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TPS4178 Background: Somatostatin receptor ligands (SRLs) are first-line standard of care therapies for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), showing efficacy in tumor/symptom control with an established safety profile. Yet, disease progression may occur despite standard-dose SRL treatment, requiring more aggressive and toxic therapies. Retrospective/non-randomized data suggest higher-dose SRLs may benefit patients with GEP-NETs who do not respond to standard-dose treatment and provide improved disease control. Octreotide depot (CAM2029) is a novel high-exposure, subcutaneous (SC) formulation. Clinical trials showed ̃500% higher CAM2029 bioavailability versus octreotide long-acting release (LAR) (Tiberg et al. 2015), and maintenance/reduction of NET symptoms (Pavel et al. 2019). Prospective, randomized data are needed to confirm the efficacy/safety of novel SRLs with higher bioavailability such as CAM2029, vs standard-dose SRLs including octreotide LAR and lanreotide Autogel (ATG). Methods: SORENTO is a randomized, multi-center, open-label, active-controlled Phase 3 trial, aiming to enroll 302 adults with GEP-NETs. Key eligibility criteria: advanced, well-differentiated NET of GEP/presumed GEP origin; ≥1 measurable SR positive (by nuclear imaging) lesion according to RECIST 1.1; no or < 6 months consecutive treatment with long-acting SRLs. Notably, patients with Grade 3 GEP-NETs (excluded by CLARINET/PROMID trials) are eligible. Patients will be randomized 1:1 to CAM2029 20 mg Q2W, or active comparator (octreotide LAR 30 mg intramuscular or lanreotide ATG 120 mg SC, Q4W). CAM2029 self/carer administration is allowed after ≥3 successful supervised administrations. Randomization stratified by: histological grade, tumor origin, intended comparator. Primary outcome: progression free survival (PFS; time from randomization to date of first documented disease progression [RECIST 1.1] or death), assessed by a Blinded Independent Review Committee. The study is powered to detect a hazard ratio of 0.65. Key secondary outcomes: overall survival; response rate; rescue medication use; patient satisfaction; adverse events. After primary PFS analysis, patient overall survival will be followed for up to 2 years. If CAM2029 displays superiority in the primary analysis, the comparator group may switch to CAM2029 20 mg Q2W. Patients in any treatment group experiencing progressive disease in the randomized part of the study may proceed to an open-label extension with intensified CAM2029 treatment, to investigate effects of higher frequency dosing. First patient randomized in Nov-2021, with readout (following 194 events) expected by 2024 end. This novel head-to-head superiority trial is anticipated to demonstrate the potential benefits of CAM2029 as a first line-therapy in patients with well-differentiated GEP-NETs. Clinical trial information: NCT05050942.

Purpose Sweetened beverage consumption is associated with type 2 diabetes (T2D) and LADA. We investigated to what extent this association is mediated by BMI and whether it is modified by genotypes of HLA, TCF7L2 rs7903146, or FTO rs9939609. Methods Swedish case–control data including incident cases of LADA (n = 386) and T2D (n = 1253) with matched population-based controls (n = 1545) was used. We estimated adjusted ORs of diabetes (95% CI) in relation to sweetened beverage intake (per daily 200 mL serving) and genotypes. The impact of BMI was estimated using causal mediation methodology. Associations with HOMA-IR and HOMA-B were explored through linear regression. Results Sweetened beverage intake was associated with increased risk of LADA (OR 1.15, 95% CI 1.03–1.29) and T2D (OR 1.21, 1.11–1.32). BMI was estimated to mediate 17% (LADA) and 56% (T2D) of the total risk. LADA was associated with risk variants of HLA (3.44, 2.63–4.50) and TCF7L2 (1.27, 1.00–1.61) but not FTO. Only among non-carriers of high-risk HLA genotypes was sweetened beverage intake associated with risk of LADA (OR 1.32, 1.06–1.56) and HOMA-IR (beta = 0.162, p = 0.0047). T2D was associated with TCF7L2 and FTO but not HLA, and the risk conferred by sweetened beverages appeared modified by FTO (OR 1.45, 95% CI 1.21–1.73 in non-carriers). Conclusions Our findings suggest that sweetened beverages are associated with LADA and T2D partly through mediation by excess weight, but possibly also through other mechanisms including adverse effects on insulin sensitivity. These effects seem more pronounced in individuals without genetic susceptibility.

Nutritional support is recommended for malnourished patients receiving anticancer treatment. In a recently executed pilot, double-blind, comparator-controlled trial evaluating the safety, and toler...

To study prevalence of diabetic retinopathy (DR) at diagnosis (DRAD) and to estimate contributing risk by sociodemographic, cardiovascular and metabolic characteristics present in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA).Patients (n=2174) recently diagnosed T2D (93%) or LADA (7%) were included upon arrival for their baseline DR screening. Fundus photographs of 4902 eyes were graded by a senior ophthalmologist according to the International Diabetic Retinopathy Disease Severity Scale. Official registers held by Statistics Sweden provided sociodemographic variables. The National Patient Register and Swedish Prescribed Drug Register were used to assess cardiovascular risk. Beta cell function (HOMA2%b) and insulin sensitivity (HOMA2%s) were estimated from fasting (f) C-Peptide using the homeostasis model assessment (HOMA) 2 calculator. Odds ratios (OR) for DRAD were estimated using generalized estimating equation models.The prevalence of DRAD was 12% (7% mild and 5% moderate) and of diabetic macular edema it was 11% (all within vascular arch). The prevalence did not significantly differ between T2D and LADA. Due to sample size, the regression analysis of LADA patients did not yield any significant estimates. In T2D low educational level (≤9years) increased risk for DRAD by 44% (OR 1.44; 95% CI 1.07-1.93) and50% beta-cell function adjusted for HbA1c and insulin sensitivity at diagnosis increased the risk by 77% (OR 1.77; 95% CI 1.28-2.44). For every unit increase in BMI, risk for DRAD decreased by 3% (OR 0.97; 95% CI 0.95-0.99).DRAD prevalence in patients recently diagnosed with T2D or is 12%. Low educational level and low beta cell function at diagnosis are risk factors for DRAD. Estimation of beta cell function from (f)C-Peptide and (f)P-Glucose may be a valuable tool in identifying patients at risk for DRAD.

Figure S1. Summary of percentage differences in volumetric mammography density observed by insulin therapy across the different observational analyses. Association of insulin therapy with volumetric mammographic density in different observational analyses with age and BMI adjusted estimates (open circles) and multivariable adjusted estimates (closed circles). Betas represent % differences in percent dense, absolute dense and absolute non-dense volume for differences in insulin exposure. (PDF 476 kb)

Supplementary methods: handing of missing covariate data. (DOCX 13 kb)

Figure S2. Association of the insulin genetic score with potential confounders. Association of 18-SNP insulin genetic score with potential confounders in Karma sub-cohort of non-diabetic women with genotyping data. Associations were tested using linear regression and (multinomial) logistic regression, adjusting for age, six principal components and genotyping array. Betas represent differences in covariate level per 1-standard deviation increment in insulin genetic score. (PDF 225 kb)

Table S1. Prescriptions of insulin and insulin analogs dispensed in the year prior to study entry in T1D and T2D patients. Table S2. Prescriptions of glucose-lowering medication dispensed in the year prior to study entry in T2D patients not receiving insulin therapy. Table S3. Single-nucleotide polymorphisms included in the insulin genetic score. Table S4. Descriptive characteristics of insulin-treated T2D patients and non-insulin-treated T2D patients. Table S5. Geometric means and percentage differences of volumetric mammographic density comparing glargine insulin users to non-glargine insulin users (case only analyes). Table S6. Geometric means and percentage differences of volumetric mammographic density comparing insulin-treated T2D patients to non-insulin treated T2D patients. Table S7. Geometric means and percentage differences of volumetric mammographic density comparing insulin-treated T1D and T2D patients to age-matched individuals without diabetes by insulin treatment duration. Table S8. Geometric means and percentage differences of volumetric mammographic density by treatment duration in insulin-treated T1D patients (case only analyses). Table S9. Associations of fasting insulin single nucleotide polymorphisms with volumetric mammographic density. (DOCX 88 kb)

Summary Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA 1c , and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. Interpretation We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes. Funding Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhalsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.

Background Long-term insulin exposure has been implicated in breast cancer etiology, but epidemiological evidence remains inconclusive. The aims of this study were to investigate the association of insulin therapy with mammographic density (MD) as an intermediate phenotype for breast cancer and to assess associations with long-term elevated circulating insulin levels using a genetic score comprising 18 insulin-associated variants. Methods We used data from the KARolinska MAmmography (Karma) project, a Swedish mammography screening cohort. Insulin-treated patients with type 1 (T1D, n = 122) and type 2 (T2D, n = 237) diabetes were identified through linkage with the Prescribed Drug Register and age-matched to 1771 women without diabetes. We assessed associations with treatment duration and insulin glargine use, and we further examined MD differences using non-insulin-treated T2D patients as an active comparator. MD was measured using a fully automated volumetric method, and analyses were adjusted for multiple potential confounders. Associations with the insulin genetic score were assessed in 9437 study participants without diabetes. Results Compared with age-matched women without diabetes, insulin-treated T1D patients had greater percent dense (8.7% vs. 11.4%) and absolute dense volumes (59.7 vs. 64.7 cm3), and a smaller absolute nondense volume (615 vs. 491 cm3). Similar associations were observed for insulin-treated T2D, and estimates were not materially different in analyses comparing insulin-treated T2D patients with T2D patients receiving noninsulin glucose-lowering medication. In both T1D and T2D, the magnitude of the association with the absolute dense volume was highest for long-term insulin therapy (≥ 5 years) and the long-acting insulin analog glargine. No consistent evidence of differential associations by insulin treatment duration or type was found for percent dense and absolute nondense volumes. Genetically predicted insulin levels were positively associated with percent dense and absolute dense volumes, but not with the absolute nondense volume (percentage difference [95% CI] per 1-SD increase in insulin genetic score = 0.8 [0.0; 1.6], 0.9 [0.1; 1.8], and 0.1 [− 0.8; 0.9], respectively). Conclusions The consistency in direction of association for insulin treatment and the insulin genetic score with the absolute dense volume suggest a causal influence of long-term increased insulin exposure on mammographic dense breast tissue. Electronic supplementary material The online version of this article (10.1186/s13058-018-1026-7) contains supplementary material, which is available to authorized users.

BackgroundDiabetes is presently classified into two main forms, type 1 (T1D) and type 2 diabetes (T2D), but especially T2D is highly heterogeneous. A refined classification could provide a powerful tool individualize treatment regimes and identify individuals with increased risk of complications already at diagnosis.MethodsWe applied data-driven cluster analysis (k-means and hierarchical clustering) in newly diagnosed diabetic patients (N=8,980) from the Swedish ANDIS (All New Diabetics in Scania) cohort, using five variables (GAD-antibodies, BMI, HbA1c, HOMA2-B and HOMA2-IR), and related to prospective data on development of complications and prescription of medication from patient records. Replication was performed in three independent cohorts: the Scania Diabetes Registry (SDR, N=1466), ANDIU (All New Diabetics in Uppsala, N=844) and DIREVA (Diabetes Registry Vaasa, N=3485). Cox regression and logistic regression was used to compare time to medication, time to reaching the treatment goal and risk of diabetic complications and genetic associations.FindingsWe identified 5 replicable clusters of diabetes patients, with significantly different patient characteristics and risk of diabetic complications. Particularly, individuals in the most insulin-resistant cluster 3 had significantly higher risk of diabetic kidney disease, but had been prescribed similar diabetes treatment compared to the less susceptible individuals in clusters 4 and 5. The insulin deficient cluster 2 had the highest risk of retinopathy. In support of the clustering, genetic associations to the clusters differed from those seen in traditional T2D.InterpretationWe could stratify patients into five subgroups predicting disease progression and development of diabetic complications more precisely than the current classification. This new substratificationn may help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.FundingThe funders of the study had no role in study design, data collection, analysis, interpretation or writing of the report.Research in contextEvidence before this studyThe current diabetes classification into T1D and T2D relies primarily on presence (T1D) or absence (T2D) of autoantibodies against pancreatic islet beta cell autoantigens and age at diagnosis (earlier for T1D). With this approach 75-85% of patients are classified as T2D. A third subgroup, Latent Autoimmune Diabetes in Adults (LADA,Added value of this studyHere we applied a data-driven cluster analysis of 5 simple variables measured at diagnosis in 4 independent cohorts of newly-diagnosed diabetic patients (N=14755) and identified 5 replicable clusters of diabetes patients, with significantly different patient characteristics and risk of diabetic complications. Particularly, individuals in the most insulin-resistant cluster 3 had significantly higher risk of diabetic kidney disease.Implications of the available evidenceThis new sub-stratification may help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Excess cortisol and GH induce insulin resistance, a central feature of type 2 diabetes (T2D). To study whether the insulin sensitizer pioglitazone affects basal cortisol levels and the GH-IGF-I axis in patients with T2D. Forty-eight patients with T2D (men/women = 28:20, age 61 ± 1 years, BMI 31 ± 0.6 kg/m(2)) were treated for 26 weeks with pioglitazone 30-45 mg daily in addition to their preexisting therapy. Insulin, proinsulin, HbA(1c), IGF-I, IGFBP-1, and basal cortisol were analyzed before and after treatment. Pioglitazone decreased proinsulin/insulin ratio and HbA(1c) decreased (HbA(1c) from 7.8 ± 0.2 to 6.6 ± 0.2% in men and from 7.6 ± 0.2 to 6.1 ± 0.2% in women, p0.001 in both). There was a redistribution of fat but no change in waist circumference. IGF-I and adiponectin increased (p ≤ 0.001) in both genders. IGFBP-1 increased but significantly only for the whole group (p = 0.033). Triglycerides decreased significantly in women only (p = 0.015). Before treatment, women had lower basal cortisol (p = 0.045). Basal cortisol increased in women (from 390 ± 26 to 484 ± 32 nmol/L, p = 0.020) but not in men and did not differ between genders at week 26. ΔIGFBP-1 correlated with Δcortisol (r = 0.458; p = 0.049) and Δadiponectin (r = 0.600; p = 0.005) in women only. In addition to the known effect of improving insulin sensitivity, pioglitazone increased IGF-I regardless of gender and in women also increased basal cortisol. Increased IGF-I may contribute to improved insulin sensitivity after treatment. There seems to be gender differences in treatment responses to pioglitazone on lipid metabolism and basal cortisol, perhaps correcting different mechanisms of insulin resistance between genders.

