Umeå University's logo

Aim/hypothesis: This study aimed to investigate whether concurrent training, when added to a palaeolithic-type diet-induced weight loss intervention, is associated with altered physiological responses and circulating lipid dynamics during exercise and recovery in individuals with type 2 diabetes.

Methods: In a previously reported clinical trial, individuals with overweight or obesity who had type 2 diabetes (n=27) were randomised to either 12 weeks of palaeolithic-type diet (PD) or PD and supervised concurrent exercise training three times weekly (PD+E). Physiological and glycaemic responses to exercise and recovery were monitored during an exercise test at baseline and following the intervention. This secondary analysis focuses on a subgroup (n=21), in which plasma samples were collected before and after exercise, and after 30 min of recovery, and lipid profiles were analysed using mass spectrometry-based lipidomics.

Results: Glycaemic management during and after the exercise test improved similarly in both groups, whereas only the PD+E group showed improvements in cardiometabolic fitness. In plasma samples obtained at rest before exercise, the intervention reduced levels of triacylglycerols in both groups, with additional reductions of very-long-chain ceramides (>C22 acyl chains) in the PD+E group. During the exercise test, sphingomyelins and ceramides increased in both groups, but only PD+E resulted in improved clearance of these bioactive lipids from circulation during recovery. The specific lipid response during recovery from exercise was associated with improvements in fat oxidation during exercise.

Conclusions/interpretation: Concurrent training during PD-induced weight loss improves cardiometabolic fitness and is associated with an enhanced ability to clear bioactive sphingomyelins and ceramides from the circulation in the recovery phase after an exercise test. The improved lipid response during recovery and its association with the capacity for fat oxidation suggest that concurrent training during PD-induced weight loss may augment lipid handling beyond diet-induced changes, although causal mechanisms cannot be established.

Context: Substantial diagnostic delay in acromegaly contributes to increased morbidity and mortality. Screening attempts in high-risk groups have yielded few positive cases, underscoring the need for simple and precise prescreening methods.

Objective: Machine-learning analysis of facial images shows promise for acromegaly detection but requires validation in larger, well-characterized cohorts using robust machine-learning frameworks as performed in this study.

Methods: Facial images from different angles were collected via smartphone from 155 acromegaly patients (79% biochemically controlled) and 153 matched controls at all Swedish university hospitals. Six machine-learning models were trained to distinguish acromegaly from control images, including 3 deep neural networks pretrained on diverse image datasets (ImageNet models: ResNet50, InceptionV2, and DenseNet121) and 1 network pretrained specifically on facial images (FaRL). Model performance was compared to assessment by 12 experienced endocrinologists.

Results: The diagnostic accuracy of the FaRL-based model was superior to all ImageNet models and matched the accuracy of human experts (area under the receiver operating characteristic curve 0.89 for both) with similar specificity (0.87 vs 0.93) but higher sensitivity (0.82 vs 0.66). Classification agreement between the best machine-learning model (FaRL) and human experts was 86% for true negatives and 60% for true positives. Machine-learning models and human experts both showed greater sensitivity in identifying acromegaly in male patients.

Conclusion: A deep learning model pretrained on facial features (FaRL) can detect acromegaly from standard photographs with accuracy comparable to that of expert endocrinologists. This supports the feasibility of face analysis as a screening tool for acromegaly.

Aims/hypothesis: Exercise elicits a spectrum of metabolic and inflammatory responses that are crucial for skeletal muscle adaptation and overall health, particularly in the context of metabolic diseases, yet the contribution of prostanoid signalling to these processes remains unclear. We hypothesised that exercise-induced thromboxane production enhances skeletal muscle glucose uptake and improves whole-body glucose control.

Methods: Plasma prostanoids were quantified in men and women with normal glucose tolerance or type 2 diabetes before, immediately after and 3 h after a single bout of exercise. Cyclooxygenase (COX-2) transcript levels were evaluated in human skeletal muscle, whole blood, peripheral blood mononuclear cells and skeletal muscle-resident immune cells. Metabolic and transcriptomic effects of thromboxane receptor activation were analysed in mouse C2C12, rat L6 and human primary skeletal muscle cells. Glucose tolerance in vivo was assessed following i.p. administration of the thromboxane receptor agonist I-BOP in male and female mice. Tissue-specific glucose uptake was quantified by measuring radiolabelled 2-deoxyglucose incorporation during an IVGTT.

