Rationale for the use of metformin and exercise to counteract statin-associated side effects.

Introduction Statins are the most widely prescribed drugs for lowering low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular morbidity and mortality. They are usually well-tolerated, but have two main safety concerns: statin-associated muscle symptoms (SAMS) and new-onset type 2 diabetes (NOD). Methods A PubMed search was carried out using the following key words were used: statins, statin-associated muscle symptoms, statin myalgia, statin-associated diabetes, metformin and statins, exercise and statins. Results Mitochondrial damage and muscle atrophy are likely the central mechanisms producing SAMS, whereas decreased glucose transport, fatty acid oxidation and insulin secretion are likely involved in the development of NOD. Metformin and exercise training share many pathways that could potentially contrast SAMS and NOD. Clinical evidence also supports the combination of statins with metformin and exercise. Conclusion This combination appears attractive both from a clinical and an economical viewpoint, since all three therapies are highly cost-effective and their combination could result in diabetes and cardiovascular disease prevention

Effect of sustained decreases in sedentary time and increases in physical activity on liver enzymes and indices in type 2 diabetes

BackgroundCurrent guidelines for nonalcoholic fatty liver disease (NAFLD) recommend high volumes and/or intensities of physical activity (PA), the achievement of which generally requires participation in supervised exercise training programs that however are difficult to implement in routine clinical practice. Conversely, counselling interventions may be more suitable, but result in only modest increases in moderate-to-vigorous-intensity PA (MVPA). This study assessed whether a counseling intervention for increasing PA and decreasing sedentary time (SED-time) is effective in improving NAFLD markers in people with type 2 diabetes.MethodsThree-hundred physically inactive and sedentary patients were randomized 1:1 to receive one-month theoretical and practical counseling once-a-year (intervention group) or standard care (control group) for 3 years. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltranspeptidase (γGT) levels were measured and fatty liver index (FLI), hepatic steatosis index (HSI), and visceral adiposity index (VAI) were calculated. Total PA volume, light-intensity PA (LPA), moderate-to-vigorous-intensity PA (MVPA), and SED-time were objectively measured by an accelerometer.ResultsThroughout the 3-year period, NAFLD markers did not change in the control group, whereas ALT, γGT, FLI, and HSI decreased in the intervention group, with significant between-group differences, despite modest MVPA increases, which however were associated with larger decrements in SED-time and reciprocal increments in LPA. Mean changes in NAFLD markers varied according to quartiles of (and correlated with) changes in MVPA (all markers) and SED-time, LPA, and PA volume (ALT, γGT, and HSI). Mean changes in MVPA or PA volume were independent predictors of changes in NAFLD markers. When included in the models, change in cardiorespiratory fitness and lower body muscle strength were independently associated with some NAFLD markers.ConclusionA behavior change involving all domains of PA lifestyle, even if insufficient to achieve the recommended MVPA target, may provide beneficial effects on NAFLD markers in people with type 2 diabetes

Level and correlates of physical activity and sedentary behavior in patients with type 2 diabetes: a cross-sectional analysis of the italian diabetes and exercise study-2

OBJECTIVE: Patients with type 2 diabetes usually show reduced physical activity (PA) and increased sedentary (SED)-time, though to a varying extent, especially for low-intensity PA (LPA), a major determinant of daily energy expenditure that is not accurately captured by questionnaires. This study assessed the level and correlates of PA and SED-time in patients from the Italian Diabetes and Exercise Study_2 (IDES_2). METHODS: Three-hundred physically inactive and sedentary patients with type 2 diabetes were enrolled in the IDES_2 to be randomized to an intervention group, receiving theoretical and practical exercise counseling, and a control group, receiving standard care. At baseline, LPA, moderate-to-vigorous-intensity PA (MVPA), and SED-time were measured by accelerometer. Physical fitness and cardiovascular risk factors and scores were also assessed. RESULTS: LPA was 3.93±1.35 hours∙day-1, MVPA was 12.4±4.6 min∙day-1, and SED-time was 11.6±1.2 hours∙day-1, with a large range of values (0.89-7.11 hours∙day-1, 0.6-21.0 min∙day-1, and 9.14-15.28 hours∙day-1, respectively). At bivariate analysis, LPA and MVPA correlated with better cardiovascular risk profile and fitness parameters, whereas the opposite was observed for SED-time. Likewise, values of LPA, MVPA, and SED-time falling in the best tertile were associated with optimal or acceptable levels of cardiovascular risk factors and scores. At multivariate analysis, age, female gender, HbA1c, BMI or waist circumference, and high-sensitivity C reactive protein (for LPA and SED-time only) were negatively associated with LPA and MPA and positively associated with SED-time in an independent manner. CONCLUSIONS: Physically inactive and sedentary patients with type 2 diabetes from the IDES_2 show a low level of PA, though values of LPA, MVPA, and SED-time vary largely. Furthermore, there is a strong correlation of these measures with glycemic control, adiposity and inflammation, thus suggesting that even small improvements in LPA, MVPA, and SED-time might be associated with significant improvement in cardiovascular risk profile