Objectives The aim of this research is to study education, income and immigration as risk factors for high hemoglobin A1c (HbA1c >70 mmol/mol (8.6%)) when diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA). Research design and methods Patients were included from the All New Diabetics in Scania study (2008-2013). Level of education, disposable income and immigration year were retrieved from the longitudinal integrated database for labour market research (LISA) register compiled by Statistics Sweden. Logistic regression models were used to estimate ORs for HbA1c >70 mmol/mol (8.6%) at diagnosis. Results A total of 3794 patients with incident T2D (n=3 525) or LADA (n=269) were included. Patients with T2D with a low (≤9 years) or medium (10-12 years) levels of education were more likely to have high HbA1c at diagnosis compared with patients with T2D with a high (>12 years) level of education (OR 1.34, 95% CI 1.08 to1.66, OR 1.26, 95% CI 1.03 to 1.54). Low-income patients with T2D (150% of median) (OR 1.35, 95% CI 1.02 to 1.79). Conclusions Patients with lower levels of education or low income and are more likely to have HbA1c is >70 mmol/mol (8.6%) when diagnosed with T2D. An understanding of how socioeconomic position influences the clinical presentation at diagnosis may facilitate screening programs designed to target populations at risk for delayed diagnosis.

Objective Sweetened beverage intake is associated with increased risk of type 2 diabetes, but its association with autoimmune diabetes is unclear. We aimed to investigate sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA); autoimmune diabetes with features of type 2 diabetes. Design/methods Data from a Swedish population-based study was used, including incident cases of LADA (n = 357) and type 2 diabetes (n = 1136) and randomly selected controls (n = 1371). Diabetes classification was based on onset age (≥35), glutamic acid decarboxylase autoantibodies (GADA) and C-peptide. Sweetened beverage intake information was derived from a validated food frequency questionnaire. ORs adjusted for age, sex, family history of diabetes, education, lifestyle, diet, energy intake and BMI were estimated using logistic regression. Results Daily intake of >2 servings of sweetened beverages (consumed by 6% of participants) was associated with increased risk of LADA (OR: 1.99, 95% CI: 1.11–3.56), and for each 200 mL daily serving, OR was 1.15 (95% CI: 1.02–1.29). Findings were similar for sugar-sweetened (OR: 1.18, 95% CI: 1.00–1.39) and artificially sweetened beverages (OR: 1.12, 95% CI: 0.95–1.32). Similarly, each daily serving increment in total sweetened beverage conferred 20% higher type 2 diabetes risk (95% CI: 1.07–1.34). In type 2 diabetes patients, high consumers displayed higher HOMA-IR levels (4.5 vs 3.5, P = 0.0002), but lower HOMA-B levels (55 vs 70, P = 0.0378) than non-consumers. Similar tendencies were seen in LADA. Conclusions High intake of sweetened beverages was associated with increased risk of LADA. The observed relationship resembled that with type 2 diabetes, suggesting common pathways possibly involving insulin resistance.

Aims/hypothesis Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10). Conclusions/interpretation We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background It is known that narrowband ultraviolet B (NB-UVB) radiation and oral vitamin D-3 supplementation can both improve serum levels of vitamin D, expressed as 25-hydroxyvitamin D-3 [25(OH)D-3]. However, surprisingly few studies have compared the effects of the two interventions in treating vitamin D deficiency. Objectives To compare the effect of NB-UVB exposure with oral vitamin D-3 supplementation on vitamin D levels in patients with vitamin D deficiency. Methods Seventy-three participants with vitamin D deficiency [25(OH)D-3

BACKGROUND: While metformin is the first line treatment in type 2 diabetes, the best way to escalate therapy is not always clear, particularly whether to add one or two oral agents or to introduce insulin. METHODS: Thirty-six patients inadequately controlled on metformin and sulfonylurea/meglitinide were randomized to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Insulin was up-titrated to achieve fasting plasma glucose 6.2%. beta-Cell function and insulin sensitivity were assessed by measuring insulin, proinsulin and adiponectin, and in a subgroup using a combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). Lipids and natriuretic peptides were measured at start and end of study. RESULTS: The reduction in HbA1c was slightly greater in the insulin glargine group and used as co-variate when analysing other variables. The effect on beta-cell function was more favourable with insulin glargine measured by proinsulin (42+/-48 to 19+/-16, p=0.01 vs. 36+/-26 to 27+/-16 p=0.04) while the improvement in insulin sensitivity measured by adiponectin (7.5+/-3.7 to 15+/-10, p

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381

ObjectiveModerate alcohol consumption is associated with a reduced risk of type 2 diabetes. Our aim was to investigate whether alcohol consumption is associated with the risk of latent autoimmune diabetes in adults (LADA), an autoimmune form of diabetes with features of type 2 diabetes.DesignA population-based case–control study was carried out to investigate the association of alcohol consumption and the risk of LADA.MethodsWe used data from the ESTRID case–control study carried out between 2010 and 2013, including 250 incident cases of LADA (glutamic acid decarboxylase antibodies (GADAs) positive) and 764 cases of type 2 diabetes (GADA negative), and 1012 randomly selected controls aged ≥35. Logistic regression was used to estimate the odds ratios (ORs) of diabetes in relation to alcohol intake, adjusted for age, sex, BMI, family history of diabetes, smoking, and education.ResultsAlcohol consumption was inversely associated with the risk of type 2 diabetes (OR 0.95, 95% CI 0.92–0.99 for every 5-g increment in daily intake). Similar results were observed for LADA, but stratification by median GADA levels revealed that the results only pertained to LADA with low GADA levels (OR 0.85, 95% CI 0.76–0.94/5 g alcohol per day), whereas no association was observed with LADA having high GADA levels (OR 1.00, 95% CI 0.94–1.06/5 g per day). Every 5-g increment of daily alcohol intake was associated with a 10% increase in GADA levels (P=0.0312), and a 10% reduction in homeostasis model assessment of insulin resistance (P=0.0418).ConclusionsOur findings indicate that alcohol intake may reduce the risk of type 2 diabetes and type 2-like LADA, but has no beneficial effects on diabetes-related autoimmunity.

Objective: It has been suggested that intake of fatty fish may protect against both type 1 and type 2 diabetes. Hypotheses rest on the high marine omega-3 fatty acid eicosapentaenoic acid+docosahexaenoic acid (EPA+DHA) and vitamin D contents, with possible beneficial effects on immune function and glucose metabolism. Our aim was to investigate, for the first time, fatty fish consumption in relation to the risk of latent autoimmune diabetes in adults (LADA). Methods: Analyses were based on data from a Swedish case–control study with incident cases of LADA (n=89) and type 2 diabetes (n=462) and randomly selected diabetes-free controls (n=1007). Diabetes classification was based on the onset of age (⩾35), glutamic acid decarboxylase autoantibodies, and C-peptide. A validated food frequency questionnaire was used to derive information on previous intake of fish, polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) and supplementation of fish oil and vitamin D. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression, adjusted for age, gender, body mass index (BMI), family history of diabetes, physical activity, smoking, education, and consumption of alcohol, fruit, vegetables and red meat. Results: Weekly fatty fish consumption (⩾1 vs

Risk factors for breast cancer vary according to breast cancer subtype. This study analyzes the impact of potential risk factors in breast cancer by androgen receptor (AR) status. A total of 17,035 women were followed in the population-based prospective Malmo Diet and Cancer Study. Baseline data included lifestyle factors including anthropometry, reproductive history, and exogenous hormone use. During follow-up (mean: 12.8 years), 747 invasive breast cancers were diagnosed. Expression of AR was determined by immunohistochemistry in tumor tissue microarrays. AR status was assessable in 516 of 747 tumors (69%). Among these, 467 tumors (90.5%) were AR positive (AR+) and 49 tumors (9.5%) were AR negative (AR-). AR negativity was significantly associated with estrogen receptor (ER) and progesterone receptor negativity, higher grade and proliferation (Ki67). Cox regression analyses stratified by AR status showed significant associations between reproductive factors and AR- breast cancer. The older the woman at first childbirth the higher the risk of AR- breast cancer; adjusted HR≤20yrs = 0.35, HR>20–≤25yrs = 0.62, HRnulliparous = 1.00, HR>25–≤30yrs = 1.29, HR>30yrs = 1.92, p trend = 0.001. No such association was seen for AR+ tumors. Similarly, ever oral contraceptive use increased the risk of AR- breast cancer [Adj. HR = 2.59, 95% CI (1.26–5.34)] compared to never use, but not for AR+ breast cancer. Advanced age at first child birth and use of oral contraceptives were associated with increased risk of AR− breast cancer. This study may contribute to enhanced understanding of the role of the AR in breast carcinogenesis and improve risk stratification tools for personalized breast cancer prevention.

Background: Thyroid hormones induce insulin resistance. Pioglitazone is a peroxisome proliferator activated receptor gamma (PPARγ) agonist, used as treatment of type 2 diabetes (T2D) to increase insulin sensitivity. PPARs and thyroid hormone receptors (TRs) induce intracellular effects through similar molecular mechanisms, and the former may inhibit activation of the latter. Pioglitazone has been shown to increase eye protrusion, a symptom linked both to disturbed thyroid hormone levels and orbital edema secondary to increased IGF-I. Aims: We investigated whether attenuation of insulin resistance with pioglitazone affects thyroid hormone status and IGF-I. Methods: 48 patients with T2D were treated with pioglitazone for 26 weeks. Thyroid hormones and IGF-I were analyzed before and after treatment. Results: After treatment, decreased free T4 decreased (from 14.2+0.4 to 13.3+0.3 pmol/L, p=0.009) and TSH increased (from 190+200 to 220+200 U/L, p = 0.004). IGF-I also increased (from 0.5 ± 0.2 to 1.0 ± 0.2 SD, p