Results: Acute exercise increased plasma thromboxane B₂ concentrations and skeletal muscle mRNA levels of PTGS2 (encoding COX-2) selectively in monocyte/macrophage populations. In skeletal muscle cells, the thromboxane receptor agonist I-BOP increased glucose uptake in a dose-dependent manner up to 2.5-fold within 4 h and enhanced glycogen synthesis by 430%. Transcriptomic and signalling analysis revealed activation of protein kinase A and cytoskeletal remodelling pathways linked to GLUT4 trafficking. In vivo, I-BOP improved glucose tolerance in male mice in a dose-dependent manner, without altering insulin levels. Thromboxane receptor stimulation increased glucose uptake in extensor digitorum longus muscle by 43%. Importantly, thromboxane receptor activation preserved its glucose-lowering efficacy in diet-induced obese male mice.

Conclusions/interpretation: Exercise induces skeletal muscle-derived thromboxane production through macrophage-specific COX-2 activation. Thromboxane receptor stimulation enhances glucose uptake and glycogen storage via cytoskeletal remodelling, partially mimicking the acute exercise transcriptomic response. In vivo, thromboxane receptor activation improves glucose tolerance and skeletal muscle glucose uptake, with preserved efficacy in obesity. These findings identify thromboxane signalling as a previously unrecognised immunometabolic axis linking inflammation to glucose regulation and highlight the thromboxane receptor as a potential therapeutic target for metabolic disease.

PURPOSE: The effect of mandibular advancement device therapy on daytime sleepiness remains unclear. Here, we evaluate the effect of a mandibular advancement device on daytime sleepiness using the Karolinska Sleepiness Scale.

METHODS: We randomized 88 snoring patients with an apnea-hypopnea index < 30 and daytime sleepiness to a mandibular advancement device or a sham device for four months. The Karolinska Sleepiness Scale, which measures grades of sleepiness from 1 (very alert) to 9 (very sleepy), was used for seven consecutive days, four times each day. The results were analyzed with quantile regression at quartiles controlling for baseline, age, body mass index (kg/m²), sex, apnea-hypopnea index, and full-time work.

RESULTS: The Karolinska Sleepiness Scale score was lower with the mandibular advancement device than with the sham device at specific time intervals. The positive effect of mandibular advancement device therapy occurred at wake up and before lunch during the whole week and before lunch on weekdays at the middle quartile. The adjusted differences between the interventions favored mandibular advancement device therapy by almost one unit and normalized the Karolinska Sleepiness Scale scores at wake up and before lunch. In addition, there were positive effects of mandibular advancement device therapy before dinner at the highest quartile during the whole week, on weekdays, and on the weekend.

CONCLUSION: Mandibular advancement devices used for snoring and sleep apnea reduce daytime sleepiness, particularly at wake up and before lunch, but provide some benefit before dinner.

Context: There is a considerable diagnostic delay in acromegaly, contributing to increased morbidity. Voice changes due to orofacial and laryngeal changes are common in acromegaly.

Objective: Our aim was to explore the use of digital voice analysis as a biomarker for acromegaly using broad acoustic analysis and machine learning.

Methods: Voice recordings from patients with acromegaly and matched controls were collected using a mobile phone at Swedish university hospitals. Anthropometric and clinical data and the Voice Handicap Index (VHI) were assessed. Digital voice analysis of a sustained and stable vowel [a] resulted in 3274 parameters, which were used for training of machine learning models classifying the speaker as “acromegaly” or “control.” The machine learning models were trained with 76% of the data and the remaining 24% was used to assess their performance. For comparison, voice recordings of 50 pairs of participants were assessed by 12 experienced endocrinologists.

Results: We included 151 Swedish patients with acromegaly (13% biochemically active and 10% newly diagnosed) and 139 matched controls. The machine learning model identified patients with acromegaly more accurately (area under the receiver operating curve [ROC AUC] 0.84) than experienced endocrinologists (ROC AUC 0.69). Self-reported voice problems were more pronounced in patients with acromegaly than matched controls (median VHI 6 vs 2, P < .01) with higher prevalence of clinically significant voice handicap (VHI ≥20: 22.5% vs 3.6%).

