebo by minimisation allocation. The main outcome measure was change in HbA1c level from baseline to week 24.Study answer and limitations Liraglutide was associated with a significant reduction of 16.9 mmol/mol (1.5%) in HbA1c versus 4.6 mmol/mol (0.4%) for placebo, difference −12.3 mmol/mol (95% confidence interval −15.8 to −8.8 mmol/mol; −1.13%, −1.45 to −0.81 mmol/mol). Body weight was significantly reduced in participants in the liraglutide compared with placebo group (3.8 v 0.0 kg, difference −3.8, −4.9 to −2.8 kg), and total daily insulin doses were significantly reduced, by 18.1 units and 2.3 units (difference −15.8, −23.1 to −8.5 units). Reductions in mean and standard deviation of glucose levels estimated by masked continuous glucose monitoring were significantly greater in the liraglutide group than placebo group (−1.9 and −0.5 mmol/L). Neither group experienced severe hypoglycaemic events nor were there any significant differences in symptomatic or asymptomatic non-severe hypoglycaemia (<4.0 or <3.0 mmol/L). The mean number of non-severe symptomatic hypoglycaemic events (<4.0 mmol/L) during follow-up was 1.29 in the liraglutide group and 1.24 in the placebo group (P=0.96). One of the study’s limitations was its relatively short duration. Sustained effects of liraglutide have, however, been found over lengthier periods in connection with other treatment regimens. Cardiovascular safety and potential adverse events during longer exposure to liraglutide need to be evaluated. Nausea was experienced by 21 (32.8%) participants in the liraglutide group and 5 (7.8%) in the placebo group and 3 (5%) and 4 (7%) participants in these groups, respectively, had any serious adverse event.What this study adds Adding liraglutide to multiple daily insulin injections in people with type 2 diabetes improves glycaemic control without an increased risk of hypoglycaemia, reduces body weight, and enables patients to lower their insulin doses.Funding, competing interests, data sharing This study was an investigator initiated trial, supported in part by Novo Nordisk and InfuCare. Potential competing interests have been reported and are available on thebmj.com.Study registration EudraCT 2012-001941-42.

Introduction Non-diabetic ketoacidosis is a rare condition which can be caused by starvation. Lack of glucose can force the body into ketogenesis causing a metabolic acidosis. As previously reported in the literature, ketoacidosis might, on rare occasions, be caused by a diet with low carbohydrate content. However, to the best of our knowledge this is the first reported case in the literature of ketoacidosis, in a non-diabetic patient, associated with a combination of low carbohydrate, high fat diet and lactation. Case presentation A healthy non-diabetic, 32-year old white woman started a low carbohydrate, high fat diet when she was breastfeeding her son of 10 months of age. After 10 days she was admitted to our hospital with nausea and vomiting and a serum pH of 7.20 and base excess of −19. Clinical signs and blood samples were compatible with ketoacidosis. She was given fluids intravenously and insulin. No anamnestic or clinical signs of diabetes were found. She recovered quickly and was discharged 3 days later. Conclusions Ketogenic diets like low carbohydrate, high fat may induce ketoacidosis. Lactation might further aggravate the condition and can perhaps even be the trigger into ketoacidosis. Health services should be aware of the risks associated with ketogenic diets, and be able to recognize this serious condition when it is presented.

