Association of thyroid function with non-alcoholic fatty liver disease in recent-onset diabetes.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has been linked to type 2 diabetes (T2D), but also to hypothyroidism. Nevertheless, the relationship between thyroid function and NAFLD in diabetes is less clear. This study investigated associations between free thyroxine (fT4) or thyroid-stimulating hormone (TSH) and NAFLD in recent-onset diabetes. METHODS: Participants with recent-onset type 1 diabetes (T1D, n = 358), T2D (n = 596) or without diabetes (CON, n = 175) of the German Diabetes Study (GDS), a prospective longitudinal cohort study, underwent Botnia clamp tests and assessment of fT4, TSH, fatty liver index (FLI) and in a representative subcohort 1 H-magnetic resonance spectroscopy. RESULTS: First, fT4 levels were similar between T1D and T2D (p = .55), but higher than in CON (T1D: p < .01; T2D: p < .001), while TSH concentrations were not different between all groups. Next, fT4 correlated negatively with FLI and positively with insulin sensitivity only in T2D (ß = -.110, p < .01; ß = .126, p < .05), specifically in males (ß = -.117, p < .05; ß = .162; p < .01) upon adjustments for age, sex and BMI. However, correlations between fT4 and FLI lost statistical significance after adjustment for insulin sensitivity (T2D: ß = -.021, p = 0.67; males with T2D: ß = -.033; p = .56). TSH was associated positively with FLI only in male T2D before (ß = .116, p < .05), but not after adjustments for age and BMI (ß = .052; p = .30). CONCLUSIONS: Steatosis risk correlates with lower thyroid function in T2D, which is mediated by insulin resistance and body mass, specifically in men, whereas no such relationship is present in T1D.

Impact of physical fitness and exercise training on subcutaneous adipose tissue beiging markers in humans with and without diabetes and a high-fat diet-fed mouse model.

AIMS: Exercise training induces white adipose tissue (WAT) beiging and improves glucose homeostasis and mitochondrial function in rodents. This could be relevant for type 2 diabetes in humans, but the effect of physical fitness on beiging of subcutaneous WAT (scWAT) remains unclear. This translational study investigates if beiging of scWAT associates with physical fitness in healthy humans and recent-onset type 2 diabetes and if a voluntary running wheel intervention is sufficient to induce beiging in mice. MATERIALS AND METHODS: Gene expression levels of established beiging markers were measured in scWAT biopsies of humans with (n = 28) or without type 2 diabetes (n = 28), stratified by spiroergometry into low (L-FIT; n = 14 each) and high physical fitness (H-FIT; n = 14 each). High-fat diet-fed FVB/N mice underwent voluntary wheel running, treadmill training or no training (n = 8 each group). Following the training intervention, mitochondrial respiration and content of scWAT were assessed by high-resolution respirometry and citrate synthase activity, respectively. RESULTS: Secreted CD137 antigen (Tnfrsf9/Cd137) expression was three-fold higher in glucose-tolerant H-FIT than in L-FIT, but not different between H-FIT and L-FIT with type 2 diabetes. In mice, both training modalities increased Cd137 expression and enhanced mitochondrial content without changing respiration in scWAT. Treadmill but not voluntary wheel running led to improved whole-body insulin sensitivity. CONCLUSIONS: Higher physical fitness and different exercise interventions associated with higher gene expression levels of the beiging marker CD137 in healthy humans and mice on a high-fat diet. Humans with recent-onset type 2 diabetes show an impaired adipose tissue-specific response to physical activity.

Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease.

BACKGROUND & AIMS: Adipose tissue dysfunction is involved in the development of insulin resistance and is responsible for excessive lipid delivery to other organs such as the liver. We tested the hypothesis that impaired mitochondrial function is a common feature of subcutaneous (SAT) and visceral adipose tissue (VAT), but may differently contribute to adipose tissue insulin resistance (IR) in obesity, non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). METHODS: In this cross-sectional study, we analyzed tissue-specific insulin sensitivity using stable isotope dilution and hyperinsulinemic-normoglycemic clamp tests. We also assessed mitochondrial respiration, mRNA and protein expression, and tissue morphology in biopsies of SAT and VAT from obese humans without NAFL, with NAFL or with NASH (n = 22/group). RESULTS: Compared to individuals without liver disease, persons with NAFL and NASH had about 30% (p = 0.010) and 33% (p = 0.002) lower maximal mitochondrial respiration, respectively, in VAT, but not in SAT. The lower maximal mitochondrial respiration of VAT was associated with lower adipose tissue insulin sensitivity (ß = 0.985, p = 0.041) and with increased VAT protein expression of tumor necrosis factor A across all groups (ß = -0.085, p = 0.040). VAT from individuals with NASH was characterized by lower expression of oxidative phosphorylation complex IV (p = 0.042) and higher mRNA expression of the macrophage marker CD68 (p = 0.002) than VAT from participants without NAFL. CONCLUSIONS: Humans with non-alcoholic fatty liver disease have distinct abnormalities of VAT energy metabolism, which correlate with adipose tissue dysfunction and may favor progression of NAFL to NASH. LAY SUMMARY: Adipose tissue (commonly called body fat) can be found under the skin (subcutaneous) or around internal organs (visceral). Dysfunction of adipose tissue can cause insulin resistance and lead to excess delivery of fat to other organs such as the liver. Herein, we show that dysfunction specifically in visceral adipose tissue was associated with fatty liver disease. CLINICAL TRIAL NUMBER: NCT01477957.

Correlates of Skeletal Muscle Mass and Differences Between Novel Subtypes in Recent-Onset Diabetes.

CONTEXT: Low skeletal muscle mass (SMM) is associated with long-standing diabetes but little is known about SMM in newly diagnosed diabetes. OBJECTIVE: We aimed to identify correlates of SMM in recent-onset diabetes and to compare SMM between novel diabetes subtypes. METHODS: SMM was normalized to body mass index (SMM/BMI) in 842 participants with known diabetes duration of less than 1 year from the German Diabetes Study (GDS). Cross-sectional associations between clinical variables, 79 biomarkers of inflammation, and SMM/BMI were assessed, and differences in SMM/BMI between novel diabetes subtypes were analyzed with different degrees of adjustment for confounders. RESULTS: Male sex and physical activity were positively associated with SMM/BMI, whereas associations of age, BMI, glycated hemoglobin A1c, homeostatic model assessment for ß-cell function, and estimated glomerular filtration rate with SMM/BMI were inverse (all P < .05; model r2 = 0.82). Twenty-three biomarkers of inflammation showed correlations with SMM/BMI after adjustment for sex and multiple testing (all P < .0006), but BMI largely explained these correlations. In a sex-adjusted analysis, individuals with severe autoimmune diabetes had a higher SMM/BMI whereas individuals with severe insulin-resistant diabetes and mild obesity-related diabetes had a lower SMM/BMI than all other subtypes combined. However, differences were attenuated after adjustment for the clustering variables. CONCLUSION: SMM/BMI differs between diabetes subtypes and may contribute to subtype differences in disease progression. Of note, clinical variables rather than biomarkers of inflammation explain most of the variation in SMM/BMI.

Physical Fitness and Cardiovascular Risk Factors in Novel Diabetes Subgroups.

CONTEXT: Physical inactivity promotes insulin resistance and increases the risk of diabetes and cardiovascular disease. Recently introduced clustering based on simple clinical measures identified diabetes subgroups (clusters) with different risks of diabetes-related comorbidities and complications. OBJECTIVE: This study aims to determine differences in physical fitness and cardiovascular risk between diabetes subgroups and a glucose-tolerant control group (CON). We hypothesized that the severe insulin-resistant diabetes (SIRD) subgroup would be associated with lower physical fitness and increased cardiovascular risk. METHODS: The physical fitness and cardiovascular risk of 746 participants with recent-onset diabetes (diabetes duration of < 12 months, aged 18-69 years) and 74 CONs of the German Diabetes Study (GDS), a prospective longitudinal cohort study, were analyzed. Main outcome measures included physical fitness (VO2max from spiroerogometry), endothelial function (flow- and nitroglycerin-mediated dilation), and cardiovascular risk scores (Framingham Risk Scores for Coronary Heart Disease [FRS-CHD] and Atherosclerotic CardioVascular Disease [ASCVD] risk score). RESULTS: VO2max was lower in SIRD than in CON, severe autoimmune diabetes (SAID) (both P < .001), and mild age-related diabetes (MARD) (P < .01) subgroups, but not different compared to severe insulin-deficient diabetes (SIDD) (P = .98) and moderate obesity-related diabetes (MOD) subgroups (P = .07) after adjustment for age, sex, and body mass index. Endothelial function was similar among all groups, whereas SAID had lower FRS-CHD and ASCVD than SIRD, MOD, and MARD (all P < .001). CONCLUSION: Despite comparable endothelial function across all groups, SIRD showed the lowest physical fitness. Of note, SAID had the lowest cardiovascular risk within the first year after diabetes diagnosis compared to the other diabetes subgroups.

Physical Activity and Risk of Major Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Physical activity is a cornerstone in diabetes management; however, evidence synthesis on the association between physical activity and long-term diabetes-related complications is scarce. PURPOSE: To summarize and evaluate findings on physical activity and diabetes-related complications, we conducted a systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Web of Science, and the Cochrane Library for articles published up to 6 July 2021. STUDY SELECTION: We included prospective studies investigating the association between physical activity and incidence of and mortality from diabetes-related complications, i.e., cardiovascular disease (CVD), coronary heart disease, cerebrovascular events, heart failure, major adverse cardiovascular events, and microvascular complications such as retinopathy and nephropathy, in individuals with diabetes. DATA EXTRACTION: Study characteristics and risk ratios with 95% CIs were extracted. Random-effects meta-analyses were performed, and the certainty of evidence and risk of bias were evaluated with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. DATA SYNTHESIS: Overall, 31 studies were included. There was moderate certainty of evidence that high versus low levels of physical activity were inversely associated with CVD incidence, CVD mortality (summary risk ratio 0.84 [95% CI 0.77, 0.92], n = 7, and 0.62 [0.55, 0.69], n = 11), and microvascular complications (0.76 [0.67, 0.86], n = 8). Dose-response meta-analyses showed that physical activity was associated with lower risk of diabetes-related complications even at lower levels. For other outcomes, similar associations were observed but certainty of evidence was low or very low. LIMITATIONS: Limitations include residual confounding and misclassification of exposure. CONCLUSIONS: Physical activity, even below recommended amounts, was associated with reduced incidence of diabetes-related complications.

Effects of Blood Flow Restriction Exercise and Possible Applications in Type 2 Diabetes.

Blood flow restriction resistance training (BFRT) employs partial vascular occlusion of exercising muscles via inflation cuffs. Compared with high-load resistance training, mechanical load is markedly reduced with BFRT, but induces similar gains in muscle mass and strength. BFRT is thus an effective training strategy for people with physical limitations. Recent research indicates that BFRT has beneficial effects on glucose and mitochondrial metabolism. BFRT may therefore qualify as a valuable exercise alternative for individuals with type 2 diabetes (T2D), a disorder characterized by impaired glucose metabolism, musculoskeletal decline, and exacerbated progression of sarcopenia. This review covers the effects of BFRT in healthy populations and in persons with impaired physical fitness, the mechanisms of action of this novel training modality, and possible applications for individuals with T2D.