Muscular Adaptations to Concurrent Resistance Training and High-Intensity Interval Training in Adults with Type 2 Diabetes: A Pilot Study

This pilot study aimed to compare the effects of eight weeks of concurrent resistance training (RT) and high-intensity interval training (HIIT) vs. RT alone on muscle performance, mass and quality in adults with type 2 diabetes (T2DM). Twelve T2DM adults were randomly allocated to the RT + HIIT (n = 5) or RT (n = 7) group. Before and after training, maximal oxygen uptake (VO2max), muscle strength and power were evaluated by calorimetry, dynamometry and one-repetition maximum (1RM) test. Quadriceps muscle volume was determined by MRI, and muscle quality was estimated. After RT, VO2max (+12%), knee muscle power (+20%), quadriceps muscle volume (+5.9%) and quality (leg extension, +65.4%; leg step-up, +223%) and 1RM at leg extension (+66.4%), leg step-up (+267%), lat pulldown (+60.9%) and chest press (+61.2%) significantly increased. The RT + HIIT group improved on VO2max (+27%), muscle volume (+6%), muscle power (+9%) and 1RM at lat pulldown (+47%). No other differences were detected. Among groups, changes in muscle quality at leg step-up and leg extension and VO2max were significantly different. The combination of RT and HIIT effectively improves muscle function and size and increases cardiorespiratory fitness in adults with T2DM. However, HIIT combined with RT may interfere with the development of muscle quality

Muscular Adaptations to Concurrent Resistance Training and High-Intensity Interval Training in Adults with Type 2 Diabetes: A Pilot Study

This pilot study aimed to compare the effects of eight weeks of concurrent resistance training (RT) and high-intensity interval training (HIIT) vs. RT alone on muscle performance, mass and quality in adults with type 2 diabetes (T2DM). Twelve T2DM adults were randomly allocated to the RT + HIIT (n = 5) or RT (n = 7) group. Before and after training, maximal oxygen uptake (VO2max), muscle strength and power were evaluated by calorimetry, dynamometry and one-repetition maximum (1RM) test. Quadriceps muscle volume was determined by MRI, and muscle quality was estimated. After RT, VO2max (+12%), knee muscle power (+20%), quadriceps muscle volume (+5.9%) and quality (leg extension, +65.4%; leg step-up, +223%) and 1RM at leg extension (+66.4%), leg step-up (+267%), lat pulldown (+60.9%) and chest press (+61.2%) significantly increased. The RT + HIIT group improved on VO2max (+27%), muscle volume (+6%), muscle power (+9%) and 1RM at lat pulldown (+47%). No other differences were detected. Among groups, changes in muscle quality at leg step-up and leg extension and VO2max were significantly different. The combination of RT and HIIT effectively improves muscle function and size and increases cardiorespiratory fitness in adults with T2DM. However, HIIT combined with RT may interfere with the development of muscle quality

Invest in METs, not in Meds

A 1-MET increase is reasonably achievable, but continuous counseling and supervision are required to maintain benefits. Increasing fitness, at a population level, should be a priority for governments when designing public health policies, because health and economic benefits of exercise far outweigh its costs

Renal Expression and Localization of the Receptor for (Pro)renin and Its Ligands in Rodent Models of Diabetes, Metabolic Syndrome, and Age-Dependent Focal and Segmental Glomerulosclerosis

The (pro)renin receptor ((P)RR), a versatile protein found in various organs, including the kidney, is implicated in cardiometabolic conditions like diabetes, hypertension, and dyslipidemia, potentially contributing to organ damage. Importantly, changes in (pro)renin/(P)RR system localization during renal injury, a critical information base, remain unexplored. This study investigates the expression and topographic localization of the full length (FL)-(P)RR, its ligands (renin and prorenin), and its target cyclooxygenase-2 and found that they are upregulated in three distinct animal models of renal injury. The protein expression of these targets, initially confined to specific tubular renal cell types in control animals, increases in renal injury models, extending to glomerular cells. (P)RR gene expression correlates with protein changes in a genetic model of focal and segmental glomerulosclerosis. However, in diabetic and high-fat-fed mice, (P)RR mRNA levels contradict FL-(P)RR immunoreactivity. Research on diabetic mice kidneys and human podocytes exposed to diabetic glucose levels suggests that this inconsistency may result from disrupted intracellular (P)RR processing, likely due to increased Munc18-1 interacting protein 3. It follows that changes in FL-(P)RR cellular content mechanisms are specific to renal disease etiology, emphasizing the need for consideration in future studies exploring this receptor’s involvement in renal damage of different origins

Mutual Regulation between Redox and Hypoxia-Inducible Factors in Cardiovascular and Renal Complications of Diabetes

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes