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Background and Purpose: This study aimed at training and validating a multi-institutional deep learning (DL) auto segmentation model for nodal clinical target volume (CTVn) in high-risk breast cancer (BC) patients with both training and validation dataset created with multi-institutional participation, with the overall aim of national clinical implementation in Denmark., Materials and Methods: A gold standard (GS) dataset and a high-quality training dataset were created by 21 BC delineation experts from all radiotherapy centres in Denmark. The delineations were created according to ESTRO consensus delineation guidelines. Four models were trained: One per laterality and extension of CTVn internal mammary nodes. The DL models were tested quantitatively in their own test-set and in relation to interobserver variation (IOV) in the GS dataset with geometrical metrics, such as the Dice Similarity Coefficient (DSC). A blinded qualitative evaluation was conducted with a national board, presented to both DL and manual delineations., Results: A median DSC > 0.7 was found for all, except the CTVn interpectoral node in one of the models. In the qualitative evaluation 'no corrections needed' were acquired for 297 (36 %) in the DL structures and 286 (34 %) for manual delineations. A higher rate of 'major corrections' and 'easier to start from scratch' was found in the manual delineations. The models performed within the IOV of an expert group, with two exceptions., Conclusion: DL models were developed on a national consensus cohort and performed on par with the IOV between BC experts and had a comparable or higher clinical acceptance than expert manual delineations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The prescription-based Rx-risk index has previously been developed to measure multimorbidity. We aimed to adapt and evaluate the validity of the Rx-risk index in prediction of mortality among persons with type 2 diabetes., Design: Registry-based study., Setting: Adults with type 2 diabetes in Norway identified within the 'Outcomes and Multimorbidity In Type 2 diabetes' cohort, with linkage to prescriptions from the Norwegian Prescription Database and mortality from the Population Registry., Participants: We defined a calibration sample of 42 290 adults diagnosed with type 2 diabetes 1950-2013, and a temporal validation sample of 7085 adults diagnosed 2014-2016 to evaluate the index validity over time PRIMARY OUTCOME MEASURE: All-cause mortality METHODS: For the calibration sample, dispensed drug prescriptions in 2013 were used to define 44 morbidity categories. Weights were estimated using regression coefficients from a Cox regression model with 5 year mortality as the outcome and all morbidity categories, age and sex included as covariates. The Rx-risk index was computed as a weighted sum of morbidities. The validity of the index was evaluated using C-statistic and calibration plots., Results: In the calibration sample, mean (SD) age at start of follow-up and duration of diabetes was 63.8 (12.4) and 10.1 (7.0) years, respectively. The overall C-statistic was 0.82 and varied from 0.74 to 0.85 when stratifying on age groups, sex, level of education and country of origin. In the validation sample, mean (SD) age and duration of diabetes was 59.7 (13.0) and 2.0 (0.8) years, respectively. Despite younger age, shorter duration of diabetes and later time period, the C-index was high both in the total sample (0.84) and separately for men (0.83) and women (0.84)., Conclusions: The Rx-risk index showed good discrimination and calibration in predicting mortality and thus presents a valid tool to assess multimorbidity among persons with type 2 diabetes., Competing Interests: Competing interests: JI is the head of the Core Facility for Biostatistics and Data Analysis (BIOS) at the University of Bergen which has performed contracted research for Sanofi Aventis and Pfizer on antiseizure medications, not related to this work. ESB is a previous employee of Novo Nordisk (2011–2016) and has offered medical consulting and lectures to Novo Nordisk, Sanofi Aventis and MundiPharma. All other authors declare no conflicts of interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective : We opted to study how support staff operational capacity and diabetes competences may impact the timeliness of basal insulin-initiation in general practice patients with type 2 diabetes (T2D). Design/Setting/Outcomes: This was an observational and retrospective study on Norwegian primary care patients with T2D included from the ROSA4-dataset. Exposures were (1) support staff size, (2) staff size relative to number of GPs, (3) clinic access to a diabetes nurse and (4) share of staff with diabetes course (1 and 2 both relate to staff operational capacity, whereas 3 and 4 are both indicatory of staff diabetes competences). Outcomes were 'timely basal insulin-initiation' (primary) and 'attainment of HbA 1c <7%' after insulin start-up (secondary). Associations were analyzed using multiple linear regression, and directed acyclic graphs guided statistical adjustments. Subjects: Insulin naïve patients with 'timely' ( N  = 294), 'postponed' ( N  = 219) or 'no need of' ( N  = 3,781) basal insulin-initiation, respectively. Results: HbA 1c [median (IQR)] increased to 8.8% (IQR, 8.0, 10.2) prior to basal insulin-initiation, which reduced HbA 1c to 7.3 (6.8-8.1) % by which only 35% of the subjects reached HbA 1c <7%. Adjusted risk of 'timely basal insulin-initiation' was more than twofold higher if access to a diabetes nurse (OR = 2.40, [95%CI, 1.68, 3.43]), but related only vaguely to staff size (OR = 1.01, [95%CI, 1.00, 1.03]). No other staff factors related significantly to neither the primary nor the secondary outcome. Conclusion: In Norwegian general practice, insulin initiation in people with T2D may be affected by therapeutic inertia but access to a diabetes nurse may help facilitating more timely insulin start-up.

Introduction: People with young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, have a high lifetime risk of vascular complications. We aimed to estimate the prevalence of YOD among adults with type 2 diabetes (T2D) in Norwegian general practice and explore associations between age at diabetes diagnosis and retinopathy overall and in men and women., Research Design and Methods: We collected cross-sectional data from general practice electronic medical records of 10 241 adults with T2D in 2014, and repeated measurements of hemoglobin A 1c (HbA 1c ) from 2012 to 2014. Using multivariate logistic regression, we assessed associations between YOD and later-onset T2D, sex and retinopathy., Results: Of all individuals with T2D, 10% were diagnosed before 40 years of age in both sexes. Compared with later-onset T2D, HbA 1c increased faster in YOD, and at the time of diagnosis HbA 1c was higher in men, particularly in YOD. Retinopathy was found in 25% with YOD, twice as frequently as in later onset. After adjustments for confounders (age, country of origin, education, body mass index), OR of retinopathy was increased in both men with YOD (OR 2.6 (95% CI 2.0 to 3.5)) and women with YOD (OR 2.2 (1.5 to 3.0)). After further adjustments for potential mediators (diabetes duration and HbA 1c ), the higher OR persisted in men with YOD (OR 1.8 (1.3 to 2.4)) but was attenuated and no longer significant for women with YOD., Conclusions: Retinopathy prevalence was more than twice as high in YOD as in later-onset T2D. The increased likelihood of retinopathy in YOD was partly mediated by higher HbA 1c and longer T2D duration, but after accounting for these factors it remained higher in men with YOD., Competing Interests: Competing interests: ESB is a previous employee of Novo Nordisk (2011-2016) and has offered medical consulting and lectures to Novo Nordisk, Sanofi Aventis and MundiPharma. All other authors declare no conflicts of interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Diabetes educational programmes should be offered to patients with type 2 diabetes mellitus (T2DM). We assessed the proportion of diabetes educational program participation among adults with T2DM, and its associations with place of residence in Norway, education, and immigrant background., Methods: We identified 28,128 diagnosed with T2DM (2008-2019) in the Outcomes & Multi-morbidity In Type 2 diabetes cohort. To examine associations between sociodemographic factors and participation in diabetes start courses (yes/no), we computed adjusted risk ratios (95% CI) using log-binomial regression., Results: Overall, 18% participated on the diabetes start course, but partaking differed by Norwegian counties (range:12-34%). Individuals with an immigrant background were 29% less likely to participate (RR 0.71, CI 0.65-0.79). Similarly, those with a lower educational level were 23% less likely to participate (RR 0.77, CI 0.72-0.83) than those with the highest education. The association between education and start course participation was not significant in the subgroup of immigrant individuals (RR 0.88 CI 0.70-1.12)., Conclusions: We found that diabetes start course participation was overall low, especially in individuals with low education and immigrant background., Practice Implications: More efforts are needed to promote diabetes start courses in patients with T2DM., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: To study the relationship between education level and vascular complications in individuals with type 2 diabetes in Norway., Research Design and Methods: Multiregional population-based cross-sectional study of individuals with type 2 diabetes in primary care. Data were extracted from electronic medical records in the period 2012-2014. Information on education level was obtained from Statistics Norway. Using multivariable multilevel regression analyses on imputed data we analyzed the association between education level and vascular complications. We adjusted for age, sex, HbA1c, low-density lipoprotein cholesterol, systolic blood pressure, smoking and diabetes duration. Results are presented as ORs and 95% CIs., Results: Of 8192 individuals with type 2 diabetes included, 34.0% had completed compulsory education, 49.0% upper secondary education and 16.9% higher education. The prevalence of vascular complications in the three education groups was: coronary heart disease 25.9%, 23.0% and 16.9%; stroke 9.6%, 7.4% and 6.6%; chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ) 23.9%, 16.8% and 12.6%; and retinopathy 13.9%, 11.5% and 11.7%, respectively. Higher education was associated with lower odds for coronary heart disease (OR 0.59; 95% CI 0.49 to 0.71) and chronic kidney disease (OR 0.75; 95% CI 0.60 to 0.93) compared with compulsory education when adjusting for age, sex, HbA1c, low-density lipoprotein cholesterol, systolic blood pressure, smoking and diabetes duration., Conclusions: In a country with equal access to healthcare, high education level was associated with lower odds for coronary heart disease and chronic kidney disease in individuals with type 2 diabetes., Competing Interests: Competing interests: ESB has received honoraria for medical consulting and lectures to Novo Nordisk, Sanofi-Aventis and Mundipharma., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To explore whether the general practitioners' (GPs') performance of recommended processes of care was associated with estimated risk of cardiovascular disease (CVD) and poor glycaemic control in patients with type 2 diabetes., Methods: A cross-sectional study from Norwegian general practice including 6015 people with type 2 diabetes <75 years old, without CVD and their 275 GPs. The GPs were split into quintiles based on each GP's average performance of six recommended processes of care. The quintiles were the exposure variable in multilevel regression models with 10-year risk of cardiovascular events estimated by NORRISK 2 (total and modifiable fraction) and poor glycaemic control (HbA 1c >69 mmol/mol (>8.5%)) as outcome variables., Results: The mean total and modifiable estimated 10-year CVD risk was 12.3% and 3.3%, respectively. Compared with patients of GPs in the highest-performing quintile, patients treated by GPs in the lowest quintile had an adjusted total and modifiable CVD risk that was 1.88 (95% CI 1.17-2.60) and 1.78 (1.14-2.41) percent point higher. This represents a relative mean difference of 16.6% higher total and 74.8% higher modifiable risk among patients of GPs in the lowest compared with the highest quintile. For patients with GPs in the lowest-performing quintile, the adjusted odds of poor glycaemic control was 1.77 (1.27-2.46) times higher than that for patients with a GP in the highest quintile., Conclusions: We found a pattern of lower CVD risk and better glycaemic control in patients of GPs performing more recommended diabetes processes of care., (© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Context: Low birth weight (LBW; <2500 g) is linked to the development of insulin resistance and limbic-hypothalamic-pituitary-adrenal (LHPA) axis hyperactivity., Objective: Our first aim was to study insulin action, LHPA axis function, and limbic brain structures in young, healthy LBW men vs normal birthweight (NBW) controls (part 1). Our second aim was to investigate the effects of escitalopram vs placebo in LBW men in the LHPA axis and insulin sensitivity (part 2)., Design Setting, Participants, and Intervention: The maximal (Rdmax) and submaximal (Rdsubmax) rates of insulin-stimulated glucose turnover, LHPA axis, and brain morphology were examined in 40 LBW men and 20 matched NBW men using two-stage hyperinsulinemic euglycemic clamp, 24-hour hormone plasma profiles, and magnetic resonance imaging. Subsequently, all LBW subjects underwent randomized and double-blind treatment with escitalopram 20 mg/d or placebo for 3 months followed by a complete reexamination., Main Outcome Measures (part 2): Changes in Rdmax/Rdsubmax and plasma-free cortisol 24-hour area under the curve., Results: In LBW vs NBW, Rdsubmax and Rdmax were ∼16% (P = 0.01) and ∼12% (P = 0.01) lower, respectively, and 24-hour free cortisol levels were ∼20% higher (P = 0.02), primarily driven by a ∼99% increase at 05:00 am (P < 0.001). Furthermore, these changes were related to structural alterations within left thalamus and ventromedial prefrontal cortex. However, in LBW men, exposure to escitalopram normalized the free cortisol levels and improved the Rdsubmax by ∼24% (P = 0.04) compared with placebo., Conclusions: LBW vs NBW displayed alterations in key brain structures modulating the LHPA axis, elevated free cortisol levels, and insulin resistance. Escitalopram administration ameliorated these defects, suggesting a potential for LHPA axis modulation compounds to improve insulin action in LBW subjects., (Copyright © 2017 Endocrine Society)

Objective: We investigated the association of early achieved HbA 1c level and magnitude of HbA 1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin., Research Design and Methods: This was a population-based cohort study including all metformin initiators with HbA 1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA 1c achieved (<6.5% or higher) and by magnitude of HbA 1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA 1c and other confounding factors., Results: We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA 1c achieved compared with a target HbA 1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA 1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA 1c change (Δ = 0)., Conclusions: A large initial HbA 1c reduction and achievement of low HbA 1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes., (© 2017 by the American Diabetes Association.)

Aims: To examine the usage and real-life effectiveness of intensification therapies in people with Type 2 diabetes treated with basal insulin., Methods: We used population-based healthcare databases in Denmark during 2000-2012 to identify all individuals with a first basal insulin prescription (with or without oral drugs), and evaluated subsequent intensification therapy with bolus insulin, premixed insulin or glucagon-like peptide-1 (GLP-1) receptor agonists. Poisson regression was used to compute the adjusted relative risks of reaching glycaemic control targets., Results: We included 7034 initiators of basal insulin (median age 64 years, diabetes duration 5.3 years, 84% with oral co-medication and median (interquartile range) pre-insulin HbA 1c level 77 (65-92) mmol/mol [9.2% (8.1-10.6%)]. Of these, 3076 (43.7%) received intensification therapy after a median of 11 months: 58.5% with premixed insulin, 29.0% with bolus insulin, 10.6% with GLP-1 receptor agonists, and 1.9% with more than one add-on. Overall, 22% had attained an HbA 1c level of < 53 mmol/mol (< 7%) by 3-6 months after intensification, while 38% attained an HbA 1c < 58 mmol/mol (< 7.5%). Compared with premixed insulin intensification, attainment of HbA 1c < 53 and < 58 mmol/mol was similar with bolus insulin add-on [adjusted relative risk 1.03 (95% CI 0.86-1.24) and 1.02 (95% CI 0.91-1.15), and higher for GLP-1 receptor agonist add-on [adjusted relative risk 1.56 (95% CI 1.27-1.92) and 1.27 (1.10-1.47)]., Conclusions: Among people with Type 2 diabetes, 22 and 38% reached a target HbA 1c < 53 mmol/mol (< 7%) or < 58 mmol/mol (< 7.5%), respectively, after intensification of their basal insulin therapy. Compared with premixed insulin, target attainment was similar with bolus insulin and higher with GLP-1 receptor agonists., (© 2016 Diabetes UK.)

Aims: To identify individual predictors of early glycaemic control in people with Type 2 diabetes mellitus after initiation of first glucose-lowering drug treatment in everyday clinical practice., Methods: Using medical registries, we identified a population-based cohort of people with a first-time glucose-lowering drug prescription in Northern Denmark in the period 2000-2012. We used Poisson regression analysis to examine patient-level predictors of success in reaching early glycaemic control [HbA 1c target of < 53 mmol/mol (7%)] < 6 months after treatment start., Results: Among the 38 418 people (median age 63 years), 27 545 (72%) achieved early glycaemic control. The strongest predictor of achieving early control was pre-treatment HbA 1c level; compared with a pre-treatment HbA 1c level of ≤ 58 mmol/mol (7.5%), the adjusted relative risks of attaining early control were 0.63 (95% CI 0.61-0.64) for baseline HbA 1c levels of > 58 and ≤ 75 mmol/mol (> 7.5 and ≤ 9%), and 0.58 (95% CI 0.57-0.59) for a baseline HbA 1c level of > 9% (> 75 mmol/mol). All other examined predictors were only weakly associated with the chance of achieving early control. After adjustment, the only characteristics that remained independently associated with early control (in addition to high baseline HbA 1c ) were being widowed (adjusted relative risk 0.95; 95% CI 0.93-0.97) and having a high Charlson comorbidity index score (score ≥ 3; adjusted relative risk 0.94; 95% CI 0.90-0.97)., Conclusions: In a real-world clinical setting, people with Type 2 diabetes mellitus initiating glucose-lowering medication had a similar likelihood of achieving glycaemic control, regardless of sex, age, comorbidities and other individual factors; the only strong and potentially modifiable predictor was HbA 1c before therapy start., (© 2016 Diabetes UK.)

Aims/hypothesis: The aims of this work were to assess glycaemic control in metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs., Methods: We carried out a population-based cohort study using healthcare databases in northern Denmark during 2000-2012. We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years. Attainment of recommended HbA1c goals within 6 months of add-on was investigated, using Poisson regression analysis adjusted for age, sex, baseline HbA(1c), diabetes duration, complications and Charlson Comorbidity Index., Results: Median metformin treatment duration at intensification was 12 months (interquartile range [IQR] 4-23 months) and pre-intensification HbA(1c) was 8.0% (IQR 7.2-9.2%) (64 [IQR 55-77] mmol/mol). Median HbA(1c) dropped 1.2% (13 mmol/mol) with a sulfonylurea (SU) add-on, 0.8% (9 mmol/mol) with a dipeptidyl peptidase-4 (DPP-4) inhibitor, 1.3% (14 mmol/mol) with a glucagon-like peptide-1 (GLP-1) receptor agonist, 0.9% (10 mmol/mol) with other non-insulin drugs and 2.4% (26 mmol/mol) with insulin. Compared with SU add-on, attainment of HbA(1c) <7% (<53 mmol/mol) was higher with GLP-1 receptor agonists (adjusted RR [aRR] 1.10; 95% CI 1.01, 1.19) and lower with DPP-4 inhibitors (aRR 0.94; 95% CI 0.89, 0.99), other drugs (aRR 0.86; 95% CI 0.77, 0.96) and insulin (aRR 0.88; 95% CI 0.77, 0.99). The proportion of metformin add-on users who attained HbA(1c) <7% (<53 mmol/mol) increased from 46% in 2000-2003 to 59% in 2010-2012, whereas attainment of HbA(1c) <6.5% (<48 mmol/mol) remained 30% among patients aged <65 years without comorbidities., Conclusions/interpretation: Among early type 2 diabetes patients receiving their first metformin add-on treatment, HbA(1c) reduction with different non-insulin drugs is similar to, and comparable with, that observed in randomised trials, yet 41% do not achieve HbA(1c) <7% (<53 mmol/mol) within 6 months.

Aim: To examine real-life time trends in early glycaemic control in patients with type 2 diabetes between 2000 and 2012., Methods: We used population-based medical databases to ascertain the association between achievement of glycaemic control with initial glucose-lowering treatment in patients with incident type 2 diabetes in Northern Denmark. Success in reaching glycated haemoglobin (HbA1c) goals within 3-6 months was examined using regression analysis., Results: Of 38 418 patients, 91% started with oral glucose-lowering drugs in monotherapy. Metformin initiation increased from 32% in 2000-2003 to 90% of all patients in 2010-2012. Pretreatment (interquartile range) HbA1c levels decreased from 8.9 (7.6-10.7)% in 2000-2003 to 7.0 (6.5-8.1)% in 2010-2012. More patients achieved an HbA1c target of <7% (<53 mmol/mol) in 2010-2012 than in 2000-2003 [80 vs 60%, adjusted relative risk (aRR) 1.10, 95% confidence interval (CI) 1.08-1.13], and more achieved an HbA1c target of <6.5% [(<48 mmol/mol) 53 vs 37%, aRR 1.07 95% CI 1.03-1.11)], with similar success rates observed among patients aged <65 years without comorbidities. Achieved HbA1c levels were similar for different initiation therapies, with reductions of 0.8% (from 7.3 to 6.5%) on metformin, 1.5% (from 8.1 to 6.6%) on sulphonylurea, 4.0% (from 10.4 to 6.4%) on non-insulin combination therapies, and 3.8% (from 10.3 to 6.5%) on insulin monotherapy., Conclusions: Pretreatment HbA1c levels in patients with incident type 2 diabetes have decreased substantially, which is probably related to earlier detection and treatment in accordance with changing guidelines. Achievement of glycaemic control has improved, but 20% of patients still do not attain an HbA1c level of <7% within the first 6 months of initial treatment., (© 2015 John Wiley & Sons Ltd.)

Aims/hypothesis: Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide (gb) and gliclazide (gc), with high and low myocardial K(ATP) channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and myocardial glycogen, lactate and alanine content before and after ischaemia/reperfusion (I/R)., Methods: Non-diabetic Wistar and diabetic Goto-Kakizaki rat hearts were investigated in a Langendorff preparation. Gb (0.1 μmol/l) and gc (1.0 μmol/l) were administrated throughout the study. Infarct size was evaluated after 120 min of reperfusion. Myocardial metabolite content was measured before and after ischaemia., Results: Infarct size was smaller in diabetic hearts than in non-diabetic hearts (0.33 ± 0.03 vs 0.51 ± 0.05, p < 0.05). Gb increased infarct size (0.54 ± 0.04 vs 0.33 ± 0.03, p < 0.05) and reduced post-ischaemic LV developed pressure (60 ± 3 vs 76 ± 3 mmHg, p < 0.05) and coronary flow (4.9 ± 0.5 vs 7.1 ± 0.4 ml min(-1) g(-1), p < 0.05) in gb-treated diabetic rats compared with untreated diabetic rats. On comparing gb-treated diabetic rats with untreated diabetic rats, glycogen content was reduced before (9.1 ± 0.6 vs 13.6 ± 1.0 nmol/mg wet weight, p < 0.01) and after ischaemia (0.9 ± 0.2 vs 1.8 ± 0.2 nmol/mg wet weight, p < 0.05), and lactate (4.8 ± 0.4 vs 3.2 ± 0.3 nmol/mg wet weight, p < 0.01) and alanine (1.38 ± 0.12 vs 0.96 ± 0.09 nmol/mg wet weight, p < 0.05) contents were increased during reperfusion. Gc-treatment of diabetic and non-diabetic rats did not affect any of the measured variables., Conclusions/interpretations: Gb, but not gc, exacerbates I/R injury and deteriorates LV function in diabetic hearts. These effects of gb on diabetic hearts may be due to detrimental effects on myocardial carbohydrate metabolism.

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4-5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser(473) phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P < 0.05 vs. Cx), whole body insulin resistance (P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser(473) phosphorylation. The ESC treatment normalized corticosterone secretion (P < 0.05 vs. LBW), whole body insulin sensitivity (P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P < 0.05), and red muscle PKB Ser(473) phosphorylation (P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.

Individuals born with a low birth weight (LBW) have an increased prevalence of type 2 diabetes, but the mechanisms responsible for this association are unknown. Given the important role of insulin resistance in the pathogenesis of type 2 diabetes, we examined insulin sensitivity in a rat model of LBW due to intrauterine fetal stress. During the last 7 days of gestation, rat dams were treated with dexamethasone and insulin sensitivity was assessed in the LBW offspring by a hyperinsulinemic euglycemic clamp. The LBW group had liver-specific insulin resistance associated with increased levels of PEPCK expression. These changes were associated with pituitary hyperplasia of the ACTH-secreting cells, increased morning plasma ACTH concentrations, elevated corticosterone secretion during restraint stress, and an approximately 70% increase in 24-h urine corticosterone excretion. These data support the hypothesis that prenatal stress can result in chronic hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in increased plasma corticosterone concentrations, upregulation of hepatic gluconeogenesis, and hepatic insulin resistance.

Background/aims: Disturbance in glucose metabolism is a common feature in liver diseases and this is associated with skeletal muscle insulin resistance. However, the underlying molecular mechanisms are unclear. To characterize skeletal muscle insulin resistance associated with liver disease, we examined muscles from animals after an acute, 5 weeks perturbation of the common bile duct. Clinical findings, elevated plasma levels of liver enzymes and histological examinations confirmed cirrhosis., Methods/results: : Cirrhotic animals were insulin resistant and this was associated with reduced glucose transport into muscles. Interestingly, activity in the proximal part of the insulin signaling cascade was not decreased, as evinced by increased activity of key enzymes in the signal to glucose transport. Expression of the glucose transporter, GLUT4, was normal. So together these results indicate that signaling downstream of PKB/Akt and/or the translocation of GLUT4 is impaired in skeletal muscle from cirrhotic animals., Conclusions: In conclusion, in an animal model of liver cirrhosis whole body insulin resistance is associated with insulin resistance in skeletal muscles. Unlike other common forms of insulin resistance, muscles from cirrhotic animals have increased activity in the proximal insulin signaling cascade. This emphasizes the fact that skeletal muscle insulin resistance associated with liver cirrhosis is a unique entity.

Lifestyle interventions including exercise programs are cornerstones in the prevention of obesity-related diabetes. The AMP-activated protein kinase (AMPK) has been proposed to be responsible for many of the beneficial effects of exercise on glucose and lipid metabolism. The effects of long-term exercise training or 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside (AICAR) treatment, both known AMPK activators, on the development of diabetes in male Zucker diabetic fatty (ZDF) rats were examined. Five-week-old, pre-diabetic ZDF rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group. In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats (P < 0.01). In addition, pancreatic beta-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve beta-cell function. Our results suggest that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in beta-cell function associated with type 2 diabetes.

Physical activity is known to increase insulin action in skeletal muscle, and data have indicated that 5'-AMP-activated protein kinase (AMPK) is involved in the molecular mechanisms behind this beneficial effect. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) can be used as a pharmacological tool to repetitively activate AMPK, and the objective of this study was to explore whether the increase in insulin-stimulated glucose uptake after either long-term exercise or chronic AICAR administration was followed by fiber-type-specific changes in insulin signaling and/or changes in GLUT-4 expression. Wistar rats were allocated into three groups: an exercise group trained on treadmill for 5 days, an AICAR group exposed to daily subcutaneous injections of AICAR, and a sedentary control group. AMPK activity, insulin-stimulated glucose transport, insulin signaling, and GLUT-4 expression were determined in muscles characterized by different fiber type compositions. Both exercised and AICAR-injected animals displayed a fiber-type-specific increase in glucose transport with the most marked increase in muscles with a high content of type IIb fibers. This increase was accompanied by a concomitant increase in GLUT-4 expression. Insulin signaling as assessed by phosphatidylinositol 3-kinase and PKB/Akt activity was enhanced only after AICAR administration and in a non-fiber-type-specific manner. In conclusion, chronic AICAR administration and long-term exercise both improve insulin-stimulated glucose transport in skeletal muscle in a fiber-type-specific way, and this is associated with an increase in GLUT-4 content.

The insulin resistance syndrome is characterized by several risk factors for cardiovascular disease. Chronic chemical activation of AMP-activated protein kinase by the adenosine analog 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside (AICAR) has been shown to augment insulin action, upregulate mitochondrial enzymes in skeletal muscles, and decrease the content of intra-abdominal fat. Furthermore, acute AICAR exposure has been found to reduce sterol and fatty acid synthesis in rat hepatocytes incubated in vitro as well as suppress endogenous glucose production in rats under euglycemic clamp conditions. To investigate whether chronic AICAR administration, in addition to the beneficial effects on insulin sensitivity, is capable of improving other phenotypes associated with the insulin resistance syndrome, obese Zucker (fa/fa) rats (n = 6) exhibiting insulin resistance, hyperlipidemia, and hypertension were subcutaneously injected with AICAR (0.5 mg/g body wt) daily for 7 weeks. Obese control rats were either pair-fed (PF) (n = 6) or ad libitum-fed (AL) (n = 6). Lean Zucker rats (fa/-) (n = 8) served as a reference group. AICAR administration significantly reduced plasma triglyceride levels (P < 0.01 for AICAR vs. AL, and P = 0.05 for AICAR vs. PF) and free fatty acids (P < 0.01 for AICAR vs. AL, and P < 0.05 for AICAR vs. PF) and increased HDL cholesterol levels (P < 0.01 for AICAR vs. AL and PF). AICAR treatment also lowered systolic blood pressure by 14.6 +/- 4.3 mmHg (P < 0.05), and AICAR-treated animals exhibited a tendency toward decreased intra-abdominal fat content. Furthermore, AICAR administration normalized the oral glucose tolerance test and decreased fasting concentrations of glucose and insulin close to the level of the lean animals. Finally, in line with previous findings, AICAR treatment was also found to enhance GLUT4 protein expression and to increase maximally insulin-stimulated glucose transport in primarily white fast-twitch muscles. Our data provide strong evidence that long-term administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model. The present study gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.

To study the regulation of the mitochondrial uncoupling protein 2 and 3 (UCP2 and UCP3), we studied the effect of insulin and muscle contraction on UCP mRNA expression in rat skeletal muscle in vitro. Insulin dose-dependently increased skeletal muscle UCP2 and UCP3 mRNA expression in m. extensor digitorum longus (EDL) with maximal stimulation obtained at around 0.6-6 nM. The concentration of insulin giving half-maximal stimulation was 60 pM for the UCP2 and 48 pM for the UCP3 mRNA expression. The effect of insulin was maximal after 2 h and the effect was sustained during the whole study period (6 h). The insulin-induced increase in UCP mRNA was independent of the glucose uptake (as UCP mRNA was stimulated even in incubations without glucose). In addition, electrically induced contractions (in vitro) increased UCP2 and UCP3 mRNA expression 60-120 min after a single bout of contraction (for 10 min). Both the increment of UCP2 and UCP3 mRNA were sustained throughout the study period (4 h) (153 +/- 62 and 216 +/- 71% above basal, P < 0.05 respectively). Finally, 5-aminoimidazole-4-carboxamid-ribosid (AICAR), an activator of the AMP-activated protein kinase (AMPK), that is activated during exercise, was able to mimic the increase in UCP2 and UCP3 mRNA expression. In conclusion, UCP2 and UCP3 mRNA expression in skeletal muscle are stimulated rapidly by insulin and contraction in vitro, thus the stimulation is direct and not caused by changes in other hormones or metabolites. Even a brief bout of contraction induces an increase in UCP2 and UCP3 expression, an effect that could be mimicked by activation of the AMP-activated protein kinase by AICAR., (Copyright 2001 Academic Press.)

Recent studies have demonstrated that chronic administration of AICAR (5-aminoimidazole-4-carboxamide- 1-beta-D-ribofuranoside), an activator of the AMP-activated protein kinase, increases hexokinase activity and the contents of total GLUT4 and glycogen in rat skeletal muscles. To explore whether AICAR also affects insulin-stimulated glucose transport and GLUT4 cell surface content, Wistar rats were subcutaneously injected with AICAR for 5 days in succession (1 mg/g body wt). Maximally insulin-stimulated (60 nmol/l) glucose uptake was markedly increased in epitrochlearis (EPI) muscle (average 63%, P < 0.001, n = 18-19) and in extensor digitorum longus muscle (average 26%, P < 0.001, n = 26-30). In contrast, administration of AICAR did not maximally influence insulin-stimulated glucose transport in soleus muscle. Studies of EPI muscle with the 4,4'-O-[2-[2-[2-[2-[2-[6-(biotinylamino)hexanoyl]amino]ethoxy]ethoxy] ethoxy]-4-(1-azi-2,2,2,-trifluoroethyl)benzoyl]amino-1,3-propanediyl]bis-D-mannose photolabeling technique showed a concomitant increase (average 68%, P < 0.02) in cell surface GLUT4 content after insulin exposure in AICAR-injected rats when compared with controls. In conclusion, 5 days of AICAR administration induces a pronounced fiber type-specific increase in insulin-stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI). These results are comparable with the effects of chronic exercise training, and it brings the AMP-activated protein kinase into focus as a new interesting target for future pharmacological intervention in insulin-resistant conditions.