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Objective. Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway. Methods. Forty db/db mice with diabetes ( random blood glucose ≥ 250 mg / dL ) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting. Results. Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2α-ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2α-ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice. Conclusion. Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2α-ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation.

Skeletal muscle physiology remains of paramount importance in understanding insulin resistance. Due to its high lipid turnover rates, regulation of intramyocellular lipid droplets (LDs) is a key factor. Perilipin 5 (PLIN5) is one of the most critical agents in such regulation, being often referred as a protector against lipotoxicity and consequent skeletal muscle insulin resistance. We examined area fraction, size, subcellular localization and PLIN5 association of LDs in two fiber types of type 2 diabetic (T2D), obese (OB) and healthy (HC) individuals by means of fluorescence microscopy and image analysis. We found that T2D type II fibers have a significant sub-population of large and internalized LDs, uncoated by PLIN5. Based on this novel result, additional hypotheses for the pathophysiology of skeletal muscle insulin resistance are formulated, together with future research directions. peerReviewed

Introduction: Physical activity (PA) is important in the prevention and treatment of impaired glucose metabolism. However, association of physical inactivity during the transition between childhood and adulthood with glucose metabolism is unknown. Therefore, we studied the association of persistent physical inactivity since childhood with glucose metabolism in adulthood. Methods: Data were drawn from the ongoing, Cardiovascular Risk in Young Finns Study with repeated follow-ups between 1980 and 2011 (baseline age, 3-18 yr; n = 3596). Impaired glucose metabolism was defined as having impaired fasting glucose (6.1-6.9 mmol·L-1) or type 2 diabetes in adulthood. Leisure-time PA habits were repeatedly collected with a standardized questionnaire and expressed as a PA Index. Using PA Index, four groups were formed (n = 2000): 1) persistently low PA, 2) decreasingly active, 3) increasingly active, and 4) persistently active subjects. Poisson regression model was used to examine the association between PA groups and impaired glucose metabolism. Results: The proportion of the sample with impaired glucose metabolism was 16.1% in individuals with persistently low PA, 14.5% in decreasingly active, 6.8% in increasingly active, and 11.1% in persistently active. Compared with individuals with persistently low PA, age and sex-adjusted risk for impaired glucose metabolism were lower in those who increased PA (relative risk [RR], 0.47; 95% confidence interval [CI], 0.29-0.76) and in those who were persistently active (RR, 0.70; 95% CI, 0.51-0.97), but similar in those who decreased PA (RR, 0.93; 95% CI, 0.66-1.36). Conclusions: Persistently physically inactive lifestyle from youth to adulthood is associated with increased risk of impaired glucose metabolism in adulthood. Importantly, a moderate increase in PA lowered the risk. The results highlight the importance of avoiding physically inactive lifestyle at all stages of life.

Type 2 diabetes (T2D) is one of the most rapidly increasing non-communicable diseases worldwide. Lifestyle interventions are effective in preventing T2D but also resource intensive. This study evaluated with discrete event simulation (DES) the relative budget impacts of three hypothetical diabetes prevention programs (DPP), including group-based contact intervention, digital program with human coaching and fully automated program. The data for simulation were derived from research literature and national health and population statistics. The model was constructed using the iGrafx Process for Six Sigma software and simulations were carried out for 10 years. All simulated interventions produced cost savings compared to the situation without any intervention. However, this was a modeling study and future studies are needed to verify the results in real-life. Decision makers could benefit the predictive models regarding the long-term effects of diabetes prevention interventions, but more data is needed in particular on the usage, acceptability, effectiveness and costs of digital intervention tools. peerReviewed

Objective. The purpose of the study was to examine the acute effects of the timing of exercise on the glycemic control during and after exercise in T2D. Methods. This study included 26 T2D patients (14 women and 12 men) who were treated with metformin. All patients were tested on four occasions: metformin administration alone (Metf), high-intensity interval training (HIIT) performed at 30 minutes (EX30), 60 minutes (EX60), and 90 minutes (EX90) postbreakfast, respectively. Glucose, insulin, and superoxide dismutase (SOD) activity were examined. Results. Glucose decreased significantly after the exercise in EX30, EX60, and EX90. Compared with Metf, the decline in glucose immediately after the exercise was larger in EX30 (−2.58 mmol/L; 95% CI, −3.36 to −1.79 mmol/L; p<0.001), EX60 (−2.13 mmol/L; 95% CI, −2.91 to −1.34 mmol/L; p<0.001), and EX90 (−1.87 mmol/L; 95% CI, −2.65 to −1.08 mmol/L; p<0.001), respectively. Compared with Metf, the decrease in insulin was larger in EX30 and EX60 (both p<0.001). Conclusions. Timing of exercise is a factor to consider when prescribing exercise for T2D patients treated with metformin. This trial is registered with ChiCTR-IOR-16008469 on 13 May 2016.