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Abstract Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

Abstract Background Viral respiratory infections may precipitate type 1 diabetes (T1D). A possible association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, and the incidence of T1D is being determined. This study was carried out using Portuguese registries, aiming at examining temporal trends between COVID-19 and T1D. Methods Hospital data, comparing the incidence before and during the COVID-19 pandemic, from children and young adults diagnosed with new-onset T1D, was acquired beginning in 2017 and until the end of 2022. Data was obtained from nine different Portuguese hospital units. The impact of the COVID-19 pandemic, beginning in March 2020, was assessed comparing the annual numbers of new-onset T1D cases. The annual median levels of glucose, glycated hemoglobin (HbA1c) and fasting C-peptide at T1D diagnosis were compared. The annual number of diabetic ketoacidosis (DKA) episodes among new T1D cases was also assessed at two centers. Results In total, data from 574 newly diagnosed T1D patients was analyzed, including 530 (92.3%) children. The mean ages for child and adult patients were 9.1 (SD 4.4) and 32.8 (SD 13.6) years, respectively. 57.8% (331/573) were male, one patient had unknown sex. The overall median (25–75 percentiles) levels of glucose, HbA1c and fasting C-peptide at diagnosis were 454 mg/dL (356–568), 11.8% (10.1–13.4) and 0.50 µg/L (0.30–0.79), respectively. DKA at T1D diagnosis was present in 48.4% (76/157). For eight centers with complete 2018 to 2021 data (all calendar months), no overall significant increase in T1D cases was observed during the COVID-19 pandemic, i.e. 90 cases in 2018, 90 cases in 2019, 112 in 2020 and 100 in 2021 (P for trend = 0.36). Two of the centers, Faro (CHUA) and Dona Estefânia (CHULC) hospitals, did however see an increase in T1D from 2019 to 2020. No significant changes in glucose (P = 0.32), HbA1c (P = 0.68), fasting C-peptide (P = 0.20) or DKA frequency (P = 0.68) at the time of T1D diagnosis were observed over the entire study period. Conclusion The T1D incidence did not increase significantly, when comparing the years before and during the COVID-19 pandemic, nor did key metabolic parameters or number of DKA episodes change.

Aim: We investigated whether a high-intensity interval training (HIIT) protocol could restore beta-cell function in type 2 diabetes compared with sedentary obese and lean individuals. Materials and methods: In patients with type 2 diabetes, and age-matched, glucose-tolerant obese and lean controls, we examined the effect of 8 weeks of supervised HIIT combining rowing and cycling on the acute (first-phase) and second-phase insulin responses, beta-cell function adjusted for insulin sensitivity (disposition index), and serum free fatty acid (FFA) levels using the Botnia clamp (1-h IVGTT followed by 3-h hyperinsulinemic–euglycemic clamp). Results: At baseline, patients with type 2 diabetes had reduced insulin sensitivity (~40%), acute insulin secretion (~13- fold), and disposition index (>35-fold), whereas insulin-suppressed serum FFA was higher (⁓2.5-fold) compared with controls (all P < 0.05). The HIIT protocol increased insulin sensitivity in all groups (all P < 0.01). In patients with type 2 diabetes, this was accompanied by a large (>200%) but variable improvement in the disposition index (P < 0.05). Whereas insulin sensitivity improved to the degree seen in controls at baseline, the disposition index remained markedly lower in patients with type 2 diabetes after HIIT (all P < 0.001). In controls, HIIT increased the disposition index by ~20–30% (all P < 0.05). In all groups, the second-phase insulin responses and insulin-suppressed FFA levels were reduced in response to HIIT (all P < 0.05). No group differences were seen in these HIIT-induced responses. Conclusion: HIIT combining rowing and cycling induced a large but variable increase in beta-cell function adjusted for insulin sensitivity in type 2 diabetes, but the disposition index remained severely impaired compared to controls, suggesting that this defect is less reversible in response to exercise training than insulin resistance. Trial registration: ClinicalTrials.gov (NCT03500016).

Abstract Background While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. Methods In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (

One of the components of a health system as defined by the World Health Organization (WHO) is data that the health system collects, generates, and uses to improve the health of its population. The aim of this paper is to describe key lessons from Denmark in planning, implementing, and using health system-generated data, using Type 1 diabetes as a tracer. A broad literature search was complemented with a review of grey literature, two series of interviews with Danish experts, and feedback from a presentation of these findings to two expert meetings. Denmark, through its unique identifier and data environment, enables the health system to collect a variety of data on Type 1 diabetes. Facilitators and challenges exist for data collection, data aggregation, use of data, communication of data and results, and intangible factors. For each of these, the environment, infrastructure, health system, and Danish society act as facilitators. Barriers relate to data being collected primarily for clinical and administrative purposes, and not necessarily for research, planning, policymaking, or advocacy. Fora are lacking to facilitate the communication and presentation of these results. An intangible element is the trust Danes have in their system, which is hard to replicate. As shown in the Danish setting, contextual factors cannot be negated in developing and implementing data-related solutions at a population level. The lessons from Denmark show that there is the need to conceive and act on all aspects of the data from its collection, aggregation, use, and communication. The last step of interaction between science and policy and practice requires a range of factors, including networks and knowledge brokers.

Purpose: To evaluate the proliferative diabetic retinopathy (PDR) progression rates and identify the demographic and clinical characteristics of patients who later developed PDR compared with patients who did not progress to that state. Design: A national 5-year register-based cohort study including 201 945 patients with diabetes. Subjects: Patients with diabetes who had attended the Danish national screening program (2013–2018) for diabetic retinopathy (DR). Methods: We used the first screening episode as the index date and included both eyes of patients with and without subsequent progression of PDR. Data were linked with various national health registries to investigate relevant clinical and demographic parameters. The International Clinical Retinopathy Disease Scale was used to classify DR, with no DR as level 0, mild DR as level 1, moderate DR as level 2, severe DR as level 3, and PDR as level 4. Main Outcome Measures: Hazard ratios (HRs) for incident PDR for all relevant demographic and clinical parameters and 1-, 3-, and 5-year incidence rates of PDR according to baseline DR level. Results: Progression to PDR within 5 years was identified in 2384 eyes of 1780 patients. Proliferative diabetic retinopathy progression rates from baseline DR level 3 at 1, 3 and 5 years were 3.6%, 10.9%, and 14.7%, respectively. The median number of visits was 3 (interquartile range, 1–4). Progression to PDR was predicted in a multivariable model by duration of diabetes (HR, 4.66 per 10 years; 95% confidence interval [CI], 4.05–5.37), type 1 diabetes (HR, 9.61; 95% CI, 8.01–11.53), a Charlson Comorbidity Index score of > 0 (score 1: HR, 4.62; 95% CI, 4.14–5.15; score 2: HR, 2.28; 95% CI, 1.90–2.74; score ≥ 3: HR, 4.28; 95% CI, 3.54–5.17), use of insulin (HR, 5.33; 95% CI, 4.49–6.33), and use of antihypertensive medications (HR, 2.23; 95% CI, 1.90–2.61). Conclusions: In a 5-year longitudinal study of an entire screening nation, we found increased risk of PDR with increasing baseline DR levels, longer duration of diabetes, type 1 diabetes, systemic comorbidity, use of insulin, and blood pressure–lowering medications. Most interestingly, we found lower risk of progression from DR level 3 to PDR compared with that in previous studies. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Background Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease. Methods Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013. Setting Exploratory sub-study using data from the nationwide EPICOM study. Participants Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code. Main outcome measures This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples. Results We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM. Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX). Conclusions These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.

Purpose: Diabetic retinopathy (DR) is a hypoxic retinal disease, but so far, the association with systemic hypoxia is poorly understood. Hence, the aim of this study was to evaluate cross-sectional and longitudinal associations between DR and chronic respiratory failure (CRF) in a national cohort. Design: Cross-sectional and 5-year longitudinal register-based cohort study. Methods: Between 2013 and 2018, we included patients with diabetes from the Danish Registry of Diabetic Retinopathy, who were each age and sex matched with five controls without diabetes. At index date, the prevalence of CRF was compared between cases and controls, and the longitudinal relationship between DR and CRF was assessed in a five-year follow-up. Results: At baseline, we identified 1,980 and 9,990 patients with CRF among 205,970 cases and 1,003,170 controls. The prevalence of CRF was higher among cases than controls (OR 1.75, 95% CI 1.65–1.86), but no difference between cases with and without DR was found.During follow-up, we identified 1,726 and 5,177 events of CRF among cases and controls, respectively. The incidence of CRF was higher among both cases with and without DR compared to controls (DR level 0: HR 1.24, 95% CI 1.16–1.33, DR level 1–4: HR 1.86, 95% CI 1.63–2.12), and higher among cases with DR compared to cases without DR (HR 1.54, 95% CI 1.38–1.72). Conclusion: In this study based on nationwide data, we found an increased risk of present and incident CRF in patients with diabetes with or without DR, and we identified DR as a predictor of future CRF.

Abstract Migraine is a disease characterized by cerebral vasodilation. While diabetes has previously been associated with a lower risk of migraine, it is not known if diabetic retinopathy (DR), a retinal peripheral vascular occlusive disease, is a potential biomarker of protection against migraine. Therefore, we aimed to examine diabetic retinopathy as a marker of prevalent and 5-year incident migraine. In a national cohort, we compared patients with diabetes attending DR screening from The Danish National Registry of Diabetic Retinopathy (cases, n = 205,970) to an age- and gender-matched group of patients without diabetes (controls, n = 1,003,170). In the cross-sectional study, a multivariable model demonstrated a lower prevalence of migraine among cases compared with controls (OR 0.83, 95% CI 0.81–0.85), with a lower risk in cases with DR than in those without (OR 0.69, 95% CI 0.65–0.72). In the prospective study, a lower risk of incident migraine was found in a multivariable model in cases (HR 0.76, 95% CI 0.70–0.82), but this did not depend upon the presence of DR. To conclude, in a national study of more than 1.2 million people, patients screened for DR had a lower risk of present migraine, but DR was not a protective marker of incident migraine.

Abstract Background Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients. Methods This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed. Results A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918–1720) pg/mL with empagliflozin, and 1299 (952–1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03–1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = – 0.23, p = 0.031), and end-diastolic volume (R = – 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86–1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97–1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01. Conclusion Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP. Trial registration: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.

IntroductionHabitual physical activity behaviors of individuals with new-onset type 2 diabetes are largely unknown. We aimed to investigate accelerometer-derived physical activity behaviors in individuals with newly diagnosed type 2 diabetes. We also examined sociodemographic and health-related correlates of a high-risk physical activity profile.MethodsThis cross-sectional study used data from 768 participants enrolled in an intervention study nested within the Danish Centre for Strategic Research in Type 2 diabetes (DD2) cohort. Physical activity was assessed by 24-h dual monitor accelerometry. Prevalence ratios of having a high-risk physical activity profile were estimated using Poisson regression adjusted for age and sex.ResultsStudy participants spent on average 9.7 (25th and 75th percentiles, 8.3; 11.1) hours/day sitting, walked for 1.1 (0.8; 1.6) hours/day and accumulated 4,000 (2,521; 5,864) steps/day. Still, 62% met the recommendations for physical activity. Characteristics associated with a high-risk physical activity profile (observed in 24.5% of participants) included older age, higher body mass index (BMI), unemployment, retirement, comorbidities, and current smoking. Hence, participants aged 60–69, 70–79 and 80+ years had prevalence ratios of 2.12 (95% CI 1.31; 3.42), 1.99 (1.18; 3.34) and 3.09 (1.42; 6.75) for a high-risk activity profile, respectively, versus participants

Abstract The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five doses of tablet codeine 25 mg; the last dose was administered together with oral metformin (1 g), and (D) five doses of tablet codeine 25 mg; the last dose was administered together with metformin (0.5 g) intravenously. Blood samples were drawn for 24 h after administration of metformin, and for 6 h after administration of codeine and analyzed using liquid chromatography and tandem mass spectrometry. Healthy volunteers genotyped as CYP2D6 normal metabolizers (*1/*1) without known reduced function variants in the OCT1 gene (rs12208357, rs34130495, rs34059508, and rs72552763) were invited. The median absorption fraction of metformin was 0.31 and was not influenced by codeine intake. The median time to maximum concentration (Tmax) after oral intake of metformin was 2 h without, and 3 h with codeine (p = 0.06). The geometric mean ratios of the areas under the plasma concentration time‐curve (AUCs) for morphine and its metabolites M3G and M6G for oral intake of metformin‐to‐no metformin were 1.21, 1.31, and 1.27, respectively, and for i.v. metformin‐to‐no metformin 1.28, 1.34, and 1.30, respectively. Concomitant oral and i.v. metformin increased the plasma levels of morphine, M3G and M6G. These small pharmacokinetic changes may well contribute to an increased risk of early discontinuation of metformin. Hence, a clinically relevant drug‐drug interaction between metformin and codeine seems plausible.

AimsNon-weight-bearing high-intensity interval training (HIIT) involving several muscle groups may efficiently improve metabolic health without compromising adherence in obesity and type 2 diabetes. In a non-randomized intervention study, we examined the effect of a novel HIIT-protocol, recruiting both lower and upper body muscles, on insulin sensitivity, measures of metabolic health and adherence in obesity and type 2 diabetes.MethodsIn 15 obese men with type 2 diabetes and age-matched obese (n=15) and lean (n=18) glucose-tolerant men, the effects of 8-weeks supervised HIIT combining rowing and cycling on ergometers (3 sessions/week) were examined by DXA-scan, incremental exercise test and hyperinsulinemic-euglycemic clamp combined with indirect calorimetry.ResultsAt baseline, insulin-stimulated glucose disposal rate (GDR) was ~40% reduced in the diabetic vs the non-diabetic groups (all p95%) in all groups and no injuries were reported.ConclusionsA novel HIIT-protocol recruiting lower and upper body muscles efficiently improves insulin sensitivity, VO2max and body composition with intact responses in obesity and type 2 diabetes. The high adherence and lack of injuries show that non-weight-bearing HIIT involving several muscle groups is a promising mode of exercise training in obesity and type 2 diabetes.

ObjectiveCoronavirus disease-2019 (COVID-19) increases risk of hospitalization and death in diabetes and diabetes-related conditions. We examined the temporal trends in COVID-19-related hospitalization and mortality in the total Danish population by diabetes and diabetes-related conditions in the two first waves of COVID-19 in Denmark.Materials and methodsWe identified all persons with diabetes in the whole Danish population using national registries. COVID-19-related risks of hospitalization and death were assessed using Cox regression analysis in wave 1 (1 March-31 August 2020) and wave 2 (1 September 2020-28 February 2021) of the pandemic for persons with (n=321,933) and without diabetes (n=5,479,755). Analyses were stratified according to status of hypertension, obesity, cardiovascular and microvascular disease.ResultsThe cumulative incidence of COVID-19 hospitalization increased from wave 1 to wave 2 in both persons without (from 4 to 10 in 10,000) and with diabetes (from 16 to 54 per 10,000). The relative risk of hospitalization, however, increased more in patients with diabetes compared to persons without (age-, sex- and co-morbidity-adjusted HR [aHR] 1.40 (95% CI 1.27, 1.55) versus 1.76 (1.65, 1.87), p

Aims. To compare metabolic profiles and the long-term risk of metabolic dysfunction between women with previous gestational diabetes mellitus (pGDM) and women without pGDM (non-GDM) matched on age, prepregnancy body mass index (BMI), and parity. Methods. In total, 128 women with pGDM (median follow-up: 7.8 years) and 70 non-GDM controls (median follow-up: 10.0 years) completed a 2 h oral glucose tolerance test (OGTT) with assessment of glucose, C-peptide, insulin, and other metabolic measures. Additionally, anthropometrics, fat mass, and blood pressure were assessed and indices of insulin sensitivity and beta cell function were calculated. Results. The prevalence of type 2 diabetes mellitus (T2DM) was significantly higher in the pGDM group compared to the non-GDM group (26% vs. 0%). For women with pGDM, the prevalence of prediabetes (38%) and the metabolic syndrome (MetS) (59%) were approximately 3-fold higher than in non-GDM women (p’s

Abstract The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab‐positive if diagnosed with diabetes or pre‐diabetes. This EPICOM study is a prospective follow‐up study focussing on pregnancies complicated by maternal T1D. The EPICOM study includes offspring (n = 278) born to mothers with pre‐gestational T1D between 1993 and 1999 and matched un‐exposed controls (n = 303). Age at the time of follow‐up was 16.7 years (13.0–20.4 years). GAD65aab was measured using the Glutamic Acid Decarboxylase Autoantibody RIA kit from RSR©. An Oral Glucose Tolerance Test (OGTT) was performed, and abnormal glucose tolerance was defined as having either diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). GAD65aab could be measured in 561 participants. Of these, 17 (3%) were positive for GAD65aab (≥25 U/ml) with 11 (4%) offspring being born to women with T1D and 6 (2%) controls. The difference in GAD65aab status was not statistically significant (p = .2). One was diagnosed with GAD65aab‐negative diabetes during the study, 18 were diagnosed with IFG, and 44 with IGT. Overall, more were GAD65aab‐positive if diagnosed with abnormal glucose tolerance (p = .03). We found no association between GAD65aab status and HOMA‐IR, HOMA‐IS, birthweight, mode of delivery or maternal BMI prior to pregnancy. Our study found no overall difference in GAD65 status between offspring born to women with T1D and their matched controls. However, among the participants diagnosed with pre‐diabetes more were GAD65‐positive.

In obesity, excessive abdominal fat, especially the accumulation of visceral adipose tissue (VAT), increases the risk of metabolic disorders, such as type 2 diabetes mellitus (T2DM), cardiovascular disease, and non-alcoholic fatty liver disease. Excessive abdominal fat is associated with adipose tissue dysfunction, leading to systemic low-grade inflammation, fat overflow, ectopic lipid deposition, and reduced insulin sensitivity. Physical activity is recommended for primary prevention and treatment of obesity, T2DM, and related disorders. Achieving a stable reduction in body weight with exercise training alone has not shown promising effects on a population level. Because fat has a high energy content, a large amount of exercise training is required to achieve weight loss. However, even when there is no weight loss, exercise training is an effective method of improving body composition (increased muscle mass and reduced fat) as well as increasing insulin sensitivity and cardiorespiratory fitness. Compared with traditional low-to-moderate-intensity continuous endurance training, high-intensity interval training (HIIT) and sprint interval training (SIT) are more time-efficient as exercise regimens and produce comparable results in reducing total fat mass, as well as improving cardiorespiratory fitness and insulin sensitivity. During high-intensity exercise, carbohydrates are the main source of energy, whereas, with low-intensity exercise, fat becomes the predominant energy source. These observations imply that HIIT and SIT can reduce fat mass during bouts of exercise despite being associated with lower levels of fat oxidation. In this review, we explore the effects of different types of exercise training on energy expenditure and substrate oxidation during physical activity, and discuss the potential effects of exercise training on adipose tissue function and body fat distribution.

Insulin resistance in skeletal muscle in type 2 diabetes (T2D) is characterized by more pronounced metabolic and molecular defects than in obesity per se. There is increasing evidence that adipose tissue dysfunction contributes to obesity-induced insulin resistance in skeletal muscle. Here, we used an unbiased approach to examine if adipose tissue dysfunction is exaggerated in T2D and linked to diabetes-related mechanisms of insulin resistance in skeletal muscle. Transcriptional profiling and biological pathways analysis were performed in subcutaneous adipose tissue (SAT) and skeletal muscle biopsies from 17 patients with T2D and 19 glucose-tolerant, age and weight-matched obese controls. Findings were validated by qRT-PCR and western blotting of selected genes and proteins. Patients with T2D were more insulin resistant and had lower plasma adiponectin than obese controls. Transcriptional profiling showed downregulation of genes involved in mitochondrial oxidative phosphorylation and the tricarboxylic-acid cycle and increased expression of extracellular matrix (ECM) genes in SAT in T2D, whereas genes involved in proteasomal degradation were upregulated in the skeletal muscle in T2D. qRT-PCR confirmed most of these findings and showed lower expression of adiponectin in SAT and higher expression of myostatin in muscle in T2D. Interestingly, muscle expression of proteasomal genes correlated positively with SAT expression of ECM genes but inversely with the expression of ADIPOQ in SAT and plasma adiponectin. Protein content of proteasomal subunits and major ubiquitin ligases were unaltered in the skeletal muscle of patients with T2D. A transcriptional signature of exaggerated adipose tissue dysfunction in T2D, compared with obesity alone, is linked to low plasma adiponectin and increased transcriptional activation of proteasomal degradation in skeletal muscle.

Purpose: In previous smaller studies, associations were demonstrated between diabetic retinopathy (DR) and obstructive sleep apnea (OSA), but longitudinal relationships have not been evaluated in larger cohorts. The aim of the present study was to assess the cross-sectional and prospective associations between DR and OSA in a national cohort of patients with type 2 diabetes. Design: Cross-sectional and 5-year longitudinal registry-based cohort study. Participants: For cases, we included 153 238 patients with type 2 diabetes who had attended diabetic eye screening and were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each of these were matched by 5 control participants without diabetes of the same age and gender (n = 746 148). Methods: Exposure and outcome data as well as systemic morbidity and use of medications were identified in national registers, including the DiaBase, the Danish National Patient Register, the Danish National Prescription Registry, and the Danish Civil Registration System. The index date was defined as the date of the first DR screening registered in DiaBase. Main Outcome Measures: Exposure was defined as present and level-specific DR, and main outcomes were crude, age- and gender-adjusted, and multivariable adjusted odds ratios (ORs) for prevalent OSA as well as hazard ratios (HR) for 5-year incident OSA and DR. Results: Patients with type 2 diabetes independently were more likely to have prevalent OSA (OR, 2.01; 95% confidence interval [CI], 1.95–2.08) and to develop OSA within 5 years (HR, 1.55; 95% CI, 1.46–1.64). Patients with type 2 diabetes and DR at baseline were less likely to have prevalent OSA (OR, 0.57; 95% CI, 0.52–0.62) or to demonstrate incident OSA (HR, 0.86; 95% CI, 0.74–0.99). Likewise, patients with OSA had a lower risk to develop DR (HR, 0.83; 95% CI, 0.74–0.92). Conclusions: In a registry-based national cohort study, patients with type 2 diabetes had a higher risk of OSA. However, a 43% decreased risk of prevalent OSA was demonstrated in patients with DR, and prospectively, OSA and DR both were related inversely with each other.

Abstract Background People with chronic renal disease are insulin resistant. We hypothesized that in a healthy population, baseline renal function is associated with insulin sensitivity three years later. Methods We studied 405 men and 528 women from the European Group for the study of Insulin Resistance - Relationship between Insulin Sensitivity and Cardiovascular disease cohort. Renal function was characterized by the estimated glomerular filtration rate (eGFR) and by the urinary albumin-creatinine ratio (UACR). At baseline only, insulin sensitivity was quantified using a hyperinsulinaemic-euglycaemic clamp; at baseline and three years, we used surrogate measures: the Matsuda insulin sensitivity index (ISI), the HOmeostasis Model Assessment of Insulin Sensitivity (HOMA-IS). Associations between renal function and insulin sensitivity were studied cross-sectionally and longitudinally. Results In men at baseline, no associations were seen with eGFR, but there was some evidence of a positive association with UACR. In women, all insulin sensitivity indices showed the same negative trend across eGFR classes, albeit not always statistically significant; for UACR, women with values above the limit of detection, had higher clamp measured insulin sensitivity than other women. After three years, in men only, ISI and HOMA-IS showed a U-shaped relation with baseline eGFR; women with eGFR> 105 ml/min/1.73m2 had a significantly higher insulin sensitivity than the reference group (eGFR: 90–105 ml/min/1.73m2). For both men and women, year-3 insulin sensitivity was higher in those with higher baseline UACR. All associations were attenuated after adjusting on significant covariates. Conclusions There was no evidence to support our hypothesis that markers of poorer renal function are associated with declining insulin sensitivity in our healthy population.

Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. Keywords: O-GlcNAc signaling, Type 2 diabetes, N-acetyl-d-glucosamine, Tissue cross talk, Epigenetic regulation of Il15 transcription, Insulin sensitivity

Background/aims: Polycystic ovary syndrome (PCOS) is associated with insulin resistance, adrenal hyperactivity and decreased mental health. We aimed to investigate the changes in adrenal activity, metabolic status and mental health in PCOS during treatment with escitalopram or placebo. Methods: Forty-two overweight premenopausal women with PCOS and no clinical depression were randomized to 12-week SSRI (20 mg escitalopram/day, n = 21) or placebo (n = 21). Patients underwent clinical examination, fasting blood samples, adrenocorticotroph hormone (ACTH) test, 3-h oral glucose tolerance test (OGTT) and filled in questionnaires regarding mental health and health-related quality of life (HRQoL): WHO Well-Being Index (WHO-5), Major Depression Inventory (MDI), Short Form 36 (SF-36) and PCOS questionnaire. Results: Included women were aged 31 (6) years (mean (s.d.)) and had body mass index (BMI) 35.8 (6.5) kg/m2 and waist 102 (12) cm. Escitalopram was associated with increased waist (median (quartiles) change 1 (0; 3) cm), P = 0.005 vs change during placebo and increased cortisol levels (cortisol 0, cortisol 60, peak cortisol and area under the curve for cortisol during ACTH test), all P < 0.05 vs changes during placebo. Escitalopram had no significant effect on measures of insulin sensitivity, insulin secretion, fasting lipids, mental health or HRQoL. Conclusion: Waist circumference and cortisol levels increased during treatment with escitalopram in women with PCOS and no clinical depression, whereas metabolic risk markers, mental health and HRQol were unchanged.

Background: To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4. Methods: Nine overweight/obese individuals completed three 6-h oral glucose tolerance tests (OGTTs) in a crossover design. At −30 min, participants consumed either: no oil, 6 g of hydrolyzed pine nut oil (PNO-FFA), or a combination of 3 g hydrolyzed pine nut oil and 3 g olive oil (PNO-OO) in delayed-release capsules. Repeated measures of glucose, insulin, C-peptide, GLP-1, GIP, ghrelin, subjective appetite and gastrointestinal tolerability were done. Results: PNO-FFA augmented GLP-1 secretion from 0–360 min compared to no oil and PNO-OO (p < 0.01). GIP secretion was increased from 240–360 min after both PNO-FFA and PNO-OO versus no oil (p < 0.01). Both oil treatments suppressed subjective appetite by reducing hunger and prospective food consumption and increasing satiety (p < 0.05). Conclusions: In support of previous findings, 6 g of delayed-release hydrolyzed pine nut oil enhanced postprandial GLP-1 secretion and reduced appetite. However, no synergistic effect of combining hydrolyzed pine nut oil and olive oil on GLP-1 secretion was observed. These results need further evaluation in long-term studies including effects on bodyweight and insulin sensitivity.

Summary: Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs. : Tencerova et al. show that in human obesity, BM-MSCs exhibit a hypermetabolic state defined by upregulation of insulin signaling with enhanced adipogenesis and increased intracellular reactive oxygen species (ROS), leading to a senescence bone microenvironment contributing to bone fragility. Moreover, increased abundance of IR+ and LEPR+ BM-MSCs is characteristic of this phenotype, with an activated metabolic rate in obese subjects. Keywords: obesity, skeletal fragility, bone marrow skeletal stem cells, adipose-derived stem cells, differentiation potential, adipogenesis, insulin signaling

Introduction: Mitochondria are essential in energy metabolism and cellular survival, and there is growing evidence that insulin resistance in chronic metabolic disorders, such as obesity, type 2 diabetes (T2D), and aging, is linked to mitochondrial dysfunction in skeletal muscle. Protein profiling by proteomics is a powerful tool to investigate mechanisms underlying complex disorders. However, despite significant advances in proteomics within the past two decades, the technologies have not yet been fully exploited in the field of skeletal muscle proteome. Area covered: Here, we review the currently available studies characterizing the mitochondrial proteome in human skeletal muscle in insulin-resistant conditions, such as obesity, T2D, and aging, as well as exercise-mediated changes in the mitochondrial proteome. Furthermore, we outline technical challenges and limitations and methodological aspects that should be considered when planning future large-scale proteomics studies of mitochondria from human skeletal muscle. Authors’ view: At present, most proteomic studies of skeletal muscle or isolated muscle mitochondria have demonstrated a reduced abundance of proteins in several mitochondrial biological processes in obesity, T2D, and aging, whereas the beneficial effects of exercise involve an increased content of muscle proteins involved in mitochondrial metabolism. Powerful mass-spectrometry-based proteomics now provides unprecedented opportunities to perform in-depth proteomics of muscle mitochondria, which in the near future is expected to increase our understanding of the complex molecular mechanisms underlying the link between mitochondrial dysfunction and insulin resistance in chronic metabolic disorders.

Aims. To investigate how circulating microvesicle phenotypes correlate with insulin sensitivity, body composition, plasma lipids, and hepatic fat accumulation. We hypothesized that changes elicited by testosterone replacement therapy are reflected in levels of microvesicles. Methods. Thirty-nine type 2 diabetic males with lowered testosterone levels were assigned to either testosterone replacement therapy or placebo and evaluated at baseline and after 24 weeks. Microvesicles were analysed by flow cytometry and defined as lactadherin-binding particles within the 0.1–1.0 μm gate. Microvesicles of platelet, monocyte, and endothelial cell origin were identified by cell-specific markers and their expression of CD36 was investigated. Results. Triglycerides correlated positively with all investigated microvesicle phenotypes in this study (p

BACKGROUND: Monozygotic twins discordant for type 2 diabetes constitute an ideal model to study environmental contributions to type 2 diabetic traits. We aimed to examine whether global DNA methylation differences exist in major glucose metabolic tissues from these twins. METHODOLOGY/PRINCIPAL FINDINGS: Skeletal muscle (n = 11 pairs) and subcutaneous adipose tissue (n = 5 pairs) biopsies were collected from 53-80 year-old monozygotic twin pairs discordant for type 2 diabetes. DNA methylation was measured by microarrays at 26,850 cytosine-guanine dinucleotide (CpG) sites in the promoters of 14,279 genes. Bisulfite sequencing was applied to validate array data and to quantify methylation of intergenic repetitive DNA sequences. The overall intra-pair variation in DNA methylation was large in repetitive (LINE1, D4Z4 and NBL2) regions compared to gene promoters (standard deviation of intra-pair differences: 10% points vs. 4% points, P

Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZDs) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZDs in PCOS is, in part, mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy women. Treatment with pioglitazone improved insulin-stimulated glucose metabolism and plasma adiponectin, and reduced fasting serum insulin (all P