Aims Coffee consumption is associated with a reduced risk of Type2 diabetes. Our aim was to investigate if coffee intake may also reduce the risk of latent autoimmune diabetes in adults, an autoimmune form of diabetes with features of Type2 diabetes. Methods We used data from a population-based case-control study with incident cases of adult onset (35years) diabetes, including 245 cases of latent autoimmune diabetes in adults (glutamic acid decarboxylase antibody positive), 759 cases of Type2 diabetes (glutamic acid decarboxylase antibody negative), together with 990 control subjects without diabetes, randomly selected from the population. Using questionnaire information on coffee consumption, we estimated the odds ratio of latent autoimmune diabetes in adults and Type2 diabetes adjusted for age, sex, BMI, smoking, physical activity, alcohol, education and family history of diabetes. Results Coffee intake was inversely associated with Type2 diabetes (odds ratio0.92, 95%CI 0.87-0.98 per cup/day). With regard to latent autoimmune diabetes in adults, the general trend was weak (odds ratio1.04, 95%CI 0.96-1.13), but stratification by degree of autoimmunity (median glutamic acid decarboxylase antibody levels) suggested that coffee intake may be associated with an increased risk of high glutamic acid decarboxylase antibody latent autoimmune diabetes in adults (odds ratio1.11, 95%CI 1.00-1.23 per cup/day). Furthermore, for every additional cup of coffee consumed per day, there was a 15.2% (P=0.0268) increase in glutamic acid decarboxylase antibody levels. Conclusions Our findings confirm that coffee consumption is associated with a reduced risk of Type2 diabetes. Interestingly, the findings suggest that coffee may be associated with development of autoimmunity and possibly an increased risk of more Type1-like latent autoimmune diabetes in adults.

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.

While metformin is the first line treatment in type 2 diabetes, the best way to escalate therapy is not always clear, particularly whether to add one or two oral agents or to introduce insulin.Thirty-six patients inadequately controlled on metformin and sulfonylurea/meglitinide were randomized to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Insulin was up-titrated to achieve fasting plasma glucose6 mmol/l. Pioglitazone was increased to 45 mg/day after 16 weeks if HbA1c6.2%. beta-Cell function and insulin sensitivity were assessed by measuring insulin, proinsulin and adiponectin, and in a subgroup using a combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). Lipids and natriuretic peptides were measured at start and end of study.The reduction in HbA1c was slightly greater in the insulin glargine group and used as co-variate when analysing other variables. The effect on beta-cell function was more favourable with insulin glargine measured by proinsulin (42+/-48 to 19+/-16, p=0.01 vs. 36+/-26 to 27+/-16 p=0.04) while the improvement in insulin sensitivity measured by adiponectin (7.5+/-3.7 to 15+/-10, p0.01 vs. 8.7+/-4 to 7.6+/-3, p=0.04) and HDL cholesterol (1.10+/-0.24 to 1.24+/-0.3, p0.01 vs. 1.08+/-0.35 to 1.04+/-0.33, ns) (all p between groups0.01) was more favourable in pioglitazone group. Pioglitazone caused significant increase in natriuretic peptides (BNP pmol/l 6.6+/-5.2 to 13.7+/-16.1, p=0.04 vs. 8.8+/-11.6 to 8.6+/-10.6, ns, p between groups 0.028).The results demonstrate characteristic differences in the effects of insulin glargine vs. pioglitazone on measures of beta-cell function and insulin sensitivity as well as cardiac load.

Background. To validate a test for independent assessment of insulin secretion and insulin sensitivity during the same occasion for metabolic studies in clinical practice, i.e. combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). Subjects and methods. We measured C-peptide response to 0.5 mg of intravenous glucagon followed 30 min later by administration of 0.05 U kg(-1) insulin (insulin tolerance test, ITT). Ten subjects with normal glucose tolerance participated on different days in an ITT, glucagon-C-peptide test, ITT followed by glucagon-C-peptide test and glucagon-C-peptide test followed by ITT to establish whether and how the tests could be combined. The test was then repeated in nine patients with type 2 diabetes to investigate its reproducibility. In 20 subjects with varying degrees of glucose tolerance, the test was compared with the Botnia clamp (an intravenous glucose tolerance test combined with a euglycaemic hyperinsulinemic clamp). Results. When ITT preceded the glucagon test, C-peptide response was blunted. Therefore, we first administered glucagon and then insulin (GITT). The K(ITT) from the GITT was reproducible (CV = 13 %) and correlated strongly with the glucose disposal rate from the Botnia clamp (r = 0.87, r(2) = 0.75, P < 0.001). The C-peptide response to glucagon was reproducible (CV = 13 %). The disposition index, providing a measure of beta-cell function adjusted for insulin sensitivity, calculated from the GITT showed good discrimination between individuals with varying degrees of glucose tolerance. Conclusions. The GITT provides simple, reproducible and independent estimates of insulin sensitivity and secretion on the same occasion for metabolic studies in individuals with normal and abnormal glucose tolerance. (Less)

Objectives. To examine pioglitazone as add-on to metformin and insulin secretagogues in patients with type 2 diabetes and inadequate glycaemic control and its effect on glycaemic control, surrogate measures of insulin sensitivity (adiponectin) and b-cell function (proinsulin/insulin) and fluid retention. Design and setting. Prospective open-label study of 54 patients with type 2 diabetes and HbA1c ‡6.5% admitted to outpatient unit at Malmo¨ University Hospital. The patients received 30–45 mg pioglitazone daily during 26 weeks in addition to their existing antidiabetic medication. After 26 weeks, one-third of patients were followed for 3 months without pioglitazone. Results. HbA1c decreased (7.8 ± 0.9–6.3 ± 0.9%, P < 0.001) with 61% of patients achieving levels

Summary Objective Changes in eye protrusion in patients treated with pioglitazone. Design Open-label prospective. Patients Thirty-six patients with type 2 diabetes and HbA1c ≥ 6·5% were included in a study where pioglitazone was added to current therapy with metformin and sulphonylurea. Measurements The degree of eye protrusion before and 26 weeks after treatment with pioglitazone was measured using Krahn's exophthalmometer. Results Thirteen patients (group A) exhibited an increase of ≥ 2 mm and 23 patients (group B) exhibited an increase of

Aim: The importance of the androgen receptor (AR) as a prognostic factor and a possible treatment target is currently debated. However, the impact of lifestyle factors on AR status in breast cancer has not yet been addressed. The aim of this study was to evaluate the influence of hormonal lifestyle factors on AR-defined breast cancer risk. Materials and methods: The population-based prospective Malmö Diet and Cancer Study including 16,459 women were followed using record-linkage with national cancer registries. Baseline data of all women in the cohort included socioeconomic factors, reproductive factors including use of exogenous hormones and anthropometry. During an average follow-up of 12.8 years, 747 cases of invasive breast cancer were diagnosed. AR was assessed immunohistochemically by monoclonal antibody Ab-1 (Clone AR441, Thermo Scientific, USA). A tumor was considered AR positive (AR+) when >10% positive nuclei. A valid AR score was obtained from 516 tumors. The expression of ER, PR, Ki67 along with information on HER2 status, tumor size, histological type, tumor grade and axillary lymph node involvement was obtained. Reproductive factors were compared with tumor characteristics based on AR status. Distribution of clinicopathological data and odds ratios in relation to AR status were analyzed. Hazard ratios (HR) were calculated using Cox's proportional hazards analysis. Survival analyses in relation to AR status were carried out using Kaplan-Meier Log Rank test. Results: A total of 467 tumors (90.5%) were AR+ and 49 tumors (9.5%) were AR negative (AR-). AR positivity correlated significantly to lower tumor grade, lower proliferation and ER and PR co-expression. There was a significant trend of increasing risk of AR- breast cancer by increasing age at first childbirth (HR30 yrs =2.01, Ptrend=0.002 among parous women). The risk for AR+ breast cancer was not affected by age at first birth. Ever oral contraceptive (OC) users had an increased risk of AR- breast cancer (HR=2.10, 95% CI 1.16-3.81, P=0.015) compared to never users. OC use was neither associated with risk for breast cancer in general nor with AR+ breast cancer. The use of combined estrogen and progestin hormonal replacement therapy (cHRT) was significantly associated with increased risk for breast cancer (HRall=2.13, P= Conclusion: In conclusion, reproductive factors and exogenous hormones influenced the risk for AR-defined breast cancer. Specifically, the older the age at first childbirth, the higher the risk for AR- breast cancer. Similarly, ever OC users had a higher risk of AR- breast cancer compared to never users. This study contributes to a deepened understanding of AR in relation to breast cancer risk factors and may yield improved risk stratification tools for breast cancer prevention and treatment. Citation Format: Karin Elebro, Salma Butt, Mozhgan Dorkhan, Helena Jernström, Signe Borgquist. Oral contraceptives and late first childbirth increase the risk of androgen receptor-negative breast cancer: The Malmö Diet and Cancer cohort. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A126.

Introduction The aim of the present study was to use real-world data from Swedish primary-care and national registries to understand clinical outcomes in patients with Type 2 diabetes (T2D) treated with liraglutide in clinical practice, and to compare with data from those treated with sitagliptin. Methods This was a non-interventional, retrospective study conducted between February 2014 and September 2014 using T2D patient data from Swedish primary-care centers and national healthcare registries. The primary objective was to assess the effectiveness of liraglutide in control of glycemia and body weight in clinical practice (stage 1). The secondary objective was to compare the clinical effectiveness of liraglutide with sitagliptin on glycemic control and body weight in clinical practice in a propensity-score-matched population (stage 2). Results In stage 1 (n = 402), 39.4% of patients treated with liraglutide achieved ≥1.0% (10.9 mmol/mol) reduction in glycated hemoglobin (HbA1c) after 180 days of treatment and 54.9% achieved the target HbA1c of

