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The metabolic syndrome (MetS) comprises cardiometabolic risk factors frequently found in individuals with obesity. Guidelines to prevent or reverse MetS suggest limiting fat intake, however, lowering carbohydrate intake has gained attention too. The aim for this review was to determine to what extent either weight loss, reduction in caloric intake, or changes in macronutrient intake contribute to improvement in markers of MetS in persons with obesity without cardiometabolic disease. A meta-analysis was performed across a spectrum of studies applying low-carbohydrate (LC) and low-fat (LF) diets. PubMed searches yielded 17 articles describing 12 separate intervention studies assessing changes in MetS markers of persons with obesity assigned to LC (<40% energy from carbohydrates) or LF (<30% energy from fat) diets. Both diets could lead to weight loss and improve markers of MetS. Meta-regression revealed that weight loss most efficaciously reduced fasting glucose levels independent of macronutrient intake at the end of the study. Actual carbohydrate intake and actual fat intake at the end of the study, but not the percent changes in intake of these macronutrients, improved diastolic blood pressure and circulating triglyceride levels, without an effect of weight loss. The homeostatic model assessment of insulin resistance improved with both diets, whereas high-density lipoprotein cholesterol only improved in the LC diet, both irrespective of aforementioned factors. Remarkably, changes in caloric intake did not play a primary role in altering MetS markers. Taken together, these data suggest that, beyond the general effects of the LC and LF diet categories to improve MetS markers, there are also specific roles for weight loss, LC and HF intake, but not reduced caloric intake, that improve markers of MetS irrespective of diet categorization. On the basis of the results from this meta-analysis, guidelines to prevent MetS may need to be re-evaluated.
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Synthetic glucocorticoids are potent anti-inflammatory drugs but show dose-dependent metabolic side effects such as the development of insulin resistance and obesity. The precise mechanisms involved in these glucocorticoid-induced side effects, and especially the participation of adipose tissue in this are not completely understood. We used a combination of transcriptomics, antibody arrays and bioinformatics approaches to characterize prednisolone-induced alterations in gene expression and adipokine secretion, which could underlie metabolic dysfunction in 3T3-L1 adipocytes. Several pathways, including cytokine signalling, Akt signalling, and Wnt signalling were found to be regulated at multiple levels, showing that these processes are targeted by prednisolone. These results suggest that mechanisms by which prednisolone induce insulin resistance include dysregulation of wnt signalling and immune response processes. These pathways may provide interesting targets for the development of improved glucocorticoids.
Background: Chronic low-grade inflammatory profile (CLIP) is one of the pathways involved in type 2 diabetes (T2D). Currently, there is limited evidence for ameliorating effects of combined lifestyle interventions on CLIP in type 2 diabetes. We investigated whether a 13-week combined lifestyle intervention, using hypocaloric diet and resistance exercise plus high-intensity interval training with or without consumption of a protein drink, affected CLIP in older adults with T2D. Methods: In this post-hoc analysis of the PROBE study 114 adults (≥55 years) with obesity and type 2 (pre-)diabetes had measurements of C-reactive protein (CRP), pro-inflammatory cytokines interleukin (IL)-6, tumor-necrosis-factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1, anti-inflammatory cytokines IL-10, IL-1 receptor antagonist (RA), and soluble tumor-necrosis-factor receptor (sTNFR)1, adipokines leptin and adiponectin, and glycation biomarkers carboxymethyl-lysine (CML) and soluble receptor for advanced glycation end products (sRAGE) from fasting blood samples. A linear mixed model was used to evaluate change in inflammatory biomarkers after lifestyle intervention and effect of the protein drink. Linear regression analysis was performed with parameters of body composition (by dual-energy X-ray absorptiometry) and parameters of insulin resistance (by oral glucose tolerance test). Results: There were no significant differences in CLIP responses between the protein and the control groups. For all participants combined, IL-1RA, leptin and adiponectin decreased after 13 weeks (p = 0.002, p < 0.001 and p < 0.001), while ratios TNF-α/IL-10 and TNF-α/IL-1RA increased (p = 0.003 and p = 0.035). CRP increased by 12 % in participants with low to average CLIP (pre 1.91 ± 0.39 mg/L, post 2.13 ± 1.16 mg/L, p = 0.006) and decreased by 36 % in those with high CLIP (pre 5.14 mg/L ± 1.20, post 3.30 ± 2.29 mg/L, p < 0.001). Change in leptin and IL-1RA was positively associated with change in fat mass (β = 0.133, p < 0.001; β = 0.017, p < 0.001) and insulin resistance (β = 0.095, p = 0.024; β = 0.020, p = 0.001). Change in lean mass was not associated with any of the biomarkers. Conclusion: 13 weeks of combined lifestyle intervention, either with or without protein drink, reduced circulating adipokines and anti-inflammatory cytokine IL-1RA, and increased inflammatory ratios TNF-α/IL-10 and TNF-α/IL-1RA in older adults with obesity and T2D. Effect on CLIP was inversely related to baseline inflammatory status.
Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.
Background: Weight loss is key to treatment of older adults with obesity and type 2 diabetes, but also a risk for muscle mass loss. This study investigated whether a whey protein drink enriched with leucine and vitamin D could preserve muscle mass and improve glycemic control during combined lifestyle intervention in this population. Methods: 123 older adults with obesity and type 2 diabetes were randomized into a 13-week lifestyle intervention with dietary advice and exercise, receiving either the enriched protein drink (test) or an isocaloric control (control). Muscle mass was assessed with dual-energy X-ray absorptiometry and glycemic control by oral glucose tolerance test. Statistical analyses were performed using a linear mixed model. Results: There was a nonsignificant increase in leg muscle mass (+0.28 kg; 95% CI, −0.01 to 0.56) and a significant increase in appendicular muscle mass (+0.36 kg; 95% CI, 0.005 to 0.71) and total lean mass (+0.92 kg; 95% CI, 0.19 to 1.65) in test vs. control. Insulin sensitivity (Matsuda index) also increased in test vs. control (+0.52; 95% CI, 0.07 to 0.97). Conclusions: Use of an enriched protein drink during combined lifestyle intervention shows beneficial effects on muscle mass and glycemic control in older adults with obesity and type 2 diabetes.
This research article shows that a high intensity exercise program compared to a low intensity exercise program of the same session duration and frequency, increases insulin sensitivity to a larger extend in healthy subjects. It also shows that the short insulin tolerance test can be used to detect differences in insulin sensitivity in intervention studies.
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