Conclusion: Digital voice analysis can identify patients with acromegaly from short voice recordings with high accuracy. Patients with acromegaly experience more voice disorders than matched controls.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) within sub-Saharan Africa (SSA) is increasing. Despite the pathophysiology of T2D differing by ethnicity and sex, risk stratification and guidelines for the prevention of T2D are generic, relying on evidence from studies including predominantly Europeans. Accordingly, this study aims to develop ethnic-specific and sex-specific risk prediction models for the early detection of dysglycaemia (impaired glucose tolerance and T2D) to inform clinically feasible, culturally acceptable and cost-effective risk management and prevention strategies using dietary modification in SSA and European populations.

METHODS AND ANALYSIS: This multinational collaboration will include the prospective cohort data from two African cohorts, the Middle-Aged Soweto Cohort from South Africa and the Research on Obesity and Diabetes among African Migrants Prospective cohort from Ghana and migrants living in Europe, and a Swedish cohort, the Pre-Swedish CArdioPulmonary bioImage Study. Targeted proteomics, as well as targeted and untargeted metabolomics, will be performed at baseline to discover known and novel ethnic-specific and sex-specific biomarkers that predict incident dysglycaemia in the different longitudinal cohorts. Dietary patterns that explain maximum variation in the biomarker profiles and that associate with dysglycaemia will be identified in the SSA and European cohorts and used to build the prototypes for dietary interventions to prevent T2D. A comparative cost-effectiveness analysis of the dietary interventions will be estimated in the different populations. Finally, the perceptions of at-risk participants and healthcare providers regarding ethnic-specific and sex-specific dietary recommendations for the prevention of T2D will be assessed using focus group discussions and in-depth interviews in South Africa, Ghana, Germany (Ghanaian migrants) and Sweden.

ETHICS AND DISSEMINATION: Ethical clearance has been obtained from all participating sites. The study results will be disseminated at scientific conferences and in journal publications, and through community engagement events and diabetes organisations in the respective countries.

Objective: To explore depot-specific functional aspects of adipose tissue, examining the putative role for menopause and HIV status on insulin sensitivity (SI) and beta-cell function in Black South African women.

Methods: Women (n = 92) from the Middle-Aged Soweto Cohort, including premenopausal HIV-negative women (n = 21); premenopausal women living with HIV (LWH; n = 11); postmenopausal HIV-negative women (n = 42); and postmenopausal women LWH (n = 18) underwent the following tests: body composition (dual-energy x-ray absorptiometry); fasting bloods for sex hormones, inflammation, and adipokines; frequently sampled intravenous glucose tolerance test for SI and beta-cell function (disposition index, DI); abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) biopsies for cell size, and mRNA expression of adipokines, inflammation, and estrogen receptors (ER).

Results: Depot-specific associations between gene expression and insulin parameters did not differ by HIV or menopause status. Pooled analysis showed significant models for SI (P = .002) and DI (P = .003). Higher SI was associated with lower leptin and CD11c expression in aSAT and higher adiponectin in gSAT. Higher DI was associated with higher aSAT and gSAT expression of adiponectin, lipoprotein lipase, ER alpha, and PPAR gamma, and lower leptin in aSAT. Women LWH had higher expression of adiponectin and lower expression of leptin in both aSAT (P = .002 and P = .005) and gSAT (P = .004 and P = .002), respectively, and a larger proportion of smaller cells in aSAT (P < .001).

Conclusion: Insulin sensitivity and beta-cell function were distinctively associated with aSAT and gSAT. While menopause did not influence these relationships, HIV had a significant effect on adipose tissue, characterized by variations in cell size distribution and transcript levels within the depots.

Context: Sex hormone–binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk.

Objective: This work aimed to investigate whether the associations between SHBG, testosterone, and T2D risk differ by HIV and menopausal status in Black African women living with HIV (WH) and without HIV (WOH).

Methods: This cross-sectional observational study took place at the Health Research Unit in Soweto, Johannesburg, South Africa. A total of 81 premenopausal (57 WOH, 24 WH) and 280 postmenopausal (236 WOH, 44 WH) women from the Middle-Aged Soweto Cohort (MASC) participated. Main outcome measures included circulating SHBG and sex hormones, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (Matsuda index), secretion (insulinogenic index) and clearance, and β-cell function (disposition index, DI). Dysglycemia was defined as either impaired fasting or postprandial glucose or T2D.

Results: SHBG was higher and total and free testosterone were lower in postmenopausal WH than WOH (all P ≤ .023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance, and DI and inversely with HOMA-IR (all P < .011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (P = .043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (P = .021) and positively associated with HOMA-IR (homeostatic model assessment of insulin resistance) in premenopausal and not postmenopausal women (P = .015 for interaction).

Conclusion: We show for the first time that midlife African WH have higher SHBG and lower total and free testosterone than WOH, which corresponded to their higher β-cell function, suggesting a putative protective effect of SHBG on T2D risk in WH.

BACKGROUND: This study examined whether sick leave due to severe stress (stress leave) and duration of leave are associated with future cancer risk.

METHODS: We conducted a matched case-control study using complete-population data from Swedish national registers (2005 to 2018), including 516,678 primary cancer cases and 2,357,433 matched controls. Odds ratios (OR) were calculated by conditional logistic regression and adjusted for pre-specified confounders.

RESULTS: Stress leave of any duration, reported to the Swedish Social Insurance Register, was associated with a slightly increased cancer risk, with the highest risk estimate for 1-30 versus 0 days (adjusted OR 1.05, 95% CI 1.02-1.09). In men, a clear exposure-response trend was present. We observed increased risks of prostate cancer (adjusted OR for > 90 days: 1.10, 95% CI 1.01-1.20) and cervical cancer (adjusted OR for > 90 days: 1.11, 95% CI 1.05-1.17, including cancer in situ). In etiology-based analyses, a positive association was found for smoking-related cancers, and the risk relationship for non-cervical HPV-related cancers was similar to that for cervical cancer. Risk estimates were above one for several types of stress in relation to overall cancer risk, including an exposure-response trend for acute stress reactions (p-trend 4.0 × 10-4) but a null association for post-traumatic stress disorder.

CONCLUSIONS: Stress leave was associated with a modestly higher risk of cancer overall and prostate and cervical cancers specifically. Regardless of whether the link is biological or reflective of lifestyle mediators or for cervical cancer, lower participation in screening, these findings suggest a potential relevance of severe stress for cancer prevention.

Object: Type 2 diabetes (T2D) is an established risk factor for cardiovascular disease (CVD), with increased risk already observed in the prediabetic state. This study aimed to investigate the association of insulin sensitivity, secretion, and clearance with subclinical atherosclerosis in a randomly selected cohort of Swedish adults aged 50–64 years without known diabetes.

Material and Methods: For this cross-sectional analysis, data from the Umeå site of the Swedish CArdioPulmonary BioImage Study (SCAPIS) were used, which included 2507 individuals aged 50–64 years. After applying exclusion criteria, 2054 participants remained. Insulin sensitivity, secretion, and clearance were calculated using an oral glucose tolerance test (OGTT). Atherosclerosis was assessed by coronary computed tomography angiography (CCTA) and carotid ultrasound, yielding coronary artery calcification scores (CACS), coronary segment involvement scores (SIS), and total carotid plaque counts. Ordinal regression models analyzed associations between insulin measures and atherosclerosis, adjusting for cardiovascular risk factors.

Results: Lower insulin sensitivity, as measured by the GUTT index, was associated with higher CACS and SIS, but not with carotid plaque count. No significant relationship was found between insulin secretion (Insulinogenic Index) and any atherosclerotic marker. Reduced insulin clearance was associated with CACS and SIS in unadjusted analyses; however, these associations did not persist after multivariable adjustment.

Conclusion: In individuals without diabetes, insulin resistance is associated with markers of subclinical coronary atherosclerosis, reinforcing its role in early CVD. Insulin secretion or clearance are not directly associated with measures of subclinical atherosclerosis in this population but may contribute indirectly via effects on circulating insulin levels.