Screening for MODY Mutations, GAD Antibodies, and Type 1 Diabetes– Associated HLA Genotypes in Women With Gestational Diabetes Mellitus Jianping Weng , MD, PHD 1 , Magnus Ekelund , MD 1 , Markku Lehto , PHD 1 , Haiyan Li , BM 1 , Göran Ekberg , MD 1 , Anders Frid , MD, PHD 2 , Anders Åberg , MD, PHD 3 , Leif C. Groop , MD, PHD 1 and Kerstin Berntorp , MD, PHD 1 1 Department of Endocrinology, Malmö University Hospital, Lund University, Malmö, Sweden 2 Department of Internal Medicine, Lund University Hospital, Lund University, Lund, Sweden 3 Department of Obstetrics and Gynecology, Lund University Hospital, Lund University, Lund, Sweden Abstract OBJECTIVE —To investigate whether genetic susceptibility to type 1 diabetes or maturity-onset diabetes of the young (MODY) increases susceptibility to gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS —We studied mutations in MODY1–4 genes, the presence of GAD antibodies, and HLA DQB1 risk genotypes in 66 Swedish women with GDM and a family history of diabetes. An oral glucose tolerance test was repeated in 46 women at 1 year postpartum. RESULTS —There was no increase in type 1 diabetes–associated HLA-DQB1 alleles or GAD antibodies when compared with a group of type 2 diabetic patients ( n = 82) or healthy control subjects ( n = 86). Mutations in known MODY genes were identified in 3 of the 66 subjects (1 MODY2, 1 MODY3, and 1 MODY4). Of the 46 GDM subjects, 2 had diabetes (4%) and 17 had impaired glucose tolerance (IGT) (37%) at 1 year postpartum. Of the two subjects who developed manifest diabetes, one carried a MODY3 mutation (A203H in the hepatocyte nuclear factor-1α gene). There was no increase in high-risk HLA alleles or GAD antibodies in the women who had manifest diabetes or IGT at 1 year postpartum. CONCLUSIONS —MODY mutations but not autoimmunity contribute to GDM in Swedish women with a family history of diabetes and increase the risk of subsequent diabetes. GCK, glucokinase GDM, gestational diabetes mellitus HNF, hepatocyte nuclear factor IGT, impaired glucose tolerance IPF1, insulin promoter factor-1 MODY, maturity-onset diabetes of the young NGT, normal glucose tolerance OGTT, oral glucose tolerance test PCR, polymerase chain reaction SSCP, single-strand conformation polymorphism Footnotes Address correspondence and reprint requests to Dr. Magnus Ekelund, Department of Endocrinology, Malmö University Hospital, S-205 02, Malmö, Sweden. E-mail address: magnus.ekelund{at}skane.se . Received for publication 9 May 2001 and accepted in revised form 9 October 2001. J.W. is currently affiliated with the Department of Endocrinology, the First Affiliated Hospital of SUMS, Guangzhou, China. M.L. is currently affiliated with the Department of Molecular Medicine, Intracellular Transport Unit, National Public Health Institute, Helsinki, Finland. J.W. and M.E. contributed equally to this work. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Aims To identify predictors of diabetes development up to 5 years after gestational diabetes mellitus (GDM) and to develop a prediction model for individual use. Methods Five years after GDM, a 75-g oral glucose tolerance test (OGTT) was performed in 362 women, excluding women already diagnosed with diabetes at 1- to 2-year follow-up or later ( n  = 45). All but 21 women had results from follow-up at 1–2 years, while 84 women were lost from that point. Predictive variables were identified by logistic regression analysis. Results Five years after GDM, 28/362 women (8 %) were diagnosed with diabetes whereas 187/362 (52 %) had normal glucose tolerance (NGT). Of the latter, 139/187 (74 %) also had NGT at 1- to 2-year follow-up. In simple regression analysis, using NGT at 1–2 years and at 5 years as the reference, diabetes at 1- to 2-year follow-up or later was clearly associated with easily assessable clinical variables, such as BMI at 1- to 2-year follow-up, 2-h OGTT glucose concentration during pregnancy, and non-European origin ( P  < 0.0001). A prediction model based on these variables resulting in 86 % correct classifications, with an area under the receiver-operating characteristic curve of 0.91 (95 % CI 0.86–0.95), was applied in a function-sheet line diagram illustrating the individual effect of weight on diabetes risk. Conclusions The results highlight the importance of BMI as a potentially modifiable risk factor for diabetes after GDM. Our proposed prediction model performed well, and should encourage validation in other populations in future studies.

Introduction We investigated the safety of, and glucose control by, the insulin-only configuration of the iLet ® bionic pancreas delivering fast-acting insulin aspart (faster aspart), using the same insulin-dosing algorithm but different time to maximal serum drug concentration ( t max ) settings, in adults with type 1 diabetes. Methods We performed a single-center, single-blinded, crossover (two 7-day treatment periods) escalation trial over three sequential cohorts. Participants from each cohort were randomized to a default t max setting ( t 65  [ t max  = 65 min]) followed by a non-default t max setting ( t 50 [ t max  = 50 min; cohort 1], t 40 [ t max  = 40 min; cohort 2], t 30 [ t max  = 30 min; cohort 3]), or vice versa, all with faster aspart. Each cohort randomized eight new participants if escalation-stopping criteria were not met in the previous cohort. Results Overall, 24 participants were randomized into three cohorts. Two participants discontinued treatment, one due to reported ‘low blood glucose’ during the first treatment period of cohort 3 ( t 30 ). Mean time in low sensor glucose (< 54 mg/dl, primary endpoint) was < 1.0% for all t max settings. Mean sensor glucose in cohorts 1 and 2 was significantly lower at non-default versus default t max settings, with comparable insulin dosing. The mean time sensor glucose was in range (70–180 mg/dl) was > 70% for all cohorts, except the default t max setting in cohort 1. No severe hypoglycemic episodes were reported. Furthermore, there were no clinically significant differences in adverse events between the groups. Conclusion There were no safety concerns with faster aspart in the iLet at non-default t max settings. Improvements were observed in mean sensor glucose without increases in low sensor glucose at non-default t max settings. Trial Registration ClinicalTrials.gov, NCT03816761. Plain Language Summary One way to give insulin is to use an insulin delivery system. The iLet ® is a new type of insulin delivery system that works together with a continuous sugar monitoring tool (CGM). The CGM shows the blood sugar level in the body throughout the day. Based on this, the iLet automatically gives the insulin that is needed to control the blood sugar. Fast-acting insulin aspart (faster aspart) is a type of insulin that doctors can prescribe for use with insulin pens and insulin pumps. The researchers wanted to test the safety of faster aspart when given to people at different delivery settings in the iLet. Twenty-four men and women with type 1 diabetes from the USA took part. The different insulin delivery settings were the standard setting ( t max 65 = 65 min) and new settings ( t max 50 = 50 min; t max 40 = 40 min; t max 30 = 30 min). The shorter the t max setting, the faster the insulin was assumed to be absorbed into the body by the iLet. People had good blood sugar control with faster aspart delivered using the iLet. The time with low blood sugar (i.e., < 54 mg/dl) was low for both the standard setting and the new settings. The average blood sugar was lower with the shorter, non-standard t max settings. No people had serious side effects. No severe hypoglycemic episodes were reported. In this study, researchers found that it was safe to use faster aspart with the different settings in the iLet.

Introduction The majority of elderly patients (≥ 65 years of age) with type 2 diabetes mellitus (T2DM) will eventually require insulin therapy, but they are particularly vulnerable to hypoglycemia and challenging to treat. Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart administered in a single injection, either once or twice daily with main meals. Methods A combined analysis of the phase 3 BOOST INTENSIFY PREMIX I (NCT01009580) and BOOST INTENSIFY ALL (NCT01059812) trials has previously reported lower rates of hypoglycemia during the maintenance period in patients with T2DM treated with IDegAsp twice daily (BID) versus biphasic insulin aspart 30 (BIAsp 30) BID. This post hoc analysis examined the safety and efficacy of IDegAsp versus BIAsp 30 in elderly patients from the global population of these two trials, and also from the Japanese cohort of BOOST INTENSIFY ALL. Results Change in HbA 1c was similar for IDegAsp versus BIAsp 30 ( p  > 0.5). Compared with BIAsp 30, IDegAsp resulted in significant reductions in fasting plasma glucose ( p  < 0.0001), numerically lower rates of overall and nocturnal hypoglycemia (global estimated rate ratios: 0.92 [0.67; 1.26] 95% confidence interval [CI] , p  = 0.5980 and 0.67 [0.39; 1.18] 95% CI , p   = 0.1676, respectively), and a significantly lower total daily insulin dose at end of trial (global estimated treatment difference 0.79 [0.73; 0.87] 95% CI , p   < 0.0001) in elderly patients. Conclusion The results described here are consistent with those of the overall trial populations, demonstrating that IDegAsp BID is efficacious in elderly patients and suggesting that there is no need for special safety precautions. Funding Novo Nordisk. Trial Registration ClinicalTrials.gov identifiers, NCT01009580 and NCT01059812. Plain Language Summary Plain language summary available for this article.