Figure S3. Association of the insulin genetic score with volumetric mammographic density measures after additional adjustment for benign breast disease. Association of 18-SNP insulin genetic score with volumetric mammographic density in Karma sub-cohort of non-diabetic women with genotyping data, overall and stratified by genotyping array and with additional adjustment for benign breast disease. Associations with volumetric mammographic density were tested by linear regression, adjusting for age, body mass index, menopausal status, six principal components and benign breast disease. Analyses in total sub-cohort were additionally adjusted for genotyping array. All volumetric mammographic density measures were log-transformed prior to analyses, with betas representing % differences in volumetric mammographic density per 1-standard deviation increment in insulin genetic score. (PDF 146 kb)

Magnus Dencker1, Martin Stagmo2, Mozhgan Dorkhan31Unit of Clinical Physiology and Nuclear Medicine, Department of Clinical Sciences, 2Division of Cardiology, 3Division of Diabetes and Endocrinology, Malmö University Hospital, Malmö, SwedenAbstract: This study evaluated the relationship between natriuretic peptide levels and a wide range of echocardiography parameters in a population of thirty-three patients with poorly regulated type 2 diabetes, and no known heart failure. Natriuretic peptides brain natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-proBNP) were measured. Transthoracic echocardiography was performed and cardiac volumes and ejection fraction were measured. Doppler and tissue Doppler were measured and diastolic function was stratified according to recent guidelines. Very few echocardiography parameters were correlated with BNP or NT-proBNP levels. However, left atrial end-systolic volume indexed for body surface area was correlated with natural logarithm (ln) BNP and ln NT-proBNP (r = 0.62 and r = 0.60; P < 0.05). There were significant differences in ln BNP and ln NT-proBNP levels between those with normal and those with abnormal diastolic function (1.4 vs 3.1; P < 0.001 and 3.4 vs 5.8; P < 0.001). This study showed that very few echocardiography parameters were correlated with BNP or NT-proBNP levels in patients with poorly regulated type 2 diabetes, which in part contradicts previous studies in other diabetic populations. The exception was left atrial end-systolic volume that showed a moderate correlation with BNP or NT-proBNP levels. There were significant differences in BNP and NT-proBNP levels between the group with normal left ventricular diastolic function and the group with abnormal diastolic function.Keywords: type 2 diabetes, natriuretic peptides, echocardiography

Table S1. Prescriptions of insulin and insulin analogs dispensed in the year prior to study entry in T1D and T2D patients. Table S2. Prescriptions of glucose-lowering medication dispensed in the year prior to study entry in T2D patients not receiving insulin therapy. Table S3. Single-nucleotide polymorphisms included in the insulin genetic score. Table S4. Descriptive characteristics of insulin-treated T2D patients and non-insulin-treated T2D patients. Table S5. Geometric means and percentage differences of volumetric mammographic density comparing glargine insulin users to non-glargine insulin users (case only analyes). Table S6. Geometric means and percentage differences of volumetric mammographic density comparing insulin-treated T2D patients to non-insulin treated T2D patients. Table S7. Geometric means and percentage differences of volumetric mammographic density comparing insulin-treated T1D and T2D patients to age-matched individuals without diabetes by insulin treatment duration. Table S8. Geometric means and percentage differences of volumetric mammographic density by treatment duration in insulin-treated T1D patients (case only analyses). Table S9. Associations of fasting insulin single nucleotide polymorphisms with volumetric mammographic density. (DOCX 88 kb)

Background Both insulin and thiazolidinediones (TZDs) are effective in the treatment of hyperglycaemia and amelioration of insulin resistance in type 2 diabetes but have side effects including weight gain and fluid retention. The use of TZDs has been further hampered by the risk of adverse cardiovascular events including heart failure. The present study evaluated the effect of pioglitazone or insulin glargine on cardiac function and size as well as on surrogate markers of fluid retention such as weight, haemoglobin and natriuretic peptides. Methods Thirty patients with inadequate glycaemic control on metformin and sulfonylurea were randomised to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Echocardiographic data and blood samples were collected from the two groups before the start of the treatment and after 26 weeks. Left ventricular end-diastolic and left atrial end-systolic volumes were quantified, weight measured and blood samples analyzed. Results After 26 weeks of treatment, the changes in HbA1c, weight and haemoglobin were similar between the two groups. HDL increased significantly in the pioglitazone group. While there was an increase in natriuretic peptides in the pioglitazone group (NT-proBNP 11.4 ± 19.6 to 22.8 ± 44.0, p = 0.046), the difference between the treatment groups was not significant. Left ventricular end-diastolic volume increased by 11% and left atrial end-systolic volume by 17% in the pioglitazone group (Both, p < 0.05, between treatment groups). There was a borderline significant increase in ejection fraction in the pioglitazone group. Conclusion This randomised pilot-study showed that six-month treatment with pioglitazone induced significant increases in natriuretic peptides and alterations of cardiac size. These changes were not observed with insulin glargine, which also is known to induce fluid retention. Larger randomised trials are warranted to confirm these findings.