Background Insulin degludec/insulin aspart (IDegAsp) is a fixed soluble co‐formulation of basal and bolus insulin. Objective To evaluate efficacy and safety of IDegAsp in pediatric patients with type 1 diabetes (T1D). Subjects Children and adolescents (aged 1 to <18 years) with T1D. Methods A 16‐week, phase 3b, treat‐to‐target, parallel‐group, open‐label, non‐inferiority trial was conducted at 63 sites in 14 countries from October 2013 to November 2014. Patients were randomized 1:1 (age stratified: 1‐<6 years; 6‐<12 years; 12‐<18 years) to IDegAsp once daily (OD) plus insulin aspart (IAsp) for remaining meals (IDegAsp + IAsp), or IDet OD or twice daily plus mealtime IAsp (IDet + IAsp). The primary end‐point was HbA1c change from baseline at week 16. Results A total of 362 participants were randomized to IDegAsp + IAsp (n = 182) or IDet + IAsp (n = 180). HbA1c decreased from baseline to week 16 by 0.3% in both groups (estimated treatment difference: −0.04%‐points [−0.23; 0.15]95%CI (−0.45 mmol/mol [−2.51; 1.60]95%CI), confirming non‐inferiority. There were no significant differences between treatment groups in fasting or self‐measured plasma glucose. Confirmed hypoglycemia rates did not significantly differ between groups. There was a significant reduction in basal and total insulin dose with IDegAsp + IAsp vs IDet + IAsp (post hoc analysis). Mean number of injections/day was 3.6 and 4.9 with IDegAsp + IAsp and IDet + IAsp, respectively (post hoc analysis). A non‐significant higher rate of severe hypoglycemia was observed with IDegAsp + IAsp vs IDet + IAsp. The most frequent adverse events in both groups were hypoglycemia, headache, and nasopharyngitis. Conclusions IDegAsp + IAsp was non‐inferior to IDet + IAsp regarding HbA1c, had similar hypoglycemia rates and required fewer injections.

Introduction The effects of the GLP-1 analogue liraglutide on time in hypoglycaemia, time in hyperglycaemia, and time in range for type 2 diabetes patients initially treated with multiple daily insulin injections (MDI) were investigated. Variables associated with hypoglycaemia in the current population were also identified. Methods Analyses were based on data from a previously performed double-blind, placebo-controlled trial in which 124 MDI-treated patients with type 2 diabetes were randomized to liraglutide or placebo. Masked continuous glucose monitoring (CGM) was performed at baseline and week 24 in 99 participants. Results The mean time in hypoglycaemia was similar for participants receiving liraglutide and those receiving placebo after 24 weeks of treatment. Mean time in target was greater in the liraglutide group than in the placebo group: 430 versus 244 min/24 h ( p  < 0.001) and 960 versus 695 min/24 h ( p  < 0.001) for the two glycaemic ranges considered, 4–7 mmol/l and 4–10 mmol/l, respectively. Mean time in hyperglycaemia was lower in the liraglutide group: 457 versus 723 min/24 h ( p  = 0.001) and 134 versus 264 min/24 h ( p  = 0.023) for the two cutoffs considered, > 10 mmol/l and > 14 mmol/l, respectively. Lower mean glucose level, lower C-peptide, and higher glucose variability were associated with an increased risk of hypoglycaemia in both treatment groups. Higher proinsulin level was associated with a lower risk of hypoglycaemia in the liraglutide group. Conclusion For type 2 diabetes patients initially treated with MDI, introducing liraglutide had a beneficial effect on glucose profiles estimated by masked CGM. Mean glucose level, glycaemic variability, C-peptide, and proinsulin level influenced the risk of hypoglycaemia in this population. Trial Registration ClinicalTrials.gov, number (EudraCT nr: 2012-001941-42). Funding Novo Nordisk funded this study. The Diabetes Research Unit, NU-Hospital Group funded the journal’s Rapid Service Fee.